EPA/630/R-14/101
April 2014
,. .
Agency www.epa.Rpv/ins
United States April 2014
Environmental Protection
Draft Development Materials for the
Integrated Risk Information System (IRIS)
Toxicological Review of Inorganic Arsenic
[CASRN 7440-38-2]
Bimonthly Public Meeting: June 2014
NOTICE:
This is a draft comprised of development materials. This information is distributed solely
for the purpose of pre-dissemination review under applicable information quality
guidelines. It has not been formally disseminated by EPA. It does not represent and should
not be construed to represent any Agency determination or policy.
April 2014
U. S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Assessment
Washington, D.C.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Disclaimer
This information is distributed solely for the purpose of pre-dissemination review under applicable
information quality guidelines. It has not been formally disseminated by EPA. It does not represent and
should not be construed to represent any Agency determination or policy. Mention of trade names or
commercial products does not constitute endorsement or recommendation for use.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 ii Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
TABLE OF CONTENTS
PREFACE viii
1 ASSESSMENT DEVELOPMENT PLAN 1-1
1.1 EXECUTIVE SUMMARY 1-1
Key Points -Executive Summary 1-1
1.2 BACKGROUND 1-2
Key Points -Background 1-2
1.2.1 Previous EPA Assessments on Inorganic Arsenic 1-2
1.2.2 Congressional Directive for EPA Toxicological Review of Inorganic Arsenic 1-3
1.2.3 Overview of NRC Interim Report "Critical Aspects of EPA's IRIS Assessment of Inorganic
Arsenic" 1-4
1.3 DEVELOPING THE TOXICOLOGICAL REVIEW 1-11
Key Points -Development 1-11
1.3.1 Goals of the Assessment Development Plan 1-11
1.3.2 Agency Partner and Public Stakeholder Engagement 1-12
1.3.3 Transparency 1-12
1.3.4 Timeline for Completion 1-13
1.4 CONCEPTUAL MODEL FOR THE TOXICOLOGICAL REVIEW 1-14
Key Points - Conceptual Model -15
.4.1 Scope of the Toxicological Review -15
.4.2 Sources -18
.4.3 Stressors -20
.4.4 Exposure Pathways -24
.4.5 Receptors 1-27
.4.6 Endpoints 1-30
.4.7 Risk Metrics 1-34
.4.8 Overall Conceptual Model 1-38
1.5 ANALYSIS PLAN FOR THE TOXICOLOGICAL REVIEW 1-40
Key Points - Analysis Plan 1-40
.5.1 Approaches to Source Considerations 1-40
.5.2 Approaches to Stressor Considerations 1-41
.5.3 Approaches to Exposure Pathway Considerations 1-42
.5.4 Approaches to Receptor Considerations 1-43
.5.5 Approaches to Endpoint Considerations 1-45
.5.6 Approaches to RiskMetric Considerations 1-62
1.6 APPENDIX OF MATERIALS FOR EVALUATING LITERATURE 1-67
1.7 REFERENCES FOR ASSESSMENT DEVELOPMENT PLAN 1-99
2 LITERATURE SEARCH STRATEGY AND SYSTEMATIC REVIEW FOR
DEVELOPMENT OF THE TOXICOLOGICAL REVIEW OF INORGANIC ARSENIC 2-1
2.1 OVERVIEW OF LITERATURE SEARCH STRATEGY 2-1
2.2 COMPUTERIZED KEYWORD SEARCH 2-2
2.3 HEALTH EFFECTS CLUSTER DETERMINATION 2-3
2.4 CATEGORIZATION OF REFERENCES 2-5
2.4.1 Categorization of Health Effects Literature Based on Title and Abstract 2-5
2.4.2 Further Categorization of Epidemiologic and Animal Hazard Identification Studies 2-7
2.5 CHARACTERIZATION OF STUDIES AND DEVELOPMENT OF "SUMMARY OF
EPIDEMIOLOGICAL/TOXICOLOGICAL STUDIES FOR HAZARD IDENTIFICATION" TABLES 2-8
2.6 EVALUATION OF POTENTIAL RISK OF BIAS 2-9
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
2.6.1 General Approach for Risk of Bias Evaluation 2-10
2.6.2 Assessing Risk of Bias for Arsenic Studies 2-10
2.7 DEVELOPMENT OF EVIDENCE TABLES FOR HAZARD IDENTIFICATION 2-13
2.7.1 Epidemiology Data 2-13
2.7.2 Animal Data 2-15
2.8 DRAFT OHAT GUIDANCE FOR RISK OF BIAS EVALUATION AND ASSESSMENT-SPECIFIC
CLARIFICATIONS 2-16
3 SUMMARY OF LITERATURE IDENTIFIED TO SUPPORT HAZARD IDENTIFICATION
FOR INORGANIC ARSENIC 3-1
3.1 OVERVIEW OF EPIDEMIOLOGY STUDIES IDENTIFIED 3-1
3.1.1 Summary of Epidemiology Studies for Hazard Identification for Bladder Effects 3-2
3.1.2 Summary of Epidemiology Studies for Hazard Identification for Cardiovascular Disease 3-5
3.1.3 Summary of Epidemiology Studies for Hazard Identification for Clinical Chemistry and
Urinalysis 3-10
3.1.4 Summary of Epidemiology Studies for Hazard Identification for Developmental Effects including
Neurodevelopmental 3-12
3.1.5 Summary of Epidemiology Studies for Hazard Identification for Digestive System Effects .3-15
3.1.6 Summary of Epidemiology Studies for Hazard Identification for Endocrine System Effects
including Diabetes 3-18
3.1.7 Summary of Epidemiology Studies for Hazard Identification for Hematology, Hematopoietic
System 3-21
3.1.8 Summary of Epidemiology Studies for Hazard Identification for Liver Effects 3-23
3.1.9 Summary of Epidemiology Studies for Hazard Identification for Immune System and Lymphatic
Effects 3-25
3.1.10 Summary of Epidemiology Studies for Hazard Identification for Renal Effects 3-27
3.1.11 Summary of Epidemiology Studies for Hazard Identification for Mortality 3-30
3.1.12 Summary of Epidemiology Studies for Hazard Identification for Nervous System Effects ..3-31
3.1.13 Summary of Epidemiology Studies for Hazard Identification for Other Effects 3-34
3.1.14 Summary of Epidemiology Studies for Hazard Identification for Reproductive System Effects
including Pregnancy Outcomes 3-36
3.1.15 Summary of Epidemiology Studies for Hazard Identification for Respiratory Effects 3-39
3.1.16 Summary of Epidemiology Studies for Hazard Identification for Skin Diseases 3-44
3.2 SUMMARY OF TOXICOLOGY LITERATURE IDENTIFIED TO SUPPORT HAZARD IDENTIFICATION FOR
INORGANIC ARSENIC 3-51
3.2.1 Overview of Toxicology Studies Identified 3-51
3.2.2 Summary of Toxicology Studies for Hazard Identification for Bladder Effects 3-52
3.2.3 Summary of Toxicology Studies for Hazard Identification for Cardiovascular Disease 3-53
3.2.4 Summary of Toxicology Studies for Hazard Identification for Clinical Chemistry and Urinalysis
3-55
3.2.5 Summary of Toxicology Studies for Hazard Identification for Developmental Effects including
Neurodevelopmental 3-57
3.2.6 Summary of Toxicology Studies for Hazard Identification for Digestive System Effects 3-59
3.2.7 Summary of Toxicology Studies for Hazard Identification for Endocrine System Effects including
Diabetes 3-60
3.2.8 Summary of Toxicology Studies for Hazard Identification for Hematology, Hematopoietic
System 3-62
3.2.9 Summary of Toxicology Studies for Hazard Identification for Immune System and Lymphatic
Effects 3-64
3.2.10 Summary of Toxicology Studies for Hazard Identification for Liver Effects 3-66
3.2.11 Summary of Toxicology Studies for Hazard Identification for Mortality 3-68
3.2.12 Summary of Toxicology Studies for Hazard Identification for Nervous System Effects 3-69
3.2.13 Summary of Toxicology Studies for Hazard Identification for Other 3-71
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.14 Summary of Toxicology Studies for Hazard Identification for Renal Effects 3-73
3.2.15 Summary of Toxicology Studies for Hazard Identification for Reproductive System Effects
including Pregnancy Outcomes 3-75
3.2.16 Summary of Toxicology Studies for Hazard Identification for Respiratory Effects 3-78
3.2.17 Summary of Toxicology Studies for Hazard Identification for Skin Diseases 3-80
4 SUMMARY OF RISK OF BIAS EVALUATIONS FOR INORGANIC ARSENIC
EPIDEMIOLOGIC STUDIES 4-1
4.1 RISK OF BIAS OVERVIEW-CLINICAL CHEMISTRY AND URINALYSIS 4-1
4.2 RISK OF BIAS OVERVIEW-ENDOCRINE SYSTEM EFFECTS INCLUDING DIABETES 4-2
4.3 RISK OF BIAS OVERVIEW - HEMATOLOGY, HEMATOPOIETIC SYSTEM 4-6
4.4 RISK OF BIAS OVERVIEW-LIVER EFFECTS 4-7
4.5 RISK OF BIAS OVERVIEW-IMMUNE SYSTEM AND LYMPHATIC EFFECTS 4-9
4.6 RISK OF BIAS OVERVIEW-RENAL EFFECTS 4-11
4.7 RISK OF BIAS OVERVIEW-MORTALITY 4-14
4.8 RISK OF BIAS OVERVIEW-DIGESTIVE SYSTEM EFFECTS 4-15
4.9 RISK OF BIAS OVERVIEW-CARDIOVASCULAR DISEASE 4-17
4.10 RISK OF BIAS OVERVIEW-OTHER 4-23
4.11 RISK OF BIAS OVERVIEW - REPRODUCTIVE SYSTEM EFFECTS INCLUDING PREGNANCY OUTCOMES 4-25
4.12 RISK OF BIAS OVERVIEW-SKIN DISEASES 4-27
4.13 RISK OF BIAS OVERVIEW-RESPIRATORY EFFECTS 4-33
4.14 RISK OF BIAS OVERVIEW-NERVOUS SYSTEM EFFECTS 4-38
4.15 REFERENCES FOR RISK OF BIAS EVALUATIONS FOR EPIDEMIOLOGIC STUDIES 4-41
5 EVIDENCE TABLES FOR INORGANIC ARSENIC EPIDEMIOLOGIC STUDIES 5-1
5.1 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
BLADDER EFFECTS 5-1
5.1.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Bladder Effects 5-18
5.2 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
CARDIOVASCULAR DISEASE 5-21
5.2.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Cardiovascular Disease 5-62
5.3 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
CLINICAL CHEMISTRY AND URINALYSIS 5-66
5.3.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Clinical Chemistry and Urinalysis 5-67
5.4 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
DEVELOPMENTAL EFFECTS INCLUDING NEURODEVELOPMENTAL 5-69
5.4.1 References Summary of Observational Epidemiology Studies for Health Effect Category:
Developmental Effects including Neurodevelopmental 5-114
5.5 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
DIGESTIVE SYSTEM EFFECTS 5-117
5.5.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Digestive System Effects 5-122
5.6 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
ENDOCRINE SYSTEM EFFECTS INCLUDING DIABETES 5-124
5.6.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Endocrine System Effects Including Diabetes 5-143
5.7 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
HEMATOLOGY, HEMATOPOIETIC SYSTEM 5-146
5.7.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Hematology, Hematopoietic System 5-148
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.8 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
IMMUNE SYSTEM AND LYMPHATIC EFFECTS 5-149
5.8.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Immune System and Lymphatic Effects 5-161
5.9 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY: LIVER
EFFECTS 5-163
5.9.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Liver Effects 5-167
5.10 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
MORTALITY 5-169
5.10.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Mortality 5-171
5.11 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
NERVOUS SYSTEM EFFECTS 5-172
5.11.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Nervous System Effects 5-195
5.12 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY: OTHER ..5-197
5.12.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Other 5-198
5.13 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY: RENAL
EFFECTS 5-200
5.13.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Renal Effects 5-209
5.14 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
REPRODUCTIVE SYSTEM EFFECTS INCLUDING PREGNANCY OUTCOMES 5-210
5.14.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Reproductive System Effects including Pregnancy Outcomes 5-216
5.15 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY:
RESPIRATORY EFFECTS 5-217
5.15.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Respiratory Effects 5-241
5.16 SUMMARY OF OBSERVATIONAL EPIDEMIOLOGY STUDIES FOR HEALTH EFFECT CATEGORY: SKIN
DISEASES 5-244
5.16.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Skin Diseases 5-269
6 SUMMARY OF RISK OF BIAS EVALUATIONS FOR INORGANIC ARSENIC ANIMAL
STUDIES 6-1
6.1 RISK OF BIAS OVERVIEW - DEVELOPMENTAL EFFECTS INCLUDING NEURODEVELOPMENTAL 6-1
6.2 RISK OF BIAS OVERVIEW-IMMUNE SYSTEM AND LYMPHATIC EFFECTS 6-3
6.3 RISK OF BIAS OVERVIEW-LIVER EFFECTS 6-4
6.4 REFERENCES FOR RISK OF BIAS EVALUATIONS FOR ANNIMAL TOXICOLOGY STUDIES 6-5
7 EVIDENCE TABLES FOR INORGANIC ARSENIC ANIMAL STUDIES 7-1
7.1 SUMMARY OF OBSERVATIONAL ANIMAL STUDIES FOR HEALTH EFFECT CATEGORY:
DEVELOPMENTAL EFFECTS INCLUDING NEURODEVELOPMENTAL 7-1
7.1.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Developmental Effects including Neurodevelopmental 7-11
7.2 SUMMARY OF OBSERVATIONAL ANIMAL STUDIES FOR HEALTH EFFECT CATEGORY: IMMUNE
SYSTEM AND LYMPHATIC EFFECTS 7-12
7.2.1 References for Summary of Observational Epidemiology Studies for Health Effect Category: :
Immune System and Lymphatic Effects 7-14
7.3 SUMMARY OF OBSERVATIONAL ANIMAL STUDIES FOR HEALTH EFFECT CATEGORY: LIVER
EFFECTS 7-16
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
7.3.1 References for Summary of Observational Epidemiology Studies for Health Effect Category:
Liver Effects 7-20
8 MODE OF ACTION (MOA) LITERATURE SEARCH STRATEGY FOR THE
TOXICOLOGICAL REVIEW OF INORGANIC ARSENIC 8-1
8.1 OVERVIEW OF LITERATURE SEARCH STRATEGY 8-1
9 INORGANIC ARSENIC MODE OF ACTION (MOA) HYPOTHESIS SUMMARIES ... 9-1
9.1 PREAMBLE 9-1
9.1.1 Background 9-1
9.1.2 Considerations relevant across all hypothesized MO As 9-2
9.2 HYPOTHESIZED MO A: CYTOTOXICITY AND REGENERATIVE PROLIFERATION 9-5
9.3 HYPOTHESIZED MO A: EFFECTS MEDIATED BY ENDOCRINE SIGNALING 9-10
9.4 HYPOTHESIZED MO A: EFFECTS MEDIATED BY EPIGENETIC MECHANISMS 9-14
9.5 HYPOTHESIZED MO A: IMMUNE MEDIATED EFFECTS 9-21
9.6 HYPOTHESIZED MO A: OXIDATIVE STRESS 9-27
10 PRELIMINARY MECHANISTIC AND SUSCEPTIBILITY DATA TABLES 10-1
10.1 PRELIMINARY DATA ON EFFECTS MEDIATED BY CYTOTOXICITY AND REGENERATIVE
PROLIFERATION 10-1
10.2 PRELIMINARY DATA ON EFFECTS MEDIATED BY ENDOCRINE SIGNALING 10-8
10.3 PRELIMINARY DATA ON EFFECTS MEDIATED BY EPIGENETIC MECHANISMS 10-23
10.4 PRELIMINARY DATA ON EFFECTS MEDIATED BY THE IMMUNE SYSTEM 10-36
10.5 PRELIMINARY DATA ON EFFECTS MEDIATED BY OXIDATIVE STRESS 10-47
10.6 PRELIMINARY DATA ON POTENTIAL INTERACTIONS BETWEEN INORGANIC ARSENIC EXPOSURE AND
OTHER CHEMICALS OR STRESSORS 10-62
10.7 REFERENCES FOR MODE OF ACTION HYPOTHESIS SUMMARIES AND PRELIMINARY ADVERSE
OUTCOME PATHWAY TABLES 10-64
11 ALL REFERENCES 11-1
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
PREFACE
1 EPA has released information pertinent to the development of the Toxicological Review
2 of Inorganic arsenic. The information in this document provides an overview of EPA's
3 assessment approaches and scientific information that EPA will consider during the
4 development of the draft Toxicological Review of Inorganic arsenic. The approaches and
5 scientific information were informed by the National Research Council's (NRC. 2013)
6 Interim Report entitled, Critical Aspects of EPA 's IRIS Assessment of Inorganic arsenic.
7 Over the next several months, EPA will continue to release to the public scientific
8 information and examples of how the approaches described below are implemented. Due
9 to the large scientific database associated with health effects related to inorganic arsenic
10 exposure, the scientific information contained in this package is extensive. EPA is
11 currently developing approaches to efficiently represent the scientific information into an
12 assessment that is both complete and concise.
13 EPA has identified several topics for discussion regarding the development of EPA's
14 draft Toxicological Review of Inorganic Arsenic (cancer and noncancer effects). These
15 general topics are described in greater detail below. Key science issues to be discussed
16 can be found on the IRIS Public Meetings website
17 (http://www.epa.gov/ncea/iris/publicmeeting/).
18 This information includes the following:
19 1. Assessment Development Plan (ADP) for the Toxicological Review of
20 Inorganic Arsenic - The ADP contains a conceptual model and an analysis plan.
21 Generally, the ADP provides scoping information, assumptions, and EPA's
22 approach for developing the Toxicological Review of Inorganic Arsenic. The
23 ADP utilized information and needs identified during scoping meetings held for
24 Agency partners and public stakeholders
25 (http://www.epa.gov/iris/irisworkshops/arsenic/meetings.htm). In 2013, NRC
26 (http://www.nap.edu/catalog.php?record_id=18594) reviewed EPA's draft ADP.
27 The NRC provided support for many of EPA's approaches contained in the
28 document and recommendations as to how EPA should revise the ADP. EPA has
29 incorporated NRC's recommendations in the current draft ADP.
30 2. Literature Search Strategy and Systematic Review for Development of the
31 Toxicological rReview of Inorganic Arsenic - A computerized keyword search
32 of PubMed, Web of Science, and Toxline using search terms is presented with
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 search updates conducted through April 2014. Health effects cluster
2 determination was conducted using natural language processing to group studies
3 based on the similarity of their titles and abstracts and then clustering references
4 around known relevant "seed" studies to identify a subset for further review. The
5 literature search for arsenic will be periodically updated. A cut-off date for the
6 draft assessment submitted for public comment will be July 2014. The references
7 identified in the updated literature search will bypass the natural language
8 processing step and enter into primary screening. Similarly, references
9 recommended by Agency partners, public stakeholders, or reviewers will
10 undergo secondary screening, bypassing both natural language processing and
11 primary screening. All of the screening process results and studies identified
12 through this literature search will be available on EPA's HERO database
13 (http://hero.epa.gov).
14 3. Summary of Literature Identified to Support Hazard Identification for
15 Inorganic Arsenic - Following categorization by title and abstract, studies were
16 further evaluated through full text review. The purpose of the full text review was
17 to identify studies that would be relevant to hazard identification for inorganic
18 arsenic; this review was not an exclusion step. All epidemiology and toxicology
19 studies identified as likely to contain information supporting hazard identification
20 based on title and abstract review were further characterized to identify
21 characteristics of the study design and the health effects reported in the study.
22 Based upon the full text review, epidemiology and animal toxicology studies
23 considered relevant to hazard identification were selected for risk of bias
24 evaluations. References were categorized by subject based on manual review of
25 the title and abstract of each, thereby identifying the toxicology and
26 epidemiology studies that support the identification of a human hazard for
27 inorganic arsenic. Characterization of studies and development of endpoint
28 identification tables was conducted using the previously identified toxicology
29 and epidemiology studies, resulting in an overview of the available literature for
30 hazard identification.
31 4. Summary of Risk of Bias Evaluations for Inorganic Arsenic Epidemiologic
32 Studies - Risk of bias evaluations are not exclusion criteria, rather, they
33 represent evaluations that will determine the primary literature considered for
34 hazard identification. Studies with a high risk of bias may provide supporting
35 evidence, but will not be presented in evidence tables. Risk of bias has been
36 evaluated using a modified draft Office of Health Assessment and Translation
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 (OHAT) approach (NTP. 2013). The OHAT approach identifies studies and
2 extracts data from all of the available studies, regardless of potential risk of bias.
3 The risk of bias evaluations are a series of questions addressing selection bias,
4 performance bias, attrition/exclusion bias, detection bias, and selective reporting
5 bias applied to each study. For each of the risk of bias elements, individual
6 studies are assessed using a 4-point scale from high to low risk of bias. Risk of
7 bias ratings for the individual questions will be used to tier the studies as high to
8 low risk of bias. Studies identified as low risk of bias will subsequently have data
9 extracted and considered principal evidence for developing hazard identification
10 conclusions; and high risk of bias studies may provide supporting evidence.
11 Examples of potential health hazards include: lung, skin, and bladder cancer;
12 ischemic heart disease; skin lesions; prostate and renal cancer; diabetes;
13 nonmalignant respiratory diseases; pregnancy outcomes; neurodevelopmental
14 toxicity; immune effects; liver and pancreatic cancer; renal disease; hypertension;
15 and stroke.
16 5. Evidence tables for Inorganic Arsenic Epidemiologic Studies - Data from low
17 risk of bias studies have been extracted and presented in evidence tables.
18 Evidence tables present data from studies related to a specific outcome or
19 endpoint of toxicity. At a minimum, these evidence tables include the relevant
20 information for comparing key features such as study design, exposure metrics,
21 and dose-response information. Evidence tables will serve as an additional
22 method for presenting and evaluating the suitability of the data to inform hazard
23 identification for inorganic arsenic. For each health effect domain, a series of
24 specific questions or criteria will be developed to help inform the suitability of
25 the data for hazard identification and potential utility for dose-response
26 assessment. Criteria specific for each health effect domain are needed because
27 experimental design considerations or data analysis techniques may have a
28 greater impact on particular health effect data.
29 6. Summary of Risk of Bias Evaluations for Inorganic Arsenic Animal Studies
30 - Animal studies for hazard identification have been identified by screening the
31 health effect cluster from the comprehensive literature search product, as well as
32 by primary screening of the literature search updates. Toxicological data has been
33 evaluated using a modified approach for risk of bias based upon the OF£AT
34 approach (NTP. 2013). Similar to the epidemiology studies, risk of bias
35 evaluations will not be used to exclude studies, rather, these evaluations will be
36 used to determine potential bias in the data. For each of the risk of bias elements,
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 individual studies are assessed using a 4-point scale from high to low risk of bias.
2 Risk of bias ratings for the individual questions will be used to tier the studies as
3 high to low risk of bias. Low risk of bias studies will be considered the principal
4 data, subsequently will have data extracted and will be presented for comparison
5 with epidemiologic data in evidence tables. High risk of bias studies may provide
6 supporting evidence. To date, EPA has conducted risk of bias evaluations for
7 immune, liver and developmental effects based upon the recommendation from
8 NRC (2013) that animal studies for these health effects may provide critical
9 information. EPA will evaluate health effects data from animal studies for
10 additional endpoints in the near future.
11 7. Evidence tables for Inorganic Arsenic Animal Studies - Data from low risk of
12 bias studies have been extracted and presented in evidence tables. Evidence
13 tables present data from studies related to a specific outcome or endpoint of
14 toxicity. At a minimum, these evidence tables will include the relevant
15 information for comparing key features such as study design, exposure metrics,
16 and dose-response information. Evidence tables will serve as an additional
17 method for presenting and evaluating the suitability of the data to inform hazard
18 identification for inorganic arsenic. For each health effect domain, a series of
19 specific questions or criteria will be developed to help inform the suitability of
20 the data for hazard identification and potential utility for dose-response
21 assessment. Criteria specific for each health effect domain are needed because
22 experimental design considerations or data analysis techniques may have a
23 greater impact on particular health effect data.
24 8. Mode of Action (MOA) Literature Search Strategy for the Toxicological
25 Review of Inorganic Arsenic - Mechanistic data will be identified through
26 natural language processing based on previous human health assessments of
27 inorganic arsenic, as well as focused literature searches. For hazard
28 identification, human relevance will be informed by mechanistic data. Studies
29 identified through this literature search will be available on EPA's HERO
30 database (http: //hero. epa. gov).
31 9. Inorganic Arsenic Mode of Action (MOA) Hypothesis Summaries - To
32 facilitate discussions at the bimonthly meeting, EPA has developed qualitative
33 hypothesis summaries for several potential MOAs associated with health effects
34 of inorganic arsenic. The hypothesized MOAs were selected based on available
3 5 information from authoritative reports and reviews on inorganic arsenic MOA
36 (Cohen etal.. 2013; NRC. 2013; Jomovaetal.. 2011; Kitchin and Conolly. 2010;
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 Prins. 2008). Potential MOAs may include, but are not limited to, cytotoxicity
2 and regenerative proliferation, oxidative stress following generation of reactive
3 oxygen species and depletion of antioxidant enzymes, and alteration of
4 epigenetic mechanisms (e.g., DNA methylation). These qualitative MOA
5 hypothesis summaries briefly summarize the available mechanistic data for
6 several potential modes of action relevant to cancer and non-cancer health effects
7 associated with inorganic arsenic. Five examples of MOA hypothesis summaries
8 are included in this package to facilitate discussion on MOA-relevant topics
9 detailed in Section 1. The information presented in these example summaries is
10 not comprehensive, but intended to organize useful discussions with Agency
11 partners and public stakeholders. Based on information provided by reviewers of
12 these materials and the results of EPA's MOA literature search (outlined in
13 Section 10), these MOAs will be refined and additional documentation will be
14 added. Additional MOAs may also be identified through discussion in the
15 bimonthly meeting. Information on MOAs associated with health effects that are
16 causal or likely causal related to inorganic arsenic exposures will support the
17 development of an adverse outcome pathways (AOP). AOPs characterize
18 existing scientific information between a molecular initiating event and an
19 adverse outcome for individual and population level responses. The AOP
20 framework will not displace the mode of action framework defined by the Cancer
21 Guidelines (U.S. EPA. 2005). but be inclusive of mode of action analysis. More
22 information on the use of MOA analyses and AOP framework in the inorganic
23 arsenic IRIS assessment is available in the ADP (Section 1).
24 10. Preliminary Mechanistic and Susceptibility Data Tables - Mechanistic data
25 will be considered during hazard identification and dose-response analysis. For
26 hazard identification, qualitative MOA analyses informed by the MOA
27 hypothesis summaries (Section 9) will be developed for each health endpoint.
28 Qualitative MOA analyses will be organized using tables that may support AOP
29 development. Examples of this organization are provided in summary tables. The
30 summary tables currently contain data relevant to a particular MOA, which may
31 relate to multiple health effects. The data used to create these summary tables is
32 available in the EPA HERO database (http://hero.epa.gov). These qualitative
33 MOA analyses will be used to inform causal determinations for individual health
34 effects.
3 5 For causal or likely causal health effects, mechanistic and susceptibility data will be
36 organized into an AOP. These AOP analyses will be used to inform the dose-response
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 analyses, including potential impact of susceptibility factors on the dose-response.
2 Preliminary data on some potential susceptibility factors are provided to facilitate further
3 discussion.
4 The extent to which an AOP can inform dose-response analyses is dependent upon the
5 available mechanistic data. Data may be insufficient to support an AOP for particular
6 health effects. If the mode of action is unknown, the adverse outcome will be considered
7 relevant to humans. Data gaps preventing a complete AOP will be considered sources of
8 uncertainty. Mechanistic data or AOPs will not be a requirement for evaluating observed
9 health effects due to exposure to inorganic arsenic.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 xiii Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 ASSESSMENT DEVELOPMENT PLAN
1.1 Executive Summary
1 The U.S. Environmental Protection Agency (EPA) National Center for Environmental
2 Assessment (NCEA) is developing a state-of-the-science toxicological review on
3 inorganic arsenic for the Integrated Risk Information System (IRIS) Program. During
4 development of the toxicological review, IRIS is committed to engaging Agency partners
5 and public stakeholders. Agency partners and public stakeholders have been active
6 participants in the scoping and planning process. On the basis of their recommendations,
7 as well as Congressional mandate, the toxicological review will examine the cancer and
8 noncancer effects from oral, inhalation, and dermal inorganic arsenic exposure. The IRIS
9 toxicological review will consist of hazard identification and dose-response assessment.
10 Exposure assessment and risk characterization are outside the scope of an IRIS
11 toxicological review.
Key Points - Executive Summary
State-of-the science toxicological review on inorganic arsenic to be developed by
EPA
Congressional mandate directs EPA to contract with NRC to conduct a review of
inorganic arsenic toxicological review
Toxicological review consists of hazard identification and dose-response
Cancer and noncancer effects of inorganic arsenic exposure will be considered
Oral, inhalation, and dermal routes of inorganic arsenic exposure will be examined
Assessment development plan serves as the problem formulation for the toxicological
review
Assessment development plan consists of conceptual model and analysis plan
Assessment development plan revised to incorporate NRC (2013) recommendations
Multiple opportunities to engage Agency partners and public stakeholders
12 This assessment development plan serves as the problem formulation for the
13 toxicological review and consists of two components: a conceptual model and an analysis
14 plan. The conceptual model identifies specific relationships examined in the toxicological
15 review, as well as those relationships which are beyond the scope of the toxicological
16 review. Relationships outlined in the conceptual model will be analyzed and interpreted
17 using approaches described in the analysis plan. The analysis plan has been substantially
18 revised to incorporate NRC recommendations in the interim report "Critical Aspects of
19 EPA's IRIS Assessment of Inorganic arsenic" (NRC. 2013). Both the conceptual model
20 and analysis plan may be revised as new data, methods, or risk management needs arise.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-1 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 Accordingly, the assessment development process includes multiple opportunities for
2 Agency partners and public stakeholders to provide input.
1.2 Background
3 Inorganic arsenic is a naturally occurring element widely distributed throughout the
4 Earth's crust. In addition to natural sources, industrial activities such as coal combustion
5 and smelting operations can release inorganic arsenic. Low concentrations of inorganic
6 arsenic are found in water, food, soil, and air. This prevalence increases the potential for
7 human exposure; therefore, characterization of the human health impacts of inorganic
8 arsenic exposure is important to Agency partners and public stakeholders.
Key Points - Background
1988: EPA published an IRIS assessment of inorganic arsenic
2003: EPA began updating IRIS assessment of inorganic arsenic
2005: EPA released draft IRIS assessment of inorganic arsenic (cancer health effects
of oral exposure) for public comment and peer review
2010: EPA released a revised draft IRIS assessment of inorganic arsenic (cancer
health effects of oral exposure) for public comment and peer review
2011: Congress directed EPA to contract with the NRC to conduct a review of EPA's
draft inorganic arsenic assessment
2013: NRC released interim report "Critical Aspects of EPA's IRIS Assessment of
Inorganic arsenic" providing recommendations for developing draft inorganic arsenic
assessment
1.2.1 Previous EPA Assessments on Inorganic Arsenic
9 EPA completed a health assessment of inorganic arsenic in 1988. In 1996, EPA requested
10 that the National Research Council (NRC) evaluate the inorganic arsenic database and
11 recommend revisions to the 1988 assessment. In response, the NRC published the 1999
12 report "Arsenic in Drinking Water" (NRC. 1999).
13 In 2000, EPA requested NRC update their 1999 report as well as review the Primary
14 Drinking Water Standard for Arsenic. In response, NRC published "Arsenic in Drinking
15 Water - 2001 Update" (NRC. 2001). which concluded that (1) the database on the human
16 carcinogenic effects of inorganic arsenic was adequate for risk assessment, (2) lung and
17 bladder cancer should be the focus of inorganic arsenic risk assessment, and (3)
18 epidemiology studies from southwestern Taiwan are the most appropriate dataset. Also,
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-2 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 in 2001, EPA established the Primary Drinking Water Standard which set a maximum
2 contaminant level of 10 (ig/L in drinking water. In 2003, the EPA Office of Research and
3 Development and Office of Water decided to jointly revise the 1988 IRIS inorganic
4 arsenic assessment to incorporate recommendations from the 1999 and 2001 NRC
5 reports.
6 In 2005, the assessment was divided into two parts - one focused on noncancer outcomes
7 and the other focused on cancer outcomes. In 2005, IRIS released a draft assessment
8 focused on cancer health effects following oral exposure to inorganic arsenic for public
9 comment and review by EPA's Science Advisory Board (SAB). The SAB provided
10 recommendations in 2007 (SAB. 2007) and EPA revised the draft inorganic arsenic
11 assessment to incorporate the SAB recommendations. The revised draft IRIS assessment
12 focused on cancer health effects following oral exposure to inorganic arsenic and was
13 released for public comment and review by the SAB in 2010 (U.S. EPA. 2010). The SAB
14 provided comments and recommendations on the revised draft IRIS assessment in 2011
15 (SAB. 2011).
1.2.2 Congressional Directive for EPA Toxicological Review of
Inorganic Arsenic
16 EPA received additional direction from Congress in December 2011, through The
17 Consolidated Appropriations Act (U.S. Congress. 2011). to contract with the NRC to
18 conduct a review of EPA's draft inorganic arsenic assessment considering both cancer
19 and noncancer hazards from oral exposure to inorganic arsenic. In accordance with this
20 Congressional mandate, the draft inorganic arsenic assessment will be reviewed by the
21 NRC. The NRC review consists of two phases. The first phase consists of NRC meetings
22 discussing the scope and key science issues for the draft assessment. Upon completion of
23 this phase, the NRC will provide recommendations for developing the draft assessment.
24 EPA will incorporate, where possible, the NRC recommendations and draft an inorganic
25 arsenic assessment of cancer and noncancer hazards. The draft assessment will be
26 provided to the NRC for the second phase of their review. In this second phase, NRC will
27 provide critical scientific peer review of the draft assessment, according to their review
28 criteria.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-3 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1.2.3 Overview of NRC Interim Report "Critical Aspects of EPA's IRIS
Assessment of Inorganic Arsenic"
1 The first phase of the NRC review began in July 2012 and was completed in November
2 2013. As part of first phase of the NRC review, EPA provided the NRC draft materials
3 for comment. These draft materials included planning and scoping documents as well as a
4 draft ADP outlining proposed approaches for literature searches, literature evaluation,
5 hazard identification, and dose-response analyses. In November 2013, the NRC delivered
6 the interim report "Critical Aspects of EPA's IRIS Assessment of Inorganic arsenic"
7 (NRC. 2013). The interim report provided recommendations for the toxicological review
8 of inorganic arsenic on key science issues. These scientific recommendations are
9 summarized in Table 1-1 and discussed further in the revised conceptual model (Section
10 1.4) and analysis plan (Section 1.5).
Table 1-1 Summary of NRC Recommendations on IRIS Assessment of
Inorganic arsenic
NRC Recommendation
Exposure considerations - consider contribution of inorganic arsenic
intake from rice in South Asian and Taiwanese population
Exposure Considerations - consider probabilistic approach to estimate
daily intake from rice to account for variability in rice consumption and
concentration of inorganic arsenic in rice
Exposure Considerations - IRIS assessment can benefit from examining
studies which provide estimates of both external exposure and
biomarker of exposure data are provided
Exposure Considerations - Hazard identification should take into
account that some people are more susceptible because of relative
inability to metabolize inorganic arsenic
IRIS Assessment Development Plans - EPA should design mode of action
tables
IRIS Assessment Development Plans - for microarray/NextGen sequence
data -for conclusions based solely on expression, need detailed
analysis of data supporting conclusion, including pre-processing and
statistical analysis, which will require raw data
IRIS Assessment Development Plans - Meta-analyses for hazard
identification if < 3 peer-reviewed studies; meta-analyses for dose-
response if < 3 doses tested
IRIS Assessment Development Plans - As part of systematic review
process, risk of bias should be evaluated using established guidelines
ADP Section
1.5.1 Approaches to Source
Considerations
1.5.1 Approaches to Source
Considerations
1.5.3 Approaches to Exposure
Pathway Considerations
1.5.4 Approaches to Receptor
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-4 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
NRC Recommendation
IRIS Assessment Development Plans - Conducting meta-analyses of
aggregated data from published studies is an appropriate alternative to
analyzing raw data for individual level meta-analyses
Hazard identification - For non-cancer effects, consider diseases with
high prevalence in U.S. population to determine if inorganic arsenic
contributes to disease burden [e.g. cardiovascular disease (CVD),
respiratory disease, kidney disease, diabetes]
Hazard identification - Observation epidemiologic studies preferred for
determining association between inorganic arsenic exposure and skin
lesions
Hazard identification - EPA consider skin studies that have histologic
specificity
Hazard identification - Focus on human studies that investigate
coronary arterial disease, myocardial infarctions, CVD, and overall CVD
mortality.. .can exclude peripheral arterial disease based on dose-
response and associations in populations with poor
nutrition. ...cerebrovascular disease can be included. ..hypertension is
less of a priority
Hazard identification - Critical synthesis of human population studies
with mode of action underlying different non-malignant respiratory
outcomes/phenotypes should be focus
Hazard identification - US data on drinking-water arsenic (inorganic) and
bladder cancer in US should be evaluated by EPA, particularly with
respect to smoking
Hazard identification - Studies of incidence, rather than mortality, may
better reflect the impact of inorganic arsenic on kidneys
Hazard identification - Essential to evaluate potential adverse effects on
fetal and postnatal exposure to inorganic arsenic
Hazard identification - Effects of inorganic arsenic in elderly populations
is a particular research need
Hazard identification - Recent epidemiologic studies supporting
association between inorganic arsenic and diabetes at low to moderate
concentrations should be carefully reviewed and included quantitatively
Hazard identification - Given evidence and burden of prostate disease in
US men, should at least consider prostate cancer
Hazard identification - Hazard assessment should include epidemiologic
and experimental evidence and integrate mode of action where
possible
ADP Section
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-5 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
NRC Recommendation
Hazard identification - Strength of evidence judgments characterized
using modified Hill (1965) criteria
Mode of action - Rigorously examine epidemiologic studies using Hill
(1965) criteria to examine appropriateness for risk assessment
Dose-response Analysis - Evaluate data on multiple outcomes to assess
whether they are appropriate for estimating health outcomes in range
of epidemiologic observations
Dose-response Analysis - Update selected health outcomes as new data
becomes available
Dose-response Analysis - Consider evidence of life-stage sensitivity
when considering less-than-lifetime exposure
Exposure Considerations - Dose-response relationship from
epidemiologic studies concerning health effects of inorganic arsenic in
drinking water should include likelihood that doses derived from
drinking water alone does not represent the total inorganic arsenic dose
IRIS Assessment Development Plans - Meta-analyses for hazard
identification if < 3 peer-reviewed studies; meta-analyses for dose-
response if < 3 doses tested
IRIS Assessment Development Plans - Conducting meta-analyses of
aggregated data from published studies is appropriate alternative to
analyzing raw data for individual level meta-analyses
Hazard identification - May be possible to model dose-response
relationships from estimated relative risk associated with categories of
exposure. ..may necessitate assessment of confounding by cigarette
smoking. ..associations could be specific to histological type requires
biomarker concentration
Hazard identification - Major consideration for respiratory mode of
action should be epidemiologic and animal studies that identify
potential pathogenic mechanisms in response to low/moderate
inorganic arsenic exposures
Hazard identification - Important respiratory mode of action
consideration is whether in utero/perinatal exposure poses significant
risk of lung disfunction/disease
Hazard identification - Consider evidence that chronic inflammation and
reactive oxygen species are central to pathogenesis of inorganic arsenic-
induced CVD
Hazard identification - For CVD, address potential uncertainties from
differences between study population and general population
ADP Section
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-6 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
NRC Recommendation
Hazard identification - Mode of action analysis will need to consider
that there may be multiple mechanisms by which inorganic arsenic can
cause bladder cancer.. ..crucial to assess exposure on an individual level
and include biomarkers/relevant co-factors where possible. ...examine
incidence rather than mortality and examine susceptible groups of the
population
Hazard identification - Consider whether inorganic arsenic/diabetes
have interaction effects on renal function and chronic kidney disease
Hazard identification - Data that can be used for dose-response
concerning birth size and infant growth, possibly infant mortality
Hazard identification - MAPK/extracellular signal-related kinase
pathway should be considered as to whether it might be an underlying
cause of learning deficits
Hazard identification - Recent epidemiologic studies supporting
association between inorganic arsenic and diabetes at low to moderate
concentration should be carefully reviewed and included quantitatively
Hazard identification - Both innate and adaptive immune responses
should be considered
Hazard identification - Hazard assessment should include epidemiologic
and experimental evidence and integrate mode of action where
possible
Hazard identification - With respect to mode of action, important to
consider dose and time-dependence of exposure to key immunological
events
Hazard identification - Important to consider timing with respect to life-
stage, duration of exposure, and latent period for the health outcome
Susceptibility Factors - Evaluate whether early life exposure may affect
the risk of inorganic arsenic-related effects in adults
Susceptibility Factors - Timing of exposure should be considered in
evaluating epidemiologic studies for dose-response assessment
Susceptibility Factors - It is essential to evaluate sex differences in
inorganic arsenic metabolism and toxicity to protect the most
susceptible population
Susceptibility Factors - Assessment should consider nutritional status of
study populations when examining dose-response relationships
reported in the epidemiologic literature
ADP Section
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.5 Approaches to Endpoint
Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-7 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
NRC Recommendation
ADP Section
Susceptibility Factors - Factors important to evaluating potential for
inorganic arsenic to interact with background disease processes on a
population level: overall mode of action and disease mechanism;
prevalence of disease, prevalence of pre-clinical disease
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - Consideration should be given to whether
people may be vulnerable to effects because disease processes impair
defense mechanisms or act in concert with inorganic arsenic mode of
action
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - May be possible for non-cancer assessment to
describe increased disease risk associated with any particular dose - if
RfD derived, can be described as dose associated with particular
increase in risk
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - Consider whether dose-response will focus on
population as a whole or involve separate assessments for general
population and susceptible subgroups
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - Plausible quantitative approach is sensitivity
analysis to determine how smoking-interaction synergism changes
potency calculation of dose-response
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - Evaluation of size/nature of vulnerable
populations will help determine if epidemiologic studies adequately
capture these groups
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - Co-exposure may be worth mentioning as
additional mechanistic explanation to explain some endpoints
associated with inorganic arsenic exposure; consider co-exposure to
metals and PAH
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - Helpful to assess how interacting metals/PAHs
might co-occur in the epidemiologic study populations in comparison
with target populations of risk assessment
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - Potency adjustment for susceptible populations
is feasible if appropriate dose-response data are available in
comparison with the general population
1.5.6 Approaches to Risk
Metric Considerations
Susceptibility Factors - When sizeable population is vulnerable, it's
reasonable to extend dose-response below range of observation by
modest extrapolation
1.5.6 Approaches to Risk
Metric Considerations
Mode of action - Identifying mode of action data gaps and their
potential effects on ability to extrapolate to low exposures is important
1.5.6 Approaches to Risk
Metric Considerations
Mode of action - Committee recommends following TCE and chloroform
when beginning mode of action analysis
1.5.6 Approaches to Risk
Metric Considerations
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-8 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
NRC Recommendation
Mode of action - Important aspect will be Mode of action for each
observed health outcome, including supporting and contradictory
evidence
Dose-response Analysis - 1-5 u.g/L is reasonable estimate for US
background
Dose-response Analysis - Derive risk estimates for health effects then
derive risk-specific doses to address needs of analyses that would
typically use a RfD... provide guidance on how RfD might be selected
among risk-specific doses
Dose-response Analysis - Consider study-selection options to facilitate
dose-response options, with preference to studies in low-moderate
exposure ranges and using biomarkers of exposure
Dose-response Analysis - Common exposure metric is needed to
integrate across studies
Dose-response Analysis - Use limited extrapolation by using modeled
shape of the dose-response relationship to provide data-informed
estimate of potential dose-response relationships below range of
observation
ADP Section
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
1.5.6 Approaches to Risk
Metric Considerations
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8
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14
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The NRC also provided recommendations on the approaches proposed in the draft
assessment development plan. The NRC recommendations on the proposed approaches
are summarized below.
In the draft materials submitted to NRC for review, the EPA provided the NRC with a
draft planning and scoping summary outlining the needs of EPA partners and public
stakeholders for a toxicological review of inorganic arsenic. In addition, these materials
highlighted EPA's commitment to communicate with Agency partners and public
stakeholders throughout development of the draft toxicological review. The NRC
commented that these materials clearly demonstrated that EPA is incorporating
recommendations from previous NRC committees (NRC. 2011. 2009) to involve risk
managers, risk assessors, and stakeholders early in the development process.
EPA also submitted draft materials to the NRC outlining approaches for (1) literature
search and evaluation, (2) scope of hazard identification, (3) mode-of-action analyses,
and (4) scope of the dose-response analyses. The NRC found that the draft plans for
literature search and evaluations captured the salient information from epidemiologic
studies, but indicated that similar approaches to animal and in vitro data could be
important for mode-of-action analyses. The NRC further commented that the outlined
approaches to incorporate systematic review further demonstrated that EPA is
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-9 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 incorporating recommendations from previous NRC committees (NRC, 2011. 2009). The
2 NRC committee on inorganic arsenic recommended searching for studies on specific
3 outcomes, with specific criteria including individual measures of inorganic arsenic
4 exposure, inorganic arsenic measurement preceding outcome, and low-to-moderate
5 exposure (<100 (ig/L in water).
6 For hazard identification, EPA proposed evaluating the relationship between inorganic
7 arsenic exposure and human health effects using a causal determination framework (U.S.
8 EPA. 2013). The NRC supported this approach for hazard identification, recommending
9 consideration of animal and mechanistic data as supporting the causal determination. The
10 NRC also highlighted particular health end points of concern that should be evaluated for
11 hazard identification. The NRC also supported EPA's use of evidence tables to present
12 information. The NRC stressed the importance of explaining causal determination
13 judgments in the synthesis text.
14 The NRC supported EPA's proposal to perform mode-of-action analyses on health
15 endpoints considered "causal" or "likely causal." The NRC recommended possible
16 consideration of "suggestive" endpoints to determine if mechanistic data supported a
17 stronger causal association. The NRC agreed with EPA's proposal that even if a mode-of-
18 action cannot be determined, health endpoints with "causal" or "likely causal"
19 relationships with inorganic arsenic should undergo dose-response analysis.
20 Several dose-response analysis recommendations were provided by the NRC. The NRC
21 recommended developing risk estimates across the array of health effects for which there
22 is adequate epidemiologic evidence. The NRC also stated that dose-response analyses
23 should be performed in the range of epidemiologic observations. When those data are
24 unavailable, the NRC recommended using mechanistic data for extrapolation; however,
25 the NRC cautioned that extrapolations become increasingly uncertain as they go further
26 below the observed range. The NRC commented that the needs of assessing health risks
27 can be facilitated by characterizing dose-response relationships down to background
28 concentrations. The NRC recommended that EPA derive risk-specific doses, which
29 would facilitate efforts to evaluate cumulative risk, conduct risk-benefit assessments, or
30 comparative analyses.
31 The NRC agreed with EPA's proposal to use probabilistic approaches to consider
32 uncertainty and variability associated with susceptibility factors. Susceptibility due to
33 pre-existing disease, early-life exposure, and sex differences in metabolism were among
34 several factors recommended for consideration by the NRC. On the basis of available
35 evidence, the NRC suggested considering whether dose-response assessment should
36 focus on the population as a whole or involve separate approaches for the general
37 population and susceptible groups.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-10 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 EPA is developing an IRIS assessment of inorganic arsenic that incorporates the
2 recommendations from the NRC. This new IRIS assessment of inorganic arsenic will
3 examine the available scientific database on cancer and noncancer health effects from
4 inorganic arsenic exposure.
1.3 Developing the Toxicological Review
Key Points - Development
Collaborative approach to developing the toxicological review
An iterative process informed through engaging Agency partners and public
stakeholders
Assessment development plan informed by planning and scoping phase
Two products: conceptual model and analysis plan
Posting to the IRIS database in 2016
1.3.1 Goals of the Assessment Development Plan
5 This assessment development plan describes the problem formulation for the
6 toxicological review of inorganic arsenic. Problem formulation is an iterative process that
7 identifies factors for consideration in the toxicological review. Goals of problem
8 formulation include explaining the purpose of the toxicological review, defining
9 problems for consideration, and outlining a plan for characterizing risk. The assessment
10 development plan for inorganic arsenic consists of two products: a conceptual model
11 (Section 1.4) and an analysis plan (Section 1.5).
12 A conceptual model considers the sources, stressors, exposure pathways, receptors,
13 endpoints, and risk metrics that may be evaluated in the toxicological review. The
14 conceptual model provides a starting point to integrate the available data and outline
15 relationships between these features. On the basis of scientific judgement and the needs
16 of Agency partners and public stakeholders, the conceptual model identifies specific
17 relationships to be considered in the toxicological review, as well as those relationships
18 beyond the scope of the toxicological review. The decisions outlined in the conceptual
19 model inform the analysis plan. The analysis plan outlines the analytic and interpretive
20 approaches for evaluating the relationships identified in the conceptual model. As new
21 data or risk management needs arise, it is anticipated that both the conceptual model and
22 analysis plan will be revised.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 In addition to the assessment development plan, EPA will develop several other
2 documents supporting key elements of the toxicological review. These supplementary
3 documents will provide additional information considered during development of the
4 toxicological review. For instance, these supplementary materials may outline
5 considerations used to make underlying conclusions or decisions presented in the
6 toxicological review of inorganic arsenic. These supporting documents will be an
7 opportunity to transparently document supplementary approaches and analyses used to
8 develop the toxicological review of inorganic arsenic.
1.3.2 Agency Partner and Public Stakeholder Engagement
9 EPA is committed to engaging partners within the EPA and public stakeholders
10 throughout the development of the toxicological review of inorganic arsenic. Agency
11 partners (including other federal agencies) and public stakeholders (e.g., non-
12 governmental organizations, industry groups, citizens, academia, etc.) have been active
13 participants in planning and scoping meetings, identifying their needs for the
14 toxicological review of inorganic arsenic, and making scientific recommendations for
15 consideration. Multiple opportunities to provide feedback on the toxicological review,
16 including public comment periods, webinars, and public reviews, have been, and will
17 continue to be, important components of the development process. The participation of
18 Agency partners and public stakeholders will ensure the toxicological review meets the
19 needs of the risk management community and the public.
1.3.3 Transparency
20 EPA is committed to developing the toxicological review of inorganic arsenic in a
21 transparent process. For the toxicological review, transparency means sufficient
22 information will be available to understand the scientific rationale behind decisions, as
23 well as reproduce methods used to identify and evaluate data. To ensure transparency to
24 Agency partners and public stakeholders, materials used to develop the toxicological
25 review (e.g., literature search products, evidence tables, exposure response arrays) will be
26 made available for public review. In addition, future materials will provide links to
27 EPA's HERO database (http://hero.epa.gov) to assist in transparency and public access to
28 the peer reviewed literature citations. When possible, the toxicological review will
29 present options for key decision points and provide rationale for choosing a particular
30 option.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1.3.4 Timeline for Completion
1 The critical importance of inorganic arsenic to Agency partners and public stakeholders
2 for the toxicological review is reflected in the unique approach NCEA has adopted for the
3 toxicological review. The NRC recommendations outline a scientifically defensible
4 approach for identifying, evaluating, and quantifying data on the health effects of
5 inorganic arsenic. These recommendations will inform development of the toxicological
6 review, as well as decisions on key science issues such as low-dose extrapolation and
7 mode of action.
8 EPA will release an assessment development plan, literature search product, risk of bias
9 evaluations, evidence tables, and qualitative mode of action hypothesis summaries for
10 public input and discussion. These public discussions will inform draft development of
11 the toxicological review of inorganic arsenic.
12 The draft toxicological review will undergo internal EPA review and review by other
13 federal agencies and the public before being released for external peer review. External
14 peer review of the toxicological review will be managed by the NRC. Following
15 revisions and additional review by EPA and other federal agencies , the toxicological
16 review is anticipated to post to the IRIS database in 2016. The current timeline for
17 developing the toxicological review of inorganic arsenic is shown in Table 1-2.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Table 1-2 Draft Timeline for Development of the Toxicological Review of
Inorganic Arsenic
PROPOSED PROCESS
Internal EPA Partner Scoping and Problem
Formulation Workshop
Public Stakeholder Workshop - Planning
and Scoping
NRC Phase 1 Review
IRIS Bimonthly Public Meeting
Completed draft Inorganic arsenic
Toxicological Review
Complete Internal Agency Review
Complete Interagency Science
Consultation
Release draft for Public Comment
NRC Phase 2 review
Complete NRC Phase 2 review
Complete Internal Agency/I nteragency
Science Discussion
Post to IRIS website
TIMELINE
Completed
September 2012
http://www.epa.gov/iris/irisworkshops/arsenic/index.htm
Completed
January 2013
http://www.epa.gov/iris/irisworkshops/arsenic/index.htm
Completed
January - November 2013
http://www.epa.gov/iris/irisworkshops/arsenic/index.htm
June 2014
Summer 2014
Summer 2014
Fall 2014
Winter 2014
Spring 2015
Winter 2015
Spring 2016
Summer 2016
1.4 Conceptual Model for the Toxicological Review
1 This conceptual model describes the rationale for developing the toxicological review of
2 inorganic arsenic. The conceptual model consists of a written description and visual
3 representation of the predicted relationships between inorganic arsenic exposure and
4 human health effects. It is based upon the general conceptual model framework shown in
5 Figure 1-1.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Points - Conceptual Model
Scope of the toxicological review
Identifies factors and endpoints to be evaluated in the toxicological review
Written and visual representation of predicted relationships between exposure and
human health effects
Iterative process that can be refined during development of the toxicological review
Revised in response to NRC recommendations in the interim report "Critical Aspects
of EPA's IRIS Assessment of Inorganic arsenic"
1 A conceptual model identifies the sources, stressors, receptors, exposure pathways, and
2 health effects considered in the toxicological review. Predicted relationships between
3 these factors are indicated in the visual diagram and described in the written portion of
4 the conceptual model. Predicted relationships between inorganic arsenic exposure and
5 human health effects may be revised as data become available; therefore, this conceptual
6 model is considered a flexible framework that can be adapted as necessary during
7 development of the toxicological review of inorganic arsenic.
1.4.1 Scope of the Toxicological Review
1.4.1.1 Summary
8 This section describes the scope of the toxicological review. Agency partner and public
9 stakeholder input provided context for the development of the conceptual model. In
10 addition, the conceptual model has been revised in response to NRC recommendations in
11 the interim report "Critical Aspects of EPA's IRIS Assessment of Inorganic arsenic"
12 (NRC. 2013V
1.4.1.2 Components of an IRIS Toxicological Review
13 When considering scope, it is important to distinguish a risk assessment from an IRIS
14 toxicological review. A risk assessment consists of four components: hazard
15 identification, dose-response analysis, exposure assessment, and risk characterization.
16 Comparatively, an IRIS toxicological review considers hazard identification and
17 dose-response analysis. Although exposure assessment and risk characterization are
18 beyond the scope of an IRIS toxicological review, information in the toxicological review
19 of inorganic arsenic is anticipated to serve as part of the scientific basis for complete risk
20 assessments of inorganic arsenic.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Sources
Source(s) of stressors in the environment
Stressors
Physical, chemical, or biological agents
that cause an effect
Exposure Pathways
Processes by which receptor is exposed
to stressor
Receptors
Populations, including life stages,
exposed to the stressor
Endpoints
Measure of stressor effects or biological
systems impacted
Risk Metrics
Measure by which risk is quantified
Figure 1-1 General Framework for the Conceptual Model
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1.4.1.3 Agency Partner and Public Stakeholder Needs
1 The conceptual model for the toxicological review of inorganic arsenic was informed by
2 Agency partners and public stakeholders. Agency partners and public stakeholders
3 discussed their needs for the toxicological review of inorganic with the IRIS program in
4 an internal meeting with Agency partners (September 2012) and a public stakeholder
5 meeting (January 2013). Meeting reports are available online
6 (http://www.epa.gov/iris/irisworkshops/arsenic/meetings.htm). and needs identified in
7 those meetings are summarized here. Agency partners and public stakeholders have
8 requested consideration of both naturally occurring and anthropogenic sources of
9 inorganic arsenic. Stressors of interest to Agency partners and public stakeholders
10 included inorganic arsenic as well as arsenic metabolites. Agency partners and public
11 stakeholders requested consideration of oral, inhalation, and dermal exposure pathways.
12 Humans were the principal receptor of interest, and Agency partners and public
13 stakeholders recommended considering susceptible populations and life stages. When
14 evaluating health endpoints, Agency partners and public stakeholders have requested
15 consideration of both cancer and noncancer health effects, emerging health effects, and
16 the need for mode of action and adverse outcome pathway analyses. With respect to the
17 dose-response analyses, Agency partners and public stakeholders have indicated the need
18 to estimate excess risk (i.e., risk above naturally occurring levels) at potential exposure
19 levels for cancer and noncancer endpoints, including any potential risk at naturally
20 occurring levels of inorganic arsenic. Agency partners and public stakeholders have
21 recommended harmonization of cancer and noncancer dose-response analyses and
22 multiple approaches to low-dose extrapolation (e.g., linear, nonlinear, probabilistic, etc.).
1.4.1.4 NRC Recommendations
23 The NRC interim report "Critical Aspects of EPA's IRIS Assessment of Inorganic
24 arsenic" (NRC. 2013) provided recommendations for developing the toxicological
25 review. Specific recommendations are addressed in the analysis plan (Section 1.5).
26 General recommendations on the conceptual model are summarized here.
27 The NRC indicated that there are numerous potential natural and anthropogenic sources
28 of inorganic arsenic. The NRC indicated that the toxicological review would focus on
29 inorganic arsenic as the stressor; however, the NRC recommended considering the
30 contribution of metabolites of inorganic arsenic to health endpoints. The NRC
31 recommended considering dietary sources of inorganic arsenic, particularly rice, as a
32 potential exposure pathway. The NRC recognized that a major goal of the toxicological
33 review is to identify hazards associated with chronic inorganic arsenic exposure in
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 humans and supported humans as the receptors of interest. When considering health
2 effect endpoints, NRC recommended considering diseases with high prevalence in the
3 United States. In addition, the NRC recommended that susceptibility factors to inorganic
4 arsenic (e.g., life stages, impaired metabolism, sex, nutrition, or underlying disease state)
5 should be considered. The NRC recommended that animal and in vitro data should be
6 considered for mode-of-action analyses. The NRC also recommended that mode-of-
7 action analyses should be conducted to inform confidence in the assessment of risk of
8 inorganic arsenic at low doses. The NRC indicated that animal and in vitro studies are not
9 the focus of dose-response analyses for inorganic arsenic. Rather, the NRC recommended
10 that multiple human health outcomes should be evaluated for dose-response analyses.
11 These evaluations should determine if data are appropriate for direct estimation of risk in
12 the range of epidemiologic observation. The NRC recommended minimizing dose-
13 response extrapolations beyond the observed evidence.
1.4.2 Sources
1.4.2.1 Summary
14 This section discusses natural and anthropogenic sources of inorganic arsenic. An
15 assessment parameter that environmental exposure is widespread owing to both natural
16 and man-made sources of inorganic arsenic is reached. The potential impact of this
17 assessment parameter is that data limitations on inorganic arsenic sources may increase
18 uncertainty in estimating exposure dose.
1.4.2.2 Naturally Occurring Sources of Inorganic Arsenic
19 Inorgnic arsenic is widely distributed throughout the Earth's crust and is present in more
20 than 200 mineral species (IARC. 2009; ATSDR. 2007; Health Canada. 2006). Natural
21 sources of inorganic arsenic result in naturally occurring, or "background," levels of
22 inorganic arsenic in soil. Natural sources can also contribute to inorganic arsenic in
23 water, particularly groundwater from wells in arsenic-rich geological formations.
24 Volcanic activity releases, volatilization, and dusts are some natural sources of inorganic
25 arsenic released in the atmosphere. It is estimated that approximately one-third of
26 atmospheric inorganic arsenic comes from natural sources.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1.4.2.3 Anthropogenic Sources of Arsenic
1 Inorganic arsenic, primarily as arsenic trioxide, is released to the environment through
2 mining, smelting, and burning fossil fuels (IARC. 2009; ATSDR. 2007). In addition,
3 inorganic arsenicals are used in the manufacturing and processing of several products,
4 including semi-conductors, textiles, ceramics, and pressure treated wood. To a lesser
5 extent, organic arsenicals have been used as pesticides and veterinary drugs (Health
6 Canada. 2006). Industrial, agricultural, and mining activities all contribute to
7 anthropogenic sources of arsenic in the environment. Soil contaminated from mining
8 activities, smelter waste, or agricultural pesticides can have arsenic concentrations higher
9 than naturally occurring levels. Water levels of inorganic arsenic may be elevated
10 through industrial effluents, mining, and smelting. Emissions from mining, smelting,
11 burning fossil fuels, and use of organic arsenic pesticides contribute to elevated levels of
12 arsenic in the air.
1.4.2.4 Considerations of Sources in the Toxicological Review
13 An exposure assessment is beyond the scope of this toxicological review. For the
14 toxicological review, inorganic arsenic is considered to be widespread in the
15 environment, with both natural and anthropogenic sources contributing to total arsenic
16 exposure. Effects of environmental inorganic arsenic exposure will be considered
17 independent from source considerations, such that endpoints will not be attributed to
18 particular natural or anthropogenic sources.
1.4.2.5 Summary of Assessment Parameters for Sources
19 The assessment parameters for sources of inorganic arsenic exposure are summarized
20 below. The rationale for the assessment parameter is described, as is the potential
21 qualitative impact of this decision on the hazard identification.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Assessment Parameters for
Sources
Inorganic arsenic exposure is
widespread.
Effects of inorganic arsenic
exposure will be considered
independent of source.
Rationale
Natural and anthropogenic
sources contribute to inorganic
arsenic exposure.
An exposure assessment is
beyond the scope of the
toxicological review.
Potential Impact on
Toxicological Review
Underestimation of exposure
dose due to data limitations on
inorganic arsenic sources in the
environment.
Potential impact on the utility of
the toxicological review for
complete risk assessments.
1.4.3 Stressors
1.4.3.1 Summary
1
2
3
4
5
6
7
8
9
10
A stressor is a chemical, physical, or biological agent that causes an effect. In this
section, the chemical properties of arsenic are summarized and candidate stressors for the
toxicological review are considered. Based upon several considerations, inorganic arsenic
is selected as the principal stressor in the toxicological review for the determination of
risk metrics. Arsenic speciation was considered, resulting in an assessment parameter that
valence state of inorganic arsenic in the environment is unlikely to impact health effects
from exposure. The potential impacts of these assessment parameters are no estimation of
health effects from environmental exposure to organic arsenic compounds, including
metabolites of inorganic arsenic, and underestimating the potential impact of speciation
on inorganic arsenic toxicity.
1.4.3.2 Chemical Properties
11
12
13
14
15
16
Elemental arsenic, or metallic arsenic, is a steel grey solid with chemical and physical
properties intermediate between a metal and non-metal (IARC. 2009). Arsenic can exist
in 4 oxidation states: -3, 0, +3, or +5. Because of its reactivity, elemental arsenic
(oxidation state 0) is rarely found in the environment (ATSDR. 2007: U.S. EPA. 2006V
Instead, arsenic is often found combined with other elements. These arsenic compounds,
for the purposes of the toxicological review of inorganic arsenic, are organized into three
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1
2
3
4
5
6
7
groups: organic arsenic compounds, arsine gas, and inorganic arsenic compounds (IARC,
2009).
Organic arsenic compounds have arsenic combined with carbon or hydrogen (ATSDR.
2007). Arsine gas specifically refers to AsH3; however, the term arsine is often used to
describe organic arsenic compounds where arsine is combined with aryl or alkyl groups.
Inorganic arsenic compounds are those in which arsenic is combined with other elements
such as oxygen, chlorine, or sulfur (ATSDR. 2007). Some arsenic compounds are shown
in Table 1-3.
Table 1-3 Some Arsenic Compounds in the Environment
Chemical Name
Arsenic
Arsenite
Arsenate
Arsenic trioxide
Arsenic pentoxide
Sodium arsenite
Sodium arsenate
Arsine
Arsenobetaine
Dimethylarsine acid
Methanearsonic acid
Sodium dimethyl arsinate
Sodium methane arsonate
Trimethylarsine
Formula
As
As(OH)3
AsO(OH)3
AS203
AS205
NaAsO2
NA2HAsO4
AsH3
(CH3)3As+CH2CO2~
(Ch3)2HAsO2
Ch3H2AsO3
(CH3)2NaAsO2
CH3NaHAsO3
(CH3)3As
CAS Number
7440-38-2
13464-58-9
7778-39-4
1327-53-3
1303-28-2
7784-46-5
7778-43-0
7784-42-1
64436-13-1
75-60-5
124-58-3
124-65-2
2163-80-6
593-88-4
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1.4.3.3 Stressor Consideration - Organic and Inorganic Arsenic Compounds
1 All three groups of arsenic compounds were considered as candidate stressors for the
2 toxicological review. Based upon toxicological and exposure considerations, as well as
3 Agency partner and public stakeholder needs, inorganic arsenic was selected as the
4 stressor for the toxicological review.
5 Total environmental arsenic consists of both organic and inorganic forms (WHO. 2011;
6 ATSDR, 2007). although toxicity varies between organic and inorganic arsenic
7 compounds. In general, direct exposure to organic arsenic compounds is considered less
8 toxic than inorganic arsenic compounds (WHO. 2011; ATSDR, 2007). Inorganic arsenic
9 is metabolized to organic arsenic in the human body, and some of these organic
10 metabolites may play a role in exacerbating the effects of exposure to inorganic arsenic
11 (WHO. 2011). While some of these organic arsenic metabolites are found in the
12 environment, it can be hypothesized that effects of environmental arsenic exposure are
13 largely attributable to the inorganic arsenic component of total arsenic.
14 Exposure considerations also support selecting inorganic arsenic as the stressor for the
15 toxicological review. For instance, arsine is a highly toxic gaseous organic arsenical, but
16 this volatile compound is unlikely to be found at levels of concern in the environment.
17 Similarly, methylated arsenic compounds are assumed to be a minor component of
18 atmospheric arsenic (WHO. 2000) and inorganic arsenic is the primary form found in
19 drinking water and soil (IARC. 2009; Health Canada. 2006). Dietary exposure to organic
20 arsenic can occur through consumption of fish and shellfish; however, the arsenobetaine
21 or arsenocholine found in fish and shellfish are considered mostly non-toxic (Health
22 Canada. 2006). These factors influenced the decision to consider inorganic arsenic the
23 stressor for the toxicological review.
24 Agency partners and public stakeholders also influenced the consideration of stressors for
25 the toxicological review. Some Agency partners and public stakeholders have indicated
26 that total environmental arsenic is the stressor of concern, while others indicated that
27 certain environmental organic arsenicals (e.g., pesticides or pressure treated wood
28 compounds) influence their risk management decisions. The majority, however,
29 emphasized that effects from inorganic arsenic, as the toxic moiety, are the primary
30 considerations for their risk management decisions. Given the higher toxicity, relevant
31 environmental exposure levels, and risk management needs, the toxicological review will
32 consider inorganic arsenic the stressor of concern.
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1.4.3.4 Stressor Consideration - Inorganic Arsenic Speciation
1 Oxidation state of inorganic arsenic was considered during stressor selection. Inorganic
2 arsenic can be found in different oxidation states depending upon environmental
3 conditions. Arsenic found in soil forms insoluble complexes which are relatively
4 immobile; however, under reducing conditions arsenic may become soluble and enter
5 into ground water (ATSDR. 2007). In an aquatic environment, inorganic arsenic exists
6 primarily as a mixture of two oxidation states. The +5 oxidation state (arsenate or As[V])
7 is the most stable form in an oxygenated environment, whereas the +3 oxidation state
8 (arsenite or As[III]) is the more common in a reducing environment (ATSDR. 2007). In
9 air, inorganic arsenic also exists as a mixture of arsenate and arsenite, although As(V)
10 predominates (IARC. 2009).
11 As the inorganic arsenic species found most frequently in the environment, As(III) and
12 As(V) were considered as candidate stressors. An assessment parameter was established
13 that oxidation state will not impact the toxicity of inorganic arsenic. This assessment
14 parameter is based upon inorganic arsenic metabolism. In the human body, inorganic
15 arsenic is reduced from As(V) to As(III) as the initial step in metabolism. Therefore,
16 environmental exposure to As(V) or As(III) leads to increased levels of As(III) in the
17 human body. Because environmental exposure to As(III) or As(V) leads to increased
18 internal levels of As(III) in humans, it was hypothesized that oxidation state of
19 environmental inorganic arsenic would not significantly impact health effects from
20 exposure.
1.4.3.5 Summary of Assessment Parameters for Stressors
21 This section summarizes the assessment parameters outlined during stressor selection for
22 the toxicological review. The rationales for these assessment parameters are described, as
23 are the potential qualitative impacts of these decisions.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Assessment Parameters for
Stressor
Rationale
Potential Impact on
Toxicological Review
Effects of environmental
exposure to arsenic are largely
attributable to inorganic forms
of arsenic.
Inorganic arsenic forms are
generally more toxic than
organic arsenic compounds;
inorganic compounds are more
prevalent in exposure routes of
concern, and inorganic arsenic is
a risk driver for Agency partners
and public stakeholders.
Overestimation of inorganic
arsenic exposure dose due to
limitations in exposure
characterization (i.e., arsenic
speciation) in human studies.
Oxidation state of environmental
inorganic arsenic will not
significantly impact health
effects from exposure.
Metabolism reduces As(V) to
As(lll); therefore, exposure to
As(V)orAs(lll)willleadto
increased internal dose levels of
As(lll).
Underestimation of impact of
speciation on inorganic arsenic
toxicity.
1.4.4 Exposure Pathways
1.4.4.1 Summary
1
2
3
4
5
6
7
This section considers routes by which inorganic arsenic exposure may occur. Sources of
inorganic arsenic suggest that oral, inhalation, and dermal pathways are all potential
routes of exposure. An assessment parameter is established that inorganic arsenic
exposure occurs through oral, inhalation, or dermal pathways, likely simultaneously. The
potential impact of this assessment parameter is that limitations in inorganic arsenic
exposure data may underestimate the total environmental exposure to inorganic arsenic
and increase uncertainty in estimating exposure to inorganic arsenic.
1.4.4.2 Oral Exposure Pathways of Inorganic Arsenic
8 Oral exposure is the primary route of environmental exposure to inorganic arsenic,
9 occurring through dietary intake of contaminated food or drinking arsenic contaminated
10 water. Inorganic arsenic is found in meats, poultry, dairy products and cereal (IARC.
11 2009). In young children, oral exposure to inorganic arsenic may occur through hand-to-
12 mouth activity with contaminated soil. Naturally occurring levels of inorganic arsenic in
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 soil are approximately 5 mg/kg, but can range from 1 mg/kg to 40 mg/kg depending upon
2 the geological formation. In addition, certain foods grown in soil containing inorganic
3 arsenic have been shown to concentrate arsenic. For the general population within the
4 United States, the hypothesized primary route of exposure is dietary intake.
5 Surface water generally contains less than 10 (ig/L of arsenic; however, concentrations
6 can vary depending upon proximity to anthropogenic or natural sources of arsenic. Levels
7 of inorganic arsenic in water can exceed 1,000 (ig/L in regions with arsenic-rich
8 geological formations. For populations living in these regions, drinking groundwater or
9 well-water contaminated with arsenic could contribute to inorganic arsenic exposure
10 (IARC. 2009). In addition, preparation of food in water containing inorganic arsenic
11 could also increase arsenic content of food. Exposure to high levels of inorganic arsenic
12 in drinking water has been documented in several regions of the world, including China,
13 Taiwan, Bangladesh, and South America. In the United States, that average inorganic
14 arsenic content of drinking water is 2 (ig/L, although 12% of water supplies from surface
15 water in the central United States and 12% of ground water sources in the western United
16 States exceed 20 (ig/L (ATSDR. 2007).
1.4.4.3 Inhalation Exposure Pathways of Inorganic Arsenic
17 For the general population, inhalation of inorganic arsenic from air is not a primary route
18 of exposure. Exposures range from 0.02-0.6 (ig/day in areas without substantial inorganic
19 arsenic emissions from anthropogenic sources. Higher levels of inhalation exposure to
20 inorganic arsenic are observed in more "polluted" areas, and smokers can reach up to
21 10 (ig/day of arsenic exposure PARC. 2009: ATSDR. 2007).
22 Inhalation is the principal route of exposure in occupational exposure settings. Industries
23 with potential inorganic arsenic exposure include smelting, coal-fired power plants,
24 pressure-treated wood, glass manufacturing, and electronics industry. It is likely that
25 ingestion and dermal exposure occurs simultaneously in certain occupational settings
26 (IARC. 2009).
1.4.4.4 Dermal Exposure Pathways of Inorganic Arsenic
27 Evidence of dermal exposure to inorganic arsenic in humans is limited, although
28 evidence in animals does suggest that dermal exposure has toxicological effects (ATSDR,
29 2007). Dermal exposure to inorganic arsenic has been investigated as a route of exposure
30 in occupational settings, although these dermal exposures are most likely concurrent with
31 inhalation and oral exposure. Although inorganic arsenic is widespread at low-levels in
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 the soil, it usually forms insoluble complexes with iron, aluminum, or magnesium oxide
2 in soils surfaces which are relatively immobile and poorly absorbed in humans (ATSDR.
3 2007). Thus, exposure through inhalation or ingestion would likely remain predominant
4 exposure routes.
1.4.4.5 Exposure Pathways for the Toxicological Review
5 For the purposes of the toxicological review, oral, inhalation, and dermal routes of
6 exposure will be considered as contributors to environmental inorganic arsenic exposure.
7 This assessment parameter is based upon the available exposure data as well as Agency
8 partner and public stakeholder needs for the toxicological review.
9 Sources of environmental inorganic arsenic suggest that oral, inhalation, and dermal
10 routes of exposure are all possible. Oral exposure, either through dietary exposure or
11 drinking water exposure, is the primary source of exposure. Inhalation exposure to
12 inorganic arsenic, either in occupational settings or in locations with high levels of
13 arsenic emissions, likely contributes to overall exposure to inorganic arsenic. Although
14 dermal exposure data is limited, the presence of inorganic arsenic in soils and building
15 materials suggest that dermal exposure is likely a contributor to overall environmental
16 arsenic exposure. In addition, Agency partners and public stakeholders have requested
17 that oral, inhalation, and dermal routes of exposure be evaluated in the toxicological
18 review.
1.4.4.6 Summary of Assessment Parameters for Exposure Pathways
19 This section of the conceptual model summarizes the assessment parameters outlined
20 during evaluation of the exposure pathways for inorganic arsenic. The rationale for the
21 assessment parameter is described, as is the potential qualitative impact of this decision
22 on the hazard identification.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Assessment Parameters for
Exposure Pathways
Rationale
Potential Impact on
Toxicological Review
Oral, inhalation, and dermal
exposure pathways all
contribute to environmental
inorganic arsenic exposure.
Sources of environmental
inorganic arsenic indicate
potential for oral, inhalation, and
dermal exposure; Agency
partner and public stakeholder
requested all three routes of
exposure be considered.
Underestimating exposure dose
due to limitations in exposure
characterization data based
upon route of exposure which
would limit dose estimation.
1.4.5 Receptors
1.4.5.1 Summary
1
2
3
4
5
6
7
A receptor is the population exposed to inorganic arsenic. Characterization of a receptor
also includes consideration of life stages or susceptible populations that may have
increased sensitivity to inorganic arsenic. This section outlines the decision to focus the
toxicological review of inorganic arsenic on human health effects. With respect to
susceptibility, an assessment parameter is made that considers the early life period a
susceptible life stage for exposure to inorganic arsenic. The potential impact of this
assessment parameter is to underestimate the health impact of subsequent inorganic
arsenic exposure in individuals exposed during perinatal development.
1.4.5.2 Receptor Considerations for the Toxicological Review
9 Inorganic arsenic is widespread in the environment and it is possible that inorganic
10 arsenic exposure could impact both human health and ecosystems. The toxicological
11 review of inorganic arsenic will focus on human health impacts of inorganic arsenic
12 exposure. This decision is based on toxicological considerations as well as Agency
13 partner and public stakeholder needs.
14 Based upon the available data, humans are more sensitive to inorganic exposure than
15 animals. Interspecies metabolism differences likely explain the differences in toxicity
16 between animals and humans, with animals requiring higher exposure doses to reach
17 internal doses of inorganic arsenic comparable to those observed in humans. At
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1 environmental exposure levels of inorganic arsenic, humans are likely to be the most
2 sensitive species. In addition, the toxicological review is expected to provide scientific
3 support for risk management decisions. These decisions are generally based on human
4 health impacts of chemical exposure; therefore, focusing on human health effects of
5 inorganic arsenic exposure will ensure that the toxicological review meets Agency
6 partner and public stakeholder needs.
1.4.5.3 Consideration of Susceptible Life Stages and Populations
7 Several factors may modify the association between exposure to inorganic arsenic and
8 health outcomes among potentially susceptible populations. These factors can be
9 considered in three broad categories: life stage, human variability, and environmental
10 factors. Modification by life stage postulates that inorganic exposure at a particular life
11 stage (e.g. in utero or geriatric) may have an exacerbated impact compared to exposure
12 during other life stages. Modification due to human variability postulates that certain
13 human populations are more sensitive to inorganic arsenic exposure. For example, such
14 human populations may be characterized by particular socioeconomic or genetic traits
15 which modify their response to inorganic arsenic. Environmental factors, such as diet,
16 smoking, alcohol consumption, and exposure to mixtures, could also serve as at-risk
17 factors by potentially exacerbating the effects of inorganic arsenic through co-exposures
18 or epigenetic mechanisms.
19 Based on available health effect data on in utero exposures, the toxicological review will
20 consider early life of human development a susceptible life stage. To identify other
21 susceptible life stages and populations, the potential impact of life stage, human
22 variability, and environmental factors will be evaluated using a strength of evidence
23 framework. As shown in Table 1-4, evidence across scientific disciplines will be
24 evaluated to examine coherence of effects and determine biological plausibility. The
25 collective results will be used to determine if a particular factor increases effects from
26 inorganic arsenic exposure. When data are available to identify populations or life stages
27 potentially at increased risk to inorganic arsenic exposure, these populations or life stages
28 will be considered.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Table 1-4 Strength of Evidence Framework for Susceptibility
Descriptor*
Strength of Evidence Considerations9*
Adequate Evidence
There is substantial, consistent evidence within a discipline to conclude that a
factor results in a population or life stage being at increased risk of inorganic
arsenic-related health effect(s) relative to some reference population or life
stage. Where applicable this includes coherence across disciplines. Evidence
includes multiple high-quality studies.
Suggestive Evidence
The collective evidence suggests that a factor results in a population or life stage
being at increased risk of an inorganic arsenic-related health effect relative to
some reference population or life stage, but the evidence is limited due to some
inconsistency within a discipline or, where applicable, a lack of coherence across
disciplines.
Inadequate
evidence
The collective evidence is inadequate to determine if a factor results in a
population or life stage being at increased risk of an inorganic arsenic-related
health effect relative to some reference population or life stage. The available
studies are of insufficient quantity, quality, consistency, and/or statistical power
to permit a conclusion to be drawn.
Evidence of
no effect
There is substantial, consistent evidence within a discipline to conclude that a
factor does not result in a population or life stage being at increased risk of
inorganic arsenic-related health effect(s) relative to some reference population
or life stage. Where applicable this includes coherence across disciplines.
Evidence includes multiple high-quality studies.
*Adapted from the Integrated Science Assessment for Lead (U.S. EPA, 2013)
1.4.5.4 Summary of Assessment Parameters for Receptors
1 This section summarizes the assessment parameters described for identifying the receptor
2 for the toxicological review. The rationales for the assessment parameters are described,
3 as are potential qualitative impacts of these decisions.
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Assessment Parameters for
Receptors
Rationale
Potential Impact on
Toxicological Review
The toxicological review will
focus on human health
effects.
Humans are more susceptible to
inorganic arsenic exposure than
animal species; human health effects
are the driver for risk management
decisions
Underestimate the impact of
inorganic arsenic on ecosystems
(not applicable to the
toxicological review).
Populations or life stages
with increased sensitivity to
inorganic arsenic exposure
will be considered
susceptible.
Life stages, intrahuman variability,
and environmental factors may
exacerbate the effects of inorganic
arsenic exposure.
Underestimate the impact of
exposure to inorganic arsenic
due to insufficient data on
susceptible populations.
Early life period of human
development as a
susceptible life stage.
Emerging data in humans, as well as
animal data, suggest that in utero
exposure to inorganic arsenic may
have lasting impacts.
Underestimate the health impact
of subsequent inorganic arsenic
exposure in individuals exposed
during perinatal development.
1.4.6 Endpoints
1.4.6.1 Summary
1
2
3
4
5
6
7
8
9
10
11
12
13
Endpoints are measures of the effects of inorganic arsenic exposure. This section
describes a causality framework for evaluating cancer and noncancer human health
effects data. This section also describes several assessment parameters regarding the
human relevance of health effects data. The first assessment parameter considers health
effects reported in epidemiology studies relevant to humans, regardless of country of
origin. This assessment parameter may result in endpoints included that may be specific
to susceptible populations. A second assessment parameter states that health effects
associated with inorganic arsenic exposure in epidemiological studies with no known
mode of action are relevant to humans. A third assessment parameter states that health
effects due to exposure to inorganic arsenic exposure in animals, in the absence of an
animal-specific mode of action, are relevant to humans regardless of dose. The potential
impacts of these assessment parameters are overestimating the number of health effects
relevant to humans.
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1.4.6.2 Evaluating Health Effects Data
1 The toxicological review of inorganic arsenic will consider health effects data for cancer
2 and noncancer endpoints from subchronic and chronic exposures to inorganic arsenic.
3 Three broad types of studies, if available, will be used to inform human health effects:
4 controlled human exposures, epidemiologic, and toxicological studies. Controlled human
5 exposures provide evidence of health effects following direct exposure, as well as
6 information on the biological plausibility of associations observed in epidemiologic
7 studies. Some study design features of controlled human exposure studies, such as small
8 sample size and short exposure times, are limitations for estimating the effects of lifetime
9 exposure to inorganic arsenic. In addition, controlled human exposures generally include
10 individuals who are relatively healthy, limiting the ability to extrapolate health effects
11 data to the general population or identify potential susceptibilities. Such study design
12 limitations may underestimate the response to inorganic arsenic exposure.
13 Epidemiologic studies report associations between environmental exposure and health
14 effects. Evaluating epidemiologic data requires consideration of several factors. The three
15 factors most likely to impact the evaluation of epidemiologic data on inorganic arsenic
16 are consideration of multiple chemical exposures, exposure measurement error, and effect
17 modification. Inorganic arsenic is likely a component of multipollutant exposures in
18 environmental exposures; therefore the contribution of inorganic arsenic to a health effect
19 in a multipollutant exposure will be an important factor for consideration. Exposure
20 misclassification is uncertainty associated with the measurements used to represent
21 exposure. Epidemiologic studies often do not control chemical exposures and ecological
22 studies often use environmental sources to estimate exposure; therefore, the impact of
23 exposure misclassification on the health effects data for inorganic arsenic is an important
24 consideration. Effect modification occurs when a risk modifier changes the association
25 between exposure and health effect in different subgroups. Effect modification is an
26 important consideration for identifying potential susceptible populations or factors
27 impacting the observed health effects of inorganic arsenic.
28 In vivo toxicological studies in animals provide evidence of health effects under
29 controlled exposure circumstances. For inorganic arsenic health effects data, a significant
30 human database is available. Data from in vivo toxicological studies in animals will
31 likely provide supporting evidence for human data in the toxicological review of
32 inorganic arsenic, except when effects are only observed in in vivo toxicology studies. In
33 such instances, the ability to extrapolate endpoints observed in animals to health
34 outcomes in humans will be evaluated.
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1.4.6.3 Role of Mechanistic Data in Hazard Identification
1 Mechanistic or mode of action data are informative for questions of human relevance,
2 susceptibility, and dose-response relationships. For hazard identification, mechanistic
3 data will be used specifically to address human relevance of the health effects data and
4 for causal determination. Using mode of action data to inform susceptibility and dose-
5 response relationships will be discussed in the next section of the conceptual model
6 (Section 1.4.7- Risk Metrics).
7 The toxicological review will consider health effects data from human studies and animal
8 studies. Health effects reported in epidemiology studies will be considered relevant to
9 humans, regardless of the country of origin. In addition, human health effects with no
10 known mode of action will be considered relevant to humans. On the basis of these
11 assessment parameters, evaluating mechanistic data for hazard identification is of limited
12 value to inform the human relevance of human health effects data.
13 Conversely, the human relevance of in vivo toxicology data is informed by mode of
14 action data. If health effects are reported exclusively in animal studies, mechanistic data
15 will be used to determine human relevance of these effects. In the absence of mechanistic
16 data indicating a mode of action not relevant to humans, health effects data from in vivo
17 toxicology studies will be considered relevant to humans, regardless of exposure dose.
1.4.6.4 Framework for Causal Determination of Human Health Effect Endpoints
18 The toxicological review will assess relevant health effects data to draw conclusions on
19 the causal relationships between inorganic arsenic exposure and human health effects.
20 Determination of causality will focus on a range of inorganic arsenic exposure doses
21 rather than determining causality at a specific exposure dose. The toxicological review
22 will use a five-level hierarchy to determine causality for health effects (U.S. EPA. 2013).
23 Table 1-5 shows the five causality descriptors for health effects and outlines the weight of
24 evidence considerations for each descriptor. Weight of evidence evaluation will involve
25 evaluation and integration of health effects data, as well as characterization of evidence
26 upon which causal determination is based. This characterization will identify any data
27 gaps which would inform future causal determinations for inorganic arsenic.
28 Determination of causality for health effects corresponds with cancer descriptors for
29 carcinogenic effects (U.S. EPA. 2005): therefore, this causal determination framework
30 will be used for both cancer and noncancer health effects associated with inorganic
31 arsenic exposure.
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Table 1-5 Causal Determination Framework
Descriptor
Causal Determination Considerations
Causal relationship
Evidence is sufficient to conclude that there is a causal relationship with
relevant pollutant exposures (i.e., doses or exposures generally within one to
two orders of magnitude of current levels). That is, the pollutant has been
shown to result in health effects in studies in which chance, bias, and
confounding could be ruled out with reasonable confidence. For example:
(1) controlled human exposure studies that demonstrate consistent effects; or
(2) observational studies that cannot be explained by plausible alternatives or
are supported by other lines of evidence (e.g., animal studies or mode of action
information). Evidence includes multiple high-quality studies.
Likely to be a causal
relationship
Evidence is sufficient to conclude that a causal relationship is likely to exist with
relevant pollutant exposures, but important uncertainties remain. That is, the
pollutant has been shown to result in health effects in studies in which chance
and bias can be ruled out with reasonable confidence but potential issues
remain. For example: (1) observational studies show an association, but
copollutant exposures are difficult to address and/or other lines of evidence
(controlled human exposure, animal, or mode of action information) are limited
or inconsistent; or (2) animal toxicological evidence from multiple studies from
different laboratories that demonstrate effects, but limited or no human data
are available. Evidence generally includes multiple high-quality studies.
Suggestive of a
causal relationship
Evidence is suggestive of a causal relationship with relevant pollutant exposures,
but is limited. For example; (1) at least one high-quality epidemiologic study
shows an association with a given health outcome but the results of other
studies are inconsistent; or (2) a well-conducted toxicological study, such as
those conducted in the National Toxicology Program (NTP), shows effects in
animal species.
Inadequate to infer
a causal
relationship
Evidence is inadequate to determine that a causal relationship exists with
relevant pollutant exposures. The available studies are of insufficient quantity,
quality, consistency, or statistical power to permit a conclusion regarding the
presence or absence of an effect.
Not likely to be a
causal relationship
Evidence is suggestive of no causal relationship with relevant pollutant
exposures. Several adequate studies, covering the full range of levels of
exposure that human beings are known to encounter and considering at-risk
populations, are mutually consistent in not showing an effect at any level of
exposure.
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1.4.6.5 Summary of Assessment Parameters for Endpoints
1 This section summarizes the assessment parameters outlined for evaluating endpoints.
2 The rationales for the assessment parameters are described, as are the potential qualitative
3 impacts of these decisions.
Assessment Parameters for
Endpoints
Rationale
Potential Impact on
Toxicological Review
Health effects data in human
studies are relevant to humans,
regardless of country of origin.
All available health effects data
are considered for hazard
identification and causal
determination. Issues of
susceptibility are addressed in
the dose-response analysis.
Effects observed in susceptible
populations considered relevant
to the general population for
hazard identification.
Human health effects with no
known mode of action are
relevant to humans.
Emerging health effects data
may lack the mechanistic data,
but may be important to human
health. Human health effects are
considered relevant in the
absence of mode of action
information.
Consideration of emerging
health endpoints or health
endpoints with limited
mechanistic data in the hazard
identification.
In the absence of mode of action
data indicating otherwise,
endpoints from animal studies
are relevant to humans
regardless of administered dose.
Animal studies, through study
design advantages, may indicate
effects at particular life stages or
provide insight into progression
of health effects. Animal data
may be important for hazard
identification and dose-
response.
Consideration of emerging
health endpoints which may
have limited data in human
populations. Species
extrapolation will depend upon
available scientific data (e.g.,
dosimetry data).
1.4.7 Risk Metrics
4
5
6
1.4.7.1 Summary
Risk metrics are the measure by which risk is quantified. Although risk characterization
is beyond the scope of the toxicological review of inorganic arsenic, this section
describes how endpoints will be selected for dose-response analysis, as well as the role of
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1 mechanistic data for susceptibility and dose extrapolation. The issues of dose
2 extrapolation and susceptibility will be informed using an adverse outcome pathway
3 framework.
1.4.7.2 Selection of Endpoints for Dose-response
4 Health effect endpoints for which inorganic arsenic exposure is "causal" or "likely
5 causal" will be included in the dose-response analysis (see Table 1-5). Health effect
6 endpoints which have a "suggestive," "inadequate," or "not likely" causal relationship
7 will not be considered for dose-response analysis.
1.4.7.3 Role of Mechanistic Data in Dose-Response Analysis: Adverse Outcome
Pathway Framework
8 Agency partners and public stakeholders recommended evaluating the health effects of
9 inorganic arsenic exposure using an adverse outcome pathway framework. An adverse
10 outcome pathway connects a molecular initiating event to an endpoint at a biological
11 level of organization. The advantage of an adverse outcome pathway is that mechanistic
12 data are organized to answer questions in support of risk assessment decisions. However,
13 mechanistic data or adverse outcome pathways will not be a requirement for evaluating
14 observed health effects due to exposure to inorganic arsenic.
15 In the dose-response analysis of the toxicological review of inorganic arsenic, the adverse
16 outcome pathway will address two considerations. The first consideration is uncertainty
17 in the dose-response analysis. An adverse outcome pathway can identify where data gaps
18 increase uncertainty in the dose-response analyses. The second consideration is
19 variability. Human variability in response to chemical exposure may be due to various
20 factors that affect an individual's or subpopulation's susceptibility (e.g., nutritional
21 status). The adverse outcome pathway can inform how sources of variability (i.e.
22 susceptibility factors) in the mode of action may impact dose-response. For instance, an
23 adverse outcome pathway may identify molecular initiating events to which certain
24 human populations may show additional sensitivity.
25 Adverse outcome pathways for the toxicological review will be developed, if possible,
26 for causal or likely causal health effect outcomes (see Figure 1-2). Effects in this figure
27 are examples and more effects may be attributed to inorganic arsenic. Pathways may also
28 involve more steps. There are two important considerations for the adverse outcome
29 pathway analysis. First, as outlined in the endpoints section, a health effect with no
30 known mode of action is assumed to be relevant to humans. Therefore, human health
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1
2
3
toxicity values would still be derived even in the absence of data on molecular initiating
events. Secondly, regulatory decisions of Agency partners and public stakeholders are
partially based upon the observation of health effects from inorganic arsenic exposure.
Anchor 1
(adverse outcome)
Mode of Action
Anchor 2
(initiating event)
Fecundity
Disease Prevalence
Lethality
Cancer
Noncancer effects
Altered physiology
Disrupted homeostasis
Altered function or
development
Gene activation
Proliferation
Cytotoxicity
Receptor/ligand
interaction
DNA binding
Protein oxidation
Chemical Properties
Population Response
t
Individual Responses
t
Organ Responses
t
Cellular Responses
t
Macro-Molecular
Interactions
t
Metabolism
Inorganic Arsenic
Figure 1-2 General framework for Adverse Outcome Pathway Analyses for
Inorganic Arsenic
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1.4.7.4 Consideration of Exposure Dose: Total Arsenic versus Inorganic Arsenic
1 Exposure misclassification should be considered when evaluating epidemiological studies
2 for dose-response analyses. Ecological studies often lack individual exposure data,
3 instead reporting human exposure using environmental sources. These environmental
4 sources are often estimates of "total arsenic" exposure, a mixture of organic and
5 inorganic forms of arsenic. In addition, ecological exposure metrics are often single
6 measurements, further increasing the challenge of estimating exposure dose.
7 For the purposes of the toxicological review, total arsenic exposure will be considered
8 exposure to inorganic arsenic unless exposure data are available to delineate between
9 inorganic arsenic and total arsenic. This assessment parameter is based on two factors:
10 the geography within which "highly" exposed populations reside and the source of
11 inorganic arsenic exposure. Most of the ecological exposure data comes from populations
12 living in arsenic-rich geographical regions. Generally, in populations with high levels of
13 arsenic exposure, the primary route of exposure is consuming arsenic contaminated well
14 water. Because the primary form of arsenic in ground water from arsenic-rich
15 geographical regions is inorganic arsenic, it is hypothesized that the majority of intake is
16 inorganic arsenic. The potential impact of this assessment parameter is underestimation
17 of inorganic arsenic toxicity, as the level of inorganic arsenic in the source exposure is
18 likely less than the reported levels of "total arsenic."
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1.4.7.5 Summary of Assessment Parameters for Risk Metrics
1 This section summarizes the assessment parameters discussed for dose-response analyses.
2 Rationales for assessment parameters are described, as are potential qualitative impacts of
3 these decisions.
Assessment Parameters for Risk
Metrics
Rationale
Potential Impact on
Toxicological Review
For ecological studies, total
arsenic will be considered
exposure to inorganic arsenic.
Populations studied usually
reside in arsenic-rich
geographical regions and
consume arsenic in drinking
water; inorganic arsenic is the
primary form of arsenic in well-
water from arsenic-rich
geography.
Underestimation of inorganic
arsenic toxicity, as inorganic
arsenic concentration is likely
less than total arsenic level.
1.4.8 Overall Conceptual Model
4 Based upon the assessment parameters outlined in these sections, the overall conceptual
5 model for the toxicological review is presented in Figure 1-3. Black lines indicate
6 relationships that will be considered in the toxicological review, whereas gray lines
7 indicate aspects of inorganic arsenic exposure that are beyond the scope of the
8 toxicological review. This conceptual model may be revised based on as scientific data
9 become available or based on recommendations from Agency partners and public
10 stakeholders.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Sourc
Sources
Natural and anthropogenic
sources contribute
Evidence of arsenic in soil,
air, and water
Stressors
For scientific and risk
management needs,
inorganic arsenic selected as
stressor
Valence state hypothesized
as unlikely to impact toxicity
Exposure Pathways
Exposure to inorganic arsenic
can occur through oral,
inhalation and dermal
pathways
Receptors
Humans selected as
receptor
In utero exposure
considered susceptible
life stage
Endpoints
Human study data are
relevant to humans,
regardless of country
Effects with no known mode
of action are relevant to
humans
Risk Metrics
"Causal" and "likely causal"
endpoints for dose response
Adverse outcome pathway
will inform dose-response
analysis
"Total arsenic" considered
as exposure dose of
inorganic arsenic
e: Adapted from NRC (2009)
Natural Sources Anthropogenic Soi
i
Food/ Soil Air V
1 ' \
\ , \
Arsinegas Organic Arsenic Inorgar
i 1
I 1
1 1
Dermal Inhalation (
II '
L 1
1 1 1
1 1
Ecosystem Humans Ir
1
1 1
Cancer Health Effects Noncancer Healtl"
1 1
Causal Determination
1
Adverse Outcome Pathway
i
Dose-Response Analyses
jrces
Vater
lie Arsenic
Dral
i utero
i Effects
Figure 1-3 Overall Conceptual Model for Toxicological Review of Inorganic Arsenic
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1.5 Analysis Plan for the Toxicological Review
1 This analysis plan is the implementation plan for developing the toxicological review of
2 inorganic arsenic. The analysis plan expands on the conceptual model framework,
3 describing approaches for evaluating the relationships outlined in the conceptual model.
Key Points - Analysis Plan
The analysis plan is the implementation plan for the toxicological review
Describes approaches to evaluate the relationships outlined in the conceptual model
Flexible framework that can be modified during development of the toxicological
review
Revised in response to NRC recommendations in the interim report "Critical Aspects
of EPA's IRIS Assessment of Inorganic arsenic"
4 Like the conceptual model, the analysis plan has been revised in response to NRC
5 recommendations in the interim report "Critical Aspects of EPA's IRIS Assessment of
6 Inorganic arsenic" (NRC, 2013). The analysis plan provides proposed EPA responses to
7 NRC recommendations. When a NRC recommendation may impact multiple sections of
8 the analysis plan, the proposed EPA responses are provided in all of the relevant sections
9 of the analysis plan. The analysis plan can be further modified as data become available,
10 if novel relationships become apparent during data analysis, and to implement advances
11 in human health assessment methodology.
1.5.1 Approaches to Source Considerations
12 An exposure assessment is beyond the scope of the toxicological review. For the
13 purposes of the toxicological review, inorganic arsenic will be considered widely
14 distributed throughout the environment; specific natural or anthropogenic sources of
15 inorganic arsenic in soil, air, or water will not be considered. Aspects of source
16 characterization, however, are important considerations for estimating exposure to
17 inorganic arsenic. For the purpose of estimating total daily exposure, the NRC report
18 (NRC. 2013) indicates that delineation of exposure sources (e.g., drinking water, diet,
19 etc.) should be characterized, preferably utilizing probabilistic approaches.
20 In response to the NRC recommendation, EPA will evaluate in a qualitative and, where
21 possible, quantitative manner relationships between exposure source and biomarkers of
22 exposure. The EPA evaluations will focus on delineating exposures to inorganic arsenic
23 versus other forms (e.g., MMA, DMA,), with emphasis on characterizing the contribution
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1 of specific foods (e.g., rice, fruit juices). Where possible a range of estimates regarding
2 the contribution of unique sources of inorganic arsenic based upon an average
3 background exposure should be evaluated as well as identification of where the lack of
4 scientific information exists (i.e., data gaps). All studies conducted in the United States
5 population and other populations (e.g., Taiwan, Bangladesh, etc.) will be evaluated for
6 hazard identification and a determination may be made as to whether or not an
7 adjustment is warranted in estimating potency in the United States population.
8 Additionally, the available scientific information should be characterized for the
9 bioavailability of inorganic arsenic in various media (e.g., soil, water, foodstuffs, etc.).
1.5.1.1 Supplementary Materials Related to Source Considerations
10 Supplementary materials for source consideration will be source characterization
11 summary reports. These reports will characterize, based upon available data, the range of
12 background exposures to inorganic arsenic. Background exposures to inorganic arsenic
13 shall include all potential sources of exposure to inorganic arsenic, including but not
14 limited to dietary, inhalation, oral, and dermal exposures. The source characterization
15 summary reports shall be updated as new data become available. The data used to create
16 source characterization summary reports shall be organized and maintained on EPA's
17 HERO database (http://hero.epa.gov/).
18 Based upon NRC recommendations, the source characterization summary reports will
19 focus on background exposures to inorganic arsenic for the United States population. If
20 necessary, source characterization summary reports may be generated for non-United
21 States populations, based upon available data.
1.5.2 Approaches to Stressor Considerations
22 For the purposes of the toxicological review, different oxidation states of inorganic
23 arsenic will be considered to have the same biological effect. This assessment parameter
24 is based upon the metabolism of inorganic arsenic, which reduces As(V) to As(III) in
25 humans. Therefore, environmental exposure to As(V) or As(III) will result in increased
26 internal concentrations of As(III). As exposure to inorganic arsenic in either oxidation
27 state results in increased As(III), inorganic arsenic (either in the +3 or +5 oxidation state),
28 is the principle stressor for the toxicological review.
29 The toxicological review shall summarize potential impact of chemical properties on the
30 toxicological effects of inorganic arsenic exposure. Potential chemical properties could
31 include forms of arsenic in the environment (e.g., organic or inorganic) or oxidation
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1 states of the exposure compounds. Inorganic arsenic is metabolized to organic arsenic in
2 the human body; therefore, health effects of inorganic arsenic exposure data will be
3 informed by data on organic arsenic metabolites. Analysis of organic arsenic metabolite
4 data will be used to address specific hypothesis regarding the effects of inorganic arsenic
5 exposure. For instance, metabolite data may serve as a biomarker of exposure or inform
6 adverse outcome pathway analyses. In addition, uncertainty with respect to the stressor
7 (e.g., potential levels of organic arsenicals in exposure dose) will be considered
8 qualitatively and/or quantitatively in dose-response analyses. The health effects of
9 environmental exposure to organic arsenic compounds are beyond the scope of the
10 toxicological review.
1.5.3 Approaches to Exposure Pathway Considerations
11 The toxicological review will characterize pathways of exposure to inorganic arsenic.
12 Exposure pathways are processes by which a receptor is exposed to the stressor. For the
13 purposes of the toxicological review, inorganic arsenic exposure will be considered as
14 occurring through oral, inhalation, and dermal routes, and in some exposure scenarios,
15 simultaneously. A critical aspect of exposure pathway considerations is capability to
16 estimate exposure dose and/or internal dose based on available data. EPA will evaluate
17 the feasibility for qualitative and quantitative analyses based upon the available data and
18 physiologically based pharmacokinetic (PBPK) models. In the absence of exposure data
19 for particular exposure route, the contribution of the route of exposure will be considered
20 as naturally occurring levels of inorganic arsenic. For instance, if exposure data are
21 available for dermal and oral exposure only, then inhalation exposure would be estimated
22 at naturally occurring levels of inorganic arsenic.
23 Another important aspect of exposure pathway consideration is exposure
24 misclassification. Studies may report arsenic concentrations for a particular route of
25 exposure (e.g., drinking water), but not consider contribution from other sources such as
26 dietary or inhalation exposure. Studies may report arsenic exposure concentrations from a
27 particular source (e.g., community water supply) rather than individual exposure levels.
28 Furthermore, these source concentrations may be estimated from samples taken over a
29 limited period of time and extrapolated to lifetime exposures. Therefore, studies with
30 exposure data on individuals are hypothesized to introduce less uncertainty into
31 associations between health effect and inorganic arsenic.
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1.5.3.1 Supplementary Materials Related to Exposure Pathways
1 Supplementary materials for exposure pathway considerations will include (1) a survey
2 of available PBPK and/or toxicokinetic models for inorganic arsenic, (2) evaluate the
3 applicability of PBPK models to estimate biomarkers of exposures such as inorganic
4 arsenic and/or its metabolites levels in urine, (3) use PBPK model(s) for the forward
5 estimation of biomarkers of exposures (e.g. urine levels) and reverse calculations of total
6 ingested inorganic arsenic levels related to risk-estimated biomarkers, and (4) feasibility
7 study for modifying adult mouse PBPK model for developmental exposures to inorganic
8 arsenic.
9 The survey of available PBPK models for inorganic arsenic will be used to determine the
10 capability for qualitatively or quantitatively estimating exposure dose and/or internal dose
11 based on available epidemiological data. Similarly, a reverse dosimetry model using
12 internal biomarker concentrations would inform estimates of exposure misclassification
13 from available drinking water exposure data.
14 The NRC, as well as Agency partners and public stakeholders, indicated that an
15 important consideration for the toxicological review is developmental exposure to
16 inorganic arsenic. In response to these recommendations, EPA shall perform a feasibility
17 study on modifying an adult mouse PBPK model (Gentry et al., 2004) for inorganic
18 arsenic for developmental exposure. This model shall estimate inorganic arsenic and its
19 metabolites levels in prenatal and postnatal tissues in mice. Depending on availability of
20 literature data, a scale up developmental PBPK model will also be considered for a
21 humans. This study will determine (1) availability of human or animal physiological
22 parameters and data for developing fetus and preweened offspring, (2) possibility of
23 inorganic arsenic transport and metabolism in placental and fetal tissues, (3) availability
24 of information to estimate metabolic and transport kinetics in placental and fetal tissues if
25 needed, (4) availability of data and information on exposure and toxicokinetics of
26 inorganic arsenic in lactating pups. Based on this feasibility study, EPA will develop a
27 summary of the added value for constructing a mouse developmental exposure PBPK
28 model to inform the health assessment of inorganic arsenic, including the arguments for
29 and against construction of the developmental PBPK model for mice and humans.
30
1.5.4 Approaches to Receptor Considerations
31 Receptors are populations, including life stages, which are exposed to the stressor. For
32 the purposes of the toxicological review, the receptor selected was humans. Potential
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 human receptors include the general population and populations that may be at increased
2 risk to inorganic arsenic exposure because of certain factors (e.g., diet, pre-existing
3 diseases, smoking, alcohol consumption, exposure to mixtures, and life stages). The
4 toxicological review will evaluate human populations and life stages for susceptibility
5 using a strength of evidence framework. This framework evaluates data across scientific
6 disciplines to determine if a factor results in a population or life stage being at increased
7 risk of exposure to inorganic arsenic.
8 A reference population is necessary for comparisons to susceptible populations. The
9 reference population for the toxicological review will be the United States population. As
10 part of characterizing the reference population, EPA will examine potential associations
11 between drinking water exposure and health effect endpoints (e.g., mortality, bladder
12 cancer, cardiovascular disease, diabetes) in the United States. There are potential impacts
13 for selecting as a reference receptor the United States population. The United States
14 standard of living, including access to health care and ability to relocate from
15 environmental sources of exposure, could also lead to a healthier population with fewer
16 health effects relative to other countries or nationalities. In addition, the United States
17 population consists of several ethnic groups, which may limit the ability to determine the
18 impact of genetic susceptibility or ethnicity on health effects from inorganic arsenic
19 exposure.
20 Identification of susceptible life stages requires comparison of effects with a reference
21 life stage. Life stages will be categorized, where possible, on the basis of biological
22 development rather than age ranges. The reference life stage for the toxicological review
23 will be sexually mature adults. The toxicological review will consider early-life as a
24 susceptible life stage in humans.
25 Receptor considerations are also important for dose-response analyses. Factors, such as
26 smoking, life stage, or underlying disease, may increase susceptibility relative to the
27 reference population. EPA will develop sensitivity analyses to determine how receptor
28 considerations impact dose-response analyses for inorganic arsenic.
1.5.4.1 Supplementary Materials Related to Receptors
29 Supplementary materials for receptor considerations will include (1) receptor evidence
30 tables, (2) receptor sensitivity analyses, and (3) an analysis of potential associations
31 between drinking water exposure to inorganic arsenic exposure and health effect
32 endpoints. The data used to create these supplementary materials will be available on
33 EPA's HERO database (http://hero.epa.gov/').
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 Receptor evidence tables will summarize the available evidence considered during
2 evaluation of potential receptors for the IRIS toxicological review of inorganic arsenic.
3 At a minimum, these tables will include the relevant bibliographic information,
4 description of study design/quality, reported effects of inorganic arsenic exposure, and
5 dose-response information. These tables will be updated as new data become available.
6 Receptor sensitivity analyses will inform how receptor considerations impact dose-
7 response analyses for inorganic arsenic. Receptor considerations for sensitivity analyses
8 will include, but are not limited to, smoking synergism size effect for health effects
9 associated with inorganic arsenic.
10 Analyses examining the potential associations between drinking water exposure and
11 health effect endpoints in the United States will also be provided as supplementary
12 material. Endpoints may include, but are not limited to, mortality, bladder cancer,
13 cardiovascular disease, and diabetes. These data will inform comparisons of susceptible
14 populations with the general population of the United States.
1.5.5 Approaches to Endpoint Considerations
15 Endpoints are measures of the health effects of exposure to inorganic arsenic. Potential
16 endpoints associated with exposure to inorganic arsenic to be considered in this
17 toxicological review include both cancer and noncancer health effects.
18 The endpoint evaluation process for inorganic arsenic includes multiple steps. The first
19 step is identification of available literature relevant for hazard identification. After
20 identifying the relevant literature, risk of bias (internal validity) evaluations will be
21 performed using the draft approach developed by the National Toxicology Program
22 (NTP) Office of Health Assessment and Translation (OHAT) (NTT. 2013). Studies and
23 risk of bias evaluations will inform strength of evidence determinations on the causal
24 relationships between inorganic arsenic exposure and particular health effects. Based
25 upon the causal determinations, particular health endpoints will be considered for dose-
26 response analysis (see Section 1.5.6 - Approaches to Risk Metric Considerations).
1.5.5.1 Approaches to Endpoint Considerations - Identifying Relevant Literature
27 EPA is committed to evaluating the available literature on inorganic arsenic by
28 incorporating elements of systematic review. Systematic review is a scientific
29 investigation of a specific question that uses explicit, pre-specified methods to identify,
30 select, summarize, and assess relevant study findings. For the literature search, this
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 involves an iterative process for identifying and selecting relevant scientific information
2 needed to address assessment-specific questions. The systematic review process
3 formulates specific strategies to identify and select studies relating to each question,
4 evaluates study methods based on clearly defined criteria, and transparently documents
5 the process and its outcomes.
6 The initial literature search process for the toxicological review of inorganic arsenic
7 includes: selecting databases of references, defining search terms, documenting search
8 strategies, and a strategy for periodically updating the literature search. In addition,
9 public submissions of relevant studies will be considered during development of the
10 toxicological review. These literature search products will be publicly available through
11 HERO (http://hero.epa. gov/). The end product of this initial literature search process is a
12 comprehensive list of the available scientific literature on inorganic arsenic.
13 Figure 1-4 outlines the overall literature search strategy for the toxicological review.
14 Searches will be conducted using the HERO interface and periodically updated.
15 Databases will be searched using the appropriate forms of the chemical name and CAS
16 number to "cast a wide net." The main databases that will be used in the literature search
17 are PubMed, Web of Science, and Toxline. Duplication records will be removed. The
18 gray lines in Figure 1-4 indicate literature which were removed from the literature search
19 process, whereas the dark lines indicate literature which will be considered during
20 development of the toxicological review.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Databases
PubMed, Web of
, Science, Toxline v
1
De-duplication y X
Not peer-reviewed
Ahctrartc/ nnctorc
Comprehensive List * Review articles
Nnn-Fnplkh
\^ " J
Group references using natural language processing
1
( Periodic ^ Mechanistic Data Cluster
Literature X
^ Searches J f ~\
[Primary Screening
1
Reviewer y
input A C Focused literature ^|
| search;
W ^ full text review J
1
Health Effect Cluster
^
Primary Screening 1
title and abstract \ f ">
tNot considered
for hazard
Secondary "| [_ identification
screening:
full text
X ^
, . . Fit-for-purpose
included in .
. , Review
^ table J |
\
Evidence Tables
\
Risk of Bias Evaluation/ | Not
Fit-for-purpose Review j included in
L table j
Evidence Tables
/
... . .. Causal Determination
inadequate
,,,," Framework
v
Adverse Outcome Pathway
^
Dose Response Analysis
Figure 1-4
Overall Process for Identifying Studies for the Toxicological Review
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 From the comprehensive list of references identified by this literature search strategy,
2 non-peer reviewed articles, abstracts and posters, review articles, and non-English
3 references will be removed from the initial screening. Review articles will be considered
4 in the development of the toxicological review; however, the toxicological review
5 generally evaluates data from primary source material. The remaining references in the
6 considered list will be grouped using natural language processing. A computer algorithm
7 groups references into "clusters" based on similarity in the title and abstract. The
8 clustering process is a tool to organize the arsenic literature database; it is not an
9 exclusion step.
10 References in these clusters will undergo primary screening by title and abstract. The
11 purpose of the primary screening is to categorize studies, it does not exclude studies from
12 consideration. Studies in other categories will be considered, as needed, to address other
13 questions such as toxicokinetics, mode of action, or susceptibility. The categories for the
14 primary screening of the health effect cluster are shown in in the Appendix (Section 1.6,
15 see Table 1-9).
16 Following categorization by title and abstract, studies were further reviewed using full
17 text. The purpose of the full text review was to identify studies that would be relevant to
18 hazard identification for inorganic arsenic. All epidemiologic and toxicological studies
19 identified as likely to contain information supporting hazard identification based on title
20 and abstract review were further characterized to identify characteristics of the study
21 design and the health effects reported in the study. Based upon the full text review,
22 epidemiologic and animal toxicology studies considered relevant to hazard identification
23 were selected for risk of bias evaluations.
24 The literature search for arsenic will be periodically updated. The references identified in
25 the updated literature search will bypass the natural language processing step and enter
26 into primary screening. Similarly, references recommended by Agency partners, public
27 stakeholders, or reviewers will undergo secondary screening, bypassing both natural
28 language processing and primary screening. All of the screening processes will be
29 captured in a publicly available database.
1.5.5.2 Approaches to Endpoint Considerations - Evaluating Risk of Bias
30 Following primary literature screening, studies will be evaluated for potential risk of bias.
31 These risk of bias evaluations are not exclusion criteria, rather, the evaluations will
32 determine the primary literature considered for hazard identification. Although studies
33 with a relatively high risk of bias will not be presented in evidence tables, these studies
34 may be considered supporting evidence for hazard identification. The magnitude and the
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 direction of the bias will be evaluated in order to consider the coherence of findings from
2 these supporting studies, within the context of the full body of evidence.
3 Risk of bias will be evaluated using a modified draft OHAT approach (NTP. 2013). The
4 draft OHAT approach identifies studies and extracts data from all of the available studies,
5 regardless of potential risk of bias. After data extraction, a series of questions addressing
6 selection bias, performance bias, attrition/exclusion bias, detection bias, and selective
7 reporting bias are applied to each study (Table 1-6). Individual studies are assessed for
8 risk of bias on an outcome basis using a 4-point scale (definitely low bias, probably low
9 bias, probably high bias, and definitely high bias). In the next step of the OHAT
10 approach, confidence ratings are developed that the group of studies on a particular
11 outcome reflect the true relationship between exposure to substance and that outcome.
12 Confidence ratings consider study design, factors that decrease confidence (such as risk
13 of bias or indirectness) and factors that increase confidence such as evidence of dose-
14 response or consistency across animal species. These confidence ratings are translated
15 into evidence of health effects and integrated to develop hazard identification
16 conclusions.
17 The toxicological review for inorganic arsenic will evaluate risk of bias using a
18 modification of the OHAT approach. These modifications are necessary because of the
19 different types of questions addressed in evidence-based medicine compared to a
20 toxicological review. For evidence-based medicine, the question addressed is typically
21 narrowly focused in scope, resulting in a smaller literature database for evaluation. In
22 contrast, the scope of an IRIS toxicological review is much broader, addressing potential
23 toxicity in multiple tissue types across a broad dose range for various populations. As a
24 result, the relevant literature database for an IRIS toxicological review of inorganic
25 arsenic is much larger. Effective use of resources to develop a toxicological review
26 incorporating systematic review methods requires modifications to the draft OHAT
27 approach. The draft OHAT approach was modified such that potential risk of bias was
28 determined before extracting data from the studies.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Table 1-6 Example Risk of Bias Considerations
Category
Selection
Performance
Attrition
Detection
Selective Reporting
Bias
Other
Risk of Bias Questions*
1. Was administered dose or exposure level adequately randomized?
2. Was allocation to study groups adequately concealed?
3. Were the comparison groups appropriate?
4. Did the study design or analysis account for important confounding and
modifying variables?
5. Did researchers adjust or control for other exposures that are anticipated to
bias results?
6. Were experimental conditions identical across study groups?
7. Did researchers adhere to the study protocol?
8. Were the research personnel and human subjects blinded to the study group
during the study?
9. Were outcome data complete without attrition or exclusion from analysis?
10. Were the outcome assessors blinded to study group or exposure level?
11. Were confounding variables assessed consistently across groups using valid
and reliable measures?
12. Can we be confident in the exposure characterization?
13. Can we be confident in the outcome assessment?
14. Were all measured outcomes reported?
15. Were there no potential threats to internal validity (e.g., statistical methods
were appropriate)?
*Note, in consultation with OHAT, questions number 7, 9 and 15 were restated from the 2013 draft (NTP. 2013) so that
answering "yes" would consistently indicate lower risk of bias, while answering "no" would indicate higher risk of bias.
1
2
3
4
5
6
Analysis of risk of bias necessarily requires subjective conclusions by an expert scientist.
Thus, to ensure consistency across the evaluators, OHAT drafted guidance for each risk
of bias question to ensure the ratings are applied as objectively and transparently as
possible. Each risk of bias question is assigned one of four standard ratings, ranging from
definitely low risk of bias to definitely high risk of bias (see Table 1-7). The evaluation of
each question depends on the availability of evidence of biased practices.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Table 1-7 General Risk of Bias Ratings
Rating
(++) Definitely Low
risk of bias
(+) Probably Low
risk of bias
(-) Probably High
risk of bias
(- -) Definitely High
risk of bias
Description
There is direct evidence of low risk of bias practices (Direct evidence is an
explicit statement, generally from the study report or through contacting the
authors) (May include specific examples of relevant low risk of bias practices)
There is indirect evidence of low risk of bias practices OR it is deemed by the
risk of bias evaluator that deviations from low risk of bias practices for these
criteria during the study would not appreciably bias results, including
consideration of direction and magnitude of bias (Indirect evidence provides
information to address the risk of bias question but falls short of direct
evidence)
There is indirect evidence of high risk of bias practices OR there is insufficient
information provided about relevant risk of bias practices
There is direct evidence of high risk of bias practices (May include specific
examples of relevant high risk of bias practices)
1.5.5.2.1 Risk of Bias Evaluation Criteria for Epidemiologic Studies
1 For evaluation of the inorganic arsenic literature, each study will be independently
2 evaluated by two scientists who refer to the OHAT Guidance for Assessing Risk of Bias -
3 Appendix 2 (NTP. 2013). After independently reviewing a given study, the two reviewers
4 discuss differences and resolve discrepancies between their ratings.
5 As a starting point, case-control, cohort, and cross-sectional studies were evaluated.
6 Other study types, such as ecological studies, provide less direct support for causal
7 determinations because individual-level exposure information is not used in the analyses.
8 Ecological studies are not excluded from consideration in the overall causal
9 determination for a given health outcome and will be used to provide further support in
10 making causal inferences when other types of studies are not available. Some ecological
11 studies are expected to provide supporting information regarding exposure during
12 sensitive development times (e.g., in utero or childhood exposures) or exposure to
13 susceptible populations. The Appendix (Section 1-6, see Table 1-10) provides additional
14 information used in evaluating risk of bias for inorganic arsenic. The table provides
15 criteria for the risk of bias standard ratings for each OHAT question considered.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1.5.5.2.2 Risk of Bias Evaluation Criteria for Animal Toxicology Studies
1 For evaluation of the inorganic arsenic literature, each study will be independently
2 evaluated by two scientists who refer to the OHAT Guidance for Assessing Risk of Bias -
3 Appendix 2 (NTP. 2013). After independently reviewing a given study, the two reviewers
4 discuss differences and resolve discrepancies between their ratings. The Appendix
5 (Section 1-6, see Table 1-11) provides additional information used in evaluating risk of
6 bias for inorganic arsenic. The table provides criteria for the risk of bias standard ratings
7 for each OHAT question considered.
1.5.5.3 Approaches to Endpoint Considerations - Impact of Risk of Bias on Hazard
Identification
8 Risk of bias evaluations will not be used to exclude studies from consideration. Rather,
9 the risk of bias evaluations will be used to tier studies based on the risk of bias ratings for
10 the individual questions. Data from studies with low risk of bias ratings on many
11 elements will be considered "low risk of bias studies," whereas data from studies with
12 high risk of bias on many elements will be considered "high risk of bias studies."
13 Although "high risk of bias" studies will not have data extracted, these studies will be
14 considered supporting evidence for hazard identification. Data with "low risk of bias"
15 will be extracted and considered principal evidence for hazard identification.
16 Risk of bias determinations will be made using a modified version of the draft OHAT
17 approach (NTP. 2013). In the modified OHAT approach, individual studies will be
18 evaluated using a series of questions. Each question will be scored using a 4- point scale
19 (definitely low bias, probably low bias, probably high bias, and definitely high bias), such
20 that each individual study will have a rating for each of the 15 risk of bias questions. The
21 modified OHAT approach will not produce an "overall" risk of bias rating for each study.
22 The evaluation strategy for setting tiers will be unique depending upon the available
23 database; however, all epidemiologic studies can be evaluated using a single strategy
24 because the same risk of bias questions are applied across all studies. Similarly, all
25 animal toxicology studies can be evaluated using a single strategy.
/. 5.5.3.1 Risk of Bias Tiering for Epidemiologic Studies
26 The evaluation strategy for tiering epidemiologic studies based on risk of bias outlined
27 here is specific for inorganic arsenic. The evaluation strategy for inorganic arsenic is
28 intended to be inclusive; therefore, the evaluation strategy for tiering studies based on
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1
2
O
4
5
6
7
8
9
10
11
12
13
14
15
risk of bias will focus on four elements or risk of bias questions. These four components
will be:
confidence in the observed association based on a study design allowing for
evaluation of association between exposure and outcome
confidence in the exposure characterization
confidence in the outcome assessment
confidence that there were no other threats to internal validity of the study
Of the 15 risk of bias questions evaluated, six were selected as most informative to
address potential risk of bias of the available data. The six questions that will be used for
tiering epidemiologic studies based on the risk of bias are shown below in Table 1-8.
Based upon the risk of bias ratings for these questions, data will be considered either
"low risk of bias" and used for hazard identification or "high risk of bias" and used to
support hazard identification conclusions. Potential scenarios for responses to the six
questions located in column 1 result in a determination for risk of bias in the last row
(Tiering data) of Table 1-8.
Table 1-8 Determining data tiers using risk of bias evaluations
OHAT Risk of Bias
Questions
Were the
comparison groups
appropriate?
(Confidence in
observed
association)
Did the study
design or analysis
account for
important
confounding and
modifying
variables?
(Confidence in
observed
association)
Risk of bias ratings
++
or +
++
or +
Any of the
six
questions
isa--
Any of the
six
questions
isa--
Any
Any
Two of the
three
questions
are-
Two of the
three
questions
are-
-
-
Three of
the other
four
questions
are-
Three of
the other
four
questions
are-
No more than one
of the other five
questions
isa-
No more than one
of the other five
questions is -
++or +
++or +
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
OHAT Risk of Bias
Questions
Did researchers
adjust or control
for other exposures
that are anticipated
to bias results?
(Confidence in
observed
association)
Can we be
confident in the
exposure
characterization?
(Confidence in
exposure
characterization)
Can we be
confident in the
outcome
assessment?
(Confidence in
outcome
assessment)
Were there no
other potential
threats to internal
validity (e.g.,
statistical methods
were appropriate)?
(Other Threats to
Internal Validity)
Risk of bias ratings
or +
or +
++
or +
or +
Any of the
six
questions
isa--
Any of the
six
questions
isa--
Any of the
six
questions
isa--
Any of the
six
questions
isa--
Any
_
_
-
Two of the
three
questions
are-
++or +
++or +
-
-
_
_
Any
Three of
the other
four
questions
are-
_
++or +
Three of
the other
four
questions
are-
No more than one
of the other five
questions is -
_
No more than one
of the other five
questions is -
No more than one
of the other five
questions is -
++or +
_
++or +
++or +
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
OHAT Risk of Bias
Questions
Additional
considerations
Tiering data
Risk of bias ratings
Low
risk
of
bias
High Risk
of Bias
High
Risk
of
Bias
High Risk
of Bias
High
Risk
of
Bias
High Risk
of Bias
If one of those
questions is
unintended
exposure and the
study is an
occupational
setting, then
study would be
further
considered for
data extraction.
If exposure
characterization
received a -
because the study
did not measure
arsenic then low
risk of bias
Low risk of bias
If exposure
characterization
received a -
because the study
did not measure
arsenic then the
study would be
further
considered for
data extraction.
Low risk of bias
1.5.5.3.2 Risk of Bias Tiering for Animal Toxicology Studies
1 The evaluation strategy for tiering animal toxicology studies based on risk of bias
2 outlined here is specific for inorganic arsenic. The evaluation strategy for inorganic
3 arsenic is intended to be inclusive; therefore, the evaluation strategy for tiering studies
4 based on risk of bias will focus on two elements of risk of bias questions. These two
5 components will be:
6 confidence in the exposure characterization
7 confidence in the outcome assessment
8 Of the 15 risk of bias questions evaluated, two were selected as most helpful to address
9 potential risk of bias in the available data. The two risk of bias questions that will be used
10 for tiering studies based on the risk of bias are Question 12 and Question 13 (see Table
11 1-7). Based upon the risk of bias ratings for these questions, data will be considered
12 either "low risk of bias" and used for hazard identification or "high risk of bias" and used
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 to support hazard identification conclusions. The following decision criteria were used to
2 distinguish studies based upon risk of bias for the animal toxicology data:
3 Studies receiving ratings of either definitely or probably low risk of bias (i.e., + or
4 ++) for Question 13 and also receiving the same ratings (i.e., + or ++) for at least
5 half of the remaining questions were included as primary evidence for a given
6 health effect.
7 Studies receiving ratings of either definitely or probably high risk of bias (i.e., - or
8 - -) for Question 13 and also receiving ratings of either definitely or probably high
9 risk of bias (i.e., - or - -) for at least half of the remaining questions were judged to
10 pose a high potential risk of bias. These studies were set aside to be reviewed after
11 all other literature.
12 Any studies receiving a rating of definitely high risk of bias (i.e., - -) for Question
13 12 were set aside for additional review.
14 Studies that did not meet any of the above criteria were identified to be included as
15 supporting evidence for a given health effect.
16 All animal studies identified as primary evidence for hazard identification based on the
17 risk of bias evaluation were included in the evidence tables for arsenic.
1.5.5.4 Approaches to Endpoint Considerations - Study Evaluation
18 Risk of bias evaluations will be used to assess internal validity or how credible are the
19 study findings based on study design and conduct. Risk of bias ratings will also be used
20 to tier studies for use later in the evaluation. Individual studies are considered within the
21 context of the full body of evidence for hazard identification, with more weight given to
22 stronger studies with relatively low risk of bias. Studies with high risk of bias ratings on
23 many questions will be considered "high risk of bias" studies and may be used to support
24 findings from studies with relatively low risk of bias, but will not have data extracted.
25 Studies with low risk of bias ratings will be considered "low risk of bias" studies and
26 considered the principal data for hazard identification. Data from low risk of bias studies
27 will be extracted and presented in evidence tables. Evidence tables will present data from
28 studies related to a specific outcome or endpoint of toxicity. At a minimum, these
29 evidence tables will include the relevant information for comparing key features such as
30 study design, exposure metrics, and dose-response information.
31 Evidence tables will serve as an additional method for presenting and evaluating whether
32 the data are fit-for-purpose (i.e., informing hazard identification for inorganic arsenic).
33 For each health effect domain, a series of specific questions or criteria will be developed
34 to help inform the fit-for-purpose, based upon NRC recommendations (NRC. 2013).
3 5 Criteria specific for each health effect domain are needed because experimental design
36 considerations or data analysis techniques may have a greater impact on a particular
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 health effect domain. For instance, a litter design may be important for developmental
2 toxicity studies, but not as important for chronic bioassays. In addition, these specific
3 criteria may focus the hazard evaluation to particular dose ranges or populations for
4 particular health effects.
5 The criteria for these endpoint-specific evaluations will be described for each individual
6 health effect in the hazard identification syntheses. Although, EPA is proposing to
7 modify the OHAT approach (NTP. 2013) by evaluating fit-for-purpose after the risk of
8 bias evaluation, because the use of endpoint or outcome specific criteria is considered
9 critical for fit-for-purpose evaluations. The hazard identification syntheses shall evaluate
10 the available data on individual endpoints associated with exposure to inorganic arsenic,
11 including data presented in evidence tables. Where possible, meta-analyses for hazard
12 identification will be performed and discussed in these synthesis sections.
1.5.5.5 Approaches to Endpoint Considerations - Causal Determination for Hazard
Identification
13 The hazard identification syntheses will draw conclusions on the relationship between
14 inorganic arsenic exposure and individual human health effects, using a causality
15 framework. Causality will be determined across a range of inorganic arsenic exposures
16 using a five-level hierarchy (see Table 1-5). The weight of evidence evaluation will be
17 based on the evaluation and integration of health effects, along with the characterization
18 of evidence upon which the causal determination is based. Aspects of an association that
19 suggest causality are drawn from Hill (1965). elaborated by Rothman and Greenland
20 (1998). and referred to in other risk assessment documents (IOM. 2008; IARC. 2006;
21 U.S. EPA. 2005; HHS. 2004). These aspects are described below. Recommendations
22 from the upcoming NRC IRIS review to evaluate evidence will be also be considered.
23 Greater strength of association lends greater confidence that the association is not due to
24 chance or bias. Strength encompasses not only magnitude of the association, but
25 statistical confidence in effect measure estimates. Higher precision, as reflected by
26 narrow confidence bounds or smaller standard errors, also adds confidence in the
27 observed association.
28 Consistency of the association across studies is another important consideration for
29 causal determination. Observing an association in different study types, study
30 populations, and exposure scenarios makes it less likely that the association is due to
31 confounding or other factors specific to a given study, or is confined to a specific
32 susceptible population. Characterizations of consistency should distinguish between
33 heterogeneity of findings which may be explained (e.g., due to differences in populations,
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 exposure measures, ranges of exposures, potential co-exposures, and other factors
2 specific to the exposure and health outcomes under evaluation) and unexplained
3 variability suggesting potentially spurious findings.
4 Specificity is established when a single cause causes a specific effect. When established,
5 specificity may lend greater confidence in an association; however, the absence of
6 specificity should not detract from an association. For example, many environmental
7 exposures may have carcinogenic action, but all contribute to a single health outcome.
8 Conversely, a single exposure may be linked to a range of health outcomes. Therefore,
9 evaluation of specificity should be considered in context with other criteria when
10 determining causal relationships.
11 Temporality is necessary for an association to be causal. The exposure must precede the
12 health outcome. In terms of epidemiologic studies, temporality is often cited as a main
13 weakness of cross-sectional study designs. However, in evaluating a body of evidence,
14 other study designs which do inform temporality can lend strength to the group of studies
15 as a whole.
16 The exposure-response relationship is another aspect which lends confidence to an
17 observed association. Observing incremental changes in the risk of a health outcome
18 which correspond to incremental changes in the exposure of interest is an argument
19 against a spurious association. In evaluating a body of epidemiologic studies, it may be
20 that any one study only includes a portion of the range of exposure. Piecing together
21 evidence from multiple studies may yield a fuller understanding of the response and the
22 shape of the exposure-response curve over the full range of exposures. Similarly, an
23 observed lack of response in any one study does not imply a lack of an association
24 between exposure and a health outcome.
25 Biologic plausibility, coherence and analogy are addressed when weighing the totality of
26 evidence including human, animal and mode of action. Generally, the association
27 between exposure and a health outcome should be consistent with known scientific
28 principles or other existing information from epidemiology, toxicology, clinical
29 medicine, or other disciplines. A difficulty in applying these aspects is the reliance on
30 current information, or the 'state of the science'. Associations in the epidemiologic
31 literature may be observed well in advance of experiments being performed or insight
32 into mechanism or mode of action, but confidence that an association exists is
33 strengthened by these aspects.
34 The final aspect is the existence of natural experiments, occurring when environmental
3 5 conditions change in such a way as to mimic a controlled experiment or randomized trial,
36 such as a change which reduces exposure. When change in exposure is followed by
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1 changes in the risk of a health outcome of interest, this result provides greater confidence
2 that an association exists.
3 In evaluating epidemiologic studies, consideration of many study design factors and
4 issues must be taken into account to properly inform their interpretation and determine
5 whether observed associations are likely to represent the truth or if there are reasonable
6 alternative explanations (e.g. biases or other threats to internal validity). Such alternative
7 explanations include "reverse causality" where the health outcome precedes exposures,
8 chance, bias (selection bias and information bias) and confounding. These alternatives are
9 considered in the evaluation of the aspects of causality and of the evidence as a whole.
10 Temporality is an essential aspect of causality and ensures that "reverse causation" is
11 unlikely. Chance can always be a potential explanation for the results in any collection of
12 studies but is less likely as more studies are accrued that have similar observations across
13 different settings, study designs and populations. Selection bias may occur when study
14 groups (e.g., exposed and unexposed, cases and controls) are not sufficiently comparable.
15 Selection bias may alter epidemiologic findings when participation or follow-up rates are
16 related to the probability of exposure and to the outcome of interest. Selection bias can
17 lead to either an overestimate or underestimate of risk, and the potential direction and
18 size of the bias must be considered when deciding whether individual studies are given
19 more weight or less weight for a hazard evaluation. Studies where selection bias is less of
20 a concern are typically given more weight.
21 The potential effects of measurement error can lead to information bias. One example is
22 the uncertainty associated with using surrogate exposure metrics to represent the actual
23 exposure of an individual or population. This exposure measurement error can be an
24 important contributor to variability in epidemiologic study results. Exposure
25 measurement error can lead to misclassification that under- or over-estimates
26 epidemiologic associations between exposures and health outcomes, distort exposure-
27 response relationships and widen confidence intervals around effect estimates (i.e.
28 decrease precision). There are several components that contribute to exposure
29 measurement error in epidemiologic studies, including the difference between true and
30 measured concentrations and the use of average population exposure rather than
31 individual exposure estimates. The importance of exposure misclassification varies with
32 study design and is dependent on the spatial and temporal aspects of the available data.
33 For a given set of epidemiologic studies informing a hazard evaluation, results from
34 studies with more accurate exposure estimates (minimizing exposure misclassification)
35 are given more weight, barring other serious design limitations (e.g., selection bias).
36 Generally, exposure misclassification, when nondifferential, results in a bias toward the
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1 null and is a potential explanation for relatively small effect estimates or for variability in
2 results across studies with different degrees of exposure misclassification.
3 Confounding is a type of bias in which the apparent effect of the exposure is distorted
4 because the effect of an extraneous factor is mistaken for or mixed with the actual
5 exposure effect (Rothman and Greenland. 1998). Scientific judgment is needed to
6 evaluate the likely sources and extent of confounding, together with consideration of how
7 well study designs, results, and analyses address potential confounders. The ability to
8 statistically adjust for confounding in an epidemiologic study is dependent on the ability
9 to identify and measure potential confounders. Consistency in reported effect estimates
10 across multiple studies, conducted in various settings using different populations or
11 exposures, can increase confidence that unmeasured confounding is an unlikely
12 alternative explanation for the observed associations. Such consistency also reduces the
13 likelihood of chance as an alternative explanation through the accumulation of a larger
14 body of similar evidence. The observations of exposure-response trends across different
15 studies similarly reduce the likelihood that chance, confounding, or other biases can
16 explain the observed association. Studies in which confounding is a minimal concern are
17 typically given more weight.
18 Although these aspects provide a framework for assessing the evidence, they should not
19 be considered as a simple formula of evidence leading to conclusions about causality
20 (Hill. 1965). In particular, not meeting one or more of the aspects does not automatically
21 preclude a determination of causality. Rather, these aspects are taken into account with
22 the goal of producing an objective appraisal of the evidence, which includes weighing
23 alternative explanations. Scientific judgment is needed to evaluate individual studies and
24 to weigh the overall body of evidence.
1.5.5.6 Approaches to Endpoint Considerations - Evaluation of Toxicological and Mode
of Action Information for Hazard Identification
25 A causal determination for hazard identification may be based entirely on human
26 evidence; however, evidence from animal and mode of action studies can influence the
27 causal determination. Therefore, toxicological and mechanistic data will be considered
28 for hazard identification.
29 Animal studies for hazard identification will be identified by screening the health effect
30 cluster from the comprehensive literature search product, as well as by primary screening
31 of the literature search updates. Toxicological data will be evaluated using the modified
32 approach for risk of bias based upon the draft OHAT approach [(NTP. 2013); see Section
33 5.5.2]. Similar to the epidemiologic studies, risk of bias evaluations will not be used to
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1 exclude studies, rather, these evaluations will be used to inform risk of bias and to tier
2 studies based on risk of bias. Those studies with high risk of bias for multiple elements
3 will be considered supporting evidence and studies with low risk of bias will be
4 considered the principal data for hazard identification. Toxicological data with low risk
5 of bias will be presented for comparison with epidemiologic data in evidence tables. The
6 evidence tables shall contain, at a minimum, relevant information for comparing key
7 features such as study design, sample size, and dose-response information.
8 Mechanistic data will be identified through natural language processing based on
9 previous human health assessments of inorganic arsenic, as well as focused literature
10 searches. For hazard identification, human relevance will be informed by mechanistic
11 data. Mechanistic data will be organized into a qualitative mode of action for each health
12 endpoint. Qualitative mode of action analyses will provide sufficient detail to inform the
13 causal determination for each health effect. Qualitative mode of action analyses will be
14 organized based upon an adverse outcome pathway, but are not intended to inform dose-
15 response analyses. Health effects reported in epidemiologic studies with no known mode
16 of action will be considered relevant to humans. Similarly, if mechanistic data are
17 insufficient to indicate a mode of action is not relevant to humans, effects observed in
18 animal studies will be considered relevant to humans.
1.5.5.7 Supplementary Materials Related to Endpoints
19 Beyond the overview of the literature search product described in the toxicological
20 review, EPA will generate additional materials during the literature search process. One
21 of these products will be a literature search strategy document that provides additional
22 details on the identification and evaluation of literature for hazard identification. This
23 literature search strategy document will describe the identification of references, the use
24 of natural language processing to group studies, and the categorization of references by
25 title, abstract, and/or full text review.
26 Hazard identification summary tables will be provided as supplementary material for
27 endpoint considerations. Hazard identification summary tables provide an overview of
28 the types and numbers of inorganic arsenic studies available for each health effect
29 category. Specific outcomes as reported in the studies are characterized by health effect
30 category, and cancer and non-cancer effects are considered together in the appropriate
31 system. These hazard identification summary tables provide a synopsis of the data
32 considered for hazard identification in the toxicological review.
33 EPA will develop qualitative hypotheses summaries as a starting point for mode of action
34 analyses. These qualitative mode of action hypotheses summaries will briefly present the
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1 available mechanistic data for several potential modes of action of inorganic arsenic.
2 Potential modes of action may include, but are not limited to, apoptosis and cellular
3 proliferation, activation of reactive oxygen species, and changes in gene expression
4 and/or regulation. In addition, tables will be prepared summarizing the available evidence
5 considered during qualitative evaluation of potential modes of action for inorganic
6 arsenic. These summary tables shall be updated as new data become available. The data
7 used to create these summary tables shall be organized and maintained on EPA's HERO
8 database (http: //hero. epa. gov/).
9 The NRC recommended supporting the mode of action analyses for inorganic arsenic-
10 related health effects with microarray data. Available microarray data on inorganic
11 arsenic will be evaluated using the Systematic Omics Analysis Review (SOAR) tool
12 (Mcconnell. 2013). The SOAR evaluation shall be used as guidance for determining if
13 the data are appropriate for consideration in the toxicological review. Microarray
14 evidence considered in the toxicological review will be summarized in tables. At a
15 minimum, these tables should include the relevant bibliographic information, description
16 of study design/quality, SOAR scores, and dose-response information. These tables shall
17 be updated as new data become available. The data used to create these evidence tables
18 shall be organized and maintained on EPA's HERO database (http://hero.epa.gov/).
1.5.6 Approaches to Risk Metric Considerations
19 Risk metrics are measures by which effects of inorganic arsenic exposure are quantified.
20 Dose-response analyses will be developed for cancer and noncancer health endpoints for
21 which inorganic arsenic is "causal" or "likely causal." Mechanistic information and
22 susceptibility will be evaluated for the potential to inform dose-response analyses.
1.5.6.1 Approaches to Risk Metric Considerations - Data Selection for Dose-Response
Analyses
23 Dose-response analyses describe how the likelihood and severity of adverse health effects
24 are related to the amount and condition of exposure. For inorganic arsenic, dose-response
25 analyses will be performed for health effects for which inorganic arsenic is "causal" or
26 "likely causal." The causal determinations required risk of bias and fit-for-purpose
27 evaluations of the available literature for hazard identification. Similarly, these
28 evaluations will determine which data are used for dose-response analyses. These fit-for-
29 purpose criteria will likely be dependent upon the available data for each health effect.
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1 Generally, it is anticipated that dose-response analyses for these health effects will be
2 performed using epidemiologic data. Animal toxicology or in vitro data will provide a
3 mechanistic understanding and interpretation of low dose effects observed in
4 epidemiologic studies. When possible, dose-response analyses will be performed in the
5 range of epidemiologic observations. Therefore, studies examining low-to-moderate
6 levels of inorganic arsenic exposure (i.e., < 100 (ig/L arsenic in drinking water or
7 comparable equivalent) will be prioritized for dose-response analyses. Furthermore,
8 studies characterizing exposure in low-to-moderate range measuring arsenic-exposure
9 biomarkers will be given preference over studies characterizing only water exposure at
10 moderate-to-high arsenic levels. Other factors influencing selection of studies for dose-
11 response analyses may include number of subjects, methods of endpoint assessment,
12 controlling for confounders, and exposure misclassification.
1.5.6.2 Approaches to Risk Metric Considerations - Variability and Uncertainty Analysis
13 Uncertainty and variability represent important components that have been considered to
14 a limited extent in human health assessment. Uncertainty represents unavailable or
15 incomplete information on a specific variable for which the impact on human health
16 toxicity could be described in quantitative analyses if the variable was fully
17 characterized. Variability represents the diversity or heterogeneity of a factor that can
18 impact the response within an individual or across a population. With respect to
19 variability, there are many factors that play a role in determining an individual's risk
20 from exposure, including concurrent background exposures to other chemicals, and the
21 individual's biologic susceptibility due to genetic, lifestyle, health and other factors. In
22 turn, population responses to chemical exposures depend on the distribution of these
23 varying individual determinants in the population. The toxicological review of inorganic
24 arsenic will use mechanistic data to inform the variability and uncertainty
25 characterizations.
1.5.6.2.1 Adverse Outcome Pathway Analysis
26 Dose-response analyses for causal or likely causal cancer and noncancer endpoints will
27 be informed by mechanistic information. Specifically, mechanistic information will be
28 used to inform variability and uncertainty in the dose-response analyses. In addition,
29 mechanistic information could inform interpretation of low dose effects of inorganic
30 arsenic. Mechanistic information for each endpoint will be organized into adverse
31 outcome pathways (see Figure 1-2). Adverse outcome pathways characterize existing
32 scientific information between a molecular initiating event and an adverse outcome for
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 individual and population level responses. The adverse outcome pathway framework will
2 not displace the mode of action framework defined by the Cancer Guidelines (U.S. EPA.
3 2005). but be inclusive of mode of action analyses.
4 The extent to which an adverse outcome pathway can inform dose-response analyses is
5 dependent upon the available mechanistic data. Data may be insufficient to support an
6 adverse outcome pathway for particular health effects. If the mode of action is unknown,
7 the health effect will be considered relevant to humans. Mechanistic data informing
8 adverse outcome pathways will be identified through natural language processing based
9 on previous human health assessments of inorganic arsenic, as well as focused literature
10 searches. These data will be sorted by health effect and organized into the levels
11 corresponding to an adverse outcome pathway. Data gaps preventing a complete adverse
12 outcome pathway will be considered sources of uncertainty.
/. 5.6.2.2 Susceptibility Analyses
13 The adverse outcome pathway structure will be used to inform variability in the dose-
14 response. An analysis of adverse outcome pathways may be useful in characterizing the
15 potential impact of sources of variability for health effects, such as the increased risk for
16 particular key events or adverse outcomes. One potential source of variability is
17 susceptibility. Using an adverse outcome pathway framework, the potential impacts of
18 individual-level factors (e.g., sex, genetic polymorphisms, nutritional status, and cigarette
19 smoking status) and life stages (e.g., in utero and childhood) on inorganic arsenic health
20 effects will be characterized. To qualitatively or quantitatively evaluate contributions of
21 susceptibility to inorganic arsenic health effects, the susceptibility factors will be linked
22 to adverse outcome pathway(s) for each health effect. Qualitatively or quantitatively,
23 these evaluations for susceptibility will inform the selection of the most appropriate dose-
24 response model for individual and population level responses.
1.5.6.3 Approaches to Risk Metric Considerations - Dose-response Modeling
Approaches
25 After organizing the available mechanistic data into an adverse outcome pathway and
26 characterizing potential susceptibilities, dose-response analyses will be performed on
27 endpoints for which inorganic arsenic is "causal" or "likely causal." Probabilistic
28 methods will be incorporated into the dose-response analyses when the necessary data are
29 available. These probabilistic approaches are meant to characterize the uncertainty and
30 variability in the dose-response analysis, including dose estimation, model selection, and
31 individual and population susceptibility.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 The NRC and others have recommended using novel approaches that result in a
2 probabilistic characterization of risk as a function of dose, while incorporating issues of
3 vulnerability. The use of probabilistic approaches to incorporate information on
4 uncertainty and variability into the derivation of human health toxicity values for cancer
5 and non-cancer endpoints will lead to an improved use of the available scientific
6 information as well as promotion of research to characterize these factors. The
7 toxicological review will qualitatively and/or quantitatively consider uncertainty and
8 variability as separate factors impacting the derivation of human health toxicity values.
9 Probabilistic risk assessment approaches to the dose-response analyses for inorganic
10 arsenic will be incorporated in a tiered manner. Each tier is associated with certain
11 assumptions, such that higher tiers relax or eliminate assumptions made in lower tiers.
12 Approaches described in higher tiers will likely require additional sources of information
13 to define relationships that were fixed by assumption in lower tiers. Consequently, while
14 it may be feasible to perform Tier 1 and Tier 2 analyses for most endpoints, the extent to
15 which a Tier 3 analysis can be performed will be highly dependent on the availability of
16 data for factors that impact inter-individual variability.
/. 5.6.3.1 Tier 3 Probabilistic Dose-response Analyses - Inter-Individual Variability
17 In this tier, inter-individual level variability will be characterized when data are available.
18 This approach will evaluate if it is possible to approximate to variability in background
19 parameters via a probability density function, using standard sources of population-level
20 risk data (e.g., CDC disease rate tables, NHANES data, etc.). These analyses will also
21 examine means of integrating distributions of model predictions associated with such an
22 analysis (derived from the distributions of background parameters) with the model-
23 predicted distribution of estimates. For example, through Monte Carlo simulation one
24 might be able to synthesize the variability associated with within-model uncertainty,
25 across-model uncertainty, and inter-individual variability. These analyses may also be
26 used to inform the impacts of susceptibility factors or other co-chemical exposures on the
27 dose-response for inorganic arsenic.
/. 5.6.3.2 Tier 2 Probabilistic Dose-response Analyses - Inter-Model and Inter-Study
Uncertainty
28 The first phase of this tier will involve the implementation of approaches to better
29 characterize between-model uncertainty for data from a given study.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 A weighted model-averaging analysis will be implemented similar to the approach
2 described by Wheeler and Bailer (2009). Model weights will be assigned based on
3 individual model fit statistics obtained from the Tier 1 analysis (e.g., Akaike or Bayesian
4 Information Criteria) and biological considerations (e.g., with respect to the likelihood of
5 a flattening at either the low or high end of the dose-response). Sensitivity analyses will
6 be performed to determine the impact of weight assignments and comparisons will be
7 made with individual model results to assess the extent model averaging can reduce
8 uncertainties in the predictions, even for extrapolated levels of interest. Nonparametric
9 approaches will be implemented where possible and Bootstrap-based methods will be
10 applied to the averaged estimates to provide a more-complete characterization of the
11 uncertainty in the risk or dose estimates obtained from the model averaging approach.
12 The product of this Tier 2 analysis will consist of probability distributions for all the
13 estimates of interest, whether from a single model or a model average aggregate. The use
14 of different models will illustrate the magnitude of the impact of model selection (NRC.
15 2013).
16 To address inter-study uncertainty, when the data are available, meta-analyses of study-
17 specific results will be conducted. A non-parametric (spline-based) analysis will be
18 completed and parametric analyses employing the relative risk models from the
19 bootstrapping and model averaging approaches will also be examined. The goal of that
20 examination, using maximum likelihood approaches, will be to further evaluate the
21 relative merits of those models for risk predictions (especially at extrapolated levels), as
22 well as to evaluate assumptions about population-to-population variability in model
23 parameter values (e.g., background rates, and whether they differ).
/. 5.6.3.3 Tier 1 Probabilistic Dose-response Analyses - Within-model uncertainty
24 Tier 1 consists of fitting a suite of dose-response relative risk models, selecting the best
25 model in accordance with EPA standard BMD guidance (U.S. EPA. 2012). and making
26 life-table-based predictions of risk. This tier evaluates within-model variability and
27 represents the baseline probabilistic risk assessment approach. Study selection will be
28 focused to facilitate the dose-response analyses, and preference may be given to studies
29 with low-to-moderate exposure levels. To the extent possible, dose or exposure
30 uncertainty will be incorporated via Monte Carlo analysis. One aspect of uncertainty
31 relates to the likelihood that doses derived from drinking water alone do not represent the
32 total inorganic arsenic dose. Consideration will be given to the possibility that
33 background exposure differ across study populations. A consistent exposure metric will
34 be required in order to allow comparisons across studies.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 Relative risk models will be run on the datasets available. The analysis will generate
2 summaries with respect to model predictions for points of departure (PODs).
3 Consideration will be given to PODs both within and below the range of observations
4 (dovetailing with the Tier 2 analyses described above).
1.5.6.4 Approaches to Risk Metric Considerations - Extrapolation
5 In previous efforts, extrapolations performed for quantitative dose-response analyses
6 have been controversial. This controversy was recognized in the NRC interim report
7 "Critical Aspects of EPA's IRIS Assessment of Inorganic arsenic" (NRC. 2013). To
8 move the protection of public health beyond debates about the shape of the dose-response
9 curve, the NRC recommended using observed data to characterize dose-response
10 relationships. The NRC recommended limited extrapolation using the modeled shape of
11 the dose-response relationship to provide data-informed estimates of the potential dose-
12 response relationship below the range of observation. Further, the NRC recommended
13 characterizing dose-response relationships down to background levels, which the NRC
14 estimated background concentrations of as 1-5 (ig/L inorganic arsenic in urine for the
15 United States populations. The NRC indicated that the risks posed by background
16 concentrations should be characterized to the extent feasible, but that needs of assessing
17 health risks should be facilitated by characterizing the risk down to background
18 concentrations. Extrapolations in the toxicological review of inorganic arsenic will be
19 informed by these recommendations.
1.6 Appendix of Materials for Evaluating Literature
20 This appendix provides additional details for the identification of literature as well as the
21 evaluation of risk of bias for epidemiologic and toxicology studies. For additional
22 information, details on the approaches to screening and evaluating the literature, please
23 refer to Section 1.5 - Analysis Plan for the Toxicological Review of Inorganic arsenic.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Table 1-9 Categories for Primary Literature Screening
Primary Screening Category
Hazard identification
Episodic exposure/acute exposure
Physical Chemistry/Engineering
Exposure Assessment
Non-arsenic
Non-peer reviewed
Ecology
Review/Risk Assessment/Guidance
document
Study Characteristics
Human studies relevant for hazard identification of chronic
exposure to inorganic arsenic including meta analyses;
animal studies relevant for hazard identification of chronic
exposure to inorganic arsenic.
Poisonings or short-term exposures (up to 30 days) unlikely
to inform chronic health effects of inorganic arsenic
exposure. This category also included case reports and case
series as well as medical uses of arsenic. In some of the case
series, exposure could be longer than acute or short term,
but such studies are categorized here because they are
supportive of the health effects of inorganic arsenic but may
not be as informative for the hazard identification. If the
hazard identification requires further justification, studies in
this category can be reviewed at a later date if necessary.
Studies that examine the chemical properties of arsenic or
use arsenic for chemical engineering.
Studies that only describe the sources/dose of arsenic in the
air, water, food, particulate matter, plant/animal life
(including feed used for livestock that humans consume), and
other media. This includes bioavailability studies for the
different media and studies that measured levels in humans
(e.g., in nails, urine, blood) but did not evaluate any type of
health effect in association with the measurements.
Studies that do not consider arsenic exposure or studies
where arsenic was mentioned but was not the primary focus
of the publication.
Studies that have not undergone peer review (e.g.,
newspaper articles, abstracts, posters, news and views,
opinion papers, editorials, comments and replies to
comments).
Studies that describe the impact of arsenic on non-
mammalian animal models (e.g., fish) or plant life.
References that provide reviews of the available literature or
references that used EPA guidelines to evaluate risk in a
certain area based on exposure levels but did not directly
evaluate health outcomes.
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Primary Screening Category
Study Characteristics
Susceptibility
Studies in which health effects are evaluated based on
factors other than dose (e.g., genetic polymorphisms,
susceptibility due to methylation capacity or genetic markers,
socio-economic factors, ethnicity). If the study also assessed
the effects of inorganic arsenic before assessing the effects of
the susceptibility factors, it was considered for the hazard
identification.
Mode of Action
Studies that examine the molecular events occurring after
inorganic arsenic exposure (e.g., in vitro models, genomics,
proteomics).
PBPK/TK
Papers that examine internal dose metrics, absorption,
excretion, distribution, metabolism, etc. (toxicokinetics orTK)
or detailed physiologically based pharmacokinetic (PBPK)
models that model inorganic arsenic kinetics in humans or
animals.
Other
Additional papers that do not fit in the above categories,
including:
Public health campaigns/community knowledge,
Analytical technique papers that do not include
information on dose metrics or ADME,
Co-exposure studies where inorganic arsenic cannot be
separated,
Effects of a different compound in reversing the health
effects of arsenic,
Arsenic bioremediation or removal of arsenic from
contaminated locations,
Treatment methods for arsenic-induced disease, and
Effects on bacteria that are not related to MOA/bacterial
tolerance.
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Table 1-10 Additional Information for Risk of Bias Determinations for
Epidemiological Studies
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
1. Was administered dose or exposure level adequately randomized?
Human Controlled Trial: There is direct evidence that subjects were allocated to any study group
including controls using a method with a random component. Acceptable methods of
randomization include: referring to a random number table, using a computer random number
generator, coin tossing, shuffling cards or envelopes, throwing dice, or drawing of lots (Higgins et
al., 2008). Restricted randomization (e.g., blocked randomization) to ensure particular allocation
ratios will be considered low risk of bias. Similarly, stratified randomization and minimization
approaches that attempt to minimize imbalance between groups on important factors prognostic
factors (e.g., body weight) will be considered acceptable.
Assessment-specific Clarification: None.
Human Controlled Trial: There is indirect evidence that subjects were allocated to study groups
using a method with a random component (i.e., authors state that allocation was random, without
description of the method used) OR it is deemed that allocation without a clearly random
component during the study would not appreciably bias results. For example, approaches such as
biased coin or urn randomization, replacement randomization, mixed randomization, and maximal
randomization may require consultation with a statistician to determine risk of bias rating (Higgins
etal.. 2008).
Assessment-specific Clarification: None.
Human Controlled Trial: There is indirect evidence that subjects were allocated to study groups
using a method with a non-random component OR there is insufficient information provided about
how subjects were allocated to study groups. Non-random allocation methods may be systematic,
but have the potential to allow participants or researchers to anticipate the allocation to study
groups. Such "quasi-random" methods include alternation, assignment based on date of birth, case
record number, or date of presentation to study (Higgins et al.. 2008).
Assessment-specific Clarification: None.
Human Controlled Trial: There is direct evidence that subjects were allocated to study groups using
a non-random method including judgment of the clinician, preference of the participant, the results
of a laboratory test or a series of tests, or availability of the intervention (Higgins et al., 2008).
Assessment-specific Clarification: None.
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Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
2. Was allocation to study groups adequately concealed?
Human Controlled Trial: There is direct evidence that at the time of recruitment the research
personnel and subjects did not know what study group subjects were allocated to, and it is unlikely
that they could have broken the blinding of allocation until after recruitment was complete and
irrevocable. Methods used to ensure allocation concealment include central allocation (including
telephone, web-based and pharmacy-controlled randomization); sequentially numbered drug
containers of identical appearance; sequentially numbered, opaque, sealed envelopes; or
equivalent methods.
Assessment-specific Clarification: None.
Human Controlled Trial: There is indirect evidence that the research personnel and subjects did
not know what study group subjects were allocated to OR it is deemed that lack of adequate
allocation concealment would not appreciably bias results.
Assessment-specific Clarification: None.
Human Controlled Trial: There is indirect evidence that at the time of recruitment it was possible
for the research personnel and subjects to know what study group subjects were allocated to, or it
is likely that they could have broken the blinding of allocation before recruitment was complete
and irrevocable OR there is insufficient information provided about allocation to study groups.
Note: Inadequate methods include using an open random allocation schedule (e.g., a list of random
numbers), assignment envelopes used without appropriate safeguards (e.g., if envelopes were
unsealed or nonopaque or not sequentially numbered), alternation or rotation; date of birth; case
record number; or any other explicitly unconcealed procedure. For example, if the use of
assignment envelopes is described, but it remains unclear whether envelopes were sequentially
numbered, opaque and sealed.
Assessment-specific Clarification: None.
Human Controlled Trial: There is direct evidence that at the time of recruitment it was possible for
the research personnel and subjects to know what study group subjects were allocated to, or it is
likely that they could have broken the blinding of allocation before recruitment was complete and
irrevocable.
Assessment-specific Clarification: None.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-71 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
3. Were the comparison groups appropriate?
Cohort, Cross-sectional: There is direct evidence that subjects (both exposed and non-exposed)
were similar (e.g., recruited from the same eligible population, recruited with the same method of
ascertainment using the same inclusion and exclusion criteria, and were of similar age and health
status), recruited within the same time frame, and had the similar participation/response rates.
Case-Control: There is direct evidence that cases and controls were similar (e.g., recruited from the
same eligible population including being of similar age, gender, ethnicity, and eligibility criteria
other than outcome of interest as appropriate), recruited within the same time frame, and controls
are described as having no history of the outcome. Note: A study will be considered low risk of bias
if baseline characteristics of groups differed but these differences were considered as potential
confounding or stratification variables (see question #4).
Assessment-specific Clarification: Comparison groups selected adequately. Study provides table of
subject characteristics by exposure levels and/or by case status. Cross-sectional studies can be
considered low risk of bias if a general table of subject characteristics is provided and analyses are
adjusted for confounders.
Cohort, Cross-sectional: There is indirect evidence that subjects (both exposed and non-exposed)
were similar (e.g., recruited from the same eligible population, recruited with the same method of
ascertainment using the same inclusion and exclusion criteria, and were of similar age and health
status), recruited within the same time frame, and had the similar participation/response rates OR
differences between groups would not appreciably bias results.
Case-Control: There is indirect evidence that cases and controls were similar (e.g., recruited from
the same eligible population, recruited with the same method of ascertainment using the same
inclusion and exclusion criteria, and were of similar age), recruited within the same time frame, and
controls are described as having no history of the outcome OR differences between cases and
controls would not appreciably bias results.
Assessment-specific Clarification: Recruitment methods stated to be similar, but no table of
information or text provided on potential differences in study subjects' characteristics that could
bias results, OR no breakdown of subject characteristics by exposure group (or by case status) to
display potential differences.
Cohort, Cross-sectional: There is indirect evidence that subjects (both exposed and non-exposed)
were not similar, recruited within very different time frames, or had the very different
participation/response rates OR there is insufficient information provided about the comparison
group including a different rate of non-response without an explanation.
Case-Control: There is direct evidence that controls were drawn from a very dissimilar population
than cases or recruited within very different time frames OR there is insufficient information
provided about the appropriateness of controls including rate of response reported for cases only.
Assessment-specific Clarification: None.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-72 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Cohort, Cross-sectional: There is direct evidence that subjects (both exposed and non-exposed)
were not similar, recruited within very different time frames, or had very different
participation/response rates.
Case-Control: There is direct evidence that controls were drawn from a very dissimilar population
than cases or recruited within very different time frames.
Assessment-specific Clarification: At least one known difference between the groups was not
accounted for (e.g., the study authors acknowledged that the groups were different with respect to
a variable that is a potential confounder not considered in the analysis), OR recruitment methods
were very different (e.g., recruitment completed during different time frames, different criteria
were used for recruitment).
4. Did the study design or analysis account for important confounding and modifying variables?
Human Controlled Trial, Cohort, Cross-sectional, Case Series/report: There is direct evidence that
appropriate adjustments or explicit considerations were made for primary covariates and
confounders in the final analyses through the use of statistical models to reduce research-specific
bias including standardization, case matching, adjustment in multivariate model, stratification,
propensity scoring, or other methods were appropriately justified. Acceptable consideration of
appropriate adjustment factors includes cases when the factor is not included in the final
adjustment model because the author conducted analyses that indicated it did not need to be
included.
Case-Control: There is direct evidence that appropriate adjustments were made for primary
covariates and confounders in the final analyses through the use of statistical models to reduce
research specific bias including standardization, matching of cases and controls, adjustment in
multivariate model, stratification, propensity scoring, or other methods were appropriately
justified.
Assessment-specific Clarification: Study adjusted for or addressed important potential
confounders. Age, gender, education, and socioeconomic status are potential confounders that
need to be addressed and considered in the study design or analyses. In addition, specific
important confounders for this assessment depend on the health outcome and include smoking for
lung cancer, sun exposure for skin lesions, and alcohol drinking for hepatic outcomes. Other
confounders might also be judged important for certain health outcomes. A low risk of bias rating
was assigned for this question if potential confounders deemed important were adequately
addressed (e.g., distribution of variables was compared between groups, and there was no
statistically significant difference).
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is
indirect evidence that appropriate adjustments were made for most primary covariates and
confounders OR it is deemed that not considering or only considering a partial list of covariates or
confounders in the final analyses would not appreciably bias results.
Assessment-specific Clarification: Study adjusted only for some important potential confounders
(e.g., sex and age), but it is likely that other confounders were present and not addressed (i.e.,
minimal number of confounders addressed).
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-73 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial, Cohort, Cross-sectional, Case Series/report: There is indirect evidence
that the distribution of primary covariates and known confounders differed between the groups
and was not appropriately adjusted for in the final analyses OR there is insufficient information
provided about the distribution of known confounders.
Case-Control: There is indirect evidence that the distribution of primary covariates and known
confounders differed between cases and controls and was not investigated further OR there is
insufficient information provided about the distribution of known confounders in cases and
controls.
Assessment-specific Clarification: Design or analysis did not adjust for important potential
confounders. Adjustments were made for some potential confounders, but at least one major
confounder was not addressed (e.g., no adjustment for smoking when evaluating lung cancer, no
adjustment for sun exposure when evaluating skin cancer).
Human Controlled Trial, Cohort, Cross-sectional, Case Series/report: There is direct evidence that
the distribution of primary covariates and known confounders differed between the groups,
confounding was demonstrated, and was not appropriately adjusted for in the final analyses.
Case-Control: There is direct evidence that the distribution of primary covariates and known
confounders differed between cases and controls, confounding was demonstrated, but was not
appropriately adjusted for in the final analyses.
Assessment-specific Clarification: None.
5. Did researchers adjust or control for other exposures that are anticipated to bias results?
Human Controlled Trial: There is direct evidence that other exposures anticipated to bias results
were not present or were appropriately adjusted for.
Cohort, Case- Control, Cross-sectional, Case Series/report: There is direct evidence that other
exposures anticipated to bias results were not present or were appropriately adjusted for. For
occupational studies or studies of contaminated sites, other chemical exposures known to be
associated with those settings were appropriately considered.
Assessment-specific Clarification: Researchers adjusted for other chemicals or accounted for
occupational exposures likely to be associated with the outcome.
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is
indirect evidence that other co-exposures anticipated to bias results were not present or were
appropriately adjusted for OR it is deemed that co-exposures present would not appreciably bias
results. Note, as discussed above, this includes insufficient information provided on co-exposures in
general population studies.
Assessment-specific Clarification: No evidence that co-exposures were addressed as confounders,
but other specific chemicals or occupational exposures were addressed.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-74 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial: There is indirect evidence that the control group may have received the
treatment or there was an unbalanced provision of additional co-exposures which were not
appropriately adjusted for.
Cohort, Cross-sectional, Case Series/report: There is indirect evidence that there was an
unbalanced provision of additional co-exposures across the primary study groups, which were not
appropriately adjusted for OR there is insufficient information provided about co-exposures in
occupational studies or studies of contaminated sites where high exposures to other chemical
exposures would have been reasonably anticipated.
Case-Control: There is indirect evidence that there was an unbalanced provision of additional co-
exposures across cases and controls, which were not appropriately adjusted for OR there is
insufficient information provided about co-exposures in occupational studies or studies of
contaminated sites where high exposures to other chemical exposures would have been reasonably
anticipated.
Assessment-specific Clarification: There is evidence that co-exposures might not have been
addressed. Examples include a study population with farmers and/or other types of workers but
occupational co-exposures (e.g., to pesticides) not addressed; or a study with known co-exposures,
but the relevance of the co-exposure to inorganic arsenic effects is unknown, or it is not clear if
other compounds were adjusted for in the analyses.
Human Controlled Trial: There is direct evidence that the control group received the treatment or
there was an unbalanced provision of additional co-exposures which were not appropriately
adjusted for.
Cohort, Cross-sectional, Case Series/report: There is direct evidence that there was an unbalanced
provision of additional co-exposures across the primary study groups, which were not appropriately
adjusted for.
Case-Control: There is direct evidence that there was an unbalanced provision of additional co-
exposures across cases and controls, which were not appropriately adjusted for.
Assessment-specific Clarification: Known differential exposure to other chemical/pollutant also
associated with the health outcome of interest occurred with inorganic arsenic, and exposure was
not addressed by study authors. An example is a study of copper smelter workers where the study
authors either (a) list other chemicals likely to be associated with the health outcome that the
subjects were exposed to, or (b) provide levels of the other compounds, AND there were
statistically significant differences related to the inorganic arsenic exposure that were not
addressed. Such differences might have resulted from differential exposure to another compound
or inorganic arsenic; thus, it cannot be determined which exposure impacted the results.
6. Were experimental conditions identical across study groups?
NA
NA
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
7. Did researchers adhere to the study protocol?
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct
evidence that there were no deviations from the protocol (i.e., the study report explicitly provides
this level of detail).
Assessment-specific Clarification: None.
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is
indirect evidence that there were no deviations from the protocol (i.e., authors did not report any
deviations) OR deviations from the protocol are described and it is deemed that they would not
appreciably bias results.
Assessment-specific Clarification: Taking into consideration typical reporting practices, it seems
unlikely that deviations from the protocol will be explicitly reported in most studies. Thus, unless
stated otherwise by the authors (i.e., evidence of deviation is reported), or it is clear from the study
report that deviations from the planned approach occurred, assume that no deviations occurred. It
is anticipated that this approach will result in a rating of "probably low risk of bias" (+) for most
studies. If there are deviations, the rating reflects how the deviations changed direction, magnitude
and/or significance of the results.
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is
indirect evidence that there were large deviations from the protocol as outlined in the methods or
study report.
Assessment-specific Clarification: None.
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct
evidence that there were large deviations from the protocol as outlined in the methods or study
report.
Assessment-specific Clarification: None.
8. Were the research personnel and human subjects blinded to the study group during the study?
Human Controlled Trial: There is direct evidence that the subjects and research personnel were
adequately blinded to study group, and it is unlikely that they could have broken the blinding
during the study. Methods used to ensure blinding include central allocation, sequentially
numbered drug containers of identical appearance; sequentially numbered, opaque, sealed
envelopes; or equivalent methods.
Assessment-specific Clarification: None.
Human Controlled Trial: There is indirect evidence that the research personnel and subjects were
adequately blinded to study group, and it is unlikely that they could have broken the blinding
during the study, OR it is deemed that lack of adequate blinding during the study would not
appreciably bias results.
Assessment-specific Clarification: None.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-76 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial: There is indirect evidence that it was possible for research personnel or
subjects to infer the study group, OR there is insufficient information provided about blinding of
study group. Inadequate methods include using an open random allocation schedule (e.g., a list of
random numbers), assignment envelopes used without appropriate safeguards (e.g., if envelopes
were unsealed or nonopaque or not sequentially numbered), alternation or rotation; date of birth;
case record number; or any other explicitly unconcealed procedure. For example, if the use of
assignment envelopes is described, but it remains unclear whether envelopes were sequentially
numbered, opaque and sealed.
Assessment-specific Clarification: None.
Human Controlled Trial: There is direct evidence for lack of adequate blinding of the study group
including no blinding or incomplete blinding of research personnel and subjects. For some
treatments, such as behavioral interventions, allocation to study groups cannot be concealed.
Assessment-specific Clarification: None.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-77 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
9. Were outcome data complete without attrition or exclusion from analysis?
Human Controlled Trial: There is direct evidence that there was no loss of subjects during the study
and outcome data were complete OR loss of subjects (i.e., incomplete outcome data) was
adequately addressed and reasons were documented when human subjects were removed from a
study. Review authors should be confident that the participants included in the analysis are exactly
those who were randomized into the trial. Acceptable handling of subject attrition includes: very
little missing outcome data (less than 10% in each group); reasons for missing subjects unlikely to
be related to outcome (for survival data, censoring unlikely to be introducing bias); missing
outcome data balanced in numbers across study groups, with similar reasons for missing data
across groups OR analyses (such as intention-to-treat analysis) in which missing data have been
imputed using appropriate methods(insuring that the characteristics of subjects lost to follow up or
with unavailable records are described in an identical way and are not significantly different from
those of the study participants).
NOTE: participants randomized but subsequently found not to be eligible need not always be
considered as having missing outcome data (Higgins et al., 2008).
Cohort: There is direct evidence that loss of subjects (i.e., incomplete outcome data) was
adequately addressed and reasons were documented when human subjects were removed from a
study. Acceptable handling of subject attrition includes: very little missing outcome data; reasons
for missing subjects unlikely to be related to outcome (for survival data, censoring unlikely to be
introducing bias); missing outcome data balanced in numbers across study groups, with similar
reasons for missing data across groups; OR missing data have been imputed using appropriate
methods, AND characteristics of subjects lost to follow up or with unavailable records are
described in identical way and are not significantly different from those of the study participants.
Case-Control, Cross-sectional: There is direct evidence that exclusion of subjects from analyses was
adequately addressed, and reasons were documented when subjects were removed from the study
or excluded from analyses.
Assessment-specific Clarification: There are no reported data lost to attrition, and the numbers in
the results tables sum to the total number of subjects, OR less than 10% of data are missing, OR
there are some missing outcome data but study report clearly identifies missing data and how it
was handled (e.g., loss to follow-up for a cohort study is determined to be minimal if there are
some missing data for either the exposure or outcome for certain subjects at a specific time
measured and the authors clearly explain what happened to everyone and which results were used
in the analyses).
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-78 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial: There is indirect evidence that loss of subjects (i.e., incomplete outcome
data) was adequately addressed and reasons were documented when human subjects were
removed from a study OR it is deemed that the proportion lost to follow-up would not appreciably
bias results (less than 20% in each group). This would include reports of no statistical differences in
characteristics of subjects lost to follow up or with unavailable records from those of the study
participants. Generally, the higher the ratio of participants with missing data to participants with
events, the greater potential there is for bias. For studies with a long duration of follow-up, some
withdrawals for such reasons are inevitable. Cohort: There is indirect evidence that loss of subjects
(i.e., incomplete outcome data) was adequately addressed and reasons were documented when
human subjects were removed from a study OR it is deemed that the proportion lost to follow-up
would not appreciably bias results. This would include reports of no statistical differences in
characteristics of subjects lost to follow up or with unavailable records from those of the study
participants. Generally, the higher the ratio of participants with missing data to participants with
events, the greater potential there is for bias. For studies with a long duration of follow-up, some
withdrawals for such reasons are inevitable.
Case-Control, Cross-sectional: There is indirect evidence that exclusion of subjects from analyses
was adequately addressed, and reasons were documented when subjects were removed from the
study or excluded from analyses.
Assessment-specific Clarification: No direct evidence of loss to follow-up or attrition provided. The
tables of results do not include the number of subjects and it is not stated that there was any loss
data missing. There appear to be no or very few missing data, OR in a cohort study, there is no
mention of loss to follow-up.
Human Controlled Trial: There is indirect evidence that loss of subjects (i.e., incomplete outcome
data) was unacceptably large (greater than 20% in each group) and not adequately addressed OR
there is insufficient information provided about numbers of subjects lost to follow-up. Cohort:
There is indirect evidence that loss of subjects (i.e., incomplete outcome data) was unacceptably
large and not adequately addressed OR there is insufficient information provided about numbers of
subjects lost to follow-up.
Case-Control, Cross-sectional: There is indirect evidence that exclusion of subjects from analyses
was not adequately addressed, OR there is insufficient information provided about why subjects
were removed from the study or excluded from analyses.
Assessment-specific Clarification: Missing outcome data with no explanation of why data was
missing, and it is unclear from the characteristics table or other information provided in the report
why the data might be missing.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-79 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial, Cohort: There is direct evidence that loss of subjects (i.e., incomplete
outcome data) was unacceptably large and not adequately addressed. Unacceptable handling of
subject attrition includes: reason for missing outcome data likely to be related to true outcome,
with either imbalance in numbers or reasons for missing data across study groups; or potentially
inappropriate application of imputation.
Case-Control, Cross-sectional: There is direct evidence that exclusion of subjects from analyses was
not adequately addressed. Unacceptable handling of subject exclusion from analyses includes:
reason for exclusion likely to be related to true outcome, with either imbalance in numbers or
reasons for exclusion across study groups.
Assessment-specific Clarification: The missing outcome data are clearly related to exposure (more
missing data for exposed compared to unexposed groups), but the study authors do not address
why.
10. Were the outcome assessors blinded to study group or exposure level?
Human Controlled Trial: There is direct evidence that the outcome assessors (including study
subjects, if outcomes were self-reported) were adequately blinded to the study group, and it is
unlikely that they could have broken the blinding prior to reporting outcomes.
Cohort, Cross-sectional, Case Series/report: There is direct evidence that the outcome assessors
(including study subjects, if outcomes were self-reported) were adequately blinded to the exposure
level, and it is unlikely that they could have broken the blinding prior to reporting outcomes.
Case-Control: There is direct evidence that the outcome assessors (including study subjects, if
outcomes were self-reported) were adequately blinded to the exposure level when reporting
outcomes.
Assessment-specific Clarification: The study report states that outcome assessors were blinded to
subjects' exposure levels, OR in a case-control study, researchers who assigned exposure levels
based on drinking water level were blinded to the case/control status of the participant.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-80 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial: There is indirect evidence that the outcome assessors (including study
subjects, if outcomes were self-reported) were adequately blinded to the study group, and it is
unlikely that they could have broken the blinding prior to reporting outcomes, OR it is deemed that
lack of adequate blinding of outcome assessors would not appreciably bias results, which may vary
by outcome (i.e., blinding is especially important for subjective measures).
Cohort, Cross-sectional, Case Series/report: There is indirect evidence that the outcome assessors
were adequately blinded to the exposure level, and it is unlikely that they could have broken the
blinding prior to reporting outcomes OR it is deemed that lack of adequate blinding of outcome
assessors would not appreciably bias results (including that subjects self-reporting outcomes were
likely not aware of reported links between the exposure and outcome lack of blinding is unlikely to
bias a particular outcome).
Case-Control: There is direct evidence that the outcome assessors were adequately blinded to the
exposure level when reporting outcomes OR it is deemed that lack of adequate blinding of
outcome assessors would not appreciably bias results (including that subjects self-reporting
outcomes were likely not aware of reported links between the exposure and outcome or lack of
blinding is unlikely to bias a particular outcome).
Assessment-specific Clarification: No direct statement that outcome assessors were blind, but it is
likely that they were (e.g., pathologists conducting histopathology on the tissue would most likely
be blind to the exposure status), OR outcomes were assessed using an automated instrument,
making it unlikely that the results would be biased since automated instrument would not be
biased.
Human Controlled Trial: There is indirect evidence that it was possible for outcome assessors
(including study subjects if outcomes were self-reported) to infer the study group prior to reporting
outcomes, OR there is insufficient information provided about blinding of outcome assessors.
Cohort, Cross-sectional, Case Series/report: There is indirect evidence that it was possible for
outcome assessors to infer the exposure level prior to reporting outcomes (including that subjects
self-reporting outcomes were likely aware of reported links between the exposure and outcome)
OR there is insufficient information provided about blinding of outcome assessors.
Case-Control: There is indirect evidence that it was possible for outcome assessors to infer the
exposure level prior to reporting outcomes (including that subjects self-reporting outcomes were
likely aware of reported links between the exposure and outcome) OR there is insufficient
information provided about blinding of outcome assessors.
Assessment-specific Clarification: Not enough information to determine if outcome assessors were
blind to exposure status and possibility exists that they could have knowledge (e.g., it is a cohort
and exposure was assessed prior to outcome), OR likely that outcome assessors were aware of
exposure, but not necessarily level of exposure (e.g., outcome was assessed in subject's home,
which is in either the control village or exposed village, but the study report evaluated different
exposure levels in village so that when assessing the outcome, assessors would be aware that
subjects were exposed or controls but not exact exposure level).
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial: There is direct evidence for lack of adequate blinding of outcome
assessors (including study subjects if outcomes were self-reported), including no blinding or
incomplete blinding.
Cohort, Cross-sectional, Case Series/report: There is direct evidence that outcome assessors were
aware of the exposure level prior to reporting outcomes (including that subjects self-reporting
outcomes were aware of reported links between the exposure and outcome).
Case-Control: There is direct evidence that outcome assessors were aware of the exposure level
prior to reporting outcomes (including that subjects self-reporting outcomes were aware of
reported links between the exposure and outcome).
Assessment-specific Clarification: There is direct evidence that outcome assessor knew exposure
status (e.g., same situation as above with outcome assessed in the village, but the report only
evaluates exposure as "exposed versus unexposed/' with no arsenic levels measured).
11. Were confounding variables assessed consistently across groups using valid and reliable measures?
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct
evidence that primary covariates and confounders were assessed using valid and reliable
measurements.
Assessment-specific Clarification: Methods provide specific details on how confounders were
measured (e.g., for body weight, details provided to indicate precision of measurement instrument
and, ideally, calibration of instrument). Validated or pretested questionnaires used.
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is
indirect evidence primary covariates and confounders were assessed using valid and reliable
measurements OR it is deemed that the measures used would not appreciably bias results (i.e., the
authors justified the validity of the measures from previously published research).
Assessment-specific Clarification: Self-administered questionnaire, OR questionnaire administered
by a single interviewer for all subjects (thus eliminating the possibility for interviewer agreement
bias), OR methods for assessing confounders were mixed (e.g., some methods well-conducted and
consistent, but others may have been obtained from questionnaires not stated to be validated).
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is
indirect evidence that primary covariates and confounders were assessed using measurements of
unknown validity OR there is insufficient information provided about the measures used.
Assessment-specific Clarification: Not enough details were provided on how the confounders were
assessed. Questionnaire used and administered by several interviewers with no details on
validity/reliability of the questionnaire or on consistency between the interviewers.
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct
evidence that primary covariates and confounders were assessed using non valid measurements.
Assessment-specific Clarification: There is direct evidence of selective recall by disease status.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
12. Can we be confident in the exposure characterization?
Human Controlled Trial: There is direct or indirect evidence that the test material is confirmed as
< 99% pure (or impurities have been characterized and not considered to be of serious concern),
and that the concentration, stability, and homogeneity of stock material and formulation have
been verified as appropriate (Note: < 99% purity value is considered achievable based on current
advertised purity from Sigma-Aldrich); AND FOR INTERNAL DOSIMETRY STUDIES there is direct
evidence that most data points for the chemical are above the level of quantitation (LOQ) for the
assay; AND the study utilized spiked samples to confirm assay performance and the stability of the
chemical in biological samples was appropriately addressed; AND studies took measures to assess
potential contamination that might have occurred during sample collection and analysis, including
method blanks. Note: Use of method blanks is necessary to identify potential sources of
contamination in blood and urine but cannot rule out all possible sources of contamination. The
risk of contamination for blood-based measurements is likely higher than for urinary
measurements in part because sterile plastic blood collection containers can increase the number
of sources of contamination and because of higher levels of protein and lipid levels in blood versus
urine. Preferred practices include (1) measurement of the chemical for blood measurements, and
(2) use of isotopically labeled dosing material (e.g., deuterated) to avoid issues of contamination,
although we will not "downgrade" if a study did not follow these preferred practices.
Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct evidence that most data
points for the chemical are above the level of quantitation (LOQ) for the assay; AND the study
utilized spiked samples to confirm assay performance and the stability of the chemical in biological
samples was appropriately addressed; AND studies took measures to assess potential
contamination that might have occurred during sample collection and analysis including method
blanks. Note: Use of method blanks is necessary to identify potential sources of contamination in
blood and urine but cannot rule out all possible sources of contamination. The risk of
contamination for blood-based measurements is likely higher than for urinary measurements in
part because sterile plastic blood collection containers can increase the number of sources of
contamination and because of higher levels of protein and lipid levels in blood versus urine.
Preferred practices include (1) measurement of the chemical for blood measurements, and (2)
inclusion of multiple measurements of the chemical because a single sample from an individual
does not appear to be strong predictor of a subject's exposure category. Use of a single
measurement in large sample size studies such as NHANES is less of an issue because the number
of participants offsets potential concern for differential exposure misclassification. We will not
downgrade if a study did not follow these preferred practices.
Assessment-specific Clarification: Single spot urine samples are reported for a large number of
subjects (over 1,000), OR multiple (repeated) spot urine samples were reported. Individual-level
drinking water levels (e.g., obtained from household tap or household well, but not village-level
well) with methods well-described, including reporting of levels of detection (LODs). Toenail and
hair samples were cleaned, AND the recovery rate of the method or use of internal standards is
reported. More than one arsenic exposure assessment (more than one matrix, and/or more than
one measurement) and at least one of them is excellent (e.g., the large HEALS cohort and spot
urine spot samples, in addition to village-level water inorganic arsenic measurements) and a
correlation reported between the different measurements.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-83 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial: There is direct or indirect evidence that purity was < 98%, (or impurities
have been characterized and not considered to be of serious concern i.e., purity was independently
confirmed by lab, purity is reported in paper or obtained through author query, or purity not
reported but the source is listed and the supplier of the chemical provides documentation of the
purity of the chemical; AND FOR INTERNAL DOSIMETRY STUDIES there is indirect evidence that
most data points for the chemical are above the level of quantitation (LOQ) for the assay, i.e., the
central estimate (median, mean, geometric mean) is above the LOQ but results for individual data
values are not presented or the presentation of variance estimates do not permit assessment of
whether most data points are likely above the LOQ; AND the study utilized spiked samples to
confirm assay performance and the chemical in biological samples was appropriately addressed;
AND studies took measures to assess potential contamination that might have occurred during
sample collection and analysis including method blanks.
Cohort, Case-Control, Cross-sectional, Case Series/report: There is indirect evidence that most
data points for the chemical are above the LOQ for the assay, i.e., the central estimate (median,
mean, geometric mean) is above the LOQ but results for individual data values are not presented
or the presentation of variance estimates do not permit assessment of whether most data points
are likely above the LOQ; AND the study utilized spiked samples to confirm assay performance and
the stability of the chemical in biological samples has been appropriately addressed; AND studies
took measures to assess potential contamination that might have occurred during sample
collection and analysis including method blanks; OR use of questionnaire items where results of
biomonitoring studies support the use of the questionnaire item(s) as an indicator of relative level
of exposure; OR job description for occupational studies where levels in the work environment or
results of biomonitoring studies support the use of job description as an indicator of relative level
of exposure.
Assessment-specific Clarification: Single spot urine samples with a moderate number of subjects
(i.e., hundreds or more). Adequate measurements and methods, but LODs are not provided.
Exposure based on occupational title but supported by some arsenic monitoring (air, urine or other
biomarker).
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-84 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial: Neither the source or purity of the chemical was reported in the study and
information on purity could not be obtained through author query/vendor documentation; AND
FOR INTERNAL DOSIMETRY STUDIES there is direct or indirect evidence that most data points for
the chemical are above the level of quantitation (LOQ) for the assay BUT no steps were taken to
assess potential contamination that might have occurred during sample collection and analysis; OR
there is indirect or direct evidence that most individual data points for the chemical are below the
level of quantitation (LOQ) for the assay; OR method to measure the chemical used ELISA which is
less accepted as providing quantitatively accurate values and because of potential uncharacterized
antibody cross-reactivity with conjugates and endogenous components of sample matrices
Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct or indirect evidence that
most data points for the chemical are above the level of quantitation (LOQ) for the assay BUT no
steps were taken to assess potential contamination that might have occurred during sample
collection and analysis; OR there is indirect or direct evidence that most individual data points for
the chemical are below the level of quantitation (LOQ) for the assay; OR method to measure the
chemical used ELISA which leads to concern because of uncharacterized antibody cross-reactivity
with conjugates and endogenous components of sample matrices; OR use of questionnaire items
that are not supported by results of biomonitoring studies; OR job description for occupational
studies that are not supported by information on levels in the work environment or results of
biomonitoring studies
Assessment-specific Clarification: Exposure based on single spot urine sample for a limited number
of subjects (less than 100), OR exposure based on occupational title with no arsenic monitoring, OR
cumulative arsenic levels based on self-reported duration/resident history and group well water
measurements.
Human Controlled Trial: There is indirect or direct evidence that purity was <98%; AND FOR
INTERNAL DOSIMETRY STUDIES there is direct evidence of uncontrolled contamination.
Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct evidence of uncontrolled
contamination; OR not reporting of methods used to assess exposure and this information could
not be obtained through author query; OR self-report exposure.
Assessment-specific Clarification: No measured arsenic concentrations. Exposure assessed based
on presence/absence of skin lesions OR self-reported duration of drinking water or living in a
certain area OR Lifetime cumulative arsenic exposure determined using self-reported information
on residential history and drinking-water daily consumption rates, and village-level median
inorganic arsenic concentration in drinking water.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
13. Can we be confident in the outcome assessment?
Human Controlled Trial, Cohort: There is direct evidence that the outcome was assessed using
well-established methods, the "gold standard" or with validity and reliability >0.70 and subjects had
been followed for the same length of time in all study groups. Acceptable assessment methods will
depend on the outcome, but examples of such methods may include: objectively measured with
diagnostic methods, measured by trained interviewers, obtained from registries.
Case-Control: There is direct evidence that the outcome was assessed in cases using well-
established methods (the gold standard) and subjects had been followed for the same length of
time in all study groups.
Cross-sectional, Case Series/report: There is direct evidence that the outcome was assessed using
well-established methods (the gold standard).
Assessment-specific Clarification: Cancer cases are histologically confirmed, OR data obtained
from nationwide registry are accepted as valid and complete (e.g., Taiwan), OR outcome diagnosed
by physician, OR outcome obtained from medical record data or validated with such data (if self-
reported).
Human Controlled Trial, Cohort: There is indirect evidence that the outcome was assessed using
acceptable methods [i.e., deemed valid and reliable but not the gold standard or with validity and
reliability < 0.40] and subjects had been followed for the same length of time in all study groups OR
it is deemed that the outcome assessment methods used would not appreciably bias results.
Acceptable, but not ideal assessment methods will depend on the outcome, but examples of such
methods may include proxy reporting of outcomes and mining of data collected for other purposes.
Case-Control: There is indirect evidence that the outcome was assessed in cases (i.e., case
definition) using acceptable methods and subjects had been followed for the same length of time in
all study groups OR it is deemed that the outcome assessment methods used would not
appreciably bias results.
Cross-sectional, Case Series/report: There is indirect evidence that the outcome was assessed
using acceptable methods OR it is deemed that the outcome assessment methods used would not
appreciably bias results.
Assessment-specific Clarification: Death certificates are used, but there is no statement that they
were coded by certified nosologist, OR information on the accuracy/validity/completeness of the
death certificates is missing, OR incident cancer cases are not stated to be histologically confirmed,
but the study was conducted in a hospital setting (e.g., hospital-based case-control study).
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial, Cohort: There is indirect evidence that the outcome assessment method is
an insensitive instrument, the authors did not validate the methods used, or the length of follow up
differed by study group OR there is insufficient information provided about validation of outcome
assessment method.
Case-Control: There is indirect evidence that the outcome was assessed in cases using an
insensitive instrument or was not adequately validated OR there is insufficient information
provided about how cases were identified.
Cross-sectional, Case Series/report: There is indirect evidence that the outcome assessment
method is an insensitive instrument or was not adequately validated OR there is insufficient
information provided about validation of outcome assessment method.
Assessment-specific Clarification: Outcome is self-reported (e.g., "ever been diagnosed by a
physician") and not verified by medical records or other means. There is insufficient information on
quality of self-report or validation of answers. Outcome is assessed by nurses and there is no
information on assessor agreement.
Human Controlled Trial, Cohort: There is direct evidence that the outcome assessment method is
an insensitive instrument, or the length of follow up differed by study group.
Case-Control: There is direct evidence that the outcome was assessed in cases using an insensitive
instrument.
Cross-sectional, Case Series/report: There is direct evidence that the outcome assessment method
is an insensitive instrument.
Assessment-specific Clarification: Self-reported outcome when question is not worded "as
diagnosed by a physician" and cannot be verified.
14. Were all measured outcomes reported?
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct
evidence that all of the study's measured outcomes (primary and secondary) outlined in the
protocol, methods, abstract, and/or introduction (that are relevant for the evaluation) have been
reported. This would include outcomes reported with sufficient detail to be included in meta-
analysis or fully tabulated during data extraction.
Assessment-specific Clarification: None.
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is
indirect evidence that all of the study's measured outcomes (primary and secondary) outlined in
the protocol, methods, abstract, and/or introduction (that are relevant for the evaluation) have
been reported OR analyses that had not been planned at the outset of the study (i.e., retrospective
unplanned subgroup analyses) are clearly indicated as such and it is deemed that the omitted
analyses were not appropriate and selective reporting would not appreciably bias results. This
would include outcomes reported with insufficient detail such as only reporting that results were
statistically significant (or not).
Assessment-specific Clarification: All outcomes outlined in abstract, introduction, and methods are
reported.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Epidemiology Studies
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is
indirect evidence that all of the study's measured outcomes (primary and secondary) outlined in
the protocol, methods, abstract, and/or introduction (that are relevant for the evaluation) have
been reported OR there is insufficient information provided about selective outcome reporting.
Assessment-specific Clarification: If an outcome mentioned in a part of the study report is
obviously missing from the results.
Human Controlled Trial, Cohort, Case-Control, Cross-sectional, Case Series/report: There is direct
evidence that all of the study's measured outcomes (primary and secondary) outlined in the
protocol, methods, abstract, and/or introduction (that are relevant for the evaluation) have not
been reported. In addition to not reporting outcomes, this would include reporting outcomes
based on composite score without individual outcome components or outcomes reported using
measurements, analysis methods or subsets of the data (e.g., subscales) that were not pre-
specified or reporting outcomes not pre-specified (unless clear justification for their reporting is
provided, such as an unexpected effect).
Assessment-specific Clarification: None.
15. Were there no other potential threats to internal validity (e.g., statistical methods were
appropriate)?
On a project specific basis, additional questions for other potential threats to internal validity can
be added and applied to study designs as appropriate.
Assessment-specific Clarification: Statistical analyses were appropriate and no other threats to
internal validity were identified. Study authors might acknowledge limitations, but these are not
expected to affect the study's internal validity.
Assessment-specific Clarification: There are study limitations likely to bias the results towards or
away from the null, but adequate sample size was available in each cell (n< 5), OR sample size is
small and acknowledged as a potential limitation by study authors, but significant results were still
observed.
Assessment-specific Clarification: There are study limitations likely to bias results towards or away
from the null, OR analyses were conducted on a small number of subjects (n<5 in any given cell)
and no statistically significant results were observed.
Assessment-specific Clarification: None.
Source: Adapted from NTP (2013)
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Table 1-11 Additional Information for Risk of Bias Determinations for Animal
Toxicology Studies
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
1. Was administered dose or exposure level adequately randomized?
There is direct evidence that animals were allocated to any study group including controls using a
method with a random component. Acceptable methods of randomization include: referring to a
random number table, using a computer random number generator, coin tossing, shuffling cards or
envelopes, throwing dice, or drawing of lots (Higgins et al., 2008). Restricted randomization (e.g.,
blocked randomization) to ensure particular allocation ratios will be considered low risk of bias.
Similarly, stratified randomization and minimization approaches that attempt to minimize
imbalance between groups on important factors prognostic factors (e.g., body weight) will be
considered acceptable. This type of approach is used by NTP and included in OECD guidelines for
toxicology protocols, i.e., random number generator with body weight as a covariate such that
body weight is consistent across study groups. Discrimination criteria applied prior to
randomization across study groups (e.g., only female rats displaying normal estrus cycles in the
prior 3 months were included; rats were then randomly assigned to study groups using a random
number table) will also be considered acceptable. Investigator-selection of animals from a cage is
not considered random allocation because animals may not have an equal chance of being
selected, e.g., investigator selecting animals with this method may inadvertently choose healthier,
easier to catch, or less aggressive animals. Use of concurrent controls is required as an indication
that randomization covered all study groups.
Assessment-specific Clarification: None.
There is indirect evidence that animals were allocated to study groups using a method with a
random component (i.e., authors state that allocation was random, without description of the
method used) OR it is deemed that allocation without a clearly random component during the
study would not appreciably bias results. For example, approaches such as biased coin or urn
randomization, replacement randomization, mixed randomization, and maximal randomization
may require consultation with a statistician to determine risk-of-bias rating (Higgins et al., 2008).
Use of concurrent controls is required as an indication that randomization covered all study groups.
Assessment-specific Clarification: None.
There is indirect evidence that animals were allocated to study groups using a method with a non-
random component OR there is insufficient information provided about how subjects were
allocated to study groups. Non-random allocation methods may be systematic, but have the
potential to allow researchers to anticipate the allocation of animals to study groups (Higgins et al..
2008). Such "quasi-random" methods include investigator-selection of animals from a cage,
alternation, assignment based on shipment receipt date, date of birth, or animal number. A study
reporting lack of concurrent controls is another indication that randomization to all study groups
was not conducted.
Assessment-specific Clarification: None.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
There is direct evidence that animals were allocated to study groups using a non-random method
including judgment of the investigator, the results of a laboratory test or a series of tests (Higgins et
al., 2008). A study reporting lack of concurrent controls is another indication that randomization to
all study groups was not conducted.
Assessment-specific Clarification: None.
2. Was allocation to study groups adequately concealed?
There is direct evidence that at the time of assigning study groups the research personnel did not
know what group animals were allocated to, and it is unlikely that they could have broken the
blinding of allocation until after assignment was complete and irrevocable. Methods used to ensure
allocation concealment include sequentially numbered treatment containers of identical
appearance or equivalent methods.
Assessment-specific Clarification: None.
There is indirect evidence that at the time of assigning study groups the research personnel did not
know what group animals were allocated to OR it is deemed that lack of adequate allocation
concealment would not appreciably bias results.
Assessment-specific Clarification: Rarely reported; risk of bias based on information on
randomization unless direct evidence provided in the study. If animals were randomized, it is
expected that knowledge of the study groups would not appreciably bias the results unless the
randomization method allows for bias.
There is indirect evidence that at the time of assigning study groups it was possible for the research
personnel to know what group animals were allocated to, or it is likely that they could have broken
the blinding of allocation before assignment was complete and irrevocable OR there is insufficient
information provided about allocation to study groups.
Assessment-specific Clarification: None.
There is direct evidence that at the time of assigning study groups it was possible for the research
personnel to know what group animals were allocated to, or it is likely that they could have broken
the blinding of allocation before assignment was complete and irrevocable.
Assessment-specific Clarification: None.
3. Were the comparison groups appropriate?
N/A
N/A - only applies to epidemiological studies.
4. Did the study design or analysis account for important confounding and modifying variables?
There is direct evidence that appropriate adjustments were made for body weight, litter size in
studies of offspring (especially when the outcome measure is growth-related and assessed prior to
weaning) or any other relevant covariates.
Assessment-specific Clarification: None.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
There is indirect evidence that appropriate adjustments were made for body weight, litter size in
studies of offspring (especially when the outcome measure is growth-related and assessed prior to
weaning), or any other relevant covariates OR it is deemed that not considering or only considering
a partial list of covariates or confounders in the final analyses would not appreciably bias results.
Assessment-specific Clarification: None.
There is indirect evidence that appropriate adjustments were not made for body weight, litter size
in studies of offspring (especially when the outcome measure is growth-related and assessed prior
to weaning), or any other relevant covariates OR there is insufficient information provided about
analysis of relevant covariates.
Assessment-specific Clarification: None.
There is direct evidence that appropriate adjustments were not made for body weight, litter size in
studies of offspring (especially when the outcome measure is growth-related and assessed prior to
weaning), or any other relevant covariates.
Assessment-specific Clarification: None.
5. Did researchers adjust or control for other exposures that are anticipated to bias results?
There is direct evidence that other exposures anticipated to bias results were not present or were
appropriately adjusted for. For estrogenic exposures or endpoints anticipated to be affected by
estrogenic or endocrine pathways, this would include if animals were fed a phytoestrogen-free or
low phytoestrogen diet.
Assessment-specific Clarification: None.
There is indirect evidence that other exposures anticipated to bias results were not present or were
appropriately adjusted for OR it is deemed that co-exposures present would not appreciably bias
results.
Assessment-specific Clarification: Note that issues related to exposures to compound of interest
addressed in question 12 regarding exposure characterization.
There is indirect evidence that the control group may have received the treatment or there was an
unbalanced provision of additional co-exposures which were not appropriately adjusted for. For
estrogenic exposures or endpoints anticipated to be affected by estrogenic or endocrine pathways,
this would include if animals were likely fed a diet that did not minimize or eliminate phytoestrogen
content (or phytoestrogen content of diet was not reported).
Assessment-specific Clarification: None.
There is direct evidence that the control group received the treatment or there was an unbalanced
provision of additional co-exposures which were not appropriately adjusted for. For estrogenic
exposures or endpoints anticipated to be affected by estrogenic or endocrine pathways, this would
include that animals were fed a diet that did not minimize or eliminate phytoestrogen content.
Assessment-specific Clarification: None.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
6. Were experimental conditions identical across study groups?
There is direct evidence that non-treatment-related experimental conditions were identical across
study groups (i.e., the study report explicitly provides this level of detail) and the same vehicle was
used in control and experimental animals.
Assessment-specific Clarification: Specific housing conditions reported and appear to be within
standard protocol ranges without potential differences between groups
There is indirect evidence that the same vehicle was used in control and experimental animals OR it
is deemed that the vehicle used would not appreciably bias results. As described above, identical
non-treatment-related experimental conditions are assumed if authors did not report differences in
housing or husbandry.
Assessment-specific Clarification: None.
There is indirect evidence that the vehicle differed between control and experimental animals OR
authors did not report the vehicle used.
Assessment-specific Clarification: No concurrent vehicle was used, OR vehicle was different from
that used for the treatment group, OR insufficient information to determine type of control used.
There is direct evidence from the study report that non-treatment-related experimental conditions
were not comparable between study groups or control animals were untreated, or treated with a
different vehicle than experimental animals.
Assessment-specific Clarification: None.
7. Did researchers adhere to the study protocol?
There is direct evidence that there were no deviations from the protocol (i.e., the study report
explicitly provides this level of detail).
Assessment-specific Clarification: None.
There is indirect evidence that there were no deviations from the protocol (i.e., authors did not
report any deviations) OR deviations from the protocol are described and it is deemed that they
would not appreciably bias results.
Assessment-specific Clarification: None.
There is indirect evidence that there were large deviations from the protocol as outlined in the
methods or study report.
Assessment-specific Clarification: None.
There is direct evidence that there were large deviations from the protocol as outlined in the
methods or study report.
Assessment-specific Clarification: None.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
8. Were the research personnel and human subjects blinded to the study group during the study?
There is direct or indirect evidence that the research personnel were adequately blinded to study
group, and it is unlikely that they could have broken the blinding during the study. Methods used to
ensure blinding include central allocation, sequentially numbered drug containers of identical
appearance; sequentially numbered animal cages; or equivalent methods.
Assessment-specific Clarification: None.
Blinding was not reported OR blinding was not possible but research personnel took steps to
minimize potential bias, such as randomized necropsy order.
Assessment-specific Clarification: None.
There is indirect evidence that the research personnel were not adequately blinded to study group
and did not take steps to minimize potential bias.
Assessment-specific Clarification: None.
There is direct evidence that the research personnel were not adequately blinded to study group
and did not take steps to minimize potential bias.
Assessment-specific Clarification: None.
9. Were outcome data complete without attrition or exclusion from analysis?
There is direct evidence that loss of animals was adequately addressed and reasons were
documented when animals were removed from a study. Acceptable handling of attrition includes:
very little missing outcome data; reasons for missing animals unlikely to be related to outcome (or
for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in
numbers across study groups, with similar reasons for missing data across groups; missing
outcomes is not enough to impact the effect estimate OR missing data have been imputed using
appropriate methods (insuring that characteristics of animals are not significantly different from
animals retained in the analysis).
Assessment-specific Clarification: None.
There is indirect evidence that loss of animals was adequately addressed and reasons were
documented when animals were removed from a study OR it is deemed that the proportion of
animals lost would not appreciably bias results. This would include reports of no statistical
differences in characteristics of animals removed from the study from those remaining in the study.
Assessment-specific Clarification: Number of samples for each outcome reported.
There is indirect evidence that loss of animals was unacceptably large and not adequately
addressed OR there is insufficient information provided about loss of animals.
Assessment-specific Clarification: Number of animals treated not specified; number of samples not
specified.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-93 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
There is direct evidence that loss of animals was unacceptably large and not adequately addressed.
Unacceptable handling of attrition includes: reason for loss is likely to be related to true outcome,
with either imbalance in numbers or reasons for loss across study groups.
Assessment-specific Clarification: Mortality occurs in enough groups to make majority of data
unusable.
10. Were the outcome assessors blinded to study group or exposure level?
There is direct evidence that the outcome assessors were adequately blinded to the study group,
and it is unlikely that they could have broken the blinding prior to reporting outcomes.
Assessment-specific Clarification: None.
There is indirect evidence that the outcome assessors were adequately blinded to the study group,
and it is unlikely that they could have broken the blinding prior to reporting outcomes OR it is
deemed that lack of adequate blinding of outcome assessors would not appreciably bias results,
which may vary by outcome (i.e., blinding is especially important for subjective measures). For
some outcomes, particularly pathology assessment, outcome assessors are not blind to study group
as they require comparison to the control to appropriately judge the outcome, but additional
measures such as multiple levels of independent review by trained pathologists can minimize this
potential bias.
Assessment-specific Clarification: Blinding not reported but not expected to bias the results
because results obtained from analytical methods or other non-subjective means, OR two different
individuals conducted independent analyses. Tests based on timing or counts are considered to be
objective as is assessment of presence or absence of developmental malformations.
There is indirect evidence that it was possible for outcome assessors to infer the study group prior
to reporting outcomes without sufficient quality control measures OR there is insufficient
information provided about blinding of outcome assessors.
Assessment-specific Clarification: Blinding not reported and method of analysis is subjective. For
example, behavioral tests can be subjective if assessors not blinded or if includes subjective
measures (e.g., response to tail pinch). Assessment of other developmental malformations such as
degree of deformity is considered to be subjective.
There is direct evidence for lack of adequate blinding of outcome assessors, including no blinding or
incomplete blinding without quality control measures.
Assessment-specific Clarification: None.
11. Were confounding variables assessed consistently across groups using valid and reliable measures?
There is direct evidence that primary covariates and confounders were assessed using valid and
reliable measurements.
Assessment-specific Clarification: Methods provide specific details on how confounders measured
(e.g., details regarding precision and calibration related to measurement of body weight provided).
Litter size and sex considered to be observational results and assumed to be recorded accurately.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
There is indirect evidence primary covariates and confounders were assessed using valid and
reliable measurements OR it is deemed that the measures used would not appreciably bias results
(i.e., the authors justified the validity of the measures from previously published research).
Assessment-specific Clarification: Methods for the confounder were not provided (e.g., body
weight was measured, but details were not provided); assume confounders consistently assessed
unless specifically stated otherwise, OR no confounders assessed and information for body weight
or litter size provided in study and reported to be consistently measured.
There is indirect evidence that primary covariates and confounders were assessed using
measurements of unknown validity OR there is insufficient information provided about the
measures used.
Assessment-specific Clarification: None.
There is direct evidence that primary covariates and confounders were assessed using non valid
measurements.
Assessment-specific Clarification: None.
N/A
Assessment-specific Clarification: No confounders assessed; rating not applicable.
12. Can we be confident in the exposure characterization?
There is direct or indirect evidence that the test material is confirmed as < 99% pure (or impurities
have been characterized and not considered to be of serious concern), and that the concentration,
stability, and homogeneity of stock material and formulation have been verified as appropriate
(Note: < 99% purity value is considered achievable based on current advertised purity from Sigma-
Aldrich); AND the study provides information about consumption through measurement of the
dosing medium and dose intake quantity, e.g., feed or water consumption; AND FOR INTERNAL
DOSIMETRY STUDIES there is direct evidence that most data points for the chemical are above the
level of quantitation (LOQ) for the assay; AND the study utilized spiked samples to confirm assay
performance and the stability of the chemical in biological samples was appropriately addressed;
AND studies took measures to assess potential contamination that might have occurred during
sample collection and analysis including method blanks. Note: Use of method blanks is necessary to
identify potential sources of contamination in blood and urine but cannot rule out all possible
sources of contamination. The risk of contamination for blood-based measurements is likely higher
than for urinary measurements in part because sterile plastic blood collection containers can
increase the number of sources of contamination and because of higher levels of protein and lipid
levels in blood versus urine. Preferred practices include (1) measurement of the chemical for blood
measurements, and (2) use of isotopically labeled dosing material (e.g., deuterated) is ideal to
avoid issues of contamination, although we will not "downgrade" if a study did not follow these
preferred practices.
Assessment-specific Clarification: Analytical grade considered to be high purity, OR when
substance administered in food or water, homogeneity, stability, and frequency of dose
preparation reported; spillage of food and water only considered if specifically noted to be an issue
or noted that it was not addressed.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
There is direct or indirect evidence that purity was < 98% pure (or impurities have been
characterized and not considered to be of serious concern),, i.e., purity was independently
confirmed by lab, purity is reported in paper or obtained through author query, or purity not
reported but the source is listed and the supplier of the chemical provides documentation of the
purity of the chemical; BUT the study does not provide information about consumption through
measurement of the dosing medium and dose intake quantity, e.g., feed or water consumption;
AND FOR INTERNAL DOSIMETRY STUDIES there is indirect evidence that most data points for the
chemical are above the level of quantitation (LOQ) for the assay, i.e., the central estimate (median,
mean, geometric mean) is above the LOQ but results for individual data values are not presented
or the presentation of variance estimates do not permit assessment of whether most data points
are likely above the LOQ; AND the study utilized spiked samples to confirm assay performance and
the stability of the chemical in biological samples has been appropriately addressed; AND studies
took measures to assess potential contamination that might have occurred during sample
collection and analysis including method blanks.
Assessment-specific Clarification: Purity >95% and methods described and appropriate, OR
homogeneity and/or stability not reported and there was no evidence that they were a concern, OR
substance administered via water or food and study reports animals housed in groups so that
individual intake cannot be estimated but individual measures (e.g., serum or tissue levels)
reported.
Neither the source or purity of the chemical was reported in the study and information on purity
could not be obtained through author query/vendor documentation; AND FOR INTERNAL
DOSIMETRY STUDIES there is direct or indirect evidence that most data points for the chemical are
above the level of quantitation (LOQ) for the assay BUT no steps were taken to assess potential
contamination that might have occurred during sample collection and analysis; OR there is indirect
or direct evidence that most individual data points for the chemical are below the level of
quantitation (LOQ) for the assay; OR method to measure the chemical used ELISA which is less
accepted as providing quantitatively accurate values and because of potential uncharacterized
antibody cross-reactivity with conjugates and endogenous components of sample matrices
Assessment-specific Clarification: Spillage of food and water not reported and were noted to be an
issue, OR substance administered via water or food and study reports animals housed in groups so
that individual intake cannot be estimated.
There is indirect or direct evidence that purity was <98%; AND FOR INTERNAL DOSIMETRY STUDIES
there is direct evidence of uncontrolled contamination.
Assessment-specific Clarification: Same criteria, but use a purity cutoff of <95%.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
13. Can we be confident in the outcome assessment?
There is direct evidence that the outcome was assessed using well-established methods (the gold
standard) assessed at the same length of time after initial exposure in all study groups.
Assessment-specific Clarification: Study report provides specific details on outcome assessment
including coefficient of variation, limits of detection, treatment of samples above or below limits of
detection (e.g., values below detection imputed with specific value or samples diluted when above
a certain range). Histopathology evaluation by pathologist and functional observational battery
(FOB) with details reported are considered well-established, valid, and reliable methods.
There is indirect evidence that the outcome was assessed using acceptable methods (i.e., deemed
valid and reliable but not the gold standard) assessed at the same length of time after initial
exposure in all study groups OR it is deemed that the outcome assessment methods used would
not appreciably bias results.
Assessment-specific Clarification: Details provided to indicate methods seem reasonable for
measuring outcome, OR commercial kit used for evaluation but limits of detection and treatment of
samples above and below limits not provided.
There is indirect evidence that the outcome assessment method is an insensitive instrument, the
authors did not validate the methods used, or the length of time after initial exposure differed by
study group OR there is insufficient information provided about validation of outcome assessment
method.
Assessment-specific Clarification: Details not provided for methods, OR evaluation of outcome
expected to be subjective, OR evaluation method not appropriate, OR steps not taken to ensure
outcome or validate method.
There is direct evidence that the outcome assessment method is an insensitive instrument or the
length of time after initial exposure differed by study group.
Assessment-specific Clarification: None.
14. Were all measured outcomes reported?
There is direct evidence that all of the study's measured outcomes (primary and secondary)
outlined in the protocol, methods, abstract, and/or introduction (that are relevant for the
evaluation) have been reported. This would include outcomes reported with sufficient detail to be
included in meta-analysis or fully tabulated during data extraction.
Assessment-specific Clarification: Details provided for all outcomes either in report or
supplemental materials.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Risk of Bias Questions and Rating Guidelines - Animal Toxicology Studies
There is indirect evidence that all of the study's measured outcomes (primary and secondary)
outlined in the protocol, methods, abstract, and/or introduction (that are relevant for the
evaluation) have been reported OR analyses that had not been planned at the outset of the study
(i.e., retrospective unplanned subgroup analyses) are clearly indicated as such and it is deemed that
the omitted analyses were not appropriate and selective reporting would not appreciably bias
results. This would include outcomes reported with insufficient detail such as only reporting that
results were statistically significant (or not).
Assessment-specific Clarification: All outcomes reported but data not provided for all outcomes
(e.g., statement that results not statistically significant without presentation of results). If
histopathology conducted on numerous tissues, analysis of every organ does not need to be
reported in results.
There is indirect evidence that all of the study's measured outcomes (primary and secondary)
outlined in the protocol, methods, abstract, and/or introduction (that are relevant for the
evaluation) have been reported OR there is insufficient information provided about selective
outcome reporting.
Assessment-specific Clarification: Results for some outcomes, other than histopathology results,
not reported.
There is direct evidence that all of the study's measured outcomes (primary and secondary)
outlined in the protocol, methods, abstract, and/or introduction (that are relevant for the
evaluation) have not been reported. In addition to not reporting outcomes, this would include
reporting outcomes based on composite score without individual outcome components or
outcomes reported using measurements, analysis methods or subsets of the data (e.g., subscales)
that were not pre-specified or reporting outcomes not pre-specified (unless clear justification for
their reporting is provided, such as an unexpected effect).
Assessment-specific Clarification: None.
15. Were there no other potential threats to internal validity (e.g., statistical methods were
appropriate)?
On a project specific basis, additional questions for other potential threats to internal validity can
be added and applied to study designs as appropriate.
Assessment-specific Clarification: Evaluation of appropriateness of statistical analyses and
evaluation to determine statistical power (i.e., if number of animals sufficient to detect effect)
either based on guidelines or study report of observed statistically significant results.
Source: Adapted from NTP (2013)
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1.7 References for Assessment Development Plan
ATSDR (Agency for Toxic Substances and Disease Registry). (2007). Toxicological Profile for Arsenic
(Update, 2007). (NTIS/03060214_a). Atlanta, Georgia, http://www.atsdr.cdc.gov/toxprofiles/tp2.pdf
Gentry. PR: Covington. TR: Mann. S: Shipp. AM: Yager. JW: HJ. CI. (2004). Physiologically based
pharmacokinetic modeling of arsenic in the mouse. J Toxicol Environ Health A 67: 43-71.
http://dx.doi.org/10.1080/15287390490253660
Health Canada. (2006). Guidelines for Canadian drinking water quality: Guideline technical document Arsenic.
Ottawa, Ontario: Water Quality and Health Bureau, Healthy Environments and Consumer Safety Branch,
Health Canada, http://www.hc-sc.gc.ca/ewh-semt/alt formats/hecs-sesc/pdf/pubs/water-eau/arsenic/arsenic-
eng.pdf
HHS (U.S. Department of Health and Human Services). (2004). The health consequences of smoking: A report
of the Surgeon General. Washington, DC.
http://www.cdc.gov/tobacco/data statistics/sgr/2004/complete report/index.htm
Higgins. JPT: Green. S: Collaboration. TC. (2008). Cochrane handbook for systematic reviews of interventions
version 5.0. 2: The Cochrane Collaboration.
Hill AB. (1965). The environment and disease: Association or causation? Proc R Soc Med 58: 295-300.
IARC (International Agency for Research on Cancer). (2006). Preamble to the IARC monographs. Lyon, France.
http://monographs.iarc.fr/ENG/Preamble/
IARC (International Agency for Research on Cancer). (2009). A review of human carcinogens. Part C: Arsenic,
metals, fibres, and dusts. In IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. Lyon,
France: World Health Organization; International Agency for Research on Cancer.
http://monographs.iarc.fr/ENG/Monographs/vollOOC/monolOOC-l.pdf
IOM (Institute of Medicine). (2008). Improving the presumptive disability decision-making process for veterans.
In JM Samet; CC Bodurow (Eds.). Washington, DC: National Academies Press.
http://www.nap.edu/openbook.php7record id=l 1908
Mcconnell. ER. (2013) Systematic omics analysis review tool to support risk assessment (Duke University,
Durham, NC. Retrieved from http://dukespace.lib.duke.edu/dspace/handle/10161/6699
NRC (National Research Council). (1999). Arsenic in drinking water. Washington, DC: National Academy
Press, http://www.nap.edu/catalog/6444.html
NRC (National Research Council). (2001). Arsenic in drinking water: 2001 update. Washington, DC: National
Academy Press, http://www.nap.edu/openbook.php7record id=10194&page=Rl
NRC (National Research Council). (2009). Science and decisions: Advancing risk assessment. Washington, DC:
National Academies Press, http://www.nap.edu/catalog/12209.html
NRC (National Research Council). (2011). Review of the Environmental Protection Agency's draft IRIS
assessment of formaldehyde. Washington, DC: National Academies Press.
http://www.nap.edu/catalog/13142.html
NRC (National Research Council). (2013). Critical aspects of EPA's IRIS assessment of inorganic arsenic:
Interim report. Washington, D.C: The National Academies Press.
NTP (National Toxicology Program). (2013). Draft OHAT approach for systematic review and evidence
integration for literature-based health assessments February 2013. National Institute of Environmental Health
Sciences, National Institutes of Health.
http://ntp.niehs.nih.gov/ntp/ohat/evaluationprocess/draftohatapproach_februarv2013.pdf
Rothman. KJ: Greenland. S. (1998). Modern epidemiology (2nd ed.). Philadelphia, PA: Lippincott, Williams, &
Wilkins.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 1-99 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
SAB (Science Advisory Board). (2007). Advisory onEPAs assessments of carcinogenic effects of organic and
inorganic arsenic: A report of the US EPA Science Advisory Board. (EPA-SAB-07-008). Washington, D.C.:
U.S. Environmental Protection Agency, http://cfpub.epa.gov/ncea/iris drafts/recordisplav.cfm?deid=219111
SAB (Science Advisory Board). (2011). Review Comments onEPAs Responsiveness to SAB 2007
Recommendations for the Revision of Cancer Assessment of Inorganic arsenic. (EPA-SAB-11-003).
Washington, D.C.: U.S. Environmental Protection Agency.
http://vosemite.epa.gov/sab/sabproduct.nsf/9FCEE4E20ABD6EB48525784600791AC2/$File/EPA-SAB-ll-
003-unsigned.pdf
U.S. Congress. (2011). Consolidated Appropriations Act, 2012. (Pub. L. No. 112-74; 125 STAT. 786). 112th
U.S. Congress. http://www.gpo.gov/fdsvs/pkg/PLAW-l 12publ74/pdf/PLAW-l 12publ74.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2005). Guidelines for carcinogen risk assessment.
(EPA/630/P-03/00IF). Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum.
http://www.epa.gov/cancerguidelines/
U.S. EPA (U.S. Environmental Protection Agency). (2006). Revised re-registration eligibility decision document
forMSMA, DSMA, CAMA, andcacodylic acid [EPA Report]. (EPA/738-R-06-021). Washington, DC.
U.S. EPA (U.S. Environmental Protection Agency). (2010). IRIS Toxicological review of inorganic arsenic
(cancer) - external review draft. (EPA/635/R-10/001). Washington, DC.
http://cfpub.epa.gov/ncea/iris drafts/recordisplav.cfm?deid=219111
U.S. EPA (U.S. Environmental Protection Agency). (2012). Benchmark dose technical guidance. (EPA/100/R-
12/001). Washington, DC: Risk Assessment Forum.
http://www.epa.gov/raf/publications/pdfs/benchmark dose guidance.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2013). Integrated science assessment for lead [EPA
Report]. (EPA/600/R-10/075F). Research Triangle Park, NC.
http://ofmpub.epa.gov/eims/eimscomm.getfile7p download id=514513
Wheeler. M: Bailer. AJ. (2009). Comparing model averaging with other model selection strategies for
benchmark dose estimation. EnvironEcol Stat 16: 37-51. http://dx.doi.org/10.1007/sl0651-007-0071-7
WHO (World Health Organization). (2000). Air quality guidelines for Europe (2nd ed.). Copenhagen, Denmark:
World Health Organization, Regional Office for Europe, http://www.euro.who.int/en/what-we-do/health-
topics/environmental-health/air-qualitv/publications/pre2009/air-qualitv-guidelines-for-europe
WHO (World Health Organization). (2011). Safety evaluation of certain contaminants in food. (WHO Food
Additives Series: 63. FAO JECFA Monographs 8). Geneva, Switzerland: prepared by the Seventy-second
meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA.
http://whqlibdoc.who.int/publications/2011/9789241660631 eng.pdf
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
2 LITERATURE SEARCH STRATEGY AND
SYSTEMATIC REVIEW FOR DEVELOPMENT OF
THE TOXICOLOGICAL REVIEW OF INORGANIC
ARSENIC
2.1 Overview of Literature Search Strategy
1 This document describes EPA's systematic approach to literature search, screening and
2 evaluation to identify relevant studies for the toxicological review of inorganic arsenic
3 and summarizes the results of application of this approach. The methods that have been
4 applied for inorganic arsenic are based on evolving EPA guidance on the IRIS process
5 and methods for evaluating potential risk of bias proposed by the National Toxicology
6 Program (NTP) at NIEHS. This approach includes the following components:
7 Computerized keyword search of PubMed, Web of Science, and Toxline using
8 search terms presented here with search updates conducted through December
9 2013;
10 Health effects cluster determination using natural language processing to group
11 studies based on the similarity of their titles and abstracts and then clustering
12 references around known relevant "seed" studies to identify a subset for further
13 review;
14 Categorization of references by subject based on manual review of the title and
15 abstract of each, thereby identifying the toxicology and epidemiology studies that
16 support the identification of a human hazard for inorganic arsenic;
17 Characterization of studies and development of hazard identification tables
18 using the previously identified toxicology and epidemiology studies, resulting in
19 an overview of the available hazard identification literature;
20 Evaluation of potential risk of bias of studies, enabling the identification of the
21 literature likely to serve as primary evidence; and
22 Development of evidence tables for each health effect category that summarize
23 the primary evidence available.
24 Figure 2-1 below outlines the steps in the literature search and review process leading up
25 to development of the hazard identification tables and figures. The results of the
26 systematic review of the inorganic arsenic literature are summarized as well, including
27 the numbers of references identified and screened.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
PubMed
Filters
\ None /
\ / \
Toxline, TSCATS, & DART
Not
PubMed /
Web of Science
V Research ~7
\ Areas /
| 21,489 Articles
13,340 Articles
18,210 Articles)
| 43,802 Articles
[_ Identified from other sources | + 53
*
^
/
- 9,237
- 16,171
- 23,952
-1,280
Arsenic Lit Flow Diagram- Draft 3/27/2013
[ Foreign-l anguage; Reviews; Not peer-
' reviewed
Not found in health effects cluster
Duplicates (83)
Title Screen; No abstract
Book chapter (9)
Not peer-reviewed (394)
Supporting study; Not hazard (705)
Not relevant to Arsenic (89)
Other Studies Total (1765)**
Supporting studies (i.e., reviews, MOA,
susceptibility, PBPK) (751)
Acute exposure (175)
Lxposure (439)
Nori-Arsenk (158)
Not poor-reviewed (104)
Ecology (187)
Other misc. (571)
-158
Misclassiticd; Not inorganic arsenic;
Lead arsenate; No results for arsenic;
Duplicates
* One study included bdth animal and hum.-in results
** Some studies were categorized to multiple
categories
*Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total
number of studies presented in the figure.
Figure 2-1
Literature Flow Diagram
2.2 Computerized Keyword Search
1 The objective of the literature search was to systematically identify and evaluate
2 published literature to consider during development of the toxicological review. To
3 ensure the capture of all of the scientific literature pertinent to assessing the chronic
4 human health effects of exposure to inorganic arsenic, the initial literature search
5 conducted in January 2013 included the PubMed, Web of Science, and Toxline
6 databases. The search strings used for each database are provided in Table 2-1. This
7 initial search resulted in 53,039 references, and after duplicate studies were removed (i.e.,
8 studies that appeared in the search results of multiple databases), 43,802 unique
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 references remained. Additional references submitted for consideration by Agency
2 partners and public stakeholders were added to the list of potentially relevant studies.
3 References identified as foreign-language, not peer-reviewed, or review articles were set
4 aside
5 The initial literature search is updated monthly to identify new literature recently
6 published; unique studies are added to the overall literature database. Those studies that
7 are published in English, peer reviewed, and present original research (i.e., not review
8 articles) are carried through the process to determine if they are relevant to the hazard
9 identification for inorganic arsenic. The current appendices include studies identified in
10 the literature search updates conducted through December 2013.
2.3 Health Effects Cluster Determination
11 The subset of unique references in hand after completion of the first step were then
12 clustered into groups on the basis of language similarity using OmniViz reference
13 visualization software. Using natural language processing, the titles and abstracts of the
14 references were grouped based on similarity. To identify references relevant for hazard
15 identification, approximately 900 references were used as "seed" references. "Seed"
16 references are those previously identified by experts as relevant to hazard identification in
17 peer reviewed inorganic arsenic human health risk assessments. Reference clusters
18 containing one or more of these "seed" references were used to create the health effects
19 cluster of 3,732 references. These 3,732 references formed the basis of subsequent
20 screening for relevance for hazard identification.
21 References identified after the initial literature search were screened manually and
22 clustering was not applied.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Table 2-1 Search Strings for Initial Literature Search
Database
Search String
PubMed
("arsenic"[MeSH Terms] OR "arsenic"[AII Fields]) OR "7440-38-2"[AII Fields] OR
"inorganic arsenic"[AII Fields] OR "monomethylarsenic"[AII Fields] OR
"dimethylarsenic"[AII Fields] OR "methyl arsenic"[AII Fields] OR "monomethylarsonic
acid"[All Fields] OR (124[AII Fields] AND 58[AII Fields] AND 3[AII Fields]) OR
"monomethylarsonous acid"[AII Fields] OR "dimethylarsinic acid"[AII Fields] OR "75-60-
5"[AII Fields] OR "dimethylarsinous acid"[AII Fields] OR "arsenate"[AII Fields] OR
(12523[AII Fields] AND 21[AII Fields] AND 6[AII Fields]) OR "arsenite"[AII Fields] OR
(7784[AII Fields] AND 46[AII Fields] AND 5[AII Fields]) OR "cacodylic acid"[AII Fields] NOT
"arsenic trioxide"[AII Fields])
Web of
Science
(TS=arsenic ORTS="7440-38-2" ORTS="inorganic arsenic" ORTS=monomethylarsenic
OR TS=dimethylarsenic OR TS=methylarsenic OR TS="monomethylarsonic acid" OR
TS="124-58-3" OR TS="monomethylarsonous acid" OR TS="dimethylarsinic acid" OR
TS="cacodylic acid" ORTS="75-60-5" ORTS="dimethylarsenous acid" ORTS=arsenate
OR TS="12523-21-6" OR TS=arsenite OR TS="7784-46-5") NOT TS="arsenic trioxide" NOT
WC="Geochemistry Geophysics" NOT WC="Physics Applied" NOT WC="Physics
Condensed Matter" NOT WC="Materials Science Coatings Films" NOT WC=Optics NOT
WC="Chemistry Physical" NOT WC=Mechanics NOT WC="lnstruments Instrumentation"
NOT WC="Engineering Manufacturing" NOT WC="Materials Science Characterization
Testing" NOT WC=Electrochemistry NOT WC="Metallurgy Metallurgical Engineering"
NOT WC="Chemistry Analytical" NOT WC="Engineering Environmental" NOT
WC="Materials Science Multidisciplinary" NOT WC="Chemistry Inorganic Nuclear" NOT
WC="Engineering Electrical Electronic" NOT WC="Engineering Chemical" NOT
WC=Spectroscopy NOT WC=Crystallography NOT WC="Engineering Civil" NOT
WC="Nanoscience Nanotechnology" NOT WC=Mineralogy NOT WC="Physics Atomic
Molecular Chemical" NOT WC="Mining Mineral Processing" NOT WC="Energy Fuels"
NOT WC="Materials Science Paper Wood" NOT WC="Materials Science Ceramics" NOT
WC="Materials Science Characterization Testing" NOT WC="Physics Nuclear" NOT
WC="Polymer Science" NOT WC=Geology NOT WC=Limnology NOT WC="Engineering
Manufacturing" NOT WC="Agricultural Engineering" NOT WC="Engineering Mechanical"
NOT WC="Computer Science Hardware Architecture" NOT WC="lmaging Science
Photographic Technology")
Toxline
(7440-38-2 OR 124-58-3 OR 75-60-5 OR 7784-46-5 OR arsenic OR "inorganic+arsenic" OR
monomethylarsenic OR dimethylarsenic OR methylarsenic OR "monomethylarsonic
acid" OR "monomethylarsonous acid" OR "dimethylarsinic acid" OR "dimethylarsinous
acid" OR arsenate OR arsenite OR arsenicals) NOT "arsenic trioxide"
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
2.4 Categorization of References
1 Categorization and all steps following were performed in a database to facilitate data
2 management, record-keeping with respect to decisions, and consistency across
3 evaluations conducted by multiple reviewers.
2.4.1 Categorization of Health Effects Literature Based on Title and
Abstract
4 Studies in the health effects cluster were categorized based on review of the title and
5 abstract and placed in one or more of the following pre-determined categories. The
6 primary purpose of this step was to identify epidemiology and toxicology studies
7 potentially relevant to the hazard identification for inorganic arsenic. Studies in other
8 categories might prove useful to development of other sections of the toxicological
9 review and were set aside for later review.
10 Two individuals independently assigned one or more categories to each reference. In
11 cases where the two reviewers' categorization decisions differed, a third senior reviewer
12 evaluated the information and made the final decision. The primary screening identified
13 653 epidemiology studies and 99 animal studies. The full list of categories used in this
14 step included the following study categories.
15 Epidemiologic hazard identification: Human studies relevant for hazard
16 identification of chronic exposure to inorganic arsenic; this included meta-
17 analyses.
18 Animal hazard identification: Animal studies relevant for hazard identification
19 of chronic exposure to inorganic arsenic.
20 Episodic exposure/acute exposure: Poisonings or short-term exposures (up to 30
21 days) that are supportive of the health effects of inorganic arsenic but not related to
22 chronic health effects of inorganic arsenic exposure. This category also included
23 case reports and case series as well as medical uses of arsenic. In some of the case
24 series, exposure could be longer than acute or short term, but such studies are
25 categorized here because they are supportive of the health effects of inorganic
26 arsenic but may not be as informative for the hazard identification. If the hazard
27 identification requires further justification, studies in this category can be reviewed
28 at a later date if necessary.
29 Physical chemistry/engineering: Studies that examine the chemical properties of
30 arsenic or uses of arsenic in chemical engineering.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 Exposure assessment: Studies that only describe the sources/dose of arsenic in the
2 air, water, food, participate matter, plant/animal life (including feed used for
3 livestock that humans consume), and other media. This includes bioavailability
4 studies for the different media and studies that measured levels in humans (e.g., in
5 nails, urine, blood) but did not evaluate any type of health effect in association
6 with the measurements.
7 Non-arsenic: Studies that do not consider arsenic exposure or studies where
8 arsenic was mentioned but was not the primary focus of the publication.
9 Non-peer reviewed: Studies that have not undergone peer review (e.g., newspaper
10 articles, abstracts, posters, news and views, opinion papers, editorials, comments
11 and replies to comments).
12 Ecology: Studies that describe the impact of arsenic on non-mammalian animal
13 models (e.g., fish) or plant life.
14 Review, risk assessment, or guidance document: References that provide
15 reviews of the available literature or references that used EPA guidelines to
16 evaluate risk in a certain area based on exposure levels but did not directly evaluate
17 health outcomes.
18 Susceptibility: Studies in which health effects are evaluated based on factors other
19 than dose (e.g., genetic polymorphisms, susceptibility due to methylation capacity
20 or genetic markers, socio-economic factors, ethnicity). If the study also assessed
21 the effects of inorganic arsenic before assessing the effects of the susceptibility
22 factors, it was considered for the hazard identification.
23 Mode of action (MOA): Studies that examine the molecular events occurring after
24 inorganic arsenic exposure (e.g., in vitro models, genomics, proteomics,
25 genotoxicity, reactive oxygen species).
26 PBPK/TK: Papers that examine internal dose metrics, absorption, excretion,
27 distribution, and metabolism (i.e., toxicokinetics, or TK) or detailed
28 physiologically based pharmacokinetic (PBPK) models that model inorganic
29 arsenic kinetics in humans or animals.
30 Other: Additional papers that do not fit in the above categories, including:
31 Public health campaigns/community knowledge,
32 Analytical technique papers that do not include information on dose metrics
33 orADME,
34 Co-exposure studies where inorganic arsenic cannot be separated,
35 Effects of a different compound in reversing the health effects of inorganic
36 arsenic,
37 Arsenic bioremediation or removal of arsenic from contaminated locations,
38 Treatment methods for arsenic-induced disease, and
39 Effects on bacteria that are not related to MOA/bacterial tolerance.
40
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 Studies with no abstract were evaluated separately and placed into one of the following
2 groups:
3 Book chapters;
4 Not peer-reviewed, including abstracts (identified based on a single page
5 reference), letters, comments, and editorials;
6 Supporting studies;
7 Not relevant to arsenic; or
8 Epidemiologic or animal hazard identification (references in this group were
9 further categorized as described below).
10 Duplicate references were set aside, and only one instance of the study advanced to the
11 next round of screening.
2.4.2 Further Categorization of Epidemiologic and Animal Hazard
Identification Studies
12 Epidemiology studies were further categorized to identify studies reporting effects
13 associated with inorganic arsenic exposure. The evaluation of these references was also
14 conducted by two reviewers independently, with a third individual evaluating the study
15 when the first two reviewers differed. Studies were set aside if they reported the
16 following types of exposures:
17 Exposure to organic arsenic only;
18 Exposure other than to inorganic arsenic only, including cases where the arsenic
19 exposure could not or was not evaluated separately from other possible exposures;
20 Occupational exposure where there was no evaluation of arsenic only (e.g.,
21 evaluation of effects in glass workers or copper smelter workers compared to the
22 general population without any other qualifying exposure information);
23 Environmental exposure where there was no evaluation of arsenic only;
24 Studies where arsenic was not the primary focus (e.g., arsenic was only noted as a
25 confounder for evaluating other chemical exposures); and
26 Studies of exposure to arsenical pesticides or lead arsenate.
27 These studies might be reviewed later in the development; however, they will not serve
28 as primary evidence for development of the hazard identification and causal
29 determination for inorganic arsenic.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
References were also reserved for review in the next step if it was not possible, based on
review of the title and abstract, to determine if results were reported for exposure to
inorganic arsenic only. These included:
Studies reporting exposure to an unknown form of arsenic;
Occupational study where arsenic was evaluated separately from other chemical
exposures; and
Environmental exposure (e.g., air or dust) where results were evaluated separately
for arsenic.
In cases where only urinary or blood levels of arsenic were available, it was not always
possible to identify the type of arsenic exposure based on review of title and abstract.
Because inorganic arsenic is metabolized, the metabolites can be measured in the urine or
blood. Studies reporting urinary or blood arsenic levels of metabolites only were
categorized as "not inorganic arsenic only." Reviewers tended to err on the side of
inclusion in cases where categorization was not clear based on title and abstract review,
so that the full text of studies could be reviewed in the following step. However, if both
reviewers selected "not inorganic arsenic only," the study was characterized as such and
not further evaluated.
2.5 Characterization of Studies and Development of
"Summary of Epidemiological/Toxicological studies for
Hazard Identification" Tables
18 The full text of all epidemiology and toxicology studies identified as reporting inorganic
19 arsenic exposure, including exposure to unknown forms of arsenic, was reviewed to
20 determine the following characteristics.
Epidemiology Studies
Toxicology Studies
Route of exposure
Country in which the study population
lived
Study design
Health effects observed, grouped by
system
Route of exposure
Species and strain
Study design
Health effects observed, grouped by
system
21
22
The information was entered into DRAGON by one reviewer, and each entry was
independently checked by another reviewer.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 In many studies, more than one route of exposure is possible (e.g., an occupational study
2 can evaluate exposures via inhalation and dermal, or a study focusing on oral exposures
3 can also have dermal components if the subjects also bathed in the water). In these cases,
4 the primary route of exposure was used for characterization purposes. In cases where
5 only measurements in blood or urine were available and the study did not indicate the
6 possible exposure route (e.g., only urine levels available in subjects who live in a rural
7 environment with no indication of potential exposure), the study was characterized as
8 both oral and inhalation.
9 Health effects were categorized using a pre-determined standard vocabulary included in
10 DRAGON. In general, health effect categories represent biological systems and health
11 effects can be logically assigned to the appropriate system. In a few cases, the category is
12 more general and represents a collection of outcomes that are not easily categorized in a
13 specific system (e.g., eye effects are assigned to the "Other" group).
14 At any point in these characterizations, a study could be considered misclassified and
15 assigned back to one of the original categories used a priori in the Primary Screen. For
16 example, a publication might re-evaluate data previously published elsewhere. If the
17 publication provides an independent evaluation of data, it was included as part of the
18 hazard identification. However, if the main objective of the publication was a critique of
19 the methods used by others and not a truly independent review (i.e., one presenting
20 previously unpublished evaluation results), it was categorized under "review/risk
21 assessment/guidance document" for potential use as supporting evidence.
22 The tables in the appendix provide an overview of the types and numbers of inorganic
23 arsenic studies available for each health effect category. Epidemiology studies are
24 characterized based on study design, route of exposure, country, and health effects
25 reported. Specific outcomes as reported in the studies are characterized by health effect
26 category, and cancer and non-cancer effects are considered together in the appropriate
27 system. The specific health effect is included in the hazard identification tables, with
28 cancer outcomes listed as "neoplastic lesions." When no studies of a particular type or
29 exposure route were identified, placeholders for those study types or routes are omitted
30 from the tables and figures.
2.6 Evaluation of Potential Risk of Bias
31 The next step in the evaluation process was the analysis of the risk of bias for each study.
32 Because the literature database was still large after the initial screening, categorization,
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1 and characterization steps, assessing risk of bias can help to further differentiate primary
2 evidence from supporting evidence for hazard identification.
2.6.1 General Approach for Risk of Bias Evaluation
3 The Office of Health Assessment and Translation (OHAT) at the National Institute of
4 Environmental Health Science (NIEHS) developed a draft protocol in 2013 for
5 systematic evaluation of risk of bias in human and animal studies. A version of this draft
6 protocol (which continues to evolve) has been adopted for use in this assessment of
7 inorganic arsenic because it provides a unified approach for evaluating risk of bias from
8 animal and epidemiology studies. The OHAT draft protocol includes 14 risk of bias
9 questions grouped in five domains based on the type of potential bias: selection,
10 performance, attrition, detection, and reporting bias. These questions, as discussed in
11 Table 1-6 of the ADP, were derived by OHAT based on guidance from the Agency for
12 Healthcare Research and Quality (AHRQ). The questions are intended to be applied on
13 an outcome-specific basis when evaluating risk of bias (i.e., the rating for some questions
14 depending on what types of health effects are of interest). Not all questions are applicable
15 to both animal and epidemiology studies or to all types of study designs.
16 For each of these 15 questions, a reviewer assigns one of four standard risk of bias
17 ratings, ranging from definitely low risk of bias to definitely high risk of bias (see Table
18 1-7). The rating assigned for each question is intended to represent the bias (or lack
19 thereof) in the related methods and practices employed by the study authors. The set of
20 ratings obtained for a study then can be used to inform an overall risk of bias conclusion
21 for a study. Some of the questions can be assigned different ratings within a given study
22 for different health outcomes, and therefore it is possible to obtain a range of outcome-
23 specific ratings for a single study. Included in the draft OHAT protocol are guidelines for
24 assigning ratings for each question, with separate guidance developed for review of
25 epidemiology and animal studies. The draft OHAT risk of bias rating guidelines are
26 included in Section 2.8 of this summary.
2.6.2 Assessing Risk of Bias for Arsenic Studies
27 For the evaluation of studies identified as potentially relevant to the hazard identification
28 for inorganic arsenic, the draft OHAT risk of bias protocol was applied using the
29 DRAGON database as a framework for managing and recording evaluation results and
30 decisions. The goal of this aspect of the assessment was to assign a rating for each
31 category for every study assessed as objectively as possible. Analysis of risk of bias,
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1 however, necessarily requires subjective conclusions by an expert scientist. To increase
2 consistency across the evaluations conducted in this assessment, each study was
3 independently evaluated by two scientists, and each reviewer's assessment results were
4 recorded independently in DRAGON. Assessment results included both the overall rating
5 associated with a risk of bias question (i.e., ++, +, -, or --) and a written rationale
6 supporting the rating. Reviewers referred to the draft OHAT protocol during their review
7 (with key questions embedded in the DRAGON software for reference). In some cases,
8 the draft OHAT guidelines were augmented with inorganic arsenic-specific guidelines
9 developed for the current assessment. Any additions to the OHAT guidelines are also
10 included in the tables in Attachment A and are clearly marked as specific to this
11 assessment.
12 After independently reviewing a given inorganic arsenic study, the two assigned
13 reviewers discussed and resolved any differences in ratings entered for a question. In
14 some cases, tertiary review by a third senior scientist was conducted of individual ratings
15 or the overall study (plus endpoint) conclusions, and additional quality control reviews
16 were conducted for studies for which conclusions were not straightforward. The resolved
17 ratings for each study were then considered to develop an overall risk of bias conclusion
18 for the study. Because the ratings for some risk of bias questions can vary by health
19 endpoint (e.g., some outcome assessment methods are more reliable than others), a range
20 of overall risk of bias evaluations is possible for a given study (if multiple endpoints were
21 considered in the study). The development of overall risk of bias evaluations for
22 inorganic arsenic animal studies is discussed in Section 6.
23 The risk of bias evaluation process is time-intensive, requiring two scientists to review
24 the full-text version of an article, develop responses to each question, resolve differences,
25 and enter answers and conclusions for each question. Consequently, for the assessment of
26 arsenic literature, an additional sorting step was conducted following the characterization
27 step (described in Section 4) and before full risk of bias evaluation to identify studies less
28 likely to be useful in the overall hazard identification for inorganic arsenic. This step uses
29 several criteria to identify studies considered lower priority for hazard identification, and
30 these studies were set aside without conducting a complete risk of bias evaluation. In
31 addition, key data were not extracted from these studies into evidence tables. It is noted
32 that these studies were not fully "excluded" from consideration for hazard identification;
33 some studies might be used later in this assessment where additional evidence regarding
34 health hazard is needed. Criteria used to identify these lower-priority epidemiology and
35 animal studies are described in the following sections.
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2.6.2.1 Prioritization and Assessing Risk of Bias in Epidemiology Studies
1 For epidemiology studies, all studies with a case-control, cohort, or cross-sectional design
2 were subjected to a full risk of bias evaluation and were extracted into evidence tables.
3 Other studies, including those designed as ecological studies, case series, and case
4 reports, were not evaluated because individual-level exposure information is not used in
5 the analyses and thus they provide less direct support for causal determinations. These
6 studies might be used to provide further support in making causal inferences when other
7 types of studies are not available. For example, some ecological studies are expected to
8 provide supporting information regarding exposure during sensitive development times
9 (e-g-, in utero or childhood exposures) or exposure to susceptible populations.
10 Following this prioritization step, the risk of bias evaluation was conducted for all
11 remaining epidemiology studies in accordance with the guidelines presented in the
12 Appendix (Section 1.6 of the ADP). The results of the risk of bias evaluation are
13 summarized in Section 4 and Section 5, which indicates ratings for each relevant risk of
14 bias question.
2.6.2.2 Prioritization and Assessing Risk of Bias in Animal Arsenic Studies
15 For animal studies, studies that do not include adequate information relevant to hazard
16 identification were eliminated from full risk of bias evaluation. Studies primarily focused
17 on mode of action-related outcomes were not evaluated, including:
18 mode of action studies presenting only data on liver weight for hazard
19 identification; and
20 mode of action studies presenting histopathology data with only descriptions and
21 no incidence data reported.
22 Studies that only evaluated clinical chemistry endpoints as measures of liver toxicity
23 were not evaluated, because this was considered to support clinical chemistry hazard
24 identification rather than identification of liver effects. In addition, developmental studies
25 that presented only pup weight, and/or studies without controls were not evaluated.
26 Following this prioritization step, the risk of bias evaluation was conducted for all
27 remaining animal studies in accordance with the guidelines presented in Section 6.
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2.7 Development of Evidence Tables for Hazard
Identification
2.7.1 Epidemiology Data
2.7.1.1 Criteria for Identifying Primary Evidence Based on Risk of Bias
1 The results of the potential risk of bias evaluation were used to select studies for
2 inclusion in evidence tables. Studies with the lowest potential risk of bias were selected
3 to serve as the primary evidence supporting a causal relationship between inorganic
4 arsenic exposure and outcomes for a given health effect category. Other relevant and
5 useful studies, including those that may pose a higher risk of bias, were identified as
6 providing supporting evidence. The most critical qualities of an epidemiology study with
7 respect to risk of bias were identified to be:
8 Confidence in the observed association based on a study design that allows for
9 evaluation of an association between the exposure and the outcome;
10 Confidence in the exposure assessment;
11 Confidence in the outcome assessment; and
12 Confidence in the overall internal validity of the study.
13 Of the risk of bias questions evaluated for epidemiology studies, six were selected as
14 most informative for addressing these four critical study qualities.
15 Question 3: Were the comparison groups appropriate? (Confidence in observed
16 association)
17 Question 4: Did the study design or analysis account for important confounding
18 and modifying variables? (Confidence in observed association)
19 Question 5: Did researchers adjust or control for other exposures that are
20 anticipated to bias results? (Confidence in observed association)
21 Question 12: Can we be confident in the exposure characterization? (Confidence in
22 exposure assessment)
23 Question 13: Can we be confident in the outcome assessment? (Confidence in
24 outcome assessment)
25 Question 15: Were there no other potential threats to internal validity (e.g.,
26 statistical methods were appropriate)? (Internal validity)
27 Studies receiving a rating of definitely or probably low risk of bias (i.e., + or ++) for all
28 six core questions were identified as primary evidence.
29 Studies receiving a rating of definitely high risk of bias (i.e., - -) for any of the six
30 questions listed above were classified as supporting evidence. These studies might be
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1 considered later in making causal determinations for an effect after evaluation of all
2 primary evidence, but the information in these studies was not extracted into the current
3 evidence tables.
4 Other studies classified as supporting include those receiving a rating of probably high
5 risk of bias (-) for the following questions and combinations of questions:
6 for all 3 observed association questions and exposure assessment and outcome
7 assessment
8 for 2 of the 3 observed association questions and internal validity
9 for exposure assessment, outcome assessment, and internal validity
10 for exposure assessment and 3 of the 4 questions for observed association and
11 internal validity
12 for exposure assessment and 2 of the 5 other questions for observed association,
13 outcome assessment, and internal validity
14 or exposure assessment and unintended exposure if the study is occupational
15 for exposure assessment because the study did not measure arsenic (e.g., skin
16 lesions versus no skin lesions or just control versus exposed with no arsenic
17 measurements)
18 For the epidemiology studies meeting the criteria for "primary" studies, we reviewed the
19 results of the evaluation of potential risk of bias and identified a subset of studies to
20 include in the evidence tables. The evidence tables are not intended to be comprehensive,
21 but rather to provide an overview of the more robust evidence. Thus, following the
22 review of all primary studies, some were not included in the evidence tables. Any studies
23 in this category of "primary but not included in evidence tables" are flagged with a
24 footnote in the attached risk of bias summary tables. Primary studies not included in the
25 evidence tables include studies focused on susceptibility factors, studies stratifying the
26 population based on an existing disease, studies with inorganic arsenic water
27 concentrations exceeding 150 (ig/L, and some additional studies. These studies will be
28 considered in the causal determination along with ecological studies, toxicology studies,
29 and those with potentially high risk of bias (i.e., studies providing "supporting"
30 evidence). In summary, studies selected for inclusion in the evidence tables are an
31 overview of the available data supporting hazard identification.
2.7.1.2 Creation of Evidence Tables
32 Using the studies selected for inclusion in the evidence tables, data were extracted to
33 support a weight of evidence discussion for on the basis of health outcome category.
34 While the hazard identification tables provide an overview of all the information
35 available for any given health effect system, the evidence tables provide more specific
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1 information and present the specific data that support the strongest causal inference
2 conclusions (e.g., using the Hill Criteria) regardless of results (positive, negative, or null).
3 In selecting specific study results and data to present in the evidence table, adjusted
4 statistical estimates were presented rather than crude estimates when possible. All
5 presented matrices of inorganic arsenic exposure (including water, hair, nails, urine) were
6 selected when more than one was available. When multiple inorganic arsenic metrics
7 were presented for the same exposure matrix, cumulative arsenic levels were selected
8 preferentially over other metrics, when available. Total urinary arsenic levels were
9 selected over concentrations of individual metabolites, when available. Within a health
10 effect system, the different measures of the health effect (e.g., pinprick score in left leg,
11 in right leg, in left arm, and in right arm) are included as separate columns in the table.
12 All statistically significant results were included, regardless of health outcome. The null
13 results were included for the main health effects, including lung cancer, bladder cancer,
14 skin cancer, skin lesions, diabetes, and ischemic heart disease. Null results for the health
15 effects not included in this list are described qualitatively.
2.7.2 Animal Data
2.7.2.1 Criteria for Identifying Primary Evidence Based on Risk of Bias
16 As with the epidemiology studies, toxicology studies with the lowest potential risk of bias
17 were selected to serve as the primary evidence to demonstrate evidence of a causal
18 relationship between inorganic arsenic exposure and outcomes for a given health effect
19 category. For toxicology studies, confidence in the outcome assessment was considered
20 to be the most critical quality of a study with respect to risk of bias (i.e., Question 13,
21 "Can we be confident in the outcome assessment?"). Question 12 pertaining to exposure
22 characterization (i.e., "Can we be confident in the exposure characterization?") was also
23 considered to be of importance. Based on these assumptions, the following decision
24 criteria were used to determine a study's utility with respect to evidence.
25 Studies receiving ratings of either definitely or probably low risk of bias
26 (i.e., + or ++) for Question 13 and also receiving the same ratings (i.e., + or ++)
27 for at least half of the remaining questions were included as primary evidence for a
28 given health effect.
29 Studies receiving ratings of either definitely or probably high risk of bias
30 (i.e., - or - -) for Question 13 and also receiving ratings of either definitely or
31 probably high risk of bias (i.e., - or - -) for at least half of the remaining questions
32 were judged to pose a high potential risk of bias. These studies were set aside to be
3 3 reviewed after all other literature.
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1 Any studies receiving a rating of definitely high risk of bias (i.e., - -) for
2 Question 12 were set aside for additional review.
3 Studies that did not meet any of the above criteria were identified to be included as
4 supporting evidence for a given health effect.
5 All animal studies identified as primary evidence for hazard identification based on the
6 risk of bias evaluation were included in the evidence tables for inorganic arsenic.
2.7.2.2 Creation of Evidence Tables
7 The accompanying evidence tables present an overview of the available data for selected
8 health effect categories, using the studies identified as primary evidence in the analysis of
9 risk of bias. The tables are meant to summarize what is known about the effects of
10 inorganic arsenic exposure in animals and do not include every outcome listed in every
11 study. The following types of data were systematically omitted from data extraction and
12 are not included in the attached evidence tables.
13 Hematology, clinical chemistry, and urinalysis results.
14 Histopathology results except when results are expected to potentially inform the
15 causal determination for a health effect for which there is little epidemiologic data;
16 in these cases, relevant significant and nonsignificant results were extracted.
17 Organ weights, except data on thymus weights which immunologists consider a
18 predictor of immune toxicity.
19 Data on cytokines as this information more specifically informs mode of action
20 determinations.
21 Data presented in figures only; a qualitative description of the data was extracted.
2.8 Draft OHAT Guidance for Risk of Bias Evaluation and
Assessment-specific Clarifications
22 Risk of bias questions and rating guidelines for epidemiology studies and animal studies
23 are described in the ADP (Tables 1 -10 and 1 -11).
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3 SUMMARY OF LITERATURE IDENTIFIED TO
SUPPORT HAZARD IDENTIFICATION FOR
INORGANIC ARSENIC
3.1 Overview of Epidemiology Studies Identified
Count of Endpoints by Health Effect Categories
2
t5
i
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.1 Summary of Epidemiology Studies for Hazard Identification for
Bladder Effects
Health Effect Category
Route of Exposure
Study Type
Bladder Effects
Oral
Case-control
Cross-sectional
Cohort
Ecological
Other
Inhalation
Case-control
Cohort
Ecological
Other
Route Unknown.
Case-control
14
27
2
l|
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE-CONTROL
Study References
Bates etal. (1995)
Bates et al. (2004)
Chen etal. (1986)
Chen et al. (2003b)
Chung etal. (2011)
Chung etal. (2013)
Feki-Tounsietal. (2013)
Ferreccio et al. (2013b)
Hsu etal. (2008)
Huang et al. (2008b)
Karagasetal. (2004)
Kurttio etal. (1999)
Meliker et al. (2010)
Pu et al. (2007)
Steinmaus et al. (2003)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
United States
Argentina
Taiwan
Taiwan
Taiwan
Taiwan
Tunisia
Chile
Taiwan
Taiwan
United States
Finland
United States
Taiwan
United States
Health Effect
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions
urinary tract: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
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Steinmaus et al. (2013)
Wang et al. (2009d)
Wu et al. (2012a)
Wu et al. (2013)
Oral
Oral
Oral
Oral
Chile
Taiwan
Taiwan
Taiwan,
Province Of
China
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions
CASE-CONTROL (NESTED)
Study References
Michaud et al. (2004)
Michaud et al. (2004)
Michaud et al. (2004)
Route of
Exposure
Inhalation
Oral
Route
unknown
Country
Finland
Finland
Finland
Health Effect
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
COHORT (PROSPECTIVE)
Study References
Baastrup et al. (2008)
Chen et al. (2010b)
Chiouetal. (1995)
Chiou et al. (2001a)
Chung etal. (2012)
Cuzicketal. (1992)
Hsuetal. (2013a)
Huang et al. (2008a)
Sawadaetal. (2013)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Denmark
Taiwan
Taiwan
Taiwan
Taiwan
United
Kingdom
Taiwan
Taiwan
Japan
Health Effect
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions (2
Types)
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions (2
Types)
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions
urinary tract: neoplastic lesions
urinary bladder: neoplastic lesions
COHORT (RETROSPECTIVE)
Study References
Enterline and Marsh (1982)
Lewis etal. (1999)
Lubin etal. (1981)
Pinto etal. (1978)
Tsuda etal. (1995)
Route of
Exposure
Inhalation
Oral
Inhalation
Inhalation
Oral
Country
United States
United States
United States
United States
Japan
Health Effect
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions (2
Types)
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions
urinary bladder: neoplastic lesions
CROSS-SECTIONAL
Study References
Paul etal. (2013)
Route of
Exposure
Oral
Country
India
Health Effect
urine: parameters
ECOLOGICAL
Study References
Route of
Exposure
Country
Health Effect
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Buchet and Lison (1998)
Chen etal. (1985)
Chen and Wang (1990)
Chen etal. (1992)
Fernandez etal. (2012)
Guo etal. (1997)
Quo etal. (1997)
Guo (2011)
Han etal. (2009)
Hinwood etal. (1999)
Hopenhavn-Rich et al. (1996)
Hopenhavn-Rich et al. (1998)
Lamm et al. (2003)
Lamm etal. (2004)
Marshall etal. (2007)
Meliker et al. (2007)
Morales et al. (2000)
Mouly etal. (2012)
Pou et al. (2011)
Rivaraetal. (1997)
Rivaraetal. (1997)
Smith etal. (1998)
Smith et al. (2012)
Su etal. (2011)
Tsai etal. (1999)
Wu etal. (1989)
Yang et al. (2005)
Yorifuji etal. (2011)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Belgium
Taiwan
Taiwan
Taiwan
Chile
Taiwan
Taiwan
Taiwan
United States
Australia
Argentina
Argentina
Taiwan
United States
Chile
United States
Taiwan
France
Argentina
Chile
Chile
Chile
Chile
Taiwan
Taiwan
Taiwan
Taiwan
Japan
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urethra: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary tract: neoplastic lesions
OTHER
Study References
Begum etal. (2012)
Chu and Crawford-Brown (2006)
Pinto etal. (1977)
Route of
Exposure
Oral
Oral
Inhalation
Country
United States,
Taiwan,
Bangladesh,
West Bengal,
Inner
Mongolia, and
China
Various
United States
Health Effect
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
urinary bladder: neoplastic lesions
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3.1.2 Summary of Epidemiology Studies for Hazard Identification for
Cardiovascular Disease
Health Effect Category
Route of Exposure
Study Type
Cardiovascular Disease
Oral
Case-control
Cross-sectional
Cohort
Ecological
Other
Inhalation
Case-control
Cross-sectional
Cohort
Other
Route Unknown...
Cross-sectional
181
161
14
74
45
23
2
17 |
4
1
10
3|
3
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE SERIES
Study References
Mazumder (2003)
Zaldivar(1980)
Route of
Exposure
Oral
Oral
Country
India
Chile
Health Effect
vascular: disease
heart: function - ischemia
CASE-COHORT
Study References
Chen et al. (2013b)
Chen et al. (2013b)
Route of
Exposure
Oral
Oral
Country
Bangladesh
Bangladesh
Health Effect
cardiovascular disease (2 Types)
cerebrovascular disease
CASE-CONTROL
Study References
Axelsonetal. (1978)
Chen etal. (1988)
Ghosh (2013)
Ghosh (2013)
Ghosh (2013)
Route of
Exposure
Inhalation
Oral
Oral
Oral
Oral
Country
Sweden
Taiwan
India
India
India
Health Effect
vascular: disease
vascular: disease
heart: function - unspecified
heart: neoplastic lesions
heart: nonneoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-5 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Lagerkvist et al. (1988)
Wu et al. (2006)
Inhalation
Oral
Sweden
Taiwan
blood pressure: unspecified (3
Types)
vascular: disease
CASE-CONTROL (NESTED)
Study References
Hsiehetal. (2008a)
Hsiehetal. (2008b)
Hsuehetal. (1998)
Kim et al. (2013)
Liao et al. (2009)
Wang et al. (2007c)
Wu et al. (2010)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Taiwan
Taiwan
Taiwan
United States
Taiwan
Taiwan
Taiwan
Health Effect
vascular: function (2 Types)
vascular: disease
heart: function - ischemia
blood pressure: unspecified
heart: function - rhythm (2 Types)
vascular: disease
vascular: disease
COHORT (PROSPECTIVE)
Study References
Chen etal. (1996)
Chen et al. (2006b)
Chen etal. (2011b)
Chen et al. (2013c)
Cuzick etal. (1992)
Gong and O'Brvant (2012)
Hawkesworth et al. (2013)
Liao et al. (2012)
Moon et al. (2013)
Moon et al. (2013)
Pi et al. (2005)
Sohel etal. (2009)
Wang etal. (2002)
Wang etal. (2010)
Wang etal. (2011a)
Wang etal. (2011a)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Taiwan
Bangladesh
Bangladesh
Bangladesh
United
Kingdom
United States
Bangladesh
Taiwan
United States
United States
China
Bangladesh
Taiwan
Taiwan
Taiwan
Taiwan
Health Effect
heart: function - ischemia
vascular: function
vascular: disease (4 Types)
heart: function - rhythm (3 Types)
vascular: disease
blood pressure: unspecified
blood pressure: unspecified (2
Types)
cardiovascular disease (2 Types)
cardiovascular disease (4 Types)
cerebrovascular disease (2 Types)
vascular: disease
vascular: disease
vascular: disease (3 Types)
vascular: disease (2 Types)
blood pressure: unspecified
vascular: disease
COHORT (RETROSPECTIVE)
Study References
Chiou et al. (2005)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Hertz-Picciotto et al. (2000)
Route of
Exposure
Oral
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Country
Taiwan
United States
United States
United States
United States
United States
Health Effect
vascular: disease
cerebrovascular disease
heart: function - contractility
heart: nonneoplastic lesions
vascular: disease
cardiovascular system:
nonneoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-6 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Jarupetal. (1989)
Jarupetal. (1989)
Lewis etal. (1999)
Lewis etal. (1999)
Lewis etal. (1999)
Lewis etal. (1999)
Lubin etal. (1981)
Marsh etal. (2009)
Pinto etal. (1978)
Rahman etal. (1999a)
Wade etal. (2009)
Wade etal. (2009)
Welch etal. (1982)
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Inhalation
Sweden
Sweden
United States
United States
United States
United States
United States
United States
United States
Bangladesh
China
China
United States
heart: function - ischemia
vascular: disease
cardiovascular disease (7 Types)
cerebrovascular disease
vascular: disease
vascular: function
vascular: disease
vascular: disease
vascular: disease
blood pressure: unspecified
heart: function - rhythm
vascular: disease
heart: function - ischemia
CROSS-SECTIONAL
Study References
Ahmad et al. (2006)
Bosnjaketal. (2008)
Burgess et al. (2013)
Chen et al. (2013a)
Chen etal. (1995)
Chen et al. (2007b)
Chen et al. (2007b)
Chen et al. (2007b)
Chen et al. (2012b)
Chen et al. (2012b)
Chiou etal. (1997)
Chiou et al. (2001b)
Guha Mazumder et al. (2012)
Quo etal. (2007)
Huang et al. (2007)
Huang etal. (2009b)
Islam etal. (2012a)
Islam etal. (2012a)
Islam etal. (2012a)
Jensen and Hansen (1998)
Jones etal. (2011)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Route
unknown
Route
unknown
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Country
Bangladesh
Croatia
United States,
Mexico
Bangladesh
Taiwan
Bangladesh
Bangladesh
Bangladesh
Taiwan,
Province Of
China
Taiwan,
Province Of
China
Taiwan
Taiwan
India
Mongolia
Taiwan
Taiwan
Bangladesh
Bangladesh
Bangladesh
Denmark
United States
Health Effect
heart: function - rhythm
cardiovascular disease
vascular: disease
cardiovascular disease
blood pressure: unspecified
blood pressure: diastolic
blood pressure: systolic
blood pressure: unspecified (2
Types)
blood pressure: unspecified (2
Types)
gene expression
vascular: disease (2 Types)
vascular: disease
blood pressure: unspecified
blood pressure: unspecified
blood pressure: unspecified
vascular: disease
blood pressure: diastolic
blood pressure: systolic
blood pressure: unspecified (3
Types)
blood pressure: systolic
blood pressure: unspecified
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-7 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Ka rim et al. (2013)
Ka rim et al. (2013)
Ka rim et al. (2013)
Ka rim et al. (2013)
Kim and Lee (2011)
Kunrathetal. (2013)
Kwoketal. (2007)
Kwoketal. (2007)
Li et al. (2013a)
Li et al. (2009)
Li et al. (2013b)
Mordukhovich et al. (2009)
Mumford et al. (2007)
Osorio-Yanez et al. (2013)
Rahman and Axelson (2001)
Tseng etal. (1996)
Tseng etal. (1997)
Tseng et al. (2003)
Wang etal. (2009a)
Xia etal. (2009)
Xia etal. (2009)
Yildiz et al. (2008)
Zhang etal. (2013a)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Bangladesh
Bangladesh
Bangladesh
Bangladesh
South Korea
Romania
China
China
China
Taiwan
China
United States
China
Mexico
Bangladesh
Taiwan
Taiwan
Taiwan
Taiwan
China
China
Turkey
China
antibody (B cell) mediated
immunity: general (2 Types)
cholesterol (5 Types)
high sensitivity C reactive protein
(hs-CRP)
inflammatory markers
blood pressure: unspecified
blood pressure: unspecified (12
Types)
blood pressure: diastolic
blood pressure: systolic
blood pressure: unspecified
vascular: disease
blood pressure: unspecified
heart: function - rhythm (2 Types)
heart: function - rhythm (2 Types)
cardiovascular disease (2 Types)
blood pressure: unspecified
vascular: disease
vascular: disease
heart: function - ischemia
heart: function - rhythm (11 Types)
cardiovascular disease
cerebrovascular disease
heart: function - contractility
blood pressure: unspecified
ECOLOGICAL
Study References
Buchet and Lison (1998)
Chang et al. (2004)
Cheng etal. (2010)
Chiu et al. (2007)
Dastgiri et al. (2010)
Engel and Smith (1994)
Jovanovicetal. (2012)
Lisabeth etal. (2010)
Medrano et al. (2010)
Meliker et al. (2007)
Tsai etal. (1999)
Tsai etal. (1999)
Tsai etal. (1999)
Tseng (1977)
Tseng (1989)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Belgium
Taiwan
Taiwan
Taiwan
Iran
United States
Serbia
United States
Spain
United States
Taiwan
Taiwan
Taiwan
Taiwan
Taiwan
Health Effect
heart: nonneoplastic lesions
heart: function - ischemia
vascular: disease
vascular: disease
blood pressure: unspecified
vascular: disease
vascular: function
vascular: disease
vascular: disease
vascular: disease
blood pressure: unspecified
heart: function - ischemia
vascular: disease
vascular: disease
vascular: disease
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-8 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Tseng et al. (2005)
Valentine et al. (1992)
Varsanvi etal. (1991)
Wang etal. (2003)
Wuetal. (1989)
Yang (2006)
Yeh (1973)
Yuan etal. (2007)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Taiwan
United States
Hungary
Taiwan
Taiwan
Taiwan
Taiwan
Chile
vascular: disease
clinical observation
vascular: disease
vascular: disease
vascular: disease
vascular: disease
vascular: disease
vascular: disease
OTHER
Study References
Lagerkvist et al. (1986)
Pinto etal. (1977)
Route of
Exposure
Inhalation
Inhalation
Country
Sweden
United States
Health Effect
vascular: function
heart: function - ischemia
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-9 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.3 Summary of Epidemiology Studies for Hazard Identification for
Clinical Chemistry and Urinalysis
Health Effect Category
Route of Exposure
Study Type
Clinical Chemistry and Urinalysis
Oral
Case-control
Cross-sectional
Cohort
Inhalation.
Cross-sectional
Route Unknown.
Case-control
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE-CONTROL
Study References
Nabietal. (2005)
Nabietal. (2005)
Nabietal. (2005)
Nabietal. (2005)
Shenetal. (2013)
Route of
Exposure
Oral
Oral
Oral
Oral
Route
unknown
Country
Bangladesh
Bangladesh
Bangladesh
Bangladesh
China
Health Effect
alanine aminotransferase (ALT)
alkaline phosphatase (ALP)
aspartate aminotransferase (AST)
cholesterol
urine: parameters (5 Types)
CASE-CONTROL (NESTED)
Study References
Kim etal. (2013)
Route of
Exposure
Oral
Country
United States
Health Effect
albumin
COHORT (PROSPECTIVE)
Study References
Chen et al. (2011c)
Route of
Exposure
Oral
Country
Bangladesh
Health Effect
total protein
CROSS-SECTIONAL
Study References
Casale et al. (2013)
Casale et al. (2013)
Casale et al. (2013)
Route of
Exposure
Inhalation
Oral
Inhalation
Country
Italy
Italy
Italy
Health Effect
alanine aminotransferase (ALT)
alanine aminotransferase (ALT)
aspartate aminotransferase (AST)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-10 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Casale et al. (2013)
Casale et al. (2013)
Casale et al. (2013)
Das et al. (2012a)
Das et al. (2012a)
Das et al. (2012a)
Das et al. (2012a)
Islam et al. (2011)
Islam et al. (2011)
Islam etal. (2011)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Mazumderetal. (2013)
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Italy
Italy
Italy
India
India
India
India
Bangladesh
Bangladesh
Bangladesh
India
India
India
India
India
India
India
India
India
India
India
aspartate aminotransferase (AST)
gamma-glutamyl transpeptidase
(GGT)
gamma-glutamyl transpeptidase
(GGT)
alanine aminotransferase (ALT)
alkaline phosphatase (ALP)
aspartate aminotransferase (AST)
bilirubin
alanine aminotransferase (ALT)
alkaline phosphatase (ALP)
aspartate aminotransferase (AST)
alanine aminotransferase (ALT)
albumin
alkaline phosphatase (ALP)
aspartate aminotransferase (AST)
bilirubin
creatinine
gamma-glutamyl transpeptidase
(GGT)
globulin
total protein
uric acid
urine: parameters
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-11 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.4 Summary of Epidemiology Studies for Hazard Identification for
Developmental Effects including Neurodevelopmental
Health Effect Category
Route of Exposure
Study Type
Developmental Effects including Neurod
Oral
Case-control
Cross-sectional
Cohort
Ecological
Other
Inhalation
Case-control
Cross-sectional
Cohort
Ecological
In Utero..
Cohort
Route Unknown...
Cross-sectional
Cohort
166
123
2
76
36
16 |
1
7
6
2
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE-CONTROL
Study References
Jin etal. (2013)
Jin etal. (2013)
Zierler etal. (1988)
Route of
Exposure
Inhalation
Oral
Oral
Country
China
China
United States
Health Effect
congenital malformation
congenital malformation
congenital malformation
COHORT (PROSPECTIVE)
Study References
Gardner etal. (2013)
Gardner etal. (2013)
Gardner etal. (2013)
Gardner etal. (2013)
Hamadani etal. (2010)
Route of
Exposure
Inhalation
Oral
In utero
Route
unknown
Oral
Country
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Health Effect
developmental milestone (6 Types)
developmental milestone (6 Types)
developmental milestone (6 Types)
developmental milestone (6 Types)
CNS: function - cognition (4 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-12 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Hamadani et al. (2011)
Hopenhavn et al. (2003)
Huvck et al. (2007)
Rahman et al. (2007)
Rahman et al. (2007)
Rahman et al. (2009)
Rahman et al. (2009)
Rahman et al. (2009)
Rahman et al. (2009)
Rahman et al. (2010)
Sahaetal. (2012)
Tofail et al. (2009)
Tofail et al. (2009)
Tofail et al. (2009)
Tofail et al. (2009)
Tofail et al. (2009)
Tofail et al. (2009)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
In utero
Oral
In utero
Oral
In utero
Bangladesh
Chile
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
CNS: function - cognition (3 Types)
birth weight
birth weight
neonatal/infant mortality (3 Types)
number of dead fetuses
birth length
birth weight
growth
head circumference
neonatal/infant mortality
growth (6 Types)
CNS: function - behavioral
CNS: function - behavioral
CNS: function - cognition (2 Types)
CNS: function - cognition (2 Types)
motor activity
motor activity
COHORT (RETROSPECTIVE)
Study References
Sen and Chaudhuri (2007)
Soheletal. (2010)
Route of
Exposure
Oral
Oral
Country
India
Bangladesh
Health Effect
age at first estrous/menses
neonatal/infant mortality
CROSS-SECTIONAL
Study References
Calderon et al. (2001)
Calderon et al. (2001)
Chakraborti et al. (2003)
Gelmann et al. (2013)
Guanetal. (2012)
Guanetal. (2012)
Guanetal. (2012)
Guanetal. (2012)
Khan et al. (2012)
Kippleretal. (2012)
Kippleretal. (2012)
Kwoketal. (2006)
Kwoketal. (2006)
Milton et al. (2005)
Mukherjee et al. (2005)
Mukherjee et al. (2005)
Naharetal. (2014)
Route of
Exposure
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Mexico
Mexico
India
Romania
China
China
China
China
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
India
India
Bangladesh
Health Effect
CNS: function - cognition (7 Types)
CNS: function - cognition (7 Types)
birth weight
birth weight
birth height
birth heightt console
birth height
birth weight
chest circumference
head circumference
CNS: function - cognition (3 Types)
growth (4 Types)
head circumference
birth weight (3 Types)
external malformation
neonatal/infant mortality
birth weight
neonatal/infant mortality
CNS: function - behavioral
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-13 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Naharetal. (2014)
Parvezetal. (2011)
Rocha-Amador et al. (2007)
Rov et al. (2011)
Tsai et al. (2003)
Vail etal. (2012)
Vail etal. (2012)
Vail etal. (2012)
Vail etal. (2012)
Vail etal. (2012)
Von Ehrenstein et al. (2006)
von Ehrenstein et al. (2007)
Wang etal. (2007a)
Wasserman et al. (2004)
Wasserman et al. (2007)
Wasserman et al. (2011)
Wright et al. (2006)
Wright et al. (2006)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Route
unknown
Route
unknown
Bangladesh
Bangladesh
Mexico
Mexico
Taiwan
Spain
Spain
Spain
Spain
Spain
India
India
Bangladesh
Bangladesh
Bangladesh
Bangladesh
United States
United States
10
CNS: function - cognition (5 Types)
CNS: function - cognition (3 Types)
CNS: function - behavioral (4 Types)
CNS: function - behavioral (4 Types)
birth length
birth weight
gestational age at birth (humans)
head circumference
preterm birth/delivery (<37 weeks)
neonatal/infant mortality (2 Types)
CNS: function - cognition (10 Types)
CNS: function - cognition
CNS: function - cognition (3 Types)
CNS: function - cognition (4 Types)
CNS: function - cognition (5 Types)
developmental milestone (8 Types)
10 (3 Types)
ECOLOGICAL
Study References
Aelion et al. (2013)
Chakraborti et al. (2013a)
Cherry et al. (2010)
Engel and Smith (1994)
Gerr et al. (2000)
Hopenhavn-Rich et al. (1999)
Hopenhavn-Rich et al. (2000)
Myers et al. (2010)
Myers et al. (2010)
Route of
Exposure
Inhalation
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Country
United States
Bangladesh;
India
Bangladesh
United States
United States
Chile
Chile
China
China
Health Effect
birth weight
birth weight (2 Types)
neonatal/infant mortality
congenital malformation
CNS: function - behavioral
neonatal/infant mortality
neonatal/infant mortality
birth weight
neonatal/infant mortality
OTHER
Study References
Dong and Su (2009)
Route of
Exposure
Oral
Country
China
Health Effect
CNS: function - cognition
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-14 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.5 Summary of Epidemiology Studies for Hazard Identification for
Digestive System Effects
Health Effect Category
Route of Exposure
Study Type
Digestive System Effects
Oral
Case-control
Cross-sectional
Cohort
Ecological
Inhalation ,
Cohort
Ecological
Other
Dermal.
Other
In Utero.
Cohort
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE REPORT
Study References
Kerr(1875)
Kerr(1875)
Route of
Exposure
Inhalation
Dermal
Country
United
Kingdom
United
Kingdom
Health Effect
clinical observation
clinical observation
CASE-CONTROL
Study References
Amaraletal. (2012)
Route of
Exposure
Oral
Country
Spain
Health Effect
pancreas: neoplastic lesions
COHORT (PROSPECTIVE)
Study References
Baastrup et al. (2008)
Farzan et al. (2013)
Garcia-Esquinas et al. (2013)
Garcia-Esquinas et al. (2013)
Route of
Exposure
Oral
In utero
Oral
Oral
Country
Denmark
United States
United States
United States
Health Effect
digestive system: neoplastic lesions
diarrhea
large intestine: neoplastic lesions
stomach: neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-15 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Hsuetal. (2013b)
Hsuetal. (2013b)
Rahman et al. (2011)
Rahman et al. (2011)
Sawadaetal. (2013)
Sawadaetal. (2013)
Oral
Oral
Oral
In utero
Oral
Oral
Taiwan
Taiwan
Bangladesh
Bangladesh
Japan
Japan
large intestine: neoplastic lesions (2
Types)
stomach: neoplastic lesions
diarrhea
diarrhea
digestive system: neoplastic lesions
stomach: neoplastic lesions
COHORT (RETROSPECTIVE)
Study References
Bulbulyan et al. (1996)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Kreuzeretal. (2012)
Lewis etal. (1999)
Lewis etal. (1999)
Lewis etal. (1999)
Lubin etal. (1981)
Lubin etal. (1981)
Pinto etal. (1978)
Tsuda etal. (1995)
Route of
Exposure
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Inhalation
Inhalation
Inhalation
Oral
Country
Russia
United States
United States
United States
Germany
United States
United States
United States
United States
United States
United States
Japan
Health Effect
stomach: neoplastic lesions
digestive system: neoplastic lesions
large intestine: neoplastic lesions
stomach: nonneoplastic lesions
stomach: neoplastic lesions
digestive system: neoplastic lesions
large intestine: neoplastic lesions
stomach: neoplastic lesions
digestive system: neoplastic lesions
(2 Types)
digestive system: nonneoplastic
lesions
digestive system: neoplastic lesions
large intestine: neoplastic lesions
CROSS-SECTIONAL
Study References
Sved etal. (2013)
Route of
Exposure
Oral
Country
Bangladesh
Health Effect
oral cavity: nonneoplastic lesions (3
Types)
ECOLOGICAL
Study References
Cebrian etal. (1983)
Chen etal. (1985)
Hinwoodetal. (1999)
Hopenhayn-Rich et al. (1996)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Route of
Exposure
Oral
Oral
Oral
Oral
Inhalation
Oral
Inhalation
Oral
Inhalation
Oral
Country
Mexico
Taiwan
Australia
Argentina
Chile
Chile
Chile
Chile
Chile
Chile
Health Effect
clinical observation
large intestine: neoplastic lesions
digestive system: neoplastic lesions
stomach: neoplastic lesions
digestive system: neoplastic lesions
(3 Types)
digestive system: neoplastic lesions
(3 Types)
esophagus: neoplastic lesions
esophagus: neoplastic lesions
stomach: neoplastic lesions
stomach: neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-16 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Tsaietal. (1999)
Valentine et al. (1992)
Wuetal. (1989)
Yang et al. (2008b)
Oral
Oral
Oral
Oral
Taiwan
United States
Taiwan
Taiwan
digestive system: neoplastic lesions
clinical observation
digestive system: neoplastic lesions
large intestine: neoplastic lesions
OTHER
Study References
Pinto etal. (1977)
Route of
Exposure
Inhalation
Country
United States
Health Effect
digestive system: neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-17 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.6 Summary of Epidemiology Studies for Hazard Identification for
Endocrine System Effects including Diabetes
Health Effect Category
Route of Exposure
Study Type
Endocrine System Effects including Diabe
Oral
Case-control
Cross-sectional
Cohort
Ecological
Inhalation.
Case-control
Cross-sectional
Cohort
Ecological
Other
Dermal.
Route Unknown...
Cross-sectional
16 I
2
6
5
1
ll
4 I
4
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE-COHORT
Study References
James etal. (2013)
Route of
Exposu re
Oral
Country
United States
Health Effect
diabetes mellitus
CASE-CONTROL
Study References
Coronado-Gonzalez et al. (2007)
Nizam etal. (2013)
Pan etal. (2013)
Rahman and Axelson (1995)
Rahman etal. (1996)
Route of
Exposure
Oral
Oral
Oral
Inhalation
Inhalation
Country
Mexico
Bangladesh
Bangladesh
Sweden
Sweden
Health Effect
diabetes, type 2
diabetes mellitus
diabetes, type 2
diabetes mellitus
diabetes mellitus
CASE-CONTROL (NESTED)
Study References
Hsiehetal. (2008a)
Hsiehetal. (2008a)
Route of
Exposure
Oral
Oral
Country
Taiwan
Taiwan
Health Effect
growth hormone
testosterone (2 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-18 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Kim et al. (2013)
Kim et al. (2013)
Oral
Oral
United States
United States
blood: glucose (2 Types)
diabetes mellitus
COHORT (PROSPECTIVE)
Study References
Chenetal. (2012a)
Ettinger et al. (2009)
Garcia-Esquinas et al. (2013)
Hsu et al. (2013b)
Hsu et al. (2013b)
Sawada et al. (2013)
Tseng et al. (2000)
Route of
Exposu re
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Taiwan
United States
United States
Taiwan
Taiwan
Japan
Taiwan
Health Effect
diabetes mellitus
gestational diabetes
pancreas: neoplastic lesions
diabetes mellitus
pancreas: neoplastic lesions
pancreas: neoplastic lesions
diabetes mellitus
COHORT (RETROSPECTIVE)
Study References
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Lewis etal. (1999)
Lewis etal. (1999)
Lubin etal. (1981)
Rahman etal. (1998)
Route of
Exposure
Inhalation
Inhalation
Oral
Oral
Inhalation
Oral
Country
United States
United States
United States
United States
United States
Bangladesh
Health Effect
diabetes mellitus (2 Types)
thyroid gland: neoplastic lesions
diabetes mellitus
pancreas: neoplastic lesions
endocrine system: nonneoplastic
lesions (2 Types)
diabetes mellitus
CROSS-SECTIONAL
Study References
Chenetal. (2010c)
Chenetal. (2010c)
Chenetal. (2011a)
Ciarrocca etal. (2012)
Ciarrocca etal. (2012)
Ciarrocca etal. (2012)
Ciarrocca etal. (2012)
Ciarrocca etal. (2012)
Del Razo etal. (2011)
Del Razo etal. (2011)
Del Razo etal. (2011)
Drobna et al. (2013)
Gribbleetal. (2012)
Quo et al. (2007)
Islam etal. (2012b)
Jensen and Hansen (1998)
Jovanovic et al. (2013)
Kim and Lee (2011)
Lai etal. (1994)
Route of
Exposure
Oral
Oral
Oral
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Country
Bangladesh
Bangladesh
Taiwan
Italy
Italy
Italy
Italy
Italy
Mexico
Mexico
Mexico
Mexico
United States
Mongolia
Bangladesh
Denmark
Serbia
South Korea
Taiwan
Health Effect
diabetes mellitus
urine: glucose
diabetes mellitus
diabetes mellitus
thyroglobulin
thyroid stimulating hormone (TSH)
thyroxine (T4)
triiodothyronine (T3)
diabetes mellitus
insulin
insulin resistance
diabetes mellitus
diabetes mellitus
urine: glucose
diabetes, type 2
blood: glucose
diabetes, type 2
diabetes mellitus
diabetes mellitus
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-19 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Lietal. (2013a)
Maitietal. (2012)
Makrisetal. (2012)
Meeker et al. (2009)
Meeker et al. (2009)
Navas-Acien et al. (2008)
Navas-Acien et al. (2009)
Rahman etal. (1999b)
Rahman and Axelson (2001)
Rhee etal. (2013)
Rhee etal. (2013)
Rhee etal. (2013)
Rhee etal. (2013)
Steinmausetal. (2009)
Zierold et al. (2004)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Route
unknown
Route
unknown
Route
unknown
Route
unknown
Oral
Oral
China
India
Cyprus
United States
United States
United States
United States
Bangladesh
Bangladesh
Korea,
Republic Of
Korea,
Republic Of
Korea,
Republic Of
Korea,
Republic Of
United States
United States
diabetes, type 2
blood: glucose
diabetes, type 2
prolactin (PRL)
thyroid stimulating hormone (TSH)
diabetes, type 2
diabetes, type 2
urine: glucose (2 Types)
urine: glucose
diabetes mellitus
glucose stimulated insulin secretion
impaired glucose tolerance
insulin resistance
diabetes, type 2
diabetes, type 2
ECOLOGICAL
Study References
Chang etal. (1991)
Chiu etal. (2006)
Liu-Mares etal. (2013)
Meliker etal. (2007)
Rivaraetal. (1997)
Rivaraetal. (1997)
Tsai etal. (1999)
Wang etal. (2003)
Yorifuii etal. (2011)
Route of
Exposure
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Country
Taiwan
Taiwan
United States
United States
Chile
Chile
Taiwan
Taiwan
Japan
Health Effect
thyroid gland: gross pathology
diabetes mellitus
pancreas: neoplastic lesions
diabetes mellitus
pancreas: neoplastic lesions
pancreas: neoplastic lesions
diabetes mellitus
diabetes mellitus
pancreas: neoplastic lesions
META-ANALYSIS
Study References
Wang et al. (2014)
Wang et al. (2014)
Wang et al. (2014)
Route of
Exposu re
Inhalation
Oral
Dermal
Country
Health Effect
diabetes, type 2
diabetes, type 2
diabetes, type 2
OTHER
Study References
Oiaiarvi etal. (2000)
Route of
Exposure
Inhalation
Country
Multiple
Health Effect
pancreas: neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-20 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.7 Summary of Epidemiology Studies for Hazard Identification for
Hematology, Hematopoietic System
Health Effect Category
Route of Exposure
Study Type
Hematology, Hematopoietic System
Oral
Case-control
Cross-sectional
Cohort
Ecological
Other
Inhalation ...
Ecological
11
5
6
l|
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE SERIES
Study References
Mazumder (2003)
Route of
Exposure
Oral
Country
India
Health Effect
anemia
CASE-CONTROL
Study References
Ghosh (2013)
Route of
Exposure
Oral
Country
India
Health Effect
blood: coagulation/thrombosis
COHORT (PROSPECTIVE)
Study References
Hopenhavn et al. (2006)
Sahaetal. (2013)
Sahaetal. (2013)
Sahaetal. (2013)
Sahaetal. (2013)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Country
Chile
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Health Effect
hematocrit (packed cell volume)
hematocrit (packed cell volume)
hemoglobin
leukocyte count
leukocyte differential
CROSS-SECTIONAL
Study References
Del Razoetal. (2011)
Guoetal. (2007)
Heck et al. (2008)
Maiti et al. (2012)
Route of
Exposure
Oral
Oral
Oral
Oral
Country
Mexico
Mongolia
Bangladesh
India
Health Effect
HbAlc
blood: oxygen
hemoglobin
erythrocyte count
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-21 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Maiti et al. (2012)
Majumdaretal. (2009)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
India
India
India
India
India
India
India
hematocrit (packed cell volume)
hemoglobin
leukocyte count
leukocyte differential
mean corpuscular hemoglobin
concentration
mean corpuscular volume
hemoglobin
ECOLOGICAL
Study References
Buchet and Lison (1998)
Buchet and Lison (1998)
Hinwoodetal. (1999)
Rivaraetal. (1997)
Rivaraetal. (1997)
Wu et al. (1989)
Yorifujietal. (2011)
Route of
Exposure
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Country
Belgium
Belgium
Australia
Chile
Chile
Taiwan
Japan
Health Effect
bone marrow: nonneoplastic
lesions
leukemia
leukemia
leukemia
leukemia
leukemia
hematopoietic system: neoplastic
lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-22 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.8 Summary of Epidemiology Studies for Hazard Identification for
Liver Effects
Health Effect Category
Route of Exposure
Study Type
Liver Effects
Oral
Case-control
Cross-sectional
Cohort
Ecological
Other
Inhalation ...
Cohort
Ecological
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE REPORT
Study References
Morris etal. (1974)
Zaldivaretal. (1981)
Route of
Exposure
Oral
Oral
Country
United
Kingdom
Chile
Health Effect
liver: nonneoplastic lesions
liver: nonneoplastic lesions
CASE SERIES
Study References
Datta etal. (1979)
Mazumder (2003)
Route of
Exposure
Oral
Oral
Country
India
India
Health Effect
liver: nonneoplastic lesions
clinical observation
CASE-CONTROL
Study References
Chen etal. (1986)
Ghosh (2013)
Wadhwaetal. (2011a)
Route of
Exposure
Oral
Oral
Oral
Country
Taiwan
India
Pakistan
Health Effect
liver: neoplastic lesions
liver: gross pathology
liver: neoplastic lesions
COHORT (PROSPECTIVE)
Study References
Baastrup et al. (2008)
Chung etal. (2012)
Route of
Exposure
Oral
Oral
Country
Denmark
Taiwan
Health Effect
liver: neoplastic lesions
liver: neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-23 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Garcia-Esquinas et al. (2013)
Hsuetal. (2013b)
Sawadaetal. (2013)
Oral
Oral
Oral
United States
Taiwan
Japan
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
COHORT (RETROSPECTIVE)
Study References
Enterline and Marsh (1982)
Lewis etal. (1999)
Tsudaetal. (1995)
Route of
Exposure
Inhalation
Oral
Oral
Country
United States
United States
Japan
Health Effect
liver: nonneoplastic lesions (2
Types)
liver: neoplastic lesions
liver: neoplastic lesions
CROSS-SECTIONAL
Study References
Quo etal. (2007)
Maiumdaretal. (2009)
Paul etal. (2013)
Route of
Exposure
Oral
Oral
Oral
Country
Mongolia
India
India
Health Effect
liver: nonneoplastic lesions (2
Types)
liver: gross pathology
liver: neoplastic lesions
ECOLOGICAL
Study References
Buchet and Lison (1998)
Chen etal. (1985)
Chen and Wang (1990)
Chen etal. (1992)
Quo (2003)
Han etal. (2009)
Hinwoodetal. (1999)
Hopenhavn-Rich et al. (1998)
Liaw et al. (2008)
Lin et al. (2013)
Meliker et al. (2007)
Morales et al. (2000)
Rivaraetal. (1997)
Rivaraetal. (1997)
Smith etal. (1998)
Smith et al. (2012)
Tsai etal. (1999)
Wu etal. (1989)
Yorifuji etal. (2011)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Country
Belgium
Taiwan
Taiwan
Taiwan
Taiwan
United States
Australia
Argentina
Chile
Taiwan
United States
Taiwan
Chile
Chile
Chile
Chile
Taiwan
Taiwan
Japan
Health Effect
liver: nonneoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
liver: nonneoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-24 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.9 Summary of Epidemiology Studies for Hazard Identification for
Immune System and Lymphatic Effects
Health Effect Category
Route of Exposure
Study Type
Immune System and Lymphatic Effects
Oral
Case-control
Cross-sectional
Cohort
Ecological
Inhalation.
Cohort
In Utero..
Cohort
Route Unknown...
Cross-sectional
55
44
_2
_29
11
_2
5
5
I
4
4
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE-CONTROL
Study References
Infante-Rivard et al. (2001)
Lu and Chen (1991)
Route of
Exposure
Oral
Oral
Country
Canada
Taiwan
Health Effect
leukemia
cell-mediated immunity effects
COHORT (PROSPECTIVE)
Study References
Ahmed et al. (2012)
Ahmed et al. (2012)
Garcia-Esquinas et al. (2013)
Moore et al. (2009)
Moore et al. (2009)
Raqibetal. (2009)
Raqibetal. (2009)
Raqibetal. (2009)
Sahaetal. (2013)
Soheletal. (2009)
Route of
Exposure
In utero
In utero
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Bangladesh
Bangladesh
United States
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Health Effect
thymus: function
thymus: gross pathology
lymph node: neoplastic lesions
thymus: absolute weight
thymus: relative weight
nonspecific/innate immunity effects
T cells
thymus: function (3 Types)
immunoglobulin
clinical observation
COHORT (RETROSPECTIVE)
Study References
Route of
Country
Health Effect
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-25 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Enterline and Marsh (1982)
Lewis etal. (1999)
Lubinetal. (1981)
Marsh etal. (2009)
Pinto etal. (1978)
Exposure
Inhalation
Oral
Inhalation
Inhalation
Inhalation
United States
United States
United States
United States
United States
lymphoma
lymphoma
lymphoma (2 Types)
clinical observation
lymphoma
CROSS-SECTIONAL
Study References
Biswas et al. (2008)
Biswas et al. (2008)
Bosnjaket al. (2008)
Islam etal. (2007)
Josvula et al. (2006)
Mazumderetal. (2000)
Milton et al. (2001)
Milton and Rahman (2002)
Pesola et al. (2012)
Shiue (2013)
Shiue (2013)
Von Ehrenstein et al. (2005)
Wu et al. (2012b)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Route
unknown
Oral
Oral
Country
India
India
Croatia
Bangladesh
United States
India
Bangladesh
Bangladesh
Bangladesh
United States
United States
India
Bangladesh
Health Effect
cell (Tcell) mediated immunity:
general
nonspecific/innate immunity effects
(6 Types)
nonspecific/innate immunity effects
immunoglobulin
nonspecific/innate immunity effects
(5 Types)
clinical observation
clinical observation
clinical observation
clinical observation
immediate-type hypersensitivity
response (4 Types)
immediate-type hypersensitivity
response (4 Types)
clinical observation
inflammatory markers (6 Types)
ECOLOGICAL
Study References
Han etal. (2009)
Tsai etal. (1999)
Route of
Exposure
Oral
Oral
Country
United States
Taiwan
Health Effect
lymphoma
lymphoma
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-26 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.10 Summary of Epidemiology Studies for Hazard Identification
for Renal Effects
Health Effect Category
Route of Exposure
Study Type
Renal Effects
Oral
Case-control
Cross-sectional
Cohort
Ecological
Inhalation
Case-control
Cross-sectional
Cohort
Ecological
Route Unknown.
Case-control
22
11
1
3
5
2
ll
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE-CONTROL
Study References
Boffetta et al. (2011)
Feng et al. (2013)
Feng et al. (2013)
Ferreccio et al. (2013a)
Ferreccio et al. (2013a)
Huang etal. (2011)
Huang etal. (2012)
Kurttio etal. (1999)
Mostafa and Cherry (2013)
Palaneeswari et al. (2013)
Route of
Exposure
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Route
unknown
Country
Czech
Republic;
Poland;
Romania;
Russian
Federation
China
China
Chile
Chile
Taiwan
Taiwan
Finland
Bangladesh
India
Health Effect
kidney: nonneoplastic lesions
kidney: function
urine: parameters
kidney: neoplastic lesions (3 Types)
ureter: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions (3 Types)
kidney: function
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-27 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
COHORT (PROSPECTIVE)
Study References
Baastrup et al. (2008)
Enterlineetal. (1995)
Garcia-Esquinas et al. (2013)
Hawkesworth et al. (2013)
Hsuetal. (2013b)
Hsuetal. (2013b)
Pi et al. (2005)
Sawadaetal. (2013)
Route of
Exposure
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Country
Denmark
United States
United States
Bangladesh
Taiwan
Taiwan
China
Japan
Health Effect
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: function (2 Types)
kidney: neoplastic lesions
urinary bladder: neoplastic lesions
urine: parameters
kidney: neoplastic lesions
COHORT (RETROSPECTIVE)
Study References
Chiou et al. (2005)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Lewis etal. (1999)
Lewis etal. (1999)
Lubin etal. (1981)
Yuan etal. (2010)
Route of
Exposure
Oral
Inhalation
Inhalation
Oral
Oral
Inhalation
Oral
Country
Taiwan
United States
United States
United States
United States
United States
Chile
Health Effect
kidney: function
kidney: neoplastic lesions
kidney: nonneoplastic lesions (2
Types)
kidney: neoplastic lesions
kidney: nonneoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
CROSS-SECTIONAL
Study References
Chen etal. (2011a)
Eom et al. (2011)
Garcia-Vargas et al. (1994)
Hernandez-Zavala et al. (1999)
Javatilakeetal. (2013)
Jayatilakeetal. (2013)
Ng etal. (2005)
Nordbergetal. (2005)
Route of
Exposure
Oral
Oral
Oral
Oral
Inhalation
Oral
Inhalation
Inhalation
Country
Taiwan
Korea
Mexico
Mexico
Sri Lanka
Sri Lanka
China
China
Health Effect
kidney: function (3 Types)
kidney: function
urine: parameters
urine: parameters
kidney: nonneoplastic lesions
kidney: nonneoplastic lesions
urine: parameters
kidney: function
ECOLOGICAL
Study References
Buchet and Lison (1998)
Chen etal. (1985)
Chen and Wang (1990)
Chen etal. (1992)
Chiu and Yang (2005)
Quo etal. (1997)
Quo etal. (1997)
Han etal. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Belgium
Taiwan
Taiwan
Taiwan
Taiwan
Taiwan
Taiwan
United States
Health Effect
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: function
kidney: neoplastic lesions
ureter: neoplastic lesions
kidney: neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-28 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Hinwoodetal. (1999)
Hopenhavn-Rich et al. (1998)
Meliker et al. (2007)
Meliker et al. (2007)
Moulyetal. (2012)
Rivaraetal. (1997)
Rivaraetal. (1997)
Smith etal. (1998)
Smith et al. (2012)
Tsai etal. (1999)
Tsai etal. (1999)
Wang etal. (2003)
Wang etal. (2009b)
Wu etal. (1989)
Xie etal. (2001)
Yang et al. (2004)
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Australia
Argentina
United States
United States
France
Chile
Chile
Chile
Chile
Taiwan
Taiwan
Taiwan
China
Taiwan
China
Taiwan
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: function
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: neoplastic lesions
kidney: function
kidney: neoplastic lesions
kidney: nonneoplastic lesions
kidney: function
kidney: function
kidney: neoplastic lesions
urine: parameters
kidney: neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-29 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.11 Summary of Epidemiology Studies for Hazard Identification
for Mortality
Health Effect Category
Route of Exposure
Study Type
Mortality
Oral
Cohort
Ecological
Inhalation .
Cohort
13
8
5
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
COHORT (PROSPECTIVE)
Study References
Argos et al. (2010)
Rahman et al. (2013)
Soheletal. (2009)
Soheletal. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Country
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Health Effect
mortality
mortality (2 Types)
mortality
total body neoplastic lesions
COHORT (RETROSPECTIVE)
Study References
Enterline and Marsh (1982)
Lubinetal. (1981)
Pinto etal. (1978)
Tsudaetal. (1994)
Tsuda etal. (1995)
Wade etal. (2009)
Welch etal. (1982)
Route of
Exposure
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Inhalation
Country
United States
United States
United States
Japan
Japan
China
United States
Health Effect
mortality (2 Types)
mortality (2 Types)
mortality
mortality
mortality
total body neoplastic lesions
mortality
ECOLOGICAL
Study References
Brown and Chen (1995)
Medrano et al. (2010)
Smith etal. (1998)
Tsai etal. (1999)
Tseng (1977)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Country
Taiwan
Spain
Chile
Taiwan
Taiwan
Health Effect
mortality
mortality
mortality
mortality
mortality
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-30 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.12 Summary of Epidemiology Studies for Hazard Identification
for Nervous System Effects
Health Effect Category
Route of Exposure
Study Type
Oral
Case-control
Cross-sectional
Cohort
Ecological
Inhalation.
Cross-sectional
Cohort
Ecological
Other
Dermal.
Other
Route Unknown.
Case-control
85
65
2
17
36
31
3
1
1
ll
I
5
Count
*Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number of
studies presented in the figure.
CASE REPORT
Study References
Kerr(1875)
Kerr(1875)
Route of
Exposure
Inhalation
Dermal
Country
United
Kingdom
United
Kingdom
Health Effect
clinical observation
clinical observation
CASE-CONTROL
Study References
Adams etal. (2013)
Ghosh (2013)
Park etal. (2014)
Route of
Exposure
Route
unknown
Oral
Route
unknown
Country
United States
India
Korea,
Republic Of
Health Effect
CNS: function - behavioral (4 Types)
PNS: function
CNS: function - cognition
COHORT (RETROSPECTIVE)
Study References
Route of
Country
Health Effect
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-31 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Chiou et al. (2005)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Lewis etal. (1999)
Navas-Acien et al. (2002)
Exposure
Oral
Inhalation
Inhalation
Oral
Inhalation
Taiwan
United States
United States
United States
Sweden
sensory neuropathy
eye: neoplastic lesions
nervous system: neoplastic lesions
nervous system: neoplastic lesions
brain: neoplastic lesions
CROSS-SECTIONAL
Study References
AN etal. (2010)
Blom etal. (1985)
Chakraborti et al. (2003)
Feldman etal. (1979)
Feldman etal. (1979)
Ghosh etal. (2007b)
Ghosh etal. (2007b)
Gong etal. (2011)
Quo etal. (2007)
Hafeman et al. (2005)
Halatek etal. (2009)
Kreiss etal. (1983)
Kreiss etal. (1983)
Lagerkvist and Zetterlund (1994)
Li et al. (2006)
Lilis etal. (1985)
Lin et al. (2008)
Mackenzie and Kyle (1984)
Mao et al. (2010)
O'Brvantetal. (2011)
Otto et al. (2006)
Otto et al. (2007)
Paul etal. (2013)
Paul etal. (2013)
Rosado et al. (2007)
See et al. (2007)
Siriczuk-Walczak et al. (2010)
Sihczuk-Walczak et al. (2010)
Tseng et al. (2006)
Zierold et al. (2004)
Route of
Exposure
Oral
Inhalation
Oral
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Inhalation
Oral
Inhalation
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Inhalation
Oral
Oral
Country
Bangladesh
Sweden
India
United States
United States
India
India
United States
Mongolia
Bangladesh
Poland
United States
United States
Sweden
China
Canada
Taiwan
Canada
China
United States
China
China
India
India
Mexico
Taiwan
Poland
Poland
Taiwan
United States
Health Effect
cholinesterase activity
PNS: function (2 Types)
sensory neuropathy
sensory function (3 Types)
sensory neuropathy (2 Types)
eye: nonneoplastic lesions
sensory neuropathy
CNS: function - cognition
sensory neuropathy (4 Types)
sensory neuropathy (2 Types)
brain: function (other than FOB) (4
Types)
sensory function (10 Types)
sensory neuropathy
PNS: function (10 Types)
sensory neuropathy (4 Types)
clinical observation
eye: nonneoplastic lesions
PNS: function (2 Types)
brain: function (other than FOB)
CNS: function - cognition (6 Types)
sensory function (4 Types)
sensory neuropathy (8 Types)
eye: function
sensory neuropathy
CNS: function - cognition (11 Types)
eye: nonneoplastic lesions (4 Types)
brain: function (other than FOB) (3
Types)
clinical observation (4 Types)
sensory neuropathy
CNS: function - behavioral
ECOLOGICAL
Study References
Route of
Exposure
Country
Health Effect
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-32 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Ahamed et al. (2006b)
Ahamed et al. (2006a)
Buchet and Lison (1998)
Chakraborti et al. (2013a)
Gerr et al. (2000)
Rahman et al. (2003)
Tseng (2003)
Valentine etal. (1992)
Wang etal. (2003)
Wang etal. (2003)
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Bangladesh
India
Belgium
Bangladesh;
India
United States
India
Taiwan
United States
Taiwan
Taiwan
sensory neuropathy
sensory neuropathy
nervous system: nonneoplastic
lesions
sensory neuropathy
PNS: function
sensory neuropathy
sensory function (9 Types)
clinical observation
eye: nonneoplastic lesions
nervous system: nonneoplastic
lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-33 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.13 Summary of Epidemiology Studies for Hazard Identification
for Other Effects
Health Effect Category
Route of Exposure
Study Type
Oral
Cross-sectional
Cohort
Ecological
Other
Inhalation
Case-control
Cross-sectional
Cohort
Route Unknown...
Cross-sectional
4 I
4
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE SERIES
Study References
Choprapawon and Porapakkham
(2001)
Route of
Exposure
Oral
Country
Thailand
Health Effect
total body neoplastic lesions
CASE-CONTROL
Study References
Sobeletal. (1987)
Route of
Exposure
Inhalation
Country
United States
Health Effect
soft tissue: neoplastic lesions
COHORT (PROSPECTIVE)
Study References
Chiouetal. (1995)
Chung etal. (2012)
Enterlineetal. (1995)
Hsuetal. (2013b)
Wang etal. (2011a)
Route of
Exposure
Oral
Oral
Inhalation
Oral
Oral
Country
Taiwan
Taiwan
United States
Taiwan
Taiwan
Health Effect
total body neoplastic lesions
total body neoplastic lesions (2
Types)
bone: neoplastic lesions
total body neoplastic lesions
total body neoplastic lesions
COHORT (RETROSPECTIVE)
Study References
Route of
Country
Health Effect
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-34 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Bulbulvanetal. (1996)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Nakadaira et al. (2002)
Pinto etal. (1978)
Tsudaetal. (1995)
Exposure
Inhalation
Inhalation
Inhalation
Oral
Inhalation
Oral
Russia
United States
United States
Japan
United States
Japan
total body neoplastic lesions
bone: neoplastic lesions
total body neoplastic lesions
total body neoplastic lesions
total body neoplastic lesions
total body neoplastic lesions
CROSS-SECTIONAL
Study References
Akbal etal. (2013)
Cordova et al. (2013)
Fujinoetal. (2004)
Kurttio etal. (1998)
Maiumdaretal. (2009)
Mazumderetal. (2013)
Mitra et al. (2002)
Paul etal. (2013)
Siriczuk-Walczak et al. (2010)
Syed etal. (2012)
Route of
Exposure
Route
unknown
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Country
Turkey
Mexico
China
Finland
India
India
Bangladesh
India
Poland
Bangladesh
Health Effect
bone: gross pathology (4 Types)
genetic endpoints (2 Types)
brain: function (other than FOB)
clinical observation
clinical observation
hair follicle: gross pathology
clinical observation
bone: neoplastic lesions
clinical observation (4 Types)
CNS: function - behavioral
ECOLOGICAL
Study References
Cebrian etal. (1983)
Dastgiri et al. (2010)
Han etal. (2009)
Mazumderetal. (2009)
Moore et al. (2002)
Smith et al. (2012)
Tsai etal. (1998)
Tsai etal. (1999)
Tsai etal. (1999)
Varsanvi etal. (1991)
Yorifuji etal. (2011)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Mexico
Iran
United States
Cambodia
United States
Chile
Taiwan
Taiwan
Taiwan
Hungary
Japan
Health Effect
clinical observation
hair follicle: nonneoplastic lesions
total body neoplastic lesions
clinical observation
total body neoplastic lesions
total body neoplastic lesions
total body neoplastic lesions
bone: neoplastic lesions
total body neoplastic lesions
total body neoplastic lesions
total body neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-35 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.14 Summary of Epidemiology Studies for Hazard Identification
for Reproductive System Effects including Pregnancy Outcomes
Health Effect Category
Route of Exposure
Study Type
Reproductive System Effects including Pr
Oral
Case-control
Cross-sectional
Cohort
Ecological
Inhalation
Case-control
Cohort
Ecological
Route Unknown.
Case-control
Cohort
60
50
3
16
14
I
1
1
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE-CONTROL
Study References
Ihrig etal. (1998)
Sengupta etal. (2013)
Shenetal. (2013)
Route of
Exposure
Inhalation
Oral
Route
unknown
Country
United States
India
China
Health Effect
stillbirth
sperm parameters (2 Types)
male reproductive system:
nonneoplastic lesions
CASE-CONTROL (NESTED)
Study References
Garland etal. (1996)
Route of
Exposure
Oral
Country
United States
Health Effect
mammary gland: neoplastic lesions
COHORT (PROSPECTIVE)
Study References
Baastrup et al. (2008)
Baastrup et al. (2008)
Garcia-Esquinas et al. (2013)
Route of
Exposure
Oral
Oral
Oral
Country
Denmark
Denmark
United States
Health Effect
female reproductive system:
neoplastic lesions
male accessory sex gland:
neoplastic lesions
male accessory sex gland:
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-36 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Garcia-Esquinas et al. (2013)
Pollack etal. (2013)
Rahman etal. (2010)
Rahman etal. (2010)
Sawadaetal. (2013)
Sawadaetal. (2013)
Sawadaetal. (2013)
Oral
Route
unknown
Oral
Oral
Oral
Oral
Oral
United States
United States
Bangladesh
Bangladesh
Japan
Japan
Japan
neoplastic lesions
mammary gland: neoplastic lesions
female reproductive system
disease/dysfunction
spontaneous abortion/miscarriage
stillbirth
female reproductive system:
neoplastic lesions
male accessory sex gland:
neoplastic lesions
mammary gland: neoplastic lesions
COHORT (RETROSPECTIVE)
Study References
Enterline and Marsh (1982)
Lewis etal. (1999)
Lewis etal. (1999)
Lewis etal. (1999)
Tsuda etal. (1995)
Route of
Exposure
Inhalation
Oral
Oral
Oral
Oral
Country
United States
United States
United States
United States
Japan
Health Effect
testis: neoplastic lesions
female reproductive system:
neoplastic lesions (2 Types)
male accessory sex gland:
neoplastic lesions
uterus: neoplastic lesions
uterus: neoplastic lesions
CROSS-SECTIONAL
Study References
Ahmad etal. (2001)
Chakraborti et al. (2003)
Chakraborti et al. (2003)
Kwok etal. (2006)
Milton et al. (2005)
Milton et al. (2005)
Mukherjee et al. (2005)
Mukherjee et al. (2005)
Mukherjee et al. (2005)
Sen and Chaudhuri (2008)
Sen and Chaudhuri (2008)
Von Ehrenstein et al. (2006)
Von Ehrenstein et al. (2006)
Xu et al. (2012)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Bangladesh
India
India
Bangladesh
Bangladesh
Bangladesh
India
India
India
India
India
India
India
China
Health Effect
postimplantation loss
preterm birth/delivery (<37 weeks)
stillbirth
stillbirth
spontaneous abortion/miscarriage
stillbirth
preterm birth/delivery (<37 weeks)
spontaneous abortion/miscarriage
stillbirth
spontaneous abortion/miscarriage
stillbirth
spontaneous abortion/miscarriage
stillbirth
sperm parameters (3 Types)
ECOLOGICAL
Study References
Aelion et al. (2013)
Ahamed et al. (2006b)
Ahamed et al. (2006b)
Route of
Exposure
Inhalation
Oral
Oral
Country
United States
Bangladesh
Bangladesh
Health Effect
preterm birth/delivery (<37 weeks)
preterm birth/delivery (<37 weeks)
stillbirth
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-37 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Chakraborti et al. (2013a)
Chen and Wang (1990)
Cherry et al. (2008)
Hinwoodetal. (1999)
Meliker et al. (2007)
Myers et al. (2010)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Stocks (1960)
Tsaietal. (1999)
Tsaietal. (1999)
Wuetal. (1989)
Yang et al. (2003)
Yang et al. (2008a)
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Inhalation
Oral
Inhalation
Oral
Inhalation
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Bangladesh;
India
Taiwan
Bangladesh
Australia
United States
China
Chile
Chile
Chile
Chile
Chile
Chile
Chile
Chile
England
Taiwan
Taiwan
Taiwan
Taiwan
Taiwan
spontaneous abortion/miscarriage
male accessory sex gland:
neoplastic lesions
stillbirth
male reproductive system:
neoplastic lesions
female reproductive system:
neoplastic lesions
stillbirth
cervix: neoplastic lesions
cervix: neoplastic lesions
male accessory sex gland:
neoplastic lesions
male accessory sex gland:
neoplastic lesions
mammary gland: neoplastic lesions
mammary gland: neoplastic lesions
testis: neoplastic lesions
testis: neoplastic lesions
mammary gland: neoplastic lesions
cervix: neoplastic lesions
male reproductive system:
neoplastic lesions
male accessory sex gland:
neoplastic lesions
preterm birth/delivery (<37 weeks)
male accessory sex gland:
neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-38 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.15 Summary of Epidemiology Studies for Hazard Identification
for Respiratory Effects
Health Effect Category
Route of Exposure
Study Type
Respiratory Effects
Oral
Case-control
Cross-sectional
Cohort
Ecological
Other
Inhalation
Case-control
Cross-sectional
Cohort
Ecological
Other
In Utero..
Cohort
Route Unknown.
Case-control
2
28
4
1
9 I
9
3|
3
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE SERIES
Study References
Mazumder (2003)
Route of
Exposure
Oral
Country
India
Health Effect
clinical observation
CASE-CONTROL
Study References
Axelsonetal. (1978)
Chen etal. (1986)
D'Erricoetal. (2009)
Dauphineet al. (2013)
Ferreccio et al. (1998)
Ferreccio et al. (2000)
Ferreccio et al. (2013b)
Ghosh (2013)
Route of
Exposure
Inhalation
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Country
Sweden
Taiwan
Italy
United States
Chile
Chile
Chile
India
Health Effect
lung: neoplastic lesions
lung: neoplastic lesions
nasal cavity: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
cough
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-39 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Ghosh (2013)
Ghosh (2013)
Ghosh (2013)
Grimsrud etal. (2005)
Heck et al. (2009)
Hu etal. (1999)
Khlifi et al. (2014)
Khlifi et al. (2014)
Khlifi et al. (2014)
Mostafa et al. (2008)
Steinmaus et al. (2013)
T Mannetie et al. (2011)
Taylor etal. (1989)
Wadhwaetal. (2011b)
Oral
Oral
Oral
Inhalation
Oral
Inhalation
Route
unknown
Route
unknown
Route
unknown
Oral
Oral
Inhalation
Inhalation
Oral
India
India
India
Norway
United States
Canada
Tunisia
Tunisia
Tunisia
Bangladesh
Chile
Central/Easter
n Europe and
UK
China
Pakistan
lung: spirometry
respiratory system: neoplastic
lesions
respiratory system: nonneoplastic
lesions
lung: neoplastic lesions
lung: neoplastic lesions (2 Types)
lung: neoplastic lesions
larynx: neoplastic lesions
pharynx: neoplastic lesions
respiratory system: neoplastic
lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
CASE-CONTROL (NESTED)
Study References
Ades and Kazantzis (1988)
Lee-Feldstein (1989)
Route of
Exposure
Inhalation
Inhalation
Country
FRANCE
United States
Health Effect
lung: neoplastic lesions
lung: neoplastic lesions
COHORT (PROSPECTIVE)
Study References
Baastrup et al. (2008)
Chen et al. (2004a)
Chen et al. (2010a)
Chiou etal. (1995)
Chung etal. (2012)
Enterlineetal. (1995)
Farzan et al. (2013)
Garcia-Esquinas et al. (2013)
Hsuetal. (2013a)
Hsuetal. (2013b)
Mazumdaret al. (1989)
Parvezetal. (2013)
Parvezetal. (2010)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Inhalation
In utero
Oral
Oral
Oral
Inhalation
Oral
Oral
Country
Denmark
Taiwan
Taiwan
Taiwan
Taiwan
United States
United States
United States
Taiwan
Taiwan
United States
Bangladesh
Bangladesh
Health Effect
respiratory system: neoplastic
lesions
lung: neoplastic lesions
lung: neoplastic lesions (6 Types)
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
respiratory system: nonneoplastic
lesions (7 Types)
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: function (2 Types)
clinical observation (3 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-40 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Rahman et al. (2011)
Rahman et al. (2011)
Raqibetal. (2009)
Sawadaetal. (2013)
Smith etal. (2013)
Oral
In utero
Oral
Oral
Oral
Bangladesh
Bangladesh
Bangladesh
Japan
Bangladesh
cough (2 Types)
cough (2 Types)
lung: function
lung: neoplastic lesions
lung: function (8 Types)
COHORT (RETROSPECTIVE)
Study References
Bulbulvan etal. (1996)
Dauphineetal. (2011)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Enterline and Marsh (1982)
Enterline etal. (1987)
Jarupetal. (1989)
Lewis etal. (1999)
Lewis etal. (1999)
Lewis etal. (1999)
Lubin etal. (1981)
Lubin etal. (1981)
Lubin etal. (1981)
Lubin etal. (1981)
Lubin et al. (2000)
Lubin etal. (2008)
Nakadaira et al. (2002)
Pinto etal. (1978)
Pinto etal. (1978)
Smith etal. (2011)
Sorahan (2009)
Tsuda etal. (1995)
Welch etal. (1982)
Welch etal. (1982)
Route of
Exposure
Inhalation
Oral
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Inhalation
Inhalation
Oral
Inhalation
Oral
Inhalation
Inhalation
Country
Russia
Chile
United States
United States
United States
United States
United States
United States
Sweden
United States
United States
United States
United States
United States
United States
United States
United States
United States
Japan
United States
United States
Chile
United States
Japan
United States
United States
Health Effect
lung: neoplastic lesions
lung: function (5 Types)
larynx: neoplastic lesions
lung: function (4 Types)
lung: neoplastic lesions
lung: nonneoplastic lesions
respiratory system: neoplastic
lesions
lung: neoplastic lesions
lung: neoplastic lesions
airway obstruction
respiratory system: neoplastic
lesions
respiratory system: nonneoplastic
lesions
larynx: neoplastic lesions (2 Types)
lung: function (3 Types)
lung: neoplastic lesions
respiratory system: neoplastic
lesions (2 Types)
respiratory system: neoplastic
lesions
respiratory system: neoplastic
lesions
lung: neoplastic lesions
lung: function
respiratory system: neoplastic
lesions
lung: function
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
respiratory system: nonneoplastic
lesions
CROSS-SECTIONAL
Study References
Route of
Country
Health Effect
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-41 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Chakraborti et al. (2013b)
Chattopadhvav et al. (2010)
De et al. (2004)
Ghosh etal. (2007b)
Guoetal. (2007)
Halatek etal. (2009)
Halatek etal. (2009)
Maiumdaretal. (2009)
Mazumderetal. (2005)
Milton et al. (2001)
Nafees etal. (2011)
Parvezetal. (2008)
Paul etal. (2013)
Paul etal. (2013)
Exposure
Oral
Oral
Oral
Oral
Oral
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
India
India
India
India
Mongolia
Poland
Poland
India
India
Bangladesh
Pakistan
Bangladesh
India
India
bronchitis
lung: spirometry
lung: spirometry
lung: function
lung: function
clara cell protein (CC16)
lung: spirometry
lung: nonneoplastic lesions
lung: nonneoplastic lesions
respiratory system: nonneoplastic
lesions
lung: function (3 Types)
lung: spirometry (3 Types)
lung: function
lung: neoplastic lesions
ECOLOGICAL
Study References
Buchet and Lison (1998)
Chen etal. (1985)
Chen and Wang (1990)
Chen and Wang (1990)
Chen etal. (1992)
Chiu et al. (2004)
Engel and Smith (1994)
Engel and Smith (1994)
Quo (2004)
Guoetal. (2004)
Han etal. (2009)
Hinwoodetal. (1999)
Hopenhavn-Rich et al. (1998)
Marshall etal. (2007)
Meliker et al. (2007)
Meliker et al. (2007)
Morales et al. (2000)
Mouly etal. (2012)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Rivaraetal. (1997)
Smith etal. (1998)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Inhalation
Oral
Oral
Country
Belgium
Taiwan
Taiwan
Taiwan
Taiwan
Taiwan
United States
United States
Taiwan
Taiwan
United States
Australia
Argentina
Chile
United States
United States
Taiwan
France
Chile
Chile
Chile
Chile
Chile
Health Effect
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
nasal cavity: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: function
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
respiratory system: neoplastic
lesions
lung: neoplastic lesions
lung: neoplastic lesions
lung: function
respiratory system: neoplastic
lesions
lung: neoplastic lesions
lung: neoplastic lesions
larynx: neoplastic lesions
larynx: neoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions
airway obstruction
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-42 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Smith etal. (1998)
Smith et al. (2006)
Smith et al. (2006)
Smith et al. (2012)
Stocks (1960)
Stocks (1960)
Su etal. (2011)
Tsai etal. (1999)
Tsai etal. (1999)
Wu etal. (1989)
Yorifuii etal. (2011)
Oral
Oral
Oral
Oral
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Chile
Chile
Chile
Chile
England
England
Taiwan
Taiwan
Taiwan
Taiwan
Japan
lung: neoplastic lesions
lung: function
lung: neoplastic lesions
larynx: neoplastic lesions
clinical observation
lung: neoplastic lesions
lung: neoplastic lesions
airway obstruction
respiratory system: neoplastic
lesions
lung: neoplastic lesions
lung: neoplastic lesions
OTHER
Study References
Begum etal. (2012)
Pinto etal. (1977)
Route of
Exposure
Oral
Inhalation
Country
United States,
Taiwan,
Bangladesh,
West Bengal,
Inner
Mongolia, and
China
United States
Health Effect
lung: neoplastic lesions
respiratory system: neoplastic
lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-43 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.1.16 Summary of Epidemiology Studies for Hazard Identification
for Skin Diseases
Health Effect Category
Route of Exposure
Study Type
Skin Diseases
Oral
Case-control
Cross-sectional
Cohort
Ecological
Other
Inhalation
Case-control
Cross-sectional
Cohort
Ecological
Dermal.
Ecological
Route Unknown.
Ecological
156
144
28
56
15
37
10
3
2
ll
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CASE REPORT
Study References
Zaldivaretal. (1981)
Route of
Exposure
Oral
Country
Chile
Health Effect
skin and subcutaneous tissue:
neoplastic lesions
CASE SERIES
Study References
Cabrera and Gomez (2003)
Cabrera and Gomez (2003)
Choprapawon and Porapakkham
Dharetal. (1997)
Route of
Exposure
Oral
Oral
Oral
Oral
Country
Argentina
Argentina
Thailand
Bangladesh
Health Effect
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-44 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Mazumder (2003)
Mazumder (2003)
Yehetal. (1968)
Oral
Oral
Oral
India
India
Taiwan
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
CASE-CONTROL
Study References
Applebaum etal. (2007)
Beane Freeman et al. (2004)
Bhowmick et al. (2013)
Breton et al. (2006)
Chen et al. (2003a)
Ghosh (2013)
Gilbert-Diamond et al. (2013)
Graham etal. (1961)
Guoetal. (2006b)
Hon etal. (2012)
Karagasetal. (2001)
Karagasetal. (2002)
Leonard! etal. (2012)
Lindberg et al. (2010)
McCartv et al. (2006)
McDonald etal. (2007)
Pesch et al. (2002)
Rahman etal. (2006b)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Country
United States
United States
India
Bangladesh
Taiwan
India
United States
United States
Inner
Mongolia
China
United States
United States
Hungary,
Romania,
Slovakia
Bangladesh
Bangladesh
Bangladesh
Slovakia
Bangladesh
Health Effect
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (3 Types)
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions (2 Types)
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-45 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Rahman et al. (2006a)
Ranft et al. (2003)
Ranft et al. (2003)
Rosales-Castillo et al. (2004)
Surduetal. (2013)
Oral
Inhalation
Oral
Oral
Inhalation
Bangladesh
Slovakia
Slovakia
Mexico
Hungary,
Romania,
Slovakia
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
CASE-CONTROL (NESTED)
Study References
Chen et al. (2007c)
Hall etal. (2006)
Haque et al. (2003)
Lindberg et al. (2008)
Route of
Exposure
Oral
Oral
Oral
Oral
Country
Bangladesh
Bangladesh
India
Bangladesh
Health Effect
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
COHORT (PROSPECTIVE)
Study References
Argosetal. (2011)
Baastrup et al. (2008)
Hsuetal. (2013a)
Hsuetal. (2013a)
Hsueh etal. (1997)
Melkonianetal. (2011)
Pierce etal. (2011)
Seowetal. (2012)
Valentine etal. (1991)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Bangladesh
Denmark
Taiwan
Taiwan
Taiwan
Bangladesh
Bangladesh
Bangladesh
United States
Health Effect
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
neoplastic lesions (2 Types)
skin and subcutaneous tissue:
neoplastic lesions (2 Types)
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
nonneoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-46 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
COHORT (RETROSPECTIVE)
Study References
Enterline and Marsh (1982)
Lewis etal. (1999)
Lubinetal. (1981)
Route of
Exposure
Inhalation
Oral
Inhalation
Country
United States
United States
United States
Health Effect
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
CROSS-SECTIONAL
Study References
Ahmad etal. (1999)
Ahsan et al. (2000)
Ahsan etal. (2006)
Argos et al. (2007)
Barati et al. (2010)
Borgono etal. (1977)
Chakraborti et al. (2013b)
Chakraborti et al. (2013b)
Chakraborti et al. (2003)
Chen et al. (2006a)
Fatmi et al. (2009)
Fatmi et al. (2013)
Ghosh etal. (2007b)
Ghosh etal. (2007b)
Quo etal. (2006a)
Guo etal. (2007)
Hashim etal. (2013)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Bangladesh
Bangladesh
Bangladesh
Bangladesh
Iran
Chile
India
India
India
Bangladesh
Pakistan
Pakistan
India
India
China
Mongolia
Cambodia
Health Effect
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (3 Types)
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (6 Types)
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (5 Types)
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-47 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Hsuehetal. (1995)
Knobelochetal. (2006)
Lamm et al. (2007)
Lammetal. (2007)
Li et al. (2013a)
Liu et al. (2013)
Madenetal. (2011)
Maharjan etal. (2005)
Maharian etal. (2007)
Mazumderetal. (1998)
Mazumderetal. (2013)
Mitra et al. (2002)
Mosaferi et al. (2008)
Paul etal. (2013)
Pavittranon et al. (2003)
Pei etal. (2013)
Perry et al. (1948)
Pesola et al. (2012)
Schafer etal. (1999)
Smith et al. (2000)
Tondel etal. (1999)
Valenzuela et al. (2005)
Xia etal. (2009)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Oral
Inhalation
Oral
Oral
Oral
Oral
Taiwan
United States
China
China
China
China
Nepal
Nepal
Nepal
India
India
Bangladesh
Iran
India
Thailand
China
Not Specified
Bangladesh
Germany
Chile
Bangladesh
Mexico
China
nonneoplastic lesions (4 Types)
skin and subcutaneous tissue:
nonneoplastic lesions
soft tissue: neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-48 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
nonneoplastic lesions
ECOLOGICAL
Study References
Ahamed et al. (2006b)
Ahamed et al. (2006a)
Bencko et al. (2009)
Besuschio et al. (1980)
Biswas etal. (1998)
Brown et al. (1989)
Cebrian etal. (1983)
Chakraborti et al. (2013a)
Chen etal. (1985)
Chen and Wang (1990)
Del Razo etal. (1997)
Quo etal. (1998)
Guo etal. (2001)
Hinwood etal. (1999)
Hopenhavn-Rich et al. (1998)
Maharian etal. (2006)
Mazumderetal. (2009)
Mazumderetal. (2010)
Mcdonald et al. (2006)
Morton etal. (1976)
Mouly etal. (2012)
Route of
Exposure
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Country
Bangladesh
India
Slovakia
Argentina
Bangladesh
Taiwan
Mexico
Bangladesh;
India
Taiwan
Taiwan
Mexico
Taiwan
Taiwan
Australia
Argentina
Nepal
Cambodia
India
Bangladesh
United States
France
Health Effect
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-49 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Philippetal. (1983)
Philippetal. (1983)
Philippetal. (1983)
Rahman et al. (2003)
Rahman et al. (2005c)
Rahman et al. (2005a)
Rahman et al. (2005b)
Rivaraetal. (1997)
Rivaraetal. (1997)
Saha and Poddar (1986)
Smith etal. (1998)
Tsaietal. (1999)
Tseng etal. (1968)
Tseng (1977)
Valentine etal. (1992)
Valentine etal. (1992)
Wheeler etal. (2013)
Wu etal. (1989)
Yeh (1973)
Yu etal. (2007)
Inhalation
Oral
Dermal
Oral
Oral
Oral
Oral
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Route
unknown
Oral
Oral
Oral
United
Kingdom
United
Kingdom
United
Kingdom
India
India
India
India
Chile
Chile
India
Chile
Taiwan
Taiwan
Taiwan
United States
United States
United
Kingdom
Taiwan
Taiwan
China
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions (2 Types)
skin and subcutaneous tissue:
neoplastic lesions
clinical observation
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-50 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2 Summary of Toxicology Literature Identified to Support
Hazard Identification for Inorganic Arsenic
3.2.1 Overview of Toxicology Studies Identified
Count of Endpoints by h
Reproductive System Effects including Pregnancy...
Developmental Effects including...
Clinical Chemistry and Urinalysis
ealth Effect Categories
Nervous System Effects
Hematology, Hematopoietic System
o Liver Effects
w>
| Other _^HHH^HB
£ Renal Effects §
t Endocrine System Effects including Diabetes §
LLJ ~ -J 1
£ Immune System and Lymphatic Effects ^^^^^B
« Respiratory Effects §
Cardiovascular Disease
Bladder Effects
Skin Diseases
Digestive System Effects
Mortality
i
i
0 20 40 60 80 100 120
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-51 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.2 Summary of Toxicology Studies for Hazard Identification for
Bladder Effects
Health Effect Category
Route of Exposure
Study Type
Bladder Effects
Oral
Chronic (>90 days)
Reproductive/Developmental
Inhalation
Subchronic (30 days to < 90 days)
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Nain and Smits (2012)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Species
rat
mice
Health Effect
urinary bladder: nonneoplastic
lesions
urinary bladder: nonneoplastic
lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Tokaretal. (2010b)
Tokaretal. (2010b)
Tokaretal. (2011)
Tokaretal. (2012)
Tokaretal. (2012)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
mice
mice
mice
mice
mice
mice
mice
Health Effect
urinary bladder: neoplastic lesions
(4 Types)
urinary bladder: nonneoplastic
lesions (2 Types)
urinary bladder: nonneoplastic
lesions (2 Types)
urinary bladder: neoplastic lesions
urinary bladder: nonneoplastic
lesions
urinary bladder: nonneoplastic
lesions (2 Types)
urinary bladder: neoplastic lesions
urinary bladder: nonneoplastic
lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-52 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Route of
Exposure
Inhalation
Inhalation
Species
mice
rat
Health Effect
urinary bladder: nonneoplastic
lesions
urinary bladder: nonneoplastic
lesions
3.2.3 Summary of Toxicology Studies for Hazard Identification for
Cardiovascular Disease
Health Effect Category
Route of Exposure
Study Type
Cardiovascular Disease
Oral.
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation
Subchronic (30 days to < 90 days)
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Bunderson et al. (2004)
Bunderson et al. (2004)
Nain and Smits (2012)
Sanchez-Soria et al. (2012)
Sanchez-Soria et al. (2012)
Sanchez-Soria et al. (2012)
Sanchez-Soria et al. (2012)
Simeonova et al. (2003)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
mice
rat
mice
mice
mice
mice
mice
Health Effect
inflammatory markers
vascular: nonneoplastic lesions (2
Types)
vascular: nonneoplastic lesions
blood pressure: diastolic
blood pressure: systolic
cardiovascular system:
nonneoplastic lesions
heart: relative weight
vascular: nonneoplastic lesions (2
Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-53 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Soucy et al. (2005)
Srivastava et al. (2009)
Stepniketal. (2009)
Oral
Oral
Oral
mice
mice
mice
vascular: gross pathology (2 Types)
heart: nonneoplastic lesions (2
Types)
heart: nonneoplastic lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Rogers et al. (2014)
Route of
Exposure
Oral
Species
rat
Health Effect
blood pressure: systolic (2 Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Lemaire et al. (2011)
Lemaireetal. (2011)
Sharma and Sharma (2013)
Soucy et al. (2005)
Srivastava et al. (2009)
Route of
Exposure
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Species
mice
rat
mice
mice
rat
mice
mice
Health Effect
cardiovascular system:
nonneoplastic lesions
cardiovascular system:
nonneoplastic lesions
cardiovascular system:
nonneoplastic lesions
vascular: nonneoplastic lesions
vascular: function
vascular: gross pathology (4 Types)
heart: nonneoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-54 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.4 Summary of Toxicology Studies for Hazard Identification for
Clinical Chemistry and Urinalysis
Health Effect Category
Route of Exposure
Study Type
Clinical Chemistry and Urinalysis
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
47
45
23
13
9
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Das et al. (2012b)
Arteel et al. (2008)
Dwivedi and Flora (2011)
Dwivedi and Flora (2011)
Liu et al. (2000)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Simeonova et al. (2003)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
goat
mice
rat
rat
mice
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
mice
Health Effect
clinical chemistry, unspecified (3
Types)
clinical chemistry, unspecified
alanine aminotransferase (ALT)
aspartate aminotransferase (AST)
clinical chemistry, unspecified (2
Types)
alanine aminotransferase (ALT)
alkaline phosphatase (ALP)
aspartate aminotransferase (AST)
blood urea nitrogen (BUN)
blood: glucose
chloride
creatine kinase
creatinine
gamma-glutamyl transpeptidase
(GGT)(2Types)
potassium
sodium
total protein
clinical chemistry, unspecified (2
Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-55 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Srivastava et al. (2009)
Srivastava et al. (2009)
Wang et al. (2009b)
Wangetal. (2009b)
Wu et al. (2004)
Oral
Oral
Oral
Oral
Oral
mice
mice
rat
rat
mice
cholesterol (2 Types)
triglycerides (2 Types)
blood: glucose
N-acetyl-beta-D-glucosaminidase
(NAG)
urine: parameters
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Rogers et al. (2014)
Ahmad etal. (2013)
Antonio Garcia et al. (2013)
Davila-Esqueda et al. (2011)
Davila-Esqueda et al. (2011)
Davila-Esqueda et al. (2011)
Srivastava et al. (2007)
Srivastava et al. (2007)
Srivastava et al. (2007)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
mice
rat
rat
rat
rat
mice
mice
mice
Health Effect
clinical chemistry, unspecified
clinical chemistry, unspecified
clinical chemistry, unspecified
cholesterol (2 Types)
clinical chemistry, unspecified
triglycerides
cholesterol
clinical chemistry, unspecified
triglycerides
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Fouad etal. (2012)
Owumi et al. (2013)
Patra etal. (2012)
Patra etal. (2012)
Kharroubi etal. (2014)
Kharroubi etal. (2014)
Kharroubi etal. (2014)
Kharroubi etal. (2014)
Lemaireetal. (2011)
Majhi etal. (2011)
Sharma and Sharma (2013)
Srivastava et al. (2009)
Srivastava et al. (2009)
Route of
Exposure
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
mice
mice
rat
goat
goat
rat
rat
rat
rat
mice
rat
rat
mice
mice
Health Effect
clinical chemistry, unspecified
clinical chemistry, unspecified
alanine aminotransferase (ALT)
clinical chemistry, unspecified
alanine aminotransferase (ALT)
aspartate aminotransferase (AST)
alanine aminotransferase (ALT)
alkaline phosphatase (ALP)
aspartate aminotransferase (AST)
clinical chemistry, unspecified
clinical chemistry, unspecified
clinical chemistry, unspecified (2
Types)
clinical chemistry, unspecified
cholesterol
triglycerides
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-56 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.5 Summary of Toxicology Studies for Hazard Identification for
Developmental Effects including Neurodevelopmental
Health Effect Category
Route of Exposure
Study Type
Developmental Effects including Neurod
Oral
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Reproductive/Developmental
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Nagymaitenyi et al. (1985)
Nagymajtenyi et al. (1985)
Nagymaitenyi et al. (1985)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Colomina etal. (1997)
Colomina etal. (1997)
Gandhi etal. (2012)
Gandhi etal. (2012)
Gandhi etal. (2012)
Gandhi etal. (2012)
Gandhi etal. (2012)
Mivazaki et al. (2005)
Reillv etal. (2013)
Rogers et al. (2014)
Route of
Exposure
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
mice
mice
rat
rat
rat
rat
rat
mice
mice
rat
rat
rat
rat
rat
mice
rat
rat
Health Effect
fetal body weight (2 Types)
number of dead fetuses
skeletal variation, malformation, or
anomaly
crown-rump length
external malformation
fetal body weight
skeletal variation, malformation, or
anomaly
soft-tissue variation, malformation,
or anomaly
developmental milestone (2 Types)
functional observation
battery/neuro-behavioral (7 Types)
developmental milestone
external malformation
functional observation
battery/neuro-behavioral
motor activity
reflex ontogeny (9 Types)
fetal body weight
day at vaginal opening
birth weight (2 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-57 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Ahmad et al. (2013)
Ahmad et al. (2013)
Antonio Garcia et al. (2013)
Antonio Garcia et al. (2013)
Chattopadhvav et al. (2002)
Chattopadhyay et al. (2002)
Chattopadhvav et al. (2002)
Cronican et al. (2013)
Cronican et al. (2013)
He et al. (2007)
He et al. (2007)
He et al. (2007)
Herrera et al. (2013)
Herrera et al. (2013)
Herrera et al. (2013)
Luoetal. (2013)
Luoetal. (2013)
Markowski et al. (2012)
Markowski et al. (2012)
Markowski et al. (2012)
Markowski et al. (2012)
Markowski et al. (2012)
Markowski et al. (2012)
Markowski et al. (2012)
Martinez et al. (2008)
Martinez-Finlev et al. (2009)
Martinez-Finley et al. (2009)
Ramsevetal. (2013a)
Ramsevetal. (2013c)
Ramsevetal. (2013c)
Rios et al. (2009)
Rodriguez et al. (2002)
Rodriguez et al. (2002)
Rodriguez et al. (2002)
Rodriguez et al. (2002)
Rodriguez et al. (2002)
Rodriguez et al. (2002)
Xi et al. (2009)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
mice
mice
rat
rat
rat
rat
rat
mice
mice
mice
mice
mice
rat
rat
rat
rat
rat
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
rat
rat
rat
rat
rat
rat
rat
rat
developmental milestone
functional observation
battery/neuro-behavioral (9 Types)
body weight
crown-rump length
brain: gross pathology
motor activity
number of dead fetuses
birth weight
external malformation
litter weight (2 Types)
postnatal body weight
soft-tissue variation, malformation,
or anomaly
brain: absolute weight
brain: relative weight
postnatal body weight
brain: nonneoplastic lesions
functional observation
battery/neuro-behavioral
anogenital distance (2 Types)
body weight gain (2 Types)
crown-rump length (2 Types)
developmental milestone (6 Types)
functional observation
battery/neuro-behavioral (9 Types)
motor activity (2 Types)
onset of puberty (2 Types)
functional observation
battery/neuro-behavioral (3 Types)
brain: absolute weight
functional observation
battery/neuro-behavioral (2 Types)
birth weight (2 Types)
birth length
birth weight
brain: nonneoplastic lesions
body weight
CNS: function - cognition (4 Types)
developmental milestone (6 Types)
locomotor activity (2 Types)
motor activity (2 Types)
postnatal body weight
CNS: function - cognition (7 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-58 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Xi et al. (2009)
Xi et al. (2009)
Xi et al. (2009)
Oral
Oral
Oral
rat
rat
rat
developmental milestone (12
Types)
locomotor activity
postnatal body weight
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Nagaraja and Desiraju (1993)
Nagaraia and Desiraiu (1993)
Route of
Exposure
Oral
Oral
Species
rat
rat
Health Effect
brain: absolute weight
developmental milestone
3.2.6 Summary of Toxicology Studies for Hazard Identification for
Digestive System Effects
Health Effect Category
Route of Exposure
Study Type
Subchronic (30 days to < 90 days)
Count
Digestive System Effects
Reproductive/Developmental
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Stepniketal. (2009)
Route of
Exposure
Oral
Species
mice
Health Effect
digestive system: nonneoplastic
lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Tokaretal. (2011)
Tokaretal. (2011)
Route of
Exposure
Oral
Oral
Species
mice
mice
Health Effect
digestive system: neoplastic lesions
(8 Types)
digestive system: nonneoplastic
lesions (2 Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Route of
Species
Health Effect
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-59 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Blair etal. (1990b)
Blair etal. (1990b)
Exposure
Inhalation
Inhalation
mice
rat
pancreas: nonneoplastic lesions
pancreas: nonneoplastic lesions
3.2.7 Summary of Toxicology Studies for Hazard Identification for
Endocrine System Effects including Diabetes
Health Effect Category
Route of Exposure
Study Type
Endocrine System Effects including Diabe
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
28
26
_2
2
22
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Nain and Smits (2012)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Species
rat
mice
Health Effect
thyroid gland: nonneoplastic lesions
endocrine system: nonneoplastic
lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Reillv etal. (2013)
Reilly etal. (2013)
Reillv etal. (2013)
Reillv etal. (2013)
Davila-Esqueda et al. (2012)
Davila-Esqueda et al. (2012)
Davila-Esqueda et al. (2011)
Davila-Esqueda et al. (2011)
Davila-Esqueda et al. (2011)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
rat
rat
rat
rat
rat
rat
rat
rat
Health Effect
estrogen
estrous cyclicity
growth hormone
luteinizing hormone (LH)
adrenal gland: absolute weight
adrenal gland: nonneoplastic
lesions
blood: glucose (4 Types)
hematology, unspecified (5 Types)
pancreas: nonneoplastic lesions (2
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-60 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Goggin et al. (2012)
Martinez et al. (2008)
Tokaretal. (2010b)
Tokaretal. (2010b)
Tokaretal. (2011)
Tokaretal. (2012)
Waalkes et al. (2004b)
Waalkes et al. (2006a)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Waalkes et al. (2003)
Waalkes et al. (2003)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
Types)
glucocorticoids
corticosterone
adrenal gland: neoplastic lesions (2
Types)
adrenal gland: nonneoplastic
lesions
adrenal gland: neoplastic lesions (2
Types)
adrenal gland: neoplastic lesions
adrenal gland: neoplastic lesions (3
Types)
adrenal gland: neoplastic lesions
thyroid gland: nonneoplastic lesions
adrenal gland: neoplastic lesions
thyroid gland: neoplastic lesions
adrenal gland: neoplastic lesions (3
Types)
thyroid gland: neoplastic lesions (2
Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Paul etal. (2007)
Yen et al. (2007)
Route of
Exposure
Inhalation
Inhalation
Oral
Oral
Species
mice
rat
mice
mice
Health Effect
endocrine system: nonneoplastic
lesions
endocrine system: nonneoplastic
lesions
blood: glucose
pancreas: nonneoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-61 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.8 Summary of Toxicology Studies for Hazard Identification for
Hematology, Hematopoietic System
Health Effect Category
Route of Exposure
Study Type
Hematology, Hematopoietic System
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
26
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Ghataketal. (2011)
Dwivedi and Flora (2011)
Dwivedi and Flora (2011)
Dwivedi and Flora (2011)
Dwivedi and Flora (2011)
Dwivedi and Flora (2011)
Dwivedi and Flora (2011)
Dwivedi and Flora (2011)
Dwivedi and Flora (2011)
Flora etal. (2012)
Nain and Smits (2012)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
rat
rat
rat
rat
rat
rat
rat
rat
mice
rat
mice
Health Effect
hematology, unspecified (2 Types)
erythrocyte count
hematocrit (packed cell volume)
hemoglobin
leukocyte count
mean corpuscular hemoglobin
mean corpuscular hemoglobin
concentration
mean corpuscular volume
platelet count and morphologic
assessment
hematology, unspecified
spleen: nonneoplastic lesions
bone marrow: nonneoplastic
lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Antonio Garcia et al. (2013)
Davila-Esqueda et al. (2011)
Tokaretal. (2010b)
Tokaretal. (2010b)
Route of
Exposure
Oral
Oral
Oral
Oral
Species
rat
rat
mice
mice
Health Effect
hematology, unspecified
hematology, unspecified
leukemia (4 Types)
spleen: nonneoplastic lesions (2
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-62 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Tokaretal. (2012)
Waalkesetal. (2004b)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2003)
Oral
Oral
Oral
Oral
Oral
mice
mice
mice
mice
mice
Types)
vascular: neoplastic lesions (2
Types)
spleen: nonneoplastic lesions (2
Types)
spleen: nonneoplastic lesions
spleen: neoplastic lesions
spleen: neoplastic lesions (2 Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990a)
Hong etal. (1989)
Hong etal. (1989)
Hong etal. (1989)
Hong etal. (1989)
Hong etal. (1989)
Hong etal. (1989)
Ferzand et al. (2008)
Ferzand et al. (2008)
Odstrcil et al. (2010)
Sankaretal. (2013)
Yen et al. (2007)
Route of
Exposure
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Species
rat
mice
rat
rat
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
rat
rat
mice
Health Effect
hematology, unspecified
hematology, unspecified
spleen: absolute weight
spleen: nonneoplastic lesions
spleen: nonneoplastic lesions
spleen: relative weight
hematology, unspecified (2 Types)
bone marrow: nonneoplastic
lesions (3 Types)
hematology, unspecified
hematopoietic system:
nonneoplastic lesions
spleen: absolute weight
spleen: nonneoplastic lesions
spleen: relative weight
hematology, unspecified
spleen: nonneoplastic lesions
hematology, unspecified
spleen: relative weight
hematology, unspecified
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-63 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.9 Summary of Toxicology Studies for Hazard Identification for
Immune System and Lymphatic Effects
Health Effect Category
Route of Exposure
Study Type
Immune System and Lymphatic Effects
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Das et al. (2012b)
Das et al. (2012b)
Nain and Smits (2012)
Nain and Smits (2012)
Stepniketal. (2009)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Species
goat
goat
rat
rat
mice
mice
Health Effect
cell-mediated immunity effects
immunoglobulin
antibody (B cell) mediated
immunity: general (2 Types)
innate immunity/inflammation:
general
immune and lymphatic system:
nonneoplastic lesions
lymphoma
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Ramsey etal. (2013b)
Ramsey etal. (2013b)
Tokaretal. (2010b)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Waalkes et al. (2003)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
mice
mice
mice
mice
mice
mice
Health Effect
innate immunity/inflammation:
functional (2 Types)
innate immunity/inflammation:
general (2 Types)
lymphoma (2 Types)
thymus: nonneoplastic lesions
lymphoma
thymus: neoplastic lesions
thymus: neoplastic lesions (2 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-64 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Kozul et al. (2009)
Kozul et al. (2009)
Kozul et al. (2009)
Kozul et al. (2009)
Ramsey etal. (2013b)
Sankaretal. (2013)
Sankaretal. (2013)
Route of
Exposure
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
mice
rat
mice
mice
mice
mice
mice
mice
rat
rat
Health Effect
immune and lymphatic system:
nonneoplastic lesions
immune and lymphatic system:
nonneoplastic lesions
thymus: absolute weight
thymus: absolute weight
innate immunity/inflammation:
functional
innate immunity/inflammation:
general
lymph node: function
lymph node: gross pathology
innate immunity/inflammation:
functional (2 Types)
antibody-mediated immunity
effects (2 Types)
immunoglobulin (2 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-65 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.10 Summary of Toxicology Studies for Hazard Identification
for Liver Effects
Health Effect Category
Route of Exposure
Study Type
Liver Effects
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
36
32
11
8
13
4
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Ghataketal. (2011)
Ghataketal. (2011)
Arteel et al. (2008)
Arteel et al. (2008)
Arteel et al. (2008)
Flora etal. (2012)
Liu et al. (2000)
Liu et al. (2000)
Nain and Smits (2012)
Stepniketal. (2009)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
mice
mice
mice
mice
mice
mice
mice
rat
mice
mice
Health Effect
liver: biochemistry
liver: nonneoplastic lesions (2
Types)
liver: absolute weight
liver: nonneoplastic lesions
liver: relative weight
liver: nonneoplastic lesions
liver: nonneoplastic lesions (2
Types)
liver: relative weight (2 Types)
liver: nonneoplastic lesions
liver: neoplastic lesions
liver: nonneoplastic lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Reilly etal. (2013)
Kozul-Horvath etal. (2012)
Pineda etal. (2013)
Pineda etal. (2013)
Rios et al. (2012)
Tokaretal. (2010b)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
mice
rat
rat
rat
mice
Health Effect
liver: nonneoplastic lesions
liver: nonneoplastic lesions
liver: absolute weight
liver: relative weight
liver: nonneoplastic lesions
liver: nonneoplastic lesions (2
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-66 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Tokaretal. (2011)
Tokaretal. (2012)
Waalkes et al. (2004b)
Waalkes et al. (2006a)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2003)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
mice
mice
mice
mice
mice
mice
mice
Types)
liver: neoplastic lesions (6 Types)
liver: neoplastic lesions (3 Types)
liver: neoplastic lesions (8 Types)
liver: neoplastic lesions (2 Types)
liver: nonneoplastic lesions
liver: neoplastic lesions
liver: neoplastic lesions (8 Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Fouad etal. (2012)
Owumi et al. (2013)
Patra etal. (2012)
Bashiretal. (2006)
Bashiretal. (2006)
Ferzand et al. (2008)
Kharroubi etal. (2014)
Odstrcil et al. (2010)
Route of
Exposure
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
rat
mice
rat
mice
rat
goat
rat
rat
mice
rat
rat
Health Effect
liver: nonneoplastic lesions
liver: nonneoplastic lesions
liver: relative weight
liver: relative weight
liver: nonneoplastic lesions
liver: nonneoplastic lesions
liver: nonneoplastic lesions
liver: absolute weight
liver: nonneoplastic lesions
liver: nonneoplastic lesions
liver: nonneoplastic lesions
liver: gross pathology
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-67 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.11 Summary of Toxicology Studies for Hazard Identification
for Mortality
Health Effect Category
Route of Exposure
Study Type
Mortality
Oral
Reproductive/Developmental
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Miyazaki et al. (2005)
Route of
Exposure
Oral
Species
mice
Health Effect
mortality
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-68 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.12 Summary of Toxicology Studies for Hazard Identification
for Nervous System Effects
Health Effect Category
Route of Exposure
Study Type
Nervous System Effects
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
(Nagaraia and Desiraiu, 1993, pp.
author-year)
(Nagaraia and Desiraiu, 1993, pp.
author-year)
Bardullasetal. (2009)
Bardullasetal. (2009)
Dwivedi and Flora (2011)
Flora etal. (2012)
Liu et al. (2012)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
rat
mice
mice
rat
mice
mice
mice
Health Effect
brain: absolute weight
brain: biochemical parameters (2
Types)
brain: neurotransmitter (14 Types)
locomotor activity (2 Types)
cholinesterase activity (2 Types)
brain: nonneoplastic lesions
brain: nonneoplastic lesions
nervous system: nonneoplastic
lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Chattopadhyay et al. (2002)
Chattopadhyay et al. (2002)
Herrera et al. (2013)
Martinez et al. (2008)
Rios et al. (2012)
Srivastava et al. (2007)
Xi et al. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
rat
rat
mice
rat
mice
rat
Health Effect
brain: gross pathology
motor activity
cholinesterase activity
brain: biochemical parameters
brain: nonneoplastic lesions
vascular: function
CNS: function - cognition (3 Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-69 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Nagaraja and Desiraju (1994)
Nagaraja and Desiraju (1994)
Nagaraia and Desiraiu (1994)
Garcia-Chavez et al. (2007)
Garcia-Chavez et al. (2007)
Nagaraia and Desiraiu (1994)
Nagaraia and Desiraiu (1994)
Nagaraia and Desiraiu (1994)
Jing etal. (2012)
Jing etal. (2012)
Luo et al. (2009)
Luo et al. (2009)
Sharma and Sharma (2013)
Sharma and Sharma (2013)
Sharma and Sharma (2013)
Wang et al. (2009c)
Zhang etal. (2013b)
Zhang etal. (2013b)
Route of
Exposure
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
mice
mice
mice
Health Effect
nervous system: nonneoplastic
lesions
nervous system: nonneoplastic
lesions
brain: absolute weight
brain: biochemical parameters
brain: function (other than FOB)
CNS: neurochemical alterations and
conduction
nervous system: neoplastic lesions
brain: absolute weight
brain: biochemical parameters
brain: function (other than FOB)
brain: function (other than FOB) (2
Types)
brain: nonneoplastic lesions
brain: function (other than FOB)
brain: nonneoplastic lesions
brain: biochemical parameters
brain: function (other than FOB)
functional observation
battery/neuro-behavioral
brain: function (other than FOB)
brain: gross pathology
brain: neurotransmitter (12 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-70 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.13 Summary of Toxicology Studies for Hazard Identification
for Other
Health Effect Category
Route of Exposure
Study Type
Other
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
30
30
8
11
11
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
(Nagaraia and Desiraiu, 1993, pp.
author-year)
(Nagaraia and Desiraiu, 1993, pp.
author-year)
Liu et al. (2000)
Nain and Smits (2012)
Nain and Smits (2012)
Nain and Smits (2012)
Stepniketal. (2009)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
rat
mice
rat
rat
rat
mice
mice
Health Effect
body weight
food consumption
body weight (2 Types)
body weight gain
food consumption
water consumption
bone: nonneoplastic lesions
musculoskeletal system:
nonneoplastic lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Shaw (1973)
Miyazaki et al. (2005)
Mehranjani and Taefi (2012)
Davila-Esqueda et al. (2012)
Davila-Esqueda et al. (2011)
Kozul-Horvathetal. (2012)
Martinez et al. (2008)
Martinez-Finley et al. (2009)
Ramsey etal. (2013c)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
mice
rat
rat
rat
mice
mice
mice
mice
Health Effect
tooth: nonneoplastic lesions (3
Types)
body weight gain
body weight
body weight
body weight
body weight gain
postnatal body weight
body weight (2 Types)
water consumption
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-71 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Ramsey et al. (2013b)
Waalkes et al. (2003)
Oral
Oral
mice
mice
body weight (2 Types)
total body neoplastic lesions (4
Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Nagaraja and Desiraju (1994)
Shaw (1973)
Nagaraia and Desiraiu (1993)
Nagaraja and Desiraju (1993)
Nagaraja and Desiraiu (1994)
Jingetal. (2012)
Kozul et al. (2009)
Lemaire et al. (2011)
Luo et al. (2009)
Odstrcil et al. (2010)
Odstrcil et al. (2010)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
rat
rat
rat
rat
rat
mice
mice
rat
rat
rat
Health Effect
body weight
tooth: nonneoplastic lesions (2
Types)
body weight
food consumption
body weight
body weight
body weight
body weight
body weight
bone: gross pathology
bone: nonneoplastic lesions (2
Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-72 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.14 Summary of Toxicology Studies for Hazard Identification
for Renal Effects
Health Effect Category
Route of Exposure
Study Type
Renal Effects
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
28
24
_4
4
16
4
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Liu et al. (2000)
Liu et al. (2000)
Nain and Smits (2012)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Oral
Oral
Species
mice
mice
rat
mice
Health Effect
kidney: nonneoplastic lesions (2
Types)
kidney: relative weight (2 Types)
kidney: nonneoplastic lesions
kidney: nonneoplastic lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Rogers et al. (2014)
Rogers et al. (2014)
Pineda et al. (2013)
Pineda et al. (2013)
Tokaretal. (2010b)
Tokaretal. (2011)
Tokaretal. (2011)
Tokaretal. (2012)
Tokaretal. (2012)
Tokaretal. (2012)
Waalkes et al. (2004b)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
rat
rat
rat
mice
mice
mice
mice
mice
mice
mice
Health Effect
kidney: function
kidney: nonneoplastic lesions
kidney: absolute weight
kidney: relative weight
kidney: nonneoplastic lesions (2
Types)
kidney: neoplastic lesions (5 Types)
kidney: nonneoplastic lesions (2
Types)
kidney: neoplastic lesions (3 Types)
kidney: nonneoplastic lesions
urinary bladder: neoplastic lesions
kidney: nonneoplastic lesions (2
Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-73 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Waalkes et al. (2006a)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Waalkes et al. (2003)
Oral
Oral
Oral
Oral
Oral
mice
mice
mice
mice
mice
kidney: neoplastic lesions
kidney: nonneoplastic lesions (2
Types)
kidney: neoplastic lesions
kidney: nonneoplastic lesions
kidney: neoplastic lesions (2 Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Ferzand et al. (2008)
Majhi etal. (2011)
Maihi etal. (2011)
Odstrcil et al. (2010)
Route of
Exposure
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Species
mice
mice
rat
rat
mice
rat
rat
rat
Health Effect
kidney: absolute weight
kidney: nonneoplastic lesions
kidney: nonneoplastic lesions
kidney: relative weight
kidney: nonneoplastic lesions
kidney: absolute weight (2 Types)
kidney: relative weight (2 Types)
kidney: gross pathology
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-74 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.15 Summary of Toxicology Studies for Hazard Identification
for Reproductive System Effects including Pregnancy Outcomes
Health Effect Category
Route of Exposure
Study Type
Reproductive System Effects including Pr
Oral
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
Reproductive/Developmental
19
65
10
9
Count
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Stepniketal. (2009)
Route of
Exposure
Oral
Species
mice
Health Effect
female reproductive system:
nonneoplastic lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Nagymaitenyi et al. (1985)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Aggarwal et al. (2007)
Gandhi et al. (2012)
Gandhi et al. (2012)
Miyazaki et al. (2005)
Reillyetal. (2013)
Mehranjani and Taefi (2012)
Route of
Exposure
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
mice
rat
rat
Health Effect
number of live fetuses
corpora lutea
implantations
number of dead fetuses
number of live fetuses
postimplantation loss
preimplantation loss
resorption: unspecified
sex ratio
uterus: absolute weight
gestation length
neonatal/infant mortality
litter size
mammary gland: nonneoplastic
lesions
testis: absolute weight
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-75 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Mehranjani and Taefi (2012)
Chattopadhvav et al. (2002)
Cronican et al. (2013)
Davila-Esqueda et al. (2012)
Davila-Esqueda et al. (2012)
Davila-Esqueda et al. (2012)
Davila-Esqueda et al. (2012)
Davila-Esqueda et al. (2012)
Davila-Esqueda et al. (2012)
He et al. (2007)
He et al. (2007)
He et al. (2007)
He et al. (2007)
Kozul-Horvathetal. (2012)
Markowski et al. (2012)
Markowski et al. (2012)
Markowski et al. (2012)
Martinez et al. (2008)
Ramsey etal. (2013a)
Ramsey etal. (2013a)
Ramsey etal. (2013a)
Ramsey et al. (2013c)
Ramsey et al. (2013c)
Ramsey etal. (2013b)
Ramsey etal. (2013b)
Tokaretal. (2010b)
Tokaretal. (2010b)
Tokaretal. (2010b)
Tokaretal. (2010b)
Tokaretal. (2011)
Tokaretal. (2011)
Tokaretal. (2011)
Tokaretal. (2011)
Tokaretal. (2011)
Waalkes et al. (2004b)
Waalkes et al. (2004b)
Waalkes et al. (2004b)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
rat
rat
mice
rat
rat
rat
rat
rat
rat
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
testis: nonneoplastic lesions
gestation index (%)
litter size
estrogen
estrous cyclicity (3 Types)
female reproductive system:
nonneoplastic lesions
ovary: absolute weight
progesterone
uterus: absolute weight
birth index (3 Types)
litter size (3 Types)
postimplantation loss (2 Types)
resorption: unspecified
live births
body weight gain
gestation length
litter size
litter size
birth weight
gestation length (3 Types)
litter size (3 Types)
gestation length
litter size
gestation length (2 Types)
litter size (2 Types)
oviduct: nonneoplastic lesions
testis: nonneoplastic lesions
uterus: neoplastic lesions (6 Types)
uterus: nonneoplastic lesions
ovary: neoplastic lesions (3 Types)
oviduct: neoplastic lesions
oviduct: nonneoplastic lesions
uterus: neoplastic lesions (4 Types)
uterus: nonneoplastic lesions
ovary: neoplastic lesions
oviduct: nonneoplastic lesions
uterus: nonneoplastic lesions
testis: nonneoplastic lesions
cervix: neoplastic lesions
ovary: neoplastic lesions
ovary: nonneoplastic lesions
oviduct: nonneoplastic lesions
urogenital system: neoplastic
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-76 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Waalkes et al. (2006b)
Waalkes et al. (2006b)
Waalkes et al. (2003)
Waalkes et al. (2003)
Waalkes et al. (2003)
Waalkes et al. (2003)
Waalkes etal. (2003)
Waalkes et al. (2003)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
mice
mice
mice
mice
mice
mice
mice
mice
lesions (6 Types)
uterus: neoplastic lesions
vulva: neoplastic lesions
ovary: neoplastic lesions (3 Types)
oviduct: neoplastic lesions (2 Types)
oviduct: nonneoplastic lesions
testis: neoplastic lesions
uterus: neoplastic lesions (2 Types)
uterus: nonneoplastic lesions
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Omuraetal. (1996)
Omuraetal. (1996)
Omuraetal. (1996)
Omuraetal. (1996)
Omuraetal. (1996)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Blair etal. (1990b)
Momeni etal. (2012)
Momeni etal. (2012)
Momeni and Eskandari (2012)
Momeni and Eskandari (2012)
Owumi et al. (2013)
Ferreira et al. (2012)
Ferreira et al. (2012)
Ferreira et al. (2012)
Ferreira et al. (2012)
Ferreira et al. (2012)
Ferreira et al. (2012)
Pant etal. (2001)
Pant etal. (2001)
Pant etal. (2001)
Pant etal. (2001)
Pant etal. (2001)
Pant etal. (2001)
Route of
Exposure
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
rat
rat
rat
rat
rat
mice
rat
rat
mice
rat
rat
rat
rat
rat
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
mice
Health Effect
epididymis: absolute weight
epididymis: relative weight
sperm parameters (4 Types)
testis: absolute weight
testis: relative weight
female reproductive system:
nonneoplastic lesions
female reproductive system:
nonneoplastic lesions
male reproductive system:
nonneoplastic lesions
male reproductive system:
nonneoplastic lesions
sperm parameters (4 Types)
testis: absolute weight
sperm parameters (6 Types)
testis: absolute weight
sperm parameters
epididymis: absolute weight
epididymis: relative weight
sperm parameters
testis: absolute weight
testis: gross pathology
testis: relative weight
epididymis: absolute weight
epididymis: relative weight
male accessory sex gland: absolute
weight (3 Types)
male accessory sex gland: relative
weight (3 Types)
sperm parameters (3 Types)
steroidogenic enzyme activity (6
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-77 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Pant etal. (2001)
Pant etal. (2001)
Oral
Oral
mice
mice
Types)
testis: absolute weight
testis: relative weight
3.2.16 Summary of Toxicology Studies for Hazard Identification
for Respiratory Effects
Health Effect Category
Route of Exposure
Study Type
Respiratory Effects
Oral.
Chronic (>90 days)
Subchronic (30 days to < 90 days)
Reproductive/Developmental
Inhalation .
Subchronic (30 days to < 90 days)
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Singh etal. (2010)
Nain and Smits (2012)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Oral
Species
mice
rat
mice
Health Effect
lung: nonneoplastic lesions
lung: nonneoplastic lesions
respiratory system: nonneoplastic
lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Lantz et al. (2009)
Ramsey etal. (2013a)
Ramsey etal. (2013a)
Ramsey etal. (2013c)
Ramsey etal. (2013c)
Ramsey etal. (2013b)
Tokaretal. (2010b)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
mice
mice
mice
mice
mice
mice
Health Effect
lung: function (2 Types)
lung: function (5 Types)
lung: gross pathology (3 Types)
lung: function (8 Types)
lung: gross pathology (2 Types)
innate immunity/inflammation:
general (6 Types)
lung: neoplastic lesions (4 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-78 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Tokaretal. (2010b)
Tokaretal. (2011)
Tokaretal. (2012)
Waalkes et al. (2004b)
Waalkes et al. (2006a)
Waalkes etal. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2003)
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
mice
mice
mice
mice
mice
mice
mice
mice
lung: nonneoplastic lesions (2
Types)
lung: neoplastic lesions (6 Types)
lung: neoplastic lesions (4 Types)
lung: neoplastic lesions (2 Types)
lung: neoplastic lesions (2 Types)
lung: nonneoplastic lesions
lung: neoplastic lesions
lung: neoplastic lesions (4 Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Blair etal. (1990b)
Lantz et al. (2009)
Ramsey etal. (2013b)
Route of
Exposure
Inhalation
Inhalation
Oral
Oral
Species
mice
rat
mice
mice
Health Effect
respiratory system: nonneoplastic
lesions
respiratory system: nonneoplastic
lesions
lung: function (2 Types)
lung: function (2 Types)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-79 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
3.2.17 Summary of Toxicology Studies for Hazard Identification
for Skin Diseases
Health Effect Category
Route of Exposure
Study Type
Skin Diseases
Oral
Chronic (>90 days)
Reproductive/Developmental
Inhalation
Subchronic (30 days to < 90 days)
Note: Studies may be placed in more than one category depending upon the data presented. Therefore, the totals may not sum to the total number
of studies presented in the figure.
CHRONIC (>90 DAYS)
Study References
Germolec et al. (1998)
Stepniketal. (2009)
Route of
Exposure
Oral
Oral
Species
mice
mice
Health Effect
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
REPRODUCTI VE/DEVELOPM ENTAL
Study References
Tokaretal. (2010b)
Waalkes et al. (2004b)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Waalkes et al. (2008)
Waalkes et al. (2003)
Route of
Exposure
Oral
Oral
Oral
Oral
Oral
Oral
Species
mice
mice
mice
mice
mice
mice
Health Effect
skin and subcutaneous tissue:
neoplastic lesions (2 Types)
skin and subcutaneous tissue:
nonneoplastic lesions (2 Types)
skin and subcutaneous tissue:
nonneoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions
skin and subcutaneous tissue:
neoplastic lesions (2 Types)
SUBCHRONIC (30 DAYS TO <90 DAYS)
Study References
Blair etal. (1990b)
Route of
Exposure
Inhalation
Species
mice
Health Effect
skin and subcutaneous tissue:
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-80 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Blair etal. (1990b)
Inhalation
rat
nonneoplastic lesions
skin and subcutaneous tissue:
nonneoplastic lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 3-81 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4 SUMMARY OF RISK OF BIAS EVALUATIONS FOR INORGANIC ARSENIC
EPIDEMIOLOGIC STUDIES
4.1 Risk of Bias Overview - Clinical Chemistry and Urinalysis
Study
Casale et al. (2013)
Chen et al. (2011c)
Dasetal. (2012a)*
Islam etal. (2011)*
Kim etal. (2013)
Maiti etal. (2012)*
Mazumder etal. (2013)*
Nabi etal. (2005)
Shenetal. (2013)
b- ?r
mary (P)
pporting
Q. i/l
P
P
P
P
P
P
P
s
P
Selection
c
o
ndomizat
SL
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
^
ocation
ncealmen
< u
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Q.
^
o
mparison
O
u
++
++
++
++
++
++
++
-
++
Confounding
hn
nfoundin
esign)
8 a
++
++
++
++
+
+
++
-
++
intended
posure
_ x
ID LLJ
_
+
+
++
+
_
++
+
+
Performance
_
Deriment;
nditions
X O
LLJ U
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
LO
c
o
(D
Q
"o
u
0
4-*
o
ol
+
+
+
+
+
+
+
+
+
>-
4-*
00
gp DP
T3 'C
s a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
CD
E
o
u
4-»
0
DO
c
'l/l (D
LO 4-1
S Q
++
++
++
+
++
++
-
-
-
Detection
o
u
nding (Ou
sessment
1^ LO
CO <
_
++
_
+
_
_
-
-
-
hn
nfoundin
nalysis)
8 <
_
+
+
+
_
_
-
-
-
0
posure
aracterizc
X -C
LLJ U
+
++
_
+
+
_
++
-
-
itcome
sessment
0 <
+
++
+
++
+
+
+
SRB
DO
O
Q.
E
o
u
4-*
0
+
+
+
+
+
+
+
_l +
H \
Other
>-
4-*
'-a
~ca
"J5
c
c
++
++
++
++
+
++
-
+
*Data not yet included in accompanying evidence tables. Abbreviations: Att (attrition/exclusion); SRB (Selective Reporting Bias)
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-1 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.2 Risk of Bias Overview - Endocrine System Effects including Diabetes
Study
Chen et al. (2012a)
Chen et al. (2010c)
Chenetal. (2011a)
Ciarroccaetal. (2012)*
Coronado-Gonzalez et al.
(2007)
Del Razoetal. (2011)
Drobnaetal. (2013)*
Enterline and Marsh
(1982)
Ettinger et al. (2009)
Garcia-Esquinas et al.
(2013)
i; 1/1
O ii.
Primary (P)
Supporting
P
P
P
P
P
P
P
S
P
P
Selection
c
Randomizat
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
"£i
Allocation
Concealmer
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Q.
3
0
13
Comparison
++
++
++
++
++
++
+
-
+
+
Confounding
DO
Confoundin
(Design)
++
+
++
++
++
++
++
++
++
Unintendec
Exposure
+
+
+
+
+
+
+
-
-
+
Performance
m
Experiment
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
LO
c
o
'4-»
>
Protocol De
+
+
+
+
+
+
+
+
+
+
DO
c
Q
DO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
CD
E
u
3
0
DO
^C
'LO CD
LO 4-»
;= to
S Q
++
++
++
++
++
++
++
+
+
Detection
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Gribbleetal. (2012)
Guo et al. (2007)
Hsiehetal. (2008a)
Hsu et al. (2013b)
Islam etal. (2012b)
James etal. (2013)
Jensen and Hansen (1998)
Jovanovic et al. (2013)
Kim and Lee (2011)
Kim et al. (2013)
Lai etal. (1994)
Lewis etal. (1999)
Lietal. (2013a)
Lubin etal. (1981)
Maiti etal. (2012)*
Makris etal. (2012)
Primary (P) or
Supporting(S)
P
S
P
P
P
P
P
S
P
P
P
P
P
S
P
S
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
-
+
++
++
++
-
-
++
++
++
+
++
-
++
++
Confounding
Confounding
(Design)
++
++
++
++
++
+
++
+
++
-
++
-
+
+
Unintended
Exposure
+
-
+
+
+
+
-
+
+
+
-
+
+
-
-
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
bfl
^c
'&_
0^
DO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
-
+
++
++
++
-
+
+
++
++
+
+
+
++
+
Detection
Blinding (Outcome
Assessment)
+
-
-
+
++
+
+
+
+
-
-
+
++
-
-
-
Confounding
(Analysis)
++
-
+
-
++
-
-
-
+
-
-
-
+
+
-
+
Exposure
Characterization
++
-
+
-
+
-
+
++
+
-
-
-
-
-
Outcome
Assessment
++
-
+
++
-
+
+
+
+
+
+
++
+
-
+
-
SRB
Outcome Reporting
+
+
+
+
+
+
+
++
+
Other
Internal Validity
-±
++
++
++
++
+
+ ++
+
+
+
+
+
+
+
-
++
+
+
+
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-3 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Navas-Acien et al. (2008)
Navas-Acien et al. (2009)
Nizam etal. (2013)
Ojajarvi etal. (2000)
Pan etal. (2013)
Rahman and Axelson
(1995)
Rahman and Axelson
(2001)
Rahman etal. (1996)
Rahman etal. (1998)
Rahman et al. (1999b)*
Rhee etal. (2013)
Sawada et al. (2013)
£2
_~ c
£1
EQ.
Q.
i- 3
Q. i/l
P
P
P
S
P
S
S
S
S
P
P
P
Selection
c
0
(D
E
0
T3
C
(D
C£
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
c
0)
n E
(D 0)
U U
0 C
< d
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
o
c
o
LO
(D
Q.
E
o
U
++
++
++
-
++
_
++
++
+
Confounding
CuO
c
T3
13 C
O CuO
c '"
5 a
++
++
++
+
++
_
++
-
!
+
++
++
T3
-a
*E ?
8 <
+
+
-
_
_
-
-
_
++
c
o
"^-»
fD
M
::. aj
3 U
LO (B
O 1-
Q. (D
£ 6
c
0) .
4-*
"S
^>
"S
c
cu
c
++
+ +t
+
+
+
+
+
+
+
+
+
++
++
++
_
-
+
++
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-4 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Steinmaus et al. (2009)
Tseng et al. (2000)
Zieroldetal. (2004)*
Primary (P) or
Supporting(S)
P
P
P
Selection
Randomization
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
Q.
3
O
Comparison Gr
++
++
++
Confounding
Confounding
(Design)
++
++
++
Unintended
Exposure
+
-
+
Performance
Experimental
Conditions
n/a
n/a
n/a
LO
c
0
Protocol Devia
+
+
+
DO
^c
'&_
0^
DO
If
co y,
n/a
n/a
n/a
Att.
CD
£
8
4-»
3
O
CuO
c
'l/l (D
LO 4-»
;= ns
S Q
++
++
+
Detection
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.3 Risk of Bias Overview - Hematology, Hematopoietic System
Study
Del Razo etal. (2011)
Ghosh (2013)
Quo et al. (2007)
Heck et al. (2008)
Hopenhayn etal. (2006)
Maiti et al. (2012)*
Maiumdaret al. (2009)
Saha etal. (2013)
Primary (P) or
Supporting (S)
P
S
S
P
S
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
-
..
++
++
-
+
Confounding
Confounding
(Design)
++
++
+
-
+
Unintended
Exposure
+
-
+
+
-
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
CuO
'&_
Q
CuO
If
CO to
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
+
-
++
++
++
++
+
Detection
Blinding (Outcome
Assessment)
-
-
-
-
-
-
-
++
Confounding
(Analysis)
+
-
-
+
+
-
-
-
Exposure
Characterization
+
-
-
++
-
-
-
-
Outcome
Assessment
+
-
-
-
-
+
-
+
SRB
Outcome Reporting
+
+
+
+
+
;
+
+
Other
Internal Validity
++
-
++
++
+
++
++
*Data not yet included in accompanying evidence tables.
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-6 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.4 Risk of Bias Overview - Liver Effects
Study
Baastrup et al. (2008)
Chen etal. (1986)
Chung etal. (2012)
Enterline and Marsh (1982)
Garcia-Esquinas et al.
(2013)
Ghosh (2013)
Guo etal. (2007)
Hsuetal. (2013b)
Lewis etal. (1999)
Majumdaretal. (2009)
Paul etal. (2013)
Sawadaetal. (2013)
M
t
o
Q.
Q.
3
Ifl
S"
ra
£ sa
p
s
p
s
p
s
s
p
p
p
p
p
Selection
c
0
ndomizat
SL
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
^_J
ocation
ncealmer
1 3
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Q.
O
C3
mparison
o
u
+
++
+
.
+
-
Confounding
nfoundin
Bsign)
5 a
++
+
++
.
++
_
intended
posure
£5 L*
+
-
+
.
+
_
1
- B -
I
+
-
++
+
-
-
++
++
+
+
+
+
Performance
periment
nditions
X 0
LLJ U
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
LO
c
0
'4-*
Q
"o
u
o
ol
+
+
+
+
+
+
+
+
+
+
+
+
>-
4-*
00
s a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
CD
E
8
o
DO
C
'(SI (D
LO 4-»
'_- (D
S Q
++
+
+
++
+
_
++
+
++
++
++
Detection
(U
E
o
° £
DO E
C to
=5 %
c y,
CO <
+
+
+
+
+
_
_
+
+
-
+
+
nfoundin
nalysis)
5 <
+
C
0
^
posure
aracteriz
LLJ C)
-
tcome
sessment
^ (f,
O <
+
+ | +t
-
.
+
_
_
_
-
-
_
-
++
.
++
_
_
_
-
-
+
-
+
++
+
_
_
++
++
-
++
++
SRB
DO
C
t
O
Q.
tcome R<
0
+
+
+
+
+
+
+
+
+
+
+
+
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>-
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...
05
C
c
-
++
++
++
++
++
_
++
-
++
++
-
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-7 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Tsudaetal. (1995)
Wadhwa et al. (2011a)
Primary (P) or Supporting
(S)
P
S
Selection
Randomization
n/a
n/a
Allocation
Concealment
n/a
n/a
Comparison Group
-
Confounding
Confounding
(Design)
++
-
Unintended
Exposure
+
-
Performance
Experimental
Conditions
n/a
n/a
Protocol Deviations
+
+
s-
T3
i a
n/a
n/a
Att.
Missing Outcome
Data
++
+
Detection
Blinding (Outcome
Assessment)
+
+
Confounding
(Analysis)
-
-
Exposure
Characterization
-
-
Outcome
Assessment
++
-
SRB
Outcome Reporting
+
-
Other
Internal Validity
+
-
April 2014
Jro/? development materials are for review purposes only and do not constitute Agency policy.
4-8 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.5 Risk of Bias Overview - Immune System and Lymphatic Effects
Study
Ahmed et al. (2012)
Biswas et al. (2008)*
Bosnjaket al. (2008)
Enterline and Marsh
(1982)
Garcia-Esquinas et al.
(2013)
Infante-Rivard et al. (2001)
Islam et al. (2007)
Josyula et al. (2006)
Lewis etal. (1999)
Lu and Chen (1991)
Lubin etal. (1981)
Primary (P) or
Supporting(S)
P
P
P
S
P
S
S
P
P
S
S
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
++
++
-
+
++
-
++
+
++
-
Confounding
Confounding
(Design)
++
+
-
-
++
+
++
Unintended
Exposure
+
+
+
-
+
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
bfl
^c
'&_
0^
DO
If
CQ y,
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
+
++
+
++
++
+
_^_
±
+
Detection
Blinding (Outcome
Assessment)
-
-
-
+
+
+
-
+
*
-
Confounding
(Analysis)
-
-
-
+
-
-
-
-
++
+
1 Exposure
+ 1 Characterization
-
-
++
-
-
+
-
-
-
Outcome
Assessment
+
++
++
++
+
++
+
+
++
++
-
SRB
Outcome Reporting
+
++
+
+
+
+
+
+
+
+
+
Other
Internal Validity
+
++
-
++
++
++
-
+
-
++
+
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-9 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Marsh etal. (2009)
Mazumderetal. (2000)
Milton and Rahman (2002)
Milton et al. (2001)
Moore et al. (2009)
Pesola et al. (2012)
Pinto etal. (1978)
Raqib etal. (2009)
Saha etal. (2013)
Shiue (2013)
Sohel etal. (2009)
Von Ehrenstein et al.
(2005)
Wu et al. (2012b)
Primary (P) or
Supporting (S)
S
S
S
S
P
P
S
P
P
P
P
S
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
++
+
+
++
++
++
Confounding
Confounding
(Design)
+
+
-
++
++
+
++
+
++
++
Unintended
Exposure
t+
-
-
-
+
+
+
+
++
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
Q
CuO
If
-I-J
CO 00
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
+
-
++
+
++
++
+
+
+
+
++
+
Detection
Blinding (Outcome
Assessment)
+
-
-
^HH
+
+
+
++
-
-
-
-
Confounding
(Analysis)
+
-
-
-
-
+
-
+
+
+
Exposure
Characterization
-
-
-
+
+
-
++
-
+
Outcome
Assessment
+
-
-
++
+
++
-
+
+
+
-
SRB
Outcome Reporting
+
+
-
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
+
-
-
+
++
++
-
++
++
++
»
++
-
* Data not yet included in accompanying evidence tables.
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-10 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.6 Risk of Bias Overview - Renal Effects
Study
Baastrup et al. (2008)
Boffetta et al. (2011)
Chenetal. (2011a)
Chiou et al. (2005)
Enterline and Marsh
(1982)
Enterline etal. (1995)
Eometal. (2011)*
Feng et al. (2013)*
Ferreccio et al. (2013a)
Primary (P) or
Supporting (S)
P
S
P
P
S
S
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
++
++
+
-
+
+
Confounding
Confounding
(Design)
++
++
++
-
-
-
++
\ «
++ ++
Unintended
Exposure
+
+
+
+
-
-
+
+
++
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
DO
C
"i_
3
0^
ao
If
CQ y,
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
+
++
++
+
tt
-
+
+
Detection
Blinding (Outcome
Assessment)
+
+
+
++
+
+
-
-
+
Confounding
(Analysis)
+
++
-
-
-
-
-
Exposure
Characterization
±
++
+
-
-
+
++
-
Outcome
Assessment
±
++
++
++
+
+
+
++
SRB
Outcome Reporting
+
Other
Internal Validity
"
1 "
+
+
+
+
+
+
-
++
++
++
+
++
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-11 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Garcia-Esquinas et al.
(2013)
Garcia-Vargas et al.
(1994)*
Hawkesworth et al. (2013)
Hernandez-Zavala et al.
(1999)*
Hsuetal. (2013b)
Huang etal. (2011)
Huang etal. (2012)
Jayatilakeetal. (2013)
Kurttio etal. (1999)
Lewis etal. (1999)
Lubin etal. (1981)
Mostafa and Cherry (2013)
Primary (P) or
Supporting (S)
P
P
P
P
P
P
P
S
P
P
S
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
+
++
-
++
+
*
-
++
+
-
+
Confounding
Confounding
(Design)
++
+
++
+
++
++
**
++
++
-
-
++
Unintended
Exposure
+
++
++
++
+
+
+
-
+
+
-
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
co 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
++
++
++
++
+
++
+
+
+
+
Detection
Blinding (Outcome
Assessment)
+
-
+
-
+
+
+
-
+
+
-
+
Confounding
(Analysis)
+
-
++
-
-
-
-
-
+
-
+
-
Exposure
Characterization
++
-
+
+
-
++
++
-
-
-
-
-
Outcome
Assessment
+
+
++
++
++
++
++
-
++
++
-
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
+
++
++
++
+
++
++
+
-
+
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-12 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Ngetal. (2005)
Palaneeswari et al. (2013)
Pietal. (2005)*
Sawadaetal. (2013)
Yuan etal. (2010)
o 2
£ .=
£" ^
£ £
Q. i/l
S
s
p
p
p
Selection
c
0
CO
M
E
T3
C
(D
CCL
n/a
n/a
n/a
n/a
n/a
4-*
c 2
'43 (D
(D 0)
U U
0 C
1 3
n/a
n/a
n/a
n/a
n/a
2
0
l/l
ro
Q.
E
o
u
+
++
Confounding
CuO
c
T3
3 C
O CuO
O i i
u B
t
++
T3
(D
i2 5
-
-
++
.
_
c
(U 0)
£ E
o £
£ 0)
0 <
+
-
+
++
+
SRB
CuO
c
t
0
Q.
DC
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.7 Risk of Bias Overview - Mortality
Study
Enterline and Marsh
(1982)
Lubinetal. (1981)
Pinto etal. (1978)
Rahman etal. (2013)
Sohel etal. (2009)
Tsuda etal. (1995)
Wade etal. (2009)
Welch etal. (1982)
Primary (P) or
Supporting(S)
S
S
S
P
P
P
P
S
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
-
-
+
+
++
++
+
-
Confounding
Confounding
(Design)
-
+
+
++
++
+
Unintended
Exposure
-
+
+
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
bfl
^c
'&_
0^
DO
If
co 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
+
+
++
-
+
++
++
+
Detection
Blinding (Outcome
Assessment)
+
+
++
-
+
++
+
Confounding
(Analysis)
-
+
-
+
+
-
-
-
Exposure
Characterization
-
-
-
-
+
-
+
-
Outcome
Assessment
++
++
++
+
++
-
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
Other
Internal Validity
++
+
-
++
++
+
++
+
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-14 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.8 Risk of Bias Overview - Digestive System Effects
Study
Amaraletal. (2012)
Baastrup et al. (2008)
Bulbulyan et al. (1996)
Enterline and Marsh (1982)
Farzan et al. (2013)
Garcia-Esquinas et al.
(2013)
Hsuetal. (2013b)
Kreuzer etal. (2012)
Lewis etal. (1999)
Lubin etal. (1981)
Pinto etal. (1977)
Pinto etal. (1978)
Primary (P) or Supporting
(S)
P
P
S
S
P
P
P
S
P
s
s
s
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
+
+
-
++
+
++
+
+
-
-
+
Confounding
Confounding
(Design)
++
++
-
-
++
++
++
+
-
:
Unintended
Exposure
++
+
+
-
+
+
+
-
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
CuO
'&_
3
CuO
If
4-J
CO 00
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
-
++
++
+
+
++
++
+
+
+
++
++
Detection
Blinding (Outcome
Assessment)
+
+
-
+
+
+
+
-
+
-
+
+
Confounding
(Analysis)
-
+
+
-
+
+
-
-
-
+
-
-
Exposure
Characterization
+
+
++
-
-
-
-
-
-
Outcome
Assessment
+
+
++
+
++
-
++
-
++
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
++
++
++
++
++
++
-
+
-
-
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-15 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Rahman etal. (2011)
Sawada et al. (2013)
Syed et al. (2013)
Tsuda etal. (1995)
M
t
O
Q.
Q.
3
Ifl
i_ ^^
O <£.
m
it
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
Q.
0
Comparison Gr
++
+
++
Confounding
Confounding
(Design)
++
++
++
-
Unintended
Exposure
+
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
10
c
o
Protocol Devial
+
+
+
+
DO
C
'&_
Q
DO
If
CQ 55
n/a
n/a
n/a
n/a
Att.
0)
0
u
4-*
O
DO
C
'10 CD
10 4-1
= to
2 Q
+
++
++
Detection
0)
E
Blinding (Outcc
Assessment)
+
+
++
+
Confounding
(Analysis)
+
++
++
-
c
Exposure
Characterizatio
++
.
++
-
Outcome
Assessment
+
++
++
++
SRB
DO
C
t
Outcome Repo
+
+
+
+
Other
!2»
Internal Validit
++
++
++
+
April 2014
TTzese Jra/? development materials are for review purposes only and do not constitute Agency policy.
4-16 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.9 Risk of Bias Overview - Cardiovascular Disease
Study
Ahmad etal. (2006)*
Axelsonetal. (1978)
Bosnjaket al. (2008)
Burgess et al. (2013)
Chen et al. (2012b)
Chen et al. (2013a)
Chen etal. (1988)
Chen etal. (1995)
Chen etal. (1996)
Chen etal. (2006b)
Chen etal. (2007b)
Chen etal. (2011b)
Primary (P) or
Supporting(S)
P
S
P
P
P
P
S
S
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
+
++
++
++
+
+
++
++
Confounding
Confounding
(Design)
++
-
-
++
++
++
E
++
++
++
++
Unintended
Exposure
-
+
+
-
-
^
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
tUO
"t_
0^
CuO
3 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
++
++
+
++
++
++
+
++
++
++
++
Detection
Blinding (Outcome
Assessment)
++
++
-
-
+
++
+
-
+
++
++
++
Confounding
(Analysis)
+
++
-
-
+
+
:
+
Exposure
Characterization
-
-
-
++
+
.
-
+
+
++
Outcome
Assessment
+
++
++
++
+
++
+
+
++
++
SRB
Outcome Reporting
+
+
+
+
++
+
+
+
+
+
+
+
Other
>-
4-*
"S
"S
c
OJ
4-*
c
++
+
-
+
++
++
++
+
+
-
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-17 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Chenetal. (2013c)
Chiouetal. (1997)
Chiouetal. (2001b)*
Chiouetal. (2005)
Cuzicketal. (1992)
Enterline and Marsh
(1982)
Ghosh (2013)
Gong and O'Bryant (2012)
Guha Mazumder et al.
(2012)
Guo et al. (2007)
Hawkesworth et al. (2013)
Hertz-Picciotto et al.
(2000)
Primary (P) or
Supporting (S)
P
P
P
P
S
S
S
S
P
S
P
S
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
+
++
+
-
-
-
+
++
++
+
Confounding
Confounding
(Design)
++
++
++
-
-
-
-
++
++
++
+
Unintended
Exposure
+
+
+
+
-
-
-
+
+
++
-
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
++
++
++
+
+
+
+
++
.
++
+
Detection
Blinding (Outcome
Assessment)
++
+
+
++
+
+
-
-
;
:
+
+
Confounding
(Analysis)
Exposure
Characterization
- "
-
+
++
-
-
-
-
-
-
++
+
+
+
+
-
-
-
-
+
-
+
-
Outcome
Assessment
++
+
+
++
+
++
-
+
++
-
++
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
++
++
++
+
++
++
++
+
-
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-18 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Hsiehetal. (2008b)
Hsiehetal. (2008a)
Hsuehetal. (1998)*
Huang etal. (2007)*
Huang etal. (2009b)*
Islam etal. (2012a)
Jarupetal. (1989)
Jensen and Hansen (1998)
Jones etal. (2011)
Karim etal. (2013)*
Kim and Lee (2011)
Kim et al. (2013)
Kunrath et al. (2013)
Kwok et al. (2007)
Primary (P) or
Supporting (S)
P
P
P
P
P
P
S
P
P
P
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
+
++
++
+
++
+
-
++
++
++
++
++
++
Confounding
Confounding
(Design)
++
++
++
++
++
++
-
+
++
++
++
+
+
-
Unintended
Exposure
+
+
+
+
+
+
+
-?-
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
+
+
++
+
+
++
++
-
++
++
+
++
++
++
Detection
Blinding (Outcome
Assessment)
+
-
+
+
-
-
+
+
+
+
+
-
+
+
Confounding
(Analysis)
-
+
-
-
-
++
-
-
+
+
+
+
-
Exposure
Characterization
+
+
-
++
+
+
-
+
++
-
+
+
-
Outcome
Assessment
+
+
+
+
+
+
+
+
+
++
+
+
+
+
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
+
++
+
+
++
++
++
++
++
++
+
++
++
+
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-19 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Lagerkvist et al. (1986)
Lagerkvist et al. (1988)
Lewis etal. (1999)
Lietal. (2013a)
Li et al. (2009)
Lietal. (2013b)
Liao etal. (2012)
Liao etal. (2009)*
Lubin etal. (1981)
Marsh et al. (2009)
Moon etal. (2013)
Mordukhovich et al. (2009)
Mumford et al. (2007)
Osorio-Yanez et al. (2013)
Primary (P) or
Supporting (S)
S
S
P
P
P
P
P
P
S
S
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
-
++
+
++
++
++
++
+
-
+
-
++
++
++
Confounding
Confounding
(Design)
++
+
-
++
++
++
++
++
-
+
++
++
++
++
Unintended
Exposure
-
-
+
+
+
+
+
+
-
-?-
+
++
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
+
+
+
+
++
+
-
+
++
++
++
++
+
Detection
Blinding (Outcome
Assessment)
-
-
+
++
++
-
+
++
-
+
-
-
++
++
Confounding
(Analysis)
-
+
-
+
-
+
-
-
+
+
+
+
-
+
Exposure
Characterization
-
-
-
-
-
+
-
-
-
-
++
++
++
-
Outcome
Assessment
++
+
++
+
+
+
+
+
-
+
++
++
++
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
-
+
-
++
++
++
++
++
+
+
++
+
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-20 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Pietal. (2005)*
Pinto etal. (1977)
Pinto etal. (1978)
Rahman and Axelson
(2001)
Rahman etal. (1999a)
Sohel etal. (2009)
Tseng etal. (1996)
Tseng etal. (1997)
Tseng et al. (2003)
Wade et al. (2009)
Wang et al. (2002)
Wang et al. (2007c)*
Wang et al. (2009a)*
Wang et al. (2010)*
Primary (P) or
Supporting (S)
P
S
S
S
P
P
P
P
P
P
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
-
+
++
++
++
+
+
++
+
++
++
Confounding
Confounding
(Design)
++
-
+
++
++
++
++
++
++
! **
D **
Unintended
Exposure
+
+
+
-
-
+
+
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ y.
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
-
++
++
++
++
+
++
++
+
++
+
+
++
++
Detection
Blinding (Outcome
Assessment)
-
+
+
-
-
-
++
++
++
++
-
++
++
+
Confounding
(Analysis)
Exposure
Characterization
- "
-
-
-
-
+
-
-
+
-
-
-
-
+
-
-
-
-
+
-
-
-
+
-
++
-
-
Outcome
Assessment
+
++
++
-
++
+
+
++
+
-
+
+
++
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
+
-
-
-
+
++
-
+
++
++
+
+
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-21 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Wang etal. (2011a)
Welch etal. (1982)
Wu et al. (2006)
Wu etal. (2010)
Xia et al. (2009)
Yildiz etal. (2008)
Zhang etal. (2013a)
o 2
mary (P)
pporting
Q. i/l
P
S
P
P
P
S
S
Selection
0
ndomizat
(D
CCL
n/a
n/a
n/a
n/a
n/a
n/a
n/a
4-*
ocation
ncealmer
= o
< u
n/a
n/a
n/a
n/a
n/a
n/a
n/a
2
u
mparison
o
u
++
.
++
++
++
++
+
Confounding
ao
c
T3
1 "£
O DO
*f= -W
3 a
++
+
++
++
++
++
+
intended
josure
3 £
+
+
+
+
++
Performance
periment
nditions
X 0
LU <_)
n/a
n/a
n/a
n/a
n/a
^1 n/a
n/a
HH
1O
c
o
'>
.
^
"S
~ca
c
OJ
c
++
+
++
++
++
^^^m
* \ '
1
+ ++
* Data not yet included in accompanying evidence tables.
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-22 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.10Risk of Bias Overview - Other
Study
Akbal etal. (2013)
Bulbulyanetal. (1996)
Chiou etal. (1995)
Chung etal. (2012)
Cordova etal. (2013)*
Enterline and Marsh (1982)
Enterlineetal. (1995)
Fuiinoetal. (2004)*
Hsuetal. (2013b)
Kurttio etal. (1998)*
Maiumdaret al. (2009)
Mazumderetal. (2013)*
M
t
0
Q.
Q.
3
l/l
O <£,
ra
*i_
Q.
S
s
p
p
p
s
s
p
p
p
p
p
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
-
+
+
+
-
-
+
++
++
+
-
Confounding
Confounding
(Design)
-
-
++
++
-
-
-
++
++
++
-
++
Unintended
Exposure
-
+
+
+
+
-
-
-
+
+
+
++
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
tUO
"t_
0^
CuO
1 ?
3 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
+
++
++
+
++
++
++
+t
Detection
Blinding (Outcome
Assessment)
+
-
-
+
+
+
+
-
t
Confounding
(Analysis)
-
-
-
-
+
t:
.
Exposure
Characterization
++
+
-
-
-
-
-
-
++
Outcome
Assessment
+
+
+
++
++
+
+
++
-
-
+
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
-
+
+
Other
Internal Validity
-
++
++
++
+
-
++
-
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-23 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Mitra et al. (2002)
Nakadairaetal. (2002)
Paul etal. (2013)
Pinto etal. (1978)
Siriczuk-Walczak et al.
(2010)
Sobel etal. (1987)
Syed et al. (2012)
Tsuda etal. (1995)
Wang etal. (2011a)
Primary (P) or Supporting
(S)
P
S
P
s
s
s
s
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
+
++
+
-
+
++
++
++
Confounding
Confounding
(Design)
-
+
++
-
+
+
+
++
-
Unintended
Exposure
+
-
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
CuO
'&_
Q
CuO
If
co 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
++
++
+
++
++
-
Detection
Blinding (Outcome
Assessment)
-
+
+
+
-
-
-
+
-
Confounding
(Analysis)
-
-
.
Exposure
Characterization
M
-
-
^
+
Outcome
Assessment
-
~
+
+
-
++
+
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
-
++
-
+
+
++
+
-
: Data not yet included in accompanying evidence tables.
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-24 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.11 Risk of Bias Overview - Reproductive System Effects including Pregnancy
Outcomes
Study
Ahmad etal. (2001)
Baastrup et al. (2008)
Chakraborti et al. (2003)
Enterline and Marsh
(1982)
Garcia-Esquinas etal.
(2013)
Garland etal. (1996)
Ihrig etal. (1998)
Kwok et al. (2006)
Lewis etal. (1999)
Milton etal. (2005)
Primary (P) or
Supporting (S)
S
P
S
S
P
P
S
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
+
-
-
+
+
++
++
+
++
Confounding
Confounding
(Design)
++
++
-
-
++
++
++
++
++
Unintended
Exposure
+
+
+
-
+
++
-
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
co 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
+
++
++
+
++
-
++
+
Detection
Blinding (Outcome
Assessment)
-
+
-
+
+
+
+
+
+
+
Confounding
(Analysis)
++
+
-
-
+
+
+
-
-
++
Exposure
Characterization
-
-
-
-
++
-
-
+
-
-
Outcome
Assessment
-
+
-
++
+
++
+
+
++
-
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
-
-
"
++
++
++
++
-
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-25 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Mukherieeetal. (2005)
Pollack etal. (2013)
Rahman etal. (2010)
Sawada et al. (2013)
Sen and Chaudhuri (2008)
Sengupta et al. (2013)
Shen etal. (2013)
Tsuda etal. (1995)
Von Ehrenstein et al.
(2006)
Xu etal. (2012)
Primary (P) or
Supporting (S)
S
P
P
P
S
P
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
-
++
++
+
+
1 +
++
++
++
++
Confounding
Confounding
(Design)
-
++
++
++
*
-
++
++
++
++
Unintended
Exposure
+
++
+
+
+
-
+
+
++
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
-
++
+
+
-
++
+
+
Detection
Blinding (Outcome
Assessment)
-
+
+
+
-
-
+
++
+
Confounding
(Analysis)
-
+
+
++
-
-
-
-
+
-
Exposure
Characterization
-
+
+
-
-
+
-
-
-
++
Outcome
Assessment
+
++
-
++
++
++
-
+
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
-
++
++
++
-
++
+
+
++
+
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-26 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.12Risk of Bias Overview - Skin Diseases
Study
Ahmad etal. (1999)
Ahsan et al. (2000)
Ahsanetal. (2006)
Applebaumetal. (2007)*
Argos et al. (2007)*
Argosetal. (2011)
Baastrup et al. (2008)
Barati et al. (2010)
Beane Freeman et al.
(2004)*
Bhowmicketal. (2013)
Borgonoetal. (1977)
Breton et al. (2006)
Primary (P) or
Supporting(S)
S
P
P
P
P
P
P
P
P
P
S
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
-
++
++
+
++
t+
Confounding
Confounding
(Design)
-
+
++
+
++
++
+ ++
_J +
++
+
-
++
++
+
++
Unintended
Exposure
+
+
+
+
+
+
+
++
-
-
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
bfl
^c
'&_
0^
DO
If
co 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
-
+
++
++
++
++
+
-
+
-
++
Detection
Blinding (Outcome
Assessment)
-
-
++
+
++
++
+
-
+
+
-
+
Confounding
(Analysis)
-
-
-
+
+
-
+
-
+
-
-
-
Exposure
Characterization
-
+
++
++
+
++
-
-
-
+
-
+
Outcome
Assessment
-
+
+
++
+
+
+
+
+
+
-
-
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
+
-
++
++
++
++
-
++
+
++
-
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-27 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Chakrabortietal. (2013b)
Chakrabortietal. (2003)
Chenetal. (2003a)*
Chenetal. (2006a)*
Chenetal. (2007c)*
Enterline and Marsh
(1982)
Fatmietal. (2009)
Fatmietal. (2013)
Ghosh et al. (2007b)
Ghosh (2013)
Gilbert-Diamond et al.
(2013)
Guo et al. (2006b)
Guo et al. (2006a)
Primary (P) or
Supporting (S)
S
S
P
P
P
S
P
P
P
S
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
-
-
+
++
-
-
++
+
++
-
++
++
++
Confounding
Confounding
(Design)
-
-
++
++
++
++
-
++
-
++
++
++
Unintended
Exposure
-
+
+
+
+
+
-
+
-
+
-
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
++
++
++
++
+
-
+
++
+
++
++
++
Detection
Blinding (Outcome
Assessment)
-
-
+
++
++
+
-
-
+
-
-
++
+
Confounding
(Analysis)
-
-
+
-
+
-
-
-
++
-
-
-
+
Exposure
Characterization
-
-
-
-
+
-
-
+
-
-
++
-
-
Outcome
Assessment
-
-
++
+
+
++
+
+
+
-
+
++
+
SRB
Outcome Reporting
-
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
-
-
++
++
++
++
++
-
++
++
++
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-28 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Guo et al. (2007)
Hall et al. (2006)
Haqueetal. (2003)
Hashimetal. (2013)
Honetal. (2012)*
Hsu et al. (2013a)
Hsuehetal. (1995)
Hsuehetal. (1997)
Karagas et al. (2001)
Knobeloch et al. (2006)
Lamm etal. (2007)*
Leonard! et al. (2012)
Lewis etal. (1999)
Lietal. (2013a)
Primary (P) or
Supporting (S)
S
P
S
P
P
P
P
P
P
P
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
++
++
++
++
++
++
++
++
+
++
+
++
Confounding
CuO
c
T3
O 00
1= '«
5 0)
O i i
++
++
-
-
++
++
++
++
+
-
++
-
++
Unintended
Exposure
+
++
-
++
+
+
+
+
+
-
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
-
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
O
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
-
++
++
-
-
++
-
++
++
++
++
++
+
+
Detection
Blinding (Outcome
Assessment)
-
++
-
-
+
+
+
+
+
+
-
++
+
++
Confounding
(Analysis)
-
-
+
-
+
-
-
-
+
+
-
+
-
+
Exposure
Characterization
-
+
++
-
-
-
-
+
++
-
-
-
-
Outcome
Assessment
-
SRB
Outcome Reporting
+
+
+
+
++ +
++
++
++
++
+
++
++
++
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
-
++
++
+
++
++
+
++
+
++
+
++
-
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-29 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Lindberg et al. (2008)
Lindbergetal. (2010)*
Liu etal. (2013)
Lubinetal. (1981)
Maden etal. (2011)
Maharian etal. (2005)
Maharian et al. (2007)*
Mazumderetal. (1998)
Mazumderetal. (2013)*
McCarty et al. (2006)*
McDonald et al. (2007)
Melkonianetal. (2011)
Mitra et al. (2002)
Mosaferi et al. (2008)
Primary (P) or
Supporting (S)
P
P
S
S
P
S
P
P
P
P
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
++
+
+
-
+
-
++
++
+
++
+
++
Confounding
Confounding
(Design)
++
++
-
-
-
+
++
i:
++
-
-
Unintended
Exposure
+
+
-
-
+
-
+
++
+
+
++
+
++
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
++
++
+
+
++
++
+
-
++
++
++
++
+
Detection
Blinding (Outcome
Assessment)
+
++
-
-
++
++
+
-
++
-
++
-
-
Confounding
(Analysis)
-
+
-
+
-
-
-
-
-
-
-
-
+
-
Exposure
Characterization
+
+
-
-
++
+
-
++
-
-
++
-
-
Outcome
Assessment
+
++
+
-
+
+
+
-
+
+
-
+
-
+
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
++
++
+
++
-
++
++
++
++
++
++
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-30 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Pauletal. (2013)
Pavittranon et al. (2003)
Peietal. (2013)
Perry et al. (1948)
Pesch et al. (2002)
Pesolaetal. (2012)
Pierce etal. (2011)
Rahman etal. (2006a)
Ranft et al. (2003)
Rosales-Castillo et al.
(2004)*
Schafer etal. (1999)*
Seow et al. (2012)
Smith etal. (2000)
Surdu etal. (2013)
Primary (P) or
Supporting (S)
P
S
P
S
S
P
P
P
P
P
P
P
S
S
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
-
-
-
++
++
++
++
++
++
-
++
-
++
Confounding
Confounding
(Design)
++
-
++
-
++
++
++
-
++
++
-
++
-
++
Unintended
Exposure
+
++
+
+
-
+
++
+
+
B
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
-
-
++
+
++
++
++
++
++
-
+
+
++
Detection
Blinding (Outcome
Assessment)
+
-
-
+
+
++
++
-
+
-
++
++
+
Confounding
(Analysis)
-
-
+
-
-
-
-
+
-
+
-
-
-
++
Exposure
Characterization
+
-
+
-
-
+
Outcome
Assessment
++
-
+
-
++
+
+
-
-
++
++
+
+
*
-
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
-
-
-
++
++
++
++
++
+
+
++
-
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-31 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Tondeletal. (1999)*
Valentine etal. (1991)
Valenzuelaetal. (2005)
Xia et al. (2009)
Primary (P) or
Supporting (S
P
S
P
P
Selection
Randomizatiot
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
2
Comparison G
.
.
++
++
Confounding
Confounding
(Design)
+
.
++
++
Unintended
Exposure
+
+
.
++
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
LO
c
o
'4-*
Protocol Devia
+
+
+
+
DO
'&_
O
DO
If
CQ 55
n/a
n/a
n/a
n/a
Att.
CD
E
0
u
4-*
O
DO
c
I/) ra
;= to
2 O
++
.
++
++
Detection
QJ
E
o
Blinding (Outc
Assessment)
.
.
++
++
Confounding
(Analysis)
.
.
.
.
c
Exposure
Characterizatk
.
.
+
+
Outcome
Assessment
.
.
+
+
SRB
DO
C
t
Outcome Repc
+
+
+
+
Other
>
Internal Validi
++
.
+
++
* Data not yet included in accompanying evidence tables.
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-32 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.13Risk of Bias Overview - Respiratory Effects
Study
Ades and Kazantzis (1988)
Axelsonetal. (1978)
Baastrup et al. (2008)
Begum etal. (2012)
Bulbulyan etal. (1996)
Chakraborti et al. (2013b)
Chattopadhyay et al.
(2010)
Chen etal. (1986)
Chen etal. (2004a)
Chen etal. (2010a)
Chiou etal. (1995)
Chung etal. (2012)
Primary (P) or
Supporting(S)
S
S
P
S
s
s
s
s
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
+
+
-
+
-
-
++
++
*
Confounding
Confounding
(Design)
-
-
++
-
-
-
-
+
++
++
; ++
Unintended
Exposure
++
+
+
+
+
-
-
-
+
++
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
CuO
'&_
3
CuO
If
CQ y,
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
-
++
++
++
+
+
++
+
-
Detection
Blinding (Outcome
Assessment)
-
++
+
-
-
-
-
+
+
+
-
+
Confounding
(Analysis)
-
+
-
+
-
+
+
-
-
-
-
1 Exposure
Characterization
-
-
++
-
++
Outcome
Assessment
-
++
+
-
-
++
++
++
+
+
SRB
Outcome Reporting
+
+
+
+
+
-
+
+
+
+
+
+
Other
Internal Validity
-
+
-
++
++
-
-
++
++
++
++
-
April 2014
Jro/? development materials are for review purposes only and do not constitute Agency policy.
4-33 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
D'Erricoetal. (2009)
Dauphineetal. (2011)
Dauphineetal. (2013)
De et al. (2004)
Enterline and Marsh
(1982)
Enterline et al. (1987)
Enterline et al. (1995)
Farzanetal. (2013)
Ferreccio et al. (1998)*
Ferreccio et al. (2000)
Ferreccio et al. (2013b)
Garcia-Esquinas et al.
(2013)
Ghosh et al. (2007b)
Primary (P) or
Supporting (S)
S
P
P
S
S
S
S
P
P
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
+
++
+
-
-
+
++
+
++
++
+
++
Confounding
Confounding
(Design)
++
++
++
+
-
+
-
++
++
++
++
++
++
Unintended
Exposure
++
++
++
+
-
-
-
+
++
++
++
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
++
++
-
+
+
++
+
+
++
+
++
++
Detection
Blinding (Outcome
Assessment)
+
-
++
-
+
+
+
+
+
+
+
+
+
Confounding
(Analysis)
-
+
-
-
-
+
-
+
+
+
-
+
++
Exposure
Characterization
-
-
+
-
-
-
-
+
-
-
-
++
-
Outcome
Assessment
++
-
++
-
++
+
+
-
++
++
++
+
+
SRB
Outcome Reporting
+
+
+
-
+
+
+
Other
Internal Validity
++
+
++
-
++
-
+
+ ++
+
+
+
+
+
++
++
++
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-34 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Ghosh (2013)
Grimsrud et al. (2005)
Guo et al. (2007)
Halatek et al. (2009)
Heck et al. (2009)
Hsu et al. (2013b)
Hsu et al. (2013a)
Huetal. (1999)
Jarupetal. (1989)
Khlifi et al. (2014)
Lee-Feldstein (1989)
Lewis etal. (1999)
Lubinetal. (1981)
Lubin etal. (2000)
Primary (P) or
Supporting (S)
S
S
S
S
P
P
P
S
S
P
S
P
S
S
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
-
+
++
++
++
++
+
+
++
+
+
-
+
Confounding
Confounding
(Design)
-
++
++
++
++
++
++
-
-
-
+
Unintended
Exposure
-
++
-
-
+
++
++
+
-
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
+
++
-
++
+
++
++
+
++
++
++
+
+
+
Detection
Blinding (Outcome
Assessment)
-
-
-
+
+
+
+
+
+
-
+
-
-
Confounding
(Analysis)
-
+
-
-
+
-
-
-
-
-
-
-
+
-
Exposure
Characterization
-
-
-
+
++
-
-
-
-
+
-
-
-
-
Outcome
Assessment
-
-
-
+
++
++
++
++
+
++
-
++
-
-
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
++
+
+
+
Other
Internal Validity
++
-
-
-
++
++
++
+
++
++
++
-
+
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-35 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Lubinetal. (2008)
Maiumdaret al. (2009)
Mazumderet al. (2005)
Milton etal. (2001)
Mostafaetal. (2008)*
Nafees et al. (2011)
Nakadairaetal. (2002)
Parvez et al. (2013)
Parvez et al. (2008)*
Parvez et al. (2010)
Paul etal. (2013)
Pinto etal. (1977)
Pinto etal. (1978)
Rahman etal. (2011)
Primary (P) or
Supporting (S)
S
P
S
S
P
P
S
P
P
P
P
S
S
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
-
++
-
++
++
+
++
++
++
++
-
+
++
Confounding
Confounding
(Design)
+
-
++
++
++
++
+
++
++
++
++
Unintended
Exposure
-
+
+
-
+
++
-
+
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ 55
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
-
++
++
-
++
+
++
+
++
++
++
++
+
Detection
Blinding (Outcome
Assessment)
-
+
-
+
+
-
++
+
+
+
+
Confounding
(Analysis)
-
++
-
+
-
-
-
-
-
+
Exposure
Characterization
-
++
+
++
+
-
-
++
Outcome
Assessment
-
+
++
+
-
++
+
-
++
++
++
+
SRB
Outcome Reporting
+
+
-
+
+
+
+
+
++
+
+
+
+
+
Other
Internal Validity
++
++
+
+
+
+
-
++
++
++
++
-
-
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-36 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Raqib et al. (2009)
Sawada et al. (2013)
Smith etal. (2011)
Smith etal. (2013)
Sorahan (2009)
Steinmausetal. (2013)
T Mannetie et al. (2011)
Taylor etal. (1989)
Tsuda etal. (1995)
Wadhwa et al. (2011b)
Welch etal. (1982)
Primary (P) or
Supporting (S)
P
P
S
P
S
P
S
S
P
S
S
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
+
++
++
-
++
++
+
++
-
-
Confounding
Confounding
(Design)
-
++
++
++
-
++
++
++
++
-
+
Unintended
Exposure
+
+
+
++
++
++
+
-
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
CuO
c
'&_
3
Q
CuO
If
CQ y.
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
+
++
+
+
-
++
++
++
-
+
Detection
Blinding (Outcome
Assessment)
+
+
++
-
-
+
+
+
+
+
+
Confounding
(Analysis)
+
++
-
:
+
-
+
-
-
-
Exposure
Characterization
++
-
-
-
-
-
-
-
Outcome
Assessment
-
++
+
++
-
++
-
++
++
++
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
++
+
++
++
++
++
++
+
-
+
* Data not yet included in accompanying evidence tables.
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-37 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.14Risk of Bias Overview - Nervous System Effects
Study
Adams et al. (2013)
Alietal. (2010)
Blometal. (1985)
Chakraborti et al. (2003)
Chiouetal. (2005)
Enterline and Marsh (1982)
Feldmanetal. (1979)
Ghosh et al. (2007b)
Ghosh (2013)
Gongetal. (2011)
Guoetal. (2007)
Hafeman et al. (2005)
Primary (P) or Supporting
(S)
P
P
S
S
P
S
S
P
S
S
S
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
+
+
-
+
-
-
++
-
+
-
"
Confounding
Confounding
(Design)
-
++
++
-
-
-
+
++
-
-
_^
+
Unintended
Exposure
+
++
-
+
+
-
-
+
-
+
-
"
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
Blinding (During
Study)
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
+
++
++
++
+
+
++
+
++
-
+
Detection
Blinding (Outcome
Assessment)
++
-
-
-
++
+
++
+
-
-
-
-
Confounding
(Analysis)
+
-
-
-
++
-
-
++
-
-
-
+
Exposure
Characterization
+
++
-
-
+
-
-
-
-
-
-
"
Outcome
Assessment
+
++
+
-
++
++
+
+
-
++
-
"
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
++
++
++
-
++
++
+
++
+
-
+
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-38 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Halatek et al. (2009)
Kreissetal. (1983)
Lagerkvist and Zetterlund
(1994)
Lewis etal. (1999)
Li et al. (2006)
Lilis etal. (1985)*
Lin et al. (2008)
Mackenzie and Kyle (1984)
Mao etal. (2010)
O'Bryantetal. (2011)
Otto et al. (2006)
Otto et al. (2007)
Park etal. (2014)
Paul etal. (2013)
Primary (P) or Supporting
(S)
S
P
S
P
P
P
P
S
S
S
P
P
P
P
Selection
Randomization
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Comparison Group
++
+
+
+
++
++
-?-
+
++
+
+
+
++
Confounding
Confounding
(Design)
_
-
++
-
++
+
+
+
++
++
++
+
++
Unintended
Exposure
-
+
+
++
+
+
-
+
-
++
++
++
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Protocol Deviations
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Blinding (During
Study)
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Att.
Missing Outcome
Data
++
++
++
+
++
+
+
-
++
-
++
+
++
++
Detection
Blinding (Outcome
Assessment)
-
++
-
+
++
++
++
-
++
+
-
++
+
+
Confounding
(Analysis)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Exposure
Characterization
+
-
-
-
-
-
-
-
-
-
-
++
-
+
Outcome
Assessment
+
++
++
++
-
-
++
-
-
++
++
++
+
++
SRB
Outcome Reporting
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Other
Internal Validity
-
+
+
-
++
++
++
+
-
++
++
++
+
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-39 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Rosado et al. (2007)
See et al. (2007)
Siriczuk-Walczak et al.
(2010)
Tseng et al. (2006)
Zierold et al. (2004)*
no
c
t
O
Q.
Q.
3
l/l
i_
O
^
£
ra
£ £.
p
p
s
p
p
Selection
andomization
cc.
n/a
n/a
n/a
n/a
n/a
Allocation
Concealment
n/a
n/a
n/a
n/a
n/a
nparison Group
++
++
.
++
++
Confounding
Confounding
(Design)
++
++
+
++
++
Unintended
Exposure
++
+
.
+
+
Performance
Experimental
Conditions
n/a
n/a
n/a
n/a
n/a
tocol Deviations
E
Q.
+
+
+
+
+
inding (During
Study)
00
n/a
n/a
n/a
n/a
n/a
Att.
ssing Outcome
Data
§
++
+
++
++
+
Detection
iding (Outcome
Assessment)
:^
00
.
++
.
-
++
Confounding
(Analysis)
+
.
.
-
+
Exposure
laracterization
u
+
.
.
+
-
Outcome
Assessment
++
++
+
+
-
SRB
come Reporting
3
O
+
+
+
+
+
Other
ternal Validity
c
++
++
+
++
+
* Data not yet included in accompanying evidence tables.
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
4-40 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
4.15References for Risk of Bias Evaluations for
Epidemiologic Studies
Adams. JB: Audhya. T: Mcdonough-Means. S: Rubin. RA: Quig. D: Geis. E: Gehn. E: Loresto. M: Mitchell J:
Atwood. S: Barnhouse. S: Lee. W. (2013). Toxicological status of children with autism vs. neurotypical
children and the association with autism severity. Biol Trace ElemRes 151: 171-180.
http://dx.doi.org/10.1007/sl2011-012-9551-l
Ades. AE: Kazantzis. G. (1988). Lung cancer in a non-ferrous smelter: the role of cadmium. Br J Ind Med 45:
435-442. http://dx.doi.0rg/10.1136/oem.45.7.435
Ahmad. SA: Khatun. F: Saved. MH: Khan. MH: Aziz. R: Hossain. MZ: Faruquee. MH. (2006).
Electrocardiographic abnormalities among arsenic-exposed persons through groundwater in Bangladesh. J
Health Popul Nutr 24: 221-227.
Ahmad. SA: Saved. MHS. U: Barua. S: Khan. MH: Faruquee. MH: Mil A: Hadi. SA: Talukder. HK. (2001).
Arsenic in drinking water and pregnancy outcomes. Environ Health Perspect 109: 629-631.
http://dx.doi.org/10.2307/3455038
Ahmad. SA: Saved. MHS. U: Hadi. SA: Faruauee. MH: Khan. MH: Mil. MA: Ahmed. R: Khan. AW. (1999).
Arsenicosis in a village in Bangladesh. Int J Environ Health Res 9: 187-195.
http://dx.doi.org/10.1080/09603129973155
Ahmed. S: Ahsan. KB: Kippler. M: Mily. A: Wagatsuma. Y: Hoque. AMW: Ngom. PT: El Arifeen. S: Raqib. R:
Vahter. M. (2012). In utero arsenic exposure is associated with impaired thymic function in newborns
possibly via oxidative stress and apoptosis. Toxicol Sci 129: 305-314. http://dx.doi.org/10.1093/toxsci/kfs202
Ahsan. H: Chen. Y: Parvez. F: Zablotska. L: Argos. M: Hussain. I: Momotaj. H: Lew. D: Cheng. Z: Slavkovich.
V: van Geen. A: Howe. GR: Graziano. JH. (2006). Arsenic exposure from drinking water and risk of
premalignant skin lesions in Bangladesh: Baseline results from the Health Effects of Arsenic Longitudinal
Study. Am JEpidemiol 163: 1138-1148. http://dx.doi.org/10.1093/aie/kwj 154
Ahsan. H: Perrin. M: Rahman. A: Parvez. F: State. M: Zheng. Y: Milton. AH: Brandt-Rauf. P: van Geen. A:
Graziano. J. (2000). Associations between drinking water and urinary arsenic levels and skin lesions in
Bangladesh. J OccupEnvironMed 42: 1195-1201. http://dx.doi.org/10.1097/00043764-200012000-00016
Akbal A: Yilmaz. H: Tutkun. E. (2013). Arsenic exposure associated with decreased bone mineralization in
male. Aging Male 1-3. http://dx.doi.org/10.3109/13685538.2013.819326
All N: Hoque. MA: Hague. A: Salam. KA: Karim MR: Rahman. A: Islam K: Saud. ZA: Khalek. MA: Akhand.
AA: Hossain. M: Mandal A: Karim. MR: Miyataka. H: Himeno. S: Hossain. K. (2010). Association between
arsenic exposure and plasma cholinesterase activity: a population based study in Bangladesh. Environ Health
9: 36. http://dx.doi.org/10.1186/1476-069X-9-36
Amaral. AFS: Porta. M: Silverman. DT: Milne. RL: Kogevinas. M: Rothman. N: Cantor. KP: Jackson. BP:
Pumarega. JA: Lopez. T: Carrato. A: Guarner. L: Real. FX: Malats. N. (2012). Pancreatic cancer risk and
levels of trace elements. Gut 61: 1583-1588. http://dx.doi.org/10.1136/gutinl-2011-301086
Applebaum. KM: Karagas. MR: Hunter. DJ: Catalano. PJ: Byler. SH: Morris. S: Nelson. HH. (2007).
Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New
Hampshire. Environ Health Perspect 115: 1231-1236. http://dx.doi.org/10.1289/ehp. 10096
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 4-41 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Argos. M: Kalra. T: Pierce. BL: Chen. Y: Parvez. F: Islam. T: Ahmed. A: Hasan. R: Hasan. K: Sarwar. G: Lew.
D: Slavkovich. V: Graziano. JH: Rathouz. PJ: Ahsan. H. (2011). A prospective study of arsenic exposure
from drinking water and incidence of skin lesions in Bangladesh. Am J Epidemiol 174: 185-194.
http://dx.doi.org/10.1093/aie/kwr062
Argos. M: Kalra. T: Rathouz. PJ: Chen. Y: Pierce. B: Parvez. F: Islam T: Ahmed. A: Rakibuz-Zaman. M:
Hasan. R: Sarwar. G: Slavkovich. V: van Geen. A: Graziano. J: Ahsan. H. (2010). Arsenic exposure from
drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort
study. Lancet 376: 252-258. http://dx.doi.org/10.1016/S0140-6736(10)60481-3
Argos. M: Parvez. F: Chen. Y: Hussain. AZ: Momotai. H: Howe. GR: Graziano. JH: Ahsan. H. (2007).
Socioeconomic status and risk for arsenic-related skin lesions in Bangladesh. Am J Public Health 97: 825-
831. http://dx.doi.org/10.2105/AJPH.2005.078816
Axelson. O: Dahlgren. E: Jansson. CD: Rehnlund. SO. (1978). Arsenic exposure and mortality: a case-referent
study from a Swedish copper smelter. Occup Environ Med 35:8-15.
Baastrup. R: Sorensen. M: Balstrem. T: Frederiksen. K: Larsen. CL: Tjonneland. A: Overvad. K: Raaschou-
Nielsen. O. (2008). Arsenic in drinking-water and risk for cancer in Denmark. Environ Health Perspect 116:
231-237. http://dx.doi.org/10.1289/ehp. 10623
Barati AH: Maleki. A: Alasvand. M. (2010). Multi-trace elements level in drinking water and the prevalence of
multi-chronic arsenical poisoning in residents in the west area of Iran. Sci Total Environ 408: 1523-1529.
http://dx.doi.0rg/10.1016/i.scitotenv.2009.12.035
Beane Freeman. LE: Dennis. LK: Lynch. CF: Thorne. PS: Just CL. (2004). Toenail arsenic content and
cutaneous melanoma in Iowa. Am J Epidemiol 160: 679-687. http://dx.doi.org/10.1093/aje/kwh267
Begum. M: Horowitz. J: Hossain. MI. (2012). Low-dose risk assessment for arsenic: a meta-analysis approach.
http://dx.doi.org/10.1177/1010539512466568
Bhowmick. S: Haider. D: Kundu. AK: Saha. D: Iglesias. M: Nriagu. J: Guha Mazumder. DN: Roman-Ross. G:
Chatterjee. D. (2013). Is saliva a potential biomarker of arsenic exposure? A case-control study in West
Bengal, India. Environ Sci Technol 47: 3326-3332. http://dx.doi.org/10.1021/es303756s
Biswas. R: Ghosh. P: Banerjee. N: Das. JK: Sau. T: Banerjee. A: Roy. S: Ganguly. S: Chatterjee. M: Mukherjee.
A: Girl AK. (2008). Analysis of T-cell proliferation and cytokine secretion in the individuals exposed to
arsenic. HumExp Toxicol 27: 381-386. http://dx.doi.org/10.1177/0960327108094607
Blom S: Lagerkvist B: Linderholm H. (1985). Arsenic exposure to smelter workers: Clinical and
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5 EVIDENCE TABLES FOR INORGANIC ARSENIC
EPIDEMIOLOGIC STUDIES
1
2
3
4
Epidemiologic studies were limited to inorganic exposure where possible. However,
measurements of asenic in urine may include inorganic arsenic, as well as arsenic
metabolites. In general, biomarkers of exposure for arsenic represent total arsenic, and
arsenic in drinking water represents inorganic arsenic.
5.1 Summary of Observational Epidemiology Studies for
Health Effect Category: Bladder Effects
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Exposure Measures
Results
Baastrupetal. (2008)
Study Type: cohort
(prospective)
Location: Denmark
(Copenhagen and
Aarhus)
Population: Danish
Cancer Registry
population (adults)
n exposed: 56,378
n total: 57,053
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure and time-weighted average
arsenic concentrations calculated for
individuals based on residential address
and history from Central Population
Registry combined with measurement
data from nearest water utility as
recorded by Geological Survey of
Denmark and Greenland (1987-2004)
Population-Level Exposure:
not available
Outcome: bladder cancer
cumulative arsenic exposure, mg
Exp. Level n IRR
continuous NR 1
Stat Method: Cox regression
M
0.98, 1.04
Exposure Surrogate: drinking water
Exposure Description: time-weighted
and cumulative arsenic concentrations
calculated for individuals based on
residential address and history from
Central Population Registry combined
with measurement data from nearest
water utility as recorded by Geological
Survey of Denmark and Greenland (1987-
Outcome: bladder cancer
time-weighted average arsenic exposure, ng/L
Exp. Level n IRR (CD
continuous NR 1.01 0.93, 1.11
Stat Method: Cox regression
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Bates et al. (1995)
Study Type: case-
control
Location: United States
(Utah)
Population: National
Bladder Cancer Survey
Utah adult respondents
likely exposed to higher
than average arsenic in
drinking water
n cases: 117
n control: 266
Exposure Measures
2004)
Population-Level Exposure:
0.7 ng/L median
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
dose estimated from historical arsenic
levels in public drinking water collected
1978-1979 combined with lifetime
residential history and drinking water
source at each residence
Population-Level Exposure:
19-53 mg range
Exposure Surrogate: urine
Exposure Description: estimated arsenic
concentration in urine based on historic
arsenic levels in public drinking water
collected 1978-1979 combined with
lifetime residential history, drinking
water source at each residence, and ratio
of water to total liquid intake
Population-Level Exposure:
8-74 (mg/L) x yr. range
Results
Outcome: bladder cancer
cumulative arsenic dose - all subjects (quartiles),
mg
Exp. Level n adiOR (CD
<19 NR 1 n/a
19-<33 NR 1.56 0.8,3.2
33-<53 NR 0.95 0.4,2.0
>53 NR 1.41 0.7,2.9
Stat Method: Unconditional multiple logistic
regression analysis
cumulative arsenic dose - ever smokers
(quartiles), mg
Exp. Level n adiOR (CD
<19 NR 1 n/a
19-<33 NR 3.33 1.0, 10.8
33-<53 NR 1.93 0.6,6.2
>53 NR 3.32 1.1,10.3
Stat Method: Unconditional multiple logistic
regression analysis
Outcome: bladder cancer
urine arsenic concentration (30-39 years
exposure) (quartiles), (mg/L) x yr.
Exp. Level n adjOR (Cl)
<8 NR 1 n/a
8-<10 NR 1.27 0.4,3.6
10-<13 NR 1.26 0.4,3.6
>13 NR 3.07 1.1,8.4
Stat Method: Unconditional multiple logistic
regression analysis
urine arsenic concentration (10-19 years
exposure) (quartiles), (mg/L) x yr.
Exp. Level n adjOR (Cl)
<8 NR 1 n/a
8-<10 NR 1.14 0.6,2.3
10-<13 NR 1.16 0.5,2.4
>13 NR 1.59 0.8,3.3
Stat Method: Unconditional multiple logistic
regression analysis
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Bates et al. (2004)
Study Type: case-
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: average arsenic
Results
urine arsenic concentration (10-19 years
exposure, subjects reported to have ever
smoked) (quartiles), (mg/L) x yr.
Exp. Level n adiOR (CD
<8 NR 1 n/a
8-<10 NR 1.36 0.5,3.9
10-<13 NR 1.57 0.5,4.5
>13 NR 2.92 1.1,8.0
Stat Method: Unconditional multiple logistic
regression analysis
urine arsenic concentration (30-39 years
exposure, subjects reported to have ever
smoked) (quartiles), (mg/L) x yr.
Exp. Level n adiOR (CD
<8 NR 1 n/a
8-<10 NR 1.86 0.4,9.7
10-<13 NR 1.48 0.3,7.4
>13 NR 8.7 1.7,44
Stat Method: Unconditional multiple logistic
regression analysis
urine arsenic concentration (all subjects)
(quartiles), (mg/L) x yr.
Exp. Level n adiOR (CD
<33 NR 1 n/a
33-<53 NR 0.69 0.3, 1.5
53-<74 NR 0.54 0.3, 1.2
>74 NR 1 0.5,2.1
Stat Method: Unconditional multiple logistic
regression analysis
urine arsenic concentration (ever smokers)
(quartiles), (mg/L) x yr.
Exp. Level n adiOR (CD
<33 NR 1 n/a
33-<53 NR 1.95 0.7,5.6
53-<74 NR 1.21 0.4,3.7
>74 NR 1.41 0.5,4.3
Stat Method: Unconditional multiple logistic
regression analysis
Outcome: bladder cancer
arsenic concentration (excluding proxy wells)
(quartiles), ng/L
Exp. Level n adiOR (CD
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
control
Location: Argentina
(Cordoba Province)
Population:
Argentinians living in
region with high
arsenic water
concentrations
n cases: 114
n control: 114
Chen et al. (2010b)
Study Type: cohort
(prospective)
Location: Taiwan
region not available
Population: adult
residents of arseniasis-
endemicarea in
northeast
n exposed: 5,798
n reference: 2,288
n total: 8,086
Exposure Measures
water concentration estimated for 6-40
years prior to interview based on
samples collected from wells near
individual's current and past residences
Population-Level Exposure:
164 |jg/L mean
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in well water estimated
based on concentration measurements
from 3,901 samples from 4,584 houses
(85.1% of total households)
Population-Level Exposure:
0. 15-3,000 ng/L range
Exposure Surrogate: drinking water
Exposure Description: concentration in
well water measured in samples from
85.1% of total households; cumulative
Results
0-50 NR 1 n/a
51-100 NR 1.11 0.3,3.7
101-200 NR 0.81 0.3,2.0
>200 NR 0.28 0.1, 1.4
Stat Method: Multivariate conditional logistic
regression
consumption of well water over past 61-70 years,
smokers only, u.Q/1
Exp. Level n adiOR (CD
No NR 1 n/a
Yes NR 2.54 1.0,6.4
Stat Method: Multivariate unconditional
logistic regression (adjusted for highest daily
number of cigarettes ever smoked)
Outcome: all urinary cancer
arsenic concentration in well water, ug/L
Exp. Level n adiRR (CD
<10 5 1 n/a
10-49.9 8 1.66 0.53,5.21
50-99.9 5 2.42 0.69,8.54
100-299.9 8 4.13 1.32, 12.9
>300 11 7.8 2.64,23.1
Unknown 8 3.4 1.05, 11.0
Stat Method: Cox proportional hazard
regression model
Outcome: urothelial carcinoma
arsenic concentration In well water, ug/L
Exp. Level n adiRR (CD
<10 3 1 n/a
10-49.9 6 1.85 0.45,7.61
50-99.9 3 2.19 0.43, 11.1
100-299.9 7 5.5 1.39,21.8
>300 10 10.8 2.90,40.3
Unknown 7 4.34 1.06, 17.7
Stat Method: Cox proportional hazard
regression model
Outcome: all urinary cancer
cumulative arsenic exposure concentration, u.Q/1-
year
Exp. Level n adiRR (CD
<400 NR 1 n/a
400-<1,000 NR 1.11 0.27,4.54
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Chiou et al. (1995)
Study Type: cohort
(prospective)
Location: Taiwan
(Southwestern coast of
Taiwan [Peimen,
Hsuechia, Putai, and
Ichu townships])
Population: BFD
patients and healthy
residents in arseniasis-
endemic townships
n exposed: 263
n reference: 2,293
n total: 2,556
Chiou et al. (2001a)
Study Type: cohort
(prospective)
Exposure Measures
exposure estimated based on self-
reported duration of well water
consumption and concentration at
current residence when actual
concentrations not available
Population-Level Exposure:
0.15-3,000 ug/L-year range
Exposure Surrogate: drinking water
Exposure Description: individual
exposure estimated using median arsenic
levels in artesian well water in each
village combined with residential history
information gathered during individual
interviews
Population-Level Exposure:
0.78 mg/L median
Exposure Surrogate: drinking water
Exposure Description: well water
samples collected and analyzed from
Results
1,000-<5,000 NR 2.33 0.86,6.36
5,000- NR 3.77 1.13, 12.6
< 10,000
> 10,000 NR 7.49 2.70,20.8
unknown NR 2.98 0.99,8.95
Stat Method: Cox proportional hazard
regression model
Outcome: urothelial carcinoma
cumulative arsenic exposure concentration, ug/L-
year
Exp. Level n adjRR (Cl)
<400 NR 1 n/a
400-<1,000 NR 1.35 0.22,8.25
1,000-<5,000 NR 3.2 0.85, 12.1
5,000- NR 6.93 1.62,29.5
< 10,000
> 10,000 NR 12.6 3.40,46.8
unknown NR 4.65 1.16, 18.7
Stat Method: method not available
Outcome: bladder cancer
average arsenic concentration in well water,
mg/L
Exp. Level n adjRR (Cl)
<0.05 6 1 n/a
0.05-0.70 7 1.8 0.6,5.3
>0.71 7 3.3 1.0, 11.1
unknown 9 1.2 0.4, 3.4
Stat Method: Cox proportional hazards
regression analysis
cumulative water arsenic exposure, mg/L-yr
Exp. Level n adjRR (Cl)
0 NR 1 n/a
0.1-19.9 NR 1.57 0.44,5.55
>20 NR 3.58 1.05, 12.19
Unknown NR 1.25 0.38,4.12
Stat Method: Cox proportional hazards
regression analysis
Outcome: cancer of urinary organs
arsenic concentration In well water, ug/L
Exp. Level n RR (Cl)
0-10.0 3 1 n/a
10.1-50.0 3 1.6 0.3,8.4
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Location: Taiwan
(Lanyang Basin)
Population: residents
of arseniasis-endemic
area of northeastern
Taiwan consuming well
water
n exposed: 8,102
n total: 8, 102
Chung etal. (2011)
Study Type: case-
control
Location: Taiwan
(Taipei)
Population: males and
females with urothelial
carcinoma identified at
hospital; controls from
same area with no prior
cancer history; most
consumed tap water
n cases: 170
n control: 402
Chung etal. (2012)
Study Type: cohort
(prospective)
Location: Taiwan
(Homei, Fuhsin,
Hsinming)
Population: residents
of arseniasis-endemic
Exposure Measures
3,901 (85.1%) households during home
interview
Population-Level Exposure:
0.15-3,590 ng/L range
Exposure Surrogate: urine
Exposure Description: spot urine
analyzed1 total arsenic ~~ sum of As(lll)
As(V), MMA(V), and DMA(V); relative
proportion of urinary arsenic species
calculated by dividing each arsenic
species level by total arsenic
Population-Level Exposure:
26.02 ng/g-creatinine mean
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure assessment determined by
duration of artesian well water use,
history or residence, and historical data;
cumulative arsenic exposure derived to
reflect long-term arsenic exposure by
median well water arsenic (population
level exposure reported here) x duration
of use
Results
50.1-100.0 2 2.3 0.4, 14.1
>100.0 7 4.9 1.2,20.0
Stat Method: Cox proportional hazards
regression analysis
Outcome: transitional cell carcinoma
arsenic concentration in well water, u.Q/1
Exp. Level n RR (CD
0-10.0 1 1 n/a
10.1-50.0 1 1.9 0.1,32.2
50.1-100.0 2 8.1 0.7,98.2
>100.0 5 15.1 1.7, 138.5
Stat Method: Cox proportional hazards
regression analysis
Outcome: urothelial carcinoma
inorganic arsenic percentage (tertiles), ug/g-
creatinine
Exp. Level n adiOR (CD
<2.86 44 1 n/a
2.86-6.03 52 1.61 0.91,2.84
>6.03 74 1.15 0.66,2
Stat Method: multiple logistic regression
total arsenic concentration (tertiles), ug/g-
creatinine
Exp. Level n adiOR (CD
<12.15 13 1 n/a
12.15-22.10 36 2.8 1.26,6.21
>22.1 121 6.71 3.14, 14.35
Stat Method: multiple logistic regression
Outcome: bladder cancer
cumulative water arsenic exposure (tertiles),
Hg/L-year
Exp. Level n adiOR (CD
<9.1 1 1 n/a
9.1-19.5 18 12.91 1.71,97.59
>19.5 19 7.74 0.97,61.51
Stat Method: Cox proportional hazard model
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-6 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Exposure Measures
Results
areas
n total: 1,563
Population-Level Exposure:
9.1-19.5 |jg/L-year range
Exposure Surrogate: drinking water
Exposure Description: information on
median arsenic level in artesian well
water of each village acquired from
previous studies carried out in the early
1960s (Lai etal., 1994); some study
subjects had moved from one village to
another, and there were differences in
arsenic concentrations between villages
Population-Level Exposure:
0.7-0.93 mg/L range
Outcome: bladder cancer
average water arsenic concentration (tertiles),
mg/L
Exp. Level n HR (CD
<0.05 1 1 n/a
0.05-0.71 15 4.35 0.56,33.52
>0.71 22 7.22 0.95,55.04
Stat Method: Cox proportional hazard model
Exposure Surrogate: urine
Exposure Description: urine samples of
1,078 subjects collected at time of
recruitment; all arsenic assays performed
within 6 months of sample collection
Population-Level Exposure:
not available
Outcome: bladder cancer
percent DMA in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR
>85.8 5 1 n/a
76.13-85.8 4 0.7 0.19,2.62
<76.13 19 3.05 1.11,8.37
Stat Method: Cox proportional hazard model
percent inorganic arsenic in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR M
<4.22 4 1 n/a
4.22-7.86 10 2.42 0.75,7.79
>7.86 14 3.53 1.16,10.77
Stat Method: Cox proportional hazard model
percent MMA in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR M
<8.34 7 1 n/a
8.34-15.31 4 0.57 0.17, 1.95
> 15.31 17 1.77 0.72,4.36
Stat Method: Cox proportional hazard model
Chung etal. (2013)
Study Type: case-
Exposure Surrogate: urine
Exposure Description: spot urine
Outcome: urinary carcinoma
percent DMA in total urinary arsenic
concentration (tertiles), ng/L
Exp. Level n adjOR
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-7 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Exposure Measures
Results
control
Location: Taiwan
(Taipei)
Population: hospital
patients with urothelial
carcinoma
n cases: 191
n control: 364
samples collected at time of recruitment
from each individual; detection limits for
As(lll), DMA(V), MMA(V), and As(V) were
0.02, 0.08, 0.05, and 0.07 ug/L,
respectively
Population-Level Exposure:
12.81-23.3 ng/L range
> 91.76 NR 1 n/a
83.56-91.76 NR 2.01 1.22,2.32
<83.56 NR 3.23 2,5.21
Stat Method: Multivariate logistic regression
percent inorganic arsenic in total urinary arsenic
concentration (tertiles), ng/L
Exp. Level n adjOR M
<2.76 NR 1 n/a
2.76-5.86 NR 1.07 0.66, 1.74
>5.86 NR 2.36 1.53,3.66
Stat Method: Multivariate logistic regression
percent MMA in total urinary arsenic
concentration (tertiles), ng/L
Exp. Level n adjOR M
<3.36 NR 1 n/a
3.36-9.13 NR 0.91 0.57, 1.45
>9.13 NR 1.76 1.15,2.71
Stat Method: Multivariate logistic regression
total urinary arsenic concentration (tertiles),
Exp. Level
<12.81
12.81-23.3
>23.3
NR
NR
NR
M
n/a
0.95, 2.82
2.80, 7.65
Stat Method: Multivariate logistic regression
Feki-Tounsi etal.
(2013)
Study Type: case-
control
Location: Tunisia
(central and southern
Tunisia)
Population: male
patients of hospital
urology department
with symptoms of
bladder cancer or
benign diseases
Exposure Surrogate: blood
Exposure Description: arsenic
concentrations in blood assessed from
whole-blood samples, before
hospitalization; subjects grouped for
analysis above and below median value
(0.70 Mg/L)
Population-Level Exposure:
4.98 ng/L mean 14.6SD
Outcome: bladder cancer
blood arsenic concentration, \ng/L
Exp. Level n adjOR (CD
0.15-0.70 NR 0.18 0.01,2.95
0.70-167.00 NR 2.44 1.11,5.35
Stat Method: Multiple logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-8 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
n cases: 86
n control: 196
Ferreccio et al. (2013b)
Study Type: case-
control
Location: Chile
(Regions 1 and II,
Northern Chile)
Population: residents
with bladder or lung
cancer in area formerly
having arsenic-
contaminated drinking
water
n cases: 538
n control: 640
Hsu et al. (2013a)
Study Type: cohort
(prospective)
Location: Taiwan
(Peimen, Hsuechia,
Putai, Ichu townships)
Population: 3 separate
subcohorts of residents
of an arseniasis-
endemic area
n exposed: 1,075
n reference: 535
n total: 2,447
Huang et al. (2008b)
Study Type: case-
control
Location: Taiwan
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: lifetime arsenic
exposure estimated by linking subject's
residence with water arsenic
concentration
Population-Level Exposure:
0-800 ng/L range
Exposure Surrogate: drinking water
Exposure Description: lifetime
cumulative arsenic exposure estimated
using median arsenic concentration in
village well where study subject lived and
duration of exposure; arsenic
concentrations in wells obtained from 2
investigations examining more than
38,565 wells across Taiwan; lifetime
cumulative arsenic exposure (CAE)
estimated using median arsenic
concentration in village well where study
subject lived and duration of exposure
Population-Level Exposure:
1-20 mg/L-yr range
Exposure Surrogate: urine
Exposure Description: single spot arsenic
measurement evaluated, including
speciation, for each individual
Results
Outcome: bladder cancer
water arsenic concentration - never smoker, ng/L
Exp. Level n adiOR (CD
<11 6 1 n/a
>355 19 8.9 3.0,26
Stat Method: Unconditional logistic
regression
water arsenic concentration - smoked >10
cigarettes/day, ng/L
Exp. Level n adiOR (CD
<11 never 6 1 n/a
smoker
<11 14 4.1 1.3, 13
>355 33 23 8.2,66
Stat Method: Unconditional logistic
regression
Outcome: urothelial carcinoma
cumulative arsenic exposure, mg/L - yr
Exp. Level n HR (CD
<1.0 NR 1 n/a
1.0-19.9 NR 1.43 0.76,2.68
>20 NR 2.97 1.58,5.60
missing NR 1.21 0.70,2.69
Stat Method: Cox regression analysis with
time-dependent covariates
Outcome: urothelial cancer
total urinary arsenic (quartiles), ng/g-creatinine
Exp. Level n adiOR (CD
<13.09 NR 1 n/a
13.10-20.29 NR 1.48 0.69,3.12
20.30-30.59 NR 3.22 1.62,6.27
> 30.60 NR 6.26 3.21,12.22
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-9 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
region not available
Population: hospital
patients with or
without urothelial
carcinomas
n cases: 171
n control: 488
Huang et al. (2008a)
Study Type: cohort
(prospective)
Location: Taiwan
(southwest [Putai
township of Chiayi
County])
Population: adult
residents in selected
villages
n exposed: 573
n reference: 138
n total: 965
Karagasetal. (2004)
Exposure Measures
Population-Level Exposure:
13.09-30.6 ng/g-creatinine range
Exposure Surrogate: drinking water
Exposure Description: arsenic levels in
well water collected in studies conducted
in the 1960s, assigned based on self-
reported information on residential
history
Population-Level Exposure:
0-0.9 mg/L range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure determined using self-reported
information on residential history and
duration of consuming high-arsenic
artesian well water; arsenic levels in well
water collected in previous studies
conducted in the 1960s
Population-Level Exposure:
0-20 mg/L-yr range
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration, including speciation,
measured from single sample for each
individual
Population-Level Exposure:
4.29-8.02 % range
Exposure Surrogate: toenails
Results
Stat Method: Logistic regression
Outcome: urothelial carcinoma
average arsenic concentration in well water,
mg/L
Exp. Level n RR (CD
0-0.4 1 1 n/a
0.41-0.7 14 5.2 0.7,39.8
0.71-0.9 9 6.7 0.8,53.4
>0.9 7 6.5 0.8,53.1
Stat Method: Cox proportional hazards model
Outcome: urothelial carcinoma
cumulative arsenic exposure index, mg/L-yr
Exp. Level n RR (CD
0 0 1 n/a
0.1-11.9 2 NR n/a
12-19.9 9 4.6 1.0,21.8
>20 20 7.9 1.7,37.9
Stat Method: Cox proportional hazards model
Outcome: urothelial carcinoma
inorganic urinary arsenic (tertiles), %
Exp. Level n RR (CD
<4.29 NR 1 n/a
4.29-8.02 NR 1.4 0.6,3.4
>8.02 NR 1.4 0.5,3.6
Stat Method: Cox proportional hazards model
Outcome: bladder cancer
toenail arsenic concentration, ug/g
Exp. Level n adiOR (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-10 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Exposure Measures
Results
Study Type: case-
control
Location: United States
(NH)
Population: adult
residents with bladder
cancer consuming
water from private
wells containing arsenic
and public water
systems
n cases: 383
n control: 641
Exposure Description: toenail arsenic
concentration measured from clean
samples
Population-Level Exposure:
0.009-2.484 ng/g range
0.009-0.059 NR 1 n/a
0.060-0.086 NR 1.37 0.96, 1.96
0.087-0.126 NR 1.08 0.74, 1.58
0.127-0.193 NR 1.04 0.66, 1.63
0.194-0.277 NR 1.33 0.71,2.49
0.278-0.330 NR 0.41 0.11, 1.50
0.331-2.484 NR 1.36 0.63,2.90
Stat Method: Logistic regression with log
transformation of the arsenic exposure
variable
Kurttioetal. (1999)
Study Type: case-
control
Location: Finland
region not available
Population: register-
based cohort of Finnish
people living outside
municipal water system
from 1967-1980; 61
bladder cancer cases,
49 kidney cancer cases
n cases: 49
n control: 275
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration measured in well-water
samples collected Jul-Nov 1996 from
locations where individuals lived from
1967-1980
Population-Level Exposure:
Outcome: bladder cancer
drinking water arsenic concentration, ng/L
Exp. Level n adjRR M
<.l NR 1 n/a
0.1-0.5 NR 1.53 0.75,3.09
>0.5 NR 2.44 1.11,5.37
Stat Method: Linear modeling after log
transformation
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
dose calculated based on duration of
exposure as reported in questionnaire
and sampled arsenic concentration in
well water; if questionnaire data not
available, assumed mean value from the
reference cohort for consumption;
arsenic concentration in drinking water
before and after well-water use was
considered null
Population-Level Exposure:
0.8 mg median
Outcome: bladder cancer
cumulative arsenic dose, mg
Exp. Level n adjRR (CD
<0.5 NR 1 n/a
0.5-2.0 NR 1.61 0.74,3.54
>2.0 NR 1.5 0.71,3.15
Stat Method: Linear modeling after log
transformation
Exposure Surrogate: drinking water
Outcome: bladder cancer
daily dose of arsenic, tig/day
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-11 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Exposure Measures
Results
Exposure Description: daily dose of
arsenic estimated from sampled arsenic
concentration in well water (collected
and measured 1996 from locations
where individuals lived from 1967-1980)
and reported consumption of well water
from the 1970s; if questionnaire data not
available assumed mean value from the
reference cohort for consumption;
arsenic concentration in drinking water
before and after well-water use
considered null
Population-Level Exposure:
0.2 u.g/day median
Exp. Level
<0.2
0.2-1.0
NR
NR
NR
M
n/a
0.66, 2.69
0.84, 4.03
Stat Method: Linear modeling after log
transformation
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: deceased
male and female
members of Latter-day
Saints church wards
n exposed: 2,203
n total: 2,203
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Outcome: bladder and other urinary organs
cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR {G}
< 1,000 NR 1.18 n/a
1,000-4,999 NR NR n/a
> 5,000 NR 1.1 n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1,000 NR 0.36 n/a
1,000-4,999 NR NR n/a
> 5,000 NR 0.95 n/a
Stat Method: standardized mortality ratios
Meliker et al. (2010)
Study Type: case-
control
Location: United States
(Southeastern Michigan
[11 counties])
Population: residents
in study area with
bladder cancer
Exposure Surrogate: drinking water
Exposure Description: lifetime exposure
to arsenic calculated from measures at
current residence and modeled
estimates for past residences based on
historical sources
Population-Level Exposure:
1-10 u.g/L range
Outcome: bladder cancer
time-weighted average (TWA) arsenic
concentration, u.Q/1
Exp. Level
continuous
(per 5 u.g/L
increase)
1-10
n
NR
NR
NR
NR
1
0.84
1.1
M
0.92, 1.20
n/a
0.63, 1.12
0.65, 1.86
Stat Method: Unconditional logistic
regression; multivariate-adjusted analyses
Exposure Surrogate: drinking water
Outcome: bladder cancer
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-12 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
diagnosed between
2000 and 2004 plus
controls
n cases: 411
n control: 566
Michaud et al. (2004)
Study Type: case-
control (nested)
Location: Finland
(southwest)
Population: cohort of
Finnish male smokers
aged 50-69 years
enrolled in Alpha-
Tocopherol, Beta-
Carotene Cancer
Prevention Study
n cases: 280
n control: 293
Pu et al. (2007)
Study Type: case-
control
Location: Taiwan
Exposure Measures
Exposure Description: lifetime exposure
to arsenic estimated using measures at
current residence and modeled
estimates for past residence using
historical sources
Population-Level Exposure:
1-10 ug/day range
Exposure Surrogate: toenails
Exposure Description: intact and
pulverized toenails cleaned prior to
analysis for arsenic; detection limit varied
across samples due to contamination and
samples with nondetectable arsenic and
high detection limits >0.09 ug/g excluded
(51/331 cases, 38/331 controls)
Population-Level Exposure:
0.05-0.161 ug/g range
Exposure Surrogate: urine
Exposure Description: single spot urine
arsenic measurement analyzed and
inorganic arsenic and its metabolites
quantified; exposure groups divided in
Results
time-weighted average (TWA) arsenic intake
from water (ug/day), ug/day
Exp. Level n adiOR (CD
continuous NR 1.01 0.92, 1.12
(per 5 ug/day
increase)
<1 NR 1 n/a
1-10 NR 0.83 0.62, 1.11
>10 NR 1.01 0.62, 1.64
Stat Method: Unconditional logistic
regression; multivariate-adjusted analyses
Outcome: bladder cancer
toenail arsenic concentration (categorized by
percentiles), ug/g
Exp. Level n adiOR (CD
<50%ile NR 1 n/a
(<0.105)
50.1-75%ile NR 1.1 0.73, 1.64
(0.105-0.160)
75.1-90%ile NR 0.93 0.56, 1.54
(0.161-0.259)
90.1-95%ile NR 1.38 0.68,2.80
(0.260-0.399)
95.1-100%ile NR 1.14 0.52,2.51
(>0.399)
Stat Method: Unconditional logistic
regression
toenail arsenic concentration (quartiles), ug/g
Exp. Level n adiOR (CD
<0.050 NR 1 n/a
0.050-0.105 NR 1.09 0.68, 1.74
0.106-0.161 NR 0.13 0.71, 1.8
>0.161 NR 1.13 0.7, 1.81
Stat Method: Unconditional logistic
regression
Outcome: urothelial carcinoma
urinary arsenic concentration (tertiles), ng/g-
creatinine
Exp. Level n adiOR (CD
<15.4 24 1 n/a
15.5-26.4 44 1.6 0.8,3.0
>26.4 109 3.2 1.8,5.9
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-13 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
(Taipei)
Population: adult
urothelial carcinoma
(UC) patients and non-
UC patients in area
where maximum
contaminant level for
arsenic in public water
reduced from 50 u.g/L
to 10 u.g/L in 2000
n cases: 177
n control: 313
Sawada et al. (2013)
Study Type: cohort
(prospective)
Location: Japan (Iwate,
Akita, Nagano,
Okinawa, Tokyo,
Ibaraki, Niigata, Kochi,
Nagasaki, Osaka)
Population: adults in
Japan Public Health
Center (JPHC)
Prospective Study
cohort
n total: 90,378
Steinmaus et al. (2003)
Study Type: case-
control
Location: United States
(Kings County, CA; 7
counties western NV)
Population: adult
residents from counties
with historically high
Exposure Measures
tertiles based on urinary arsenic
measured in control population
Population-Level Exposure:
15.4-26.4 u.g/g-creatinine range
Exposure Surrogate: diet
Exposure Description: detailed
questionnaire on food intake/frequency;
average arsenic concentrations in food
items obtained from the literature;
arsenic intake calculated by multiplying
average arsenic concentration in each
item by quantity consumed
Population-Level Exposure:
170 u.g/day mean, 88.3-253.2 u.g/day
range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure for each subject determined
using residence-specific water arsenic
measurements from historical and recent
records combined with residential
history and self-reported intake
information; analysis methods not
described
Population-Level Exposure:
6.4-82.8 mg range
Results
Stat Method: Multiple logistic regression
Outcome: bladder cancer
inorganic arsenic intake (females; quartiles),
Hg/day
Exp. Level n HR (Cl)
40.6 6 1 n/a
53.7 10 1.96 0.7,5.53
62.6 10 2.06 0.72,5.87
105.7 7 1.54 0.5,4.73
Stat Method: Multivariate regression
inorganic arsenic intake {males; quartiles),
Hg/day
Exp. Level n HR (Cl)
40.5 28 1 n/a
54.7 41 1.45 0.89,2.37
63.5 26 0.89 0.51, 1.55
99.1 46 1.56 0.95,2.55
Stat Method: Multivariate regression
Outcome: bladder cancer
cumulative arsenic concentration in drinking
water (mg), 40-year lag (tertiles), mg
Exp. Level n adiOR (Cl)
<6.4 153 1 n/a
6.4-82.8 9 1.63 0.64,4.13
>82.8 19 1.4 0.73,2.70
Stat Method: Cochran-Armitage test using
category means
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-14 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
drinking water arsenic
and nearby counties
n cases: 181
n control: 328
Steinmaus et al. (2013)
Study Type: case-
control
Location: Chile
(Antofagasta)
Population: residents
with lung cancer or
bladder cancer who
were formerly exposed
to high arsenic levels in
drinking water
n cases: 538
n control: 640
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations for each city or
town in the study area collected from
government agencies, research studies,
and water suppliers; subjects self-
reported daily water intake
Population-Level Exposure:
1,578-12,841 ng/L - yr range
Results
Outcome: bladder cancer
cumulative arsenic concentration: all years
(quartiles), ug/L - yr
Exp. Level n adiOR (CD
<1,578 34 1 n/a
1,578-4,876 33 0.86 0.49, 1.52
4,877-12,841 78 2.97 1.76,5.02
>12,841 87 5.27 2.86,9.70
Stat Method: Unconditional logistic
regression
cumulative arsenic concentration: before 1971
(quartiles), ug/L - yr
Exp. Level n adjOR (Cl)
<372 34 1 n/a
372-2,464 32 1.03 0.59, 1.8
2,465-10,319 78 3.4 2.05,5.65
>10,319 88 6.33 3.54, 11.32
Stat Method: Unconditional logistic
regression
cumulative arsenic intake: all years (quartiles),
ug
Exp. Level n adjOR (Cl)
<2,438 31 1 n/a
2,438-8,214 42 1.14 0.65, 1.99
8,215-19,093 58 2.58 1.46,4.56
>19,093 101 7.9 4.45, 14.01
Stat Method: Unconditional logistic
regression
cumulative arsenic intake: before 1971
(quartiles), ug
Exp. Level n adjOR (Cl)
<576 35 1 n/a
576-4,429 34 1.11 0.64, 1.94
4,430-14,347 71 2.99 1.80,4.97
>14,347 92 6.82 3.92, 11.87
Stat Method: Unconditional logistic
regression
lifetime average arsenic concentration: all years
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-15 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Tsuda et al. (1995)
Study Type: cohort
(retrospective)
Location: Japan
(Namiki-cho)
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic in well
water measured in 1959 (the end of the
exposure period) in 34 wells; 20 area
wells had no documented levels of
arsenic so authors inferred that arsenic
Results
(quartiles), ug/L
Exp. Level n adiOR (CD
<26 33 1 n/a
26-79 33 0.92 0.52, 1.61
80-197 71 2.62 1.53,4.50
>197 95 6 3.38, 10.64
Stat Method: Unconditional logistic
regression
lifetime average arsenic concentration: before
1971 (quartiles), ug/L
Exp. Level n adiOR (CD
<11 28 1 n/a
11-90 37 1.36 0.78,2.37
91-335 78 3.87 2.25,6.64
>335 89 6.5 3.69, 11.43
Stat Method: Unconditional logistic
regression
lifetime daily average arsenic intake: all years
(quartiles), ug/day
Exp. Level n adiOR (CD
>41 32 1 n/a
41-136 39 1.08 0.62, 1.87
137-307 64 3.06 1.75,5.35
>307 97 5.85 3.41, 10.05
Stat Method: Unconditional logistic
regression
lifetime daily average arsenic intake: before
1971 (quartiles), ug/day
Exp. Level n adiOR (CD
<21 31 1 n/a
21-159 35 1.21 0.69,2.11
160-525 70 3.15 1.84,5.38
>525 96 6.76 3.97, 11.51
Stat Method: Unconditional logistic
regression
Outcome: urinary cancer
arsenic concentration in well water in 1959, ppm
Exp. Level n SMR (CD
<0.05 00 0, 12.50
0.05-0.99 0 0 0,47.05
>1 3 31.18 8.82,91.75
Stat Method: Cox proportional hazard
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-16 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Exposure Measures
Results
Population: adults and
children living near
factory producing
arsenic trisulfide
n exposed: 189
n reference: 254
n total: 443
levels were undetectable or very low;
concentration assigned based on
residence in 1959
Population-Level Exposure:
0.05-1 ppm range
Wuetal. (2012a)
Study Type: case-
control
Location: Taiwan
region not available
Population: urothelial
cancer patients at
National Taiwan
University Hospital
diagnosed 2007-2009
and controls receiving
health examinations at
one of two Taipei
hospitals
n cases: 137
n control: 137
Exposure Surrogate: urine
Exposure Description: single spot urine
sample collected from each participant at
time of recruitment; total arsenic
exposure calculated as sum of inorganic
arsenic (As[lll] + As(V), MMA, and DMA)
and normalized against urinary creatinine
levels; LODfor As(lll), DMA(V), MMA(V),
and As(V) = 0.02, 0.06, 0.07, and 0.10
Hg/L, respectively
Population-Level Exposure:
not available
Outcome: urothelial carcinoma
total urinary arsenic, ng/g-creatinine
Exp. Level n adjOR M
< 11.38 14 1 n/a
>11.38 57 4.24 1.92,9.33
Stat Method: Multivariate logistic regression;
linear trend test
Wuetal. (2013)
Study Type: case-
control
Location: Taiwan,
Province Of China
(Taipei)
Population: hospital
patients with urothelial
carcinoma
n cases: 300
n control: 594
Exposure Surrogate: urine
Exposure Description: 50 mL sample of
spot urine collected at recruitment;
recovery rate for arsenic species ranged
from 93.8% to 102.2%
Population-Level Exposure:
11.74-20.94 ng/g-creatinine range
Outcome: urothelial carcinoma (DC)
total arsenic for each SD (14.45 (ig/g-creatinine)
increase, IL-8 TA genotype, ng/g-creatinine
Exp. Level n adjOR M
continuous NR 1.46 1.15, 1.85
Stat Method: Multivariate logistic regression
total arsenic for each SD (14.45 (ig/g-creatinine)
increase, IL-8 TT genotype, ng/g-creatinine
Exp. Level n adjOR M
continuous 188 1.75 1.45,2.11
Stat Method: Multivariate logistic regression
total arsenic for each SD (14.45 (ig/g-creatinine)
increase, TNF-alpha GG genotype, ng/g-
creatinine
Exp. Level n adjOR (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Bladder Effects
Reference and Study
Design
Exposure Measures
Results
continuous 249 1.73 1.48, 2.03
Stat Method: Multivariate logistic regression
urinary total arsenic, pg/g-creatinine
Exp. Level n adiOR (CD
< 11.74 44 1 n/a
11.74 to 63 1.42 0.9,2.25
20.94
>20.94 192 4.13 2.69,6.35
Stat Method: Multivariate logistic regression
--: not reported; n: number of cases (when presented in Results column)
5.1.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Bladder Effects
Baastrup. R: Serensen. M: Balstrem. T: Frederiksen. K: Larsen. CL: Tjenneland. A: Overvad. K: Raaschou-
Nielsen. O. (2008). Arsenic in drinking-water and risk for cancer in Denmark. Environ Health Perspect 116:
231-237. http://dx.doi.org/10.1289/ehp. 10623
Bates. MN: Rev. OA: Biggs. ML: Hopenhava C: Moore. LE: Kalmaa D: Steinmaus. C: Smith. AH. (2004).
Case-control study of bladder cancer and exposure to arsenic in Argentina. Am J Epidemiol 159: 381-389.
http://dx.doi.org/10.1093/aie/kwh054
Bates. MN: Smith. AH: Cantor. KP. (1995). Case-control study of bladder cancer and arsenic in drinking water.
Am J Epidemiol 141: 523-530.
Chen. CL: Chiou. HY: Hsu. LI: Hsueh. YM: Wu. MM: Wang. YH: Chen. CJ. (2010). Arsenic in drinking water
and risk of urinary tract cancer: A follow-up study from northeastern Taiwan. Cancer Epidemiol Bio markers
Prev 19: 101-110. http://dx.doi.org/10.1158/1055-9965.EPI-09-0333
Chiou. HY: Chiou. ST: Hsu. YH: Chou. YL: Tseng. CH: Wei. ML: Chea CJ. (2001). Incidence of transitional
cell carcinoma and arsenic in drinking water: A follow-up study of 8,102 residents in an arseniasis-endemic
area in northeastern Taiwan. Am J Epidemiol 153: 411-418. http://dx.doi.0rg/10.1093/aje/153.5.411
Chiou. HY: Hsueh. YM: Liaw. KF: Horng. SF: Chiang. MH: Pu. YS: Lia JS: Huang. CH: Chea CJ. (1995).
Incidence of internal cancers and ingested inorganic arsenic: A seven-year follow-up study in Taiwan.
Cancer Res 55: 1296-1300.
Chung. CJ: Huang. CY: Pu. YS: Shiue. HS: Su. CT: Hsueh. YM. (2013). The effect of cigarette smoke and
arsenic exposure on urothelial carcinoma risk is modified by glutathione S-transferase Ml gene null
genotype. Toxicol Appl Pharmacol 266: 254-259. http://dx.doi.0rg/10.1016/i.taap.2012.ll.005
Chung. CJ: Huang. YL: Huang. YK: Wu. MM: Chea SY: Hsueh. YM: Chen. CJ. (2012). Urinary arsenic
profiles and the risks of cancer mortality: A population-based 20-year follow-up study in arseniasis-endemic
areas in Taiwan. Environ Res 122: 25-30. http://dx.doi.0rg/10.1016/i.envres.2012.ll.007
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-18 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Chung. CJ: Pu. YS: Chen. YT: Su. CT: Wu. CC: Shiue. HS: Huang. CY: Hsueh. YM. (2011). Protective effects
of plasma alpha-tocopherols on the risk of inorganic arsenic-related urothelial carcinoma. Sci Total Environ
409: 1039-1045. http://dx.doi.0rg/10.1016/i.scitotenv.2010.ll.037
Feki-Tounsi M: Olmedo. P: Gil F: Khlifi. R: Mhiri. MN: Rebai A: Hamza-Chaffai A. (2013). Low-level
arsenic exposure is associated with bladder cancer risk and cigarette smoking: a case-control study among
men in Tunisia. Environ Sci Pollut Res Int. http://dx.doi.org/10.1007/sll356-012-1335-9
Ferreccio. C: Yuan. Y: Calle. J: Benitez. H: Parra. RL: Acevedo. J: Smith. AH: Liaw. J: Steinmaus. C. (2013).
Arsenic, tobacco smoke, and occupation: associations of multiple agents with lung and bladder cancer.
Epidemiology 24: 898-905. http://dx.doi.org/10.1097/EDE.Ob013e31829e3e03
Hsu. LI: Chen. GS: Lee. CH: Yang. TY: Chen. YH: Wang. YH: Hsueh. YM: Chiou. HY: Wu. MM: Chen. CJ.
(2013). Use of arsenic-induced palmoplantar hyperkeratosis and skin cancers to predict risk of subsequent
internal malignancy. Am J Epidemiol 177: 202-212. http://dx.doi.org/10.1093/aje/kws369
Huang. YK: Huang. YL: Hsueh. YM: Yang. MH: Wu. MM: Chen. SY: Hsu. LI: Chen. CJ. (2008a). Arsenic
exposure, urinary arsenic speciation, and the incidence of urothelial carcinoma: a twelve-year follow-up
study. Cancer Causes Control 19: 829-839. http://dx.doi.org/10.1007/sl0552-008-9146-5
Huang. YK: Pu. YS: Chung. CJ: Shiue. HS: Yang. MH: Chea CJ: Hsueh. YM. (2008b). Plasma folate level,
urinary arsenic methylation profiles, and urothelial carcinoma susceptibility. Food Chem Toxicol 46: 929-
938. http://dx.doi.0rg/10.1016/i.fct.2007.10.017
Karagas. MR: Tosteson. TD: Morris. JS: Demidenko. E: Mott LA: Heanev. J: Schned. A. (2004). Incidence of
transitional cell carcinoma of the bladder and arsenic exposure in New Hampshire. Cancer Causes Control
15: 465-472. http://dx.doi.Org/10.1023/B:CACO.0000036452.55199.a3
Kurttio. P: Pukkala. E: Kahelin. H: Auvinen. A: Pekkanen. J. (1999). Arsenic concentrations in well water and
risk of bladder and kidney cancer in Finland. Environ Health Perspect 107: 705-710.
http://dx.doi.org/10.1289/ehp.99107705
Lai. MS: Hsueh. YM: Chen. CJ: Shyu. MP: Chea SY: Kuo. TL: Wu. MM: Taj TY. (1994). Ingested inorganic
arsenic and prevalence of diabetes mellitus. Am J Epidemiol 139: 484-492.
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Meliker. JR: Slotnick. MJ: Avruskin. GA: Schottenfeld. D: Jacquez. GM: Wilson. ML: Goovaerts. P: Franzblau.
A: Nriagu. JO. (2010). Lifetime exposure to arsenic in drinking water and bladder cancer: a population-based
case-control study in Michigan, USA. Cancer Causes Control 21: 745-757. http://dx.doi.org/10.1007/sl0552-
010-9503-z
Michaud. PS: Wright ME: Cantor. KP: Taylor. PR: Virtamo. J: Albanes. D. (2004). Arsenic concentrations in
prediagnostic toenails and the risk of bladder cancer in a cohort study of male smokers. Am J Epidemiol 160:
853-859. http://dx.doi.org/10.1093/aie/kwh295
Pu. YS: Yang. SM: Huang. YK: Chung. CJ: Huang. SK: Chiu. AW: Yang. MH: Chea CJ: Hsueh. YM. (2007).
Urinary arsenic profile affects the risk of urothelial carcinoma even at low arsenic exposure. Toxicol Appl
Pharmacol 218: 99-106. http://dx.doi.0rg/10.1016/i.taap.2006.09.021
Sawada. N: Iwasaki. M: Inoue. M: Takachj R: Sasazukj S: Yamaji T: Shimazu. T: Tsugane. S. (2013). Dietary
arsenic intake and subsequent risk of cancer: The Japan Public Health Center-based (JPHC) prospective
study. Cancer Causes Control 24: 1403-1415. http://dx.doi.org/10.1007/sl0552-013-0220-2
Steinmaus. C: Yuan. Y: Bates. MN: Smith. AH. (2003). Case-control study of bladder cancer and drinking water
arsenic in the western United States. Am J Epidemiol 158: 1193-1201. http://dx.doi.org/10.1093/aie/kwg281
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-19 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Steinmaus. CM: Ferreccio. C: Acevedo Romo. J: Yuan. Y: Cortes. S: Marshall G: Moore. LE: Balmes. J. R.:
Liaw. J: Golden. T: Smith. AH. (2013). Drinking water arsenic in northern Chile: high cancer risks 40 years
after exposure cessation. Cancer Epidemiol Biomarkers Prev 22: 623-630. http://dx.doi.org/10.1158/1055-
9965.EPI-12-1190
Tsuda. T: Babazono. A: Yamamoto. E: Kurumatani. N: Mino. Y: Ogawa. T: Kishi. Y: Aoyama. H. (1995).
Ingested arsenic and internal cancer: A historical cohort study followed for 33 years. Am J Epidemiol 141:
198-209.
Wu. CC: Huang. YK: Chung. CJ: Huang. CY: Pu. YS: Shiue. HS: Lai. LA: Lia YC: Su. CT: Hsueh. YM.
(2013). Polymorphism of inflammatory genes and arsenic methylation capacity are associated with urothelial
carcinoma. Toxicol Appl Pharmacol 272: 30-36. http://dx.doi.0rg/10.1016/i.taap.2013.05.019
Wu. CC: Su. CT: Lee. HL: Chung. CJ: Huang. CY: Pu. YS: Lia P: Hsueh. YM. (2012). Joint effect of arsenic
methylation profile and NNK metabolites on urothelial carcinoma. J Urol 188: 1701-1705.
http://dx.doi.0rg/10.1016/i.iuro.2012.07.025
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.2 Summary of Observational Epidemiology Studies for
Health Effect Category: Cardiovascular Disease
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Bosnjaketal. (2008)
Study Type: cross-
sectional
Location: Croatia
(Andrijasevci)
Population: adult
residents of village with
history of higher than
average arsenic in
drinking water
n cases: n/a
n control: n/a
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from single
sample for each individual
Population-Level Exposure:
627.72 ng/g-creatinine mean, 199.5-
1,206.29 ng/g-creatinine range
Outcome: markers of cardiovascular disease
(serum total bilirubin, antibodies to Hsp60 and
folate)
urinary arsenic concentration, ng/g-creatinine
non-significant outcomes include: BMI, B9, Hsp60,
Hsp70, Hsp70 antibodies, glucose, bilirubin, CRP,
total cholesterol, HDL cholesterol, LDL cholesterol,
triglycerides, homocysteine
Burgess etal. (2013)
Study Type: cross-
sectional
Location: United
States, Mexico
(Arizona, Sonora)
Population: adult
residents of
communities with
relatively high drinking
water arsenic levels
n cases: 377
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration determined from
self-reported usage of all water sources
consumed for drinking weighted by
frequency of use of each source; arsenic
levels measured from all reported
drinking water sources
Population-Level Exposure:
7.65 Hg/Lgeo mean, 6.8-8.63 ng/L95% Cl
lower
Outcome: matrix metalloproteinase 9
drinking water arsenic concentration,
Exp. Level n corr (Cl)
coeff
drinking NR 0.135 n/a
water total
arsenic
Stat Method: multivariable linear mixed
model
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic intake calculated as the drinking
water arsenic concentration multiplied
by the average volume of drinking water
consumed daily
Outcome: matrix metalloproteinase 9
drinking water arsenic intake, ng/day
Exp. Level n corr (Cl)
coeff
drinking NR 0.072 n/a
water intake
Stat Method: multivariable linear mixed
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-21 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Population-Level Exposure:
2.47 ng/day geo mean, 1.99-3.07 ng/day
95% Cl lower
model
Exposure Surrogate: urine
Exposure Description: urinary arsenic
sum of species calculated as the sum of
As(lll), As(V), MMA(V), and DMA(V)
Population-Level Exposure:
18.44 ng/Lgeo mean, 18.86-20.17
95% Cl lower
Outcome: matrix metalloproteinase 9
urinary arsenic sum of species, ug/L
Exp. Level n corr (Cl)
coeff
urinary total NR 0.121 n/a
arsenic
Stat Method: multivariable linear mixed
model
Chen et al. (2013a)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study
(HEALS) participants
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: at baseline, water
samples from 10,971 tube wells collected
and analyzed for total arsenic
Population-Level Exposure:
81.1 |ag/Lmean
Outcome: carotid intima-media thickness (cIMT)
baseline well water arsenic concentration,
Exp. Level n adiBeta (Cl)
continuous NR 5.1 -0.2,10.3
Stat Method: multiple linear regression
Exposure Surrogate: urine
Exposure Description: spot urine
samples collected at baseline and at all
follow-up visits; total arsenic
concentration measured
Population-Level Exposure:
259.5 ng/g-creatinine mean
Outcome: carotid intima-media thickness (cIMT)
baseline urinary arsenic concentration, ug/g-
creatinine
Exp. Level n ad i Beta (Cl)
continuous NR 11.7 1.8,21.6
Stat Method: multiple linear regression
Chen et al. (2012b)
Study Type: cross-
sectional
Location: Taiwan,
Province Of China
(Nantou County)
Population: rural
residents of Taiwan
n cases: n/a
Exposure Surrogate: urine
Exposure Description: spot morning
urine samples collected into
polypropylene containers throughout
study period
Population-Level Exposure:
7.7 ng/g-creatinine mean 14.8SD
Outcome: hypertension
urinary arsenic concentration (quartiles), ug/g-
creatinine
Exp. Level
Ql (<1.4)
Q2 (1.4-4.3)
Q3 (4.3-8.0)
Q4 (>8.0)
n
21
32
24
37
M
n/a
1.0, 4.4
0.6, 2.6
1.4, 6.3
Stat Method: unconditional logistic regression
Outcome: MnSOD and OGG1 genotyping
urinary arsenic concentration (quartiles),
creatinine
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-22 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
n control: n/a
arsenic not significantly associated with MnSOD
and OGG1 genotyping
Outcome: other biochemical parameters (i.e.,
triglyceride, cholesterol, uric acid)
urinary arsenic concentration (quartiles), ug/g-
creatinine
significant ORs for > 150 mg/dl triglyceride and
> 200 mg/dl cholesterol; otherwise not significant
Chen et al. (1996)
Study Type: cohort
(prospective)
Location: Taiwan
(Southwest coast:
Peimen, Hsuechia,
Putai, Ichu, Yensui,
Hsiaying townships)
Population: adults and
children living in
arseniasis-endemic
townships
n exposed: 263
n reference: 2,293
n total: 2,556
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated as the drinking
water arsenic concentration multiplied
by self-reported years living in a
particular village and added across
individual's lifetime; arsenic levels in well
water collected in previous studies
conducted in the 1960s
Population-Level Exposure:
0.01-1.75 mg/L - yr range
Outcome: ischemic heart disease (ISHD)
cumulative water arsenic exposure, mg/L - yr
Exp. Level
0
0.1-9.9
10.0-19.9
>20.0
NR
NR
NR
NR
M
n/a
9.46, 10.16
0.83, 13.45
1.36, 17.68
Stat Method: Cox proportional-hazards
regression analysis
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations determined using
self-reported information on residential
history; arsenic levels in well water
collected in previous studies conducted
in the 1960s
Population-Level Exposure:
0.01-1.75 mg/L range
Outcome: ischemic heart disease (ISHD)
drinking water arsenic concentration, mg/L
Exp. Level n adjRR M
0 NR 1 n/a
0.01-0.50 NR 2.8 n/a
>0.51 NR 4.1 n/a
Stat Method: Cox proportional-hazards
regression analysis
Chen et al. (2006b)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: healthy,
Exposure Surrogate: drinking water
Exposure Description: at baseline,
samples of water collected from 5,967
contiguous wells in the study area
Population-Level Exposure:
0.5-439 ng/L range
Outcome: carotid artery intima-medial thickness
(IMT) >0.75 mm
baseline well arsenic (tertiles), ug/L
Exp. Level n adjOR
0.5-11 4 1 n/a
12-144 3 1.1 0.2,6.3
145-439 6 2.1 0.4, 10.5
Stat Method: unconditional logistic regression
model
Exposure Surrogate: drinking water
Outcome: carotid artery intima-medial thickness
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-23 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
normotensive
individuals participating
in the ongoing Health
Effects of Arsenic
Longitudinal Study
(HEALS)
n total: 66
(IMT) >0.75 mm
Exposure Description: at baseline,
samples of water collected from 5,967
contiguous wells in the study area;
cumulative arsenic index (CAI) calculated
as the product of amount of water
consumed per day (L/day), concentration
of arsenic in well(s) (g/L), and duration(s)
of well usage (days)
Population-Level Exposure:
5.3-4,564.1 mg range
cumulative arsenic index at baseline (tertiles),
mg
adjOR
1
0.2
1.6
Exp. Level
5.3-92.3
92.4-1,301.5
1,301.6-
4,564.1
Stat Method: unconditional logistic regression
model
n/a
0.1, 1.7
0.4,7.5
Exposure Surrogate: urine
Exposure Description: samples of urine
collected at both baseline and follow-up
visits
Population-Level Exposure:
6-209 ug/L range
Outcome: carotid artery intima-medial thickness
(IMT) >0.75 mm
baseline urinary total arsenic (tertiles), ug/L
Exp. Level n adjOR (CD
6-49 4 1 n/a
103-209 4 2.1 0.3, 13.1
>209 5 6 0.5,80.7
Stat Method: unconditional logistic regression
model
Chen et al. (2007b)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study,
adult participants
n cases: 10,910
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration calculated from
well water samples for a set of 5,966
contiguous wells in the area
Population-Level Exposure:
0.1-864 ug/L range
Outcome: diastolic hypertension
time-weighted well arsenic concentration, ug/L
Exp. Level
0.1-8.0
8.1-40.8
40.9-91.0
91.1-176.0
176.1-864.0
NR
NR
NR
NR
NR
M
n/a
0.77, 1.20
0.81, 1.25
0.75, 1.16
0.78, 1.20
Stat Method: Linear regression analysis;
logistic regression analysis
time-weighted well arsenic concentration (> 5
years of known level), ug/L
Exp. Level
0.1-8.0
8.1-40.8
40.9-91.0
91.1-176.0
176.1-864.0
ri
NR
NR
NR
NR
NR
M
n/a
0.72, 1.22
0.83, 1.38
0.72, 1.20
0.78, 1.28
Stat Method: Linear regression analysis;
logistic regression analysis
Outcome: general hypertension
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-24 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
time-weighted well arsenic concentration, ng/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-40.8 NR 1.1 0.90, 1.33
40.9-91.0 NR 1.03 0.85, 1.25
91.1-176.0 NR 1.01 0.83, 1.22
176.1-864.0 NR 1.02 0.84, 1.23
Stat Method: Linear regression analysis;
logistic regression analysis
time-weighted well arsenic concentration (> 5
years of known level), ng/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-40.8 NR 1.06 0.84, 1.34
40.9-91.0 NR 1.12 0.89, 1.41
91.1-176.0 NR 1.03 0.82, 1.30
176.1-864.0 NR 1.05 0.84, 1.31
Stat Method: Linear regression analysis;
logistic regression analysis
Outcome: pulse blood pressure
time-weighted well arsenic concentration, ng/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-40.8 NR 1.39 1.14, 1.71
40.9-91.0 NR 1.21 0.99, 1.49
91.1-176.0 NR 1.19 0.97, 1.45
176.1-864.0 NR 1.19 0.97, 1.46
Stat Method: Linear regression analysis;
logistic regression analysis
time-weighted well arsenic concentration (> 5
years of known level), ng/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-40.8 NR 1.5 1.16, 1.91
40.9-91.0 NR 1.34 1.04, 1.73
91.1-176.0 NR 1.35 1.05, 1.71
176.1-864.0 NR 1.24 0.97, 1.59
Stat Method: Linear regression analysis;
logistic regression analysis
Outcome: systolic hypertension
time-weighted well arsenic concentration (> 5
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-25 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Chen et al. (2011b)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study,
adult participants
number of subjects not
reported
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration calculated from
well water samples for a set of 5,966
contiguous wells in the area
Population-Level Exposure:
99 |jg/L mean
Results
years of known level), ng/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-40.8 NR 1.35 1.02, 1.77
40.9-91.0 NR 1.28 0.97, 1.69
91.1-176.0 NR 1.3 0.99, 1.72
176.1-864.0 NR 1.12 0.85, 1.47
Stat Method: Linear regression analysis;
logistic regression analysis
time-weighted well arsenic concentration, ng/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-40.8 NR 1.39 1.10, 1.75
40.9-91.0 NR 1.21 0.96, 1.54
91.1-176.0 NR 1.28 1.01, 1.62
176.1-864.0 NR 1.13 0.90, 1.44
Stat Method: Logistic regression analysis
Outcome: death from cerebrovascular disease
drinking water arsenic concentration at baseline,
Hg/L
Exp. Level n HR (CD
3.7 NR 1 n/a
35.9 NR 1.35 0.75,2.43
102.5 NR 1.2 0.63,2.27
265.7 NR 1.07 0.54,2.12
Stat Method: Cox proportional hazards
regression
Outcome: death from disease of circulatory
system
drinking water arsenic concentration at baseline,
W/L
Exp. Level n HR (CD
3.7 NR 1 n/a
35.9 NR 1.21 0.8, 1.84
102.5 NR 1.24 0.80, 1.93
265.7 NR 1.46 0.96,2.20
Stat Method: Cox proportional hazards
regression
Outcome: death from ischemic heart disease
drinking water arsenic concentration at baseline,
W/L
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-26 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from single
baseline sample for each individual
Population-Level Exposure:
6.6-1,100 ng/g-creatinine range
Results
Exp. Level n HR (CD
3.7 NR 1 n/a
35.9 NR 1.22 0.56,2.65
102.5 NR 1.49 0.70,3.19
265.7 NR 1.94 0.99,3.84
Stat Method: Cox proportional hazards
regression
Outcome: death from ischemic heart disease and
other forms of heart disease
drinking water arsenic concentration at baseline,
H9/L
Exp. Level n HR (CD
3.7 NR 1 n/a
35.9 NR 1.22 0.65,2.32
102.5 NR 1.35 0.71,2.57
265.7 NR 1.92 1.07,3.43
Stat Method: Cox proportional hazards
regression
Outcome: death from cerebrovascular disease
urinary arsenic concentration at baseline, ng/g-
creatlnlne
Exp. Level n HR (CD
68.5 NR 1 n/a
150.6 NR 0.96 0.52, 1.79
264.9 NR 1.6 0.88,2.90
641.5 NR 1.03 0.53,2.03
Stat Method: Cox proportional hazards
regression
Outcome: death from disease of circulatory
system
urinary arsenic concentration at baseline, u.g/g-
creatlnlne
Exp. Level n HR (CD
68.5 NR 1 n/a
150.6 NR 1.15 0.77, 1.72
264.9 NR 1.56 1.03,2.38
641.5 NR 1.55 1.01,2.37
Stat Method: Cox proportional hazards
regression
Outcome: death from ischemic heart disease
urinary arsenic concentration at baseline, ng/g-
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-27 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Chen et al. (2013c)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study
(HEALS) participants
n exposed: 237
n reference: 1,474
n total: 1,711
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: at baseline, water
samples from 10,971 contiguous wells
collected and analyzed for total arsenic;
exposure in quartiles
Population-Level Exposure:
0. 1-790 ng/L range
Results
creatinine
Exp. Level n HR (CD
68.5 NR 1 n/a
150.6 NR 1.29 0.66,2.51
264.9 NR 1.47 0.72,3.01
641.5 NR 1.9 0.91,3.98
Stat Method: Cox proportional hazards
regression
Outcome: death from ischemic heart disease and
other forms of heart disease
urinary arsenic concentration at baseline, U.Q/Q-
creatinine
Exp. Level n HR (CD
68.5 NR 1 n/a
150.6 NR 1.29 0.74,2.27
264.9 NR 1.53 0.83,2.82
641.5 NR 2.06 1.14,3.72
Stat Method: Cox proportional hazards
regression
Outcome: PR prolongation
well water arsenic concentration, u.g/L
no apparent association of either baseline well
water arsenic or baseline urinary arsenic with PR
prolongation in men or women
Outcome: QRS prolongation
well water arsenic concentration, u.g/L
no apparent association of either baseline well
water arsenic or baseline urinary arsenic with QRS
prolongation in men or women
Outcome: QTc prolongation
well water arsenic concentration (females), u.g/L
Exp. Level n adiOR (CD
continuous NR 1.24 1.05, 1.47
Stat Method: unconditional logistic regression
well water arsenic concentration {females;
quartiles), ug/L
Exp. Level n adjOR (Cl)
0.1-9 40 1 n/a
9.5-57 49 1.22 0.77, 1.93
58-144 35 0.89 0.54, 1.46
145-790 55 1.61 1.00,2.58
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-28 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Exposure Surrogate: urine
Exposure Description: spot urine
samples collected from 95.6, 94.5, and
91.2% of original cohort participants at
baseline, first follow-up, and second
follow-up visits, respectively; adjusted for
urinary creatinine
Population-Level Exposure:
1-4306 ng/g-creatinine range
Results
Stat Method: unconditional logistic regression
well water arsenic concentration (males), u.g/L
Exp. Level n adiOR (CD
continuous NR 0.99 0.73, 1.33
Stat Method: unconditional logistic regression
well water arsenic concentration (males;
quartiles), u.g/L
Exp. Level n adiOR (CD
0.1-9 17 1 n/a
9.5-57 14 0.82 0.39, 1.75
58-144 14 0.85 0.40, 1.82
145-790 13 0.76 0.34, 1.69
Stat Method: unconditional logistic regression
Outcome: QTc prolongation
urinary arsenic concentration (females), u.g/g-
creatinine
Exp. Level n adiOR (CD
continuous NR 1.24 1.01, 1.53
Stat Method: unconditional logistic regression
urinary arsenic concentration (females;
quartiles), ug/g-creatinine
Exp. Level n adiOR (CD
1-101 33 1 n/a
102-187 43 1.31 0.80,2.16
188-327 44 1.43 0.87,2.36
328-4,306 51 1.69 1.00,2.86
Stat Method: unconditional logistic regression
urinary arsenic concentration (males), ug/g-
creatinine
Exp. Level n adiOR (CD
continuous NR 0.86 0.49, 1.51
Stat Method: unconditional logistic regression
urinary arsenic concentration (males; quartiles),
ug/g-creatinine
Exp. Level n adiOR (CD
7-101 18 1 n/a
102-187 13 0.76 0.36, 1.63
188-327 14 0.83 0.39, 1.76
328-4,306 13 1.01 0.44,2.36
Stat Method: unconditional logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-29 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Chiou et al. (1997)
Study Type: cross-
sectional
Location: Taiwan
(Lanyang Basin)
Population: adults
living in arseniasis-
endemic townships
n cases: 8,102
n control: n/a
Chiou et al. (2005)
Study Type: cohort
(retrospective)
Location: Taiwan
(southwestern: Tainan
County (Yenshui,
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
levels calculated based on arsenic
concentration in well water and self-
reported years of use
Population-Level Exposure:
1-5 mg/L-yr range
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic exposure calculated from single
well water sample collected from each
household
Population-Level Exposure:
0. 1-300 ng/L range
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration as reported by the
National Taiwan University Group;
median concentration used as surrogate
if village had multiple wells
Results
Outcome: cerebral Infarction
cumulative drinking water arsenic exposure,
mg/L-yr
Exp. Level n adiOR (CD
<0.1 NR 1 n/a
0.1-4.9 NR 2.66 1.21,5.83
>5.0 NR 3.39 1.42,8.11
Stat Method: Multiple logistic regression
Outcome: cerebrovascular disease
cumulative drinking water arsenic exposure,
mg/L-yr
Exp. Level n adiOR (CD
<0.1 NR 1 n/a
0.1-4.9 NR 2.26 1.23,4.15
>5.0 NR 2.69 1.35,5.38
Stat Method: Multiple logistic regression
Outcome: cerebral Infarction
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<0.1 NR 1 n/a
0.1-50 NR 3.38 1.57,7.27
50.1-299.9 NR 4.47 2.03,9.87
>300 NR 6.9 2.91,16.38
Stat Method: Multiple logistic regression
Outcome: cerebrovascular disease
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<0.1 NR 1 n/a
0.1-50 NR 2.53 1.47,4.35
50.1-299.9 NR 2.78 1.55,4.97
>300 NR 3.6 1.83,7.11
Stat Method: Multiple logistic regression
Outcome: microvascular disease
drinking water arsenic concentration -
microvascular diseases, mg/L
Exp. Level n adiBeta (Cl)
continuous NR -1.366 n/a
Stat Method: Logistic regression model
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-30 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Beimen, and Shuechia
townships), Chiayi
County (Putai and Yichu
townships))
Population: adults and
children living in
arseniasis-endemic
townships
n total: 28,499
Population-Level Exposure:
0.1-0.6 mg/L range
Guha Mazumder et al.
(2012)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: adults and
children likely exposed
to higher than average
arsenic in drinking
water
n cases: 208
n control: 100
Exposure Surrogate: drinking water
Exposure Description: present and
previous (if available) drinking and
cooking water source samples collected
for each individual; cumulative arsenic
exposure calculated as the drinking
water arsenic concentration of each well
used multiplied by self-reported duration
of use and added across individual's
lifetime
Population-Level Exposure:
0-24.98 mg/L - yr range
Outcome: hypertension
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n
0 20
0-4.5 37
>4.5 24
M
n/a
1.02, 6.14
0.64, 6.57
Stat Method: multivariate logistic regression
Exposure Surrogate: hair
Exposure Description: arsenic
concentration measured from a cleaned
bunch of hair samples for each individual
Population-Level Exposure:
0.06-7.51 mg/kg range
Outcome: hypertension
hair arsenic concentration, mg/kg
Exp. Level n adjOR (CD
0-0.18 12 1 n/a
0.19-2.0 51 1.37 0.65,3.81
>2.0 18 2.39 0.57, 10.00
Stat Method: multivariate logistic regression
Guo et al. (2007)
Study Type: cross-
sectional
Location: Mongolia
region not available
Population: residents
of villages in the Hetao
Exposure Surrogate: drinking water
Exposure Description: arsenic samples
were taken from 94 water sources,
including wells; detection limit not
specified, but authors note reliability of
the method at <10 ng/L; arsenic
exposure determined by location of
village
Outcome: hypertension
water arsenic concentration, ng/L
Exp. Level ri Prev (CD
<50|jg/L NR 0.53 n/a
>50ng/L NR 8.09 n/a
Stat Method: not reported
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-31 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Plain, Inner Mongolia
n cases: 680
n control: 189
Population-Level Exposure:
50-1,860 ng/L range
Hawkesworth et al.
(2013)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: children in
Maternal and Infant
Nutrition Interventions
in Matlab (MINIMat)
cohort
n total: 2,499
Exposure Surrogate: maternal urine
Exposure Description: spot urine
samples from participating women
collected at 8 and 30 weeks gestation;
log transformed as continuous variable
for analysis; median maternal urinary
arsenic was 80 ng/L (10th, 90th
percentile: 24, 383 ng/L) at week 8 of
gestation and 83 ng/L (10th, 90th: 26,
415 ng/L) at week 30
Population-Level Exposure:
80 mg/L median
Outcome: diastolic blood pressure
maternal urinary arsenic concentration
(combined), mg/L
Exp. Level n adiBeta (CD
continuous NR 2.91 0.41,5.42
Stat Method: linear regression
maternal urinary arsenic concentration week 30,
mg/L
Exp. Level n ad i Beta (CD
continuous NR 2.45 -0.03,4.94
Stat Method: linear regression
maternal urinary arsenic concentration week 8,
mg/L
Exp. Level n ad i Beta (CD
continuous NR 1.75 -0.73,4.22
Stat Method: linear regression
Outcome: systolic blood pressure
maternal urinary arsenic concentration
(combined), mg/L
Exp. Level n ad i Beta (CD
continuous NR 3.69 0.74,6.63
Stat Method: linear regression
maternal urinary arsenic concentration week 30,
mg/L
Exp. Level n ad i Beta (CD
continuous NR 3.56 0.62,6.5
Stat Method: linear regression
maternal urinary arsenic concentration week 8,
mg/L
Exp. Level n ad i Beta (CD
continuous NR 1.45 -1.51,4.41
Stat Method: linear regression
Exposure Surrogate: urine
Exposure Description: urine samples
collected from participating children at
Outcome: diastolic blood pressure
infant urinary arsenic concentration 18 months,
mg/L
Exp. Level n ad i Beta (CD
continuous NR 2.75 -3.09,8.59
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-32 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
18 months of age; log transformed as
continuous variable for analysis; median
urinary arsenic was 34 ng/L (10th, 90th
percentile: 12,154 ng/L)
Population-Level Exposure:
34 mg/L median
Stat Method: linear regression
Outcome: systolic blood pressure
infant urinary arsenic concentration 18 months,
mg/L
Exp. Level n adiBeta (CD
continuous NR 8.25 1.37, 15.1
Stat Method: linear regression
Hsieh et al. (2008a)
Study Type: case-
control (nested)
Location: Taiwan
(Lanyang Basin
(arsenic-exposed
population))
Population: adult male
residents of Taiwan
from existing cohort
n cases: 129
n control: 48
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations determined from
well water samples collected during
home interview
Population-Level Exposure:
0.15-3,590 ppb range
Outcome: erectile dysfunction (IIEF < 21)
drinking water arsenic concentration, ppb
Exp. Level n adjOR M
<50 NR 1 n/a
>50 NR 3 1.0,9.2
Stat Method: Multivariable logistic regression
analysis
Outcome: severe erectile dysfunction (IIEF < 7)
drinking water arsenic concentration, ppb
Exp. Level n adjOR (CD
<50 NR 1 n/a
>50 NR 7.5 1.8,30.9
Stat Method: Multivariable logistic regression
analysis
Hsieh et al. (2008b)
Study Type: case-
control (nested)
Location: Taiwan
(northeastern; Lanyang
Basin of Nan County)
Population: adults and
children genotyped for
APOE and MCP-1
n cases: 235
n control: 244
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated based on arsenic
concentration in well water and self-
reported years of drinking well water
during successive periods of living in
different villages
Population-Level Exposure:
not available
Outcome: carotid atherosclerosis
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level
<0.2
0.3-1
NR
NR
NR
M
n/a
0.5, 2.6
0.9,3.1
Stat Method: multiple logistic regression
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations determined from
well water samples collected during
home interview
Outcome: carotid atherosclerosis
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (CD
<10 NR 1 n/a
10.1-50.0 NR 1.8 1.0,3.2
>50.1 NR 1.9 1.1,3.1
Stat Method: multiple logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-33 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Population-Level Exposure:
87.2 ng/L median, 43-182.2 ng/L 25th
percentile
Islam etal.(2012a)
Study Type: cross-
sectional
Location: Bangladesh
(Comilla, Jhenida
districts)
Population: adults
living in unions of high
arsenic contamination
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated by multiplying
arsenic concentration of single tube well
measurement for each individual with
self-reported duration of use; subjects
grouped for analysis above and below
maximum acceptable limit in drinking
water in Bangladesh (50 ng/L) and as
quartiles
Population-Level Exposure:
10-262 ng/L range
Outcome: diastolic hypertension
cumulative drinking water arsenic exposure,
Exp. Level n adjOR (CD
<50 64 1 n/a
>50 50 1.24 0.76,2.01
Stat Method: Multiple logistic regression,
Cuzick's nonparametric test for trend
Outcome: increased pulse pressure
cumulative drinking water arsenic exposure,
Exp. Level n adjOR (CD
<50 15 1 n/a
>50 26 3.54 1.46,8.57
Stat Method: Multiple logistic regression,
Cuzick's nonparametric test for trend
Outcome: overall hypertension
cumulative drinking water arsenic exposure,
Exp. Level n adjOR (CD
<50 43 1 n/a
> 50 23 0.93 0.49, 1.78
Stat Method: Multiple logistic regression,
Cuzick's nonparametric test for trend
cumulative drinking water arsenic exposure
(quartiles), u.g/L
adjOR
1
1.33
1.1
Exp. Level
10-22
23-32
33-261
>262
r\
22
19
13
12
0.96
M
n/a
0.67, 2.62
0.49, 2.44
0.42, 2.23
Stat Method: Multiple logistic regression,
Cuzick's nonparametric test for trend
Outcome: pulse pressure
cumulative drinking water arsenic exposure
(quartiles), ug/L
Exp. Level n adjOR {G}
10-22 5 1 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-34 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
23-32 10 3.87 1.22, 12.20
33-261 10 4.32 1.23, 15.11
>262 16 7.32 2.18,24.60
Stat Method: Multiple logistic regression,
Cuzick's nonparametric test for trend
Outcome: systolic hypertension
cumulative drinking water arsenic exposure,
ug/L
Exp. Level n adjOR (CD
<50 47 1 n/a
>50 30 1.11 0.61,2.02
Stat Method: Multiple logistic regression,
Cuzick's nonparametric test for trend
Jensen and Hansen
(1998)
Study Type: cross-
sectional
Location: Denmark
region not available
Population:
occupationally exposed
adult workers
n cases: 40
n control: 26
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration determined from two
urine samples collected from each
individual
Population-Level Exposure:
12-80 nmol/mmol creatinine range
Outcome: systolic blood pressure
urinary arsenic concentration by group,
nmol/mmol creatinine
Exp. Level
unexposed
colleagues of
workers
workers
handling As
directly
NR
NR
NR
mean
119.9
122.8
127.5
M
n/a
n/a
n/a
Stat Method: Kruskal-Wallis test comparing
mean values of systolic blood pressure
Jones et al. (2011)
Study Type: cross-
sectional
Location: United States
region not available
Population: NHANES
2003-2008, adult
participants with total
arsenic assessed in
urine
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from single
sample for each individual; subjects
grouped in quartiles for analysis
Population-Level Exposure:
8.3 ng/L median, 4.2-17.1 ng/L 25th
percentile
Outcome: hypertension
dimethylarsinate concentration, ug/L
Exp. Level n adjOR M
per doubling 1,761 1.11 0.99,1.24
of arsenic
Stat Method: Logistic regression
dimethylarsinate concentration (quartiles), ug/L
Exp. Level
<2.0
2.0-3.6
>3.6-6.0
>6.0
n
415
461
448
437
M
n/a
0.77, 1.42
0.84, 1.66
0.84, 1.83
Stat Method: Logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-35 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
n cases: 4,167
n control: n/a
Karim et al. (2013)
Study Type: cross-
sectional
Location: Bangladesh
(North-west (Marua,
Kestopur, Bheramara)
and Chowkoli village)
Population: Residents
from arsenic-endemic
and non-endemic areas
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: water samples
collected from tube wells used as
primary drinking water source for study
participants; no details provided on
individual-level exposure
characterization
Population-Level Exposure:
1.06 ng/Lmean 0.04SD
Results
total urinary arsenic concentration, u.g/L
Exp. Level n adiOR (CD
per doubling 1,761 0.98 0.86,1.11
of arsenic
Stat Method: Logistic regression
total urinary arsenic concentration (quartiles),
Hg/L
Exp. Level n adiOR (CD
<4.2 418 1 n/a
4.2-8.3 451 1.08 0.83, 1.40
>8.3-17.1 446 1.3 0.94, 1.80
>17.1 446 1.17 0.75, 1.83
Stat Method: Logistic regression
total urinary arsenic concentration minus
arsenobetaine, u.g/L
Exp. Level n adiOR (CD
per doubling 1,761 1.03 0.94,1.14
of arsenic
Stat Method: Logistic regression
total urinary arsenic concentration minus
arsenobetaine (quartiles), u.g/L
Exp. Level n adiOR (CD
<3.1 426 1 n/a
3.1-5.8 428 1.07 0.81, 1.40
>5.8-10.8 463 1.33 0.95, 1.85
>10.8 432 1.27 0.88, 1.83
Stat Method: Logistic regression
Outcome: C-reactive protein (CRP)
water arsenic concentration (log-transformed),
ug/L
Exp. Level n adiBeta (CD
continuous NR 0.139 0.084,0.193
Stat Method: multivariate linear regression
water arsenic concentration (tertiles), u.g/L
Exp. Level n mean (CD
0.03-13.17 NR 0.78 n/a
(non-
endemic)
0.46-69.4 NR 1.15 n/a
76-205 NR 1.75 n/a
214-546 NR 2.82 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-36 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
of Bangladesh
n cases: 218
n control: 106
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: HDL
water arsenic concentration (log-transformed),
Exp. Level n ad I Beta (CD
continuous NR -0.054 -0.068, -0.041
Stat Method: multivariate linear regression
water arsenic concentration (tertiles), \ng/L
Exp. Level
0.03-13.17
(non-
endemic)
0.46-69.4
76-205
214-546
ri
NR
NR
NR
NR
mean
42.87
32.1
31.2
29.4
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: intercellular adhesion molecule-1
(ICAM-1)
water arsenic concentration (log-transformed),
H9/L
Exp. Level n adiBeta (CD
continuous NR 0.042 0.029,0.055
Stat Method: multivariate linear regression
water arsenic concentration (tertiles), \ng/L
Exp. Level
0.03-13.17
(non-
endemic)
0.46-69.4
76-205
214-546
NR
NR
NR
NR
mean
371.4
518.1
520.3
549.2
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: LDL
water arsenic concentration (log-transformed),
H9/L
Exp. Level n ad i Beta (CD
continuous NR -0.028 -0.045, -0.011
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-37 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Stat Method: multivariate linear regression
water arsenic concentration (tertiles),
Exp. Level
0.03-13.17
(non-
endemic)
0.46-69.4
76-205
214-546
NR
NR
NR
NR
mean
88.69
68.4
71.8
80.4
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: oxidized high density lipoprotein-low
density lipoprotein (Ox-LDL/HDL)
water arsenic concentration (log-transformed),
Exp. Level n ad i Beta (CD
continuous NR 0.058 0.044, 0.072
Stat Method: multivariate linear regression
Outcome: oxidized low density lipoprotein (Ox-
LDL)
water arsenic concentration (log-transformed),
Exp. Level n ad i Beta (CD
continuous NR 0.041 0.029,0.053
Stat Method: multivariate linear regression
water arsenic concentration (tertiles), \ng/L
Exp. Level
0.03-13.17
(non-
endemic)
0.46-69.4
76-205
214-546
NR
NR
NR
NR
mean
39.7
48.9
49
56.5
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: Total Cholesterol (TC)
water arsenic concentration (log-transformed),
Exp. Level
continuous
NR
ad i Beta
-0.025
(CD
-0.035, -0.015
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-38 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Stat Method: multivariate linear regression
Outcome: vascular cell adhesion molecule-1
(VCAM-1)
water arsenic concentration (log-transformed),
Exp. Level n ad i Beta (CD
continuous NR 0.036 0.023, 0.05
Stat Method: multivariate linear regression
water arsenic concentration (tertiles), \ng/L
Exp. Level
0.03-13.17
(non-
endemic)
0.46-69.4
76-205
214-546
ri
NR
NR
NR
NR
mean
420.3
589.7
604.1
623.7
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Exposure Surrogate: hair
Exposure Description: hair samples
collected for each study participant and
washed
Population-Level Exposure:
0.61 ng/g mean0.12SD
Outcome: C-reactive protein (CRP)
arsenic concentration in hair(log-transformed),
Exp. Level n ad i Beta (CD
continuous NR 0.276 0.177,0.374
Stat Method: multivariate linear regression
arsenic concentration in hair (tertiles), \ag/g
Exp. Level
0.03-1.62
(non-
endemic)
0.25-2.37
2.45-4.95
5-37.24
ri
NR
NR
NR
NR
mean
0.78
1.74
1.37
2.64
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: HDL
arsenic concentration in hair(log-transformed),
H9/9
Exp. Level n ad i Beta (CD
continuous NR -0.085 -0.11,-0.059
Stat Method: multivariate linear regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-39 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
arsenic concentration in hair (tertiles), VLQ/Q
Exp. Level n mean (CD
0.03-1.62 NR 42.87 n/a
(non-
endemic)
0.25-2.37 NR 31.1 n/a
2.45-4.95 NR 31.3 n/a
5-37.24 NR 30.3 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: intercellular adhesion molecule-1
(ICAM-1)
arsenic concentration in hair(log-transformed),
H9/9
Exp. Level n adiBeta (CD
continuous NR 0.091 0.068, 0.114
Stat Method: multivariate linear regression
arsenic concentration in hair (tertiles), ng/g
Exp. Level n mean (CD
0.03-1.62 NR 371.4 n/a
(non-
endemic)
0.25-2.37 NR 548.9 n/a
2.45-4.95 NR 519.3 n/a
5-37.24 NR 520.5 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: LDL
arsenic concentration in hair(log-transformed),
H9/9
Exp. Level n adiBeta (CD
continuous NR -0.04 -0.078, -0.015
Stat Method: multivariate linear regression
arsenic concentration in hair (tertiles), ng/g
Exp. Level n mean (CD
0.03-1.62 NR 88.69 n/a
(non-
endemic)
0.25-2.37 NR 70 n/a
2.45-4.95 NR 70.2 n/a
5-37.24 NR 80.5 n/a
Stat Method: One-Way ANOVA followed by
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-40 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Bonferroni multicomparison test.
Outcome: oxidized high density lipoprotein-low
density lipoprotein (Ox-LDL/HDL)
arsenic concentration in hair(log-transformed),
Exp. Level n ad I Beta (CD
continuous NR 0.1 0.074, 0.127
Stat Method: multivariate linear regression
Outcome: oxidized low density lipoprotein (Ox-
LDL)
arsenic concentration in hair(log-transformed),
H9/9
Exp. Level n adiBeta (CD
continuous NR 0.086 0.064,0.108
Stat Method: multivariate linear regression
arsenic concentration in hair (tertiles), ng/g
Exp. Level
0.03-1.62
(non-
endemic)
0.25-2.37
2.45-4.95
5-37.24
NR
NR
NR
NR
mean
39.7
44.4
50.3
59.5
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: Total Cholesterol (TC)
arsenic concentration in hair(log-transformed),
Exp. Level n ad i Beta (CD
continuous NR -0.038 -0.057, -0.02
Stat Method: multivariate linear regression
arsenic concentration in hair (tertiles), \ag/g
Exp. Level
0.03-1.62
(non-
endemic)
0.25-2.37
2.45-4.95
5-37.24
NR
NR
NR
NR
mean
147.3
128.5
122.6
130.4
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-41 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Exposure Surrogate: nail
Exposure Description: nail samples
collected from each individual and
washed
Population-Level Exposure:
6.65 ng/g mean
Results
Bonferroni multicomparison test
Outcome: vascular cell adhesion molecule-1
(VCAM-1)
arsenic concentration In hair(log-transformed),
m/9
Exp. Level n adiBeta (CD
continuous NR 0.086 0.062, 0.110
Stat Method: multivariate linear regression
arsenic concentration in hair (tertiles), ng/g
Exp. Level n mean (Cl)
0.03-1.62 NR 420.3 n/a
(non-
endemic)
0.25-2.37 NR 605.1 n/a
2.45-4.95 NR 588.4 n/a
5-37.24 NR 624.2 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: C-reactive protein (CRP)
arsenic concentration In nails (tertiles), ng/g
Exp. Level n mean (Cl)
0.15-8.13 NR 0.78 n/a
(non-
endemic)
0.53-5.14 NR 1.39 n/a
5.21-10.65 NR 1.99 n/a
10.67-37.42 NR 2.33 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: HDL
arsenic concentration in nails (tertiles), ng/g
Exp. Level n mean (Cl)
0.15-8.13 NR 42.87 n/a
(non-
endemic)
0.53-5.14 NR 32.2 n/a
5.21-10.65 NR 30.3 n/a
10.67-37.42 NR 30.3 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: intercellular adhesion molecule-1
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-42 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
(ICAM-1)
arsenic concentration in nails (tertiles), VLQ/Q
Exp. Level n mean (CD
0.15-8.13 NR 371.4 n/a
(non-
endemic)
0.53-5.14 NR 530.9 n/a
5.21-10.65 NR 533.5 n/a
10.67-37.42 NR 523.8 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: LDL
arsenic concentration in nails (tertiles), VLQ/Q
Exp. Level n mean (CD
0.15-8.13 NR 88.69 n/a
(non-
endemic)
0.53-5.14 NR 73.2 n/a
5.21-10.65 NR 71.8 n/a
10.67-37.42 NR 75.8 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: oxidized low density lipoprotein (Ox-
LDL)
arsenic concentration in nails (tertiles), VLQ/Q
Exp. Level n mean (CD
0.15-8.13 NR 39.7 n/a
(non-
endemic)
0.53-5.14 NR 49.3 n/a
5.21-10.65 NR 49.9 n/a
10.67-37.42 NR 55.4 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: Total Cholesterol (TC)
arsenic concentration in nails (tertiles), VLQ/Q
Exp. Level n mean (CD
0.15-8.13 NR 147.3 n/a
(non-
endemic)
0.53-5.14 NR 126.6 n/a
5.21-10.65 NR 125.8 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-43 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
10.67-37.42 NR 129 n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Outcome: vascular cell adhesion molecule-1
(VCAM-1)
arsenic concentration in nails (tertiles), \ag/g
Exp. Level
0.15-8.13
(non-
endemic)
0.53-5.14
5.21-10.65
10.67-37.42
NR
NR
NR
NR
mean
420.3
602.1
627.3
589.1
M
n/a
n/a
n/a
n/a
Stat Method: One-Way ANOVA followed by
Bonferroni multicomparison test.
Kim and Lee (2011)
Study Type: cross-
sectional
Location: South Korea
(national)
Population: KNHANES
IV 2008, adult
participants
n cases: 1,677
n control: n/a
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from single
sample for each individual
Population-Level Exposure:
118.4 ng/g-creatinine geo mean, 112.9-
123.8 ng/g-creatinine 95% Cl lower
Outcome: blood pressure
log-transformed total urinary arsenic - comb sex,
Hg/g-creatinine
Exp. Level n adjRR M
hypertension NR 1 n/a
- no
hypertension NR 1.07 0.982, 1.167
- yes
Stat Method: multiple regression
log-transformed total urinary arsenic -female,
ug/g-creatinine
Exp. Level n adjRR (Cl)
hypertension NR 1 n/a
- no
hypertension NR 0.994 0.865, 1.144
-yes
Stat Method: multiple regression
log-transformed total urinary arsenic - male,
ng/g-creatinine
Exp. Level n adjRR {CJ}
hypertension NR 1 n/a
- no
hypertension NR 1.132 1.004, 1.276
- yes
Stat Method: multiple regression
Kim et al. (2013)
Exposure Surrogate: urine
Outcome: mean systolic blood pressure
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-44 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Study Type: case-
control (nested)
Location: United States
(Arizona)
Population:
longitudinal study
participants who
developed diabetes
within 10 years of
initial screening
n cases: 150
n control: 150
Exposure Description: concentrations of
arsenic (total and inorganic) and
metabolites measured in stored urine
samples obtained at the baseline
examination; adjusted for urinary
creatinine
Population-Level Exposure:
21.1 ng/L median, 15.3-29.4 ng/L 25th
percentile
total arsenic concentration, u.g/L
systolic blood pressure similar in cases and
controls
Kunrathetal. (2013)
Study Type: cross-
sectional
Location: Romania
(Arad County)
Population: adult men
with normal blood
pressure and low-to-
moderate arsenic
exposure from drinking
water
n cases: 19
n control: 16
Exposure Surrogate: drinking water
Exposure Description: individual
exposure assessment conducted by
collecting water samples from current
main drinking water source for each
participant; mean (SD) water inorganic As
for unexposed and exposed: 1 (0.2) and
40.2 (30.4), respectively
Population-Level Exposure:
0.1-240 ng/L range
Outcome: anticipatory stress (DBP difference
from baseline)
water arsenic exposure, ug/L
Exp. Level n mean (CD
unexposed NR 11.2 n/a
exposed NR 20 n/a
Stat Method: multivariate ANOVA
Outcome: anticipatory stress (SBP difference
from baseline)
water arsenic exposure, ug/L
arsenic not significantly associated with
anticipatory stress
Outcome: blood pressure (anticipatory stress
recovery)
water arsenic exposure, ug/L
arsenic not significantly associated with blood
pressure
Outcome: blood pressure (anticipatory stress)
water arsenic exposure, ug/L
Exp. Level n adjOR {G}
unexposed NR 1 n/a
exposed NR 6.3 1.11,35.67
Stat Method: binary logistic regression
Outcome: blood pressure (cold stress)
water arsenic exposure,
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-45 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Exp. Level n adjOR (CD
unexposed NR 1 n/a
exposed NR 4.67 1.11, 19.65
Stat Method: binary logistic regression
Outcome: cold stress (DBP difference from
baseline)
water arsenic exposure,
Exp. Level n mean (CD
unexposed NR 23.2 n/a
exposed NR 34 n/a
Stat Method: multivariate ANOVA
Outcome: cold stress (SBP difference from
baseline)
water arsenic exposure, ug/L
Exp. Level n mean (CD
unexposed NR 20.6 n/a
exposed NR 38.5 n/a
Stat Method: multivariate ANOVA
Outcome: recovery from anticipatory stress (DBP
difference from baseline)
water arsenic exposure,
Exp. Level n mean (CD
unexposed NR 10.5 n/a
exposed NR 20.9 n/a
Stat Method: multivariate ANOVA
Outcome: recovery from anticipatory stress (SBP
difference from baseline)
water arsenic exposure, ug/L
arsenic not significantly associated with recovery
from anticipatory stress
Outcome: recovery from cold stress (DBP
difference from baseline)
water arsenic exposure, ug/L
Exp. Level n mean (Cl)
unexposed NR 10.3 n/a
exposed NR 19.6 n/a
Stat Method: multivariate ANOVA
Outcome: recovery from cold stress (SBP
difference from baseline)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-46 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
water arsenic exposure, u.Q/1
Exp. Level ri mean (CD
unexposed NR 1.7 n/a
exposed NR 16.8 n/a
Stat Method: multivariate ANOVA
Kwoketal. (2007)
Study Type: cross-
sectional
Location: China (Inner
Mongolia (Lin He,
Hanggin Houqi, and Wu
Yuan counties))
Population: women
with pregnancy
outcome 12/1/1996-
12/31/1999
n cases: 2,808
n control: 5,982
Exposure Surrogate: drinking water
Exposure Description: cumulative
drinking water arsenic exposure assessed
retrospectively by matching subjects to
well water measurements from five
randomly selected families in each
subvillage
Population-Level Exposure:
0-100 ng/L range
Outcome: diastolic blood pressure
cumulative drinking water arsenic exposure,
n adjBeta (CD
NR 1 n/a
NR 2.11 1.38,2.84
NR 2.74 1.55,3.93
NR 3.08 1.84,4.31
Exp. Level
100
Stat Method: Analysis of covariance
Outcome: systolic blood pressure
cumulative drinking water arsenic exposure,
H ad j Beta (CD
NR 1 n/a
NR 1.88 1.03,2.73
NR 3.9 2.52,5.29
NR 6.83 5.39,8.27
Exp. Level
100
Stat Method: Analysis of covariance
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: deceased
male and female
members of Latter-day
Saints church wards
n exposed: 2,203
n total: 2,203
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Outcome: all heart disease
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR {G}
< 1,000 NR 1.03 n/a
1,000-4,999 NR 0.8 n/a
> 5,000 NR 61 n/a
Stat Method: standardized mortality ratio;
OCMAP adapted to nonoccupational cohort
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1,000 NR 0.87 n/a
1,000-4,999 NR 0.78 n/a
> 5,000 NR 0.74 n/a
Stat Method: standardized mortality ratio;
OCMAP adapted to nonoccupational cohort
Outcome: all other heart disease
cumulative arsenic exposure, ppb-years
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-47 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
SMR for all other heart disease unchanged from
expected in males; SMR significantly increased in
low exposure females only
Outcome: aortic aneurysm
cumulative arsenic exposure, ppb-years
SMR for aortic aneurysm unchanged from
expected in males and females
Outcome: arteriosclerosis
cumulative arsenic exposure, ppb-years
SMR for arteriosclerosis unchanged from
expected in males and females
Outcome: cerebrovascular disease
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR {CJ}
<1,000 NR 0.97 n/a
1,000-4,999 NR 1.05 n/a
> 5,000 NR 0.63 n/a
Stat Method: standardized mortality ratio;
OCMAP adapted to nonoccupational cohort
Outcome: disease of arteries and capillaries
cumulative arsenic exposure, ppb-years
SMR for disease of arteries and capillaries
unchanged from expected in males and females
Outcome: hypertension without heart disease
cumulative arsenic exposure, ppb-years
SMR for hypertension without heart disease
unchanged from expected in males and females
Outcome: hypertensive heart disease
cumulative arsenic exposure, ppb-years
SMR for hypertensive heart disease significantly
increased in low exposure males and medium
exposure females only
Outcome: ischemic heart disease
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR M
<1,000 NR 0.68 n/a
1,000-4,999 NR 0.62 n/a
> 5,000 NR 0.62 n/a
Stat Method: standardized mortality ratio;
OCMAP adapted to nonoccupational cohort
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-48 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1,000 NR 0.83 n/a
1,000-4,999 NR 0.74 n/a
> 5,000 NR 0.7 n/a
Stat Method: standardized mortality ratio;
OCMAP adapted to nonoccupational cohort
Li et al. (2013a)
Study Type: cross-
sectional
Location: China
(Tuoketuo County,
Inner Mongolia)
Population: residents
exposed to arsenic in
drinking water
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration of each tube well
measured and provided by local public
health government; cumulative arsenic
exposure (CAE) calculated for each
subject as: concentration in tube well
that subject used in his/her residential
duration multiplied by duration of water
consumption
Population-Level Exposure:
0-760 ng/L range
Outcome: hypertension
water arsenic concentration, u.g/L
Exp. Level n adjOR
<10 NR NR n/a
10-50 NR 1.417 0.767,2.618
>50 NR 1.937 1.018,3.687
Stat Method: multiple logistic regression
Li et al. (2009)
Study Type: cross-
sectional
Location: Taiwan
(southwestern)
Population: adult
residents of arseniasis-
endemic area
n cases: 142
n control: 345
Exposure Surrogate: drinking water
Exposure Description: cumulative
drinking water arsenic exposure assessed
using an index of cumulative arsenic
exposure based on median arsenic level
in village well water and years of living in
a village (self-reported); current
exposure assessed based on speciated
urinary arsenic measurements (not used
in association analyses)
Population-Level Exposure:
0.01-15 mg/L - yr range
Outcome: carotid artherosclerosis
cumulative drinking water arsenic exposure
(tertiles), mg/L - yr
Exp. Level n
<0.1 NR
0.1-15.0 NR
>15.0 NR
M
n/a
0.95, 5.09
1.34, 5.60
Stat Method: Logistic regression
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration obtained from
previous surveys, citations provided in
study
Outcome: carotid artherosclerosis
drinking water arsenic concentration (tertiles),
ppb
Exp. Level
1-700
>700
ri
NR
NR
NR
M
n/a
1.48, 6.24
.90, 4.37
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-49 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Stat Method: Logistic regression
Population-Level Exposure:
1-700 ppb range
Li et al. (2013b)
Study Type: cross-
sectional
Location: China
(Shanyin county of
Shanxi province)
Population: residents
of arsenic-
contaminated areas
n cases: 604
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure estimated based on
concentration in tube wells in mg/L and
recall of water consumption years by
questionnaire
Population-Level Exposure:
0-0.65 mg/L-yr range
Outcome: blood pressure - hypertension
cumulative arsenic exposure, mg/L-yr
Exp. Level n adjOR M
without NR 1 n/a
hypertension
hypertension NR 1.752 0.992,3.096
Stat Method: multiple logistic regression
cumulative arsenic exposure concentration in
water (tertiles), mg/L-yr
Exp. Level n adjOR {G}
<0.10 29 1 n/a
0.10-0.35 30 1.204 0.632,2.292
>0.35 45 1.871 1.022,3.424
Stat Method: multiple logistic regression
Exposure Surrogate: urine
Exposure Description: aliquot samples
used for each assay; speciation based on
hydride generation of volatile arsines;
standard reference materials used; final
adjustment by concentration of
creatinine; total arsenic calculated as
sum of inorganic arsenic, MMA, DMA;
represented by species and by
percentage
Population-Level Exposure:
93.77-250.61 ng/g-creatinine range
Outcome: blood pressure - hypertension
urinary inorganic arsenic concentration (tertiles),
Hg/g-creatinine
Exp. Level n adjOR (CD
<7.31 51 1 n/a
7.31-33.68 54 1.301 0.772,2.192
>33.68 63 1.591 0.963,2.628
Stat Method: multiple logistic regression
urinary total arsenic concentration (tertiles),
Hg/g-creatinine
Exp. Level n
<93.77 45
93.77-250.61 52
>250.61 71
M
n/a
0.641, 1.837
0.999, 2.721
Stat Method: multiple logistic regression
Liao et al. (2012)
Study Type: cohort
(prospective)
Location: Taiwan
(Homei, Fusin, and
Hsinming villages in
Putai Township)
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated from artesian well
water measured in the 1960s and
duration of water consumption; median
concentration in endemic area was 0.78
ppm prior to intervention in the 1970s,
after which concentration reduced to
Outcome: cardiovascular disease mortality
cumulative drinking water arsenic exposure
concentration, ppm-years
Exp. Level
<14.7
>14.7
NR
NR
NR
NR
HR
1
1.89
NR
M
n/a
0.50, 7.10
n/a
Stat Method: Cox proportional hazards
analysis
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-50 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Population: adult
residents of previously
arseniasis-endemic
area from existing
cohort still living in area
in 2002
n exposed: 380
n reference: 296
n total: 676
<0.01ppm
Population-Level Exposure:
0.78 ppm-years median
Moon et al. (2013)
Study Type: cohort
(prospective)
Location: United States
(AZ;ND;OK;SD)
Population: Strong
Heart Study
participants
n total: 3,575
Exposure Surrogate: urine
Exposure Description: arsenic species
concentrations were measured in urine;
participants with arsenic species
concentrations below the limit of
detection (5.1% for inorganic arsenic,
0.8% for MMA, 0.03% for DMA, and 2.1%
forarsenobetaine), levels imputed as
LOD divided by square root of 2
and arsenate) and methylated arsenic
species (DMA and MMA) as a biomarker
to integrate inorganic arsenic exposure
from multiple sources.
Population-Level Exposure:
5.8-15.7 |jg/g-creatinine range
Outcome: cardiovascular disease - incidence
concentration of inorganic plus methylated
arsenic species in urine (quartiles), ug/g-
creatinine
HR
Exp. Level
<5.8
5.8-9.7
9.8-15.7
>15.7
n
265
297
291
331
1
1.11
0.97
1.09
M
n/a
0.93, 1.32
0.80, 1.17
0.90, 1.33
Stat Method: Cox proportional hazards
models
Outcome: cardiovascular disease - mortality
concentration of inorganic plus methylated
arsenic species in urine (quartiles), ng/g-
creatinine
n HR
Exp. Level
<5.8
5.8-9.7
9.8-15.7
>15.7
86
95
115
143
1
1.02
1.15
1.29
M
n/a
0.75, 1.39
0.84, 1.58
0.93, 1.79
Stat Method: Cox proportional hazards
models
Outcome: coronary heart disease - incidence
concentration of inorganic plus methylated
arsenic species in urine (quartiles), ug/g-
creatinine
M
n/a
0.84, 1.26
0.70, 1.10
Exp. Level
<5.8
5.8-9.7
9.8-15.7
>15.7
202
206
197
241
HR
1
1.03
0.88
1.08
0.86, 1.35
Stat Method: Cox proportional hazards
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-51 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Mordukhovich et al.
(2009)
Study Type: cross-
sectional
Exposure Measures
Exposure Surrogate: toenails
Exposure Description: toenail samples
from all 10 toes collected; samples were
cleaned to remove contaminants and
then sonicated; samples digested with
Results
models
Outcome: coronary heart disease - mortality
concentration of inorganic plus methylated
arsenic species in urine (quartiles), U.Q/Q-
creatinine
Exp. Level n HR (CD
<5.8 68 1 n/a
5.8-9.7 67 0.89 0.62, 1.27
9.8-15.7 87 1.06 0.74, 1.53
>15.7 119 1.33 0.92, 1.93
Stat Method: Cox proportional hazards
models
Outcome: stroke - incidence
concentration of inorganic plus methylated
arsenic species in urine (quartiles), U.Q/Q-
creatinine
Exp. Level n HR (CD
<5.8 55 1 n/a
5.8-9.7 75 1.09 0.76, 1.57
9.8-15.7 62 1.07 0.72, 1.60
>15.7 72 1.18 0.77, 1.79
Stat Method: Cox proportional hazards
models
Outcome: stroke - mortality
concentration of inorganic plus methylated
arsenic species in urine (quartiles), ug/g-
creatinine
Exp. Level n HR (CD
<5.8 6 1 n/a
5.8-9.7 17 1.3 0.50,3.39
9.8-15.7 13 1.97 0.70,5.55
>15.7 18 2.35 0.83,6.69
Stat Method: Cox proportional hazards
models
Outcome: change in heart rate-corrected QT
interval duration (milliseconds)
toenail arsenic concentration, ug/g
Exp. Level n change (Cl)
per 0.059- NR 2.5 0.11,4.9
Ug/g (IQR)
increase
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-52 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Location: United States
(MA)
Population: elderly
men from Veterans
Administration
Normative Aging Study
n cases: n/a
n control: n/a
nitric acid and diluted with deionized
water
Population-Level Exposure:
0.069 ng/g median, 0.052-0.11 ng/g 25th
percentile
Stat Method: multivariate linear regression
Outcome: change in QT interval duration
(milliseconds)
toenail arsenic concentration, \ag/g
Exp. Level n change (CD
per 0.059- NR 3.8 0.82,6.8
Hg/g (IQR)
increase
Stat Method: multivariate linear regression
Mumfordetal. (2007)
Study Type: cross-
sectional
Location: China (Ba
Men)
Population: residents
of high, medium, and
low exposure areas for
arsenic in drinking
water
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: samples collected
from study subject's homes
Population-Level Exposure:
0.1-690 ng/L range
Outcome: heart rate
well water arsenic concentration, \ig/L
individuals with prolonged QTc demonstrated
statistical significant increase in heart rate in
medium- (p=0.0194) and high-exposure
(p=0.0018) groups (t-test)
Outcome: QT interval
well water arsenic concentration, \ig/L
Exp. Level n adjOR M
70 ng/mL NR 0.058 0.0198,0.095
Stat Method: robust multivariable linear
regression analysis
Rahman et al. U999a)
Exposure Surrogate: drinking water
Outcome: hypertension
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-53 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Study Type: cohort
(retrospective)
Location: Bangladesh
(Faridpur, Nawabgong,
Jessore, and
Narayongong districts)
Population: adults
residents of village with
history of higher than
average arsenic in
drinking water based
on existing surveys
n exposed: 1,481
n reference: 114
n total: 1,595
Sohel et al. (2009)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: Health and
Demographic
Surveillance System
1991-2000, adults and
children with
nonaccidental deaths
1991-2000
n exposed: 93,415
n total: 93,415
Tseng et al. (1996)
Study Type: cross-
sectional
Exposure Measures
Exposure Description: cumulative arsenic
levels calculated based on arsenic
concentration in well water and self-
reported years of use
Population-Level Exposure:
0-10 mg-Y/L
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations calculated as
time-weighted average based on levels
obtained from existing reports
Population-Level Exposure:
0-1 mg/L range
Exposure Surrogate: drinking water
Exposure Description: cumulative
drinking water arsenic concentration
based on current arsenic concentrations
(reasonably stable over time); average
household exposure (used as proxy for
individual exposure) calculated for each
calendar year from 1970, based on
information obtained from the current
population present in that specific
household for each year
Population-Level Exposure:
10-300 ng/L range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
levels calculated based on arsenic
concentration in well water and self-
Results
cumulative drinking water arsenic exposure, mg-
Y/L
Exp. Level n PR (M- (CD
HI
0 9 1 n/a
<1.0 13 0.8 0.3, 1.7
1.0-5.0 83 1.5 0.7,2.9
>5.0-10.0 40 2.2 1.1,4.4
>10.0 62 3 1.5,5.8
Stat Method: Linear regression model
Outcome: hypertension
drinking water arsenic concentration, mg/L
Exp. Level n PR (M- (Cl)
hi
0 9 1 n/a
<0.5 50 1.2 0.6,2.3
0.5 to 1.0 93 2.2 1.1,4.3
>1.0 55 2.5 1.2,4.9
Stat Method: Linear regression model
Outcome: cardiovascular disease deaths
cumulative water arsenic concentration
(quintiles), u.g/L
Exp. Level n adiOR (Cl)
<10 129 1 n/a
10-49 153 1.03 0.82, 1.29
50-149 476 1.16 .96, 1.40
150-299 388 1.23 1.01, 1.51
> 300 152 1.37 1.07, 1.77
Stat Method: Cox proportional hazard model
Outcome: peripheral vascular disease
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n adiOR (Cl)
0 NR 1 n/a
0.1-19.9 NR 2.77 0.84,9.14
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-54 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Location: Taiwan
(Homei, Fuhsin, and
Hsinming villages in
Putai Township)
Population: adults
living in blackfoot
disease-endemic
township
n cases: 582
n control: n/a
Tseng et al. (1997)
Study Type: cross-
sectional
Location: Taiwan
(Homei, Fuhsin, and
Hsinming villages in
Putai Township)
Population: adults
living in blackfoot
disease-endemic
township
n cases: 533
n control: n/a
Tseng et al. (2003)
Study Type: cross-
sectional
Location: Taiwan
(Homei, Fuhsin, and
Hsinming villages in
Putai Township)
Population: adults
living in blackfoot
disease-endemic
township
n cases: 462
Exposure Measures
reported years of drinking well water
during successive periods of living in
different villages
Population-Level Exposure:
0-20 mg/L-yr range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
levels calculated based on arsenic
concentration in well water and self-
reported years of drinking well water
during successive periods of living in
different villages
Population-Level Exposure:
0-20 mg/L-yr range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
levels calculated based on arsenic
concentration in well water and self-
reported years of drinking well water
during successive periods of living in
different villages
Population-Level Exposure:
0-15 mg/L-yr range
Results
> 20.0 NR 4.28 1.26, 14.54
Unknown NR 1.63 0.50,5.33
Stat Method: Multivariate logistic regression
Outcome: peripheral vascular disease
cumulative drinking water arsenic exposure, ABI
>1.2 excluded, mg/L - yr
Exp. Level n adjOR (CD
0 NR 1 n/a
0.1-19.9 NR 3.01 0.84, 10.75
>20 NR 5.6 1.50,20.92
Unknown NR 1.58 0.46,5.37
Stat Method: Multivariate logistic regression
Outcome: ischemic heart disease
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n adjOR (CD
0 NR 1 n/a
0.1-14.9 NR 1.6 0.48,5.34
>15 NR 3.6 1.11,11.65
Stat Method: Multivariate logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-55 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
n control: n/a
Wade et al. (2009)
Study Type: cohort
(retrospective)
Location: China (Shahai
village, Inner Mongolia)
Population: decreased
male and female adults
and children living in
village history of higher
than average arsenic in
drinking water
n exposed: 562
n total: 572
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic exposure calculated from single
well water sample collected from each
household; results below LOD assigned
one-half of LOD
Population-Level Exposure:
38 ng/L mean
Results
Outcome: heart disease mortality
drinking water arsenic concentration (exposed
since before 1990), \ig/L
Exp. Level n IRR (Cl)
0-5 36 1 n/a
5.1-20 12 0.75 0.37, 1.51
20.1-100 37 1.28 0.79,2.07
100.1-300 15 1.6 0.87,2.95
>300 2 5.08 1.45, 17.81
Stat Method: multivariate Poisson regression
model
drinking water arsenic concentration (exposed
since before 1995), \ig/L
Exp. Level n IRR (Cl)
0-5 44 1 n/a
5.1-20 26 1.07 0.64, 1.78
20.1-100 72 1.22 0.82, 1.82
100.1-300 17 1.55 0.88,2.73
>300 2 2.47 0.50, 12.18
Stat Method: multivariate Poisson regression
model
drinking water arsenic concentration (per 50
Hg/L Increase), ng/L
Exp. Level n IRR (Cl)
50 |jg/L NR 1.12 1.01, 1.23
increase
Stat Method: multivariate Poisson regression
model
Outcome: stroke mortality
drinking water arsenic concentration (exposed
since before 1990), \ig/L
Exp. Level n IRR (Cl)
0-5 40 1 n/a
5.1-20 13 0.62 0.33, 1.18
20.1-100 20 0.65 0.38, 1.12
100.1-300 6 0.58 0.26, 1.29
>300 1 1.64 0.31,8.77
Stat Method: multivariate Poisson regression
model
drinking water arsenic concentration (exposed
since before 1995), \ig/L
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-56 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Wang et al. (2002)
Study Type: cohort
(prospective)
Location: Taiwan
(southwestern; Homei,
Fushin, and Hsinming
villages in Putai
Township)
Population: adults
living in arseniasis-
endemic township
n exposed: 436
n total: 436
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
levels calculated based on arsenic
concentration in well water and self-
reported years of drinking well water
during successive periods of living in
different villages; arsenic levels in well
water collected in previous studies
conducted in the 1960s
Population-Level Exposure:
0-20 mg/L-yr range
Results
Exp. Level n IRR (CD
0-5 53 1 n/a
5.1-20 16 0.47 0.27,0.84
20.1-100 41 0.51 0.34,0.79
100.1-300 7 0.52 0.25, 1.10
>300 1 1.02 0.16,6.71
Stat Method: multivariate Poisson regression
model
drinking water arsenic concentration (per 50
Hg/L increase), u.g/L
Exp. Level n IRR (CD
50 ug/L NR 0.82 0.65, 1.03
increase
Stat Method: multivariate Poisson regression
model
Outcome: IMT > 1.0mm
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n adiOR (CD
0 NR 1 n/a
0.1-19.9 NR 1.9 0.9,4.1
>20 NR 2.9 1.2,6.9
Stat Method: multiple logistic regression
(multivariate) analysis
Outcome: presence of plaque
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n adiOR (CD
0 NR 1 n/a
0.1-19.9 NR 1.2 0.4,3.4
>20 NR 2.3 0.8,6.4
Stat Method: multiple logistic regression
(multivariate) analysis
Outcome: presence of plaque or IMT > 1.0mm
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n adiOR (CD
0 NR 1 n/a
0.1-19.9 NR 1.8 0.8,3.8
>20 NR 3.1 1.3,7.4
Stat Method: multiple logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-57 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Wang et al. (2009a)
Study Type: cross-
sectional
Location: Taiwan
(Homei, Fuhsin,
Hsingming villages in
Putai township)
Population: adults
living in arseniasis-
endemic townships
n cases: 441
n control: 194
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: lifetime
cumulative arsenic exposure calculated
by multiplying the median arsenic level in
specific village by duration of
consumption of artesian well water in
that village; residential history used to
sum products of concentration and
consumption for the entire period when
living in arseniasis-endemic area
Population-Level Exposure:
0-20 mg/L - yr range
Results
(multivariate) analysis
Outcome: IMT (mm)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (CD
~0 NR 0.84 n/a
0.1-19.9 NR 1.13 n/a
>20 NR 1.49 n/a
Stat Method: Adjusted P for trend
Outcome: P wave (ms)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (CD
~0 NR 93.2 n/a
0.1-19.9 NR 92.9 n/a
>20 NR 91.7 n/a
Stat Method: Adjusted P for trend
Outcome: PR interval (ms)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (Cl)
~0 NR 178.9 n/a
0.1-19.9 NR 180.1 n/a
>20 NR 79.2 n/a
Stat Method: Adjusted P for trend
Outcome: Prevalence of carotid plaque (%)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (Cl)
~0 NR 16.8 n/a
0.1-19.9 NR 33.4 n/a
>20 NR 64.5 n/a
Stat Method: Adjusted P for trend
Outcome: Prevalence of IHD (%)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (Cl)
~0 NR 5.8 n/a
0.1-19.9 NR 11.7 n/a
>20 NR 25.1 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-58 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Stat Method: Adjusted P for trend
Outcome: Prevalence of QTc-Fridericia >460 ms
(%)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (CD
~0 NR 8.5 n/a
0.1-19.9 NR 20.6 n/a
>20 NR 54.1 n/a
Stat Method: Adjusted P for trend
Outcome: QRS duration (ms)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (CD
~0 NR 87.9 n/a
0.1-19.9 NR 86.9 n/a
>20 NR 86.7 n/a
Stat Method: Adjusted P for trend
Outcome: QT (ms)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (CD
~0 NR 415.3 n/a
0.1-19.9 NR 435.5 n/a
>20 NR 462.4 n/a
Stat Method: Adjusted P for trend
Outcome: QTc-Bazett (ms)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (CD
~0 NR 416 n/a
0.1-19.9 NR 436.8 n/a
>20 NR 464.7 n/a
Stat Method: Adjusted P for trend
Outcome: QTc-Fridericia (ms)
cumulative drinking water arsenic exposure,
mg/L - yr
Exp. Level n mean (CD
~0 NR 417.2 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-59 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
0.1-19.9 NR 437.9 n/a
>20 NR 469.7 n/a
Stat Method: Adjusted P for trend
Outcome: QTc-Fridericia prolognation
cumulative drinking water arsenic exposure,
mg/L - yr
H adjOR
NR 1
NR 2.3
Exp. Level
~0
0.1-19.9
>20
NR
7.6
M
n/a
1.0, 5.3
3.1, 18.6
Stat Method: Multiple logistic regression
analysis
Wang et al. (2011a)
Study Type: cohort
(prospective)
Location: Taiwan
(Homei, Fuhsin, and
Hsinming villages in
Putai Township)
Population: adults
living in arseniasis-
endemic townships
n exposed: 352
n total: 352
Exposure Surrogate: drinking water
Exposure Description: cumulative
drinking water arsenic levels were
calculated based on arsenic
concentration in well water (median of
wells within walking distance) and self-
reported years of drinking well water
during successive periods of living in
different villages
Population-Level Exposure:
930 mg/L - yr median, 5.6-15.6 mg/L - yr
range
Outcome: hypertension
cumulative drinking water arsenic exposure
(tertiles), mg/L - yr
Exp. Level
<5.6
5.6-15.6
>15.6
ri
NR
NR
NR
M
n/a
0.55, 2.40
0.50, 2.77
Stat Method: Logistic regression
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations determined using
median of wells within walking distance
and self-reported information on
residential history; arsenic levels in well
water collected in previous studies
conducted in the 1960s
Population-Level Exposure:
930 |jg/L median
Outcome: hypertension
drinking water arsenic concentration (tertiles),
Exp. Level
<538
538-700
>700
NR
NR
NR
M
n/a
0.60, 2.34
0.40, 1.74
Stat Method: Logistic regression
Exposure Surrogate: urine
Exposure Description: urinary arsenic
Outcome: hypertension
speciated urinary arsenic concentration (As[V];
tertiles), ug/g-creatinine
Exp. Level n adjRR (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-60 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Wuetal. (2006)
Study Type: case-
control
Location: Taiwan
(Lanyang Basin of llan
County, northeastern
Taiwan)
Population: adults
living in arseniasis-
endemic township,
health examinations
1997-1998
n cases: 163
n control: 163
Wuetal. (2010)
Study Type: case-
control (nested)
Location: Taiwan
(Lanyang Basin)
Population: adults
living in arseniasis-
endemic township,
health examinations
1998-1999
n cases: 250
n control: 256
Exposure Measures
species (As[V]) measured from sample
(collected 2002-2003) for each individual
Population-Level Exposure:
1.2-2.67 |jg/g-creatinine range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
levels calculated based on arsenic
concentration in well water and self-
reported years of use
Population-Level Exposure:
1.7-4.21 ng/L-year range
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic exposure calculated from single
well water sample collected from each
household
Population-Level Exposure:
50-100.01 ng/L range
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic exposure calculated from single
well water sample collected from each
household
Population-Level Exposure:
10-300 ng/L range
Results
<1.20 NR 1 n/a
1.20-2.67 NR 1.38 0.57,3.34
>2.67 NR 2.43 1.01,5.86
Stat Method: Logistic regression
Outcome: carotid atherosclerosis
cumulative drinking water arsenic exposure
(tertiles), ng/L-year
Exp. Level n adiOR (CD
<1.70 NR 1 n/a
1.71-4.20 NR 1.7 0.9,3.2
>4.21 NR 2.9 1.6,5.3
Trend across NR 1.7 1.3,2.3
tertiles
Stat Method: Linear regression analysis
Outcome: carotid atherosclerosis
drinking water arsenic concentration (tertiles),
ug/L
Exp. Level n adjOR (Cl)
< 50.00 NR 1 n/a
50.01- NR 1.9 0.9,3.8
100.00
> 100.01 NR 2.6 1.3,5.0
Trend across NR 1.6 1.1,2.1
tertiles
Stat Method: Linear regression analysis;
logistic regression
Outcome: carotid atherosclerosis
average drinking water arsenic exposure, ug/L
Exp. Level n adiOR (Cl)
<10 NR 1 n/a
10.1-50 NR 2.58 0.70,9.56
50.1-100 NR 2.98 1.21,7.34
100.1-300 NR 3.07 1.23,7.65
>300 NR 2.62 1.04,6.60
Stat Method: logistic regression analysis
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-61 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Cardiovascular Disease
Reference and Study
Design
Exposure Measures
Results
Xia et al. (2009)
Study Type: cross-
sectional
Location: China
(Bayingnormen, Shahai
village)
Population: adults and
children living in
arseniasis-endemic
village
n cases: 11,416
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration in drinking water;
exposure calculated from single well
water sample collected from each
household
Population-Level Exposure:
37.94 ng/L mean
Outcome: cardiovascular disease
drinking water arsenic concentration (per 50
Hg/L increase) by sex, ng/L
Exp. Level n adjOR (CD
continuous NR 1.1 n/a
(males)
continuous NR 0.99 n/a
(females)
Stat Method: logistic regression model
Outcome: stroke
drinking water arsenic concentration (per 50
Hg/L increase) by sex, ng/L
Exp. Level n adjOR {G}
continuous NR 1.03 n/a
(males and
females)
Stat Method: logistic regression model
--: not reported; n: number of cases (when presented in Results column)
5.2.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Cardiovascular Disease
Bosnjak. Z: Cavar. S: Klapec. T: Milic. M: Klapec-Basar. M: Toman. M. (2008). Selected markers of
cardiovascular disease in a population exposed to arsenic from drinking water. Environ Toxicol Pharmacol
26: 181-186. http://dx.doi.0rg/10.1016/i.etap.2008.03.005
Burgess. JL: Kurzius-Spencer. M: O'Rourke. MK: Littau. SR: Roberge. J: Meza-Montenegro. MM: Gutierrez-
Millan. LE: Harris. RB. (2013). Environmental arsenic exposure and serum matrix metalloproteinase-9. J
Expo Sci Environ Epidemiol 23: 163-169. http://dx.doi.org/10.1038/ies.2012.107
Chen. CJ: Chiou. HY: Chiang. MH: Lin. LJ: Taj TY. (1996). Dose-response relationship between ischemic
heart disease mortality and long-term arsenic exposure. Arterioscler Thromb Vase Biol 16: 504-510.
Chen. SC: Chea CC: Kuo. CY: Huang. CH: Lia CH: Lu. ZY: Chea YY: Lee. HS: Wong. RH. (2012). Elevated
risk of hypertension induced by arsenic exposure in Taiwanese rural residents: Possible effects of manganese
superoxide dismutase (MnSOD) and 8-oxoguanine DNA glycosylase (OGG1) genes. Arch Toxicol 86: 869-
878. http://dx.doi.org/10.1007/s00204-011-0797-8
Chen. Y: Factor-Litvak. P: Howe. GR: Graziano. JH: Brandt-Rauf. P: Parvez. F: van Geea A: Ahsaa H. (2007).
Arsenic exposure from drinking water, dietary intakes of B vitamins and folate, and risk of high blood
pressure in Bangladesh: A population-based, cross-sectional study. Am J Epidemiol 165: 541-552.
http://dx.doi.org/10.1093/aie/kwk037
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Chen. Y: Graziano. JH: Parvez. F: Liu. M: Slavkovich. V: Kalra. T: Argos. M: Islam. T: Ahmed. A: Rakibuz-
Zaman. M: Hasan. R: Sarwar. G: Lew. D: van Geen. A: Ahsan. H. (2011). Arsenic exposure from drinking
water and mortality from cardiovascular disease in Bangladesh: prospective cohort study. B M J (Online)
342: d2431. http://dx.doi.org/10.1136/bmi.d2431
Chen. Y: Hakim. ME: Parvez. F: Islam. T: Rahman. AM: Ahsan. H. (2006). Arsenic exposure from drinking-
water and carotid artery intima-medial thickness in healthy young adults in Bangladesh. J Health Popul Nutr
24: 253-257.
Chen. Y: Wu. F: Graziano. JH: Parvez. F: Liu. M: Paul. RR: Shaheen. I: Sarwar. G: Ahmed. A: Islam. T:
Slavkovich. V: Rundek. T: Demmer. RT: Desvarieux. M: Ahsan. H. (2013a). Arsenic exposure from
drinking water, arsenic methylation capacity, and carotid intima-media thickness in Bangladesh. Am J
Epidemiol 178: 372-381. http://dx.doi.org/10.1093/aie/kwt001
Chen. Y: Wu. F: Parvez. F: Ahmed. A: Eunus. M: McClintock. TR: Patwary. TI: Islam. T: Ghosal AK: Islam. S:
Hasan. R: Lew. D: Sarwar. G: Slavkovich. V: van Geen. A: Graziano. JH: Ahsan. H. (2013b). Arsenic
exposure from drinking water and QT-interval prolongation: results from the health effects of arsenic
longitudinal study. Environ Health Perspect 121: 427-432. http://dx.doi.org/10.1289/ehp.1205197
Chiou. HY: Huang. WI: Su. CL: Chang. SF: Hsu. YH: Chen. CJ. (1997). Dose-response relationship between
prevalence of cerebrovascular disease and ingested inorganic arsenic. Stroke 28: 1717-1723.
http://dx.doi.Org/10.1161/01.STR.28.9.1717
Chiou. JM: Wang. SL: Chen. CJ: Deng. CR: Lin. W: Tai. TY. (2005). Arsenic ingestion and increased
microvascular disease risk: Observations from the south-western arseniasis-endemic area in Taiwan. Int J
Epidemiol 34: 936-943. http://dx.doi.org/10.1093/iie/dvil08
Guha Mazumder. D: Purkavastha. I: Ghose. A: Mistry. G: Saha. C: Nandv. AK: Das. A: Maiumdar. KK. (2012).
Hypertension in chronic arsenic exposure: A case control study in West Bengal. J Environ Sci Health A Tox
Hazard Subst Environ Eng 47: 1514-1520. http://dx.doi.org/10.1080/10934529.2012.680329
Guo. JX: Hu. L: Yand. PZ: Tanabe. K: Miyatalre. M: Chen. Y. (2007). Chronic arsenic poisoning in drinking
water in Inner Mongolia and its associated health effects. J Environ Sci Health A Tox Hazard Subst Environ
Eng 42: 1853-1858. http://dx.doi.org/10.1080/10934520701566918
Hawkesworth. S: Wagatsuma. Y: Kippler. M: Fulford. AJ: Arifeen. SE: Persson. LA: Moore. SE: Vahter. M.
(2013). Early exposure to toxic metals has a limited effect on blood pressure or kidney function in later
childhood, rural Bangladesh. Int J Epidemiol 42: 176-185. http://dx.doi.org/10.1093/ije/dvs215
Hsieh. FI: Hwang. TS: Hsieh. YC: Lo. HC: Su. CT: Hsu. HS: Chiou. HY: Chea CJ. (2008a). Risk of erectile
dysfunction induced by arsenic exposure through well water consumption in Taiwan. Environ Health
Perspect 116: 532-536. http://dx.doi.org/10.1289/ehp. 10930
Hsieh. YC: Hsieh. FI: Lien. LM: Chou. YL: Chiou. HY: Chen. CJ. (2008b). Risk of carotid atherosclerosis
associated with genetic polymorphisms of apolipoprotein E and inflammatory genes among arsenic exposed
residents in Taiwan. Toxicol Appl Pharmacol 227: 1-7. http://dx.doi.0rg/10.1016/i.taap.2007.10.013
Islam. MR: Khan. I: Attia. J: Hassan. SMN: McEvoy. M: D'Este. C: Azim. S: Akhter. A: Akter. S: Shahidullah.
SM: Milton. AH. (2012). Association between hypertension and chronic arsenic exposure in drinking water:
a cross-sectional study in Bangladesh. Int J Environ Res Public Health 9: 4522-4536.
http://dx.doi.org/10.3390/iierph9124522
Jensen. GE: Hansen. ML. (1998). Occupational arsenic exposure and glycosylated haemoglobin. Analyst 123:
77-80. http://dx.doi.org/10.1039/a705699k
Jones. MR: Tellez-Plaza. M: Sharrett AR: Guallar. E: Navas-Acien. A. (2011). Urine arsenic and hypertension
in US adults: The 2003-2008 National Health and Nutrition Examination Survey. Epidemiology 22: 153-161.
http://dx.doi.org/10.1097/EDE.Ob013e318207fdf2
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Karim. MR: Rahman. M: Islam. K: Mamun. AA: Hossain. S: Hossain. E: Aziz. A: Yeasmin. F: Agarwal S:
Hossain. MI: Saud. ZA: Nikkon. F: Hossain. M: Mandal A: Jenkins. RO: Haris. PI: Miyataka. H: Himeno.
S: Hossain. K. (2013). Increases in oxidized low density lipoprotein and other inflammatory and adhesion
molecules with a concomitant decrease in high density lipoprotein in the individuals exposed to arsenic in
Bangladesh. Toxicol Sci. http://dx.doi.org/10.1093/toxsci/kftl30
Kim NH: Mason. CC: Nelson. RG: Afton. SE: Essader. AS: Medlin. JE: Levine. KE: Hoppin. JA: Lin. C:
Knowler. WC: Sandier. DP. (2013). Arsenic Exposure and Incidence of Type 2 Diabetes in Southwestern
American Indians. Am J Epidemiol. http://dx.doi.org/10.1093/aie/kws329
Kim Y: Lee. BK. (2011). Association between urinary arsenic and diabetes mellitus in the Korean general
population according to KNHANES 2008. Sci Total Environ 409: 4054-4062.
http://dx.doi.0rg/10.1016/i.scitotenv.2011.06.003
Kunrath. J: Gurzau. E: Gurzau. A: Goessler. W: Gelmann. ER: Thach. TT: Mccarty. KM: Yeckel CW. (2013).
Blood pressure hyperreactivity: an early cardiovascular risk in normotensive men exposed to low-to-
moderate inorganic arsenic in drinking water. JHypertens 31: 361-369.
http://dx.doi.org/10.1097/HJH.Ob013e32835cl75f
Kwok. RK: Mendola. P: Liu. ZY: Savitz. DA: Heiss. G: Ling. HL: Xia. Y: Lobdell D: Zeng. D: Thorp. JM. Jr:
Creason. JP: Mumford. JL. (2007). Drinking water arsenic exposure and blood pressure in healthy women of
reproductive age in Inner Mongolia, China. Toxicol Appl Pharmacol 222: 337-343.
http://dx.doi.0rg/10.1016/i.taap.2007.04.003
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Li. WF: Sun. CW: Cheng. TJ: Chang. KH: Chen. CJ: Wang. SL. (2009). Risk of carotid atherosclerosis is
associated with low serum paraoxonase (PON1) activity among arsenic exposed residents in Southwestern
Taiwan. Toxicol Appl Pharmacol 236: 246-253. http://dx.doi.0rg/10.1016/i.taap.2009.01.019
Li. X: Li. B: Xi. S: Zheng. Q: Lv. X: Sun. G. (2013a). Prolonged environmental exposure of arsenic through
drinking water on the risk of hypertension and type 2 diabetes. Environ Sci Pollut Res Int 20: 8151-8161.
http://dx.doi.org/10.1007/sll356-013-1768-9
Li. X: Li. B: Xj S: Zheng. Q: Wang. D: Sun. G. (2013b). Association of urinary monomethylated arsenic
concentration and risk of hypertension: a cross-sectional study from arsenic contaminated areas in
northwestern China. Environ Health 12: 37. http://dx.doi.org/10.1186/1476-069X-12-37
Liao. YT: Chen. CJ: Li. WF: Hsu. LY: Tsai. LY: Huang. YU Sua CW: Chen. WJ: Wang. SL. (2012). Elevated
lactate dehydrogenase activity and increased cardiovascular mortality in the arsenic-endemic areas of
southwestern Taiwan. Toxicol Appl Pharmacol. http://dx.doi.0rg/10.1016/i.taap.2012.04.028
Moon. KA: Guallar. E: Umans. JG: Devereux. RB: Best LG: Francesco ni. KA: Goessler. W: Pollak. J:
Silbergeld. EK: Howard. BV: Navas-Acien. A. (2013). Association between exposure to low to moderate
arsenic levels and incident cardiovascular disease: A prospective cohort study. Ann Intern Med 159: 649-
659. http://dx.doi.org/10.7326/0003-4819-159-10-201311190-00719
Mordukhovich. I: Wright. RO: Amarasiriwardena. C: Baia. E: Baccarelli A: Suh. H: Sparrow. D: Vokonas. P:
Schwartz. J. (2009). Association between low-level environmental arsenic exposure and QT interval duration
in a general population study. Am J Epidemiol 170: 739-746. http://dx.doi.org/10.1093/aie/kwpl91
Mumford. JL: Wu. K: Xia. Y: Kwok. R: Yang. Z: Foster. J: Sanders. WE. (2007). Chronic arsenic exposure and
cardiac repolarization abnormalities with QT interval prolongation in a population-based study. Environ
Health Perspect 115: 690-694. http://dx.doi.org/10.1289/ehp.9686
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Osorio-Yanez. C: Ayllon-Vergara. JC: Aguilar-Madrid. G: Arreola-Mendoza. L: Hernandez-Castellanos. E:
Barrera-Hernandez. A: De Vizcava-Ruiz. A: Del Razo. LM. (2013). Carotid intima-media thickness and
plasma asymmetric dimethylarginine in Mexican children exposed to inorganic arsenic. Environ Health
Perspect 121: 1090-1096. http://dx.doi.org/10.1289/ehp. 1205994
Rahman. M: Tondel M: Ahmad. SA: Chowdhury. IA: Faruquee. MH: Axelson. O. (1999). Hypertension and
arsenic exposure in Bangladesh. Hypertension 33: 74-78. http://dx.doi.Org/10.1161/01.HYP.33.l.74
Sohel. N: Persson. LA: Rahman. M: Streatfield. PK: Yunus. M: Ekstrom. EC: Vahter. M. (2009). Arsenic in
drinking water and adult mortality: a population-based cohort study in rural Bangladesh. Epidemiology 20:
824-830. http://dx.doi.org/10.1097/EDE.Ob013e3181bb56ec
Tseng. CH: Chong. CK: Chen. CJ: Taj TY. (1996). Dose-response relationship between peripheral vascular
disease and ingested inorganic arsenic among residents in blackfoot disease endemic villages in Taiwan.
Atherosclerosis 120: 125-133. htto://dx.doi.org/10.1016/0021-9150(95)05693-9
Tseng. CH: Chong. CK: Chen. CJ: Taj TY. (1997). Lipid profile and peripheral vascular disease in arseniasis-
hyperendemic villages in Taiwan. Angiology 48: 321-335. http://dx.doi.org/10.1177/000331979704800405
Tseng. CH: Chong. CK: Tseng. CP: Hsueh. YM: Chiou. HY: Tseng. CC: Chen. CJ. (2003). Long-term arsenic
exposure and ischemic heart disease in arseniasis-hyperendemic villages in Taiwan. Toxicol Lett 137: 15-21.
http://dx.doi.org/10.1016/80378-4274(02)00377-6
Wade. TJ: Xia. Y: Wu. K: Li. Y: Nine. Z: Le. XC: Lu. X: Feng. Y: He. X: Mumford. JL. (2009). Increased
mortality associated with well-water arsenic exposure in Inner Mongolia, China. Int J Environ Res Public
Health6: 1107-1123. http://dx.doi.org/10.3390/ijerph6031107
Wang. CH: Chen. CL: Hsiao. CK: Chiang. FT: Hsu. LI: Chiou. HY: Hsueh. YM: Wu. MM: Chea CJ. (2009).
Increased risk of QT prolongation associated with atherosclerotic diseases in arseniasis-endemic area in
southwestern coast of Taiwan. Toxicol Appl Pharmacol 239: 320-324.
http://dx.doi.0rg/10.1016/i.taap.2009.06.017
Wang. CH: Jeng. JS: Yip. PK: Chea CL: Hsu. LI: Hsueh. YM: Chiou. HY: Wu. MM: Chen. CJ. (2002).
Biological gradient between long-term arsenic exposure and carotid atherosclerosis. Circulation 105: 1804-
1809. http://dx.doi.org/10.1161/01.CIR.0000015862.64816.B2
Wang. SL: Li. WF: Chen. CJ: Huang. YL: Chea JW: Chang. KH: Tsai. LY: Chou. KM. (2011). Hypertension
incidence after tap-water implementation: a 13-year follow-up study in the arseniasis-endemic area of
southwestern Taiwan. Sci Total Environ 409: 4528-4535. http://dx.doi.0rg/10.1016/i.scitotenv.2011.07.058
Wu. MM: Chiou. HY: Hsueh. YM: Hong. CT: Su. CL: Chang. SF: Huang. WL: Wang. HT: Wang. YH: Hsieh.
YC: Chen. CJ. (2006). Effect of plasma homocysteine level and urinary monomethylarsonic acid on the risk
of arsenic-associated carotid atherosclerosis. Toxicol Appl Pharmacol 216: 168-175.
http://dx.doi.0rg/10.1016/i.taap.2006.05.005
Wu. MM: Chiou. HY: Lee. TC: Chen. CL: Hsu. LI: Wang. YH: Huang. WL: Hsieh. YC: Yang. TY: Lee. CY:
Yip. PK: Wang. CH: Hsueh. YM: Chen. CJ. (2010). GT-repeat polymorphism in the heme oxygenase-1 gene
promoter and the risk of carotid atherosclerosis related to arsenic exposure. J Biomed Sci 17: 70.
http://dx.doi.org/10.1186/1423-0127-17-70
Xia. Y: Wade. TJ: Wu. K: Li. Y: Ning. Z: Le. XC: He. X: Chen. B: Feng. Y: Mumford. JL. (2009). Well water
arsenic exposure, arsenic induced skin-lesions and self-reported morbidity in Inner Mongolia. Int J Environ
Res Public Health 6: 1010-1025. http://dx.doi.org/10.3390/iierph6031010
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.3 Summary of Observational Epidemiology Studies for
Health Effect Category: Clinical Chemistry and
Urinalysis
Summary of Observational Epidemiology Studies for Health Effect Category: Clinical Chemistry and Urinalysis
Reference and Study
Design
Casale et al. (2013)
Study Type: cross-
sectional
Location: Italy (Central
Italy)
Population: municipal
policemen and police
drivers
n cases: n/a
n control: n/a
Chen et al. (ZOllc)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: HEALS
n total: 10,957
Exposure Measures
Exposure Surrogate: urine
Exposure Description: spot urine
samples collected from each worker at
the end of the work shift for 4 working
days in succession
Population-Level Exposure:
2.6-54.7 ng/g-creatinine range
Exposure Surrogate: drinking water
Exposure Description: water samples
from all 5,966 wells in the area were
tested at baseline; samples below LOD
reanalyzed using ICP-MS with a detection
limit of 0.1 ng/L
Population-Level Exposure:
0.1-864 ng/L range
Exposure Surrogate: urine
Exposure Description: total arsenic levels
were measured on spot urine samples
obtained at baseline and at each follow-
up visit (every 2 years)
Population-Level Exposure:
Results
Outcome: ALT/GPT
log total urinary arsenic concentration, ug/g-
creatinine
Exp. Level n adiBeta (CD
continuous NR 0.374 n/a
Stat Method: multiple linear regression
Outcome: AST/GOT
log total urinary arsenic concentration, ug/g-
creatinine
arsenic not significantly associated with AT/GOT
Outcome: y-GT (GGT)
log total urinary arsenic concentration, ug/g-
creatinine
arsenic not significantly associated with y-GT
Outcome: proteinuria
baseline well arsenic concentration (quintiles),
H9/L
Exp. Level n adjOR (Cl)
0.1-7 NR 1 n/a
8-39 NR 1.01 0.77, 1.27
40-91 NR 1.33 0.97, 1.57
92-179 NR 1.54 1.18, 1.89
180-864 NR 1.65 1.26,2
Stat Method: unconditional logistic regression
Outcome: proteinuria
change in urinary arsenic concentration since last
visit, ng/L
Exp. Level n HR (Cl)
<-70 NR 0.84 0.67, 1.04
-70 to -17 NR 0.91 0.74,1.12
-16 to 15 NR 1 n/a
16 to 68 NR 1.17 0.97,1.42
>69 NR 1.43 1.17,1.74
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Clinical Chemistry and Urinalysis
Reference and Study
Design
Kim et al. (2013)
Study Type: case-
control (nested)
Location: United States
(Arizona)
Population:
longitudinal study
participants who
developed diabetes
within 10 years of
initial screening
n cases: 150
n control: 150
Exposure Measures
1-206 ng/L range
Exposure Surrogate: urine
Exposure Description: concentrations of
arsenic (total and inorganic) and
metabolites measured in stored urine
samples obtained at the baseline
examination; adjusted for urinary
creatinine
Population-Level Exposure:
21.1 ng/L median, 15.3-29.4 ng/L 25th
percentile
Results
Stat Method: Cox proportional hazard models
baseline urinary arsenic concentration (quintiles),
Exp. Level n adiOR (CD
1-36 NR 1 n/a
37-66 NR 1.48 1.12, 1.96
67-114 NR 1.65 1.25,2.16
115-205 NR 1.53 1.16,2.02
>206 NR 1.65 1.24,2.20
Stat Method: unconditional logistic regression
Outcome: mean albumin:creatinine ratio
total arsenic concentration, u.g/L
albumin:creatinine ratio similar in cases and
controls
--: not reported; n: number of cases (when presented in Results column)
5.3.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Clinical Chemistry and Urinalysis
Casale. T: Rosati. MV: Ciarrocca. M: Samperi. I: Andreozzj G: Schifano. MP: Capozzella. A: Pimpinella. B:
Tomei G: Caciari. T: Tomei. F. (2013). Assessment of liver function in two groups of outdoor workers
exposed to arsenic. Int Arch Occup Environ Health, http://dx.doi.org/10.1007/s00420-013-0914-5
Chen. Y: Parvez. F: Liu. M: Pesola. GR: Gamble. MV: Slavkovich. V: Islam. T: Ahmed. A: Hasan. R: Graziano.
JH: Ahsan. H. (2011). Association between arsenic exposure from drinking water and proteinuria: results
from the Health Effects of Arsenic Longitudinal Study. Int J Epidemiol. http://dx.doi.org/10.1093/ije/dyr022
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Kim NH: Mason. CC: Nelson. RG: Afton. SE: Essader. AS: Medlin. JE: Levine. KE: Hoppin. JA: Lin. C:
Knowler. WC: Sandier. DP. (2013). Arsenic Exposure and Incidence of Type 2 Diabetes in Southwestern
American Indians. Am J Epidemiol. http://dx.doi.org/10.1093/aie/kws329
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.4 Summary of Observational Epidemiology Studies for
Health Effect Category: Developmental Effects including
Neurodevelopmental
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Calderon et al. (2001)
Study Type: cross-
sectional
Location: Mexico (San
Luis Potosi)
Population: children
attending Morales
elementary school 1.5
km from smelter and
comparison group
attending Martinez
school 7 km away
n cases: 41
n control: 39
Exposure Surrogate: urine
Exposure Description: first morning void
samples collected; standardized to
urinary creatinine; log-transformed;
recovery 98 +/- 4%
Population-Level Exposure:
40.28-62.91 ng/g-creatinine range
Outcome: concepts (similarities, comprehension,
vocabulary)
mean urinary arsenic concentration, ug/g-
creatinine
Exp. Level n corr (CD
coeff
40.28 NR -0.12 n/a
(Martinez)
62.91 NR -0.31 n/a
(Morales)
Stat Method: partial correlation coefficient
calculation
Outcome: IQ (full)
mean urinary arsenic concentration, ug/g-
creatinine
Exp. Level ri corr (CD
coeff
40.28 NR 0.04 n/a
(Martinez)
62.91 NR -0.33 n/a
(Morales)
Stat Method: partial correlation coefficient
calculation
Outcome: IQ (performance)
mean urinary arsenic concentration, u.g/g-
creatinine
Exp. Level n corr (CD
coeff
40.28 NR 0.22 n/a
(Martinez)
62.91 NR -0.24 n/a
(Morales)
Stat Method: partial correlation coefficient
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
calculation
Outcome: IQ (verbal)
mean urinary arsenic concentration, ug/g-
creatinine
Exp. Level n corr (CD
coeff
40.28 NR -0.24 n/a
(Martinez)
62.91 NR -0.43 n/a
(Morales)
Stat Method: partial correlation coefficient
calculation
Outcome: knowledge (vocabulary, information,
arithmetic)
mean urinary arsenic concentration, u.g/g-
creatinine
Exp. Level n corr (Cl)
coeff
40.28 NR -0.17 n/a
(Martinez)
62.91 NR -0.41 n/a
(Morales)
Stat Method: partial correlation coefficient
calculation
Outcome: sequential (arithmetic, digit span,
coding)
mean urinary arsenic concentration, u.g/g-
creatinine
Exp. Level n corr (Cl)
coeff
40.28 NR 0.2 n/a
(Martinez)
62.91 NR -0.31 n/a
(Morales)
Stat Method: partial correlation coefficient
calculation
Outcome: spatial (object assembly, block design,
picture completion)
mean urinary arsenic concentration, ug/g-
creatinine
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Exp. Level
n
NR
NR
corr (CD
coeff
n/a
40.28 NR 0.01
(Martinez)
62.91 NR -0.22 n/a
(Morales)
Stat Method: partial correlation coefficient
calculation
Gardner etal. (2013)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: children in
Maternal and Infant
Nutrition Interventions
in Matlab (MINIMat)
cohort
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration, samples collected from
1.5- and 5-year-old children
Population-Level Exposure:
35-84 ng/L range
Outcome: height
urinary arsenic exposure, ug/L
Exp. Level n ad juste (CD
dAR
low (< 5th NR 0 n/a
percentile)
high (> 95th NR -0.5 -1.2,0.21
percentile)
Stat Method: linear regression model
Outcome: height-for-age z-score
urinary arsenic exposure,
inverse association with concurrent exposure to
cadmium and arsenic
Outcome: peak height velocity
urinary arsenic exposure, ug/L
inverse association with concurrent exposure to
cadmium and arsenic
Outcome: peak weight velocity
urinary arsenic exposure, ug/L
inverse association with concurrent exposure to
cadmium and arsenic
Outcome: weight
urinary arsenic exposure, ug/L
Exp. Level n ad juste (Cl)
dAR
low (< 5th NR 0 n/a
percentile)
high (> 95th NR -0.33 -0.60,-0.06
percentile)
Stat Method: linear regression model
Outcome: weight-for-age z-score
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-71 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
urinary arsenic exposure, ug/L
inverse association with concurrent exposure to
cadmium and arsenic
Guanetal. (2012)
Study Type: cross-
sectional
Location: China
(Dalian)
Population: 125 pairs
of mothers and their
infants with prenatal
exposure to arsenic
n cases: n/a
n control: n/a
Exposure Surrogate: blood
Exposure Description: arsenic
concentrations in maternal cubital vein
blood and infant umbilical cord vein
blood collected immediately after
admission (mother) and after clamping
and before delivery of the placenta
(infant); mean values of maternal and
cord blood arsenic concentrations: 6.91
and 5.41 ug/L, respectively; median
values: 5.30 and 3.71 ug/L, respectively
Population-Level Exposure:
mean maternal blood: 6.91 ng/l; mean
cord blood: 5.41
Outcome: birth height
maternal arsenic blood concentration,
Exp. Level n adiBeta (CD
continuous NR -0.1 n/a
Stat Method: multiple linear regression
Outcome: birth weight
maternal arsenic blood concentration, ug/L
Exp. Level n adjBeta (Cl)
continuous NR -0.02 n/a
Stat Method: multiple linear regression
Outcome: chest circumference
maternal arsenic blood concentration,
Exp. Level n adjBeta (Cl)
continuous NR -0.1 n/a
Stat Method: multiple linear regression
Outcome: head circumference
fetal arsenic cord blood concentrations, ug/L
Exp. Level n adjBeta (Cl)
continuous NR -0.06 n/a
Stat Method: multiple linear regression
Hamadani et al. (2010)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: Children of
pregnant women from
a MINIMat trial cohort
in Matlab, Bangladesh
n total: 1,745
Exposure Surrogate: urine
Exposure Description: child's urine
collected at 18 months and analyzed for
arsenic and metabolites MMA and DMA;
concentrations adjusted by specific
gravity (1.009 g/ml)
Population-Level Exposure:
35 ug/L median, 18.2-80.8 ug/L 25th
percentile
Outcome: language comprehension
children's urinary arsenic concentration, ug/L
Exp. Level ri regr (Cl)
coeff
continuous NR 0.25 -0.6,1
Stat Method: multiple linear regression
analysis
Outcome: language expression
children's urinary arsenic concentration, ug/L
Exp. Level n regr (Cl)
coeff
continuous NR -0.001 -0.03,0.03
Stat Method: multiple linear regression
analysis
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-72 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Outcome: mental development index
children's urinary arsenic concentration, ug/L
Exp. Level ri regr (CD
coeff
continuous NR 0.3 -0.9,1.5
Stat Method: multiple linear regression
analysis
Outcome: psychomotor development index
children's urinary arsenic concentration, ug/L
Exp. Level ri regr (CD
coeff
continuous NR -0.07 -1.5,1.3
Stat Method: multiple linear regression
analysis
Exposure Surrogate: urine
Exposure Description: maternal urine
collected at gestation weeks 8 and 30
and analyzed for total arsenic; mean of 8-
and 30-week concentrations used to
represent exposure; concentrations
adjusted by specific gravity (1.012 g/ml)
Population-Level Exposure:
94.4 ug/L median, 45-216 ug/L 25th
percentile
Outcome: language comprehension
maternal urinary arsenic concentration, ug/L
Exp. Level n regr (CD
coeff
continuous NR -0.3 -1.3,0.6
Stat Method: multiple linear regression
analysis
Outcome: language expression
maternal urinary arsenic concentration, ug/L
Exp. Level ri regr (CD
coeff
continuous NR -0.009 -0.04,0.02
Stat Method: multiple linear regression
analysis
Outcome: mental development index
maternal urinary arsenic concentration, ug/L
Exp. Level ri regr (CD
coeff
continuous NR 0.5 -0.9,1.8
Stat Method: multiple linear regression
analysis
Outcome: psychomotor development index
maternal urinary arsenic concentration, ug/L
Exp. Level ri regr (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-73 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
coeff
continuous NR 0.3 -1.3,1.9
Stat Method: multiple linear regression
analysis
Hamadani et al. (2011)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: children in
Maternal and Infant
Nutrition Interventions
in Matlab (MINIMat)
cohort
n total: 2,260
Exposure Surrogate: maternal urine
Exposure Description: urinary arsenic
levels measured gestational weeks 8 and
30 and characterized into quartiles
Population-Level Exposure:
80 ng/L median, 25-400 ng/L 10th
percentile
Outcome: full scale IQ(FSIQ) score
maternal urinary arsenic concentration
(gestation week 30) (quartiles), u.g/L
Exp. Level
0-40
41-82
83-228
>228
NR
NR
NR
NR
mean
76.7
75.6
74.4
73.9
M
n/a
n/a
n/a
n/a
Stat Method: ANOVA
maternal urinary arsenic concentration
(gestation week 8) (quartiles), ug/L
Exp. Level
0-36
37-39
80-206
>206
ri
NR
NR
NR
NR
mean
76.6
75.9
74.2
74.2
M
n/a
n/a
n/a
n/a
Stat Method: ANOVA
loglO maternal urinary arsenic concentration
(gestation week 30; females), ug/L
Exp. Level n adiBeta (CD
continuous NR -1.3 -2.4,-0.3
Stat Method: linear regression
loglO maternal urinary arsenic concentration
(gestation week 30; males), ug/L
Exp. Level n ad i Beta (CD
continuous NR 0.1 -0.9,1.1
Stat Method: linear regression
loglO maternal urinary arsenic concentration
(gestation week 8; females), ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.9 -2.0,-0.2
Stat Method: linear regression
loglO maternal urinary arsenic concentration
(gestation week 8; males), ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.2 -1.2,0.9
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-74 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Stat Method: linear regression
Outcome: performance intelligence quotient
(PIQ)
maternal urinary arsenic concentration
(gestation week 30) (quartiles), ug/L
Exp. Level n mean (CD
0-40 NR 77.3 n/a
41-82 NR 76.6 n/a
83-228 NR 76 n/a
>228 NR 75.2 n/a
Stat Method: ANOVA
maternal urinary arsenic concentration
{gestation week 8) (quartiles), ug/L
Exp. Level n mean (CD
0-36 NR 77.6 n/a
37-39 NR 76.1 n/a
80-206 NR 75.2 n/a
>206 NR 76 n/a
Stat Method: ANOVA
Outcome: verbal IQ (VIQ) score
maternal urinary arsenic concentration
(gestation week 30) (quartiles), ug/L
Exp. Level n mean (CD
0-40 NR 81.5 n/a
41-82 NR 80.2 n/a
83-228 NR 79 n/a
>228 NR 78.8 n/a
Stat Method: ANOVA
maternal urinary arsenic concentration
(gestation week 8) (quartiles), ug/L
Exp. Level n mean (CD
0-36 NR 81.2 n/a
37-39 NR 79.5 n/a
80-206 NR 79.1 n/a
>206 NR 78.6 n/a
Stat Method: ANOVA
loglO maternal urinary arsenic concentration
(gestation week 30; females), ug/L
Exp. Level n adiBeta (CD
continuous NR -1.5 -2.6, -0.4
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-75 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Stat Method: linear regression
loglO maternal urinary arsenic concentration
(gestation week 30; males), ug/L
Exp. Level n adiBeta (CD
continuous NR 0.06 -1.0,1.1
Stat Method: linear regression
loglO maternal urinary arsenic concentration
(gestation week 8; females), ug/L
Exp. Level n ad i Beta (CD
continuous NR -1.2 -2.4,-0.06
Stat Method: linear regression
loglO maternal urinary arsenic concentration
(gestation week 8; males), ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.6 -1.7,0.5
Stat Method: linear regression
Exposure Surrogate: urine
Exposure Description: urinary arsenic
levels measured in children at 1.5 and 5
years and characterized into quartiles;
collected during home interviews;
median urinary As: 35 u.g/L and 51 u.g/L
at 1.5 and 5 years, respectively
Population-Level Exposure:
0-120 ug/L range
Outcome: full scale IQ(FSIQ) score
urinary arsenic concentration (at 1.5 years)
(quartiles), ug/L
Exp. Level
0-17
18-35
36-80
>80
n
NR
NR
NR
NR
mean
77.1
74.9
74.1
74.3
M
n/a
n/a
n/a
n/a
Stat Method: ANOVA
urinary arsenic concentration (at 5 years)
(quartiles), ug/L
Exp. Level
0-29
30-50
51-120
>120
NR
NR
NR
NR
mean
76.6
75.6
74.1
74.3
M
n/a
n/a
n/a
n/a
Stat Method: ANOVA
loglO urinary arsenic concentration (at 1.5 years;
females), ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.7 -1.9,0.4
Stat Method: linear regression
loglO urinary arsenic concentration (at 5 years;
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-76 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
females), ug/L
Exp. Level n adiBeta (CD
continuous NR -1.4 -2.7, -0.1
Stat Method: linear regression
loglO urinary arsenic concentration (at 1.5 years;
males), ug/L
Exp. Level n adiBeta (CD
continuous NR -0.5 -1.6,0.6
Stat Method: linear regression
loglO urinary arsenic concentration (at 5 years;
males), ug/L
Exp. Level n adiBeta (CD
continuous NR 0.7 -0.5, 1.8
Stat Method: linear regression
Outcome: performance intelligence quotient
(PIQ)
urinary arsenic concentration (at 1.5 years)
(quartiles), ug/L
Exp. Level n mean (CD
0-17 NR 78 n/a
18-35 NR 76.2 n/a
36-80 NR 75.5 n/a
>80 NR 75.7 n/a
Stat Method: ANOVA
urinary arsenic concentration (at 5 years)
(quartiles), ug/L
Exp. Level n mean (CD
0-29 NR 77.2 n/a
30-50 NR 76.6 n/a
51-120 NR 75.6 n/a
>120 NR 76 n/a
Stat Method: ANOVA
Outcome: verbal IQ (VIQ) score
urinary arsenic concentration (at 1.5 years)
(quartiles), ug/L
Exp. Level n mean (CD
0-17 NR 78 n/a
18-35 NR 76.2 n/a
36-80 NR 75.5 n/a
>80 NR 75.7 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-77 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Stat Method: ANOVA
urinary arsenic concentration (at 5 years)
(quartiles),
Exp. Level
0-29
30-50
51-120
>120
n
NR
NR
NR
NR
mean
81.6
80.1
78.8
78.8
M
n/a
n/a
n/a
n/a
Stat Method: ANOVA
loglO urinary arsenic concentration (at 1.5 years;
females), ug/L
Exp. Level n ad I Beta (CD
continuous NR -0.9 -2.1,0.4
Stat Method: linear regression
loglO urinary arsenic concentration (at 5 years;
females), ug/L
Exp. Level n adiBeta (CD
continuous NR -2.4 -3.8,-1.1
Stat Method: linear regression
loglO urinary arsenic concentration (at 1.5 years;
males), ug/L
Exp. Level n ad i Beta (CD
continuous NR -1 -2.1,0.16
Stat Method: linear regression
loglO urinary arsenic concentration (at 5 years;
males), ug/L
Exp. Level n ad i Beta (CD
continuous NR 0.5 -0.7,1.7
Stat Method: linear regression
Hopenhavn et al.
(2003)
Study Type: cohort
(prospective)
Location: Chile
(Antofagasta and
Valparaiso)
Exposure Surrogate: drinking water
Exposure Description: drinking water
samples collected in three households
per city; water samples verified with local
water company historical data;
consistent exposure in each city verified
using spot urine samples of subgroup of
19 women per city
Population-Level Exposure:
Outcome: birth weight
drinking water arsenic concentration by city of
residence, ug/L
Exp. Level n ad i Beta (CD
Valparaiso NR NR n/a
Antofagasta NR -57 -123,9
Stat Method: analysis of covariance; unclear
which factors were adjusted for during
analysis
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-78 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Population: pregnant
women aged 18 to 45
years enrolled at local
clinics
n exposed: 424
n reference: 420
n total: 844
0.5-40 ng/L range
Huvck et al. (2007)
Study Type: cohort
(prospective)
Location: Bangladesh
(Sirajdikhan Upazila of
the Munshiganj
District)
Population: pregnant
women in proximity to
Sirajdikhan Community
Clinic
n total: 49
Exposure Surrogate: hair
Exposure Description: arsenic
concentration in hair; samples collected
using titanium nitride scissors; stored in
paper envelopes; rinsed; external
contamination of samples removed by
sonication
Population-Level Exposure:
0.09-3.28 ng/g range
Outcome: birth weight
arsenic concentration in maternal hair at first
visit, ng/g
Exp. Level n adjOR (CD
continuous NR 0.4 0.12, 1.35
Stat Method: logistic regression
arsenic concentration in maternal hair within 2
weeks after birth, ng/g
Exp. Level n adjOR (CD
continuous NR 0.45 0.1,2.04
Stat Method: logistic regression
arsenic concentration in maternal hair at first
visit, ng/g
Exp. Level n adiBeta (CD
continuous NR -193.5 n/a
Stat Method: multivariate linear regression
Exposure Surrogate: toenails
Exposure Description: arsenic
concentration in toenails; samples
collected using titanium nitride scissors;
stored in paper envelopes; rinsed;
external contamination of samples
removed by sonication
Population-Level Exposure:
0.19-8.04 |jg/g range
Outcome: birth weight
arsenic concentration in maternal nail at first
visit, ng/g
Exp. Level n adjOR (Cl)
continuous NR 0.83 0.48, 1.42
Stat Method: logistic regression
Jin et al. (2013)
Study Type: case-
control
Exposure Surrogate: placenta
Exposure Description: arsenic levels in
placentas collected upon
delivery/pregnancy termination
Outcome: neural tube defects: anencephaly and
spina bifida
arsenic concentration in placental samples, ng/g
Exp. Level n adjOR (Cl)
<8.93 NR NR n/a
>8.93 NR 0.88 0.43, 1.78
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-79 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Location: China (rural
area of Shanxi
Province)
Population: Chinese
women living in study
area with newborns
diagnosed with neural
tube defects
n cases: 80
n control: 50
Population-Level Exposure:
8.93 ng/g median
Stat Method: multivariate logistic regression
analyses
Khan et al. (2012)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar (Haizadi,
Uchitpur, and
Khagkanda unions))
Population: Children
enrolled in ongoing
school intervention
study at 14 elementary
schools
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration in well-water samples
from each child's home
Population-Level Exposure:
119.5 ng/L mean 147.5SD
Outcome: Bangla language score
water arsenic (dichotomized),
Exp. Level n adiBeta (CD
dichotomized NR -1.71 -4.77,1.34
Stat Method: spline regression models
Outcome: English language score
water arsenic (dichotomized), \ng/L
Exp. Level n ad i Beta (CD
dichotomized NR -0.73 -4.32,2.86
Stat Method: spline regression models
Outcome: math score
water arsenic (dichotomized), \ng/L
Exp. Level n ad i Beta (CD
dichotomized NR 0.56 -2.98,4.10
Stat Method: spline regression models
Kippler et al. (2012)
Study Type: cross-
sectional
Location: Bangladesh
(Matlab)
Population: pregnant
women and their
children enrolled in
Maternal and Infant
Nutrition Interventions
Exposure Surrogate: urine
Exposure Description: individual urine
samples collected at gestational weeks 8
(range 6-14 weeks) and 30 (range 24-40
weeks); one sample below LOD
Population-Level Exposure:
160 ng/L mean
Outcome: abdominal circumference
log transformed urinary arsenic concentration,
Exp. Level n ad i Beta (CD
continuous NR 0.022 -0.024,0.069
Stat Method: mixed effect linear regression,
log transformed
Outcome: biparietal diameter
log transformed urinary arsenic concentration,
Exp. Level n ad i Beta (CD
continuous NR -0.012 -0.047,0.024
Stat Method: mixed effect linear regression,
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-80 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
of Matlab (MINIMat)
visited monthly by
community health
research worker
n cases: n/a
n control: n/a
log transformed
Outcome: femur length
log transformed urinary arsenic concentration,
Exp. Level n ad i Beta (CD
continuous NR -0.0089 -0.044,0.027
Stat Method: mixed effect linear regression,
log transformed
Outcome: head circumference
log transformed urinary arsenic concentration,
ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.0082 -0.047,0.031
Stat Method: mixed effect linear regression,
log transformed
Outcome: occipito-frontal diameter
log transformed urinary arsenic concentration,
Exp. Level n ad i Beta (CD
continuous NR -0.01 -0.045,0.025
Stat Method: mixed effect linear regression,
log transformed
Kwoketal. (2006)
Study Type: cross-
sectional
Location: Bangladesh
(Faridpur district
(Faridpur Sadar upazila)
and Chandpur district
(Matlab and Shahrasti
upazilas))
Population: residents
of 261 highly arsenic-
contaminated villages
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: water samples
collected during in-home interview from
main drinking water source used during
pregnancy
Population-Level Exposure:
0.5-668 ppb range
Outcome: birth defects
drinking water arsenic concentration, ppb
Exp. Level n adjOR M
continuous NR 1.005 1.001, 1.010
Stat Method: multivariate logistic regression
drinking water arsenic concentration, ppb
Exp. Level
11-50
51-100
101-200
201-300
>300
2
i
i
i
2
4
Prev
0.6
0.4
0.5
0.2
0.4
1.7
M
n/a
n/a
n/a
n/a
n/a
n/a
Stat Method: prevalence
Outcome: low birth weight
drinking water arsenic concentration, ppb
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-81 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Exp. Level n adiOR (CD
continuous NR 0.999 0.997, 1.000
Stat Method: multivariate logistic regression
drinking water arsenic concentration, ppb
Exp. Level n Prev (CD
<10 40 12.3 n/a
11-50 18 7.8 n/a
51-100 17 7.8 n/a
101-200 44 8.8 n/a
201-300 53 10.7 n/a
>300 22 9.3 n/a
Stat Method: prevalence
Outcome: stunting
drinking water arsenic concentration, ppb
Exp. Level n adiOR (CD
continuous NR 1 1.00, 1.001
Stat Method: multivariate logistic regression
drinking water arsenic concentration, ppb
Exp. Level n Prev (CD
<10 146 44.8 n/a
11-50 102 44.3 n/a
51-100 89 40.6 n/a
101-200 256 51.3 n/a
201-300 265 53.4 n/a
>300 146 61.9 n/a
Stat Method: prevalence
Outcome: under-weight
drinking water arsenic concentration, ppb
Exp. Level n adiOR (CD
continuous NR 1 0.999, 1.001
Stat Method: multivariate logistic regression
drinking water arsenic concentration, ppb
Exp. Level n Prev (Cl)
<10 126 38.7 n/a
11-50 86 37.4 n/a
51-100 88 40.2 n/a
101-200 227 45.5 n/a
201-300 223 45 n/a
>300 124 52.5 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-82 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Milton et al. (2005)
Study Type: cross-
sectional
Location: Bangladesh
(Comilla, Chandpur,
and Chuadanga
districts)
Population: women
living in study area with
> 1 prior pregnancy
n cases: n/a
n control: n/a
Naharetal. (2014)
Study Type: cross-
sectional
Location: Bangladesh
(Sonargaon thana)
Population:
adolescents from highly
arsenic-contaminated
area
n cases: n/a
n control: n/a
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: single well-water
measurement used to characterize
chronic arsenic exposure; arsenic
concentrations recorded as zero replaced
with 30 ng/L
Population-Level Exposure:
279 ug/L mean 355SD
Exposure Surrogate: drinking water
Exposure Description: water samples
from each respondent's tube well
collected; half the detection limit used as
the value for nondetects
Population-Level Exposure:
71.7 ug/L mean
Exposure Surrogate: urine
Exposure Description: spot urine
samples collected for measurement of
As; half the detection limit used as the
value for nondetects
Results
Stat Method: prevalence
Outcome: neonatal death
drinking water arsenic concentration, ug/L
Exp. Level n adiOR (CD
<50 16 1 n/a
>50 70 1.8 0.9,3.5
51-100 12 2.7 1.1,6.73
>100 58 1.7 0.8,3.3
Stat Method: logistic regression analysis
Outcome: intelligence quotient (IQ) percentile
water arsenic concentration, ug/L
Exp. Level n mean (CD
0.8-10 NR 52.2 n/a
11-50 NR 43.4 n/a
51-100 NR 44 n/a
>100 NR 40.7 n/a
Stat Method: one-way ANOVA, ANCOVA
Outcome: social competence (SC) score
water arsenic concentration, ug/L
Exp. Level n mean (CD
0.8-10 NR 38.6 n/a
11-50 NR 37.6 n/a
51-100 NR 36.1 n/a
>100 NR 35.9 n/a
Stat Method: one-way ANOVA, ANCOVA
Outcome: intelligence quotient (IQ) percentile
urinary arsenic concentration, ug/L
Exp. Level n mean (Cl)
1-137 NR 50.5 n/a
138-400 NR 40.6 n/a
401-1,312 NR 40.9 n/a
Stat Method: one-way ANOVA, ANCOVA
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-83 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Population-Level Exposure:
205.3 ng/L mean
Outcome: social competence (SC) score
urinary arsenic concentration, \ng/L
Exp. Level ri mean (CD
1-137 NR 39 n/a
138-400 NR 35.2 n/a
401-1,312 NR 34.7 n/a
Stat Method: one-way ANOVA, ANCOVA
Parvez et al. (2011)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: children 8-
11 years old living in
households within the
HEALS cohort of
villages
n cases: n/a
n control: n/a
Exposure Surrogate: blood
Exposure Description: venous whole
blood samples collected at field clinic and
analyzed for Pb, Mn, Se, and As
concentrations
Population-Level Exposure:
4.8 ng/L mean 3.2SD
Outcome: body coordination
blood arsenic concentration,
Exp. Level n adiBeta (CD
continuous NR -1.61 -2.70,-0.51
Stat Method: linear regression, log
transformed
Outcome: fine manual control
blood arsenic concentration, ng/L
Exp. Level n ad i Beta (CD
continuous NR -1.68 -3.19,-0.18
Stat Method: linear regression, log
transformed
Outcome: manual coordination
blood arsenic concentration, ng/L
Exp. Level n ad i Beta (CD
continuous NR -0.49 -1.73,0.76
Stat Method: linear regression, log
transformed
Outcome: strength and agility
blood arsenic concentration, ng/L
Exp. Level n ad i Beta (CD
continuous NR 0.15 -0.57,0.86
Stat Method: linear regression, log
transformed
Outcome: total motor composite
blood arsenic concentration, ng/L
Exp. Level n adjBeta (Cl)
continuous NR -3.63 -6.72,-0.54
Stat Method: linear regression, log
transformed
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-84 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Exposure Surrogate: drinking water
Exposure Description: water samples
collected from wells of use and analyzed
for As and Mn concentrations
Population-Level Exposure:
43.3 ng/L mean 73.6SD
Outcome: body coordination
drinking water arsenic concentration, \ng/L
Exp. Level n adiBeta (CD
continuous NR -0.43 -0.77,-0.06
Stat Method: linear regression, log
transformed
Outcome: fine manual control
drinking water arsenic concentration, \ng/L
Exp. Level n ad i Beta (CD
continuous NR -0.54 -1.03,-0.05
Stat Method: linear regression, log
transformed
Outcome: manual coordination
drinking water arsenic concentration, \ng/L
Exp. Level n ad i Beta (CD
continuous NR -0.15 -0.52,0.30
Stat Method: linear regression, log
transformed
Outcome: strength and agility
drinking water arsenic concentration, \ng/L
Exp. Level n ad i Beta (CD
continuous NR -0.11 -0.28,0.18
Stat Method: linear regression, log
transformed
Outcome: total motor composite
drinking water arsenic concentration, \ng/L
Exp. Level n ad i Beta (CD
continuous NR -1.18 -2.13,-0.10
Stat Method: linear regression, log
transformed
Exposure Surrogate: toenails
Exposure Description: toenails collected
from individuals and cleaned prior to
analysis
Population-Level Exposure:
Outcome: body coordination
toenail arsenic concentration, \ag/g
Exp. Level n ad i Beta (CD
continuous NR -1.86 -2.83,-0.89
Stat Method: linear regression, log
transformed
Outcome: fine manual control
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-85 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
5.9 ng/g mean 6.3SD
toenail arsenic concentration, ug/g
Exp. Level n ad I Beta (CD
continuous NR -0.84 -2.20,0.50
Stat Method: linear regression, log
transformed
Outcome: manual coordination
toenail arsenic concentration, ug/g
Exp. Level n adiBeta (CD
continuous NR -0.68 -1.80,0.42
Stat Method: linear regression, log
transformed
Outcome: strength and agility
toenail arsenic concentration, ug/g
Exp. Level n ad i Beta (CD
continuous NR -0.38 -1.02,0.25
Stat Method: linear regression, log
transformed
Outcome: total motor composite
toenail arsenic concentration, ug/g
Exp. Level n ad i Beta (CD
continuous NR -3.77 -6.52,-1.03
Stat Method: linear regression, log
transformed
Exposure Surrogate: urine
Exposure Description: urine samples
collected and analyzed for urinary As
concentrations
Population-Level Exposure:
246.5 g creatinine/L mean 183.9SD
Outcome: body coordination
creatinine adjusted urinary arsenic
concentration, g creatinine/L
Exp. Level n ad i Beta (CD
continuous NR -1.6 -2.61,-0.60
Stat Method: linear regression, log
transformed
urinary arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -1.43 -2.67,-0.61
Stat Method: linear regression, log
transformed
Outcome: fine manual control
creatinine adjusted urinary arsenic
concentration, g creatinine/L
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-86 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Exp. Level n ad I Beta (CD
continuous NR -0.88 -2.28,0.51
Stat Method: linear regression, log
transformed
urinary arsenic concentration, u.g/L
Exp. Level n adiBeta (CD
continuous NR -1.03 -2.45,0.39
Stat Method: linear regression, log
transformed
Outcome: manual coordination
creatinine adjusted urinary arsenic
concentration, g creatinine/L
Exp. Level n ad i Beta (CD
continuous NR -0.76 -1.91,0.38
Stat Method: linear regression, log
transformed
urinary arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.73 -1.89,0.44
Stat Method: linear regression, log
transformed
Outcome: strength and agility
creatinine adjusted urinary arsenic
concentration, g creatinine/L
Exp. Level n ad i Beta (CD
continuous NR -0.16 -0.83,0.49
Stat Method: linear regression, log
transformed
urinary arsenic concentration, ug/L
Exp. Level n adjBeta (Cl)
continuous NR -0.19 -0.86,0.48
Stat Method: linear regression, log
transformed
Outcome: total motor composite
creatinine adjusted urinary arsenic
concentration, g creatinine/L
Exp. Level n ad i Beta (Cl)
continuous NR -3.42 -6.27,-0.57
Stat Method: linear regression, log
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-87 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Rahman et al. (2007)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: residents
with pregnancies
between 1991-2000
n total: 29,134
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in all functioning tube
wells for each household sampled;
exposure stratified by quintiles
Population-Level Exposure:
239 ng/L mean
Results
transformed
urinary arsenic concentration, ug/L
Exp. Level n adiBeta (CD
continuous NR -3.59 -6.50, -0.68
Stat Method: linear regression, log
transformed
Outcome: fetal loss
arsenic water concentration during gestation
(quintiles), ug/L
Exp. Level n RR (CD
<10 464 1 n/a
10-166 453 0.98 0.86, 1.11
167-276 488 1.05 0.93, 1.20
277-408 528 1.14 1.01, 1.30
> 409 511 1.1 0.97, 1.25
Stat Method: logistic regression
Outcome: infant death
arsenic water concentration following birth
(quintiles), ug/L
Exp. Level n adjRR (Cl)
<10 229 1 n/a
10-163 269 1.13 0.95, 1.35
164-275 282 1.19 1, 1.42
276-408 308 1.29 1.08, 1.53
> 409 285 1.19 1, 1.41
Stat Method: logistic regression
Outcome: neonatal death
arsenic water concentration following birth
(quintiles), ug/L
Exp. Level n RR (Cl)
<10 NR 1 n/a
10-163 NR 1.11 0.89, 1.38
164-275 NR 1.18 0.95, 1.47
276-408 NR 1.17 0.94, 1.46
> 409 NR 1.21 0.98, 1.50
Stat Method: logistic regression
Outcome: postneonatal death
arsenic water concentration following birth
(quintiles), ug/L
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-88 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Rahman et al. (2009)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: residents
pregnant between
2001-2003 and their
newborn children
n total: 1,578
Rahman et al. (2010)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Exposure Measures
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentrations in samples obtained
during gestation; calculated as the sum
of inorganic arsenic and methylated
metabolites and adjusted by specific
gravity; concentration reported as
average of GW 8 and 30
Population-Level Exposure:
160 ng/L mean 163SD
Exposure Surrogate: urine
Exposure Description: urine samples
collected at ~approx gestation week 8
and gestation week 30; samples adjusted
by specific gravity rather than creatinine;
urine levels divided into quintiles
Results
Exp. Level n adiRR (CD
<10 NR 1 n/a
10-163 NR 1.22 0.91, 1.63
164-275 NR 1.26 0.94, 1.69
276-408 NR 1.55 1.17,2.05
> 409 NR 1.22 0.91, 1.63
Stat Method: logistic regression
Outcome: birth length
urinary arsenic concentration, u.g/L
Exp. Level n adiBeta (CD
continuous NR -0.06 n/a
Stat Method: least-squared linear regression
(beta coefficient)
Outcome: birth weight
urinary arsenic concentration, u.g/L
Exp. Level n adiBeta (CD
continuous NR -1.68 n/a
Stat Method: least-squared linear regression
(beta coefficient)
Outcome: chest circumference
urinary arsenic concentration, u.g/L
Exp. Level n adiBeta (CD
continuous NR -0.14 n/a
Stat Method: least-squared linear regression
(beta coefficient)
Outcome: head circumference
urinary arsenic concentration, u.g/L
Exp. Level n adiBeta (CD
continuous NR -0.05 n/a
Stat Method: least-squared linear regression
(beta coefficient)
Outcome: infant death
average urinary arsenic concentration (quintiles),
H9/L
Exp. Level n HR (CD
<38 3 1 n/a
39-67 6 1.78 0.44,7.16
68-133 6 1.83 0.45,7.35
134-267 7 2.29 0.58,9.05
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-89 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Population: pregnant
women enrolled in the
Maternal and Infant
Nutrition Intervention
in Matlab study
(MINIMat)
n total: 1,725
Population-Level Exposure:
38-2,019 ng/L range
268-2,019 14 5.01 1.41, 17.84
Stat Method: Cox proportional hazard models
Rocha-Amador et al.
(2007)
Study Type: cross-
sectional
Location: Mexico
(Moctezuma, Salitral,
and 5 de Febrero
communities)
Population: children in
rural communities
exposed to range of
arsenic drinking water
levels
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration in tap and bottled water
sampled at each individual's home on
same day as outcome evaluations
Population-Level Exposure:
not available
Outcome: full IQ
log transformed arsenic concentration in water,
Exp. Level n ad i Beta (CD
continuous NR -6.15 n/a
Stat Method: multiple linear regression
Outcome: Performance IQ
log transformed arsenic concentration in water,
H9/L
Exp. Level n ad i Beta (CD
continuous NR -4.3 n/a
Stat Method: multiple linear regression
Outcome: Verbal IQ
log transformed arsenic concentration in water,
H9/L
Exp. Level n ad i Beta (CD
continuous NR -6.4 n/a
Stat Method: multiple linear regression
Exposure Surrogate: urine
Exposure Description: arsenic
concentrations in urine collected same
day as neuropsychological evaluations;
arsenic level adjusted for urinary
creatinine
Population-Level Exposure:
not available
Outcome: full IQ
log transformed urinary arsenic concentration,
ng/g-creatinine
Exp. Level n ad i Beta (CD
continuous NR -5.72 n/a
Stat Method: multiple linear regression
Outcome: Performance IQ
log transformed urinary arsenic concentration,
ng/g-creatinine
Exp. Level n ad i Beta (CD
continuous NR -4.19 n/a
Stat Method: multiple linear regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-90 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Roy et al. (2011)
Study Type: cross-
sectional
Location: Mexico
(Torreon)
Population: first-grade
children attending
school near a metal
foundry
n cases: n/a
n control: n/a
Exposure Measures
Exposure Surrogate: urine
Exposure Description: total urinary
arsenic measured as the sum inorganic
arsenic and all arsenic metabolites
(MMA, DMA); first morning urine
samples collected after an overnight fast;
exposure stratified by quartiles
Population-Level Exposure:
55.2 ng/L median
Results
Outcome: Verbal IQ
log transformed urinary arsenic concentration,
Hg/g-creatinine
Exp. Level n adiBeta (CD
continuous NR -5.5 n/a
Stat Method: multiple linear regression
Outcome: ADHD index
total urinary arsenic concentration (quartiles),
W/L
Exp. Level n adiBeta (CD
7.7-35.9 NR NR n/a
36-55.2 NR 1.8 -0.7,4.3
55.3-75.6 NR 2.2 -0.3,4.6
75.7-215.9 NR 2.1 -0.4,4.7
Stat Method: linear regression
total urinary arsenic concentration (quartiles),
ug/L
Exp. Level n adiOR (CD
7.7-35.9 NR 1 n/a
36-55.2 NR 1.4 0.6,3.2
55.3-75.6 NR 2.4 1.1,4.9
75.7-215.9 NR 1.9 0.9,4.3
Stat Method: logistic regression, behavior
modeled as a categorical variable (T-score
<65 vs. T-score > 65)
Outcome: cognitive problems
total urinary arsenic concentration (quartiles),
ug/L
Exp. Level n adiBeta (CD
7.7-35.9 NR NR n/a
36-55.2 NR 1.6 -1.1,4.3
55.3-75.6 NR 2.7 -0.05,5.4
75.7-215.9 NR 2.6 -0.2,5.4
Stat Method: linear regression
total urinary arsenic concentration (quartiles),
W/l.
Exp. Level n adiOR (CD
7.7-35.9 NR 1 n/a
36-55.2 NR 1.3 0.6,2.6
55.3-75.6 NR 1.4 0.7,2.7
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-91 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
75.7-215.9 NR 1.5 0.8,3.1
Stat Method: logistic regression, behavior
modeled as a categorical variable (T-score
<65 vs. T-score > 65)
Outcome: hyperactive behavior
total urinary arsenic concentration (quartiles),
H9/L
Exp. Level n adiBeta (CD
7.7-35.9 NR NR n/a
36-55.2 NR 1.8 -0.9,4.6
55.3-75.6 NR 1.6 -1.2,4.3
75.7-215.9 NR 2.1 -0.7,4.9
Stat Method: linear regression
total urinary arsenic concentration (quartiles),
H9/L
Exp. Level n adiOR (CD
7.7-35.9 NR 1 n/a
36-55.2 NR 1.4 0.7,2.7
55.3-75.6 NR 1.6 0.8,3.2
75.7-215.9 NR 1.4 0.7,2.9
Stat Method: logistic regression, behavior
modeled as a categorical variable (T-score
<65 vs. T-score > 65)
Outcome: oppositional behavior
total urinary arsenic concentration (quartiles),
H9/L
Exp. Level n adiBeta (Cl)
7.7-35.9 NR NR n/a
36-55.2 NR 3.1 0.01,6.1
55.3-75.6 NR 2.5 -0.5,5.6
75.7-215.9 NR 2.1 -1.1,5.2
Stat Method: linear regression
total urinary arsenic concentration (quartiles),
H9/L
Exp. Level n adjOR (Cl)
7.7-35.9 NR 1 n/a
36-55.2 NR 2.1 1.0,4.4
55.3-75.6 NR 1.8 0.9,3.8
75.7-215.9 NR 2 1.0,4.3
Stat Method: logistic regression, behavior
modeled as a categorical variable (T-score
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-92 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Sahaetal. (2012)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: infants
born in a population-
based intervention trial
in rural area
n total: 2,372
Exposure Measures
Exposure Surrogate: urine
Exposure Description: maternal urine
samples collected 8 or 30 weeks of
pregnancy; urine samples collected from
children at 18 months of age; arsenic
exposure stratified by quintiles
Population-Level Exposure:
66.8 ng/L mean, 87.7SD, 11.7-159 ng/L
10th percentile
Results
<65 vs. T-score > 65)
Outcome: attained length (cm) at 18 months of
age
child urinary arsenic concentration (quintiles),
W/L
Exp. Level n adiBeta (CD
2.4-16 NR 1 n/a
16-26 NR 0.16 -0.21,0.53
26-46 NR -0.28 -0.65,0.093
46-96 NR -0.024 -0.39,0.35
96-937 NR 0.18 -0.20,0.55
Stat Method: multivariate logistic regression
Outcome: attained length (cm) at 24 months of
age
child urinary arsenic concentration (quintiles),
H9/L
Exp. Level n adiBeta (CD
2.4-16 NR 1 n/a
16-26 NR 0.16 -0.25,0.57
26-46 NR -0.18 -0.59,0.23
46-96 NR -0.26 -0.67,0.15
96-937 NR -0.013 -0.43,0.40
Stat Method: multivariate logistic regression
maternal urinary arsenic concentration
(quintiles), ug/L
Exp. Level n adiBeta (CD
1.2-33 NR 1 n/a
33-57 NR -0.098 -0.53,0.34
57-115 NR -0.22 -0.65,0.22
116-245 NR -0.15 -0.59,0.28
246-1,611 NR 0.29 -0.15,0.73
Stat Method: multivariate logistic regression
Outcome: attained length (cm) at 3 months of
age
maternal urinary arsenic concentration
(quintiles), ug/L
Exp. Level n adiBeta (CD
1.2-33 NR 1 n/a
33-57 NR 0.21 -0.13,0.56
57-115 NR -0.067 -0.41,0.28
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-93 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
116-245 NR 0.094 -0.27,0.45
246-1,611 NR 0.26 -0.096,0.61
Stat Method: multivariate logistic regression
Outcome: attained weight (kg) at 18 months of
age
child urinary arsenic concentration (quintiles),
H9/L
Exp. Level n adiBeta (CD
2.4-16 NR 1 n/a
16-26 NR -0.097 -0.23,0.038
26-46 NR -0.18 -0.32, -0.047
46-96 NR -0.19 -0.33, -0.57
96-937 NR -0.059 -0.20,0.076
Stat Method: multivariate logistic regression
Outcome: attained weight (kg) at 24 months of
age
child urinary arsenic concentration (quintiles),
ug/L
Exp. Level n adiBeta (CD
2.4-16 NR 1 n/a
16-26 NR -0.027 -0.18,0.12
26-46 NR -0.13 -0.28,0.019
46-96 NR -0.082 -0.23,0.067
96-937 NR 0.005 -0.14,0.16
Stat Method: multivariate logistic regression
maternal urinary arsenic concentration
(quintiles), ug/L
Exp. Level n adiBeta (Cl)
1.2-33 NR 1 n/a
33-57 NR -0.015 -0.17,0.14
57-115 NR -0.092 -0.25,0.062
116-245 NR -0.06 -0.22,0.094
246-1,611 NR 0.044 -0.11,0.20
Stat Method: multivariate logistic regression
Outcome: attained weight (kg) at 3 months of
age
maternal urinary arsenic concentration
(quintiles), ug/L
Exp. Level n adiBeta (Cl)
1.2-33 NR 1 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-94 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
33-57
57-115
116-245
246-1,611
NR
NR
NR
NR
0.11
-0.017
0.089
0.078
0.006, 0.21
-0.12,0.086
-0.019, 0.20
-0.028,0.18
Stat Method: multivariate logistic regression
Tofail et al. (2009)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: MINIMat
study cohort
n total: 1,799
Exposure Surrogate: urine
Exposure Description: spot urine
samples collected from mothers at home
at time of pregnancy testing (on average
gestational week 8) and at clinic (during
30th gestational week); arsenic
concentrations adjusted for variation in
urine dilution by specific gravity
Population-Level Exposure:
82.5 ng/L median
Outcome: "Cover" Problem Solving Test
mothers' urinary arsenic (mean of gestation
week 8 and 30), ug/L
Exp. Level n adjBeta (Cl)
continuous NR 0.4 -0.4,1.3
Stat Method: multiple regression
Outcome: "Support" Problem Solving Test
mothers' urinary arsenic (mean of gestation
week 8 and 30), ug/L
Exp. Level n adjBeta (Cl)
continuous NR -0.6 -1.5,0.4
Stat Method: multiple regression
Outcome: Psychomotor Development Index (PDI)
mothers' urinary arsenic (mean of gestation
week 8 and 30), ug/L
Exp. Level n adjBeta (Cl)
continuous NR 0.9 -0.9,2.7
Stat Method: multiple regression
Tsai et al. (2003)
Study Type: cross-
sectional
Location: Taiwan (Han
county: Chiaohsi,
Chuangwei, Wuchieh,
and Tungshan
townships)
Population:
adolescents with
chronic exposure to
arsenic in drinking
Exposure Surrogate: drinking water
Exposure Description: individual
cumulated arsenic exposure for exposed
individuals calculated from household
arsenic concentration in well water,
duration of drinking well water, and
averaged water intake per day; Taiwan
Environmental Protection Agency
reported mean tap water arsenic
concentrations in control area <1 ppb, so
control arsenic exposure omitted
because levels too low to be calculated
accurately
Population-Level Exposure:
Outcome: continuous performance test
cumulative arsenic exposure, ppm
Exp. Level n
NR
2,047.7- NR
43,882.13
64,377.79- NR 35.26 n/a
2,419,950
Stat Method: multiple linear regression
cumulative arsenic exposure, ppm
Exp. Level n
2,047.7-
43,882.13
64,377.79-
2,419,950
NR
NR
NR
mean
443.81
535.7
M
n/a
n/a
480.61 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-95 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
water
n cases: 49
n control: 60
2,047.7-2,419,950 ppm range
Stat Method: one-way ANOVA, Scheffe's test
Outcome: pattern memory
cumulative arsenic exposure, ppm
Exp. Level n ad I Beta (CD
NR
2,047.7- NR
43,882.13
64,377.79- NR 965.92 n/a
2,419,950
Stat Method: multiple linear regression
cumulative arsenic exposure, ppm
Exp. Level n mean (CD
NR 4972.24 n/a
2,047.7- NR 5437.05 n/a
43,882.13
64,377.79- NR 5961.03 n/a
2,419,950
Stat Method: one-way ANOVA, Scheffe's test
Outcome: switching attention
cumulative arsenic exposure, ppm
Exp. Level n adiBeta (CD
NR
2,047.7- NR
43,882.13
64,377.79- NR 234.78 n/a
2,419,950
Stat Method: multiple linear regression
cumulative arsenic exposure, ppm
Exp. Level
n
NR
NR
mean
635.11
801.6
M
n/a
n/a
2,047.7-
43,882.13
64,377.79- NR 861.13 n/a
2,419,950
Stat Method: one-way ANOVA, Scheffe's test
Outcome: symbol digit
cumulative arsenic exposure, ppm
Exp. Level n ad i Beta (CD
NR 0 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-96 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
2,047.7- NR 7.02 n/a
43,882.13
64,377.79- NR 15.97 n/a
2,419,950
Stat Method: multiple linear regression
cumulative arsenic exposure, ppm
Exp. Level n
NR
NR
mean
223.44
230.6
M
n/a
n/a
2,047.7-
43,882.13
64,377.79- NR 242.56 n/a
2,419,950
Stat Method: one-way ANOVA, Scheffe's test
Vail et al. (2012)
Study Type: cross-
sectional
Location: Spain
(Tenerife)
Population: Mother-
child pairs in study area
n cases: n/a
n control: n/a
Exposure Surrogate: meconium
Exposure Description: neonatal
meconium collected from infant's diaper
Population-Level Exposure:
6.79 ppb mean 1.05SD
Outcome: birth weight
arsenic concentration in meconium, ppb
Exp. Level n OR (Cl)
arsenic NR 1 1.00, 1.02
detected
arsenic non- NR NR n/a
detected
Stat Method: odd ratio; chi-square
Outcome: cranial perimeter
arsenic concentration in meconium, ppb
cranial perimeter not significantly associated with
arsenic in meconium
Outcome: gestational age at birth
arsenic concentration in meconium, ppb
gestational age at birth not significantly
associated with arsenic in meconium
Outcome: length
arsenic concentration in meconium, ppb
length not significantly associated with arsenic in
meconium
Outcome: prematurity
arsenic concentration in meconium, ppb
prematurity not significantly associated with
arsenic in meconium
Von Ehrenstein et al.
(2006)
Exposure Surrogate: drinking water
Outcome: infant mortality
arsenic concentration in drinking water, ug/L
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-97 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: women
residing in 21 villages of
West Bengal, India.
n cases: n/a
n control: n/a
Exposure Description: water samples
collected from tube wells used at least 6
months since first pregnancy; past
arsenic concentration measurements
used when wells were closed
Population-Level Exposure:
0-200 ng/L range
Exp. Level
0-49
50-199
>200
n
13
2
4
M
n/a
0.13,5.25
0.43, 4.04
Stat Method: logistic regression based on
method of generalized estimating equations
Outcome: neonatal death
arsenic concentration in drinking water, ng/L
Exp. Level n adjOR M
0-49 5 1 n/a
50-199 1 1.21 0.09, 15.4
> 200 4 2.81 0.73, 10.8
Stat Method: logistic regression based on
method of generalized estimating equations
von Ehrenstein et al.
(2007)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: children of
women participating in
pregnancy outcomes
associated with arsenic
in drinking water study
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: samples from all
tube wells used by participants for at
least 6 months collected; population-
level exposure represents average
lifetime water exposure; peak exposure
(147 +/- 322 ng/L) was highest known
annual average water concentration of
arsenic ingested by a child; prenatal
arsenic exposure based on the mother's
drinking water arsenic exposure during
pregnancy
Population-Level Exposure:
59 ng/L mean, 133SD, 1-870 ng/L range
Outcome: block design
average pregnancy arsenic concentration in
drinking water, ng/L
Exp. Level
10-49
50-99
>100
n
NR
NR
NR
NR
M
n/a
-0.34,0.17
-0.25, 0.49
-0.26, 0.23
Stat Method: linear regression
average pregnancy arsenic concentration in
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR -0.02 -0.05,0.02
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n
<10 NR
10-49 NR
50-99 NR
> 100 NR
adjBeta (CD
1 n/a
-0.01 -0.25,0.23
0.05 -0.33,0.44
-0.02 -0.23,0.22
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water (per 100 ng/L), \ig/L
Exp. Level n ad i Beta (CD
continuous NR 0.02 -0.02,0.05
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-98 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Stat Method: linear regression
Outcome: coding
average pregnancy arsenic concentration In
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.13 -0.48,0.21
50-99 NR -0.08 -0.51,0.36
>100 NR 0.031 -0.21,0.27
Stat Method: linear regression
average pregnancy arsenic concentration in
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR 0.01 -0.03,0.04
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.14 -0.47,0.20
50-99 NR -0.03 -0.48,0.43
>100 NR -0.13 -0.37,0.11
Stat Method: linear regression
peak lifetime arsenic concentration In drinking
water (per 100 ng/L), \ig/L
Exp. Level n adiBeta (CD
continuous NR 0.01 -0.02,0.04
Stat Method: linear regression
Outcome: colored progressive matrices
average pregnancy arsenic concentration in
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.08 -0.36,0.20
50-99 NR -0.07 -0.38,0.24
>100 NR -0.07 -0.30,0.17
Stat Method: linear regression
average pregnancy arsenic concentration in
drinking water (per 100 ng/L), ng/L
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-99 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Exp. Level n adiBeta (CD
continuous NR 0 -0.03,0.03
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.02 -0.28,0.24
50-99 NR -0.29 -0.57, -0.02
>100 NR -0.02 -0.28,0.24
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR 0.01 -0.02,0.04
Stat Method: linear regression
Outcome: digit span
average pregnancy arsenic concentration in
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR 0.08 -0.24,0.40
50-99 NR 0.09 -0.36,0.54
>100 NR -0.06 -0.30,0.19
Stat Method: linear regression
average pregnancy arsenic concentration in
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR 0.01 -0.02,0.04
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (Cl)
<10 NR 1 n/a
10-49 NR 0.08 -0.24,0.40
50-99 NR -0.15 -0.54,0.23
>100 NR -0.08 -0.32,0.17
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water (per 100 ng/L), ng/L
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-100 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Exp. Level n adiBeta (CD
continuous NR 0.02 -0.01,0.05
Stat Method: linear regression
Outcome: full scale
average pregnancy arsenic concentration In
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.047 -0.38,0.28
50-99 NR -0.007 -0.36,0.34
>100 NR -0.002 -0.24,0.24
Stat Method: linear regression
average pregnancy arsenic concentration in
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR 0.01 -0.02,0.03
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR 0.006 -0.31,0.33
50-99 NR -0.16 -0.56,0.23
>100 NR -0.06 -0.30,0.18
Stat Method: linear regression
peak lifetime arsenic concentration In drinking
water (per 100 ng/L), \ig/L
Exp. Level n adiBeta (CD
continuous NR -0.02 -0.02,0.05
Stat Method: linear regression
Outcome: object assembly
average pregnancy arsenic concentration in
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR 0.079 -0.31,0.47
50-99 NR 0.12 -0.28,0.51
>100 NR 0.17 -0.09,0.42
Stat Method: linear regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-101 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
average pregnancy arsenic concentration In
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR 0.02 -0.01,0.06
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR 0.16 -0.23,0.55
50-99 NR 0.014 -0.43,0.46
>100 NR 0.06 -0.18,0.31
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR 0.02 -0.02,0.06
Stat Method: linear regression
Outcome: pegboard
average pregnancy arsenic concentration in
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.18 -0.44,0.09
50-99 NR 0.09 -0.29,0.48
>100 NR -0.03 -0.23,0.17
Stat Method: linear regression
average pregnancy arsenic concentration In
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR 0 -0.02,0.03
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.1 -0.39,0.19
50-99 NR 0.13 -0.27,0.53
>100 NR 0.06 -0.14,0.26
Stat Method: linear regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-102 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
peak lifetime arsenic concentration in drinking
water (per 100 ng/L), \ig/L
Exp. Level n adiBeta (CD
continuous NR 0.01 -0.02,0.003
Stat Method: linear regression
Outcome: picture completion
average pregnancy arsenic concentration in
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR 0.08 -0.24,0.40
50-99 NR -0.25 -0.58,0.09
>100 NR -0.06 -0.29,0.17
Stat Method: linear regression
average pregnancy arsenic concentration in
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR -0.01 -0.04,0.02
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR 0.12 -0.19,0.43
50-99 NR -0.45 -0.84, -0.07
>100 NR -0.09 -0.33,0.14
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water (per 100 ng/L), \ig/L
Exp. Level n adiBeta (CD
continuous NR 0 -0.03,0.04
Stat Method: linear regression
Outcome: total sentence recall
average pregnancy arsenic concentration in
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR 0.03 -0.24,0.31
50-99 NR 0.32 -0.04,0.69
>100 NR -0.05 -0.30,0.19
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-103 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Stat Method: linear regression
average pregnancy arsenic concentration In
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR -0.03 -0.07,0.01
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR 0.11 -0.19,0.41
50-99 NR 0.28 -0.08,0.64
>100 NR -0.03 -0.27,0.21
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR -0.03 -0.05,0
Stat Method: linear regression
Outcome: vocabulary
average pregnancy arsenic concentration in
drinking water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.23 -0.54,0.08
50-99 NR -0.036 -0.40,0.33
>100 NR -0.08 -0.26,0.53
Stat Method: linear regression
average pregnancy arsenic concentration In
drinking water (per 100 ng/L), ng/L
Exp. Level n adiBeta (CD
continuous NR 0.01 -0.03,0.06
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water, ng/L
Exp. Level n adiBeta (CD
<10 NR 1 n/a
10-49 NR -0.17 -0.48,0.14
50-99 NR -0.23 -0.59,0.12
>100 NR -0.05 -0.29,0.20
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-104 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Stat Method: linear regression
peak lifetime arsenic concentration in drinking
water (per 100 ug/L), ug/L
Exp. Level n adiBeta (CD
continuous NR 0.01 -0.02,0.04
Stat Method: linear regression
Exposure Surrogate: urine
Exposure Description: child urine
samples collected during physical
examination and stratified in tertiles
(tertile concentration data not reported)
Population-Level Exposure:
78 |jg/L mean, 61SD, 2-375 ng/L range
Outcome: block design
child urinary arsenic concentration (per 100
ug/L), ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.02 -0.2,0.2
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
ug/L
Exp. Level n ad i Beta (CD
~<44.2- NR
<43.6
~>43.6- NR
<82.6 and~
>44.2-<86.1
NR
~>82.6and
>86.1
Stat Method: linear regression
-0.085 -0.34,0.17
Outcome: coding
child urinary arsenic concentration (per 100
ug/L), ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.06 -0.2,0.09
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
ug/L
Exp. Level n ad i Beta (CD
~<44.2- NR 1 n/a
<43.6
~>43.6- NR -0.14 -0.37,0.10
<82.6 and~
>44.2-<86.1
~>82.6and~ NR -0.13 -0.38,0.12
>86.1
Stat Method: linear regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-105 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Outcome: colored progressive matrices
child urinary arsenic concentration (per 100
H9/L), H9/L
Exp. Level n ad I Beta (CD
continuous NR -0.07 -0.2,0.07
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
Exp. Level
~ <44.2 -
<43.6
~ >43.6 -
<82.6and~
>44.2-<86.1
~>82.6and
>86.1
Stat Method: linear regression
NR
NR
NR
adjBeta (CD
1 n/a
0.0009 -0.22,0.23
-0.12 -0.36,0.11
Outcome: digit span
child urinary arsenic concentration (per 100
H9/L), H9/L
Exp. Level n ad i Beta (CD
continuous NR 0.04 -0.1,0.2
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
Exp. Level
~ <44.2 -
<43.6
~ >43.6 -
<82.6 and~
>44.2-<86.1
~>82.6and
>86.1
Stat Method: linear regression
n
NR
NR
NR
adjBeta (CD
1 n/a
-0.04 -0.30,0.22
-0.0004 -0.27,0.27
Outcome: full scale
child urinary arsenic concentration (per 100
H9/L), ug/L
Exp. Level n adjBeta (Cl)
continuous NR -0.07 -0.2,0.09
Stat Method: linear regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-106 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
child urinary arsenic concentration (tertiles),
n
NR
NR
NR
ad I Beta (CD
1 n/a
Exp. Level
~ <44.2 -
<43.6
~ >43.6 -
<82.6and~
>44.2-<86.1
~>82.6and
>86.1
Stat Method: linear regression
-0.11
-0.2
-0.34,0.12
-0.44, 0.03
Outcome: object assembly
child urinary arsenic concentration (per 100
ug/L), ug/L
Exp. Level n adiBeta (CD
continuous NR -0.07 -0.2,0.1
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
ug/L
Exp. Level n ad i Beta (CD
~<44.2- NR
<43.6
~>43.6- NR
<82.6 and~
>44.2-<86.1
NR
~>82.6and
>86.1
Stat Method: linear regression
-0.24 -0.49,0.01
Outcome: pegboard
child urinary arsenic concentration (per 100
ug/L), ug/L
Exp. Level n ad i Beta (CD
continuous NR 0.04 -0.1,0.2
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
ug/L
Exp. Level n adjBeta (Cl)
NR 1 n/a
~ <44.2 -
<43.6
~ >43.6 -
<82.6 and'
NR
0.15
-0.07, 0.36
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-107 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
>44.2-<86.1
~>82.6and~ NR 0.09
>86.1
Stat Method: linear regression
-0.14,0.32
Outcome: picture completion
child urinary arsenic concentration (per 100
H9/L), ug/L
Exp. Level n adiBeta (CD
continuous NR -0.1 -0.3,0.04
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
n
NR
NR
NR
ad i Beta (CD
1 n/a
Exp. Level
~<44.2-
<43.6
~>43.6-
<82.6and~
>44.2-<86.1
~>82.6and
>86.1
Stat Method: linear regression
-0.15
-0.26
-0.34,0.09
-0.51, -0.01
Outcome: total sentence recall
child urinary arsenic concentration (per 100
Exp. Level n ad j Beta (Cl)
continuous NR 0.04 -0.1,0.2
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
NR
NR
NR
ad j Beta (Cl)
1 n/a
Exp. Level
~<44.2-
<43.6
~>43.6-
<82.6and~
>44.2-<86.1
~>82.6and
>86.1
Stat Method: linear regression
0.23
0.13
0.02,0.44
-0.09,0.35
Outcome: vocabulary
child urinary arsenic concentration (per 100
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-108 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Wasserman et al.
(2004)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: children 10
years old residing in
villages within the
HEALS cohort
n cases: n/a
n control: n/a
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in 196 tube wells used for
drinking water at each residence;
exposure levels split into quartiles
Population-Level Exposure:
117.8 ng/L mean 145.2SD
Results
H9/L), ng/L
Exp. Level n adiBeta (CD
continuous NR -0.09 -0.3,0.07
Stat Method: linear regression
child urinary arsenic concentration (tertiles),
H9/L
Exp. Level n adiBeta (CD
~<44.2- NR 1 n/a
<43.6
~>43.6- NR -0.14 -0.37,0.10
<82.6and~
>44.2-<86.1
~>82.6and~ NR -0.28 -0.55, -0.008
>86.1
Stat Method: linear regression
Outcome: full scale raw score
drinking water arsenic concentration, u.g/L
Exp. Level n adiBeta (CD
continuous NR -1.64 n/a
Stat Method: linear regression analysis
drinking water arsenic concentration (quartiles),
H9/L
Exp. Level n adiBeta (CD
0.1-5.5 NR NR n/a
5.6-50.0 NR NR n/a
50.1-176 NR -7.8 n/a
177-790 NR -11.3 n/a
Stat Method: linear regression analysis
Outcome: performance raw score
drinking water arsenic concentration, u.g/L
Exp. Level n adiBeta (CD
continuous NR -1.45 n/a
Stat Method: linear regression analysis
drinking water arsenic concentration (quartiles),
H9/L
Exp. Level n adiBeta (CD
0.1-5.5 NR NR n/a
5.6-50.0 NR NR n/a
50.1-176 NR -7.3 n/a
177-790 NR -9.7 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-109 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Stat Method: linear regression analysis
Outcome: verbal raw score
drinking water arsenic concentration, ug/L
Exp. Level n adiBeta (CD
continuous NR -0.19 n/a
Stat Method: linear regression analysis
drinking water arsenic concentration (quartiles),
ug/L
Exp. Level n
0.1-5.5 NR
5.6-50.0 NR
50.1-176 NR
177-790 NR
Stat Method: linear regression analysis
Exposure Surrogate: urine
Exposure Description: arsenic
concentration in urine, adjusted for
urinary creatinine levels
Population-Level Exposure:
116.6 ng/L mean 148.8SD
Outcome: full scale raw score
urinary arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -2.9 n/a
Stat Method: linear regression analysis
Outcome: performance raw score
urinary arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -2.2 n/a
Stat Method: linear regression analysis
Outcome: verbal raw score
urinary arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.7 n/a
Stat Method: linear regression analysis
Wasserman et al.
(2007)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Exposure Surrogate: drinking water
Exposure Description: water samples
from each home collected during survey
of all wells in study region;
Population-Level Exposure:
120.1 ug/L mean 134.4SD
Outcome: full scale raw score
drinking water arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -1.06 n/a
Stat Method: linear regression analysis
Outcome: performance raw score
drinking water arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-110 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Population: 6-year-old
children of parents
enrolled in the HEALS
cohort study
n cases: n/a
n control: n/a
continuous NR -0.48 n/a
Stat Method: linear regression analysis
Outcome: processing speed raw score
drinking water arsenic concentration, u.g/L
Exp. Level n adiBeta (CD
continuous NR -0.54 n/a
Stat Method: linear regression analysis
Outcome: verbal raw score
drinking water arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.18 n/a
Stat Method: linear regression analysis
Exposure Surrogate: urine
Exposure Description: each child
provided urine specimens for
measurement of urinary As; levels of As
in urine adjusted for urinary creatinine
levels
Population-Level Exposure:
110.7 ng/g-creatinine mean 132.8SD
Outcome: full scale raw score
urinary arsenic concentration, u.g/g-creatinine
Exp. Level n ad i Beta (CD
continuous NR -1.78 n/a
Stat Method: linear regression analysis
Outcome: performance raw score
urinary arsenic concentration, ug/g-creatinine
Exp. Level n ad i Beta (CD
continuous NR -0.81 n/a
Stat Method: linear regression analysis
Outcome: processing speed raw score
urinary arsenic concentration, u.g/g-creatinine
Exp. Level n ad i Beta (CD
continuous NR -0.93 n/a
Stat Method: linear regression analysis
Outcome: verbal raw score
urinary arsenic concentration, u.g/g-creatinine
Exp. Level n ad i Beta (CD
continuous NR -0.16 n/a
Stat Method: linear regression analysis
Wasserman et al.
(2011)
Exposure Surrogate: blood
Exposure Description: venous whole
Outcome: general intellectual ability (full-scale
10)
blood arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: children 8-
11 years old living in
households within the
HEALS cohort of
villages
n cases: n/a
n control: n/a
blood samples collected at a field clinic
and analyzed for Pb, Mn, Se, and As
Population-Level Exposure:
4.81 ng/L mean 3.22SD
continuous NR -3.8 n/a
Stat Method: linear regression
Outcome: perceptual reasoning
blood arsenic concentration,,
Exp. Level n ad i Beta (CD
continuous NR -1.13 n/a
Stat Method: linear regression
Outcome: processing speed
blood arsenic concentration, \ng/L
Exp. Level n ad i Beta (CD
continuous NR -0.27 n/a
Stat Method: linear regression
Outcome: verbal comprehension
blood arsenic concentration, ng/L
Exp. Level n ad i Beta (CD
continuous NR -1.49 n/a
Stat Method: linear regression
Outcome: working memory
blood arsenic concentration, ng/L
Exp. Level n ad i Beta (CD
continuous NR -0.91 n/a
Stat Method: linear regression
Wright et al. (2006)
Study Type: cross-
sectional
Location: United States
(OK)
Population: school-age
children residing near
hazardous waste site
n cases: n/a
n control: n/a
Exposure Surrogate: hair
Exposure Description: hair samples
cleaned by sonication, rinsed and dried
Population-Level Exposure:
not available
Outcome: CELF-3
hair arsenic levels, ppb
no significant association between any CELF-3 test
scores and hair As levels
Outcome: children's category test
hair arsenic levels, ppb
no significant association between children's
category test scores and hair As levels
Outcome: CVLT-C: list A
hair arsenic levels, ppb
Exp. Level n ad i Beta (CD
continuous NR -0.26 n/a
Stat Method: unspecified
Outcome: CVLT-C: other than list A
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Study
Design
Exposure Measures
Results
hair arsenic levels, ppb
no significant association between any CVLT-C
other than list A test scores and hair As levels;
significant Mn-by-As interaction for scores
Outcome: full-Scale IQ
hair arsenic levels, ppb
Exp. Level n adjBeta (Cl)
continuous NR -0.44 n/a
Stat Method: mutivariate linear regression
Outcome: parent ratings of children on CADS-IV,
BRIEF tests
hair arsenic levels, ppb
no significant association between parent rating
and arsenic
Outcome: performance IQ
hair arsenic levels, ppb
Exp. Level n adiBeta (Cl)
continuous NR -0.27 n/a
Stat Method: scatterplot slope
Outcome: teacher ratings of children on CADS-IV,
BRIEF, BASC tests
hair arsenic levels, ppb
no significant association between teacher rating
and arsenic
Outcome: verbal IQ
hair arsenic levels, ppb
Exp. Level n ad i Beta (Cl)
continuous NR -0.51 n/a
Stat Method: mutivariate linear regression
Outcome: WRAML
hair arsenic levels, ppb
no significant association between any WRAML
test scores and hair As levels; significant Mn-by-As
interaction for scores on WRAML story memory
Outcome: WRAVMA
hair arsenic levels, ppb
no significant association between any WRAVMA
test scores and hair As levels
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
-: not reported; n: number of cases (when presented in Results column)
5.4.1 References Summary of Observational Epidemiology Studies for
Health Effect Category: Developmental Effects including
Neurodevelopmental
Calderon. J: Navarro. ME: Jimenez-Capdeville. ME: Santos-Diaz. MA: Golden. A: Rodriguez-Levva. I: Borja-
Aburto. V: Diaz-Barriga. F. (2001). Exposure to arsenic and lead and neuropsychological development in
Mexican children. Environ Res 85: 69-76. http://dx.doi.org/10.1006/enrs.2000.4106
Gardner. RM: Kippler. M: Tofail F: Bottai. M: Hamadani. J: Grander. M: Nermell B: Palm. B: Rasmussen.
KM: Vahter. M. (2013). Environmental exposure to metals and children's growth to age 5 years: a
prospective cohort study. Am J Epidemiol 177: 1356-1367. http://dx.doi.org/10.1093/aie/kws437
Guan. H: Piao. F: Zhang. X: Li. X: Li. Q: Xu. L: Kitamura. F: Yokoyama. K. (2012). Prenatal Exposure to
Arsenic and Its Effects on Fetal Development in the General Population of Dalian. Biol Trace Elem Res.
http://dx.doi.org/10.1007/sl2011-012-9396-7
Hamadani. JD: Grantham-Mcgregor. SM: Tofail F: Nermell B: Fangstrom. B: Huda. SN: Yesmin. S: Rahman.
M: Vera-Hernandez. M: Arifeen. SE: Vahter. M. (2010). Pre- and postnatal arsenic exposure and child
development at 18 months of age: a cohort study in rural Bangladesh. Int J Epidemiol 39: 1206-1216.
http://dx.doi.org/10.1093/ije/dvp369
Hamadani. JD: Tofail F: Nermell B: Gardner. R: Shiraji. S: Bottai. M: Arifeen. SE: Huda. SN: Vahter. M.
(2011). Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school
girls and boys: a population-based cohort study. Int J Epidemiol 40: 1593-1604.
http://dx.doi.org/10.1093/ije/dvrl76
Hopenhavn. C: Ferreccio. C: Browning. SR: Huang. B: Peralta. C: Gibb. H: Hertz-Picciotto. I. (2003). Arsenic
exposure from drinking water and birth weight. Epidemiology 14: 593-602.
http://dx.doi.org/10.1097/01.ede.0000072104.65240.69
Huyck. KL: Kile. ML: Mahiuddin. G: Quamruzzaman. Q: Rahman. M: Breton. CV: Dobson. CB: French. J:
Hoffman. E: Yousuf. J: Afroz. S: Islam S: Christian!. DC. (2007). Maternal arsenic exposure associated with
low birth weight in Bangladesh. J Occup Environ Med 49: 1097-1104.
http://dx.doi.org/10.1097/JOM.Ob013e3181566baO
Jin. L: Zhang. L: Li. Z: Liu. JM: Ye. R: Ren. A. (2013). Placental concentrations of mercury, lead, cadmium, and
arsenic and the risk of neural tube defects in a Chinese population. Reprod Toxicol 35:25-31.
http://dx.doi.0rg/10.1016/i.reprotox.2012.10.015
Khan. K: Wasserman. GA: Liu. X: Ahmed. E: Parvez. F: Slavkovich. V: Lew. D: Mev. J: van Geen. A:
Graziano. JH: Factor-Litvak. P. (2012). Manganese exposure from drinking water and children's academic
achievement. Neurotoxicology 33: 91-97. http://dx.doi.0rg/10.1016/i.neuro.2011.12.002
Kippler. M: Wagatsuma. Y: Rahman. A: Nermell B: Persson. LA: Raqib. R: Vahter. M. (2012). Environmental
exposure to arsenic and cadmium during pregnancy and fetal size: A longitudinal study in rural Bangladesh.
Reprod Toxicol 34: 504-511. http://dx.doi.0rg/10.1016/i.reprotox.2012.08.002
Kwok. RK: Kaufmann. RB: Jakariya. M. (2006). Arsenic in drinking-water and reproductive health outcomes: A
study of participants in the Bangladesh integrated nutrition programme. J Health Popul Nutr 24: 190-205.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-114 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Milton. AH: Smith. W: Rahman. B: Hasan. Z: Kulsum. U: Dear. K: Rakibuddin. M: All. A. (2005). Chronic
arsenic exposure and adverse pregnancy outcomes in Bangladesh. Epidemiology 16: 82-86.
http://dx.doi.org/10.1097/01.ede.0000147105.94041.e6
Nahar. MN: Inaoka. T: Fujimura. M: Watanabe. C: Shimizu. H: Tasnim S: Sultana. N. (2014). Arsenic
contamination in groundwater and its effects on adolescent intelligence and social competence in Bangladesh
with special reference to daily drinking/cooking water intake. Environ Health Prev Med 19: 151-158.
http://dx.doi.org/10.1007/sl2199-013-0369-z
Parvez. F: Wasserman. GA: Factor-Litvak. P: Liu. X: Slavkovich. V: Siddique. AB: Sultana. R: Sultana. R:
Islam T: Lew. D: Mev. JL: van Geen. A: Khan. K: Kline. J: Ahsan. H: Graziano. JH. (2011). Arsenic
exposure and motor function among children in Bangladesh. Environ Health Perspect 119: 1665-1670.
http://dx.doi.org/10.1289/ehp. 1103548
Rahman. A: Persson. LA: Nermell B: El Arifeen. S: Ekstrom. EC: Smith. AH: Vahter. M. (2010). Arsenic
exposure and risk of spontaneous abortion, stillbirth, and infant mortality. Epidemiology 21: 797-804.
http://dx.doi.org/10.1097/EDE.Ob013e3181f56aOd
Rahman. A: Vahter. M: Ekstrom EC: Rahman. M: Golam Mustafa. AH: Wahed. MA: Yunus. M: Persson. LA.
(2007). Association of arsenic exposure during pregnancy with fetal loss and infant death: A cohort study in
Bangladesh. AmJEpidemiol 165: 1389-1396. http://dx.doi.org/10.1093/aie/kwm025
Rahman. A: Vahter. M: Smith. AH: Nermell B: Yunus. M: El Arifeen. S: Persson. LA: Ekstrom EC. (2009).
Arsenic exposure during pregnancy and size at birth: a prospective cohort study in Bangladesh. Am J
Epidemiol 169: 304-312. http://dx.doi.org/10.1093/aie/kwn332
Rocha-Amador. D: Navarro. ME: Carrizales. L: Morales. R: Calderon. J. (2007). Disminucion de la inteligencia
en ninos y exposicion al fl uor y arsenico en el agua potable. Cad Saude Publica 23: S579-587.
http://dx.doi.org/10.1590/S0102-311X2007001600018
Roy. A: Kordas. K: Lopez. P: Rosado. JL: Cebrian. ME: Vargas. GG: Ronquillo. D: Stoltzfus. PJ. (2011).
Association between arsenic exposure and behavior among first-graders from Torreon, Mexico. Environ Res
111: 670-676. http://dx.doi.0rg/10.1016/i.envres.2011.03.003
Saha. KK: Engstrom A: Hamadani. JD: Tofail F: Rasmussen. KM: Vahter. M. (2012). Pre- and Postnatal
Arsenic Exposure and Body Size to Two Years of Age: a Cohort Study in Rural Bangladesh. Environ Health
Perspect. http://dx.doi.org/10.1289/ehp. 1003378
Tofail F: Vahter. M: Hamadani. JD: Nermell B: Huda. SN: Yunus. M: Rahman. M: Grantham-McGregor. SM.
(2009). Effect of arsenic exposure during pregnancy on infant development at 7 months in rural Matlab,
Bangladesh. Environ Health Perspect 117: 288-293. http://dx.doi.org/10.1289/ehp. 11670
Tsai. SY: Chou. HY: The. HW: Chen. CM: Chen. CJ. (2003). The effects of chronic arsenic exposure from
drinking water on the neurobehavioral development in adolescence. Neurotoxicology 24: 747-753.
http://dx.doi.org/10.1016/S0161-813X(03)00029-9
Vail O: Gomez-Culebras. M: Garcia-Algar. O: Joya. X: Velez. D: Rodriguez-Carrasco. E: Puig. C. (2012).
Assessment of prenatal exposure to arsenic in Tenerife Island. PLoS ONE 7: e50463.
http://dx.doi.org/10.1371/iournal.pone.0050463
Von Ehrenstein. OS: Guha Mazumder. DN: Hira-Smith. M: Ghosh. N: Yuan. Y: Windham. G: Ghosh. A:
Hague. R: Lahiri. S: Kalman. D: Das. S: Smith. AH. (2006). Pregnancy outcomes, infant mortality, and
arsenic in drinking water in West Bengal, India. Am J Epidemiol 163: 662-669.
http://dx.doi.org/10.1093/aie/kwi089
von Ehrenstein. OS: Poddar. S: Yuan. Y: Mazumder. DG: Eskenazi. B: Basu. A: Hira-Smith. M: Ghosh. N:
Lahiri. S: Hague. R: Ghosh. A: Kalman. D: Das. S: Smith. AH. (2007). Children's intellectual function in
relation to arsenic exposure. Epidemiology 18: 44-51.
http://dx.doi.org/10.1097/01.ede.0000248900.65613.a9
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Wasserman. GA: Liu. X: Parvez. F: Ahsan. H: Factor-Litvak. P: van Geen. A: Slavkovich. V: Lolacono. NJ:
Cheng. Z: Hussain. I: Momotaj. H: Graziano. JH. (2004). Water arsenic exposure and children's intellectual
function in Araihazar, Bangladesh. Environ Health Perspect 112: 1329-1333.
http://dx.doi.org/10.1289/ehp.6964
Wasserman. GA: Liu. X: Parvez. F: Factor-Litvak. P: Ahsan. H: Lew. D: Kline. J: van Geen. A: Mev. J:
Slavkovich. V: Siddique. AB: Islam. T: Graziano. JH. (2011). Arsenic and manganese exposure and
children's intellectual function. Neurotoxicology 32: 450-457. http://dx.doi.0rg/10.1016/i.neuro.2011.03.009
Wasserman. GA: Liu. XH: Parvez. F: Ahsan. H: Factor-Litvak. P: Kline. J: Van Geen. A: Slavkovich. V:
Lolacono. NJ: Lew. D: Cheng. ZQ: Graziano. JH. (2007). Water arsenic exposure and intellectual function
in 6-year-old children in Araihazar, Bangladesh. Environ Health Perspect 115: 285-289.
http://dx.doi.org/10.1289/ehp.9501
Wright RO: Amarasiriwardena. C: Woolf. AD: Jim. R: Bellinger. DC. (2006). Neuropsychological correlates of
hair arsenic, manganese, and cadmium levels in school-age children residing near a hazardous waste site.
Neurotoxicology 27: 210-216. http://dx.doi.0rg/10.1016/i.neuro.2005.10.001
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.5 Summary of Observational Epidemiology Studies for
Health Effect Category: Digestive System Effects
Summary of Observational Epidemiology Studies for Health Effect Category: Digestive System Effects
Reference and Study
Design
Exposure Measures
Results
Amaral et al. (2012)
Study Type: case-
control
Location: Spain
(Mediterranean coast)
Population: PANKRAS II
Study 1992-1995,
adults participants with
exocrine pancreatic
cancer
n cases: 118
n control: 399
Exposure Surrogate: toenails
Exposure Description: toenail arsenic
concentration measured from clean
samples
Population-Level Exposure:
0-0.75 ng/g range
Outcome: exocrine pancreatic cancer
toenail arsenic concentration (quartiles), \ag/g
Exp. Level
< 0.0518
0.0519-
0.0709
0.0710-
0.1061
>0.1061
34
21
23
35
1.22
2.02
M
n/a
n/a
n/a
n/a
Stat Method: logistic regression
Baastrup et al. (2008)
Study Type: cohort
(prospective)
Location: Denmark
(Copenhagen and
Aarhus)
Population: Danish
Cancer Registry
population (adults)
n exposed: 56,378
n total: 57,053
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure and time-weighted average
arsenic concentrations calculated for
individuals based on residential address
and history from Central Population
Registry combined with measurement
data from nearest water utility as
recorded by Geological Survey of
Denmark and Greenland (1987-2004)
Population-Level Exposure:
not available
Outcome: colorectal cancer
cumulative arsenic exposure, mg
Exp. Level n IRR (CD
continuous NR 0.98 0.96, 1.01
Stat Method: Cox regression
Exposure Surrogate: drinking water
Exposure Description: time-weighted
and cumulative arsenic concentrations
calculated for individuals based on
residential address and history from
Central Population Registry combined
Outcome: colorectal cancer
time-weighted average arsenic exposure, \ig/L
Exp. Level n IRR M
continuous NR 0.97 0.90, 1.05
Stat Method: Cox regression
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Digestive System Effects
Reference and Study
Design
Exposure Measures
Results
with measurement data from nearest
water utility as recorded by Geological
Survey of Denmark and Greenland (1987-
2004)
Population-Level Exposure:
0.7 ng/L median
Farzanetal. (2013)
Study Type: cohort
(prospective)
Location: United States
(NH)
Population: 4 month
old infants born to
pregnant women 18-45
years old in New
Hampshire, USA
n total: 214
Exposure Surrogate: urine
Exposure Description: mothers provided
spot urine sample upon enrollment (24-
28 weeks gestation); samples that
registered below the detection limit
assigned a value equal to the detection
limit divided by the square root of two;
total urinary As calculated as the sum of
inorganic As (As[lll] and As[V]) and
metabolic products MMA(V) and
DMA(V), excluding arsenobetaine
Population-Level Exposure:
6 ng/L mean 7.5SD
Outcome: acute gastrointestinal symptoms,
conditions, illnesses
maternal urinary As (In transformed; categorized
by 4 infection descriptions), ug/L
Exp. Level n RR (CD
continuous: 21 1.2 1.7,2.0
at least one
infection
continuous: 10 1.9 0.9,3.9
infection
lasting 2 or
more days
continuous: 6 3.5 0.8,15.4
infection
with a
physician
visit
continuous: 1 NR n/a
infection
treated with
prescription
medication
Stat Method: logistic regression
Garcfa-Esquinas et al.
(2013)
Study Type: cohort
(prospective)
Location: United States
(AZ;ND;OK;SD)
Population: Strong
Heart Study
participants
n total: 3,935
Exposure Surrogate: urine
Exposure Description: individual urine
samples collected and analyzed for
arsenic speciation
Population-Level Exposure:
9.7 ng/g-creatinine median, 5.8-15.6
Hg/g-creatinine 25th percentile
Outcome: colon and rectal cancer
urinary arsenic concentration, ug/g-creatinine
no significant association between arsenic and
colon or rectal cancer
Outcome: esophagus and stomach cancer
urinary arsenic concentration, ug/g-creatinine
Exp. Level n HR (CD
80th vs. 20th NR 1.09 0.45,2.66
percentiles
Stat Method: Cox proportional hazard
models; log transformed
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Digestive System Effects
Reference and Study
Design
Exposure Measures
Results
Hsu et al. (2013b)
Study Type: cohort
(prospective)
Location: Taiwan (SW:
Peimen, Hsuechia, Ichu,
and Putai Townships;
NE: Chiaohsi,
Chuangwei, Wuchieh,
and Tungshan
Townships)
Population: residents
of an arseniasis-
endemic area with and
without skin lesions
n total: 9,525
Exposure Surrogate: drinking water
Exposure Description: SW population:
median arsenic level of several wells
shared in a village derived from two
surveys; NE population: arsenic level of
well water samples collected during
home interviews
Population-Level Exposure:
10-500 ng/L range
Outcome: colon cancer
arsenic concentration in well water (non-
diabetes mellitus vs. diabetes mellitus subjects),
n
NR
NR
NR
NR
HR
1
Exp. Level
non-DMw/
As <500
DMw/As
<500
non-DMw/
As > 500
DMw/As
>500
Stat Method: Cox regression analysis
1.6
1
2.09
(CD
n/a
1.00,2.57
n/a
1.41,9.14
Outcome: rectal cancer
arsenic concentration in well water (non-
diabetes mellitus vs. diabetes mellitus subjects),
n
NR
NR
NR
NR
HR
1
Exp. Level
non-DMw/
As <500
DMw/As
<500
non-DMw/
As > 500
DMw/As
>500
Stat Method: Cox regression analysis
1.75
1
1.34
(CD
n/a
1.01,3.05
n/a
0.35,5.04
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: deceased
male and female
members of Latter-day
Saints church wards
n exposed: 2,203
n total: 2,203
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Outcome: digestive organs and peritoneum
cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR (CD
<1,000 NR 1.11 n/a
1,000-4,999 NR 0.2 n/a
> 5,000 NR 0.7 n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1,000 NR 0.57 n/a
1,000-4,999 NR 0.87 n/a
> 5,000 NR 0.73 n/a
Stat Method: standardized mortality ratios
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Digestive System Effects
Reference and Study
Design
Exposure Measures
Results
Outcome: large intestine cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR M
<1,000 NR 1.23 n/a
1,000-4,999 NR NR n/a
> 5,000 NR 0.91 n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR {G}
<1,000 NR 0.79 n/a
1,000-4,999 NR 0.45 n/a
> 5,000 NR 0.35 n/a
Stat Method: standardized mortality ratios
Outcome: stomach cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR (CD
< 1,000 NR 1 n/a
1,000-4,999 NR 0.4 n/a
> 5,000 NR 0.7 n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1,000 NR 0.67 n/a
1,000-4,999 NR 0.85 n/a
> 5,000 NR 1.2 n/a
Stat Method: standardized mortality ratios
Rahman etal. (2011)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: MINIMat
Study, mother-infant
pairs
n total: 1,552
Exposure Surrogate: maternal urine
Exposure Description: maternal urinary
arsenic concentration measured from
urine samples collected at gestation
weeks 8 and 30; arsenic exposure
calculated as sum of inorganic arsenic
and its methylated metabolites (MMA
and DMA) and the average of exposure
at gestation weeks 8 and 30; samples
261
ri
NR
NR
NR
NR
NR
M
n/a
0.83, 1.19
0.80, 1.15
1.05, 1.48
1.01, 1.43
Stat Method: Poisson regression
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Digestive System Effects
Reference and Study
Design
Sawada et al. (2013)
Study Type: cohort
(prospective)
Location: Japan (Iwate,
Akita, Nagano,
Okinawa, Tokyo,
Ibaraki, Niigata, Kochi,
Nagasaki, Osaka)
Population: adults in
Japan Public Health
Center (JPHC)
Prospective Study
cohort
n total: 90,378
Sved et al. (2013)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study,
adult participants
n cases: n/a
n control: n/a
Exposure Measures
Exposure Surrogate: diet
Exposure Description: detailed
questionnaire on food intake/frequency;
average arsenic concentrations in food
items obtained from the literature;
arsenic intake calculated by multiplying
average arsenic concentration in each
item by quantity consumed
Population-Level Exposure:
170 ug/day mean, 88.3-253.2 ug/day
range
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from single spot
sample for each individual
Population-Level Exposure:
7-5,000 ug/g-creatinine range
Results
Outcome: colorectal cancer
arsenic concentration in diet, tig/day
arsenic not significantly associated with colorectal
cancer
Outcome: stomach cancer
inorganic arsenic intake (females; quartiles),
Ug/day
Exp. Level n HR (CD
40.6 65 1 n/a
53.7 61 0.82 0.57, 1.16
62.6 74 0.93 0.66, 1.3
105.7 73 0.92 0.65, 1.29
Stat Method: Multivariate regression
inorganic arsenic intake {males; quartiles),
Ug/day
Exp. Level n HR (CD
40.5 164 1 n/a
54.7 188 1.02 0.83, 1.26
63.5 166 0.88 0.7, 1.1
99.1 168 0.89 0.71, 1.11
Stat Method: Multivariate regression
Outcome: lesions of the gums
urinary arsenic concentration (tertiles), ug/g-
creatinine
Exp. Level n adiOR (CD
7-134.0 NR 1 n/a
134.1-286.0 NR 2.01 0.75,5.4
286.1-5,000 NR 2.9 1.11,7.54
Stat Method: multinomial multivariate
regression
Outcome: lesions of the lips
urinary arsenic concentration (tertiles), ug/g-
creatinine
Exp. Level n adjOR (Cl)
7-134.0 NR 1 n/a
134.1-286.0 NR 2.34 0.60, 10.63
286.1-5,000 NR 2.68 0.67,4.24
Stat Method: multinomial multivariate
regression
Outcome: lesions of the tongue
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Digestive System Effects
Reference and Study
Design
Tsuda et al. (1995)
Study Type: cohort
(retrospective)
Location: Japan
(Namiki-cho)
Population: adults and
children living near
factory producing
arsenic trisulfide
n exposed: 189
n reference: 254
n total: 443
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic in well
water measured in 1959 (the end of the
exposure period) in 34 wells; 20 area
wells had no documented levels of
arsenic so authors inferred that arsenic
levels were undetectable or very low;
concentration assigned based on
residence in 1959
Population-Level Exposure:
0.05-1 ppm range
Results
urinary arsenic concentration (tertiles), VLQ/Q-
creatinine
Exp. Level n adiOR (CD
7-134.0 NR 1 n/a
134.1-286.0 NR 1.61 0.84,3.08
286.1-5,000 NR 2.79 1.51,5.15
Stat Method: multinomial multivariate
regression
Outcome: colon cancer
arsenic concentration in well water in 1959, ppm
Exp. Level n SMR (CD
<0.05 2 2.98 0.53, 10.89
0.05-0.99 0 0 0,22.14
>1 00 0,17.11
Stat Method: Cox proportional hazard
--: not reported; n: number of cases (when presented in Results column)
5.5.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Digestive System Effects
Amaral. AFS: Porta. M: Silverman. DT: Milne. RL: Kogevinas. M: Rothman. N: Cantor. KP: Jackson. BP:
Pumarega. JA: Lopez. T: Carrato. A: Guarner. L: Real. FX: Malats. N. (2012). Pancreatic cancer risk and
levels of trace elements. Gut 61: 1583-1588. http://dx.doi.org/10.1136/gutinl-2011-301086
Baastrup. R: Serensen. M: Balstrem. T: Frederiksen. K: Larsen. CL: Tjenneland. A: Overvad. K: Raaschou-
Nielsen. O. (2008). Arsenic in drinking-water and risk for cancer in Denmark. Environ Health Perspect 116:
231-237. http://dx.doi.org/10.1289/ehp. 10623
Farzan. SF: Korrick. S: Li. Z: Enelow. R: Gandolfi. AJ: Madan. J: Nadeau. K: Karagas. MR. (2013). Inutero
arsenic exposure and infant infection in a United States cohort: A prospective study. Environ Res 126: 24-30.
http://dx.doi.0rg/10.1016/i.envres.2013.05.001
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Garcia-Esquinas. E: Pollan. M: Umans. JG: Francesconj KA: Goessler. W: Guallar. E: Howard. B: Farley. J:
Best LG: Navas-Acien. A. (2013). Arsenic exposure and cancer mortality in a US-based prospective cohort:
the strong heart study. Cancer Epidemiol Biomarkers Prev 22: 1944-1953. http://dx.doi.org/10.1158/1055-
9965.EPI-13-0234-T
Hsu. LI: Wang. YH: Chiou. HY: Wu. MM: Yang. TY: Chen. YH: Tseng. CH: Chea CJ. (2013). The association
of diabetes mellitus with subsequent internal cancers in the arsenic-exposed area of Taiwan. J Asian Earth
Sci 73: 452-459. http://dx.doi.0rg/10.1016/i.jseaes.2013.04.048
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Rahman. A: Vahter. M: Ekstrom EC: Persson. LA. (2011). Arsenic exposure in pregnancy increases the risk of
lower respiratory tract infection and diarrhea during infancy in Bangladesh. Environ Health Perspect 119:
719-724. http://dx.doi.org/10.1289/ehp. 1002265
Sawada. N: Iwasaki. M: Inoue. M: Takachj R: Sasazukj S: Yamaji. T: Shimazu. T: Tsugane. S. (2013). Dietary
arsenic intake and subsequent risk of cancer: The Japan Public Health Center-based (JPHC) prospective
study. Cancer Causes Control 24: 1403-1415. hrtp://dx.doi.org/10.1007/sl0552-013-0220-2
Sved. EH: Melkoniaa S: Poudel KG: Yasuoka. J: Otsuka. K: Ahmed. A: Islam T: Parvez. F: Slavkovich. V:
Graziano. JH: Ahsaa H: Jimba. M. (2013). Arsenic exposure and oral cavity lesions in Bangladesh. J Occup
EnvironMed 55: 59-66. http://dx.doi.org/10.1097/JOM.Ob013e31826bb686
Tsuda. T: Babazono. A: Yamamoto. E: Kurumatani. N: Mino. Y: Ogawa. T: Kishi. Y: Aoyama. H. (1995).
Ingested arsenic and internal cancer: A historical cohort study followed for 33 years. Am J Epidemiol 141:
198-209.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.6 Summary of Observational Epidemiology Studies for
Health Effect Category: Endocrine system effects
including Diabetes
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Chen et al. (2012a)
Study Type: cohort
(prospective)
Location: Taiwan
(Putai)
Population: subjects
from community-based
cohort from an
arseniasis endemic area
with a high prevalence
of black foot disease
n exposed: 111
n reference: 136
n total: 247
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure defined as the sum of the
products, derived by multiplying the
arsenic concentration in well water by
the duration of water consumption
during consecutive periods of living at
different villages
Population-Level Exposure:
700-930 mg/L - yr range
Outcome: metabolic syndrome (MetS)
cumulative arsenic exposure (CAE), mg/L - yr
Exp. Level n adjOR M
<12.6 NR 1 n/a
12.6-18.9 NR 1.01 0.48, 1.89
>18.9 NR 1.73 0.72,4.19
Stat Method: multiple logistic regression
Exposure Surrogate: drinking water
Exposure Description: information on
artesian well water usage collected for
each participant
Population-Level Exposure:
700-930 ng/L range
Outcome: metabolic syndrome (MetS)
well water arsenic concentration (tertiles), ug/L
Exp. Level n adjOR (CD
<700 NR 1 n/a
700-767.65 NR 1.25 0.66,2.39
>767.65 NR 1.24 0.65,2.37
Stat Method: multiple logistic regression
well water arsenic concentration by metabolic
syndrome status, ug/L
Exp. Level n mean (CD
no MetS NR 569.94 n/a
with MetS NR 684.39 n/a
Stat Method: Student's t-test
Chen et al. (2010c)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic TWA concentration calculated
from well water samples for a set of
5,966 contiguous wells in the area based
on drinking duration; subjects grouped
for analysis in quintiles
Outcome: diabetes
drinking water arsenic level (TWA): Model 1 (full
population) (quintiles), ug/L
Exp. Level
0.1-8.0
8.1-41.0
41.2-91.7
91.8-176.1
n
NR
NR
NR
NR
M
n/a
.85,1.91
.80, 1.81
.61, 1.47
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Population: Health
Effects of Arsenic
Longitudinal Study,
adult participants
n cases: 11,319
n control: n/a
Exposure Measures
Population-Level Exposure:
0.1-864 ng/L range
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from single
baseline sample for each individual
Population-Level Exposure:
1-205 ng/L range
Results
176.2-864.0 NR 1.08 .71, 1.65
Stat Method: Unconditional logistic regress
drinking water arsenic level (TWA): Model 2 (BMI
<20) (quintiles), u.g/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-41.0 NR 1.74 .86,3.49
41.2-91.7 NR 1.35 .65,2.79
91.8-176.1 NR 0.83 .37, 1.87
176.2-864.0 NR 0.66 .28, 1.56
Stat Method: Unconditional logistic
regression
drinking water arsenic level (TWA): Model 2 (BMI
> 20) (quintiles), ug/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-41.0 NR 1.02 .63, 1.67
41.2-91.7 NR 1.01 .62, 1.65
91.8-176.1 NR 0.86 .51, 1.42
176.2-864.0 NR 1.13 .70, 1.82
Stat Method: Unconditional logistic
regression
drinking water arsenic level (TWA): Model 2 (full
population) (quintiles), ug/L
Exp. Level n adiOR (CD
0.1-8.0 NR 1 n/a
8.1-41.0 NR 1.35 .9,2.02
41.2-91.7 NR 1.24 .82, 1.87
91.8-176.1 NR 0.96 0.62, 1.49
176.2-864.0 NR 1.11 .73, 1.69
Stat Method: Unconditional logistic
regression
Outcome: diabetes
urinary arsenic concentration: Model 1 (full
population) (quintiles), u.g/L
Exp. Level n adiOR (CD
1-36 NR 1 n/a
37-66 NR 1.29 0.87, 1.91
67-114 NR 0.99 0.65, 1.50
115-204 NR 0.9 0.59, 1.39
>205 NR 0.87 0.56,1.36
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Stat Method: Unconditional logistic
regression
urinary arsenic concentration: Model 2 (BMI <20
only) (quintiles), u.g/L
Exp. Level n adiOR (CD
1-36 NR 1 n/a
37-66 NR 1.53 .75,3.12
67-114 NR 1.11 .52,2.34
115-204 NR 0.51 .20, 1.27
>205 NR 0.7 .30,1.60
Stat Method: Unconditional logistic
regression
urinary arsenic concentration: Model 2 (BMI > 20
only) (quintiles), ug/L
Exp. Level n adiOR (CD
1-36 NR 1 n/a
37-66 NR 1.16 .72, 1.87
67-114 NR 1.01 .61, 1.68
115-204 NR 1.14 .7, 1.87
>205 NR 1.06 .62,1.8
Stat Method: Unconditional logistic
regression
urinary arsenic concentration: Model 2 (full
population) (quintiles), ug/L
Exp. Level n adiOR (CD
1-36 NR 1 n/a
37-66 NR 1.29 .87, 1.91
67-114 NR 1.05 .69, 1.59
115-204 NR 0.94 .61, 1.44
>205 NR 0.93 .59,1.45
Stat Method: Unconditional logistic
regression
urinary arsenic concentration: Model 3 (BMI <20
only) (quintiles), u.g/L
Exp. Level n adiOR (CD
1-36 NR 1 n/a
37-66 NR 1.62 .79,3.34
67-114 NR 1.23 .56,2.69
115-204 NR 0.59 .22, 1.55
>205 NR 0.87 .34,2.25
Stat Method: Unconditional logistic
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Chen et al. (2011a)
Study Type: cross-
sectional
Location: Taiwan
(Changhua County
(central Taiwan))
Population: adult
residents of village with
history of higher than
average arsenic in
drinking water
n cases: 910
n control: 133
Coronado-Gonzalez et
al. (2007)
Exposure Measures
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from spot
sample for each individual; results below
LOD assigned one-half of LOD
Population-Level Exposure:
85.13 ng/g-creatinine median
Exposure Surrogate: urine
Exposure Description: urinary arsenic
Results
regression
urinary arsenic concentration: Model 3 (BMI > 20
only) (quintiles), u.g/L
Exp. Level n adiOR (CD
1-36 NR 1 n/a
37-66 NR 1.35 .83,2.21
67-114 NR 1.17 .69, 1.98
115-204 NR 1.46 .85,2.51
>205 NR 1.41 .77,2.59
Stat Method: Unconditional logistic
regression
urinary arsenic concentration: Model 3 (full
population) (quintiles), ug/L
Exp. Level n adiOR (CD
1-36 NR 1 n/a
37-66 NR 1.44 .97,2.17
67-114 NR 1.2 .77, 1.85
115-204 NR 1.16 .73, 1.85
>205 NR 1.22 .73,2.03
Stat Method: Unconditional logistic
regression
Outcome: diabetes mellitus
urinary arsenic concentration, u.g/g-creatinine
Exp. Level n adiOR (CD
=<35 NR 1 n/a
>35-75 NR 1.95 0.56,2.66
>75-200 NR 2.08 1.05,3.69
>200 NR 2.22 1.21,4.09
Stat Method: Multivariate logistic regression
Outcome: Type 2 diabetes mellitus
urinary arsenic concentration (50 u.g/g cutoff
tertiles), ug/g-creatinine
Exp. Level n adiOR (CD
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Study Type: case-
control
Location: Mexico
(Coahuila)
Population: adult
residents of arseniasis-
endemic region
n cases: 200
n control: 200
concentration measured from spot
sample for each individual; subjects
grouped for analysis in tertiles
Population-Level Exposure:
35-104 ng/g-creatinine range
<50 NR 1 n/a
50-100 NR 1.41 0.57,3.47
>100 NR 2.35 0.94,5.91
Stat Method: multivariate analysis model
with unconditional logistic regression
urinary arsenic concentration (ACGIH cutoff
tertiles), u.g/g-creatinine
Exp. Level n adjOR M
<35 NR 1 n/a
35-100 NR 1.58 0.83,3.02
>100 NR 2.45 1.27,4.73
Stat Method: multivariate analysis model
with unconditional logistic regression
urinary arsenic concentration (tertiles in
controls), ug/g-creatinine
Exp. Level n adjOR (CD
<63.5 NR 1 n/a
63.5-104 NR 2.16 1.23,3.79
>104 NR 2.84 1.64,4.92
Stat Method: multivariate analysis model
with unconditional logistic regression
urinary arsenic concentration (50 ug/g cutoff
tertiles), ug/g-creatinine
Exp. Level
<50
50-100
>100
n
NR
NR
NR
OR
1
1.56
2.45
M
n/a
0.81, 3.03
1.27, 4.80
Stat Method: multivariate analysis model
with unconditional logistic regression
urinary arsenic concentration (ACGIH cutoff
tertiles), u.g/g-creatinine
Exp. Level
<35
35-100
>100
NR
NR
NR
OR
1
1.12
1.95
M
n/a
0.44, 2.97
0.75, 5.20
Stat Method: multivariate analysis model
with unconditional logistic regression
urinary arsenic concentration (tertiles in
controls), ug/g-creatinine
Exp. Level n OR (CD
<63.5 NR 1 n/a
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
63.5-104 NR 1.94 1.11,3.41
>104 NR 2.65 1.54,4.58
Stat Method: multivariate analysis model
with unconditional logistic regression
Del Razo et al. (2011)
Study Type: cross-
sectional
Location: Mexico
(Zimapan and
Lagunera)
Population: residents
of arsenicosis-endemic
areas of Mexico
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: each subject
provided a sample of water used for
drinking; cumulative exposure estimated
from measurements of current and
historical concentrations of inorganic
arsenic in drinking water and duration of
exposure; estimates generated for 1993-
2008 period and for 5-year segments
1993-1997, 1998-2002, and 2003-2007
Population-Level Exposure:
0-6.73 ppm-years range
Outcome: diabetes mellitus
cumulative inorganic arsenic exposure
concentration in drinking water, ppm-years
Exp. Level n adjOR M
cumulative NR 1.03 0.77, 1.39
exposure
1993-2008
cumulative NR 3.57 0.9,14.19
exposure
2003-2007
cumulative NR 0.98 0.41,2.37
exposure
1998-2002
cumulative NR 0.88 0.52, 1.48
exposure
1993-1997
Stat Method: logistical regression
Exposure Surrogate: drinking water
Exposure Description: each subject
provided a sample of water used for
drinking; mean inorganic arsenic
concentrations in drinking water: 77.3
and 39.2 for diabetic and non-diabetic
subpopulations, respectively
Population-Level Exposure:
3.1-215.2 ppb range
Outcome: diabetes mellitus
concentration of inorganic arsenic in drinking
water, ppb
Exp. Level n adjOR {G}
current NR 1.13 1.05, 1.22
concentratio
n
NR NR NR n/a
Stat Method: logistical regression
Outcome: fasting plasma insulin (FPI)
concentration of inorganic arsenic in drinking
water (log-transformed), ppb
Exp. Level n adiBeta (CD
continuous NR -2.084 -2.72,-1.448
Stat Method: linear regression, with log-
transformation
Outcome: homeostatic model assessment -
insulin resistance (HOMA-IR)
concentration of inorganic arsenic in drinking
water (log-transformed), ppb
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Exp. Level n ad I Beta (CD
continuous NR -1.641 -2.358,-0.924
Stat Method: linear regression, with log-
transformation
Exposure Surrogate: urine
Exposure Description: spot urine sample
collected from each subject during the
medical exam; concentrations of
inorganic arsenic and methylated
metabolites measured to assess
inorganic arsenic metabolism
Population-Level Exposure:
2.3-233.7 ng/mL range
Outcome: diabetes mellitus
urinary total arsenic concentration, ng/mL
Exp. Level n adjOR M
urinary tAs NR 1.12 0.78,1.62
Stat Method: logistic regression
Outcome: fasting plasma insulin (FPI)
urinary total arsenic concentration (log-
transformed), ng/mL
Exp. Level n adiBeta (CD
continuous NR -5.313 -8.068,-2.559
Stat Method: linear regression, with log-
transformation
Outcome: homeostatic model assessment -
insulin resistance (HOMA-IR)
urinary total arsenic concentration (log-
transformed), ng/mL
Exp. Level n ad i Beta (CD
continuous NR -4.538 -7.514,-1.562
Stat Method: linear regression, with log-
transformation
Ettingeretal. (2009)
Study Type: cohort
(prospective)
Location: United States
(Tar Creek Superfund
site, Ottawa County,
OK)
Population: pregnant
women living near
Superfund site
n exposed: 399
Exposure Surrogate: blood
Exposure Description: whole-blood
arsenic concentration determined from
blood samples collected at delivery;
grouped for analysis in quartiles
Population-Level Exposure:
1.7 ng/Lgeo mean 1.5SD
Outcome: impaired glucose tolerance
blood arsenic concentration (IQR), ug/L
Exp. Level n adjOR (CD
1.2 NR 1.65 0.521.52, 1.79
Stat Method: Multivariate logistic regression
blood arsenic concentration (quartile),
Exp. Level
0.23-0.92
0.93-1.39
1.4-2.08
2.09-24.07
NR
NR
NR
NR
M
n/a
0.39, 2.69
1.12,6.36
1.13,6.87
Stat Method: Multivariate logistic regression
Exposure Surrogate: hair
Outcome: impaired glucose tolerance
hair arsenic concentration (IQR), ng/g
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
n reference: 133
n total: 532
Garcfa-Esquinas et al.
(2013)
Study Type: cohort
(prospective)
Location: United States
(AZ;ND;OK;SD)
Population: Strong
Heart Study
participants
n total: 3,935
Gribble et al. (2012)
Study Type: cross-
sectional
Location: United States
(Arizona; Oklahoma;
North Dakota; South
Dakota)
Population: Strong
Heart Study, adults
with stored urine
samples available
n cases: 2,954
n control: 971
Guo et al. (2007)
Exposure Measures
Exposure Description: hair arsenic
concentration determined from hair
samples collected at delivery from
population subset with chemically
untreated hair; grouped for analysis in
quartiles
Population-Level Exposure:
27.4 ng/g geo mean
Exposure Surrogate: urine
Exposure Description: individual urine
samples collected and analyzed for
arsenic speciation
Population-Level Exposure:
9.7 ng/g-creatinine median, 5.8-15.6
Hg/g-creatinine 25th percentile
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from spot
sample for each individual; subjects
grouped for analysis in quartiles
Population-Level Exposure:
14.1 ng/L median, 7.9-24.2 ng/L 25th
percentile
Exposure Surrogate: drinking water
Results
Exp. Level n adiOR (CD
15.3 NR 2.32 0.52, 10.39
Stat Method: Multivariate logistic regression
hair arsenic concentration (quartile), ng/g
Exp. Level n adiOR (CD
1.1-8.81 NR 1 n/a
8.93-13.11 NR 3.97 0.62,25.37
13.26-24.12 NR 5.77 0.98,33.88
24.22-724.41 NR 4.2 0.74,23.86
Stat Method: Multivariate logistic regression
Outcome: pancreatic cancer
urinary arsenic concentration, ug/g-creatinine
Exp. Level n HR (CD
80th vs. 20th 25 2.46 1.09,5.58
percentiles
Stat Method: Cox proportional hazard
models; log transformed
Outcome: diabetes
urinary arsenic concentration, u.g/L
Exp. Level n adiPR (CD
25th NR 1 n/a
percentile
75th NR 1.14 1.08, 1.20
percentile
Stat Method: Poisson regression models
urinary arsenic concentration (quartiles), u.g/L
Exp. Level n adiPR (CD
<7.9 413 1 n/a
7.9-14.1 492 1.15 1.04,1.27
14.1-24.2 503 1.21 1.08,1.34
>24.2 531 1.28 1.14, 1.44
Stat Method: Poisson regression models
Outcome: glucosuria
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Study Type: cross-
sectional
Location: Mongolia
region not available
Population: residents
of villages in the Hetao
Plain, Inner Mongolia
n cases: 680
n control: 189
Exposure Description: arsenic samples
from 94 water sources, including wells;
arsenic exposure determined by location
of village
Population-Level Exposure:
50-1,860 ng/L range
water arsenic concentration, \ng/L
arsenic not significantly associated with glucosuria
Hsieh et al. (2008a)
Study Type: case-
control (nested)
Location: Taiwan
(Lanyang Basin
(arsenic-exposed
population))
Population: adult male
residents of Taiwan
from existing cohort
n cases: 129
n control: 48
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations determined from
well water samples collected during
home interview
Population-Level Exposure:
0.15-3,590 ppb range
Outcome: free testosterone (nmol/L)
drinking water arsenic concentration, ppb
Exp. Level ri mean (CD
<50 NR 0.38 n/a
>50 NR 0.31 n/a
Stat Method: ANOVA
Outcome: sex hormone-binding globulin (SHBG)
(nmol/L)
drinking water arsenic concentration, ppb
average level of SHBG not significantly different
between subjects with or without arsenic
exposure
Outcome: testosterone (nmol/L)
drinking water arsenic concentration, ppb
Exp. Level n mean (CD
<50 NR 17.55 n/a
>50 NR 15.04 n/a
Stat Method: ANOVA
Hsu et al. (2013b)
Study Type: cohort
(prospective)
Location: Taiwan (SW:
Peimen, Hsuechia, Ichu,
and Putai Townships;
Exposure Surrogate: drinking water
Exposure Description: SW population:
median arsenic level of several wells
shared in a village derived from two
surveys; NE population: arsenic level of
well water samples collected during
home interviews
Outcome: diabetes mellitus (DM)
arsenic concentration in well water, \ng/L
Exp. Level
10-49.9
50-99.9
100-499.9
>500
missing
ri
774
505
217
397
520
595
Prev
30.8
26.4
25.8
31
43.4
33.3
M
n/a
n/a
n/a
n/a
n/a
n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-132 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
NE: Chiaohsi,
Chuangwei, Wuchieh,
andTungshan
Townships)
Population: residents
of an arseniasis-
endemic area with and
without skin lesions
n total: 9,525
Stat Method: not reported
Population-Level Exposure:
10-500 ng/L range
Outcome: pancreatic cancer
arsenic concentration in well water (non-
diabetes mellitus vs. diabetes mellitus subjects),
HR
1
Exp. Level n
non-DMw/ NR
As <500
DMw/As NR
<500
non-DMw/ NR
As > 500
DMw/As NR
>500
Stat Method: Cox regression analysis
3.03
1
1.86
(CD
n/a
1.22,7.55
n/a
0.38,9.02
Islam etal. (2012b)
Study Type: cross-
sectional
Location: Bangladesh
(Kandirpar,
Gobindogonj, Uttarda,
Modaffargonj,
Jolmuttar, Sunorpur,
Durgapur)
Population: adults
living in unions of high
arsenic contamination
n cases: 89
n control: 915
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated by multiplying
arsenic concentration of single tube well
measurement for each individual with
self-reported duration of use; subjects
grouped for analysis above and below
maximum acceptable limit in drinking
water in Bangladesh (50 ng/L) and as
quartiles
Population-Level Exposure:
159 ng/L mean 198.5SD
Outcome: type 2 diabetes
cumulative drinking water arsenic exposure,
Exp. Level n adjOR (CD
<50 NR 1 n/a
>50 NR 2.1 1.3,3.2
Stat Method: multivariate logistic regression
cumulative drinking water arsenic exposure
(quartiles), u.g/L
Exp. Level
<22
23-32
33-261
>262
n
NR
NR
NR
NR
M
n/a
0.5, 2.3
0.5, 3.2
1.1,3.5
Stat Method: multivariate logistic regression
James et al. (2013)
Study Type: case-
cohort
Location: United States
(CO)
Exposure Surrogate: drinking water
Exposure Description: residential water
samples (both private well and public
water) collected at time of interview
(n=334); arsenic concentrations in the
San Luis Valley ranged from non-
detectable to 752 ng/L with a mean
Outcome: diabetes mellitus (DM)
arsenic exposure TWA, per 15 ug/L
Exp. Level n HR (CD
per 15 ug/L NR 1.27 1.02, 1.64
increase in
TWA arsenic
Stat Method: Cox proportional hazards model
arsenic exposure TWA, u.g/L-year
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-133 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Population: San Luis
Valley Diabetes Study
(SLVDS) participants
with type II diabetes
mellitus
n cases: 141
n control: 347
concentration of 39 |jg/L
Population-Level Exposure:
39 |jg/L-year mean, 0-752 ng/L-year
range
Exp. Level
l-<4
4-<8
8-<20
> 20
n
NR
NR
NR
NR
HR
1
1.11
1.42
1.55
M
n/a
0.82, 1.95
0.94, 2.48
1.00, 2.51
Stat Method: Cox proportional hazards model
Jensen and Hansen
(1998)
Study Type: cross-
sectional
Location: Denmark
region not available
Population:
occupationally exposed
adult workers
n cases: 40
n control: 26
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration determined from two
urine samples collected from each
individual
Population-Level Exposure:
12-80 nmol/mmol creatinine range
Outcome: HbAlc
urinary arsenic concentration, nmol/mmol
creatinine
Exp. Level n adiBeta (CD
continuous NR 0.0078 n/a
Stat Method: multiple regression
Kim and Lee (2011)
Study Type: cross-
sectional
Location: South Korea
(national)
Population: KNHANES
IV 2008, adult
participants
n cases: 1,677
n control: n/a
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from single
sample for each individual
Population-Level Exposure:
118.4 ng/g-creatinine geo mean, 112.9-
123.8 ng/g-creatinine 95% Cl lower
Outcome: diabetes mellitus
log-transformed total urinary arsenic
concentration, u.g/g-creatinine
Exp. Level n adjOR M
continuous NR 1.502 1.038,2.171
(females)
continuous NR 1.126 0.803, 1.577
(males)
Continuous NR 1.312 1.040, 1.655
(all)
Stat Method: multiple logistic regression
log-transformed total urinary arsenic -female,
Hg/g-creatinine
Exp. Level n adjRR (Cl)
diabetes-no NR 1 n/a
diabetes- NR 1.238 1.025,1.494
yes
Stat Method: multiple regression
log-transformed total urinary arsenic - male,
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Hg/g-creatinine
Exp. Level n
diabetes-no NR
diabetes- NR
yes
M
n/a
0.894, 1.316
Stat Method: multiple regression
log-transformed total urinary arsenic - comb sex,
ng/g-creatinine
Exp. Level n
diabetes-no NR
diabetes- NR
yes
M
n/a
1.014, 1.314
Stat Method: multiple regression
Kim et al. (2013)
Study Type: case-
control (nested)
Location: United States
(Arizona)
Population:
longitudinal study
participants who
developed diabetes
within 10 years of
initial screening
n cases: 150
n control: 150
Exposure Surrogate: urine
Exposure Description: concentrations of
arsenic (total and inorganic) and
metabolites measured in stored urine
samples obtained at the baseline
examination; adjusted for urinary
creatinine
Population-Level Exposure:
21.1 ng/L median, 15.3-29.4 ng/L 25th
percentile
Outcome: mean 2-hour postload plasma glucose
total arsenic concentration, ng/L
2-hour postload plasma glucose was correlated
negatively with MMA and %MMA; correlations
only changed slightly when adjusted for potential
confounders
Outcome: mean fasting plasma glucose
total arsenic concentration, \ng/L
fasting plasma glucose was correlated negatively
with %MMA and positively with total arsenic,
inorganic arsenic, and DMA; correlations only
changed slightly when adjusted for potential
confounders
Outcome: type 2 diabetes (Model 3)
inorganic arsenic concentration, \ig/L
Exp. Level n adjOR M
continuous 150 1.16 0.89, 1.53
Stat Method: logistic regression
inorganic arsenic concentration (quartiles), \ng/L
Exp. Level n adjOR {G}
quartile 1 NR 1 n/a
quartiles 2-4 NR 2.14 1.19,3.85
Stat Method: logistic regression
total arsenic concentration, \ng/L
Exp. Level n adjOR
continuous 150 1.11 0.79, 1.57
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-135 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Stat Method: logistic regression
Lai et al. (1994)
Study Type: cross-
sectional
Location: Taiwan
(Homei, Fuhsin, and
Hsinming villages (Putai
Township))
Population: adults
living in arseniasis-
endemic township
n cases: 610
n control: 108
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated as the drinking
water arsenic concentration multiplied
by self-reported years living in a
particular village and added across
individual's lifetime; arsenic levels in well
water collected in previous studies
conducted in the 1960s; exposure not
calculated for 19.4% due to lack of
arsenic measurements in areas outside
endemic area
Population-Level Exposure:
0-15.1 ppm-years range
Outcome: diabetes mellitus
Duration of drinking artesian well water (years),
ppm-years
Exp. Level
0 years
1-10 years
11-20 years
> 21 years
n
NR
NR
NR
NR
M
n/a
Stat Method: Mantel-Haenszel chi-square
test
cumulative drinking water arsenic exposure,
ppm-years
Exp. Level
0
0.1-15.0
>15.1
Unknown
n
NR
NR
NR
NR
n/a
0.86,51.0
1.30,77.9
0.71,45.5
Stat Method: multivariate logistic regression
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: deceased
male and female
members of Latter-day
Saints church wards
n exposed: 2,203
n total: 2,203
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Outcome: diabetes mellitus
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR (CD
< 1,000 NR 1.14 n/a
1,000-4,999 NR 1.72 n/a
> 5,000 NR 0.89 n/a
Stat Method: standardized mortality ratio;
OCMAP adapted to nonoccupational cohort
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR (CD
<1,000 NR 0.93 n/a
1,000-4,999 NR 0.95 n/a
> 5,000 NR 0.42 n/a
Stat Method: standardized mortality ratios
Outcome: pancreatic cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR M
< 1,000 NR NR n/a
1,000-4,999 NR 0.35 n/a
> 5,000 NR 0.31 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-136 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1,000 NR 0.21 n/a
1,000-4,999 NR 1.44 n/a
> 5,000 NR 0.86 n/a
Stat Method: standardized mortality ratios
Li et al. (2013a)
Study Type: cross-
sectional
Location: China
(Tuoketuo County,
Inner Mongolia)
Population: residents
exposed to arsenic in
drinking water
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration of each tube well
measured and provided by local public
health government; cumulative arsenic
exposure (CAE) calculated for each
subject as: concentration in tube well
that subject used in his/her residential
duration multiplied by duration of water
consumption
Population-Level Exposure:
0-760 ng/L range
Outcome: type 2 diabetes (T2D)
water arsenic concentration,
Exp. Level n adjOR
<10 NR NR
10-50 NR 1.362
>50 NR 1.578
n/a
0.519,3.571
0.584,4.262
Stat Method: multiple logistic regression
Navas-Acien et al.
(2008)
Study Type: cross-
sectional
Location: United States
region not available
Population: NHANES
2003-2008, adult
participants who had
fasted before
venipuncture
n cases: 788
n control: n/a
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from spot
sample for each individual; subjects
grouped for analysis in tertiles
Population-Level Exposure:
4.8-10.8 ng/L range
Outcome: diabetes, type 2
urinary arsenic concentration
,ug/L
Exp. Level n adjOR (CD
20th NR 1 n/a
percentile
80th NR 3.58 1.18, 10.83
percentile
Stat Method: logistic regression
urinary arsenic concentration
(tertiles), ug/L
Exp. Level n
<4.8 NR
4.8-10.8 NR
>10.8 NR
M
n/a
0.36, 4.48
0.46, 5.54
Stat Method: logistic regression
Navas-Acien et al.
Exposure Surrogate: urine
Outcome: Type 2 diabetes
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-137 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
(2009)
Study Type: cross-
sectional
Location: United States
region not available
Population: NHANES
2003-2006, adult
participants who had
fasted before
venipuncture
n cases: n/a
n control: n/a
Exposure Description: urinary arsenic
concentration measured from spot
sample for each individual
Population-Level Exposure:
7.4 ng/L median
urinary arsenic concentration, ug/L
Exp. Level n adjOR
20th NR 1 n/a
percentile
80th NR 2.86 1.23,6.63
percentile
Stat Method: Statistical methods were
conducted in a similar manner to Navas-
Acien 2008
urinary arsenic concentration, ug/L
Exp. Level n adjOR (CD
<20th NR 1 n/a
percentile
>80th NR 1.78 0.6,5.30
percentile
Stat Method: Statistical methods were
conducted in a similar manner to Navas-
Acien 2008
urinary arsenic concentration in participants with
undetectable (<0.4 u.g/L) arsenobetaine, u.g/L
Exp. Level n adjOR M
20th NR 1 n/a
percentile
80th NR 2.6 1.12,6.03
percentile
Stat Method: Statistical methods were
conducted in a similar manner to Navas-
Acien 2008
urinary arsenic concentration in participants with
undetectable (<0.4 ug/L) arsenobetaine, ug/L
Exp. Level n adjOR M
<20th NR 1 n/a
percentile
>80th NR 4.26 0.83,21.8
percentile
Stat Method: Statistical methods were
conducted in a similar manner to Navas-
Acien 2008
urinary arsenic concentration minus
arsenobetaine and arsenocholine, ug/L
Exp. Level n adjOR M
20th NR 1 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
percentile
80th NR 1.72 0.85,3.45
percentile
Stat Method: Statistical methods were
conducted in a similar manner to Navas-
Acien 2008
urinary arsenic concentration minus
arsenobetaine and arsenocholine, u.g/L
Exp. Level n adjOR M
<20th NR 1 n/a
percentile
>80th NR 1.04 0.3,3.59
percentile
Stat Method: Statistical methods were
conducted in a similar manner to Navas-
Acien 2008
Nizam et al. (2013)
Study Type: case-
control
Location: Bangladesh
(Faridpur District, 130
km southwest of
Dhaka)
Population: adults in
arsenic-contaminated
area with type II
diabetes
n cases: 140
n control: 180
Exposure Surrogate: urine
Exposure Description: spot urine sample
collected at time of recruitment; arsenic
species measured; mean (95% Cl) for
absolute urinary inorganic arsenic was 20
(15.7-23.8) and 21.2 (17.9-24.5) for cases
and controls, respectively
Population-Level Exposure:
15.7-24.5 ng/L range
Outcome: type 2 diabetes
urinary inorganic arsenic percent of total
Exp. Level n mean (Cl)
non-diabetic 0 10.5 n/a
controls
diabetic 140 9.5 n/a
cases
Stat Method: three-way analysis of variance
with case-control and matching factors (sex
and union) as the fixed factors
Pan et al. (2013)
Study Type: case-
control
Location: Bangladesh
region not available
Exposure Surrogate: drinking water
Exposure Description: drinking water
collected for each individual from tube
well identified as primary drinking water
source; samples below LOD assigned
value of 0.5 ng/L; average recovery of
95%
Outcome: type 2 diabetes mellitus (T2DM)
arsenic concentration in drinking water
(quartiles), u.g/L
Exp. Level
<1.7
1.8-15.5
15.6-170.0
> 170.1
11
19
24
28
M
n/a
0.84, 4.35
1.38, 6.85
2.01, 10.09
Stat Method: logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
Population: adults with
type II diabetes mellitus
and varying levels of
arsenic exposure from
drinking water
n cases: 84
n control: 849
Population-Level Exposure:
1.7-170.1 |jg/L range
Exposure Surrogate: toenails
Exposure Description: toenail samples
collected from each individual;
concentrations corrected for systematic
errors by normalizing sample
concentration against measured average
daily NIST arsenic concentration; average
recovery of 86.5%
Population-Level Exposure:
0.93-6.19 |jg/g range
Outcome: type 2 diabetes mellitus (T2DM)
arsenic concentration in toenail samples
(quartiles), ng/g
adjOR
1
3.34
3.4
Exp. Level
<0.93
0.94-2.12
2.13-6.18
>6.19
n
10
24
22
28
6.22
M
n/a
1.46, 7.64
1.46, 7.89
2.63, 14.69
Stat Method: logistic regression
Rhee et al. (2013)
Study Type: cross-
sectional
Location: Korea,
Republic Of region not
available
Population: adults in
Korea National Health
and Nutrition
Examination Survey
(KNHANES)
n cases: n/a
n control: n/a
Exposure Surrogate: urine
Exposure Description: urine samples
collected after a fast of 8 hours; clean
mid-stream urine collected for analysis;
all samples had concentrations >LOD;
inter-assay coefficients of variation for
the urinary arsenic assay were 2.5-3.2%
in 2008 and 2.3-4.3% in 2009
Population-Level Exposure:
70.7-193.4 ng/g-creatinine range
Outcome: diabetes mellitus (DM)
urinary total arsenic concentration (quartiles),
ug/g-creatinine
H adjOR
NR 1
NR 1.11
NR 1.42
Exp. Level
<70.7
70.7-117.7
117.7-<193.4
> 193.4
NR
1.56
M
n/a
0.73, 1.68
0.94, 2.13
1.03, 2.36
Stat Method: logistic regression analysis
Outcome: glucose tolerance status
urinary total arsenic concentration, ug/g-
creatinine
arsenic not significantly associated with glucose
tolerance
Outcome: insulin resistance (HOMA2%S)
urinary total arsenic concentration, ug/g-
creatinine
arsenic not significantly associated with
HOMA2%S
Outcome: insulin secretion capacity (HOMA2%B)
urinary total arsenic concentration, ug/g-
creatinine
Exp. Level n adiBeta (CD
continuous NR -0.04 n/a
Stat Method: multivariate regression analysis
Sawada et al. (2013)
Exposure Surrogate: diet
Outcome: pancreas cancer
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Study Type: cohort
(prospective)
Location: Japan (Iwate,
Akita, Nagano,
Okinawa, Tokyo,
Ibaraki, Niigata, Kochi,
Nagasaki, Osaka)
Population: adults in
Japan Public Health
Center (JPHC)
Prospective Study
cohort
n total: 90,378
Steinmaus et al. (2009)
Study Type: cross-
sectional
Location: United States
(National)
Population: NHANES
2003-2004, adult
participants who had
fasted before
venipuncture
n cases: 795
n control: n/a
Exposure Measures
Exposure Description: detailed
questionnaire on food intake/frequency;
average arsenic concentrations in food
items obtained from the literature;
arsenic intake calculated by multiplying
average arsenic concentration in each
item by quantity consumed
Population-Level Exposure:
170 ng/day mean, 88.3-253.2 ng/day
range
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from spot
sample for each individual; subjects
grouped for analysis in tertiles
Population-Level Exposure:
16.7 ng/L mean 39.7SD
Results
inorganic arsenic intake (females; quartiles),
ug/day
Exp. Level n HR (CD
40.6 20 1 n/a
53.7 31 1.62 0.91,2.88
62.6 27 1.38 0.76,2.51
105.7 27 1.37 0.75,2.49
Stat Method: Multivariate regression
inorganic arsenic intake {males; quartiles),
ug/day
Exp. Level n HR (CD
40.5 34 1 n/a
54.7 31 0.8 0.49, 1.32
63.5 46 1.14 0.72, 1.8
99.1 31 0.78 0.47, 1.29
Stat Method: Multivariate regression
Outcome: Type 2 diabetes mellitus
estimated inorganic urinary arsenic
concentration (tertiles), ug/L
Exp. Level n adiOR (CD
<4.1 NR 1 n/a
4.2-8.5 NR 0.63 0.34, 1.15
>8.5 NR 0.98 0.53, 1.80
Stat Method: Logistic regression with non-log
transformed data
urinary arsenic concentration, ug/L
Exp. Level n adiOR (CD
=<20th NR 1 n/a
(=<3.5)
>80th NR 0.88 0.39,1.97
(> 18.3)
Stat Method: Logistic regression with non-log
transformed data
urinary arsenic concentration {tertiles), ug/L
Exp. Level n adiOR (CD
=<5.2 NR 1 n/a
5.3-11.8 NR 0.87 0.48, 1.55
>11.8 NR 0.76 0.42, 1.39
Stat Method: Logistic regression with non-log
transformed data
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
estimated inorganic urinary arsenic
concentration, u.g/L
Exp. Level n OR (CD
=<20th NR 1 n/a
NR
1.12
0.59,2.15
>80th
(> 11.9)
Stat Method: Logistic regression with non-log
transformed data
estimated inorganic urinary arsenic
concentration (tertiles), u.g/L
Exp. Level
<4.1
4.2-8.5
>8.5
n
NR
NR
NR
OR
1
0.77
0.9
M
n/a
0.46, 1.30
0.54, 1.49
Stat Method: Logistic regression with non-log
transformed data
urinary arsenic concentration, u.g/L
Exp. Level n OR (CD
=<20th NR 1 n/a
(=<3.5)
>80th NR 0.8 0.41,1.59
(> 18.3)
Stat Method: Logistic regression with non-log
transformed data
urinary arsenic concentration (tertiles), ug/L
Exp. Level n OR (Cl)
=<5.2 NR 1 n/a
5.3-11.8 NR 0.9 0.54, 1.49
>11.8 NR 0.82 0.49, 1.38
Stat Method: Logistic regression with non-log
transformed data
estimated inorganic urinary arsenic
concentration, u.g/L
Exp. Level n adjOR
=<20th NR 1 n/a
NR
1.15
0.53,2.50
>80th
(> 11.9)
Stat Method: Logistic regression with non-log
transformed data; age, BMI, blood mercury,
urinary creatinine, urinary albumin, and
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Endocrine System Effects including
Diabetes
Reference and Study
Design
Exposure Measures
Results
serum cotinine
were entered as continuous variables
Tseng et al. (2000)
Study Type: cohort
(prospective)
Location: Taiwan (three
villages on southwest
coast)
Population: adult
residents of arseniasis-
endemic villages
n exposed: 446
n reference: Not
reported
n total: 446
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated based on arsenic
concentration in well water and self-
reported years of drinking well water
during successive periods of living in
different villages
Population-Level Exposure:
17-17 mg/L x yr range
Outcome: diabetes mellitus
cumulative drinking water arsenic exposure,
mg/L x yr
Exp. Level n adjRR M
<17 NR 1 n/a
>17 NR 2.1 1.1,4.2
Stat Method: Cox's proportional hazards
model
cumulative drinking water arsenic exposure,
mg/L x yr
Exp. Level n RR (CD
<17 NR 1 n/a
>17 NR 2.5 1.4,4.7
Stat Method: Cox's proportional hazards
model
--: not reported; n: number of cases (when presented in Results column)
5.6.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Endocrine System Effects Including
Diabetes
Chen. JW: Chen. HY: Li. WF: Liou. SH: Chen. CJ: Wu. JH: Wang. SL. (2011). The association between total
urinary arsenic concentration and renal dysfunction in a community-based population from central Taiwan.
Chemosphere 84: 17-24. http://dx.doi.0rg/10.1016/i.chemosphere.2011.02.091
Chen. JW: Wang. SL: Wang. YH: Sua CW: Huang. YL: Chea CJ: Li. WF. (2012). Arsenic methylation,
GSTO1 polymorphisms, and metabolic syndrome in an arseniasis endemic area of southwestern Taiwan.
Chemosphere 88: 432-438. http://dx.doi.0rg/10.1016/i.chemosphere.2012.02.059
Chen. Y: Ahsaa H: Slavkovich. V: Peltier. GL: Gluskin. RT: Parvez. F: Liu. X: Graziano. JH. (2010). No
association between arsenic exposure from drinking water and diabetes mellitus: a cross-sectional study in
Bangladesh. Environ Health Perspect 118: 1299-1305. http://dx.doi.org/10.1289/ehp.0901559
Coronado-Gonzalez. JA: Del Razo. LM: Garcia-Vargas. G: Sanmiguel-Salazar. F: Escobedo-De la Pena. J.
(2007). Inorganic arsenic exposure and type 2 diabetes mellitus in Mexico. Environ Res 104: 383-389.
http://dx.doi.0rg/10.1016/i.envres.2007.03.004
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Del Razo. LM: Garcia-Vargas. GG: Valenzuela. OL: Castellanos. EH: Sanchez-Pena. LC: Currier. JM: Drobna.
Z: Loomis. D: Stvblo. M. (2011). Exposure to arsenic in drinking water is associated with increased
prevalence of diabetes: a cross-sectional study in the Zimapan and Lagunera regions in Mexico. Environ
Health 10: 73. http://dx.doi.org/10.1186/1476-069X-10-73
Ettinger. AS: Zota. AR: Cj Amarasiriwardena. CJ: Hopkins. MR: Schwartz. J: Hu. H: Wright RO. (2009).
Maternal arsenic exposure and impaired glucose tolerance during pregnancy. Environ Health Perspect 117:
1059-1064. http://dx.doi.org/10.1289/ehp0800533
Garcia-Esquinas. E: Pollan. M: Umans. JG: Francesconi. KA: Goessler. W: Guallar. E: Howard. B: Farley. J:
Best LG: Navas-Acien. A. (2013). Arsenic exposure and cancer mortality in a US-based prospective cohort:
the strong heart study. Cancer Epidemiol Biomarkers Prev 22: 1944-1953. http://dx.doi.org/10.1158/1055-
9965.EPI-13-0234-T
Gribble. MO: Howard. BV: Umans. JG: Shara. NM: Francesconi. KA: Goessler. W: Crainiceanu. CM:
Silbergeld. EK: Guallar. E: Navas-Acien. A. (2012). Arsenic exposure, diabetes prevalence, and diabetes
control in the strong heart study. Am J Epidemiol 176: 865-874. http://dx.doi.org/10.1093/aie/kwsl53
Guo. JX: Hu. L: Yand. PZ: Tanabe. K: Miyatalre. M: Chen. Y. (2007). Chronic arsenic poisoning in drinking
water in Inner Mongolia and its associated health effects. J Environ Sci Health A Tox Hazard Subst Environ
Eng42: 1853-1858. http://dx.doi.org/10.1080/10934520701566918
Hsieh. FI: Hwang. TS: Hsieh. YC: Lo. HC: Su. CT: Hsu. HS: Chiou. HY: Chea CJ. (2008). Risk of erectile
dysfunction induced by arsenic exposure through well water consumption in Taiwan. Environ Health
Perspect 116: 532-536. http://dx.doi.org/10.1289/ehp. 10930
Hsu. LI: Wang. YH: Chiou. HY: Wu. MM: Yang. TY: Chen. YH: Tseng. CH: Chea CJ. (2013). The association
of diabetes mellitus with subsequent internal cancers in the arsenic-exposed area of Taiwan. J Asian Earth
Sci 73: 452-459. http://dx.doi.0rg/10.1016/i.jseaes.2013.04.048
Islam. R: Khan. I: Hassan. SN: McEvoy. M: D'Este. C: Attia. J: Peel R: Sultana. M: Akter. S: Milton. AH.
(2012). Association between type 2 diabetes and chronic arsenic exposure in drinking water: a cross sectional
study in Bangladesh. Environ Health 11: 38. http://dx.doi.org/10.1186/1476-069X-ll-38
James. KA: Marshall JA: Hokanson. JE: Meliker. JR: Zerbe. GO: Byers. TE. (2013). A case-cohort study
examining lifetime exposure to inorganic arsenic in drinking water and diabetes mellitus. Environ Res.
http://dx.doi.0rg/10.1016/i.envres.2013.02.005
Jensen. GE: Hansen. ML. (1998). Occupational arsenic exposure and glycosylated haemoglobin. Analyst 123:
77-80. http://dx.doi.org/10.1039/a705699k
Kim NH: Mason. CC: Nelson. RG: Afton. SE: Essader. AS: Medlin. JE: Levine. KE: Hoppin. JA: Lin. C:
Knowler. WC: Sandier. DP. (2013). Arsenic Exposure and Incidence of Type 2 Diabetes in Southwestern
American Indians. Am J Epidemiol. http://dx.doi.org/10.1093/aie/kws329
Kim Y: Lee. BK. (2011). Association between urinary arsenic and diabetes mellitus in the Korean general
population according to KNHANES 2008. Sci Total Environ 409: 4054-4062.
http://dx.doi.0rg/10.1016/i.scitotenv.2011.06.003
Lai. MS: Hsueh. YM: Chen. CJ: Shyu. MP: Chea SY: Kuo. TL: Wu. MM: Taj TY. (1994). Ingested inorganic
arsenic and prevalence of diabetes mellitus. Am J Epidemiol 139: 484-492.
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Li. X: Li. B: Xi. S: Zheng. Q: Lv. X: Sun. G. (2013). Prolonged environmental exposure of arsenic through
drinking water on the risk of hypertension and type 2 diabetes. Environ Sci Pollut Res Int 20: 8151-8161.
http://dx.doi.org/10.1007/sll356-013-1768-9
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Navas-Acien. A: Silbergeld. EK: Pastor-Barriuso. R: Guailar. E. (2008). Arsenic exposure and prevalence of
type 2 diabetes in US adults. JAMA 300: 814-822. http://dx.doi.0rg/10.1001/jama.300.7.814
Navas-Acien. A: Silbergeld. EK: Pastor-Barriuso. R: Guallar. E. (2009). Rejoinder: Arsenic exposure and
prevalence of type 2 diabetes: updated findings from the National Health Nutrition and Examination Survey,
2003-2006 [Comment]. Epidemiology 20: 816-820. http://dx.doi.org/10.1097/EDE.Ob013e3181afef88
Nizam. S: Kato. M: Yatsuva. H: Khalequzzaman. M: Ohnuma. S: Naito. H: Nakajima. T. (2013). Differences in
urinary arsenic metabolites between diabetic and non-diabetic subjects in Bangladesh. Int J Environ Res
Public Health 10: 1006-1019. http://dx.doi.org/10.3390/iierphl0031006
Pan. WC: Seow. WJ: Kile. ML: Hoffman. EB: Quamruzzaman. Q: Rahman. M: Mahiuddin. G: Mostofa. G: Lu.
Q: Christiani. DC. (2013). Association of low to moderate levels of arsenic exposure with risk of type 2
diabetes in Bangladesh. Am J Epidemiol 178: 1563-1570. http://dx.doi.org/10.1093/aie/kwtl95
Rhee. SY: Hwang. YC: Woo. JT: Chin. SO: Chon. S: Kim YS. (2013). Arsenic exposure and prevalence of
diabetes mellitus in Korean adults. J Korean Med Sci 28: 861-868.
http://dx.doi.0rg/10.3346/ikms.2013.28.6.861
Sawada. N: Iwasaki. M: Inoue. M: Takachj R: Sasazukj S: Yamaii T: Shimazu. T: Tsugane. S. (2013). Dietary
arsenic intake and subsequent risk of cancer: The Japan Public Health Center-based (JPHC) prospective
study. Cancer Causes Control 24: 1403-1415. http://dx.doi.org/10.1007/sl0552-013-0220-2
Steinmaus. C: Yuan. Y: Smith. AH. (2009). Low-level population exposure to inorganic arsenic in the United
States and diabetes mellitus: a reanalysis. Epidemiology 20: 807-815.
http://dx.doi.org/10.1097/EDE.Ob013e3181bOfd29
Tseng. CH: Tai. TY: Chong. CK: Tseng. CP: Lai. MS: Lin. BJ: Chiou. HY: Hsueh. YM: Hsu. KH: Chen. CJ.
(2000). Long-term arsenic exposure and incidence of non-insulin-dependent diabetes mellitus: a cohort study
in arseniasis-hyperendemic villages in Taiwan. Environ Health Perspect 108: 847-851.
http://dx.doi.org/10.1289/ehp.00108847
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.7 Summary of Observational Epidemiology Studies for
Health Effect Category: Hematology, Hematopoietic
System
Summary of Observational Epidemiology Studies for Health Effect Category: Hematology, Hematopoietic System
Reference and Study
Design
Exposure Measures
Results
Del Razo et al. (2011)
Study Type: cross-
sectional
Location: Mexico
(Zimapan and
Lagunera)
Population: residents
of arsenicosis-endemic
areas of Mexico
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: each subject
provided a sample of water used for
drinking; mean inorganic arsenic
concentrations in drinking water: 77.3
and 39.2 for diabetic and non-diabetic
subpopulations, respectively
Population-Level Exposure:
3.1-215.2 ppb range
Outcome: HbAlc levels
concentration of inorganic arsenic in drinking
water (log-transformed), ppb
Exp. Level n adiBeta (CD
continuous NR 0.193 0.018,0.369
Stat Method: linear regression, with log-
transformation
Exposure Surrogate: urine
Exposure Description: spot urine sample
collected from each subject during the
medical exam; concentrations of
inorganic arsenic and methylated
metabolites measured to assess
inorganic arsenic metabolism
Population-Level Exposure:
2.3-233.7 ng/mL range
Outcome: HbAlc levels
urinary total arsenic concentration (log-
transformed), ng/mL
Exp. Level n ad i Beta (CD
continuous NR 0.164 -0.57,0.898
Stat Method: linear regression, with log-
transformation
Guo et al. (2007)
Study Type: cross-
sectional
Location: Mongolia
Population: residents
of villages in the Hetao
Plain, Inner Mongolia
n cases: 680
n control: 189
Exposure Surrogate: drinking water
Exposure Description: arsenic samples
taken from 94 water sources, including
wells; detection limit not specified, but
authors note reliability of the method at
<10 ng/L; arsenic exposure determined
by location of village
Population-Level Exposure:
50-1,860 ng/L range
Outcome: anemia
water arsenic concentration, \ng/L
arsenic not significantly associated with anemia
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Hematology, Hematopoietic System
Reference and Study
Design
Heck et al. (2008)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study
(HEALS) cohort
n cases: n/a
n control: n/a
Maiumdar et al. (2009)
Study Type: cross-
sectional
Location: India (West
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: time-weighted
arsenic exposure calculated based on
drinking water duration from each well
as reported by participants and well
concentration measured in samples;
levels below detection reanalyzed using
ICP-MS with lower detection limit;
exposure groups split in to quartiles
(quartile concentrations not provided for
women)
Population-Level Exposure:
0-200 ng/L range
Exposure Surrogate: urine
Exposure Description: total urine arsenic
level measured in spot urine samples
Population-Level Exposure:
50-200 ng/L range
Exposure Surrogate: drinking water
Exposure Description: for each
participant, water samples from private
or public tube wells analyzed for arsenic;
exposure categories developed based on
Results
Outcome: hemoglobin
time-weighted well water arsenic concentration
(all men), ug/L
Exp. Level n mean (CD
0-<50 NR 13.9 n/a
50-<100 NR 13.9 n/a
100-<200 NR 13.9 n/a
>200 NR 13.8 n/a
Stat Method: generalized linear modeling
time-weighted well water arsenic concentration
quartiles (women with Hgb < 10 g/dL), ug/L
Exp. Level n mean (CD
lowest NR 8.2 n/a
quartile
2nd quartile NR 7.2 n/a
3rd quartile NR 7.1 n/a
highest NR 6.4 n/a
quartile
Stat Method: generalized linear modeling
Outcome: hemoglobin
urine arsenic level (all men), ug/L
Exp. Level n mean (CD
<50 NR 13.9 n/a
50-99 NR 13.8 n/a
100-199 NR 13.8 n/a
200 NR 13.6 n/a
Stat Method: generalized linear modeling
urine arsenic level (women with Hgb < 10 g/dL),
H9/L
Exp. Level n mean (CD
<50 NR 10.2 n/a
50-99 NR 9.3 n/a
100-199 NR 8 n/a
200 NR 8.2 n/a
Stat Method: generalized linear modeling
Outcome: anaemia
arsenic concentration in drinking water
(females), ug/L
Exp. Level n prevOR (Cl)
<50 NR 1 n/a
>500 NR 3.85 2.6,5.5
Stat Method: prevalence odds ratio
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Hematology, Hematopoietic System
Reference and Study
Design
Exposure Measures
Results
Bengal)
Population: residents
of arsenic-affected
villages with
comparison population
from low exposure area
n cases: 3,825
n control: 3,451
arsenic levels
Population-Level Exposure:
50-500 ug/L range
calculated for each outcome comparing
highest and lowest exposure levels
arsenic concentration in drinking water (males),
Exp. Level n prevOR (CD
<50 NR 1 n/a
>500 NR 2.41 1.3,4.2
Stat Method: prevalence odds ratio
calculated for each outcome comparing
highest and lowest exposure levels
--: not reported; n: number of cases (when presented in Results column)
5.7.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Hematology, Hematopoietic System
Del Razo. LM: Garcia-Vargas. GG: Valenzuela. OL: Castellanos. EH: Sanchez-Pena. LC: Currier. JM: Drobna.
Z: Loomis. D: Stvblo. M. (2011). Exposure to arsenic in drinking water is associated with increased
prevalence of diabetes: a cross-sectional study in the Zimapan and Lagunera regions in Mexico. Environ
Health 10: 73. http://dx.doi.org/10.1186/1476-069X-10-73
Guo. JX: Hu. L: Yand. PZ: Tanabe. K: Miyatalre. M: Chen. Y. (2007). Chronic arsenic poisoning in drinking
water in Inner Mongolia and its associated health effects. J Environ Sci Health A Tox Hazard Subst Environ
Eng42: 1853-1858. http://dx.doi.org/10.1080/10934520701566918
Heck. JE: Chen. Y: Grann. VR: Slavkovich. V: Parvez. F: Ahsan. H. (2008). Arsenic exposure and anemia in
Bangladesh: A population-based study. J Occup Environ Med 50: 80-87.
http://dx.doi.org/10.1097/JOM.Ob013e31815ae9d4
Majumdar. KK: Guha Mazumder. DN: Ghose. N: Ghose. A: Lahiri. S. (2009). Systemic manifestations in
chronic arsenic toxicity in absence of skin lesions in West Bengal. Indian J Med Res 129: 75-82.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.8 Summary of Observational Epidemiology Studies for
Health Effect Category: Immune System and Lymphatic
Effects
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
Ahmed et al. (2012)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: women
and infants enrolled in
MINIMat study of
nutritional impact on
fetal and infant
development
n total: 130
Exposure Surrogate: maternal blood
Exposure Description: maternal blood
samples collected at gestation week 14
analyzed for arsenic content
Population-Level Exposure:
4.7 ng/kg median, 1.4-22.2 ng/kg 5th
percentile
Outcome: sjTRECs in cord blood
In blood arsenic at gestation week 14, ug/kg
Exp. Level n adiBeta (CD
<1.8 NR -1.27 -1.89,-0.66
> 1.8 NR 0.7 -0.01, 1.41
Stat Method: spline regression model using
spline knots at In blood arsenic 1.8
Exposure Surrogate: urine
Exposure Description: maternal urine
samples taken at gestation week 8 or 30
analyzed for inorganic arsenic and
metabolites; samples adjusted for
specific gravity
Population-Level Exposure:
69 ng/L median, 19-441 ng/L 5th
percentile
Outcome: sjTRECs in cord blood
In urinary arsenic at gestation week 8, u.g/L
Exp. Level n ad i Beta (CD
continuous NR -0.25 -0.48,-0.01
Stat Method: linear regression
In urinary arsenic at gestation week 30, ug/L
Exp. Level n ad i Beta (CD
<5 NR -0.53 -0.93,-0.13
>5 NR 0.15 -0.55,0.85
Stat Method: spline regression model using
spline knots at In urinary arsenic 5.0
Biswas et al. (2008)
Study Type: cross-
sectional
Location: India
(Murshidabad district,
West Bengal)
Population: adult
residents of area with
high arsenic water
concentrations with
Exposure Surrogate: level of exposure
Exposure Description: adult residents of
area with high arsenic water
concentrations with arsenic induced skin
lesions (individuals with arsenicosis);
comparison population with similar
socioeconomic status from area with no
arsenic contamination
Population-Level Exposure:
not available
Outcome: IFN-gamma concentration (pg/mL)
exposure status, unitless
Exp. Level n mean (Cl)
unexposed NR 1,372.3 n/a
individuals NR 7.9 n/a
with
arsenicosis
Stat Method: Mann-Whitney U test
Outcome: IL-10 concentration (pg/mL)
exposure status, unitless
Exp. Level n mean (CD
unexposed NR 90.3 n/a
individuals NR 4.6 n/a
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
arsenic induced skin
lesions
n cases: 20
n control: 18
with
arsenicosis
Stat Method: Mann-Whitney U test
Outcome: IL-2 concentration (pg/mL)
exposure status, unitless
Exp. Level n mean (CD
unexposed NR 398.5 n/a
individuals NR 12.7 n/a
with
arsenicosis
Stat Method: Mann-Whitney U test
Outcome: IL-4 concentration (pg/mL)
exposure status, unitless
Exp. Level n mean (CD
unexposed NR 142.2 n/a
individuals NR 4.7 n/a
with
arsenicosis
Stat Method: Mann-Whitney U test
Outcome: IL-5 concentration (pg/mL)
exposure status, unitless
Exp. Level n mean (CD
unexposed NR 143.9 n/a
individuals NR 1.4 n/a
with
arsenicosis
Stat Method: Mann-Whitney U test
Outcome: TNF-alpha concentration (pg/mL)
exposure status, unitless
Exp. Level n mean (CD
unexposed NR 1,852.5 n/a
individuals NR 6.7 n/a
with
arsenicosis
Stat Method: Mann-Whitney U test
Outcome: [3H] TdR incorporation (cpm)
exposure status + ConA dose (u.g/mL), unitless
Exp. Level n mean (CD
unexposed + NR 1713.95 n/a
0 |Jg/mL
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
ConA
individuals NR 2929.34 n/a
with
arsenicosis +
0 |Jg/mL
ConA
unexposed+ NR 5642.51 n/a
3 |Jg/mL
ConA
individuals NR 1862.53 n/a
with 8
arsenicosis +
3 |Jg/mL
ConA
unexposed+ NR 8199.8 n/a
5 |Jg/mL
ConA
individuals NR 1365.75 n/a
with
arsenicosis +
5 |Jg/mL
ConA
Stat Method: Mann-Whitney U test
Bosniaket al. (2008)
Study Type: cross-
sectional
Location: Croatia
(Andrijasevci)
Population: adult
residents of village with
history of higher than
average arsenic in
drinking water
n cases: n/a
n control: n/a
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from single
sample for each individual
Population-Level Exposure:
627.72 ng/g-creatinine mean, 199.5-
1,206.29 ng/g-creatinine range
Outcome: B12
urinary arsenic concentration, ug/g-creatinine
Exp. Level ri corr (CD
coeff
continuous NR 0.48 n/a
Stat Method: Spearman rank correlation
Garcfa-Esquinas et al.
(2013)
Study Type: cohort
Exposure Surrogate: urine
Exposure Description: individual urine
samples collected and analyzed for
Outcome: lymphatic and hematopoietic cancer
urinary arsenic concentration, ng/g-creatinine
Exp. Level n HR (Cl)
80th vs. 20th 40 0.46 0.22,0.96
percentiles
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
(prospective)
Location: United States
(AZ;ND;OK;SD)
Population: Strong
Heart Study
participants
n total: 3,935
arsenic speciation
Population-Level Exposure:
9.7 ng/g-creatinine median, 5.8-15.6
Hg/g-creatinine 25th percentile
Stat Method: Cox proportional hazard
models; log transformed
Josvulaetal. (2006)
Study Type: cross-
sectional
Location: United States
(Tucson and Ajo,
Arizona)
Population: adult
residents using
household tap water in
Ajo (mean As water
concentration 20.3+-
3.7 ng/L) and Tucson
(mean As water
concentration 4.0 +- 2.3
Mg/U
n cases: 40
n control: 33
Exposure Surrogate: urine
Exposure Description: first morning void
urine sample collected, analyzed for
inorganic arsenic and metabolites and
adjusted for creatinine; urine samples
with creatinine <30 mg/dL or >300 mg/dL
excluded from analysis; arsenic in toenail
samples also analyzed
Population-Level Exposure:
22 ng/L mean
Outcome: In (MMP-2/TIMP-1)
urinary inorganic arsenic concentration, ug/L
Exp. Level n adiBeta (CD
continuous NR 0.028 n/a
Stat Method: multiple linear regression
Outcome: In (MMP-9/TIMP-1)
urinary inorganic arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR 0.031 n/a
Stat Method: multiple linear regression
Outcome: In MMP-2
urinary inorganic arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.018 n/a
Stat Method: multiple linear regression
Outcome: In MMP-9
urinary inorganic arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.017 n/a
Stat Method: multiple linear regression
Outcome: In TIMP-1
urinary inorganic arsenic concentration, ug/L
Exp. Level n ad i Beta (CD
continuous NR -0.049 n/a
Stat Method: multiple linear regression
Lewis et al. (1999)
Study Type: cohort
Exposure Surrogate: drinking water
Exposure Description: arsenic
Outcome: lymphatic, hematopoietic tissue
cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR (CD
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
(retrospective)
Location: United States
(Millard County, Utah)
Population: male and
female members of
Latter-day Saints
church wards
n exposed: 2,203
n total: 2,203
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
<1,000 NR 0.94 n/a
1,000-4,999 NR 0.68 n/a
> 5,000 NR 0.45 n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1,000 NR 0.95 n/a
1,000-4,999 NR 0.65 n/a
> 5,000 NR 0.64 n/a
Stat Method: standardized mortality ratios
Moore et al. (2009)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: infants
born in rural
Bangladesh; mothers
are participants in
MINIMat study
n total: 1,556
Exposure Surrogate: maternal urine
Exposure Description: sum of
metabolites of inorganic arsenic
measured in spot urine samples;
adjusted for variation in urine dilution by
specific gravity (mean 1.0012 g/mL)
Population-Level Exposure:
102 ug/L median, 5.5-1,150 ug/L range
Outcome: thymic index
maternal urinary arsenic concentration at week
52, ug/L
Exp. Level n chi- (CD
square
continuous NR 12.93 n/a
Stat Method: multiple linear regression with
quadratic term for As
Outcome: thymic index/weight ratio
maternal urinary arsenic concentration at week
52, ug/L
arsenic not significantly associated with thymic
index/weight ratio
Pesola et al. (2012)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study
(HEALS) participants
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: well water arsenic
concentration
Population-Level Exposure:
7-179 ug/L range
Outcome: dyspnoea
well water arsenic concentration (quintiles),
Exp. Level
<7
7-<39
39 -<91
91-<179
>179
n
NR
NR
NR
NR
NR
M
n/a
0.97, 1.9
1.43, 2.7
1.56, 2.92
1.31, 2.49
Stat Method: logistic regression; Chi-squared
test for trend
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured in single spot
samples and adjusted by creatinine
concentration and stratified by quintile
Outcome: dyspnoea
urinary arsenic concentration (quintiles), ug/g-
creatinine
Exp. Level n
quintile 1 NR
quintile 2 NR
quintileS NR
M
n/a
0.97, 1.92
1.38, 2.65
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Raqib et al. (2009)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: women
and infants enrolled in
MINIMat study of
nutritional impact on
fetal and infant
development
n total: 140
Shiue (2013)
Exposure Measures
Population-Level Exposure:
not available
Exposure Surrogate: urine
Exposure Description: maternal urine
samples taken at gestation week 8 or 30
analyzed for inorganic arsenic and
metabolites; samples adjusted for
specific gravity
Population-Level Exposure:
145.8 ng/L mean 186.8SD
Exposure Surrogate: urine
Results
quintile4 NR 1.94 1.41,2.68
quintileS NR 1.87 1.36,2.58
Stat Method: logistic regression; Chi-squared
test for trend
Outcome: breast milk concentration of IL-7 at 12
months
maternal urinary arsenic at gestation week 30,
H9/L
Exp. Level n adiBeta (CD
continuous NR -0.04 -0.07, -0.02
Stat Method: multivariate linear regression
Outcome: breast milk concentration of LtF at 12
months
maternal urinary arsenic at gestation week 30,
H9/L
Exp. Level n adiBeta (CD
continuous NR -0.002 -0.003, -0.001
Stat Method: multivariate linear regression
Outcome: thymic index at 2 months
maternal urinary arsenic at gestation week 30,
H9/L
Exp. Level n adiBeta (CD
continuous NR -0.01 -0.02, -0.001
Stat Method: multivariate linear regression
Outcome: thymus index at 12 months
maternal urinary arsenic at gestation week 30,
H9/L
Exp. Level n adiBeta (CD
continuous NR -0.012 -0.02, -0.002
Stat Method: multivariate linear regression
Outcome: thymus index at 6 months
maternal urinary arsenic at gestation week 30,
H9/L
Exp. Level n adiBeta (CD
continuous NR -0.015 -0.02, -0.005
Stat Method: multivariate linear regression
Outcome: food sensitization - egg
urinary total arsenic, unitless
total arsenic not significantly associated with food
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
Study Type: cross-
sectional
Location: United States
(national)
Population: NHANES
n cases: 4,979
n control: n/a
Exposure Description: urine samples
collected from individuals
Population-Level Exposure:
not available
sensitization
Outcome: food sensitization - milk
urinary total arsenic, unitless
total arsenic not significantly associated with food
sensitization
Outcome: food sensitization - peanut
urinary total arsenic, unitless
total arsenic not significantly associated with food
sensitization
Outcome: food sensitization - shrimp
urinary total arsenic, unitless
total arsenic not significantly associated with food
sensitization
Sohel et al. (2009)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: Health and
Demographic
Surveillance System
1991-2000, adults and
children with
nonaccidental deaths
1991-2000
n exposed: 93,415
n total: 93,415
Exposure Surrogate: drinking water
Exposure Description: cumulative
drinking water arsenic concentration
based on current arsenic concentrations
(reasonably stable over time); average
household exposure (used as proxy for
individual exposure) calculated for each
calendar year from 1970, based on
information obtained from the current
population present in that specific
household for each year
Population-Level Exposure:
10-300 ng/L range
Outcome: all infections deaths
cumulative water arsenic concentration
(quintiles), u.g/L
Exp. Level
10-49
50-149
150-299
>300
ri
235
286
883
783
295
M
n/a
0.92, 1.30
1.13, 1.49
1.31, 1.75
1.33, 1.91
Stat Method: Cox proportional hazard model
Wuetal. (2012b)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: random
selection of adults over
Exposure Surrogate: drinking water
Exposure Description: water samples
and geographic coordinates collected for
10,971 contiguous wells in a well-defined
geographic area; participants used one of
the tested wells
Population-Level Exposure:
0.1-500.62 ng/L range
Outcome: MMP-9 (ng/mL)
per Log-transformed well water arsenic, \ng/L
Exp. Level n adiBeta (CD
continuous NR 1 0.98, 1.02
Stat Method: computed with the log-
transformed arsenic level entered as a
continuous variable in linear regression
models
baseline concentrations of well water arsenic
(quartiles), \ig/L
Exp. Level n ad i Beta (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
age 30 enrolled in
HEALS study
n cases: 666
n control: n/a
0.10-2.0 NR 1 n/a
2.01-23.13 NR 0.88 0.77,0.99
23.14-73.46 NR 0.96 0.85, 1.08
73.47- NR 0.99 0.88,1.12
500.62
Stat Method: models run with log
transformed inflammatory markers
Outcome: Myeloperoxidase (ng/mL)
per Log-transformed well water arsenic, ng/L
Exp. Level n adiBeta (CD
continuous NR 1 0.97, 1.02
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of well water arsenic
(quartiles), u.g/L
ad j Beta
1
0.94
0.96
NR
NR
NR
Exp. Level
0.10-2.0
2.01-23.13
23.14-73.46
73.47- NR 0.99
500.62
Stat Method: models run with log
transformed inflammatory markers
M
n/a
0.83, 1.07
0.84, 1.09
0.87, 1.13
Outcome: PAI-1 (ng/mL)
per Log-transformed well water arsenic, \ng/L
Exp. Level n adjBeta (Cl)
continuous NR 1.02 0.99, 1.04
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of well water arsenic
(quartiles), ng/L
Exp. Level r\
0.10-2.0 NR
2.01-23.13 NR
23.14-73.46 NR
73.47- NR
500.62
Stat Method: models run with log
transformed inflammatory markers
M
n/a
0.87, 1.10
0.84, 1.07
1.00, 1.28
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
Outcome: Soluble E-selectin (ng/mL)
per Log-transformed well water arsenic, ng/L
Exp. Level n ad I Beta (CD
continuous NR 1 0.98, 1.02
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of well water arsenic
(quartiles), ng/L
Exp. Level ri
0.10-2.0 NR
2.01-23.13 NR
23.14-73.46 NR
73.47- NR
500.62
Stat Method: models run with log
transformed inflammatory markers
M
n/a
0.91, 1.09
0.90, 1.08
0.91, 1.10
Outcome: Soluble ICAM-1 (ng/mL)
per Log-transformed well water arsenic, ng/L
Exp. Level n adiBeta (CD
continuous NR 1 0.97, 1.03
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of well water arsenic
(quartiles), ng/L
ad i Beta
1
0.87
0.9
NR
NR
NR
Exp. Level
0.10-2.0
2.01-23.13
23.14-73.46
73.47- NR 0.99
500.62
Stat Method: models run with log
transformed inflammatory markers
M
n/a
0.75, 1.00
0.78, 1.04
0.86, 1.15
Outcome: Soluble VCAM-1 (ng/mL)
per Log-transformed well water arsenic, ng/L
Exp. Level n ad i Beta (CD
continuous NR 1.02 1.01, 1.03
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
baseline concentrations of well water arsenic
(quartiles), ug/L
Exp. Level ri
0.10-2.0 NR
2.01-23.13 NR
23.14-73.46 NR
73.47- NR
500.62
Stat Method: models run with log
transformed inflammatory markers
M
n/a
0.97, 1.12
1.02, 1.17
1.01, 1.16
Exposure Surrogate: urine
Exposure Description: total urinary
arsenic concentration measured by
atomic absorption; all the urine samples
were detectable for total urinary arsenic.
Population-Level Exposure:
12.05-1,869.57 ng/g-creatinine range
Outcome: MMP-9 (ng/mL)
per Log-transformed urinary arsenic, u.g/g-
creatinine
Exp. Level n adiBeta (CD
continuous NR 0.98 0.93, 1.03
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of urinary arsenic
(quartiles), ug/g-creatinine
Exp. Level r\
12.05-88.21 NR
88.22-141.69 NR
141.70- NR
275.63
275.64- NR 0.95
1,869.57
Stat Method: models run with log
transformed inflammatory markers
M
n/a
0.79, 1.01
0.76, 0.97
0.84, 1.08
Outcome: Myeloperoxidase (ng/mL)
per Log-transformed urinary arsenic, ug/g-
creatinine
Exp. Level n ad i Beta (CD
continuous NR 0.98 0.93, 1.03
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of urinary arsenic
(quartiles), ug/g-creatinine
Exp. Level n ad i Beta (CD
12.05-88.21 NR 1 n/a
88.22-141.69 NR 0.87 0.76,0.99
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
NR
0.91
NR
0.92
141.70-
275.63
275.64-
1,869.57
Stat Method: models run with log
transformed inflammatory markers
0.80, 1.03
0.81, 1.05
Outcome: PAI-1 (ng/mL)
per Log-transformed urinary arsenic, ug/g-
creatinine
Exp. Level n adiBeta (CD
continuous NR 1.05 1.00, 1.11
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of urinary arsenic
(quartiles), ug/g-creatinine
Exp. Level ri
12.05-88.21 NR
88.22-141.69 NR
141.70- NR
275.63
275.64- NR 1.11
1,869.57
Stat Method: models run with log
transformed inflammatory markers
M
n/a
0.85, 1.09
0.84, 1.07
0.90, 1.26
Outcome: Soluble E-selectin (ng/mL)
per Log-transformed urinary arsenic, ug/g-
creatinine
Exp. Level n ad i Beta (CD
continuous NR 1 0.96, 1.04
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of urinary arsenic
(quartiles), ug/g-creatinine
Exp. Level
12.05-88.21
88.22-141.69
141.70-
275.63
275.64-
1,869.57
NR
NR
NR
NR
0.99
M
n/a
0.88, 1.06
0.84, 1.01
0.90, 1.09
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Study
Design
Exposure Measures
Results
Stat Method: models run with log
transformed inflammatory markers
Outcome: Soluble ICAM-1 (ng/mL)
per Log-transformed urinary arsenic,
creatinine
Exp. Level n adiBeta (CD
continuous NR 1.01 0.95, 1.07
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of urinary arsenic
(quartiles), u.g/g-creatinine
Exp. Level n
12.05-88.21 NR
88.22-141.69 NR
141.70- NR
275.63
275.64- NR
1,869.57
Stat Method: models run with log
transformed inflammatory markers
M
n/a
0.79, 1.06
0.83, 1.11
0.86, 1.16
Outcome: Soluble VCAM-1 (ng/mL)
per Log-transformed urinary arsenic, u.g/g-
creatinine
Exp. Level n ad i Beta (CD
continuous NR 1.04 1.01, 1.07
Stat Method: computed with log-transformed
arsenic level entered as a continuous
variable in linear regression models
baseline concentrations of urinary arsenic
(quartiles), ug/g-creatinine
Exp. Level
12.05-88.21
88.22-141.69
141.70-
275.63
275.64-1,869
ri
NR
NR
NR
NR
1.09
M
n/a
0.95, 1.09
1.01, 1.16
1.02, 1.17
Stat Method: models run with log
transformed inflammatory markers
--: not reported; n: number of cases (when presented in Results column)
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.8.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Immune System and Lymphatic
Effects
Ahmed. S: Ahsan. KB: Kippler. M: Mily. A: Wagatsuma. Y: Hoque. AMW: Ngom. PT: El Arifeen. S: Raqib. R:
Vahter. M. (2012). In utero arsenic exposure is associated with impaired thymic function in newborns
possibly via oxidative stress and apoptosis. Toxicol Sci 129: 305-314. http://dx.doi.org/10.1093/toxsci/kfs202
Biswas. R: Ghosh. P: Banerjee. N: Das. JK: Sau. T: Banerjee. A: Roy. S: Ganguly. S: Chatteriee. M: Mukheriee.
A: Girl AK. (2008). Analysis of T-cell proliferation and cytokine secretion in the individuals exposed to
arsenic. HumExp Toxicol 27: 381-386. http://dx.doi.org/10.1177/0960327108094607
Bosniak. Z: Cavar. S: Klapec. T: Milic. M: Klapec-Basar. M: Toman. M. (2008). Selected markers of
cardiovascular disease in a population exposed to arsenic from drinking water. Environ Toxicol Pharmacol
26: 181-186. http://dx.doi.0rg/10.1016/i.etap.2008.03.005
Garcia-Esquinas. E: Pollan. M: Umans. JG: Francesconi. KA: Goessler. W: Guallar. E: Howard. B: Farley. J:
Best LG: Navas-Acien. A. (2013). Arsenic exposure and cancer mortality in a US-based prospective cohort:
the strong heart study. Cancer Epidemiol Biomarkers Prev 22: 1944-1953. http://dx.doi.org/10.1158/1055-
9965.EPI-13-0234-T
Josvula. AB: Poplin. GS: Kurzius-Spencer. M: McClellen. HE: Kopplin. MJ: Sturup. S: Lantz. RC: Burgess. JL.
(2006). Environmental arsenic exposure and sputum metalloproteinase concentrations. Environ Res 102:
283-290. http://dx.doi.0rg/10.1016/i.envres.2006.01.003
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Moore. SE: Prentice. AM: Wagatsuma. Y: Fulford. AJC: Collinson. AC: Raqib. R: Vahter. M: Persson. LA:
Arifeen. SE. (2009). Early-life nutritional and environmental determinants of thymic size in infants born in
rural Bangladesh. Acta Paediatr 98: 1168-1175. http://dx.doi.org/10.1111/i. 1651-2227.2009.01292.x
Pesola. GR: Parvez. F: Chen. Y: Ahmed. A: Hasan. R: Ahsan. H. (2012). Arsenic exposure from drinking water
and dyspnoea risk in Araihazar, Bangladesh: a population-based study. Eur Respir J.
http://dx.doi.org/10.1183/09031936.00042611
Raqib. R: Ahmed. S: Sultana. R: Wagatsuma. Y: Mondal D: Hoque. AM: Nermell B: Yunus. M: Roy. S:
Persson. LA: Arifeen. SE: Moore. S: Vahter. M. (2009). Effects of in utero arsenic exposure on child
immunity and morbidity in rural Bangladesh. Toxicol Lett 185: 197-202.
http://dx.doi.0rg/10.1016/i.toxlet.2009.01.001
Shiue. I. (2013). Association of urinary arsenic, heavy metal, and phthalate concentrations with food allergy in
adults: National Health and Nutrition Examination Survey, 2005-2006 [Letter]. Ann Allergy Asthma
Immunol 111: 421-423. http://dx.doi.0rg/10.1016/i.anai.2013.08.006
Sohel. N: Persson. LA: Rahman. M: Streatfield. PK: Yunus. M: Ekstrom EC: Vahter. M. (2009). Arsenic in
drinking water and adult mortality: a population-based cohort study in rural Bangladesh. Epidemiology 20:
824-830. http://dx.doi.org/10.1097/EDE.Ob013e3181bb56ec
Wu. F: Jasmine. F: Kibriya. MG: Liu. M: Wojcik. O: Parvez. F: Rahaman. R: Roy. S: Paul-Brutus. R: Segers. S:
Slavkovich. V: Islam. T: Lew. D: Mev. JL: van Geen. A: Graziano. JH: Ahsan. H: Chen. Y. (2012).
Association Between Arsenic Exposure From Drinking Water and Plasma Levels of Cardiovascular Markers.
Am J Epidemiol. http://dx.doi.org/10.1093/aie/kwr464
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.9 Summary of Observational Epidemiology Studies for
Health Effect Category: Liver Effects
Summary of Observational Epidemiology Studies for Health Effect Category: Liver Effects
Reference and Study
Design
Exposure Measures
Results
Baastrupetal. (2008)
Study Type: cohort
(prospective)
Location: Denmark
(Copenhagen and
Aarhus)
Population: Danish
Cancer Registry
population (adults)
n exposed: 56,378
n total: 57,053
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure and time-weighted average
arsenic concentrations calculated for
individuals based on residential address
and history from Central Population
Registry combined with measurement
data from nearest water utility as
recorded by Geological Survey of
Denmark and Greenland (1987-2004)
Population-Level Exposure:
not available
Outcome: liver cancer
cumulative arsenic exposure, mg
Exp. Level n IRR
continuous NR 0.99
Stat Method: Cox regression
M
0.89, 1.10
Exposure Surrogate: drinking water
Exposure Description: time-weighted
and cumulative arsenic concentrations
calculated for individuals based on
residential address and history from
Central Population Registry combined
with measurement data from nearest
water utility as recorded by Geological
Survey of Denmark and Greenland (1987-
2004)
Population-Level Exposure:
0.7 ng/L median
Outcome: liver cancer
time-weighted average arsenic exposure, ug/L
Exp. Level n IRR (CD
continuous NR 1.05 0.88, 1.25
Stat Method: Cox regression
Chung etal. (2012)
Study Type: cohort
(prospective)
Location: Taiwan
(Homei, Fuhsin,
Hsinming)
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure assessment determined by
duration of artesian well water use,
history or residence, and historical data;
cumulative arsenic exposure derived to
reflect long-term arsenic exposure by
median well water arsenic (population
Outcome: liver cancer
cumulative water arsenic exposure (tertiles),
Hg/L-year
Exp. Level n
9.1-19.5
>19.5
5
11
8
M
n/a
0.49, 4.37
0.17,2.44
Stat Method: Cox proportional hazard model
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Liver Effects
Reference and Study
Design
Exposure Measures
Results
Population: residents
of arseniasis-endemic
areas
n total: 1,563
level exposure reported here) x duration
of use
Population-Level Exposure:
9.1-19.5 |jg/L-year range
Exposure Surrogate: drinking water
Exposure Description: information on
median arsenic level in artesian well
water of each village acquired from
previous studies carried out in the early
1960s (Laietal., 1994); some study
subjects had moved from one village to
another, and there were differences in
arsenic concentrations between villages
Population-Level Exposure:
0.7-0.93 mg/L range
Outcome: liver cancer
average water arsenic concentration (tertiles),
mg/L
Exp. Level n HR (CD
<0.05 3 1 n/a
0.05-0.71 12 1.29 0.34,4.83
>0.71 9 0.87 0.22,3.50
Stat Method: Cox proportional hazard model
Exposure Surrogate: urine
Exposure Description: urine samples of
1,078 subjects collected at time of
recruitment; all arsenic assays performed
within 6 months of sample collection
Population-Level Exposure:
not available
Outcome: liver cancer
percent DMA in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR
>85.8 3 1 n/a
76.13-85.8 7 1.67 0.43,6.52
<76.13 6 1.01 0.25,4.13
Stat Method: Cox proportional hazard model
percent inorganic arsenic in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR M
<4.22 3 1 n/a
4.22-7.86 4 1.05 0.23,4.70
>7.86 9 2.32 0.63,8.64
Stat Method: Cox proportional hazard model
percent MMA in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR M
<8.34 3 1 n/a
8.34-15.31 8 2.57 0.68,9.72
> 15.31 5 0.8 0.19,3.38
Stat Method: Cox proportional hazard model
Garcfa-Esquinas et al.
Exposure Surrogate: urine
Outcome: liver, gallbladder, and bile duct cancer
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Liver Effects
Reference and Study
Design
Exposure Measures
Results
(2013)
Study Type: cohort
(prospective)
Location: United States
(AZ;ND;OK;SD)
Population: Strong
Heart Study
participants
n total: 3,935
Exposure Description: individual urine
samples collected and analyzed for
arsenic speciation
Population-Level Exposure:
9.7 ng/g-creatinine median, 5.8-15.6
Hg/g-creatinine 25th percentile
urinary arsenic concentration, u.g/g-creatinine
Exp. Level n HR (CD
80th vs. 20th NR 1.34 0.66,2.72
percentiles
Stat Method: Cox proportional hazard
models; log transformed
Guo et al. (2007)
Study Type: cross-
sectional
Location: Mongolia
region not available
Population: residents
of villages in the Hetao
Plain, Inner Mongolia
n cases: 680
n control: 189
Exposure Surrogate: drinking water
Exposure Description: arsenic samples
were taken from 94 water sources,
including wells; detection limit not
specified, but authors note reliability of
the method at <10 ng/L; arsenic
exposure determined by location of
village
Population-Level Exposure:
50-1,860 ng/L range
Outcome: hepatomegaly
water arsenic concentration, u.g/1
arsenic not significantly associated with
hepatomegaly
Outcome: liver function test
water arsenic concentration, ug/L
arsenic not significantly associated with liver
function
Hsu et al. (2013b)
Study Type: cohort
(prospective)
Location: Taiwan (SW:
Peimen, Hsuechia, Ichu,
and Putai Townships;
NE: Chiaohsi,
Chuangwei, Wuchieh,
and Tungshan
Townships)
Population: residents
of an arseniasis-
endemic area with and
Exposure Surrogate: drinking water
Exposure Description: SW population:
median arsenic level of several wells
shared in a village derived from two
surveys; NE population: arsenic level of
well water samples collected during
home interviews
Population-Level Exposure:
10-500 ng/L range
Outcome: liver cancer
arsenic concentration in well water (non-
diabetes mellitus vs. diabetes mellitus subjects),
n
NR
NR
NR
NR
HR
1
Exp. Level
non-DMw/
As <500
DMw/As
<500
non-DMw/
As > 500
DMw/As
>500
Stat Method: Cox regression analysis
2.63
1
2.32
(CD
n/a
1.84,3.76
n/a
1.11,4.86
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Liver Effects
Reference and Study
Design
Exposure Measures
Results
without skin lesions
n total: 9,525
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: deceased
male and female
members of Latter-day
Saints church wards
n exposed: 2,203
n total: 2,203
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Outcome: billiary passages and liver cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR M
<1,000 NR 2.99 n/a
1,000-4,999 NR NR n/a
> 5,000 NR 1.15 n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
< 1,000 NR NR n/a
1,000-4,999 NR 2.52 n/a
> 5,000 NR NR n/a
Stat Method: standardized mortality ratios
Maiumdaretal. (2009)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: residents
of arsenic-affected
villages with
comparison population
from low exposure area
n cases: 3,825
n control: 3,451
Exposure Surrogate: drinking water
Exposure Description: for each
participant, water samples from private
or public tube wells analyzed for arsenic;
exposure categories developed based on
arsenic levels
Population-Level Exposure:
50-500 ng/L range
Outcome: hepatomegaly
arsenic concentration in drinking water
(females), u.g/L
Exp. Level n prevOR (CD
<50 NR 1 n/a
>500 NR 4.34 2.8,6.5
Stat Method: prevalence odds ratio
calculated for each outcome comparing
highest and lowest exposure levels
arsenic concentration in drinking water (males),
Exp. Level n prevOR (CD
<50 NR 1 n/a
>500 NR 5.13 3.4,7.6
Stat Method: prevalence odds ratio
calculated for each outcome comparing
highest and lowest exposure levels
Sawada et al. (2013)
Study Type: cohort
(prospective)
Location: Japan (Iwate,
Akita, Nagano,
Exposure Surrogate: diet
Exposure Description: detailed
questionnaire on food intake/frequency;
average arsenic concentrations in food
items obtained from the literature;
arsenic intake calculated by multiplying
average arsenic concentration in each
Outcome: liver cancer
inorganic arsenic intake (females; quartiles),
ug/day
Exp. Level n HR (CD
40.6 21 1 n/a
53.7 32 1.36 0.78,2.38
62.6 36 1.41 0.81,2.46
105.7 28 1.1 0.61, 1.97
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Liver Effects
Reference and Study
Design
Okinawa, Tokyo,
Ibaraki, Niigata, Kochi,
Nagasaki, Osaka)
Population: adults in
Japan Public Health
Center (JPHC)
Prospective Study
cohort
n total: 90,378
Tsuda et al. (1995)
Study Type: cohort
(retrospective)
Location: Japan
(Namiki-cho)
Population: adults and
children living near
factory producing
arsenic trisulfide
n exposed: 189
n reference: 254
n total: 443
Exposure Measures
item by quantity consumed
Population-Level Exposure:
170 ug/day mean, 88.3-253.2 ug/day
range
Exposure Surrogate: drinking water
Exposure Description: arsenic in well
water measured in 1959 (the end of the
exposure period) in 34 wells; 20 area
wells had no documented levels of
arsenic so authors inferred that arsenic
levels were undetectable or very low;
concentration assigned based on
residence in 1959
Population-Level Exposure:
0.05-1 ppm range
Results
Stat Method: Multivariate regression
inorganic arsenic intake (males; quartiles),
Ug/day
Exp. Level n HR (CD
40.5 68 1 n/a
54.7 49 0.62 0.43,0.90
63.5 78 0.87 0.62, 1.22
99.1 90 0.94 0.67, 1.31
Stat Method: Multivariate regression
Outcome: liver cancer
arsenic concentration in well water in 1959, ppm
Exp. Level n SMR (CD
<0.05 0 0 0,4.43
0.05-0.99 00 0, 15.06
>1 2 7.17 1.28,26.05
Stat Method: Cox proportional hazard
--: not reported; n: number of cases (when presented in Results column)
5.9.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Liver Effects
Baastrup. R: Serensen. M: Balstrem. T: Frederiksen. K: Larsen. CL: Tjenneland. A: Overvad. K: Raaschou-
Nielsen. O. (2008). Arsenic in drinking-water and risk for cancer in Denmark. Environ Health Perspect 116:
231-237. http://dx.doi.org/10.1289/ehp. 10623
Chung. CJ: Huang. YL: Huang. YK: Wu. MM: Chen. SY: Hsueh. YM: Chen. CJ. (2012). Urinary arsenic
profiles and the risks of cancer mortality: A population-based 20-year follow-up study in arseniasis-endemic
areas in Taiwan. Environ Res 122: 25-30. http://dx.doi.0rg/10.1016/i.envres.2012.ll.007
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Garcia-Esquinas. E: Pollan. M: Umans. JG: Francesconj KA: Goessler. W: Guallar. E: Howard. B: Farley. J:
Best LG: Navas-Acien. A. (2013). Arsenic exposure and cancer mortality in a US-based prospective cohort:
the strong heart study. Cancer Epidemiol Biomarkers Prev 22: 1944-1953. http://dx.doi.org/10.1158/1055-
9965.EPI-13-0234-T
Guo. JX: Hu. L: Yand. PZ: Tanabe. K: Miyatalre. M: Chen. Y. (2007). Chronic arsenic poisoning in drinking
water in Inner Mongolia and its associated health effects. J Environ Sci Health A Tox Hazard Subst Environ
Eng42: 1853-1858. http://dx.doi.org/10.1080/10934520701566918
Hsu. LI: Wang. YH: Chiou. HY: Wu. MM: Yang. TY: Chen. YH: Tseng. CH: Chea CJ. (2013). The association
of diabetes mellitus with subsequent internal cancers in the arsenic-exposed area of Taiwan. J Asian Earth
Sci 73: 452-459. http://dx.doi.0rg/10.1016/i.iseaes.2013.04.048
Lai. MS: Hsueh. YM: Chen. CJ: Shyu. MP: Chea SY: Kuo. TL: Wu. MM: Taj TY. (1994). Ingested inorganic
arsenic and prevalence of diabetes mellitus. Am J Epidemiol 139: 484-492.
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Majumdar. KK: Guha Mazumder. DN: Ghose. N: Ghose. A: Lahiri. S. (2009). Systemic manifestations in
chronic arsenic toxicity in absence of skin lesions in West Bengal. Indian J Med Res 129: 75-82.
Sawada. N: Iwasaki. M: Inoue. M: Takachi. R: Sasazukj S: Yamaii. T: Shimazu. T: Tsugane. S. (2013). Dietary
arsenic intake and subsequent risk of cancer: The Japan Public Health Center-based (JPHC) prospective
study. Cancer Causes Control 24: 1403-1415. http://dx.doi.org/10.1007/sl0552-013-0220-2
Tsuda. T: Babazono. A: Yamamoto. E: Kurumatanj N: Mino. Y: Ogawa. T: Kishj Y: Aoyama. H. (1995).
Ingested arsenic and internal cancer: A historical cohort study followed for 33 years. Am J Epidemiol 141:
198-209.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.10Summary of Observational Epidemiology Studies for
Health Effect Category: Mortality
Summary of Observational Epidemiology Studies for Health Effect Category: Mortality
Reference and Study
Design
Rahman et al. (2013)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: children in
AsMat study who died
non-accidental deaths
n total: 185
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure based on number of years each
well used and concentration in each well
Population-Level Exposure:
1,000-4,000 ug-yr/L range
Exposure Surrogate: drinking water
Exposure Description: well water
samples (n = 13,286) analyzed for
determination of baseline individual-level
arsenic exposure; historical drinking
water exposure information obtained
from parent/guardian interviews;
baseline, time- weighted lifetime
average, and cumulative arsenic
exposure estimated for each individual
Population-Level Exposure:
10-300 ng/L range
Results
Outcome: all-cause mortality
cumulative water arsenic exposure, ug-yr/L
Exp. Level n HR (CD
< 1,000 54 1 n/a
1,000-4,000 88 1.17 0.84, 1.65
>4,000 43 1.9 1.25,2.89
Stat Method: Cox proportional hazard
Outcome: all-cause mortality
baseline water arsenic concentration (quintiles),
ug/L
Exp. Level n HR (CD
<10 83 1 n/a
10-49 15 1.13 0.65, 1.96
50-149 13 0.81 0.45, 1.46
150-299 39 1.35 0.92, 1.97
300+ 35 1.51 1.01,2.23
Stat Method: Cox proportional hazard
time-weighted lifetime average arsenic
concentration (quintiles), ug/L
Exp. Level n HR (CD
<10 24 1 n/a
10-49 17 1.37 0.74,2.57
50-149 44 1.44 0.88,2.38
150-299 56 1.22 0.75, 1.98
300+ 44 1.88 1.14,3.10
Stat Method: Cox proportional hazard
Outcome: cancer and cardiovascular-related
mortality
baseline water arsenic concentration quartiles),
W/l.
Exp. Level n HR (CD
<10 16 1 n/a
10-50 4 1.53 0.51,4.57
51-150 4 1.29 0.43,3.87
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Mortality
Reference and Study
Design
Sohel et al. (2009)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: Health and
Demographic
Surveillance System
1991-2000, adults and
children with
nonaccidental deaths
1991-2000
n exposed: 93,415
n total: 93,415
Tsuda et al. (1995)
Study Type: cohort
(retrospective)
Location: Japan
(Namiki-cho)
Population: adults and
children living near
factory producing
arsenic trisulfide
n exposed: 189
n reference: 254
n total: 443
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: cumulative
drinking water arsenic concentration
based on current arsenic concentrations
(reasonably stable over time); average
household exposure (used as proxy for
individual exposure) calculated for each
calendar year from 1970, based on
information obtained from the current
population present in that specific
household for each year
Population-Level Exposure:
10-300 ng/L range
Exposure Surrogate: drinking water
Exposure Description: arsenic in well
water measured in 1959 (the end of the
exposure period) in 34 wells; 20 area
wells had no documented levels of
arsenic so authors inferred that arsenic
levels were undetectable or very low;
concentration assigned based on
residence in 1959
Population-Level Exposure:
0.05-1 ppm range
Results
>150 22 2.18 1.15,4.16
Stat Method: Cox proportional hazard
Outcome: all nonaccidental deaths
cumulative water arsenic concentration
(quintiles), ug/L
Exp. Level n adjOR (Cl)
<10 967 1 n/a
10-49 1,258 1.16 1.06, 1.26
50-149 3,584 1.26 1.18, 1.36
150-299 3,077 1.36 1.27, 1.47
> 300 1,076 1.35 1.23, 1.48
Stat Method: Cox proportional hazard model
Outcome: cancer deaths
cumulative water arsenic concentration
(quintiles), ug/L
Exp. Level n adiOR (Cl)
<10 55 1 n/a
10-49 71 1.1 0.77, 1.59
50-149 229 1.44 1.06, 1.95
150-299 181 1.75 1.28,2.40
>300 53 1.06 1.56,2.30
Stat Method: Cox proportional hazard model
Outcome: all deaths
arsenic concentration in well water in 1959, ppm
Exp. Level n SMR (Cl)
<0.05 56 0.87 0.67, 1.13
0.05-0.99 17 1.08 0.65, 1.73
>1 32 1.58 1.12,2.22
Stat Method: Cox proportional hazard
--: not reported; n: number of cases (when presented in Results column)
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.10.1 References for Summary of Observational Epidemiology
Studies for Health Effect Category: Mortality
Rahman. M: Sohel N: Yunus. M: Chowdhury. ME: Hore. SK: Zaman. K: Bhuiya. A: Streatfield. PK. (2013).
Increased childhood mortality and arsenic in drinking water in Matlab, Bangladesh: a population-based
cohort study. PLoS ONE 8: e55014. http://dx.doi.org/10.1371/journal.pone.0055014
Sohel N: Persson. LA: Rahman. M: Streatfield. PK: Yunus. M: Ekstrom EC: Vahter. M. (2009). Arsenic in
drinking water and adult mortality: a population-based cohort study in rural Bangladesh. Epidemiology 20:
824-830. http://dx.doi.org/10.1097/EDE.Ob013e3181bb56ec
Tsuda. T: Babazono. A: Yamamoto. E: Kurumatani. N: Mino. Y: Ogawa. T: Kishi. Y: Aoyama. H. (1995).
Ingested arsenic and internal cancer: A historical cohort study followed for 33 years. Am J Epidemiol 141:
198-209.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.11 Summary of Observational Epidemiology Studies for
Health Effect Category: Nervous System Effects
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
Adams et al. (2013)
Study Type: case-
control
Location: United States
(AZ)
Population: children
with autism;
participants recruited
with help of the Autism
Society of America-
Greater Phoenix
Chapter and the
Arizona Division of
Developmental
Disabilities
n cases: 55
n control: 44
Exposure Surrogate: blood
Exposure Description: morning blood
samples collected after overnight fast;
RBC samples provided a measure of
longer-term exposure (several months)
Population-Level Exposure:
4.32 ng/g mean
Outcome: autism
arsenic concentration in RBC, ng/g
Exp. Level ri mean (CD
neurotypical NR 4.33 n/a
group
autism group NR 4.3 n/a
Stat Method: two-sided unpaired t-test
Exposure Surrogate: blood
Exposure Description: morning blood
samples collected after overnight fast;
whole blood samples included a mixture
of long-term (cellular) and short-term
(serum) components and provided a
measure of intermediate exposure
Population-Level Exposure:
3.33 ng/L mean
Outcome: autism
whole blood arsenic concentrations, \ng/L
Exp. Level n mean (CD
neurotypical NR 3.37 n/a
group
autism group NR 3.3 n/a
Stat Method: two-sided unpaired t-test
Exposure Surrogate: blood and urine
Exposure Description: blood and urine
exposure (combined) as continuous
variable
Population-Level Exposure:
not available
Outcome: autism (severity/symptoms
determined by pervasive developmental
disorder behavior inventory [PDD-BI])
toxic metals in blood and urine, unitless
Exp. Level n adjR2 (CD
continuous NR 0.46 n/a
Stat Method: regression
Exposure Surrogate: urine
Exposure Description: morning urine
samples collected after overnight fast
(first urine); provided a measure of
recent exposure (several days)
Outcome: autism
arsenic concentration in urine by autism status,
ug/g-creatinine
Exp. Level
neurotypical
group
autism group
ri
NR
NR
mean
17.9
30.8
M
n/a
n/a
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
Stat Method: two-sided unpaired t-test
Population-Level Exposure:
24.35 |ag/g-creatinine mean
Ali et al. (2010)
Study Type: cross-
sectional
Location: Bangladesh
(Kushtia district
(northwest))
Population: residents
of areas with high
prevalence of
arsenicosis
n cases: 141
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: water samples
collected from tube wells and analyzed
for total arsenic; all samples determined
in triplicate and average values used for
data analysis; study subjects split into
tertile groups based on drinking water
arsenic concentrations
Population-Level Exposure:
224.92 ng/L mean 57.2SD
Outcome: plasma cholinesterase (PChE) activity
(U/L)xlOA4
water arsenic levels (by regulatory limits), ng/L
Exp. Level ri mean (CD
<50 NR 1.775 n/a
>50 NR 1.365 n/a
Stat Method: Independent Samples T-Test
Log water arsenic concentration, ug/L
Exp. Level ri corr (Cl)
coeff
continuous NR -0.52 n/a
Stat Method: Spearman correlation
coefficient test
Exposure Surrogate: hair
Exposure Description: hair samples ~1
cm long were collected from close to the
scalp, behind the ear; cleaned prior to
analysis
Population-Level Exposure:
5.27 |ag/g mean 7.06SD
Outcome: plasma cholinesterase (PChE) activity
(U/L)xlOA4
log hair arsenic levels, ng/g
Exp. Level n corr (Cl)
coeff
continuous NR -0.47 n/a
Stat Method: Spearman correlation
coefficient test
Exposure Surrogate: nail
Exposure Description: individual nail
samples collected and cleaned prior to
analysis
Population-Level Exposure:
7.51 |ag/g mean 7.64SD
Outcome: plasma cholinesterase (PChE) activity
(U/L)xlOA4
log nail arsenic levels, ng/g
Exp. Level ri corr (Cl)
coeff
continuous NR -0.35 n/a
Stat Method: Spearman correlation
coefficient test
Chiou et al. (2005)
Study Type: cohort
(retrospective)
Location: Taiwan
(southwestern: Tainan
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration as reported by the
National Taiwan University Group;
median concentration used as surrogate
if village had multiple wells
Outcome: Neurological disorder
drinking water arsenic concentration - non-
diabetic subjects, mg/L
Exp. Level
<0.1
0.1-0.29
0.3-0.59
>0.6
n
NR
NR
NR
NR
M
n/a
0.73, 0.97
0.98, 1.25
1.49, 1.89
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
County (Yenshui,
Beimen, and Shuechia
townships), Chiayi
County (Putai and Yichu
townships))
Population: adults and
children living in
arseniasis-endemic
townships
n total: 28,499
Population-Level Exposure:
0.1-0.6 mg/L range
Stat Method: Stratified analysis and
unconditional logistic regression
drinking water arsenic concentration - Type 2
diabetic subjects, mg/L
Exp. Level
<0.1
0.1-0.29
0.3-0.59
>0.6
n
NR
NR
NR
NR
M
n/a
0.73, 1.60
1.32, 2.46
2.01, 3.85
Stat Method: Stratified analysis and
unconditional logistic regression
Ghosh et al. (2007b)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: West
Bengal residents
exposed to arsenic in
drinking water with and
without skin lesions
and similar unexposed
residents
n cases: 725
n control: 389
Exposure Surrogate: drinking water
Exposure Description: arsenic content in
drinking water measured from 100 ml
samples provided by study participants;
instrument calibrated and readings taken
in duplicate for each sample
Population-Level Exposure:
0-1,188 ng/L range
Outcome: conjunctivitis
arsenic exposure/skin lesion status, unitless
Exp. Level n
unexposed 13
exposed, no 44
skin lesions
exposed, skin 208
lesions
Stat Method: Logistic regression analysis
M
n/a
2.45, 8.85
37.22 20.56,67.36
Outcome: peripheral neuropathy
arsenic exposure/skin lesion status, unitless
Exp. Level r\
unexposed 11
exposed, no 33
skin lesions
exposed, skin 114
lesions
Stat Method: Logistic regression analysis
M
n/a
1.95, 8.09
15.61 8.2,29.71
Guo et al. (2007)
Study Type: cross-
sectional
Location: Mongolia
(region not available)
Population: residents
of villages in the Hetao
Plain, Inner Mongolia
Exposure Surrogate: drinking water
Exposure Description: arsenic samples
were taken from 94 water sources,
including wells; detection limit not
specified, but authors note reliability of
the method at <10 |jg/L; arsenic
exposure determined by location of
village
Population-Level Exposure:
Outcome: blurred vision
water arsenic concentration, u.g/L
Exp. Level n Prev (CD
<50|jg/L NR 3.7 n/a
>50ng/L NR 17.35 n/a
Stat Method: not reported
Outcome: loss of hearing
water arsenic concentration, u.g/L
Exp. Level n Prev (CD
<50|jg/L NR 1.06 n/a
>50ng/L NR 5.88 n/a
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
n cases: 680
n control: 189
50-1,860 ng/L range (< 50
unaffected villages; >50 ng/L affected
villages)
Stat Method: not reported
Outcome: loss of taste
water arsenic concentration, u.g/L
Exp. Level ri Prev (CD
<50|jg/L NR 0 n/a
>50ng/L: NR 5.44 n/a
Stat Method: not reported
Outcome: numbness of limbs
water arsenic concentration, u.g/L
Exp. Level ri Prev (CD
<50|jg/L NR 0 n/a
>50ng/L NR 33.53 n/a
Stat Method: not reported
Hafeman et al. (2005)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: subset of
HEALS participants
randomly selected at
clinic for peripheral
neuropathy assessment
n cases: 137
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
index calculated by multiplying water
arsenic concentration by estimated
volume consumed yearly times years of
water use
Population-Level Exposure:
2.9-11,482 ug range
Outcome: index finger vibration threshold
cumulative arsenic index (tertiles), ug
Exp. Level n
2.9-159.1 NR
159.5-843.7 NR
953.3- NR
11,482.5
Stat Method: Linear regression analyses
cumulative arsenic index per 50 units, ug
Exp. Level n adiBeta (CD
continuous NR 0.00003 n/a
71
Stat Method: Linear regression analyses
Outcome: toe vibration threshold
cumulative arsenic index (tertiles), ug
Exp. Level ri
2.9-159.1 NR
159.5-843.7 NR
953.3- NR
11,482.5
Stat Method: Linear regression analyses
cumulative arsenic index per 50 units, ug
Exp. Level n ad i Beta (CD
continuous NR 0.00251 n/a
Stat Method: Linear regression analyses
Exposure Surrogate: drinking water
Outcome: index finger vibration threshold
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-175 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
Exposure Description: drinking water
samples obtained from wells of use at
recruitment to HEALS
Population-Level Exposure:
115 |jg/L mean, 140SD, 5-743 |jg/L range
drinking water arsenic concentration (tertiles),
ug/L
Exp. Level n
5-23 NR
25-125 NR
129-743 NR
Stat Method: Linear regression analyses
drinking water arsenic concentration per 50
units, ug/L
Exp. Level n adjBeta (Cl)
continuous NR -0.013 n/a
Stat Method: Linear regression analyses
Outcome: toe vibration threshold
drinking water arsenic concentration (tertiles),
ug/L
Exp. Level n adjBeta (Cl)
5-23 NR NR n/a
25-125 NR - n/a
0.00058
5
0.203 n/a
129-743
NR
Stat Method: Linear regression analyses
drinking water arsenic concentration per 50
units, ug/L
Exp. Level n ad i Beta (Cl)
continuous NR 0.025 n/a
Stat Method: Linear regression analyses
Exposure Surrogate: urine
Exposure Description: urine samples
collected at recruitment into HEALS
(2001) and again at recruitment into
subcohort (2003); mean (SD) urinary As:
326.3 (307.5) in 2001 and 252.4 (185.4)
in 2003
Population-Level Exposure:
25.5-1,736.9 ng/mg creatinine range
Outcome: index finger vibration threshold
urinary arsenic concentration (2001) (tertiles),
ug/mg creatinine
Exp. Level n ad i Beta (Cl)
25.5-148.7 NR NR n/a
149.1-325.5 NR
332.6- NR
1,736.9
Stat Method: Linear regression analyses
urinary arsenic concentration (2003) (tertiles),
u.g/mg creatinine
Exp. Level n ad i Beta (Cl)
36.5-147 NR NR n/a
150.8-270.5 NR -0.039 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-176 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Kreiss et al. (1983)
Exposure Measures
Exposure Surrogate: drinking water
Results
271.4-975.4 NR 0.129 n/a
Stat Method: Linear regression analyses
urinary arsenic concentration per 50 units (2001),
u.g/mg creatinine
Exp. Level n adiBeta (CD
continuous NR - n/a
0.00364
Stat Method: Linear regression analyses
urinary arsenic concentration per 50 units (2003),
ug/mg creatinine
Exp. Level n adiBeta (CD
continuous NR -0.008 n/a
Stat Method: Linear regression analyses
Outcome: toe vibration threshold
urinary arsenic concentration (2001) (tertiles),
ug/mg creatinine
Exp. Level n adiBeta (CD
25.5-148.7 NR NR n/a
149.1-325.5 NR 0.019 n/a
332.6- NR 0.197 n/a
1,736.9
Stat Method: Linear regression analyses
urinary arsenic concentration (2003) (tertiles),
Hg/mg creatinine
Exp. Level n adiBeta (CD
36.5-147 NR NR n/a
150.8-270.5 NR -0.039 n/a
271.4-975.4 NR -0.138 n/a
Stat Method: Linear regression analyses
urinary arsenic concentration per 50 units (2001),
u.g/mg creatinine
Exp. Level n adiBeta (Cl)
continuous NR 0.019 n/a
Stat Method: Linear regression analyses
urinary arsenic concentration per 50 units (2003),
u.g/mg creatinine
Exp. Level n adiBeta (Cl)
continuous NR 0.014 n/a
Stat Method: Linear regression analyses
Outcome: abnormal [neuropathy] exam or
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-177 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Study Type: cross-
sectional
Location: United States
(Ester Dome, Alaska)
Population: adult
residents under age 60
living for at least 2
years in area with
known elevated levels
of arsenic in well water
n cases: 147
n control: 95
Exposure Measures
Exposure Description: daily arsenic
ingestion calculated individually based on
consumption information for both well
water and water from other sources;
arsenic concentrations of home well
water analyzed
Population-Level Exposure:
1-4521 ug/day range
Results
velocity
dally arsenic Ingestion from drinking water,
Ug/day
Exp. Level n Prev (CD
0-100 NR 17 n/a
101-1000 NR 12 n/a
1001-15000 NR 3 n/a
Stat Method: multiple linear regression
Outcome: any conduction velocity below 5th
percentile
daily arsenic ingestion from drinking water,
Ug/day
Exp. Level n Prev (CD
0-100 NR 13 n/a
101-1000 NR 12 n/a
1001-15000 NR 2 n/a
Stat Method: multiple linear regression
Outcome: neuropathy by examination
daily arsenic ingestion from drinking water,
Ug/day
Exp. Level n Prev (CD
0-100 NR 4 n/a
101-1000 NR 1 n/a
1001-15000 NR 1 n/a
Stat Method: multiple linear regression
Outcome: peroneal motor nerve velocity below
5th percentile
daily arsenic Ingestion from drinking water,
Ug/day
Exp. Level n Prev (CD
0-100 NR 4 n/a
101-1000 NR 6 n/a
1001-15000 NR 0 n/a
Stat Method: multiple linear regression
Outcome: sural sensory nerve velocity below 5th
percentile
daily arsenic ingestion from drinking water,
Ug/day
Exp. Level n Prev (CD
0-100 NR 4 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-178 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: deceased
male and female
members of Latter-day
Saints church wards
n exposed: 2203
n total: 2203
Li et al. (2006)
Study Type: cross-
sectional
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Exposure Surrogate: drinking water
Exposure Description: water samples
obtained from wells of individual families
Results
101-1000 NR 3 n/a
1001-15000 NR 1 n/a
Stat Method: multiple linear regression
Outcome: ulnar motor nerve velocity: elbow-
axilla below 5th percentile
dally arsenic ingestion from drinking water,
ug/day
Exp. Level n Prev (CD
0-100 NR 4 n/a
101-1000 NR 3 n/a
1001-15000 NR 0 n/a
Stat Method: multiple linear regression
Outcome: ulnar motor nerve velocity: wrist-
elbow below 5th percentile
daily arsenic ingestion from drinking water,
Ug/day
Exp. Level n Prev (CD
0-100 NR 4 n/a
101-1000 NR 3 n/a
1001-15000 NR 1 n/a
Stat Method: multiple linear regression
Outcome: central nervous system cancer
cumulative arsenic exposure (females), ppb-
years
Exp. Level n SMR (CD
<1000 NR 1.21 n/a
1000-4999 NR NR n/a
>5000 NR NR n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR (CD
<1000 NR NR n/a
1000-4999 NR 0.9 n/a
>5000 NR NR n/a
Stat Method: standardized mortality ratios
Outcome: peripheral neuropathy - left arm
drinking water arsenic concentration, ng/L
Exp. Level n regr (CD
coeff
<20 NR 1 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-179 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Location: China
(Mongolia)
Population: residents
of Bamen region
exposed to arsenic in
drinking water
n cases: 309
n control: n/a
Lin etal. (2008)
Study Type: cross-
sectional
Location: Taiwan
(Homei, Fuhsin, and
Hsinming villages in
Putai Township, Chiayi
County)
Population: residents
of pterygium endemic
Exposure Measures
or community water sources
Population-Level Exposure:
0-700 ng/L range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated based on well water
concentrations (1960 measurements),
and duration of living in each village
(obtained from questionnaire); exposure
was classified as unknown if the arsenic
concentration was unavailable for any
village the participant had lived in
Population-Level Exposure:
0.1-15.1 mg/L-yr range
Results
100-300 NR 0.35 n/a
400-700 NR 1.7 n/a
Stat Method: categorical multivariate analysis
Outcome: peripheral neuropathy- left leg
drinking water arsenic concentration, ng/L
Exp. Level n regr (Cl)
coeff
<20 NR 1 n/a
100-300 NR 1.41 n/a
400-700 NR 2.96 n/a
Stat Method: categorical multivariate analysis
Outcome: peripheral neuropathy- right arm
drinking water arsenic concentration, ng/L
Exp. Level n regr (Cl)
coeff
<20 NR 1 n/a
100-300 NR 0.62 n/a
400-700 NR 1.51 n/a
Stat Method: categorical multivariate analysis
Outcome: peripheral neuropathy- right leg
drinking water arsenic concentration, ng/L
Exp. Level n regr (Cl)
coeff
<20 NR 1 n/a
100-300 NR NR n/a
400-700 NR 2.16 n/a
Stat Method: categorical multivariate analysis
Outcome: pterygium
cumulative arsenic exposure concentration, mg/L
-yr
Exp. Level n adiOR (Cl)
<0.1 NR 1 n/a
0.1-15.0 NR 2.04 1.04,3.99
>15.1 NR 2.88 1.42,5.83
unknown NR 1.1 0.45,2.69
Stat Method: multiple logistic regression
model
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-180 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
villages
n cases: 223
n control: 160
Otto et al. (2006)
Study Type: cross-
sectional
Location: China (Bamen
Region, Inner
Mongolia, China)
Population: children
and adults in region
with high arsenic
concentrations who
consumed water from
wells
n cases: 309
n control: n/a
Otto et al. (2007)
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: samples from
individual and community wells analyzed;
statistical analyses conducted to
determine threshold in relationship
between arsenic concentration and
outcome
Population-Level Exposure:
20-700 ng/L range
Exposure Surrogate: drinking water
Results
Outcome: vibration threshold, dominant hand,
digit 2
total water arsenic concentration, ng/L
Exp. Level n corr (CD
coeff
<170 NR -0.25 n/a
>170 NR 0.2 n/a
Stat Method: loglO transformation and linear
regression
Outcome: vibration threshold, dominant hand,
digit 5
total water arsenic concentration, ng/L
Exp. Level n corr (CD
coeff
<170 NR -0.55 n/a
>170 NR 0.4 n/a
Stat Method: loglO transformation and linear
regression
Outcome: vibration threshold, non-dominant
hand, digit 2
total water arsenic concentration, ng/L
Exp. Level n corr (Cl)
coeff
<150 NR -0.31 n/a
>150 NR 0.36 n/a
Stat Method: loglO transformation and linear
regression
Outcome: vibration threshold, non-dominant
hand, digit 5
total water arsenic concentration, ng/L
Exp. Level n corr (Cl)
coeff
<170 NR -0.51 n/a
>170 NR 0.4 n/a
Stat Method: loglO transformation and linear
regression
Outcome: pinprick score, left arm
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-181 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
Study Type: cross-
sectional
Location: China
(Farming region of Ba
Men, Inner Mongolia)
Population: residents
from 9 to 64 years of
age using wells in area
with high arsenic
concentrations in
ground water
n cases: 320
n control: n/a
Exposure Description: samples collected
from 117 wells used by study participants
on three consecutive days and results
averaged across days); no speciation
Population-Level Exposure:
270 ng/L mean 230SD
drinking water arsenic concentration, ng/L
Exp. Level n adjOR M
continuous NR 2.13 n/a
Stat Method: multivariate regression;
ordered logistic regression models
drinking water arsenic concentration, ng/L
Exp. Level ri regr (CD
coeff
continuous NR 3.23 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, left leg
drinking water arsenic concentration, \ng/L
Exp. Level n adjOR M
continuous NR 2.77 n/a
Stat Method: multivariate regression;
ordered logistic regression models
drinking water arsenic concentration, ng/L
Exp. Level n regr (CD
coeff
continuous NR 4.36 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, right arm
drinking water arsenic concentration, ng/L
Exp. Level n adjOR M
continuous NR 1.85 n/a
Stat Method: multivariate regression;
ordered logistic regression models
drinking water arsenic concentration, \ng/L
Exp. Level n regr (CD
coeff
continuous NR 2.64 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, right leg
drinking water arsenic concentration, \ig/L
Exp. Level n adjOR M
continuous NR 2.99 n/a
Stat Method: multivariate regression;
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-182 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
ordered logistic regression models
drinking water arsenic concentration, ng/L
Exp. Level ri regr (CD
coeff
continuous NR 4.65 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: vibration threshold, non-dominant
hand, fifth digit
drinking water arsenic concentration, ng/L
Exp. Level n adjR2 M
continuous NR 0.11 n/a
Stat Method: multivariate regression
Outcome: vibration threshold, non-dominant
hand, second digit
drinking water arsenic concentration, ng/L
Exp. Level n adjR2 M
continuous NR 0.11 n/a
Stat Method: multivariate regression
Exposure Surrogate: toenails
Exposure Description: cleaned and
washed toenail samples from each
participant analyzed
Population-Level Exposure:
11.85 ug/kg mean 11.85SD
Outcome: pinprick score, left arm
toenail arsenic concentration, ug/kg
Exp. Level n adjOR (CD
continuous NR 1.91 n/a
Stat Method: multivariate regression;
ordered logistic regression models
toenail arsenic concentration, ug/kg
Exp. Level n regr (CD
coeff
continuous NR 0.0548 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, left leg
toenail arsenic concentration, ug/kg
Exp. Level n adjOR
continuous NR 2.03 n/a
Stat Method: multivariate regression;
ordered logistic regression models
toenail arsenic concentration, ug/kg
Exp. Level ri regr (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-183 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
coeff
continuous NR 0.0597 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, right arm
toenail arsenic concentration,
Exp. Level n adjOR (CD
continuous NR 1.71 n/a
Stat Method: multivariate regression;
ordered logistic regression models
toenail arsenic concentration, ng/kg
Exp. Level n regr (Cl)
coeff
continuous NR 0.0454 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, right leg
toenail arsenic concentration, ng/kg
Exp. Level n adjOR
continuous NR 2.28 n/a
Stat Method: multivariate regression;
ordered logistic regression models
toenail arsenic concentration, ng/kg
Exp. Level ri regr (Cl)
coeff
continuous NR 0.0694 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: vibration threshold, non-dominant
hand, fifth digit
toenail arsenic concentration, ng/kg
Exp. Level n adjR2
continuous NR 0.12 n/a
Stat Method: multivariate regression
Outcome: vibration threshold, non-dominant
hand, second digit
toenail arsenic concentration, ng/kg
Exp. Level n ad|R2 {G}
continuous NR 0.11 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-184 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
Stat Method: multivariate regression
Exposure Surrogate: urine
Exposure Description: urine samples
collected on 3 consecutive days and
analyzed for arsenic species; total urinary
arsenic (As[lll] As[V], MMA, DMA),
inorganic arsenic (As[lll], As[V]), organic
arsenic (MMA, DMA), and arsenite
(As[lll]) calculated as average of
measurements in 3 samples
Population-Level Exposure:
374.85 ng/L mean 350.01SD
Outcome: pinprick score, left arm
urinary inorganic arsenic concentration, u.g/L
Exp. Level n regr (CD
coeff
continuous NR 0.0056 n/a
Stat Method: multivariate regression
urinary inorganic arsenic concentration, u.g/L
Exp. Level n adjOR M
continuous NR 1.88 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, left leg
urinary inorganic arsenic concentration, u.g/L
Exp. Level n regr (CD
coeff
continuous NR 0.00738 n/a
Stat Method: multivariate regression
urinary inorganic arsenic concentration, u.g/L
Exp. Level n adjOR M
continuous NR 2.29 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, right arm
urinary inorganic arsenic concentration, ug/L
Exp. Level n regr (CD
coeff
continuous NR 0.00458 n/a
Stat Method: multivariate regression
urinary inorganic arsenic concentration, ug/L
Exp. Level n adjOR M
continuous NR 1.67 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: pinprick score, right leg
urinary inorganic arsenic concentration, ug/L
Exp. Level n regr (CD
coeff
0.00844 n/a
continuous
NR
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-185 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Park et al. (2014)
Study Type: case-
control
Location: Korea,
Republic Of region not
available
Exposure Measures
Exposure Surrogate: serum
Exposure Description: nonfasting blood
samples were collected and serum
extracted; analytical methods were
validated using certified reference
material
Population-Level Exposure:
Results
Stat Method: multivariate regression
urinary inorganic arsenic concentration, ug/L
Exp. Level n adiOR (CD
continuous NR 2.58 n/a
Stat Method: multivariate regression;
ordered logistic regression models
Outcome: vibration threshold, dominant hand,
fifth digit
urinary inorganic arsenic concentration, ug/L
Exp. Level n adiR2 (CD
continuous NR 0.12 n/a
Stat Method: multivariate regression
Outcome: vibration threshold, dominant hand,
second digit
urinary inorganic arsenic concentration, ug/L
Exp. Level n adiR2 (CD
continuous NR 0.13 n/a
Stat Method: multivariate regression
Outcome: vibration threshold, non-dominant
hand, fifth digit
urinary inorganic arsenic concentration, ug/L
Exp. Level n adiR2 (CD
continuous NR 0.13 n/a
Stat Method: multivariate regression
Outcome: vibration threshold, non-dominant
hand, second digit
urinary inorganic arsenic concentration, ug/L
Exp. Level n adiR2 (CD
continuous NR 0.13 n/a
Stat Method: multivariate regression
Outcome: Alzheimer's disease (AD)
arsenic concentration in serum by Alzheimer's
Disease status, ug/L
Exp. Level n mean (Cl)
controls 67 28.66 n/a
cases 64 28.08 n/a
Stat Method: t-test
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-186 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
28.37 ng/L mean
Population: elderly
patients with probable
Alzheimer's Disease
n cases: 89
n control: 118
Paul etal. (2013)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: male and
female adult residents
with skin lesions from 3
villages with high
arsenic concentrations
n cases: 189
n control: 171
Exposure Surrogate: drinking water
Exposure Description: samples collected
directly from study participants during
2005-2006 and 2010-2011 study periods
Population-Level Exposure:
mean concentration in drinking water
ranged from 3.7 (unexposed) to 190.1
(exposed) in both analyses
Outcome: conjunctiva! irritations
drinking water arsenic concentration by
exposure status and year, unitless
n
NR
OR
1
M
n/a
NR
NR
NR
11.15
n/a
4.91, 25.32
Exp. Level
unexposed
(2005-2006
analysis)
unexposed
(2010-2011
analysis)
exposed
(2005-2006
analysis)
exposed
(2010-2011
analysis)
Stat Method: OR with 95% Cl; 2005 - 2006
data compared to 2010 - 2011 data using
Chi-Square test
20.51 9.84,42.72
Outcome: peripheral neuropathy
drinking water arsenic concentration, u.g/L
n
NR
OR
1
M
n/a
NR
NR
NR
9.08
n/a
3.48, 23.72
Exp. Level
unexposed
(2005-2006
analysis)
unexposed
(2010-2011
analysis)
exposed
(2005-2006
analysis)
exposed
(2010-2011
analysis)
Stat Method: OR with 95% Cl; 2005 - 2006
data compared to 2010 - 2011 data using
Chi-Square test
18.48 7.75,44.06
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-187 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Rosado et al. (2007)
Study Type: cross-
sectional
Location: Mexico
(Torreon)
Population: children 6-
8 years of age
attending school near a
metallurgic smelter
complex
n cases: n/a
n control: n/a
Exposure Measures
Exposure Surrogate: urine
Exposure Description: urine samples
collected the morning after subjects
fasted overnight; urinary arsenic
concentrations include inorganic As,
monomethylarsenic, dimethylarsenic,
and the sum of all metabolic species of
arsenic
Population-Level Exposure:
58.1 ug/dLmean33.2SD
Results
Outcome: attention: letter sequencing
urinary arsenic, u.g/dL
Exp.
Level
continuou
s in
children
with UAs
<50 ug/L
continuou
s in
children
with UAs
>50ug/L
Stat Methoc
n
NR
NR
j: multiple lin
adiOR
0.992
0.993
ear regressio
(CD
0.963,
1.021
0.988,
0.999
i
Outcome: attention: visual search
urinary arsenic, u.g/dL
Exp.
Level
continuou
s in
children
with UAs
<50 ug/L
continuou
s in
children
with UAs
>50ug/L
n
NR
NR
adjBeta
-0.008
-0.006
(CD
-0.022,
0.005
-0.012, 0
Stat Method: multiple linear regression
Outcome: attention: WISC-RM coding subscale
urinary arsenic, u.g/dL
arsenic not significantly associated with attention:
WISC-RM Coding Subscale
Outcome: memory: Sternberg memory
urinary arsenic, u.g/dL
Exp.
Level
continuou
sin
n
NR
adjBeta
-0.027
(CD
-0.053, -
0.002
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-188 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
children
with UAs
<50 ug/L
Continuou
NR
sin
children
with UAs
>50ug/L
Stat Method: multiple linear regression
0.002
-0.008,
0.012
Outcome: memory: stimulus discrimination
urinary arsenic, ug/dL
Exp.
Level
continuou NR
sin
children
with UAs
<50 ug/L
Continuou
NR
sin
children
with UAs
>50ug/L
Stat Method: multiple linear regression
adiOR
0.982
1.004
(CD
0.957,
1.008
1.000,
1.008
Outcome: memory: visual memory span
urinary arsenic, ug/dL
Exp. n adjBeta (CD
Level
continuou NR -0.003 -0.007,
s in 0.000
children
with UAs
<50 ug/L
continuou NR -0.001 -0.002,
s in 0.003
children
with UAs
>50ug/L
Stat Method: multiple linear regression
Outcome: memory: WISC-RM digit span subscale
urinary arsenic, ug/dL
Exp.
Level
(CD
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
NR
contmuou
s in
children
with UAs
<50ug/L
continuou
sin
children
with UAs
>50ug/L
Stat Method: multiple linear regression
NR
-0.037
-0.012
-0.065,
0.010
-0.037,
0.012
Outcome: problem solving and vocabulary: math
achievement test
urinary arsenic, ug/dL
arsenic not significantly associated with problem
solving and vocabulary: math achievement test in
children with urinary arsenic >50 ug/L, but
significantly reduced in children with urinary
arsenic <50 ug/L
Outcome: problem solving and vocabulary:
Peabody picture vocabulary test
urinary arsenic, u.g/dL
Exp. n adjBeta (CD
Level
continuou NR -0.185 -0.293,-
s in 0.078
children
with UAs
<50ug/L
continuou NR -0.058 -0.120,
s in 0.004
children
with UAs
>50ug/L
Stat Method: multiple linear regression
Outcome: problem solving and vocabulary:
visual-spatial abilities with figure design
urinary arsenic, u.g/dL
Exp. n
Level
continuou NR
s in
children
(CD
-0.096,
0.061
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
with UAs
<50ug/L
continuou NR -0.028 -0.053,
s in 0.004
children
with UAs
>50ug/L
Stat Method: multiple linear regression
Outcome: problem solving and vocabulary:
WISC-RM arithmetic subscale
urinary arsenic, ug/dL
arsenic not significantly associated with problem
solving and vocabulary: WISC-RM arithmetic
subscale
Exposure Surrogate: urine
Exposure Description: urine samples
collected the morning after subjects
fasted overnight; urinary arsenic
concentrations include inorganic As,
monomethylarsenic, dimethylarsenic,
and the sum of all metabolic species of
arsenic
Population-Level Exposure:
58.1 ng/dL mean 33.2SD
Outcome: attention: letter sequencing
urinary arsenic (overall group), ug/dL
n
Level
continuou NR
s
Stat Method: multiple linear regression
adiOR
0.992
(CD
0.987,
0.996
Outcome: attention: visual search
urinary arsenic (overall group), ug/dL
Exp.
Level
continuou
NR
(CD
-0.011,
0.002
Stat Method: multiple linear regression
Outcome: memory: Sternberg memory
urinary arsenic (overall group), ug/dL
Exp.
Level
continuou
NR
(CD
-0.007,
0.004
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
Stat Method: multiple linear regression
Outcome: memory: stimulus discrimination
urinary arsenic (overall group), ug/dL
Level
continuou
NR
adiOR
0.998
(CD
0.993,
1.004
Stat Method: multiple linear regression
Outcome: memory: visual memory span
urinary arsenic (overall group), ug/dL
Level
continuou
NR
adjBeta
0
(CD
-0.002,
0.001
Stat Method: multiple linear regression
Outcome: memory: WISC-RM digit span subscale
urinary arsenic (overall group), u.g/dL
Level
continuou
NR
adjBeta
-0.014
(CD
-0.025, -
0.002
Stat Method: multiple linear regression
Outcome: problem solving and vocabulary:
Peabody picture vocabulary test
urinary arsenic (overall group), u.g/dL
Exp.
Level
continuou
NR
adjBeta
-0.064
(CD
-0.115,
0.013
Stat Method: multiple linear regression
Outcome: problem solving and vocabulary:
visual-spatial abilities with figure design
urinary arsenic (overall group), ug/dL
Exp.
Level
continuou
NR
adjBeta
-0.024
(CD
-0.045,
0.004
Stat Method: multiple linear regression
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
See et al. (2007)
Study Type: cross-
sectional
Location: Taiwan (Putai
Township of Chiayi
County)
Population: adult
residents in arseniasis-
hyperendemic villages
who previously
consumed artesian well
water
n cases: n/a
n control: n/a
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure derived by multiplying the
arsenic concentration in artesian well
water from levels measured in 1960s by
the self-reported duration of water
consumption; subjects who moved were
categorized as having unknown exposure
levels
Population-Level Exposure:
0-20 mg/L-yr range
Results
Outcome: eye: cortical opacity
cumulative arsenic drinking water exposure,
mg/L - yr
Exp. Level n adiOR (CD
0 12 1 n/a
0.1-12.0 9 0.74 0.25,2.18
12.1-20.0 24 1.36 0.51,3.65
>20.0 37 1.25 0.42,3.69
Unknown 37 2.1 0.75,5.87
Stat Method: chi-square test
cumulative arsenic drinking water exposure,
mg/L - yr
Exp. Level n OR (Cl)
0 12 1 n/a
0.1-12.0 9 0.66 0.26, 1.69
12.1-20.0 24 2.5 1.11,5.61
>20.0 37 6.42 2.85, 14.48
Unknown 37 4.53 2.07,9.93
Stat Method: chi-square test
Outcome: eye: nuclear opacity
cumulative arsenic drinking water exposure,
mg/L - yr
Exp. Level n adiOR (Cl)
0 8 1 n/a
0.1-12.0 4 0.65 0.16,2.62
12.1-20.0 19 1.79 0.57,5.58
>20.0 28 1.74 0.51,5.90
Unknown 23 2.03 0.59,7.01
Stat Method: chi-square test
cumulative arsenic drinking water exposure,
mg/L - yr
Exp. Level n OR (Cl)
0 8 1 n/a
0.1-12.0 4 0.44 0.13, 1.54
12.1-20.0 19 2.97 1.18,7.48
>20.0 28 7.29 2.89, 18.38
Unknown 23 4.23 1.69, 10.56
Stat Method: chi-square test
Outcome: eye: overall cataract
cumulative arsenic drinking water exposure,
mg/L - yr
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Tseng et al. (2006)
Study Type: cross-
sectional
Location: Taiwan
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic exposure
based on previously conducted large-
scale study; arsenic exposure indices
based on well water samples from each
Results
Exp. Level n adiOR (CD
0 15 1 n/a
0.1-12.0 12 1.08 0.39,2.97
12.1-20.0 31 2.27 0.90,5.72
>20.0 43 2.19 0.81,5.91
Unknown 43 2.7 0.99,7.29
Stat Method: chi-square test
cumulative arsenic drinking water exposure,
mg/L - yr
Exp. Level n OR (CD
0 15 1 n/a
0.1-12.0 12 0.71 0.30, 1.64
12.1-20.0 31 2.58 1.23,5.43
>20.0 43 5.97 2.78, 12.80
Unknown 43 4.22 2.02,8.76
Stat Method: chi-square test
Outcome: eye: posterior subcapsular opacity
cumulative arsenic drinking water exposure,
mg/L - yr
Exp. Level n adiOR (CD
0 5 1 n/a
0.1-12.0 5 2.19 0.4, 12.07
12.1-20.0 15 4.78 1.03,22.18
>20.0 28 5.7 1.23,26.32
Unknown 22 4.1 0.84, 19.94
Stat Method: chi-square tes
cumulative arsenic drinking water exposure,
mg/L - yr
Exp. Level n OR (CD
0 5 1 n/a
0.1-12.0 5 0.88 0.24,3.21
12.1-20.0 15 3.75 1.26, 11.2
>20.0 28 25.1 4.01,33.97
Unknown 22 6.47 2.23, 18.76
Stat Method: chi-square test
Outcome: Sural Sensory Action Potential (SAP)
nerve conduction velocity (NCV) in m/s
arsenic concentration in well water, u.Q/1
Exp. Level n adiOR (CD
<10 NR 1 n/a
10.0-50.0 NR 0.9 0.3,3.2
>50 NR 2.4 0.7,8.1
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Nervous System Effects
Reference and Study
Design
Exposure Measures
Results
(Langyang Basin)
Population: adolescent
students with arsenic
contaminated drinking
water
n cases: 117
n control: n/a
participant's household; cumulative
arsenic dose calculated based on volume
consumed and self-reported years of
consumption; 3,901 wells were matched
to students using questionnaire
Population-Level Exposure:
0.15-3.59 ug/L range
Stat Method: multiple logistic regression
cumulative dose of arsenic concentration,
Exp. Level n adjOR (CD
<50.0 NR 1 n/a
50.1-100 NR 0.4 0.04,3.2
>100 NR 2.9 1.1,7.5
Stat Method: multiple logistic regression
length of time (years) since stopping arsenic
exposure, ug/L
Exp. Level ri
>1 NR
0-1 NR
0 NR
M
n/a
0.2, 1.7
0.4, 4.7
Stat Method: multiple logistic regression
--: not reported; n: number of cases (when presented in Results column)
5.11.1 References for Summary of Observational Epidemiology
Studies for Health Effect Category: Nervous System Effects
Adams. JB: Audhya. T: Mcdonough-Means. S: Rubin. RA: Quig. D: Geis. E: Gehn. E: Loresto. M: Mitchell J:
Atwood. S: Barnhouse. S: Lee. W. (2013). Toxicological status of children with autism vs. neurotypical
children and the association with autism severity. Biol Trace ElemRes 151: 171-180.
http://dx.doi.org/10.1007/sl2011-012-9551-l
Ali. N: Hoque. MA: Hague. A: Salam. KA: Karim MR: Rahman. A: Islam K: Saud. ZA: Khalek. MA: Akhand.
AA: Hossain. M: Mandal. A: Karim MR: Miyataka. H: Himeno. S: Hossain. K. (2010). Association between
arsenic exposure and plasma cholinesterase activity: a population based study in Bangladesh. Environ Health
9: 36. http://dx.doi.org/10.1186/1476-069X-9-36
Chiou. JM: Wang. SL: Chen. CJ: Deng. CR: Lin. W: Taj TY. (2005). Arsenic ingestion and increased
microvascular disease risk: Observations from the south-western arseniasis-endemic area in Taiwan. Int J
Epidemiol 34: 936-943. http://dx.doi.org/10.1093/iie/dvil08
Ghosh. P: Banerjee. M: De Chaudhuri. S: Chowdhury. R: Das. JK: Mukherjee. A: Sarkar. AK: Mondal L:
Baidva. K: Sau. TJ: Banerjee. A: Basu. A: Chaudhmi K: Ray. K: Girl AK. (2007). Comparison of health
effects between individuals with and without skin lesions in the population exposed to arsenic through
drinking water in West Bengal, India. J Expo Sci Environ Epidemiol 17: 215-223.
http://dx.doi.org/10.1038/sj.jes.7500510
Guo. JX: Hu. L: Yand. PZ: Tanabe. K: Miyatalre. M: Chen. Y. (2007). Chronic arsenic poisoning in drinking
water in Inner Mongolia and its associated health effects. J Environ Sci Health A Tox Hazard Subst Environ
Eng42: 1853-1858. http://dx.doi.org/10.1080/10934520701566918
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Hafeman. DM: Ahsan. H: Louis. ED: Siddique. AB: Slavkovich. V: Cheng. Z: van Geen. A: Graziano. JH.
(2005). Association between arsenic exposure and a measure of subclinical sensory neuropathy in
Bangladesh. J Occup Environ Med 47: 778-784. http://dx.doi.org/10.1097/01.jom.0000169089.54549.db
Kreiss. K: Zack. MM: Feldman. RG: Niles. CA: Chirico-Post. J: Sax. PS: Landrigan. PJ: Boyd. MH: Cox. PH.
(1983). Neurologic evaluation of a population exposed to arsenic in Alaskan well water. Arch Environ Health
38: 116-121.
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Li. Y: Xia. Y: He. L: Nine. Z: Wu. K: Zhao. B: Le. XC: Kwok. R: Schmitt. M: Wade. T: Mumford. J: Otto. D.
(2006). Neurosensory effects of chronic exposure to arsenic via drinking water in Inner Mongolia: I. signs,
symptoms and pinprick testing. J Water Health 4: 29-37. http://dx.doi.org/10.2166/wh.2005.022
Lin. W: Wang. SL: Wu. HJ: Chang. KH: Yeh. P: Chen. CJ: Quo. HR. (2008). Associations between arsenic in
drinking water and pterygium in southwestern Taiwan. Environ Health Perspect 116: 952-955.
http://dx.doi.org/10.1289/ehp. 11111
Otto. D: He. L: Xia. Y: Li. Y: Wu. K: Nine. Z: Zhao. B: Hudnell. HK: Kwok. R: Mumford. J: Geller. A: Wade.
T\ (2006). Neurosensory effects of chronic exposure to arsenic via drinking water in Inner Mongolia: II.
Vibrotactile and visual function. J Water Health 4: 39-48.
Otto. D: Xia. Y: Li. Y: Wu. K: He. L: Telech. J: Hundell. H: Prah. J: Mumford. J: Wade. T. (2007).
Neurosensory effects of chronic human exposure to arsenic associated with body burden and environmental
measures. HumExp Toxicol 26: 169-177. http://dx.doi.org/10.1177/0960327107070561
Park. JH: Lee. DW: Park. KS: Joung. H. (2014). Serum trace metal levels in Alzheimer's disease and normal
control groups. Am J Alzheimers Dis Other Demen 29: 76-83. http://dx.doi.org/10.1177/1533317513506778
Paul. S: Das. N: Bhattacharjee. P: Banerjee. M: Das. JK: Sarma. N: Sarkar. A: Bandvopadhyav. AK: Sau. TJ:
Basu. S: Banerjee. S: Maiumder. P: Girl AK. (2013). Arsenic-induced toxicity and carcinogenicity: a two-
wave cross-sectional study in arsenicosis individuals in West Bengal, India. J Expo Sci Environ Epidemiol
23: 156-162. http://dx.doi.org/10.1038/ies.2012.91
Rosado. JL: Ronquillo. D: Kordas. K: Rojas. O: Alatorre. J: Lopez. P: Garcia-Vargas. G: Caamano. MDC:
Cebrian. ME: Stoltzfus. RJ. (2007). Arsenic exposure and cognitive performance in Mexican schoolchildren.
Environ Health Perspect 115: 1371-1375. http://dx.doi.org/10.1289/ehp.9961
See. LC: Chiou. HY: Lee. JS: Hsueh. YM: Lin. SM: Tu. MC: Yang. ML: Chen. CJ. (2007). Dose-response
relationship between ingested arsenic and cataracts among residents in Southwestern Taiwan. J Environ Sci
Health A Tox Hazard Subst Environ Eng 42: 1843-1851. http://dx.doi.org/10.1080/10934520701566884
Tseng. HP: Wang. YH: Wu. MM: The. HW: Chiou. HY: Chen. CJ. (2006). Association between chronic
exposure to arsenic and slow nerve conduction velocity among adolescents in Taiwan. J Health Popul Nutr
24: 182-189.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.12Summary of Observational Epidemiology Studies for
Health Effect Category: Other
Summary of Observational Epidemiology Studies for Health Effect Category: Other
Reference and Study
Design
Exposure Measures
Results
Chung etal. (2012)
Study Type: cohort
(prospective)
Location: Taiwan
(Homei, Fuhsin,
Hsinming)
Population: residents
of arseniasis-endemic
areas
n total: 1563
Exposure Surrogate: drinking water
Exposure Description: information on
median arsenic level in artesian well
water of each village acquired from
previous studies carried out in the early
1960s (Lai etal., 1994); some study
subjects had moved from one village to
another, and there were differences in
arsenic concentrations between villages
Population-Level Exposure:
0.7-0.93 mg/L range
Outcome: all site cancers
average water arsenic concentration (tertiles),
mg/L
not significant for average urinary arsenic or
cumulative arsenic exposure in drinking water; for
arsenic profiles, only significant trend for
inorganic arsenic% (not %MMA or %DMA)
Hsu et al. (2013b)
Study Type: cohort
(prospective)
Location: Taiwan (SW:
Peimen, Hsuechia, Ichu,
and Putai Townships;
NE: Chiaohsi,
Chuangwei, Wuchieh,
and Tungshan
Townships)
Population: residents
of an arseniasis-
endemic area with skin
lesions
n total: 9525
Exposure Surrogate: drinking water
Exposure Description: SW population:
median arsenic level of several wells
shared in a village derived from two
surveys; NE population: arsenic level of
well water samples collected during
home interviews
Population-Level Exposure:
10-500 ng/L range
Outcome: all internal cancers
arsenic concentration in well water (non-
diabetes mellitus vs. diabetes mellitus subjects),
HR
1
Exp. Level
non-DMw/
As <500
DMw/As
<500
non-DMw/
As > 500
DMw/As
>500
Stat Method: Cox regression analysis with
time-dependent DM status
NR
NR
NR
1.45
1
1.72
(CD
n/a
0.24,1.70
n/a
1.33,2.22
Maiumdar et al. (2009)
Study Type: cross-
sectional
Exposure Surrogate: drinking water
Exposure Description: for each
participant, water samples from private
Outcome: weakness and diarrhea
arsenic concentration in drinking water (males),
H9/L
significant increase in weakness and diarrhea in
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Other
Reference and Study
Design
Exposure Measures
Results
Location: India (West
Bengal)
Population: residents
of arsenic-affected
villages
n cases: 3825
n control: 3451
or public tube wells analyzed for arsenic;
exposure categories developed based on
arsenic levels
Population-Level Exposure:
50-500 ng/L range
males and females exposed to >500 |jg/L
Tsuda et al. (1995)
Study Type: cohort
(retrospective)
Location: Japan
(Namiki-cho)
Population: adults and
children living near
factory producing
arsenic trisulfide
n exposed: 189
n reference: 254
n total: 443
Exposure Surrogate: drinking water
Exposure Description: arsenic in well
water measured in 1959 (the end of the
exposure period) in 34 wells; 20 area
wells had no documented levels of
arsenic so authors inferred that arsenic
levels were undetectable or very low;
concentration assigned based on
residence in 1959
Population-Level Exposure:
0.05-1 ppm range
Outcome: all cancers
arsenic concentration in well water in 1959, ppm
Exp. Level n SMR M
<0.05 11 0.78 0.41, 1.41
0.05-0.99 5 1.3 0.51,3.06
>1 18 3.63 2.25,5.71
Stat Method: Cox proportional hazard
--: not reported; n: number of cases (when presented in Results column)
5.12.1 References for Summary of Observational Epidemiology
Studies for Health Effect Category: Other
Chung. CJ: Huang. YL: Huang. YK: Wu. MM: Chen. SY: Hsueh. YM: Chen. CJ. (2012). Urinary arsenic
profiles and the risks of cancer mortality: A population-based 20-year follow-up study in arseniasis-endemic
areas in Taiwan. Environ Res 122: 25-30. http://dx.doi.0rg/10.1016/i.envres.2012.ll.007
Hsu. LI: Wang. YH: Chiou. HY: Wu. MM: Yang. TY: Chen. YH: Tseng. CH: Chea CJ. (2013). The association
of diabetes mellitus with subsequent internal cancers in the arsenic-exposed area of Taiwan. J Asian Earth
Sci 73: 452-459. http://dx.doi.0rg/10.1016/i.iseaes.2013.04.048
Lai. MS: Hsueh. YM: Chen. CJ: Shyu. MP: Chea SY: Kuo. TL: Wu. MM: Taj TY. (1994). Ingested inorganic
arsenic and prevalence of diabetes mellitus. Am J Epidemiol 139: 484-492.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Majumdar. KK: Guha Mazumder. DN: Ghose. N: Ghose. A: Lahiri. S. (2009). Systemic manifestations in
chronic arsenic toxicity in absence of skin lesions in West Bengal. Indian J Med Res 129: 75-82.
Tsuda. T: Babazono. A: Yamamoto. E: Kurumatani. N: Mino. Y: Ogawa. T: Kishi. Y: Aoyama. H. (1995).
Ingested arsenic and internal cancer: A historical cohort study followed for 33 years. Am J Epidemiol 141:
198-209.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.13Summary of Observational Epidemiology Studies for
Health Effect Category: Renal Effects
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
Exposure Measures
Results
Baastrupetal. (2008)
Study Type: cohort
(prospective)
Location: Denmark
(Copenhagen and
Aarhus)
Population: Danish
Cancer Registry
population (adults)
n exposed: 56,378
n total: 57053
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure and time-weighted average
arsenic concentrations calculated for
individuals based on residential address
and history from Central Population
Registry combined with measurement
data from nearest water utility as
recorded by Geological Survey of
Denmark and Greenland (1987-2004)
Population-Level Exposure:
not available
Outcome: kidney cancer
cumulative arsenic exposure, mg
Exp. Level n IRR
continuous NR 0.94
Stat Method: Cox regression
M
0.84, 1.06
Exposure Surrogate: drinking water
Exposure Description: time-weighted
and cumulative arsenic concentrations
calculated for individuals based on
residential address and history from
Central Population Registry combined
with measurement data from nearest
water utility as recorded by Geological
Survey of Denmark and Greenland (1987-
2004)
Population-Level Exposure:
0.7 ng/L median
Outcome: kidney cancer
time-weighted average arsenic exposure, ug/L
Exp. Level n IRR (CD
continuous NR 0.89 0.65, 1.22
Stat Method: Cox regression
Chen et al. (2011a)
Study Type: cross-
sectional
Location: Taiwan
(Changhua County
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from spot
sample for each individual; results below
LOD assigned one-half of LOD
Outcome: renal tubular dysfunction (estimated
glomerular filtration rate <60 mL/min)
urinary arsenic concentration, ug/g-creatinine
Exp. Level
=<35
>35-75
>75-200
>200
NR
NR
NR
NR
M
n/a
0.56, 1.80
0.42, 1.33
0.95, 4.99
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
(central Taiwan))
Population: adult
residents of village with
history of higher than
average arsenic in
drinking water
n cases: 910
n control: 133
Chiou et al. (2005)
Study Type: cohort
(retrospective)
Location: Taiwan
(southwestern: Tainan
County (Yenshui,
Beimen, and Shuechia
townships), Chiayi
County (Putai and Yichu
townships))
Population: adults and
children living in
arseniasis-endemic
townships
n total: 28499
Exposure Measures
Population-Level Exposure:
85.13 ng/g-creatinine median
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration as reported by the
National Taiwan University Group;
median concentration used as surrogate
if village had multiple wells
Population-Level Exposure:
0.1-0.6 mg/L range
Results
Stat Method: multivariate logistic regression
Outcome: renal tubular dysfunction (estimated
glomerular filtration rate <90 mL/min)
urinary arsenic concentration, ug/g-creatinine
Exp. Level n adiOR (CD
=<35 NR 1 n/a
>35-75 NR 1.45 0.49, 1.88
>75-200 NR 2.15 1.06,3.78
>200 NR 2.16 1.11,3.49
Stat Method: multivariate logistic regression
Outcome: renal tubular dysfunction (urinary
beta2 microglobulin >0.154 mg/L)
urinary arsenic concentration, u.g/g-creatinine
Exp. Level n adiOR (CD
=<35 NR 1 n/a
>35-75 NR 1.69 0.94,3.64
>75-200 NR 2.11 1.23,4.98
>200 NR 2.04 1.11,4.37
Stat Method: multivariate logistic regression
Outcome: Renal disease
drinking water arsenic concentration - renal
disease, mg/L
Exp. Level n adiBeta (CD
continuous NR -0.898 n/a
Stat Method: Logistic regression model
drinking water arsenic concentration - non-
diabetic subjects, mg/L
Exp. Level n adiOR (CD
<0.1 NR 1 n/a
0.1-0.29 NR 1.17 0.75, 1.83
0.3-0.59 NR 0.78 0.48, 1.24
>0.6 NR 1.3 0.85,2.00
Stat Method: Stratified analysis and
unconditional logistic regression
drinking water arsenic concentration - Type 2
diabetic subjects, mg/L
Exp. Level n adiOR (CD
<0.1 NR 1 n/a
0.1-0.29 NR 0.69 0.27, 1.81
0.3-0.59 NR 1.33 0.67,2.63
>0.6 NR 2.08 1.05,4.11
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
Exposure Measures
Results
Stat Method: Stratified analysis and
unconditional logistic regression
Ferreccio et al. (2013a)
Study Type: case-
control
Location: Chile
(Regions I and II in
northern Chile)
Population: residents
with kidney cancer in
area formerly having
arsenic-contaminated
drinking water
n cases: 122
n control: 640
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
intake calculated by multiplying each
average daily arsenic intake by 365
days/year and summing the results of all
years; exposures in the 5 years preceding
cancer diagnosis or control identification
not included
Population-Level Exposure:
10.3 mg mean
Outcome: renal pelvis and ureter cancers
(transitional cell carcinomas)
cumulative arsenic exposure, mg
Exp. Level n adjOR
<10 7 1 n/a
10-25 12 5.49 2.02, 14.88
>25 5 10.35 2.57,41.64
Stat Method: unconditional logistic regression
Exposure Surrogate: drinking water
Exposure Description: historical
concentrations of arsenic in drinking
water available for Northern Chile (1930-
1995 onward); arsenic concentrations in
1958-1970 averaged 860 ng/L;
installation of a treatment plant reduced
recent concentrations to <10 ng/L;
exposure categories based on arsenic
intake in the 3 main exposure areas of
Arica/lquique, Calama, and Antofagasta
Population-Level Exposure:
0-1000 ng/day range
Outcome: other/unclassified kidney cancers
arsenic concentration in drinking water, ug/day
arsenic not associated with other/unclassified
kidney cancers
Outcome: renal cell cancers
arsenic concentration in drinking water, ug/day
arsenic not significantly associated with renal cell
cancers
Outcome: renal pelvis and ureter cancers
(transitional cell carcinomas)
highest 5-year daily average arsenic intake,
Ug/day
Exp. Level n
<400 5
400-1,000 8
>1,000 11
M
n/a
1.65, 19.82
3.60, 34.16
Stat Method: unconditional logistic regression
highest daily arsenic intake before 1971, ug/day
Exp. Level n adjOR (CD
<400 7 1 n/a
400-1,000 6 3.36 1.02, 11.10
>1,000 11 7.13 2.61, 19.44
Stat Method: unconditional logistic regression
Garcfa-Esquinas et al.
(2013)
Exposure Surrogate: urine
Exposure Description: individual urine
Outcome: kidney cancer
urinary arsenic concentration, ug/g-creatinine
Exp. Level n HR (CD
80th vs. 20th NR 0.44 0.14,1.40
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
Exposure Measures
Results
Study Type: cohort
(prospective)
Location: United States
(AZ;ND;OK;SD)
Population: Strong
Heart Study
participants
n total: 3,935
samples collected and analyzed for
arsenic speciation
Population-Level Exposure:
9.7 ng/g-creatinine median, 5.8-15.6
Hg/g-creatinine 25th percentile
percentiles
Stat Method: Cox proportional hazard
models; log transformed
Hawkesworth et al.
(2013)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: children in
Maternal and Infant
Nutrition Interventions
in Matlab (MINIMat)
cohort
n total: 2499
Exposure Surrogate: maternal urine
Exposure Description: spot urine
samples from participating women
collected at 8 and 30 weeks gestation;
log transformed as continuous variable
for analysis; median maternal urinary
arsenic was 80 ng/L (10th, 90th
percentile: 24, 383 ng/L) at week 8 of
gestation and 83 ng/L (10th, 90th: 26,
415 ng/L) at week 30
Population-Level Exposure:
80 mg/L median
Outcome: glomerular filtration
maternal urinary arsenic concentration
(combined), mg/L
Exp. Level n adiBeta (CD
continuous NR -14.2 -32.2,3.7
Stat Method: linear regression
maternal urinary arsenic concentration week 30,
mg/L
Exp. Level n ad i Beta (CD
continuous NR 0.51 -16.2,17.2
Stat Method: linear regression
maternal urinary arsenic concentration week 8,
mg/L
Exp. Level n ad i Beta (CD
continuous NR -21.2 -39.2,-3.2
Stat Method: linear regression
Outcome: kidney volume
maternal urinary arsenic concentration
(combined), mg/L
Exp. Level n ad i Beta (CD
continuous NR 2.89 -6.17,11.96
Stat Method: linear regression
maternal urinary arsenic concentration week 30,
mg/L
Exp. Level n ad i Beta (CD
continuous NR 6.04 -3.11,15.2
Stat Method: linear regression
maternal urinary arsenic concentration week 8,
mg/L
Exp. Level n ad i Beta (CD
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
Exposure Measures
Results
continuous NR 0.75 -8.59,10.08
Stat Method: linear regression
Exposure Surrogate: urine
Exposure Description: urine samples
collected from participating children at
18 months of age; log transformed as
continuous variable for analysis
Population-Level Exposure:
34 mg/L median
Outcome: glomerular filtration
infant urinary arsenic concentration 18 months,
mg/L
Exp. Level n adjBeta (Cl)
continuous NR -33.4 -70.2,3.34
Stat Method: linear regression
Outcome: kidney volume
infant urinary arsenic concentration 18 months,
mg/L
Exp. Level n adiBeta (Cl)
continuous NR -1.9 -23.45,27.26
Stat Method: linear regression
Huang etal. (2011)
Study Type: case-
control
Location: Taiwan
region not available
Population: adults with
and without renal cell
carcinoma in region
without obvious
sources of arsenic
exposure
n cases: 132
n control: 260
Exposure Surrogate: urine
Exposure Description: total
concentration of arsenic in daytime urine
sample based on sum of individual
arsenic species measured; mean urinary
total arsenic for cases and controls: 25.16
(+/- 2.22) and 21.15 (+/-1.02) ug/L,
respectively
Population-Level Exposure:
not available
Outcome: renal cell carcinoma
total urinary arsenic concentration, u.g/g-
creatinine
Total urinary arsenic level was significantly
associated with risk of developing renal cell
carcinomas in a dose-reponse relationship after
multivariate adjustment
Huang et al. (2012)
Study Type: case-
control
Location: Taiwan
region not available
Population: adults with
and without renal cell
Exposure Surrogate: urine
Exposure Description: total
concentration of arsenic in daytime urine
sample based on sum of individual
arsenic species measured
Population-Level Exposure:
12.3-20.95 ng/g-creatinine range
Outcome: renal cell carcinoma
total urinary arsenic concentration (tertiles),
Hg/g-creatinine
Exp. Level n
< 12.30 32
12.30-20.95 44
>20.95 56
M
n/a
0.73, 2.79
1.32, 5.22
Stat Method: multiple logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
Exposure Measures
Results
carcinoma in region
without obvious
sources of arsenic
exposure
n cases: 132
n control: 245
Kurttioetal. (1999)
Study Type: case-
control
Location: Finland
region not available
Population: register-
based cohort of Finnish
people living outside
municipal water system
from 1967-1980; 61
bladder cancer cases,
49 kidney cancer cases
n cases: 49
n control: 275
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration measured in well-water
samples collected Jul-Nov 1996 from
locations where individuals lived from
1967-1980
Population-Level Exposure:
not available
Outcome: kidney cancer
drinking water arsenic concentration, \ng/L
Exp. Level n adjRR {G}
<.l NR 1 n/a
0.1-0.5 NR 0.78 0.37, 1.66
>0.5 NR 1.49 0.67,3.31
Stat Method: Linear modeling after log
transformation
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
dose calculated based on duration of
exposure as reported in questionnaire
and sampled arsenic concentration in
well water; if questionnaire data not
available, assumed mean value from the
reference cohort for consumption;
arsenic concentration in drinking water
before and after well-water use was
considered null
Population-Level Exposure:
0.8 mg median
Outcome: kidney cancer
cumulative arsenic dose, mg
Exp. Level n adjRR (CD
<0.5 NR 1 n/a
0.5-2.0 NR 0.74 0.33, 1.68
>2.0 NR 0.8 0.42,1.86
Stat Method: Linear modeling after log
transformation
Exposure Surrogate: drinking water
Exposure Description: daily dose of
arsenic estimated from sampled arsenic
concentration in well water (collected
and measured 1996 from locations
where individuals lived from 1967-1980)
and reported consumption of well water
from the 1970s; if questionnaire data not
available assumed mean value from the
reference cohort for consumption;
arsenic concentration in drinking water
Outcome: kidney cancer
daily dose of arsenic, tig/day
Exp. Level n adjRR {G}
<0.2 NR 1 n/a
0.2-1.0 NR 1.08 0.52,2.25
>1.0 NR 1.21 0.52,2.82
Stat Method: Linear modeling after log
transformation
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
Exposure Measures
Results
before and after well-water use
considered null
Population-Level Exposure:
0.2 ng/day median
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: deceased
male and female
members of Latter-day
Saints church wards
n exposed: 2203
n total: 2203
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Outcome: kidney cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR M
<1000 NR 2.36 n/a
1000-4999 NR 1.32 n/a
>5000 NR 1.13 n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1000 NR 2.51 n/a
1000-4999 NR 1.13 n/a
>5000 NR 1.43 n/a
Stat Method: standardized mortality ratios
Outcome: nephritis and nephrosis
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR {CJ}
<1000 NR 2.02 n/a
1000-4999 NR 2.1 n/a
>5000 NR 0.88 n/a
Stat Method: standardized mortality ratio;
OCMAP adapted to nonoccupational cohort
Mostafa and Cherry
(2013)
Study Type: case-
control
Location: Bangladesh
(Dhaka)
Population: patients
from a single clinic in a
rural high arsenic area
who developed renal
cancer
Exposure Surrogate: drinking water
Exposure Description: 3534 wells
sampled by British Geological Survey;
arsenic in drinking water estimated for
each subject as mean arsenic
concentration (non-detects set at 0.5
Hg/L) in wells for the area in which the
patient lived at the time of biopsy; where
address as extracted did not indicate the
area, the clinical record was reviewed
and assigned to the correct or closest
area
Population-Level Exposure:
Outcome: renal cell cancer (RCC)
water arsenic concentration, u.g/L
Exp. Level n
<10 NR
10-<50 NR
50-<100 NR
100-<200 NR
200-<300 NR
>300 NR
M
n/a
0.92, 2.06
1.27, 3.32
1.42, 3.64
2.42, 6.44
3.24, 11.12
Stat Method: multilevel logistic model
well water arsenic concentration (1994 or
earlier), u.Q/1
Exp. Level n adjOR M
<10 NR 1 n/a
10-<50 NR 2.47 1.52,4.01
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
n cases: 986
n control: 503
Sawada et al. (2013)
Study Type: cohort
(prospective)
Exposure Measures
10-300 |jg/L range
Exposure Surrogate: diet
Exposure Description: detailed
questionnaire on food intake/frequency;
Results
50-<100 NR 3.52 2.06,6.01
100-<200 NR 2.89 1.76,4.783
200-<300 NR 5.4 3.16,9.23
>300 NR 9.22 5.07,16.76
Stat Method: multilevel logistic model
well water arsenic concentration (1995 or later),
W/l-
Exp. Level n adiOR (CD
<10 NR 1 n/a
10-<50 NR 0.67 0.34, 1.32
50-<100 NR 0.79 0.30,2.05
100-<200 NR 2.5 0.77,8.11
200-<300 NR 2.86 1.12,7.30
>300 NR 2.67 0.46,13.39
Stat Method: multilevel logistic model
Outcome: renal cell cancer (RCC) and transitional
cell cancer (TCC)
water arsenic concentration, ng/L
Exp. Level n adiOR (CD
<10 NR 1 n/a
10-<50 NR 1.29 0.86, 1.91
50-<100 NR 2.12 1.33,3.39
100-<200 NR 2.41 1.53,3.81
200-<300 NR 3.84 2.38,6.19
>300 NR 6 3.29,10.98
Stat Method: multilevel logistic model
Outcome: transitional cell cancer (TCC)
water arsenic concentration, ng/L
Exp. Level n adiOR (CD
<10 NR 1 n/a
10-<50 NR 0.51 0.16, 1.63
50-<100 NR 4.59 1.70, 12.36
100-<200 NR 4.94 1.88, 12.99
200-<300 NR 4.83 1.77, 13.13
>300 NR 7.7 2.37,25.03
Stat Method: multilevel logistic model
Outcome: kidney cancer
inorganic arsenic intake (females; quartiles),
Hg/day
Exp. Level n HR (CD
40.6 13 1 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Renal Effects
Reference and Study
Design
Exposure Measures
Results
Location: Japan (Iwate,
Akita, Nagano,
Okinawa, Tokyo,
Ibaraki, Niigata, Kochi,
Nagasaki, Osaka)
Population: adults in
Japan Public Health
Center (JPHC)
Prospective Study
cohort
n total: 90378
average arsenic concentrations in food
items obtained from the literature;
arsenic intake calculated by multiplying
average arsenic concentration in each
item by quantity consumed
Population-Level Exposure:
170 |Jg/day mean, 88.3-253.2 |Jg/day
range
53.7 7 0.48 0.19, 1.23
62.6 5 0.34 0.12,0.96
105.7 9 0.64 0.27, 1.53
Stat Method: Multivariate regression
inorganic arsenic intake (males; quartiles),
ug/day
Exp. Level n HR (CD
40.5 14 1 n/a
54.7 22 1.72 0.87,3.39
63.5 21 1.66 0.83,3.35
99.1 26 2.05 1.05,4.03
Stat Method: Multivariate regression
Yuan et al. (2010)
Study Type: cohort
(retrospective)
Location: Chile (Region
II (Mejillones and
Antofagasta))
Population: residents
of areas with high
arsenic concentrations
in water
number of subjects not
reported
Exposure Surrogate: residency
Exposure Description: based on
measurements of drinking water in
Antofagasta and Mejillones 1950-1970
defined as the high exposure period, so
individuals born during this period would
have had exposure in utero and in early
childhood, but individuals born before
would only have early childhood
exposure
Population-Level Exposure:
60-870 range
Outcome: kidney cancer mortality
arsenic exposure by birth year {combined), units
not available
Exp. Level n SMR M
born 1950 - 8 7.08 3.05, 14
1970
born before 187 3.12 2.69,3.61
1950
Stat Method: Poisson regression
arsenic exposure by birth year {men only), units
not available
Exp. Level n SMR {G}
born 1950 - 4 5.63 1.52, 14.4
1970
born before 103 2.68 2.19,3.26
1950
Stat Method: Poisson regression
arsenic exposure by birth year {women only),
units not available
Exp. Level n SMR M
born 1950 - 4 9.52 2.56,24.4
1970
born before 84 3.91 3.12,4.84
1950
Stat Method: Poisson regression
--: not reported; n: number of cases (when presented in Results column)
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.13.1 References for Summary of Observational Epidemiology
Studies for Health Effect Category: Renal Effects
Baastrup. R: Sorensen. M: Balstrem. T: Frederiksen. K: Larsen. CL: Tjonneland. A: Overvad. K: Raaschou-
Nielsen. O. (2008). Arsenic in drinking-water and risk for cancer in Denmark. Environ Health Perspect 116:
231-237. http://dx.doi.org/10.1289/ehp. 10623
Chen. JW: Chea HY: Li. WF: Liou. SH: Chea CJ: Wu. JH: Wang. SL. (2011). The association between total
urinary arsenic concentration and renal dysfunction in a community-based population from central Taiwan.
Chemosphere 84: 17-24. http://dx.doi.0rg/10.1016/i.chemosphere.2011.02.091
Chiou. JM: Wang. SL: Chen. CJ: Deng. CR: Lin. W: Taj TY. (2005). Arsenic ingestion and increased
microvascular disease risk: Observations from the south-western arseniasis-endemic area in Taiwan. Int J
Epidemiol 34: 936-943. http://dx.doi.org/10.1093/ije/dyil08
Ferreccio. C: Smith. AH: Duran. V: Barlaro. T: Benitez. H: Valdes. R: Aguirre. JJ: Moore. LE: Acevedo. J:
Vasquez. MI: Perez. L: Yuan. Y: Liaw. J: Cantor. KP: Steinmaus. C. (2013). Case-control study of arsenic in
drinking water and kidney cancer in uniquely exposed Northern Chile. Am J Epidemiol 178: 813-818.
http://dx.doi.org/10.1093/aie/kwt059
Garcia-Esquinas. E: Pollan. M: Umans. JG: Francesconi. KA: Goessler. W: Guallar. E: Howard. B: Farley. J:
Best LG: Navas-Acien. A. (2013). Arsenic exposure and cancer mortality in a US-based prospective cohort:
the strong heart study. Cancer Epidemiol Biomarkers Prev 22: 1944-1953. http://dx.doi.org/10.1158/1055-
9965.EPI-13-0234-T
Hawkesworth. S: Wagatsuma. Y: Kippler. M: Fulford. AJ: Arifeen. SE: Persson. LA: Moore. SE: Vahter. M.
(2013). Early exposure to toxic metals has a limited effect on blood pressure or kidney function in later
childhood, rural Bangladesh. Int J Epidemiol 42: 176-185. http://dx.doi.org/10.1093/ije/dvs215
Huang. CY: Chu. JS: Pu. YS: Yang. HY: Wu. CC: Chung. CJ: Hsueh. YM. (2011). Effect of urinary total
arsenic level and estimated glomerular filtration rate on the risk of renal cell carcinoma in a low arsenic
exposure area. J Urol 185: 2040-2044. http://dx.doi.0rg/10.1016/i.juro.2011.01.079
Huang. CY: Su. CT: Chung. CJ: Pu. YS: Chu. JS: Yang. HY: Wu. CC: Hsueh. YM. (2012). Urinary total arsenic
and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic
exposure. Toxicol Appl Pharmacol 262: 349-354. http://dx.doi.0rg/10.1016/i.taap.2012.05.013
Kurttio. P: Pukkala. E: Kahelin. H: Auvinen. A: Pekkanen. J. (1999). Arsenic concentrations in well water and
risk of bladder and kidney cancer in Finland. Environ Health Perspect 107: 705-710.
http://dx.doi.org/10.1289/ehp.99107705
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Mostafa. M: Cherry. N. (2013). Arsenic in drinking water and renal cancers in rural Bangladesh. Occup Environ
Med 70: 768-773. http://dx.doi.org/10.1136/oemed-2013-101443
Sawada. N: Iwasaki. M: Inoue. M: Takachj R: Sasazukj S: Yamaji. T: Shimazu. T: Tsugane. S. (2013). Dietary
arsenic intake and subsequent risk of cancer: The Japan Public Health Center-based (JPHC) prospective
study. Cancer Causes Control 24: 1403-1415. http://dx.doi.org/10.1007/sl0552-013-0220-2
Yuan. Y: Marshall G: Ferreccio. C: Steinmaus. C: Liaw. J: Bates. M: Smith. AH. (2010). Kidney cancer
mortality: Fifty-year latency patterns related to arsenic exposure. Epidemiology 21: 103-108.
http://dx.doi.org/10.1097/EDE.Ob013e3181c21e46
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.14Summary of Observational Epidemiology Studies for
Health Effect Category: Reproductive System Effects
including Pregnancy Outcomes
Summary of Observational Epidemiology Studies for Health Effect Category: Reproductive System
Effects including Pregnancy Outcomes
Reference and Study
Design
Exposure Measures
Results
Baastrup et al. (2008)
Study Type: cohort
(prospective)
Location: Denmark
(Copenhagen and
Aarhus)
Population: Danish
Cancer Registry
population (adults)
n exposed: 56,378
n total: 57053
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure and time-weighted average
arsenic concentrations calculated for
individuals based on residential address
and history from Central Population
Registry combined with measurement
data from nearest water utility as
recorded by Geological Survey of
Denmark and Greenland (1987-2004)
Population-Level Exposure:
not available
Outcome: breast cancer
cumulative arsenic exposure, mg
Exp. Level n IRR (CD
continuous NR 1 0.99, 1.02
Stat Method: Cox regression
Outcome: prostate cancer
cumulative arsenic exposure, mg
Exp. Level n IRR
continuous NR 1
Stat Method: Cox regression
M
0.99, 1.03
Exposure Surrogate: drinking water
Exposure Description: time-weighted
and cumulative arsenic concentrations
calculated for individuals based on
residential address and history from
Central Population Registry combined
with measurement data from nearest
water utility as recorded by Geological
Survey of Denmark and Greenland (1987-
2004)
Population-Level Exposure:
0.7 u.g/L median
Outcome: breast cancer
time-weighted average arsenic exposure, u.g/L
Exp. Level n IRR (CD
continuous NR 1.03 0.99, 1.08
Stat Method: Cox regression
Outcome: prostate cancer
time-weighted average arsenic exposure, ug/L
Exp. Level n IRR (CD
continuous NR 1.03 0.97, 1.09
Stat Method: Cox regression
Garcfa-Esquinas et al.
(2013)
Study Type: cohort
(prospective)
Exposure Surrogate: urine
Exposure Description: individual urine
samples collected and analyzed for
arsenic speciation
Outcome: breast cancer
urinary arsenic concentration, ug/g-creatinine
no significant association between arsenic and
breast cancer
Outcome: prostate cancer
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Reproductive System
Effects including Pregnancy Outcomes
Reference and Study
Design
Location: United States
(AZ;ND;OK;SD)
Population: Strong
Heart Study
participants
n total: 3,935
Garland et al. (1996)
Study Type: case-
control (nested)
Location: United States
(11 States)
Population: Nurses'
Health Study cohort
members with no prior
history of of cancer in
1982
n cases: 427
n control: 450
Kwoketal. (2006)
Study Type: cross-
sectional
Location: Bangladesh
(Faridpur district
(Faridpur Sadar upazila)
and Chandpur district
(Matlab and Shahrasti
upazilas))
Population: residents
of 261 highly arsenic-
contaminated villages
n cases: n/a
n control: n/a
Exposure Measures
Population-Level Exposure:
9.7 ng/g-creatinine median, 5.8-15.6
Hg/g-creatinine 25th percentile
Exposure Surrogate: toenails
Exposure Description: case-control pair
samples analyzed together; 47 samples
below LOD and set to the value of LOD;
concentrations log transformed and
regressed (adjusted) for weight by
laboratory batch; exposure quintiles
derived based on distribution in controls
Population-Level Exposure:
0.12 ng/g mean
Exposure Surrogate: drinking water
Exposure Description: water samples
collected during in-home interview from
main drinking water source used during
pregnancy
Population-Level Exposure:
0.5-668 ppb range
Results
urinary arsenic concentration, u.g/g-creatinine
Exp. Level n HR (Cl)
80th vs. 20th 18 3.3 1.28,8.48
percentiles
Stat Method: Cox proportional hazard
models; log transformed
Outcome: breast cancer
toenail arsenic concentration (quintiles), ug/g
Exp. Level n adjOR (Cl)
<0.059 54 1 n/a
0.059-0.078 67 1.19 0.71, 1.98
0.079-0.103 56 1.01 0.59, 1.73
0.104-0.138 62 1.12 0.67, 1.90
>0.138 69 1.12 0.66, 1.91
Stat Method: unconditional multivariate
logistic regression
Outcome: stillbirths
drinking water arsenic concentration, ppb
Exp. Level n adiOR (Cl)
continuous NR 0.999 0.996, 1.002
Stat Method: multivariate logistic regression
drinking water arsenic concentration, ppb
Exp. Level n Prev (Cl)
<10 8 2.5 n/a
11-50 5 2.2 n/a
51-100 6 2.7 n/a
101-200 14 2.8 n/a
201-300 17 3.4 n/a
>300 3 1.3 n/a
Stat Method: prevalence
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Reproductive System
Effects including Pregnancy Outcomes
Reference and Study
Design
Exposure Measures
Results
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: deceased
male and female
members of Latter-day
Saints church wards
n exposed: 2203
n total: 2203
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Outcome: breast cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR M
<1000 NR 0.64 n/a
1000-4999 NR 0.7 n/a
>5000 NR 0.4 n/a
Stat Method: standardized mortality ratios
Outcome: other female genital organs cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR (CD
<1000 NR 0.87 n/a
1000-4999 NR 0.71 n/a
>5000 NR 1.09 n/a
Stat Method: standardized mortality ratios
Outcome: prostate cancer
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1000 NR 1.07 n/a
1000-4999 NR 1.7 n/a
>5000 NR 1.65 n/a
Stat Method: standardized mortality ratios
Outcome: uterine cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR {G}
<1000 NR 0.42 n/a
1000-4999 NR 0.49 n/a
>5000 NR 0.65 n/a
Stat Method: standardized mortality ratios
Milton et al. (2005)
Study Type: cross-
sectional
Location: Bangladesh
(Comilla, Chandpur,
and Chuadanga
districts)
Exposure Surrogate: drinking water
Exposure Description: single well-water
measurement used to characterize
chronic arsenic exposure; arsenic
concentrations recorded as zero replaced
with 30 ug/L
Population-Level Exposure:
279 ug/L mean 355SD
Outcome: spontaneous abortion
drinking water arsenic concentration,
Exp. Level
<50
>50
51-100
>100
n
NR
NR
NR
NR
M
n/a
1.5,4.3
1.2,5.1
1.5, 4.4
Stat Method: logistic regression analysis
Outcome: stillbirth
drinking water arsenic concentration, ug/L
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Reproductive System
Effects including Pregnancy Outcomes
Reference and Study
Design
Population: women
living in study area with
> 1 prior pregnancy
n cases: n/a
n control: n/a
Pollack etal. (2013)
Study Type: cohort
(prospective)
Location: United States
(CA; UT)
Population: adult
females in ENDO Study
n exposed: 495
n reference: 131
n total: 626
Rahman et al. (2010)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: pregnant
women enrolled in the
Maternal and Infant
Nutrition Intervention
in Matlab study
(MINIMat)
n total: 1725
Exposure Measures
Exposure Surrogate: urine
Exposure Description: blood and urine
specimens collected from women upon
completion of interview; urine specimens
were analyzed for 20 trace elements
Population-Level Exposure:
4.94-10.84 ng/L range
Exposure Surrogate: urine
Exposure Description: urine samples
collected at ~approx gestation week 8
and gestation week 30; samples adjusted
by specific gravity rather than creatinine;
urine levels divided into quintiles
Population-Level Exposure:
38-2019 ng/L range
Results
Exp. Level n adiOR (CD
<50 13 1 n/a
>50 49 2.5 1.3,4.9
51-100 4 1.1 0.3,3.1
>100 45 2.9 1.5,5.9
Stat Method: logistic regression analysis
Outcome: endometriosis
urinary arsenic concentration (operative cohort)
by endometriosis status, ug/L
Exp. Level n mean (Cl)
controls 283 8.37 7.50,9.33
cases 190 8.37 7.41,9.46
Stat Method: Student's t-test or Wilcoxon
nonparametric test for continuous data
urinary arsenic concentration {population cohort)
by endometriosis status, ug/L
Exp. Level n mean (Cl)
controls 113 8.69 7.26, 10.39
cases 14 7.74 4.88, 12.25
Stat Method: Student's t-test or Wilcoxon
nonparametric test for continuous data
Outcome: spontaneous abortion/miscarriage
early pregnancy urinary arsenic concentration
(quintiles), ug/L
Exp. Level n OR (Cl)
<33 45 1 n/a
33-57 57 1.28 0.85, 1.93
58-121 63 1.41 0.94,2.11
122-248 47 1.06 0.69, 1.62
249-1253 63 1.44 0.96,2.15
Stat Method: logistic regression
Outcome: stillbirths
average urinary arsenic concentration {quintiles),
ug/L
Exp. Level n adiOR (Cl)
<38 3 1 n/a
39-67 6 2.06 0.51,8.38
68-133 7 2.35 0.6,9.23
134-267 10 3.41 0.92, 12.63
268-2019 6 2.02 0.5,8.24
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Reproductive System
Effects including Pregnancy Outcomes
Reference and Study
Design
Exposure Measures
Results
Stat Method: logistic regression
Sawada et al. (2013)
Study Type: cohort
(prospective)
Location: Japan (Iwate,
Akita, Nagano,
Okinawa, Tokyo,
Ibaraki, Niigata, Kochi,
Nagasaki, Osaka)
Population: adults in
Japan Public Health
Center (JPHC)
Prospective Study
cohort
n total: 90378
Exposure Surrogate: diet
Exposure Description: detailed
questionnaire on food intake/frequency;
average arsenic concentrations in food
items obtained from the literature;
arsenic intake calculated by multiplying
average arsenic concentration in each
item by quantity consumed
Population-Level Exposure:
170 ug/day mean, 88.3-253.2 ug/day
range
Outcome: breast cancer
arsenic concentration in diet, tig/day
arsenic not significantly associated with breast
cancer
Outcome: endometrial cancer
arsenic concentration in diet, ug/day
arsenic not significantly associated with
endometrial cancer
Outcome: prostate cancer
arsenic concentration in diet, tig/day
arsenic not significantly associated with prostate
cancer
Tsuda et al. (1995)
Study Type: cohort
(retrospective)
Location: Japan
(Namiki-cho)
Population: adults and
children living near
factory producing
arsenic trisulfide
n exposed: 189
n reference: 254
n total: 443
Exposure Surrogate: drinking water
Exposure Description: arsenic in well
water measured in 1959 (the end of the
exposure period) in 34 wells; 20 area
wells had no documented levels of
arsenic so authors inferred that arsenic
levels were undetectable or very low;
concentration assigned based on
residence in 1959
Population-Level Exposure:
0.05-1 ppm range
Outcome: uterine cancer
arsenic concentration in well water in 1959, ppm
Exp. Level n SMR (CD
<0.05 0 0 0,8.01
0.05-0.99 0 0 0,37.64
>1 2 13.47 2.37,48.63
Stat Method: Cox proportional hazard
Von Ehrenstein et al.
(2006)
Study Type: cross-
sectional
Exposure Surrogate: drinking water
Exposure Description: water samples
collected from tube wells used at least 6
months since first pregnancy; past
arsenic concentration measurements
used when wells were closed
Outcome: spontaneous abortion
arsenic concentration in drinking water, ng/L
Exp. Level n adjOR M
0-49 21 1 n/a
50-199 2 0.91 0.25,3.34
>200 5 1.01 0.38,2.70
Stat Method: logistic regression based on
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Reproductive System
Effects including Pregnancy Outcomes
Reference and Study
Design
Exposure Measures
Results
Location: India (West
Bengal)
Population: women
residing in 21 villages of
West Bengal, India
n cases: n/a
n control: n/a
method of generalized estimating equations
Population-Level Exposure:
0-200 ng/L range
Outcome: stillbirths
arsenic concentration in drinking water, u.g/L
Exp. Level n adjOR {G}
0-49 8 1 n/a
50-199 1 0.8 0.10,6.66
>200 9 6.07 1.54,24.0
Stat Method: logistic regression based on
method of generalized estimating equations
Xu et al. (2012)
Study Type: cross-
sectional
Location: China
(Chongqing)
Population: male
patients at infertility
clinic
n cases: n/a
n control: n/a
Exposure Surrogate: urine
Exposure Description: urine samples
collected on same day as semen
collection (unless multiple samples
given); arsenic concentration
dichotomized with cut-offs of the median
Population-Level Exposure:
4.89 ng/g-creatinine mean 3.67SD
Outcome: semen volume
dichotomised urinary arsenic concentration,
ug/g-creatinine
Exp. Level n adjOR (CD
1 NR 1 n/a
2 NR 1.4 0.4,4.8
Stat Method: binary logistic regression
Outcome: sperm concentration
dichotomised urinary arsenic concentration,
u.g/g-creatinine
Exp. Level n adjOR M
1 NR 1 n/a
2 NR 0.6 0.1,2.2
Stat Method: binary logistic regression
Outcome: sperm motility
dichotomised urinary arsenic concentration,
ug/g-creatinine
Exp. Level n adjOR (CD
1 NR 1 n/a
2 NR 1.1 0.4,2.8
Stat Method: binary logistic regression
--: not reported; n: number of cases (when presented in Results column)
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.14.1 References for Summary of Observational Epidemiology
Studies for Health Effect Category: Reproductive System Effects
including Pregnancy Outcomes
Baastrup. R: Serensen. M: Balstrem. T: Frederiksen. K: Larsen. CL: Tjenneland. A: Overvad. K: Raaschou-
Nielsen. O. (2008). Arsenic in drinking-water and risk for cancer in Denmark. Environ Health Perspect 116:
231-237. http://dx.doi.org/10.1289/ehp. 10623
Garcia-Esquinas. E: Pollan. M: Umans. JG: Francesconi. KA: Goessler. W: Guallar. E: Howard. B: Farley. J:
Best LG: Navas-Acien. A. (2013). Arsenic exposure and cancer mortality in a US-based prospective cohort:
the strong heart study. Cancer Epidemiol Biomarkers Prev 22: 1944-1953. http://dx.doi.org/10.1158/1055-
9965.EPI-13-0234-T
Garland. M: Morris. JS: Colditz. GA: Stampfer. MJ: Spate. VL: Basket! CK: Rosner. B: Speizer. FE: Willett
WC: Hunter. DJ. (1996). Toenail trace element levels and breast cancer: a prospective study. Am J
Epidemiol 144: 653-660.
Kwok. RK: Kaufmann. RB: Jakariya. M. (2006). Arsenic in drinking-water and reproductive health outcomes: A
study of participants in the Bangladesh integrated nutrition programme. J Health Popul Nutr 24: 190-205.
Lewis. PR: Southwick. JW: Ouellet-Hellstrom. R: Rench. J: Calderon. RL. (1999). Drinking water arsenic in
Utah: A cohort mortality study. Environ Health Perspect 107: 359-365.
http://dx.doi.org/10.1289/ehp.99107359
Milton. AH: Smith. W: Rahman. B: Hasan. Z: Kulsum. U: Dear. K: Rakibuddin. M: All A. (2005). Chronic
arsenic exposure and adverse pregnancy outcomes in Bangladesh. Epidemiology 16: 82-86.
http://dx.doi.org/10.1097/01.ede.0000147105.94041.e6
Pollack. AZ: Louis. GM: Chen. Z: Peterson. CM: Sundaram. R: Croughan. MS: Sun. L: Hediger. ML: Stanford.
JB: Varner. MW: Palmer. CD: Steuerwald. AJ: Parsons. PJ. (2013). Trace elements and endometriosis: The
ENDO study. Reprod Toxicol 42: 41-48. http://dx.doi.0rg/10.1016/i.reprotox.2013.05.009
Rahman. A: Persson. LA: Nermell. B: El Arifeen. S: Ekstrom. EC: Smith. AH: Vahter. M. (2010). Arsenic
exposure and risk of spontaneous abortion, stillbirth, and infant mortality. Epidemiology 21: 797-804.
http://dx.doi.org/10.1097/EDE.Ob013e3181f56aOd
Sawada. N: Iwasaki. M: Inoue. M: Takachi. R: Sasazuki. S: Yamaji T: Shimazu. T: Tsugane. S. (2013). Dietary
arsenic intake and subsequent risk of cancer: The Japan Public Health Center-based (JPHC) prospective
study. Cancer Causes Control 24: 1403-1415. http://dx.doi.org/10.1007/sl0552-013-0220-2
Tsuda. T: Babazono. A: Yamamoto. E: Kurumatani. N: Mino. Y: Ogawa. T: Kishi. Y: Aoyama. H. (1995).
Ingested arsenic and internal cancer: A historical cohort study followed for 33 years. Am J Epidemiol 141:
198-209.
Von Ehrenstein. OS: Guha Mazumder. DN: Hira-Smith. M: Ghosh. N: Yuan. Y: Windham. G: Ghosh. A:
Hague. R: Lahiri. S: Kalman. D: Das. S: Smith. AH. (2006). Pregnancy outcomes, infant mortality, and
arsenic in drinking water in West Bengal, India. Am J Epidemiol 163: 662-669.
http://dx.doi.org/10.1093/aie/kwj089
Xu. W: Bao. H: Liu. F: Liu. L: Zhu. YG: She. J: Dong. S: Cai. M: Li. L: Li. C: Shen. H. (2012). Environmental
exposure to arsenic may reduce human semen quality: associations derived from a Chinese cross-sectional
study. Environ Health. http://dx.doi.org/10.1186/1476-069X-ll-46
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.15Summary of Observational Epidemiology Studies for
Health Effect Category: Respiratory Effects
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
Baastrupetal. (2008)
Study Type: cohort
(prospective)
Location: Denmark
(Copenhagen and
Aarhus)
Population: Danish
Cancer Registry
population (adults)
n exposed: 56,378
n total: 57053
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure and time-weighted average
arsenic concentrations calculated for
individuals based on residential address
and history from Central Population
Registry combined with measurement
data from nearest water utility as
recorded by Geological Survey of
Denmark and Greenland (1987-2004)
Population-Level Exposure:
not available
Outcome: lung cancer
cumulative arsenic exposure, mg
Exp. Level n IRR
continuous NR 1
Stat Method: Cox regression
M
0.98, 1.02
Exposure Surrogate: drinking water
Exposure Description: time-weighted
and cumulative arsenic concentrations
calculated for individuals based on
residential address and history from
Central Population Registry combined
with measurement data from nearest
water utility as recorded by Geological
Survey of Denmark and Greenland (1987-
2004)
Population-Level Exposure:
0.7 ng/L median
Outcome: lung cancer
time-weighted average arsenic exposure, u.g/L
Exp. Level n IRR (CD
continuous NR 0.99 0.92, 1.07
Stat Method: Cox regression
Chen et al. (2004a)
Study Type: cohort
(prospective)
Location: Taiwan
(Southwestern coast
Exposure Surrogate: drinking water
Exposure Description: average drinking
water arsenic concentrations calculated
using median concentration for relevant
village wells as measured in the early
1960s (southeastern cohort) or
measured concentration for relevant
Outcome: lung cancer
average drinking water arsenic concentration,
Exp. Level
10-99
100-299
300-699
27
31
17
18
M
n/a
0.63, 1.91
1.22, 4.27
1.62, 5.69
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
(Peimen, Hsuehchia,
Putai and Ichu
townships) and
northeaster Lanyang
Basin (Tungshan,
Chuangwei, Chiaohsi,
and Wuchieh
townships))
Population: adults
living in arseniasis-
endemic areas,
followed from exisiting
cohort
n total: 10591
Chen et al. (2010a)
Study Type: cohort
(prospective)
Location: Taiwan
(Lanyang Basin (Tung-
Shan, Chuang-Wei,
Chiao-His, and Wu-
Chieh Townships))
Population: adults
living in arseniasis-
endemic township
n total: 6888
Exposure Measures
personal wells (northeastern cohort) and
total years drinking artesian well water;
grouped to include enough lung cancer
cases in each category
Population-Level Exposure:
10-700 ug/L range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
levels calculated based on arsenic
concentration in well water and self-
reported years of drinking well water
Population-Level Exposure:
3523.5 ug/L-year mean 9443. 5SD
Results
>700 26 3.29 1.60,6.78
unknown 20 1.1 0.60, 2.03
Stat Method: Cox proportional hazards
regression model
Outcome: all lung cancer
cumulative arsenic exposure (ref= 0), ng/L-year
Exp. Level n adjRR (Cl)
0 NR 1 n/a
<1000 NR 0.56 0.36,0.89
1000-<5000 NR 0.78 0.5, 1.21
5000- NR 1.37 0.8,2.34
< 10,000
> 10,000 NR 1.52 0.92,2.52
Stat Method: multivariate regression
cumulative arsenic exposure (ref= <100), ug/L-
year
Exp. Level n adiRR (Cl)
<100 43 1 n/a
100-<1000 32 0.65 0.41, 1.02
100 - <1000
1000-<5000 51 0.91 0.60, 1.36
5000-<10000 23 1.6 0.96,2.65
> 10,000 29 1.78 1.11,2.85
Stat Method: multivariate regression
cumulative arsenic exposure (ref= <400), ug/L-
year
Exp. Level n adiRR (Cl)
<400 55 1 n/a
400-<1000 20 0.83 0.50, 1.39
1000-<5000 51 1.06 0.73, 1.56
5000-<10000 23 1.87 1.15,3.04
> 10,000 29 2.08 1.13,3.27
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration determined from
water samples from household wells
during home interview
Population-Level Exposure:
117.2 ng/L mean 297.2SD
Results
Stat Method: multivariate regression
Outcome: adenocarcinoma
drinking water arsenic concentration, ng/L
Exp. Level n adiRR (CD
<10 14 1 n/a
10-49.9 20 1.5 0.76,2.98
50-99.9 4 0.7 0.23,2.13
100-299.9 6 1.06 0.41,2.77
>300 7 1.63 0.65,4.05
Stat Method: multivariate regression
Outcome: all lung cancer
drinking water arsenic concentration, ng/L
Exp. Level n adiRR (CD
<10 48 1 n/a
10-49.9 51 1.1 0.74, 1.63
50-99.9 20 0.99 0.59, 1.68
100-299.9 28 1.54 0.97,2.46
>300 31 2.25 1.43,3.55
Stat Method: multivariate regression
Outcome: other histological types
drinking water arsenic concentration, ng/L
Exp. Level n adiRR (CD
<10 7 1 n/a
10-49.9 11 1.7 0.66,4.39
50-99.9 3 1.1 0.28,4.25
100-299.9 5 2.03 0.64,6.40
>300 4 2.25 0.65,7.71
Stat Method: multivariate regression
Outcome: small cell carcinoma
drinking water arsenic concentration, ng/L
Exp. Level n adiRR (CD
<10 4 1 n/a
10-49.9 8 2.02 0.61,6.73
50-99.9 0 NR n/a
100-299.9 4 2.77 0.69, 11.1
>300 6 5.15 1.44,18.4
Stat Method: multivariate regression
Outcome: squamous cell carcinoma
drinking water arsenic concentration, ng/L
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Chiou et al. (1995)
Study Type: cohort
(prospective)
Location: Taiwan
(Southwestern coast of
Taiwan (Peimen,
Hsuechia, Putai, and
Ichu townships))
Population: BFD
patients and healthy
residents in arseniasis-
endemic townships
n exposed: 263
n reference: 2293
n total: 2556
Chung etal. (2012)
Study Type: cohort
(prospective)
Location: Taiwan
(Homei, Fuhsin,
Hsinming)
Population: residents
of arseniasis-endemic
areas
n total: 1563
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: individual
exposure estimated using median arsenic
levels in artesian well water in each
village combined with residential history
information gathered during individual
interviews
Population-Level Exposure:
0.78 mg/L median
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure assessment determined by
duration of artesian well water use,
history or residence, and historical data;
cumulative arsenic exposure derived to
reflect long-term arsenic exposure by
median well water arsenic (population
level exposure reported here) x duration
of use
Population-Level Exposure:
9.1-19.5 |jg/L-year range
Exposure Surrogate: drinking water
Results
Exp. Level n adiRR (CD
<10 23 1 n/a
10-49.9 12 0.53 0.26, 1.07
50-99.9 13 1.32 0.67,2.61
100-299.9 13 1.52 0.77,3.00
>300 14 2.13 1.09,4.17
Stat Method: multivariate regression
Outcome: lung cancer
average arsenic concentration In well water,
mg/L
Exp. Level n adiRR (CD
<0.05 5 1 n/a
0.05-0.70 7 2.1 0.7,6.8
>0.71 7 2.7 0.7, 10.2
unknown 10 1.5 0.5, 4.3
Stat Method: Cox proportional hazards
regression analysis
cumulative water arsenic exposure, mg/L-yr
Exp. Level n adiRR (CD
0 NR 1 n/a
0.1-19.9 NR 2.74 0.69, 11.0
>20 NR 4.01 1.0, 16.12
Unknown NR 2.01 0.55,7.36
Stat Method: Cox proportional hazards
regression analysis
Outcome: lung cancer
cumulative water arsenic exposure (tertiles),
ug/L-year
Exp. Level n adjOR (Cl)
<9.1 10 1 n/a
9.1-19.5 13 0.9 0.39,2.09
>19.5 34 1.47 0.66,3.31
Stat Method: Cox proportional hazard model
Outcome: lung cancer
average water arsenic concentration (tertiles),
mg/L
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
Exposure Description: information on
median arsenic level in artesian well
water of each village acquired from
previous studies carried out in the early
1960s (Laietal., 1994); some study
subjects had moved from one village to
another, and there were differences in
arsenic concentrations between villages
Population-Level Exposure:
0.7-0.93 mg/L range
Exp. Level
<0.05
0.05-0.71
>0.71
7
20
30
HR
1
0.81
1.04
M
n/a
0.33, 1.97
0.43, 2.48
Stat Method: Cox proportional hazard model
Exposure Surrogate: urine
Exposure Description: urine samples of
1078 subjects collected at time of
recruitment; all arsenic assays performed
within 6 months of sample collection
Population-Level Exposure:
not available
Outcome: lung cancer
percent DMA in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR
>85.8 14 1 n/a
76.13-85.8 17 0.97 0.47, 1.98
<76.13 15 0.81 0.38, 1.71
Stat Method: Cox proportional hazard model
percent inorganic arsenic in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR M
<4.22 11 1 n/a
4.22-7.86 20 1.98 0.94,4.17
>7.86 15 1.43 0.66,3.14
Stat Method: Cox proportional hazard model
percent MMA in total urinary arsenic
concentration (tertiles), %
Exp. Level n adjOR
<8.34 14 1 n/a
8.34-15.31 15 1.04 0.5,2.15
> 15.31 17 0.85 0.41, 1.76
Stat Method: Cox proportional hazard model
Dauphineetal. (2011)
Study Type: cohort
(retrospective)
Location: Chile
(Antofagasta and Arica)
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration calculated from
municipal drinking water records and
each individual's residential history
Population-Level Exposure:
Outcome: any respiratory symptom
peak water arsenic concentration before age 10
(0-250 reference), \ig/L
Exp. Level n adjOR {G}
0-250 NR 1 n/a
>800 NR 2.63 0.78,8.92
Stat Method: multivariate logistic regression
Outcome: FEV-1 residual (ml)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-221 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Population: adult
nursing school
employees living in
village with history of
higher than average
arsenic in drinking
water
n exposed: 32
n reference: 65
n total: 97
Dauphine et al. (2013)
Study Type: case-
control
Location: United States
(CA; NV)
Population: residents
Exposure Measures
0-800 ng/L
Exposure Surrogate: drinking water
Exposure Description: over 7,000 arsenic
measurements for community-supplied
drinking water and thousands of private
domestic wells within study area
provided by Nevada State Health Division
and California Department of Health
Services; participants asked over phone
how many glasses of water and water-
Results
peak water arsenic concentration before age 10
(<50 reference), ng/L
Exp. Level n adiBeta (CD
<50 NR 0 n/a
50-250 NR -152 n/a
>800 NR -335 n/a
Stat Method: multivariate linear regression
Outcome: FVC residual (ml)
peak water arsenic concentration before age 10
(<50 reference), ng/L
Exp. Level n adiBeta (Cl)
<50 NR 0 n/a
50-250 NR -52 n/a
>800 NR -429 n/a
Stat Method: multivariate linear regression
Outcome: percent predicted FEV-1
peak water arsenic concentration before age 10
(<50 reference), ng/L
Exp. Level n adiBeta (Cl)
<50 NR 0 n/a
50-250 NR -4.6 n/a
>800 NR -11.5 n/a
Stat Method: multivariate linear regression
Outcome: percent predicted FVC
peak water arsenic concentration before age 10
(<50 reference), ng/L
Exp. Level n adiBeta (Cl)
<50 NR 0 n/a
50-250 NR -2.7 n/a
>800 NR -12.2 n/a
Stat Method: multivariate linear regression
Outcome: lung cancer
highest 5-year average arsenic concentration:
40-year lag, ng/L
Exp. Level n adiOR (Cl)
<10 169 1 n/a
11-84 15 0.84 0.40, 1.79
>85 12 1.39 0.55,3.53
Stat Method: unconditional logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-222 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
with lung cancer
n cases: 196
n control: 359
Farzanetal. (2013)
Study Type: cohort
(prospective)
Location: United States
/M LJ\
(NH)
Population: 4 month
old infants born to
women 18-45 years old
n total: 214
Exposure Measures
based beverages and foods typically
consumed 1 year prior to interview or
diagnosis, as well as 20 and 40 years
before
Population-Level Exposure:
36 |jg/L mean, 0-1460 |jg/L range
Exposure Surrogate: urine
Exposure Description: mothers provided
spot urine sample upon enrollment (24-
28 weeks gestation); samples that
registered below the detection limit
assigned a value equal to the detection
limit divided by the square root of two;
total urinary As calculated as the sum of
inorganic As (As[lll] and As[V]) and
metabolic products MMA(V) and
DMA(V), excluding arsenobetaine
Population-Level Exposure:
6 ng/L mean 7.5SD
Results
Outcome: acute respiratory symptoms,
conditions, illnesses
maternal urinary As (In transformed; categorized
by 4 infection descriptions), ug/L
Exp. Level n RR (CD
continuous: 74 1.1 0.8, 1.6
at least one
infection
continuous: 57 1.3 0.9, 1.9
infection
lasting 2 or
more days
continuous: 27 1.3 0.8, 2.0
infection
with a
physician
visit
continuous: 5 4 1.0, 15.9
infection
treated with
prescription
medication
Stat Method: logistic regression
Outcome: any lower respiratory tract infection
maternal urinary As (In transformed; categorized
by 4 infection descriptions), ug/L
Exp. Level n RR (CD
continuous: 9 1.4 0.7,3.1
at least one
infection
continuous: 9 1.4 0.7,3.1
infection
lasting 2 or
more days
continuous: 9 1.4 0.7,3.1
infection
with a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-223 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
physician
visit
continuous: 7 3.3 1.2,9.0
infection
treated with
prescription
medication
Stat Method: logistic regression
Outcome: any respiratory tract infection
maternal urinary As (In transformed; categorized
by two infection descriptions), ng/L
Exp. Level n RR (CD
with a NR 1.5 1.0,2.1
physician
visit
treated with NR 1.6 1.1,2.4
prescription
medication
Stat Method: Poisson model
Outcome: any upper respiratory tract infection
maternal urinary As (In transformed; categorized
by 4 infection descriptions), u.Q/1
Exp. Level n RR (CD
continuous: 133 1.1 0.8,1.6
at least one
infection
continuous: 111 1.2 0.9,1.7
infection
lasting 2 or
more days
continuous: 53 1.1 0.8,1.6
infection
with a
physician
visit
continuous: 28 1.6 1.0,2.5
infection
treated with
prescription
medication
Stat Method: logistic regression
Outcome: cold, runny, or stuffed nose
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-224 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
maternal urinary As (In transformed; categorized
by 4 infection descriptions), ug/L
Exp. Level n RR (CD
continuous: 126 1 0.8, 1.4
at least one
infection
continuous: 103 1.1 0.8, 1.5
infection
lasting 2 or
more days
continuous: 39 1 0.7, 1.4
infection
with a
physician
visit
continuous: 9 2.3 1.0, 5.2
infection
treated with
prescription
medication
Stat Method: logistic regression
Outcome: ear infection (otitis media)
maternal urinary As (In transformed; categorized
by 4 infection descriptions), ug/L
Exp. Level n RR (Cl)
continuous: 8 1.1 0.5,2.6
at least one
infection
continuous: 8 1.1 0.5,2.6
infection
lasting 2 or
more days
continuous: 7 1.6 0.7, 3.8
infection
with a
physician
visit
continuous: 7 1.6 0.7, 3.8
infection
treated with
prescription
medication
Stat Method: logistic regression
Outcome: eye infection (conjuctivitis)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-225 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Ferreccio et al. (2000)
Study Type: case-
control
Location: Chile
(Regions 1, II, III in
northern Chile)
Population: public
hospital adult patients
in areas with low to
high drinking water
arsenic exposure
n cases: 151
n control: 419
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations measured by
water companies (1950-1994) or
estimated based on 1950s
concentrations (1930-1957); individual
exposure calculated using self-reported
residential history and yearly average
water arsenic concentration for each
county of residence; lifetime average
exposure based on 1930-1994
concentrations; peak average exposure
based on 1958-1970 concentrations
Population-Level Exposure:
0-400 ng/L range
Results
maternal urinary As (In transformed; categorized
by 4 infection descriptions), ng/L
Exp. Level n RR (CD
continuous: 17 1.4 0.8, 2.4
at least one
infection
continuous: 14 1.4 0.6, 2.6
infection
lasting 2 or
more days
continuous: 14 1.6 0.9, 2.9
infection
with a
physician
visit
continuous: 14 1.2 0.7, 2.1
infection
treated with
prescription
medication
Stat Method: logistic regression
Outcome: lung cancer
lifetime water arsenic concentration (1930-1994),
W/L
Exp. Level n adiOR (CD
0-10 9 1 n/a
10-29 5 1.6 0.5,5.3
30-49 8 3.9 1.2, 12.3
50-199 50 5.2 2.3, 11.7
200-400 79 8.9 4.0, 19.6
Stat Method: unconditional regression
analysis
peak years average water arsenic concentration
(1958-1970), \ig/L
Exp. Level n adiOR (CD
0-10 11 1 n/a
10-29 3 0.3 0.1, 1.2
30-59 4 1.8 0.5,6.9
60-89 22 4.1 1.8,9.6
90-199 13 2.7 1.0,7.1
200-399 23 4.7 2.0, 11.0
400-699 11 5.7 1.9, 16.9
700-999 64 7.1 3.4, 14.8
Stat Method: unconditional regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-226 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
analysis
Ferreccio et al. (2013b)
Study Type: case-
control
Location: Chile
(Regions I and II,
Northern Chile)
Population: residents
with bladder or lung
cancer in area formerly
having arsenic-
contaminated drinking
water
n cases: 538
n control: 640
Exposure Surrogate: drinking water
Exposure Description: lifetime arsenic
exposure estimated by linking subject's
residence with water arsenic
concentration
Population-Level Exposure:
0-800 ng/L range
Outcome: lung cancer
water arsenic concentration - never smoker,
Exp. Level n adjOR M
<11 16 1 n/a
>355 18 2 0.8,5.0
Stat Method: Unconditional logistic
regression
water arsenic concentration - smoked >10
cigarettes/day, ng/L
Exp. Level
<11 never
smoker
>355
n
NR
28
46
3.8
16
M
n/a
1.7, 8.5
6.5, 40
Stat Method: Unconditional logistic
regression
Garcfa-Esquinas et al.
(2013)
Study Type: cohort
(prospective)
Location: United States
(AZ;ND;OK;SD)
Population: Strong
Heart Study
participants
n total: 3,935
Exposure Surrogate: urine
Exposure Description: individual urine
samples collected and analyzed for
arsenic speciation
Population-Level Exposure:
9.7 ng/g-creatinine median, 5.8-15.6
Hg/g-creatinine 25th percentile
Outcome: lung cancer
urinary arsenic concentration, ng/g-creatinine
Exp. Level n HR (CD
80th vs. 20th 78 1.56 1.02,2.39
percentiles
Stat Method: Cox proportional hazard models
Ghosh et al. (2007b)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: West
Bengal residents
Exposure Surrogate: drinking water
Exposure Description: arsenic content in
drinking water measured from 100 ml
samples provided by study participants;
instrument calibrated and readings taken
in duplicate for each sample
Population-Level Exposure:
0-1188 ng/L range
Outcome: respiratory illness
arsenic exposure/skin lesion status, ng/L
Exp. Level n adjOR M
unexposed 13 1 n/a
exposed, no 32 3.21 1.65,6.26
skin lesions
exposed, skin 118 13.54 7.45,24.62
lesions
Stat Method: Logistic regression analysis
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-227 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
exposed to arsenic in
drinking water with and
without skin lesions
and similar unexposed
residents
n cases: 725
n control: 389
Guo et al. (2007)
Study Type: cross-
sectional
Location: Mongolia
region not available
Population: residents
of villages in the Hetao
Plain, Inner Mongolia
n cases: 680
n control: 189
Heck et al. (2009)
Study Type: case-
control
Location: United States
(NH; VT)
Population: New
England Lung Cancer
Study, adult lung
cancer cases
n cases: 223
n control: 238
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic samples
were taken from 94 water sources,
including wells; detection limit not
specified, but authors note reliability of
the method at <10 ng/L; arsenic
exposure determined by location of
village
Population-Level Exposure:
50-1860 ng/L range
Exposure Surrogate: toenails
Exposure Description: toenail arsenic
concentration measured from individual
cleaned clippings obtained during
interview; results below LOD assigned
0.0015 ng/g
Population-Level Exposure:
0.05-0.1137 ng/g range
Results
Outcome: chronic bronchitis
water arsenic concentration, ng/L
arsenic not significantly associated with bronchitis
Outcome: all lung cancers
toenail arsenic concentration (quartiles), ng/g
Exp. Level n adiOR (CD
<0.05 65 1 n/a
0.05-<0.0768 58 1.34 0.71,2.53
0.0768- 58 1.1 0.55,2.20
<0.1137
> 0.1137 57 0.89 0.46,1.75
Stat Method: Unconditional logistic
regression
Outcome: lung cancer cell types previously
associated with arsenic (small cell and squamous
cells)
toenail arsenic concentration (quartiles), ng/g
Exp. Level n adiOR (CD
<0.05 65 1 n/a
0.05-<0.0768 58 2.99 1.12,7.99
0.0768- 58 1.86 0.62,5.58
<0.1137
> 0.1137 57 2.75 1.00,7.57
Stat Method: Unconditional logistic
regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-228 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
Hsu et al. (2013a)
Study Type: cohort
(prospective)
Location: Taiwan
(Peimen, Hsuechia,
Putai, Ichu townships)
Population: 3 separate
subcohorts of residents
of an arseniasis-
endemic area
n exposed: 1075
n reference: 535
n total: 2447
Exposure Surrogate: drinking water
Exposure Description: lifetime
cumulative arsenic exposure estimated
using median arsenic concentration in
village well where study subject lived and
duration of exposure; arsenic
concentrations in wells obtained from 2
investigations examining more than
38,565 wells across Taiwan; lifetime
cumulative arsenic exposure (CAE)
estimated using median arsenic
concentration in village well where study
subject lived and duration of exposure
Population-Level Exposure:
1-20 mg/L - yr range
Outcome: lung cancer
cumulative arsenic exposure, mg/L - yr
Exp. Level
1.0-19.9
>20
missing
n
NR
NR
NR
NR
HR
1
0.8
0.73
0.65
M
n/a
0.46, 1.4
0.38, 1.42
0.38, 1.12
Stat Method: Cox regression analysis with
time-dependent covariates
Khlifi et al. (2014)
Study Type: case-
control
Location: Tunisia (Sfax
and South Tunisia)
Population: hospital
patients with laryngeal
or nasopharyngeal
cancer
n cases: 145
n control: 351
Exposure Surrogate: blood
Exposure Description: 3 mL venous
blood samples collected from patients at
diagnosis and analyzed for arsenic and
cadmium
Population-Level Exposure:
0.83 ng/L median, 0.13-42 ng/L range
Outcome: laryngeal cancer (LC): differentiated
epidermoid carcinoma
blood arsenic level - continuous, ug/L
Exp. Level n adjOR M
blood arsenic NR 1.14 1.05, 1.42
level
Stat Method: conditional logistic regression
blood arsenic levels, ug/L
Exp. Level n adjOR
Low (< 2.32 49 1 n/a
High(>2.32 48 2.63
1.50,4.34
Stat Method: logistic regression analysis
Outcome: laryngeal cancer + nasopharyngeal
cancer
blood arsenic level - continuous, ug/L
Exp. Level n adjOR (CD
blood arsenic NR 1.16 1.08, 1.26
level
Stat Method: conditional logistic regression
blood arsenic levels, ug/L
Exp. Level n adjOR
Low (< 2.32 76 1
Ug/L)
M
n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-229 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
High(>2.32 69 2.41 1.56,3.71
Mg/U
Stat Method: logistic regression analysis
Outcome: nasopharyngeal cancer (NPC):
undifferentiated carcinoma
blood arsenic level - continuous, ug/L
Exp. Level n adjOR (CD
blood arsenic NR 1.16 1.06, 1.28
level
Stat Method: conditional logistic regression
blood arsenic levels, ug/L
Exp. Level n adjOR (CD
Low (< 2.32 27 1 n/a
Hg/D
High(>2.32 21 2.18 1.15,4.12
Hg/D
Stat Method: logistic regression analysis
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: male and
female members of
Latter-day Saints
church wards
n exposed: 2203
n total: 2203
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Outcome: bronchitis, emphysema, asthma
cumulative arsenic exposure, ppb-years
SMR for bronchitis, emphysema, and asthma
unchanged from expected in males and females
Outcome: nonmalignant respiratory disease
cumulative arsenic exposure, ppb-years
SMR for nonmalignant respiratory disease
unchanged from expected in females; SMR
significantly decreased in medium exposure males
only
Outcome: respiratory system cancer
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR (CD
<1000 NR 0.44 n/a
1000-4999 NR 0.66 n/a
>5000 NR 0.22 n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR M
<1000 NR 0.32 n/a
1000-4999 NR 0.96 n/a
>5000 NR 0.44 n/a
Stat Method: standardized mortality ratios
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-230 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
Maiumdar et al. (2009)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: residents
of arsenic-affected
villages
n cases: 3825
n control: 3451
Exposure Surrogate: drinking water
Exposure Description: for each
participant, water samples from private
or public tube wells analyzed for arsenic;
exposure categories developed based on
arsenic levels
Population-Level Exposure:
50-500 ng/L range
Outcome: chronic lung disease
arsenic concentration in drinking water
(females), \ig/L
Exp. Level n prevOR (CD
<50 NR 1 n/a
>500 NR 1.76 1.1,2.6
Stat Method: prevalence odds ratio
calculated for each outcome comparing
highest and lowest exposure levels
arsenic concentration in drinking water (males),
Exp. Level n prevOR (Cl)
<50 NR 1 n/a
>500 NR 0.93 0.65,1.3
Stat Method: prevalence odds ratio
calculated for each outcome comparing
highest and lowest exposure levels
Nafees et al. (2011)
Study Type: cross-
sectional
Location: Pakistan
(Mehtani and Mian Jan
Muhammad Abbassi
villages)
Population: adults and
children living in
villages with high
proportion of
contaminated drinking
water sources
n cases: 100
n control: 100
Exposure Surrogate: drinking water
Exposure Description: drinking water
concentration calculated from samples
tested at field site using portable kits;
source more frequently used for drinking
water tested when multiple sources
used; subjects grouped for analysis as
exposed (> 100 ng/L; > 250 ng/L)
Population-Level Exposure:
10-250 ng/L range
Outcome: FEV1 (mL)
drinking water arsenic concentration, \ng/L
Exp. Level n adiBeta (Cl)
> 100 NR -154.3 -324.7, 16.0
Stat Method: Multivariate linear regression
drinking water arsenic concentration, \ig/L
Exp. Level n ad i Beta (Cl)
>250 NR -226.4 -430.4,-22.4
Stat Method: Multivariate linear regression
Outcome: FEV1/FVC
drinking water arsenic concentration, \ng/L
Exp. Level n ad i Beta (Cl)
>100 NR 2 -25.3,29.4
Stat Method: Multivariate linear regression
drinking water arsenic concentration, \ng/L
Exp. Level n ad i Beta (Cl)
>250 NR 9.9 -21.8,41.6
Stat Method: Multivariate linear regression
Outcome: FVC (mL)
drinking water arsenic concentration, \ig/L
Exp. Level n ad i Beta (Cl)
>100 NR -221.9 -419.5,-24.3
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-231 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
Stat Method: Multivariate linear regression
drinking water arsenic concentration, ng/L
Exp. Level n adiBeta (CD
>250 NR -354.8 -583.6,-126.0
Stat Method: Multivariate linear regression
Parvez et al. (2013)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: subset of
Health Effects of
Arsenic Longitudinal
Study (HEALS)
participants with
respiratory symptoms
n total: 950
Exposure Surrogate: drinking water
Exposure Description: field sample
collection and laboratory analyses of
water samples; arsenic concentration
noted to be relatively stable and not to
change over time under normal
conditions; information on the status of
well and water consumption behavior
and pattern from the study participants
collected
Population-Level Exposure:
19-97 ng/L range
Outcome: lung function: forced expiratory
volume (FEV1)
well water arsenic concentration (tertiles), ng/L
Exp. Level n ad i Beta (CD
<19 NR 0 n/a
>19-97 NR -33.1 -114.6,48.4
>97 NR -80.6 -181.4,-17.5
Stat Method: multivariate logistic regression
well water arsenic concentration - per one SD
(118.1 ng/L),ng/L
Exp. Level n ad i Beta (CD
continuous NR -46.5 -83.0,-10.0
Stat Method: multivariate logistic regression
Outcome: lung function: forced vital capacity
(FVC)
well water arsenic concentration (tertiles), ng/L
Exp. Level n ad i Beta (CD
<19 NR 0 n/a
>19-97 NR -13.2 -97.3,71.0
>97 NR -97.3 -181.8,-12.7
Stat Method: multivariate logistic regression
well water arsenic concentration - per one SD
(118.1 ng/L),ng/L
Exp. Level n ad i Beta (CD
continuous NR -53.1 -90.7,-15.4
Stat Method: multivariate logistic regression
Exposure Surrogate: urine
Exposure Description: urinary arsenic
measured at baseline and biannually in
spot urine samples
Population-Level Exposure:
125-285 ng/g-creatinine
Outcome: lung function: forced expiratory
volume (FEV1)
urinary arsenic concentration (tertiles), ng/g-
creatinine
Exp. Level
<125
>125-285
>285
NR
NR
NR
M
n/a
-148.3,14.1
-173.6, -7.4
Stat Method: multivariate logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-232 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Parvez et al. (2010)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study,
adults participants who
underwent first two
follow-up visits
n total: 10833
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentration based on water
samples collected from wells from which
study participants drank regularly; results
125-285 NR -36.4 -120.4,47.0
>285 NR -81 -166.7,4.8
Stat Method: multivariate logistic regression
urinary arsenic concentration - per one SD (277.2
Hg/g-creatinine), ng/g-creatinine
Exp. Level n adiBeta (Cl)
continuous NR -55.2 -90.5, -19.9
Stat Method: multivariate logistic regression
Outcome: blood in sputum
drinking water arsenic concentration (quintiles),
H9/L
Exp. Level n HR (Cl)
<7 NR 1 n/a
7-40 NR 1.15 0.75, 1.76
7-40
40-90 NR 1.09 1.69, 1.70
90-178 NR 1.66 1.10,2.51
>178 NR 1.51 0.98,2.32
Stat Method: Cox proportional hazard models
Outcome: breathing problem
drinking water arsenic concentration (quintiles),
W/l.
Exp. Level n HR (Cl)
<7 NR 1 n/a
7-40 NR 1.44 1.20, 1.74
7-40
40-90 NR 1.52 1.25, 1.84
90-178 NR 1.42 1.16, 1.73
>178 NR 1.41 1.56, 1.72
Stat Method: Cox proportional hazard models
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-233 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration measured from spot
samples collected at each visit
Population-Level Exposure:
90-406 ng/g-creatinine range
Results
Outcome: chronic cough
drinking water arsenic concentration (quintiles),
H9/L
Exp. Level n HR (CD
<7 NR 1 n/a
7-40 NR 1.19 0.95, 1.5
7-40
40-90 NR 1.4 1.11, 1.75
90-178 NR 1.57 1.25, 1.97
>178 NR 1.6 1.27,2.01
Stat Method: Cox proportional hazard models
Outcome: blood in sputum
urinary arsenic concentration (quintiles), u.g/g-
creatinine
Exp. Level n HR (Cl)
<90 NR 1 n/a
90-160 NR 1.16 0.77, 1.74
160-246 NR 1.05 0.69, 1.60
246-406 NR 1.03 0.67, 1.58
>406 NR 1.33 0.89, 1.99
Stat Method: Cox proportional hazard models
Outcome: breathing problem
urinary arsenic concentration (quintiles), u.g/g-
creatinine
Exp. Level n HR (Cl)
<90 NR 1 n/a
90-160 NR 1.14 0.95, 1.38
160-246 NR 1.16 0.96, 1.40
246-406 NR 1.28 1.06, 1.54
>406 NR 1.27 1.05, 1.53
Stat Method: Cox proportional hazard models
Outcome: chronic cough
urinary arsenic concentration (quintiles), u.g/g-
creatinine
Exp. Level n HR (Cl)
<90 NR 1 n/a
90-160 NR 0.98 0.78, 1.23
160-246 NR 1.14 0.91, 1.42
246-406 NR 1.52 1.23, 1.88
>406 NR 1.51 1.21, 1.87
Stat Method: Cox proportional hazard models
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Paul etal. (2013)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: male and
female adult residents
with skin lesions from 3
villages with high
arsenic concentrations
n cases: 189
n control: 171
Rahman etal. (2011)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: MINIMat
Study, mother-infant
pairs
n total: 1552
Raqib et al. (2009)
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: samples collected
directly from study participants during
2005-2006 and 2010-2011 study periods
Population-Level Exposure:
mean concentration in drinking water
ranged from 3.7 (unexposed) to 190.1
(exposed) in both analyses
Exposure Surrogate: maternal urine
Exposure Description: maternal urinary
arsenic concentration measured from
urine samples collected at GW 8 and 30;
arsenic exposure calculated as sum of
inorganic arsenic and its methylated
metabolites (MMA and DMA) and the
average of exposure at GW 8 and 30;
samples 261 NR 1.69 1.36,2.09
Stat Method: Poisson regression
Outcome: severe LRTI
maternal urinary arsenic concentration
(quintiles), ug/L
Exp. Level n adiRR (Cl)
<39 NR 1 n/a
39-64 NR 1.33 1.03, 1.71
65-132 NR 1.31 1.02, 1.69
133-261 NR 1.54 1.21, 1.97
>261 NR 1.54 1.21,1.97
Stat Method: Poisson regression
Outcome: acute respiratory infection at 6-12
months
maternal urinary arsenic at gestation week 30,
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: women
and infants enrolled in
MINIMat study of
nutritional impact on
fetal and infant
development
n total: 140
Exposure Description: maternal urine
samples taken at gestation week 8 or 30
analyzed for inorganic arsenic and
metabolites; samples adjusted for
specific gravity
Population-Level Exposure:
145.8 ng/L mean 186.8SD
Exp. Level n adiBeta (CD
continuous NR 0.004 0.001,0.006
Stat Method: multiple linear regression
Sawada et al. (2013)
Study Type: cohort
(prospective)
Location: Japan (Iwate,
Akita, Nagano,
Okinawa, Tokyo,
Ibaraki, Niigata, Kochi,
Nagasaki, Osaka)
Population: adults in
Japan Public Health
Center (JPHC)
Prospective Study
cohort
n total: 90378
Exposure Surrogate: diet
Exposure Description: detailed
questionnaire on food intake/frequency;
average arsenic concentrations in food
items obtained from the literature;
arsenic intake calculated by multiplying
average arsenic concentration in each
item by quantity consumed
Population-Level Exposure:
170 ng/day mean, 88.3-253.2 ng/day
range
Outcome: lung cancer
inorganic arsenic intake (tertiles; females; never
smoker), u.g/day
HR
1
1.31
1.57
Exp. Level
lowest tertile
middle tertile
highest
tertile
Stat Method: Cox's proportional hazards
model
58
74
92
M
n/a
0.92, 1.86
1.12,2.20
inorganic arsenic intake (tertiles; males; current
smoker), u.g/day
Exp. Level n HR (CD
lowest tertile 115 1 n/a
middle tertile 137 1.2 0.93,1.55
highest 166 1.38 1.07, 1.77
tertile
Stat Method: Cox's proportional hazards
model
inorganic arsenic intake (tertiles; males; ever
smoker), tig/day
Exp. Level n HR (Cl)
lowest tertile 149 1 n/a
middle tertile 158 1.07 0.85,1.34
highest 215 1.36 1.09, 1.7
tertile
Stat Method: Cox's proportional hazards
model
total arsenic intake (tertiles; males; current
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Smith et al. (2013)
Study Type: cohort
(prospective)
Location: Bangladesh
(Matlab)
Population: children in
rural area
n exposed: 491
n reference: 159
n total: 650
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: water samples
were collected from all functioning tube
wells used at home and at school; in
utero exposure assessed during 9 months
of pregnancy based on tube well
concentrations with levels from the
2002-2003 survey used for any tube wells
where samples could not be collected
and residential histories starting 1 year
prior to the childs birth to the current
residence
Population-Level Exposure:
436.8 ng/L mean
Results
smoker), tig/day
Exp. Level n HR (CD
lowest tertile 101 1 n/a
middle tertile 153 1.41 1.09,1.82
highest 164 1.37 1.06, 1.77
tertile
Stat Method: Cox's proportional hazards
model
total arsenic intake (tertiles; males; ever
smoker), tig/day
Exp. Level n HR (CD
lowest tertile 135 1 n/a
middle tertile 180 1.24 0.99,1.56
highest 207 1.29 1.03, 1.61
tertile
Stat Method: Cox's proportional hazards
model
Outcome: asthma
in utero arsenic exposure (quartiles), u.Q/1
Exp. Level n adiOR (CD
10-199 NR 1.23 0.50,3.02
200-399 NR 1.88 0.90,3.92
400-599 NR 2.23 1.13,4.49
>600 NR 2.38 1.17,4.83
NR NR 1 n/a
Stat Method: multiple linear regression
analysis
Outcome: coughing - no cold
in utero arsenic exposure (quartiles), u.g/L
Exp. Level n adiOR (CD
10-199 NR 2.37 0.92,6.09
200-399 NR 1.62 0.64,4.11
400-599 NR 1.78 0.74,4.31
>600 NR 2.47 1.05,5.79
NR NR 1 n/a
Stat Method: multiple linear regression
analysis
Outcome: FEV1
in utero arsenic exposure {continuous), u.Q/1
Exp. Level n adiBeta (CD
continuous NR -0.013 -0.076,0.049
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
Stat Method: multiple linear regression
analysis
in utero arsenic exposure (tertiles), ug/L
Exp. Level n adiBeta (CD
<10 NR 0 n/a
10-499 NR 16.4 -25.5,58.3
500+ NR -22.6 -72.7,27.6
Stat Method: multiple linear regression
analysis
Outcome: FVC
in utero arsenic exposure (continuous), ug/L
Exp. Level n adjBeta (Cl)
continuous NR -0.007 -0.075,0.061
Stat Method: multiple linear regression
analysis
in utero arsenic exposure (tertiles), ug/L
Exp. Level n adjBeta (Cl)
<10 NR 0 n/a
10-499 NR 27 -18.5,72.5
500+ NR -17.2 -71.6,37.3
Stat Method: multiple linear regression
analysis
Outcome: shortness of breath - fast
walking/climbing
in utero arsenic exposure (quartiles), ug/L
Exp. Level
10-199
200-399
400-599
>600
NR
NR
NR
NR
NR
NR
M
0.27, 4.28
1.06, 7.91
1.56, 10.7
1.18,8.71
n/a
Stat Method: multiple linear regression
analysis
Outcome: shortness of breath - walking
in utero arsenic exposure (quartiles), ug/L
Exp. Level
10-199
200-399
400-599
>600
n
NR
NR
NR
NR
M
0.72, 7.58
0.54, 9.12
1.17, 17.3
0.88, 12.8
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Steinmaus et al. (2013)
Study Type: case-
control
Location: Chile
(Antofagasta)
Population: residents
with lung cancer or
bladder cancer who
were formerly exposed
to high arsenic levels in
drinking water
n cases: 538
n control: 640
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: drinking water
arsenic concentrations for each city or
town in the study area collected from
government agencies, research studies,
and water suppliers; subjects self-
reported daily water intake
Population-Level Exposure:
1578- 12841 ng/L-yr range
Results
NR NR NR n/a
Stat Method: multiple linear regression
analysis
Outcome: wheezing (ever)
in utero arsenic exposure (quartiles), u.g/L
Exp. Level n adiOR (CD
10-199 NR 1.98 1.03,3.80
200-399 NR 1.51 0.83,2.74
400-599 NR 3.17 1.78,5.64
>600 NR 2.12 1.19,3.76
NR NR 1 n/a
Stat Method: multiple linear regression
analysis
Outcome: wheezing - no cold
in utero arsenic exposure (quartiles), u.g/L
Exp. Level n adiOR (CD
10-199 NR 5.01 0.78,32.0
200-399 NR 1.57 0.20, 12.1
400-599 NR 8.65 1.64,45.7
>600 NR 8.21 1.56,43.1
NR NR NR n/a
Stat Method: multiple linear regression
analysis
Outcome: lung cancer
cumulative arsenic concentration: all years
(quartiles), u.g/L - yr
Exp. Level n adiOR (CD
<1578 60 1 n/a
1578-4876 61 0.95 0.61, 1.50
4877-12841 89 1.89 1.19,3.02
>12841 96 2.9 1.69,4.97
Stat Method: Unconditional logistic
regression
cumulative arsenic concentration: before 1971
(quartiles), u.g/L - yr
Exp. Level n adiOR (CD
<372 51 1 n/a
372-2464 64 1.29 0.82,2.02
2465-10319 87 2.4 1.51,3.81
>10319 100 4.82 2.79,8.34
Stat Method: Unconditional logistic
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Exposure Measures
Results
regression
cumulative arsenic intake: all years (quartiles),
ug
Exp. Level n adiOR (CD
<2438 64 1 n/a
2438-8214 58 0.84 0.54, 1.32
8215-19093 77 1.29 0.81,2.06
>19093 107 3.25 2.00,5.29
Stat Method: Unconditional logistic
regression
cumulative arsenic intake: before 1971
(quartiles), ug
Exp. Level n adiOR (CD
<576 53 1 n/a
576-4429 63 1.21 0.77, 1.89
4430-14347 78 1.92 1.22,3.03
>14347 108 4.86 2.92,8.09
Stat Method: Unconditional logistic
regression
lifetime average arsenic concentration: all years
(quartiles), ug/L
Exp. Level n adiOR (CD
<26 61 1 n/a
26-79 61 0.98 0.62, 1.53
80-197 85 1.7 1.05,2.75
>197 99 3.18 1.90,5.30
Stat Method: Unconditional logistic
regression
lifetime average arsenic concentration: before
1971 (quartiles), ug/L
Exp. Level n adiOR (CD
<11 51 1 n/a
11-90 66 1.27 0.81, 1.98
91-335 80 2 1.24,3.24
>335 105 4.32 2.60,7.17
Stat Method: Unconditional logistic
regression
lifetime daily average arsenic intake: all years
(quartiles), u.g/day
Exp. Level n adiOR (CD
>41 64 1 n/a
41-136 56 0.87 0.55, 1.36
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Respiratory Effects
Reference and Study
Design
Tsuda et al. (1995)
Study Type: cohort
(retrospective)
Location: Japan
(Namiki-cho)
Population: adults and
children living near
factory producing
arsenic trisulfide
n exposed: 189
n reference: 254
n total: 443
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic in well
water measured in 1959 (the end of the
exposure period) in 34 wells; 20 area
wells had no documented levels of
arsenic so authors inferred that arsenic
levels were undetectable or very low;
concentration assigned based on
residence in 1959
Population-Level Exposure:
0.05-1 ppm range
Results
137-307 76 1.24 0.78, 1.98
>307 110 3.16 1.98,5.03
Stat Method: Unconditional logistic
regression
lifetime daily average arsenic intake: before
1971 (quartiles), ng/day
Exp. Level n adiOR (CD
<21 53 1 n/a
21-159 64 1.19 0.76, 1.85
160-525 73 1.63 1.01,2.65
>525 112 4.89 2.99,7.99
Stat Method: Unconditional logistic
regression
Outcome: lung cancer
arsenic concentration in well water in 1959, ppm
Exp. Level n SMR (CD
<0.05 0 0 0,2.43
0.05-0.99 1 2.33 0.12, 13.39
>1 8 15.69 7.38,31.02
Stat Method: Cox proportional hazard
--: not reported; n: number of cases (when presented in Results column)
5.15.1 References for Summary of Observational Epidemiology
Studies for Health Effect Category: Respiratory Effects
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231-237. http://dx.doi.org/10.1289/ehp. 10623
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-242 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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Liaw. J: Golden. T: Smith. AH. (2013). Drinking water arsenic in northern Chile: high cancer risks 40 years
after exposure cessation. Cancer Epidemiol Biomarkers Prev 22: 623-630. http://dx.doi.org/10.1158/1055-
9965.EPI-12-1190
Tsuda. T: Babazono. A: Yamamoto. E: Kurumatani. N: Mino. Y: Ogawa. T: Kishi. Y: Aoyama. H. (1995).
Ingested arsenic and internal cancer: A historical cohort study followed for 33 years. Am J Epidemiol 141:
198-209.
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
5.16Summary of Observational Epidemiology Studies for
Health Effect Category: Skin Diseases
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Ahsan et al. (2000)
Study Type: cross-
sectional
Location: Bangladesh
(Sonargaon)
Population: residents
of three contiguous
villages where well
water had not been
previously tested
n cases: n/a
n control: n/a
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic measured
in pitcher-water obtained directly from
household (correlated with tube-well
water samples); exposure stratified by
quartiles
Population-Level Exposure:
29-991 |jg/L range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
index (CAI) calculated by multiplying
arsenic concentration in pitcher water
with estimated yearly water
consumption and years of water source
use (tube well concentration assumed to
be constant); exposure stratified by
quartiles
Population-Level Exposure:
116.4-22147.1 mg range
Exposure Surrogate: urine
Exposure Description: individual urine
samples, adjusted for creatinine content;
exposure stratified by quartiles
Population-Level Exposure:
122-1840 ng/L range
Exposure Surrogate: urine
Results
Outcome: any skin lesions
arsenic in pitcher-water (quartiles), u.g/L
Exp. Level n adiOR (CD
<29 NR 1 n/a
>29-90 NR 0.9 0.3,2.9
>90-278 NR 0.36 0.1, 1.2
>278-991 NR 1.67 0.6,5.1
Stat Method: logistic regression models
Outcome: any skin lesions
cumulative arsenic index (CAI) (quartiles), mg
Exp. Level n adiOR (CD
< 116.4 NR 1 n/a
>116.4-474.9 NR 1.3 0.4,4.4
>474.9- NR 0.6 0.15,2.2
1279.9
>1279.9- NR 2.3 0.7,7.6
22147.1
Stat Method: logistic regression models
Outcome: any skin lesions
total urinary arsenic concentration (quartiles),
ug/L
Exp. Level n adiOR (CD
<122 NR 1 n/a
>122-244 NR 1 0.3,3.6
>244-471 NR 2.1 0.6,7.4
>471-1840 NR 3.6 1.2, 12.1
Stat Method: logistic regression models
Outcome: any skin lesions
creatinine adjusted urinary arsenic concentration
(quartiles), u.g/g-creatinine
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Ahsan et al. (2006)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study
(HEALS) subcohort
exposed to full dose
range of arsenic
n cases: 11438
n control: n/a
Exposure Measures
Exposure Description: individual urine
samples; exposure stratified by quartiles
Population-Level Exposure:
242-5727 ug/g-creatinine range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
index calculated using well water arsenic
concentration times daily consumption
volume times duration of well use
Population-Level Exposure:
0.1-9609 mg range
Exposure Surrogate: drinking water
Exposure Description: time-weighted
arsenic concentration calculated using
drinking duration (data from interview)
and well arsenic concentrations (if two
wells used concentrations averaged)
Population-Level Exposure:
0. 1-864 ug/L range
Exposure Surrogate: urine
Exposure Description: total urinary
arsenic adjusted for creatinine
concentration
Population-Level Exposure:
6.6-4306 ug/g-creatinine range
Results
Exp. Level n adiOR (CD
<242 NR 1 n/a
>242-440 NR 0.83 0.2,2.9
>440-766 NR 0.88 0.2,3.1
>766-5727 NR 3.22 1.1, 10.1
Stat Method: logistic regression models
Outcome: skin lesions
cumulative arsenic index, mg
Exp. Level n adiOR (CD
0.1-48.1 53 1 n/a
48.2-226.4 90 1.83 1.25,2.69
226.5-582.6 122 2.53 1.72,3.71
582.7-1485.8 162 3.62 2.5,5.23
1485.9- 268 5.49 3.82,7.90
9609.0
Stat Method: Prevalence odds ratios (PORs)
for skin lesions analyzed using unconditional
logistic regression modeling
Outcome: skin lesions
time-weighted water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
0.1-8.0 57 1 n/a
8.1-40.0 90 1.91 1.26,2.89
40.1-91.0 144 3.03 2.05,4.50
91.1-175.0 162 3.71 2.53,5.44
175.1-864.0 242 5.39 3.69,7.86
Stat Method: Prevalence odds ratios (PORs)
for skin lesions analyzed using unconditional
logistic regression modeling
Outcome: skin lesions
urinary creatinine-adjusted arsenic
concentration, ug/g-creatinine
Exp. Level n adiOR (Cl)
6.6-90.1 60 1 n/a
90.2-158.4 99 1.75 1.23,2.48
158.5-243.4 129 2.33 1.67,3.26
243.5-396.5 153 3.08 2.19,4.35
396.6-4306.0 239 5.29 3.78,7.41
unavailable 15 NR n/a
Stat Method: Prevalence odds ratios (PORs)
for skin lesions analyzed using unconditional
logistic regression modeling
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Argos et al. (2011)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study
(HEALS) participants
without skin lesions at
baseline
n exposed: 866
n reference: 9316
n total: 10182
Baastru petal. (2008)
Study Type: cohort
(prospective)
Location: Denmark
(Copenhagen and
Aarhus)
Population: Danish
Cancer Registry
population (adults)
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: daily arsenic
intake calculated by multiplying well
water arsenic concentration of primary
well (and secondary well if applicable) by
daily consumption (self-reported)
Population-Level Exposure:
0.4-472.1 |jg/day range
Exposure Surrogate: drinking water
Exposure Description: well water
samples in study area collected; samples
below LOD reanalyzed; participants
identified primary well of use at baseline
Population-Level Exposure:
0. 1-200. lug/L range
Exposure Surrogate: urine
Exposure Description: individual urinary
total arsenic concentration measured
and adjusted for creatinine
Population-Level Exposure:
7-393 ng/g-creatinine range
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure and time-weighted average
arsenic concentrations calculated for
individuals based on residential address
and history from Central Population
Registry combined with measurement
data from nearest water utility as
recorded by Geological Survey of
Denmark and Greenland (1987-2004)
Population-Level Exposure:
Results
Outcome: incident skin lesions
daily arsenic intake, tig/day
Exp. Level n HR (CD
0.4-19.4 NR 1 n/a
19.5-100.8 NR 1.23 0.96, 1.58
100.9-233.1 NR 1.57 1.24, 1.99
233.2-472.0 NR 1.82 1.45,2.30
> 472.1 NR 2.92 2.34,3.65
Stat Method: Multivariate model
Outcome: incident skin lesions
well water arsenic concentration, ug/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 1.17 0.92, 1.49
50.1-100 NR 1.69 1.33,2.14
100.1-200 NR 1.97 1.58,2.46
> 200.1 NR 2.98 2.40,3.71
Stat Method: Multivariate model
Outcome: incident skin lesions
creatinine adjusted urinary arsenic
concentration, ng/g-creatinine
Exp. Level n HR (Cl)
7-88 NR 1 n/a
89-155 NR 0.9 0.71, 1.15
156-240 NR 1.34 1.07, 1.68
241-392 NR 1.62 1.29,2.02
>393 NR 2.39 1.92,2.97
Stat Method: Multivariate model
Outcome: melanoma skin cancer
cumulative arsenic exposure, mg
Exp. Level n IRR (Cl)
continuous NR 0.97 0.92, 1.03
Stat Method: Cox regression
Outcome: nonmelanoma skin cancer
cumulative arsenic exposure, mg
Exp. Level n IRR (Cl)
continuous NR 0.95 0.92, 0.97
Stat Method: Cox regression
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
n exposed: 56,378
n total: 57053
Barati et al. (2010)
Study Type: cross-
sectional
Location: Iran (Qorveh
and Bijar cities,
Kurdistan Province)
Population: Western
Iran residents with
prevalence of multi-
chronic arsenical
poisoning as indicated
by skin lesions,
gangrene toes and
fingers
n cases: 587
n control: n/a
Exposure Measures
not available
Exposure Surrogate: drinking water
Exposure Description: time-weighted
and cumulative arsenic concentrations
calculated for individuals based on
residential address and history from
Central Population Registry combined
with measurement data from nearest
water utility as recorded by Geological
Survey of Denmark and Greenland (1987-
2004)
Population-Level Exposure:
0.7 ng/L median
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations measured in 530 village
drinking water sources in the region;
individual exposures estimated using
village arsenic concentration
Population-Level Exposure:
42-1500 ng/L range
Results
Outcome: melanoma skin cancer
time-weighted average arsenic exposure, ug/L
Exp. Level n IRR (CD
continuous NR 0.89 0.73, 1.07
Stat Method: Cox regression
Outcome: nonmelanoma skin cancer
time-weighted average arsenic exposure, ug/L
Exp. Level n IRR (CD
continuous NR 0.88 0.81, 0.94
Stat Method: Cox regression
Outcome: depigmentation
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<50 1 1 n/a
51-200 48 9.19 1.18,71.01
201-500 42 10.34 1.33,80.62
>500 11 9.29 1.09,78.49
Stat Method: Mantel-Haenzel odds ratio
Outcome: gangrene
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<50 0 NR n/a
51-200 0 NR n/a
201-500 2 0.49 0.04,5.79
>500 3 2.31 0.22,24.31
Stat Method: Mantel-Haenzel odds ratio
Outcome: hyperpigmentation
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<50 1 1 n/a
51-200 54 10.31 1.33,79.72
201-500 39 9.61 1.23,74.99
>500 13 10.04 1.19,84.54
Stat Method: Mantel-Haenzel odds ratio
Outcome: keratosis
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Bhowmicketal. (2013)
Study Type: case-
control
Location: India (West
Bengal)
Population:
participants from cross-
sectional study carried
out in several villages
n cases: 64
n control: 37
Breton et al. (2006)
Exposure Measures
Exposure Surrogate: saliva
Exposure Description: saliva samples
collected at interview
Population-Level Exposure:
7.84 ng/L mean 12.6SD
Exposure Surrogate: urine
Exposure Description: participants
provided urine samples at interview
Population-Level Exposure:
110 |jg/L mean 154SD
Exposure Surrogate: toenails
Results
drinking water arsenic concentration, ng/L
Exp. Level n adiOR (CD
<50 3 1 n/a
51-200 75 3.85 1.10, 13.91
201-500 47 5 1.41, 17.73
>500 17 4.34 1.10, 17.42
Stat Method: Mantel-Haenzel odds ratio
Outcome: Mee's line
drinking water arsenic concentration, ng/L
Exp. Level n adiOR (CD
<50 2 1 n/a
51-200 82 7.83 1.75,34.94
201-500 54 6.65 1.45,30.05
>500 19 7.34 1.50,35.94
Stat Method: Mantel-Haenzel odds ratio
Outcome: Multi-chronic arsenical poisoning
cases
drinking water arsenic concentration, ng/L
Exp. Level n adiOR (CD
<50 NR 1 n/a
51-200 NR 1.96 0.56,6.85
201-500 NR 3.65 1.03, 12.93
>500 NR 5.93 1.51,23.25
Stat Method: Chi-square test, Mantel-Haenzel
odds ratio
Outcome: skin lesion severity score
salivary arsenic concentration, ng/L
Exp. Level n adiBeta (CD
continuous NR 0.09 0.05, 0.13
Stat Method: multiple regression
Outcome: skin lesion severity score
urinary arsenic concentration, ng/L
Exp. Level n adiBeta (CD
continuous NR 0.11 0.04, 0.17
Stat Method: multiple regression
Outcome: Skin lesions
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Study Type: case-
control
Location: Bangladesh
(Pabna district)
Population: Dhaka
Community Hospital
Trust clinic recruits
n cases: n/a
n control: n/a
Exposure Description: arsenic
concentration in toenail clippings
collected from every toe of each
participant; arsenic analyzed in five
replicate analyses
Population-Level Exposure:
3.7 ng/g median
toenail arsenic concentration,
Exp. Level n adjOR
continuous NR 1.79 1.52,2.10
Stat Method: Conditional logistic regression
spline model (main effects model)
Chen et al. (2003a)
Study Type: case-
control
Location: Taiwan
(Southwestern Taiwan)
Population: hospital
patients with skin
cancer or
fracture/cataract
n cases: 76
n control: 224
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated based on average
arsenic concentration of artesian well
water from the village in which subjects
lived
Population-Level Exposure:
0-15 mg/L - yr range
Outcome: Skin cancer
cumulative arsenic exposure, mg/L - yr
Exp. Level n adjOR M
0-2 NR 1 n/a
>2-15 NR 1.87 0.79,4.45
>15 NR 2.99 1.30,6.87
Stat Method: Multivariate logistic regression
Fatmi et al. (2009)
Study Type: cross-
sectional
Location: Pakistan
(Khairpur district, Sindh
province)
Population: residents
of three villages with
different levels of
exposure
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure calculated by arsenic level in
water source (weighted with proportion
drinking from each source) multiplied by
average drinking volume water and tea
per day multiplied by duration (years) of
drinking from same source per body
weight; water samples taken from
current drinking water sources and past
sources when available within same
village
Population-Level Exposure:
10-100 |jg/L-years/kg range
Outcome: arsenic skin lesions (arsenicosis)
cumulative arsenic exposure, ng/L-years/kg
Exp. Level
10-<50
50-<100
>100
n
NR
NR
NR
NR
Prev
5.7
11.8
56.5
38.5
M
n/a
n/a
n/a
n/a
Stat Method: estimated prevalence per 1,000
population accounting for complex survey
design (multi-stagecluster sampling)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-249 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Exposure Surrogate: urine
Exposure Description: arsenic
concentrations in urine spot samples
collected from all individuals with signs
of arsenic skin lesions (suspected cases)
and from two individuals (one male one
female) without any arsenic skin lesions
from each village
Population-Level Exposure:
10-100 ug/L range
Outcome: arsenic skin lesions (arsenicosis)
urinary arsenic concentration,
Exp. Level
10-<50
50-<100
>100
n
NR
NR
NR
NR
Prev
36.6
99.5
123.6
186
M
n/a
n/a
n/a
n/a
Stat Method: estimated prevalence per 1,000
population accounting for complex survey
design (multi-stagecluster sampling)
Fatmi et al. (2013)
Study Type: cross-
sectional
Location: Pakistan
(Gambat in Khairpur
district, Sindh province)
Population: residents
near Indus River
exposed to elevated
arsenic levels
n cases: 72
n control: 462
Exposure Surrogate: drinking water
Exposure Description:: arsenic
concentrations in drinking water based
on screening of 707 water sources
serving 610 households; results
compared to UNICEF survey for
consistency; high-risk water sources
randomly verified for arsenic level;
personal reporting of duration of
drinking from source
Population-Level Exposure:
50-400 ppb range
Outcome: arsenicosis
drinking water arsenic concentration, ppb
Exp. Level
>50-99
100-299
300-399
>400
2
47
10
13
PR
4.5
14.8
11.7
12.8
M
2.74, 6.26
10.88, 18.72
13.85, 20.23
9.24, 14.76
Stat Method: Prevalence
Gilbert-Diamond et al.
(2013)
Study Type: case-
control
Location: United States
(NH)
Population: residents
with invasive squamous
cell carcinoma
n cases: n/a
n control: n/a
Exposure Surrogate: urine
Exposure Description: urine samples
collected for cases and controls and
analyzed for urinary inorganic arsenic
Population-Level Exposure:
5.27 ug/L median, 3.38-8.52 ug/L 25th
percentile
Outcome: squamous cell carcinoma (SCC)
In-transformed total urinary arsenic, ug/L
Exp. Level n adjOR M
continuous 323 1.37 1.04, 1.80
Stat Method: generalized linear model with a
logit transform
In-transformed urinary inorganic arsenic, ug/L
Exp. Level n adjOR M
continuous 323 1.2 0.97, 1.49
Stat Method: generalized linear model with a
logit transform
total urinary arsenic (tertiles), ug/L
Exp. Level n adjOR
<3.36 323 1 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Guo et al. (2006b)
Study Type: case-
control
Location: Inner
Mongolia (Wuyuan
county)
Population: adults with
cutaneous lesions in
arsenic-affected village
n cases: 227
n control: 221
Guo et al. (2006a)
Study Type: cross-
sectional
Location: China
(Wuyuan county, Inner
Mongolia)
Population: residents
of high and low arsenic-
affected villages
n cases: 109
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water based
on samples collected in triplicate from
households using drinking water wells
Population-Level Exposure:
0-1354 ug/L range
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in water samples
collected from all tube wells used by
participants for at least 6 months in the
last 20 years (several subjects shared the
same wells); samples below the LOD
were assigned 0 ug/L
Population-Level Exposure:
50-197.3 ug/L range
Results
3.36-<5.31 323 0.94 0.60,1.45
>5.31 323 1.43 0.91,2.27
Stat Method: generalized linear model with a
logit transform
urinary inorganic arsenic (tertiles), ug/L
Exp. Level n adiOR (CD
<0.23 323 1 n/a
0.23 - <0.45 323 0.97 0.63, 1.48
> 0.45 323 1.27 0.82, 1.98
Stat Method: generalized linear model with a
logit transform
Outcome: keratosis
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<50 NR 1 n/a
51-199 NR 1.46 0.61,3.51
200-499 NR 0.92 0.45, 1.9
>500 NR 1.46 0.57,3.75
Stat Method: logistic regression
Outcome: pigment disorder
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<50 NR 1 n/a
51-199 NR 5.25 1.3,83.24
200-499 NR 10.97 1.5,79.95
>500 NR 10 1.39,71.77
Stat Method: logistic regression
Outcome: skin lesions
well water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<50 NR 1 n/a
51-99 NR 15.5 1.53,248.7
100-149 NR 16.1 3.73,69.63
>150 NR 25.7 6.43, 102.87
Stat Method: Logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
n control: 32
Guo et al. (2007)
Study Type: cross-
sectional
Location: Mongolia
region not available
Population: residents
of villages in the Hetao
Plain, Inner Mongolia
n cases: 680
n control: 189
Hall et al. (2006)
Study Type: case-
control (nested)
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study
(HEALS) participants
randomly selected and
members newly
diagnosed with skin
lesions
n cases: 303
n control: 849
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: arsenic samples
were taken from 94 water sources,
including wells; detection limit not
specified, but authors note reliability of
the method at <10 ng/L; arsenic
exposure determined by location of
village
Population-Level Exposure:
50-1860 ng/L range
Exposure Surrogate: blood
Exposure Description: arsenic
concentration in whole blood collected
and analyzed for each individual
Population-Level Exposure:
1.6-63.9 ng/L range
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration water samples from wells
collected at baseline; time-weighted
arsenic concentration based on drinking
duration and well concentration
(historical drinking source taken into
account)
Population-Level Exposure:
0.1-564 ng/L range
Results
Outcome: arsenic dermatosis
water arsenic concentration, ng/L
arsenic not significantly associated with
dermatosis
Outcome: skin lesions
arsenic concentration in blood (quintiles), ng/L
Exp. Level n IRR (CD
1.6-5.4 41 1 n/a
5.5-7.5 40 1.22 0.70,2.12
7.6-10.4 51 1.21 0.69,2.13
10.5-15 70 1.68 0.99,2.86
15.1-63.9 101 2.54 1.51,4.27
Stat Method: Cox proportional hazards
models
Outcome: skin lesions
arsenic concentration in water (quintiles), ng/L
Exp. Level n IRR (Cl)
0.1-7 48 1 n/a
8-38 31 0.92 0.50, 1.67
39-94 48 1.27 0.73,2.20
95-189 81 1.92 1.14,3.24
190-564 95 2.5 1.52,4.14
Stat Method: Cox proportional hazards
models
time-weighted arsenic concentration In water,
H9/L
Exp. Level n IRR (Cl)
0.1-7.9 40 1 n/a
8.0-41 35 1.14 0.61,2.11
42-94 51 1.44 0.81,2.58
95-175 58 1.66 0.94,2.93
176-564 101 2.85 1.66,4.89
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-252 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Stat Method: Cox proportional hazards
models
Exposure Surrogate: urine
Exposure Description: individual total
urinary arsenic concentration creatinine
adjusted (urinary arsenic concentration
not creatinine adjusted)
Population-Level Exposure:
3-1230 ug/L range
Outcome: skin lesions
arsenic concentration in urine (quintiles), ug/L
Exp. Level
3-35
36-64
65-113
114 -201
202-1230
36
54
54
68
91
IRR
1
1.63
1.73
2
3.16
M
n/a
0.92, 2.89
0.99, 3.02
1.13,3.56
1.73, 5.76
Stat Method: Cox proportional hazards
models
Hashim et al. (2013)
Study Type: cross-
sectional
Location: Cambodia
(Mekong River basin)
Population: residents
of high, medium, and
low arsenic-
contaminated areas
n cases: n/a
n control: n/a
Exposure Surrogate: hair
Exposure Description: arsenic
concentration in hair samples collected
from the nape of heads as close as
possible to the scalp, washed, and
analyzed for arsenic; arsenic recovery
rate was 94.8%; median hair As levels:
0.090, 0.240, and 4.81 ug/g for Kampong
Cham, Kratie, and Kandal, respectively
Population-Level Exposure:
not available
Outcome: hyperkeratosis
hair arsenic concentration (0.5-ng/g cutoff),
Exp. Level n Prev (CD
<0.5 5 1.97 n/a
>0.5 41 16.2 n/a
Stat Method: prevalence rate; method of
calculating significance not reported
hair arsenic concentration (1-ug/g cutoff), ug/g
Exp. Level n Prev (CD
<1 14 4.94 n/a
>1 32 18.82 n/a
Stat Method: prevalence rate; method of
calculating significance not reported
Outcome: hyperpigmentation
hair arsenic concentration (0.5-ug/g cutoff), ug/g
Exp. Level n Prev (CD
<0.5 7 2.76 n/a
>0.5 36 14.22 n/a
Stat Method: prevalence rate; method of
calculating significance not reported
hair arsenic concentration (1-ug/g cutoff), ug/g
Exp. Level n Prev (Cl)
<1 13 4.59 n/a
>1 30 17.64 n/a
Stat Method: prevalence rate; method of
calculating significance not reported
Outcome: hypomelanosis
hair arsenic concentration (0.5-ug/g cutoff), ug/g
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-253 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Exp. Level
<0.5
>0.5
Prev
M
n/a
n/a
13 5.13
63 24.9
Stat Method: prevalence rate; method of
calculating significance not reported
hair arsenic concentration (1-ng/g cutoff), u.g/g
Exp. Level n Prev (CD
<1 21 7.42 n/a
>1 55 32.35 n/a
Stat Method: prevalence rate; method of
calculating significance not reported
Outcome: mee's lines
hair arsenic concentration (0.5-ug/g cutoff), ug/g
Exp. Level n Prev (CD
<0.5 9 3.55 n/a
>0.5 24 9.48 n/a
Stat Method: prevalence rate; method of
calculating significance not reported
hair arsenic concentration (1-ng/g cutoff),
Exp. Level n Prev (Cl)
<1 14 4.94 n/a
>1 19 11.17 n/a
Stat Method: prevalence rate; method of
calculating significance not reported
Hsu et al. (2013a)
Study Type: cohort
(prospective)
Location: Taiwan
(Peimen, Hsuechia,
Putai, Ichu townships)
Population: 3 separate
subcohorts of residents
of an arseniasis-
endemic area
n exposed: 1075
n reference: 535
n total: 2447
Exposure Surrogate: drinking water
Exposure Description: lifetime
cumulative arsenic exposure estimated
using median arsenic concentration in
village well where study subject lived and
duration of exposure; arsenic
concentrations in wells obtained from 2
investigations examining more than
38,565 wells across Taiwan; lifetime
cumulative arsenic exposure (CAE)
estimated using median arsenic
concentration in village well where study
subject lived and duration of exposure
Population-Level Exposure:
1-20 mg/L-yr range
Outcome: hyperkeratosis with or without
hyperpigmentation
cumulative arsenic exposure, mg/L - yr
difference between mean arsenic exposure of
group with no arsenical skin lesions and this group
was statistically significant; means not reported
Outcome: hyperpigmentation only
cumulative arsenic exposure, mg/L - yr
difference between mean arsenic exposure of
group with no arsenical skin lesions and this group
was statistically significant; means not reported
Outcome: skin cancer (Bowen's disease or NMSC)
without hyperkeratosis
cumulative arsenic exposure, mg/L - yr
difference between mean arsenic exposure of
group with no arsenical skin lesions and this group
was statistically significant; means not reported
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-254 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Outcome: skin cancer and hyperkeratosis
cumulative arsenic exposure, mg/L - yr
difference between mean arsenic exposure of
group with no arsenical skin lesions and this group
was statistically significant; means not reported
Hsueh et al. (1995)
Study Type: cross-
sectional
Location: Taiwan (Putai
Township)
Population: residents
of Homei, Fuhsin, and
Hsingming villages
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: cumulative arsenic
exposure index, based on arsenic
concentration of well water (ppm) and
duration of water consumption (years)
for consecutive period of living in various
villages
Population-Level Exposure:
4-25 ppm-years range
Outcome: skin cancer
cumulative arsenic exposure, ppm-years
Exp. Level n adjOR M
<4 NR 1 n/a
5-24 NR 6.69 0.76,59.17
=>25 NR 9.05 1.06,77.27
Stat Method: multiple logistic regression;
multivariate-adjusted
Hsueh et al. (1997)
Study Type: cohort
(prospective)
Location: Taiwan (Putai
township)
Population: residents
of Homei, Fushin, and
Hsinming villages
n total: 654
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration in artesian well water for
each village obtained from a previous
report (~1960s)
Population-Level Exposure:
0-1.1 mg/L range
Outcome: skin cancer
average well water arsenic concentration, mg/L
Exp. Level
0
0.01-0.7
0.71-1.10
unknown
ri
1
12
13
7
M
n/a
0.42, 35.76
1.08, 65.5
0.55, 40.35
Stat Method: multivariate adjusted relative
risk using Cox's proportional hazards
regression method
Exposure Surrogate: drinking water
Exposure Description: individual
cumulative arsenic exposure based on
average arsenic concentration in drinking
water and cumulative arsenic exposure
from well water; residential history and
duration of well water consumption self-
reported; arsenic concentration in
artesian well water for each village was
obtained from a previous report (~1960s)
Population-Level Exposure:
not available
Outcome: skin cancer
cumulative arsenic exposure, mg/L - yr
Exp. Level
0
0.1-10.6
0.7-17.7
>17.7
unknown
1
2
5
18
7
M
n/a
0.25, 31.87
0.30, 22.90
0.95, 60.33
0.59, 44.41
Stat Method: multivariate adjusted relative
risk using Cox's proportional hazards
regression method
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-255 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Karagasetal. (2001)
Study Type: case-
control
Location: United States
(NH)
Population: individuals
with or without
squamous cell
carcinoma or basal cell
carcinoma
n cases: 871
n control: 524
Knobeloch et al. (2006)
Study Type: cross-
sectional
Location: United States
(Wl)
Population: residents
of 19 rural townships
with arsenic
contaminated private
drinking wells
n cases: n/a
n control: n/a
Leonard! et al. (2012)
Study Type: case-
control
Exposure Measures
Exposure Surrogate: toenails
Exposure Description: individual arsenic
concentrations based on toenail samples;
prior to analysis, nail samples were
carefully washed to remove external
contamination
Population-Level Exposure:
0.009-2.57 ng/g range
Exposure Surrogate: drinking water
Exposure Description: subjects
submitted samples from drinking water
source using provided kit
Population-Level Exposure:
2 |jg/L median, 1-3100 ng/L range
Exposure Surrogate: drinking water
Exposure Description: arsenic in drinking
water derived from measurements at
time of study and historical data when
Results
Outcome: basal cell carcinoma
toenail arsenic concentration, U.Q/Q
Exp. Level n adiOR (CD
0.009-0.089 281 1 n/a
0.090-0.133 156 1.01 0.76, 1.35
0.134-0.211 92 1.06 0.74, 1.51
0.212-0.280 22 0.72 0.40, 1.31
0.281-0.344 10 0.75 0.31, 1.81
0.345-0.81 26 1.44 0.74,2.81
Stat Method: logistic regression analysis
Outcome: Squamous cell carcinoma
toenail arsenic concentration, U.Q/Q
Exp. Level n adiOR (CD
0.009-0.089 155 1 n/a
0.090-0.133 64 0.93 0.64, 1.34
0.134-0.211 33 0.98 0.61, 1.58
0.212-0.280 14 1.1 0.55,2.21
0.281-0.344 5 1 0.33,3.01
0.345-0.81 13 2.07 0.92,4.66
Stat Method: logistic regression analysis
Outcome: skin cancer
drinking water arsenic concentration, ug/L
Exp. Level n adjOR (Cl)
<1.0 15 1 n/a
1-9.9 36 1.81 1.10,3.14
>10 23 1.92 1.01,3.68
Stat Method: multivariate logistic regression
Outcome: basal cell carcinoma
cumulative inorganic arsenic dose concentration
(quintiles), g
Exp. Level n adiOR (Cl)
0-0.01 NR 1 n/a
0.01-0.03 NR 1.09 0.72, 1.67
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-256 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Location: Hungary,
Romania, Slovakia
(Bacs-Kiskun, Bekes,
Csongrad, and Jasz-
Nagykun-Szolnok
counties (Hungary);
Arad and Bihor
counties (Romania);
Banska Bystrica county
(Slovakia))
Population: ASHRAM
(Arsenic Health Risk
Assessment and
Molecular
Epidemiology) study
participants with
chronic low-level
arsenic exposure
n cases: 529
n control: 540
Lewis et al. (1999)
Study Type: cohort
(retrospective)
Location: United States
(Millard County, Utah)
Population: male and
female members of
Latter-day Saints
church wards
n exposed: 2203
n total: 2203
Exposure Measures
available
Population-Level Exposure:
0-4.46 g range
Exposure Surrogate: drinking water
Exposure Description: arsenic in drinking
water derived from measurements at
time of study and historical data when
available; peak daily dose rate calculated
from the participant's residence with the
highest water inorganic arsenic
concentration
Population-Level Exposure:
0-242.14 u.g/day range
Exposure Surrogate: drinking water
Exposure Description: drinking water
samples collected at time of study or
historical data utilized when available
Population-Level Exposure:
1.2 u.g/L median, 0.7-13.8 u.g/L 25th
percentile
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentrations in drinking water
determined from Utah state records and
an EPA study; arsenic exposure index
score calculated individually based on
number of years residence in each
community and median drinking water
arsenic concentration in community
Population-Level Exposure:
3.5-620 ppb-years range
Results
0.03-0.13 NR 1.46 0.93,2.27
0.13-0.55 NR 1.76 1.02,3.04
0.55-4.46 NR 2.63 1.45,4.78
Stat Method: multivariable logistic regression
model
Outcome: basal cell carcinoma
peak dally Inorganic arsenic dose rate
concentration (quintiles), tig/day
Exp. Level n adiOR (CD
0-0.73 NR 1 n/a
0.73-1.48 NR 0.91 0.59, 1.39
1.48-9.09 NR 1.55 1,2.41
9.09-32.23 NR 1.76 1.01,3.07
32.23-242.14 NR 2.5 1.39,4.49
Stat Method: multivariable logistic regression
model
Outcome: basal cell carcinoma
lifetime time-weighted average inorganic arsenic
concentration (quintiles), ng/L
Exp. Level n adiOR (CD
0-0.68 NR 1 n/a
0.68-0.98 NR 1.39 0.89,2.19
0.98-7 NR 1.2 0.77, 1.88
7.1-19.43 NR 1.73 0.97,3.11
19.54-167.29 NR 3.03 1.70,5.41
Stat Method: multivariable logistic regression
model
Outcome: melanoma
cumulative arsenic exposure (females), ppb-years
Exp. Level n SMR (CD
<1000 NR 5.3 n/a
1000-4999 NR NR n/a
>5000 NR NR n/a
Stat Method: standardized mortality ratios
cumulative arsenic exposure (males), ppb-years
Exp. Level n SMR (CD
<1000 NR 0.72 n/a
1000-4999 NR 0.79 n/a
>5000 NR 1.06 n/a
Stat Method: standardized mortality ratios
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-257 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Li et al. (2013a)
Study Type: cross-
sectional
Location: China
(Tuoketuo County,
Inner Mongolia)
Population: residents
exposed to arsenic in
drinking water
n cases: n/a
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration of each tube well
measured and provided by local public
health government; cumulative arsenic
exposure (CAE) calculated for each
subject as: concentration in tube well
that subject used in his/her residential
duration multiplied by duration of water
consumption
Population-Level Exposure:
0-760 ng/L range
Outcome: skin lesions
water arsenic concentration, u.g/L
84 patients with skin lesions found in the >50-ng/L
group with symptoms of hyperpigmentation
and/or depigmentation on the trunk
Lindberg et al. (2008)
Study Type: case-
control (nested)
Location: Bangladesh
(Matlab)
Population: selected
members of Health and
Demographic
Surveillance System
(HDSS)
n cases: 504
n control: 528
Exposure Surrogate: drinking water
Exposure Description: cumulative
exposure calculated by summing up
arsenic concentration multiplied by
number of years of usage for all water
sources used since 1970
Population-Level Exposure:
1639-4107 |jg/L-year range
Outcome: Skin lesion cases
cumulative arsenic exposure concentration, u.g/L-
year
adjOR (CD
1 n/a
Exp. Level
<1639
1639-4107
>4107
NR
NR
NR
1.3
3.8
0.9, 2.0
2.7,5.5
Stat Method: Multivariate logistic regression
analysis
Exposure Surrogate: drinking water
Exposure Description: self-reported
water consumption history and water
sources used during each calendar year
since 1970 (or birth, if later than 1970);
water samples from all functional tube
wells collected; for surface water
drinking source, arsenic concentration
set to 0 ng/L; nonfunctioning wells
historical exposure reconstructed using
average tube well arsenic concentration
of village as proxy
Population-Level Exposure:
80-181 |jg/L range
Outcome: Skin lesion cases
average lifetime arsenic exposure concentration
(tertiles), ug/L
Exp. Level
<80
80-181
n
NR
NR
NR
M
n/a
0.98, 2.1
2.4, 4.8
Stat Method: Multivariate logistic regression
analysis
Exposure Surrogate: urine
Outcome: Skin lesion cases
percent urinary DMA metabolite concentration,
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-258 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Exposure Description: individual spot
urine samples analyzed for arsenic
speciation
Population-Level Exposure:
9.5-13 % range
Exp. Level
<76
76-82
>82
n
NR
NR
NR
M
n/a
0.28, 0.55
0.28, 0.60
Stat Method: Multivariate logistic regression
analysis
percent urinary inorganic arsenic metabolite
concentration, %
Exp. Level
<9.5
9.5-13
NR
NR
NR
M
n/a
0.65, 1.3
1.3, 2.6
Stat Method: Multivariate logistic regression
analysis
percent urinary MA metabolite concentration, %
Exp. Level n adjOR (CD
<7.9 NR 1 n/a
7.9-12 NR 1.1 0.74, 1.7
>12 NR 2.8 1.9,4.2
Stat Method: Multivariate logistic regression
analysis
Exposure Surrogate: urine
Exposure Description: spot urine
samples collected from individuals and
analyzed for arsenic metabolites
Population-Level Exposure:
51-124 ng/L range
Outcome: Skin lesion cases
sum of arsenic metabolites concentration in
urine, ug/L
Exp. Level
<51
51-124
>124
n
NR
NR
NR
M
n/a
0.51, 1.0
1.1,2.0
Stat Method: Multivariate logistic regression
analysis
Maden et al. (2011)
Study Type: cross-
sectional
Location: Nepal
(Nawalparasi district)
Population: residents
of program areas of
Exposure Surrogate: drinking water
Exposure Description: tubewell samples
collected from individual households;
total water arsenic calculated using
exposure duration (based on total age of
tubewell and years of residence);
exposure duration counted from 5 years
of age
Population-Level Exposure:
Outcome: arsenicosis cases
time weighted total arsenic concentration in
drinking water, u.g/L
Exp. Level n adiBeta (CD
continuous NR 2.132 n/a
Stat Method: binomial logistic regression;
stepwise backward strategic method
following parsimonious model
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-259 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Filters for Families (FFF)
in Jahada, Sarawal,
Sunawal, Sukrauli, and
Swati (development
communities) or
Ramgram
(municipality)
n cases: 120
n control: n/a
Mazumderetal. (1998)
Study Type: cross-
sectional
Location: India (West
Bengal)
Population: residents
of highly contaminated
South 24 Parganas
n cases: 7683
n control: n/a
Exposure Measures
50-50 ng/L range
Exposure Surrogate: drinking water
Exposure Description: water samples
collected from private and public tube
wells used for drinking and cooking for
each household; daily dose per body
weight computed by multiplying water
arsenic concentration by estimated daily
water intake (based on interview) and
dividing by body weight
Population-Level Exposure:
0-73.9 ng/kg-day range
Exposure Surrogate: drinking water
Exposure Description: water samples
collected from private and public
tubewells used for drinking and cooking
for each household
Population-Level Exposure:
0-3400 ng/L range
Results
Outcome: hyperpigmentation
daily arsenic dose per body weight concentration
(males and females), ng/kg-day
Exp. Level n SMR (CD
continuous NR 1.2 0.8, 1.8
Stat Method: Poisson distribution
Outcome: keratosis
daily arsenic dose per body weight concentration
(males and females), ng/kg-day
Exp. Level n SMR (CD
continuous NR 1.6 1, 2.4
Stat Method: Poisson distribution
Outcome: hyperpigmentation
arsenic concentration in drinking water
(females), \ig/L
Exp. Level n Prev (CD
<50 NR 0.3 n/a
50-99 NR 0.8 n/a
100-149 NR 5.7 n/a
150-199 NR 5.1 n/a
200-349 NR 6.5 n/a
350-499 NR 9.5 n/a
500-799 NR 5.3 n/a
> 800ng/L
> 800 NR 11.5 n/a
Stat Method: Chi-squared distribution
arsenic concentration in drinking water (males),
H9/L
Exp. Level n Prev (CD
<50 NR 0.4 n/a
50-99 NR 3.2 n/a
100-149 NR 11 n/a
150-199 NR 7.8 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-260 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
McDonald et al. (2007)
Study Type: case-
control
Location: Bangladesh
(rural Bangaldesh)
Population: women
living in villages
serviced and selected
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: tube well samples
collected from sources currently used by
subjects (three samples collected/source,
highest concentration used)
Population-Level Exposure:
0-166 ng/L range
Results
200-349 NR 13.1 n/a
350-499 NR 15.7 n/a
500-799 NR 13.8 n/a
> 800 NR 22.7 n/a
Stat Method: Chi-squared distribution
Outcome: keratosis
arsenic concentration in drinking water
(females), \ig/L
Exp. Level n Prev (CD
<50 NR 0 n/a
50-99 NR 0.4 n/a
100-149 NR 1.2 n/a
150-199 NR 2.3 n/a
200-349 NR 2 n/a
350-499 NR 2.7 n/a
500-799 NR 3.1 n/a
> 800ng/L
> 800 NR 8.3 n/a
Stat Method: Chi-squared distribution
arsenic concentration in drinking water (males),
H9/L
Exp. Level n Prev (CD
<50 NR 0.2 n/a
50-99 NR 1.5 n/a
100-149 NR 1.6 n/a
150-199 NR 4.7 n/a
200-349 NR 4.9 n/a
350-499 NR 9 n/a
500-799 NR 8.9 n/a
> 800 NR 10.7 n/a
Stat Method: Chi-squared distribution
Outcome: Skin lesions
arsenic concentration in drinking water, \ig/L
Exp. Level n OR (CD
0-10 NR 1 n/a
11-50 NR 1.33 0.77,2.28
>51 NR 2.96 1.02,8.59
Stat Method: Conditional logistic regression
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-261 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
by Gonoshashthaya
Kendra
n cases: 155
n control: 155
Melkonian et al. (2011)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: male
Health Effects of
Arsenic Longitudinal
Study (HEALS)
participants 6 year
follow-up
n exposed: 613
n reference: 3378
n total: 3991
Mitra et al. (2002)
Study Type: cross-
sectional
Location: Bangladesh
(Barisal)
Population:
dermatology
outpatients of Sher-e-
Bangla Medical College
Hospital
n cases: 123
n control: 27
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: exposure
characterized using well-water arsenic
concentration, daily intake of arsenic
from drinking water based on self-report
and primary drinking water source;
samples GFAA LOD (5 ng/L) reanalyzed
with inductively coupled plasma mass
spectrometry
Population-Level Exposure:
0.1-200.1 |jg/L range
Exposure Surrogate: urine
Exposure Description: exposure
characterized using creatinine-adjusted
urinary total arsenic concentration; spot
urine samples were obtained from 3,804
of the 3,991 subjects
Population-Level Exposure:
89-405 ng/g-creatinine range
Exposure Surrogate: drinking water
Exposure Description: water samples
from current tube wells used by the
study participants examined using
standard methods; exposure dose based
on self reported information of duration
of use of water at source
Population-Level Exposure:
0.5 mg/Lmean 0.21SD
Results
Outcome: skin lesions
well water arsenic concentration (quintiles), ng/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 1.08 0.85, 1.38
50.1-100 NR 1.52 1.19, 1.93
100.1-200 NR 1.86 1.48,2.32
> 200.1 NR 2.69 2.16,3.35
Stat Method: Multivariate log-linear
regression
Outcome: skin lesions
Urinary total arsenic (quintiles), ng/g-creatinine
Exp. Level n HR (CD
<89 NR 1 n/a
89.1-159 NR 0.89 0.70, 1.14
159.1-245 NR 1.28 1.02, 1.60
245.1-405 NR 1.38 1.10, 1.73
>405 NR 1.86 1.50,2.31
Stat Method: Multivariate log-linear
regression
Outcome: mild skin disease
drinking water arsenic concentration, mg/L
Exp. Level n Prev (CD
<0.50 22 82 n/a
0.51-0.99 4 15 n/a
>1.00 1 4 n/a
Stat Method: Chi-squared test
drinking water arsenic concentration, mg/L
Exp. Level n mean (Cl)
continuous NR 0.43 n/a
Stat Method: Mann-Whitney U-test
exposure dose (arsenic level x exposure time)
mg/L - yr, mg/L
Exp. Level n mean (Cl)
mg/L-yr NR 7.66 n/a
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-262 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Stat Method: Mann-Whitney U-test
Outcome: moderate and severe skin disease
drinking water arsenic concentration, mg/L
Exp. Level ri Prev (CD
<0.50 NR 66 n/a
0.51-0.99 NR 29 n/a
>1.00 NR 5 n/a
Stat Method: Chi-squared test
drinking water arsenic concentration, mg/L
Exp. Level n mean (Cl)
continuous NR 0.52 n/a
Stat Method: Mann-Whitney U-test
exposure dose (arsenic level x exposure time)
mg/L - yr, mg/L
Exp. Level n mean (Cl)
mg/L-yr NR 8.29 n/a
Stat Method: Mann-Whitney U-test
Mosaferi et al. (2008)
Study Type: cross-
sectional
Location: Iran
(Kurdistan province)
Population: residents
exposed to arsenic-
contaminated water in
Bijar County
n cases: 752
n control: n/a
Exposure Surrogate: drinking water
Exposure Description: total lifetime
intake of arsenic, based on arsenic levels
measured in villages once each season
for 4 testings) in the villages to obtain
mean annual concentration;
questionnaires used to determine water
source, consumption history, and
changes over time; concentration,
questionnaires, interviews and historical
data used to calculate total lifetime
intake of arsenic
Population-Level Exposure:
0-3 g range
Outcome: hyperkeratosis
total lifetime intake of arsenic, g
Exp. Level n adjOR {G}
continuous 49 1.14 1.039, 1.249
Stat Method: Logistic regression
Outcome: hyperpigmentation
total lifetime intake of arsenic, g
Exp. Level n adjOR {G}
continuous 20 1.254 1.112, 1.416
Stat Method: Logistic regression
Pei et al. (2013)
Study Type: cross-
sectional
Location: China (Shanxi
province)
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration, spot morning urine
samples collected; each sample
subjected to two replicate analyses
Population-Level Exposure:
Outcome: skin lesions
urinary arsenic concentration, ug/g-creatinine
Exp. Level n adjOR (Cl)
continuous NR 3.895 0.497,30.52
Stat Method: multiple regression analysis;
Spearman's rank correlation coefficient
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-263 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Population: residents
of arsenic endemic
rural region in Datong
n cases: 75
n control: 12
Pesola et al. (2012)
Study Type: cross-
sectional
Location: Bangladesh
(Araihazar)
Population: Health
Effects of Arsenic
Longitudinal Study
(HEALS) participants
n cases: n/a
n control: n/a
Pierce et al. (2011)
Study Type: cohort
(prospective)
Location: Bangladesh
(Araihazar)
Population: HEALS
participants in
Araihazar, Bangladesh
2000-2009
n total: 9677
Exposure Measures
not available
Exposure Surrogate: drinking water
Exposure Description: well water arsenic
concentration
Population-Level Exposure:
7-179 ng/L range
Exposure Surrogate: drinking water
Exposure Description: well water arsenic
concentrations; exposure categorized
into quintiles with adjustment to
corresponded to WHO guideline (10
Hg/L) and Bangladesh national standard
(50 ng/L); participants categorized by
quartiles of dietary intakes for 3
categories(gourd and root, vegetable,
and animal protein) as measured by food
frequency questionnaire
Population-Level Exposure:
0.1-200.1 ng/L range
Results
Outcome: skin lesions
well water arsenic concentration (quintiles), ng/L
Exp. Level n adiOR (CD
<7 NR 1 n/a
7-<39 NR 1.8 1.02,3.16
39-<91 NR 2.79 1.62,4.78
91-<179 NR 3.09 1.82,5.23
>179 NR 3.94 2.36,6.58
Stat Method: logistic regression; Chi-squared
test for trend
Outcome: incident skin lesions
water arsenic concentration by dietary pattern:
gourd and root quartile 1, ng/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 1.44 0.89,2.34
50.1-100 NR 2.26 1.42,3.6
100.1-200 NR 3.5 2.34,5.25
>200 NR 5.3 3.19,8.81
Stat Method: multivariate regression
water arsenic concentration by dietary pattern:
gourd and root quartile 2, ug/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 1.14 0.75, 1.75
50.1-100 NR 1.65 1.07,2.57
100.1-200 NR 1.8 1.23,2.65
>200 NR 3.19 2.00,5.09
Stat Method: multivariate regression
water arsenic concentration by dietary pattern:
gourd and root quartile 3, ug/L
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-264 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 1.22 0.45, 1.99
50.1-100 NR 1.58 0.97,2.59
100.1-200 NR 2.17 1.45,3.29
>200 NR 2.8 1.61,4.89
Stat Method: multivariate regression
water arsenic concentration by dietary pattern:
gourd and root quartile 4, ug/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 0.76 0.52, 1.4
50.1-100 NR 1.21 0.74, 1.98
100.1-200 NR 1.43 0.93,2.2
>200 NR 3.3 1.92,5.67
Stat Method: multivariate regression
water arsenic concentration by dietary pattern:
vegetable quartile 1, ug/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 0.96 0.55, 1.68
50.1-100 NR 1.48 0.88,2.48
100.1-200 NR 2.63 1.69,4.12
>200 NR 5.68 3.39,9.52
Stat Method: multivariate regression
water arsenic concentration by dietary pattern:
vegetable quartile 2, ug/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 1.36 0.89,2.09
50.1-100 NR 1.75 1.14,2.7
100.1-200 NR 1.89 1.26,2.83
>200 NR 3.72 2.23,6.21
Stat Method: multivariate regression
water arsenic concentration by dietary pattern:
vegetable quartile 3, ug/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 1.39 0.87,2.24
50.1-100 NR 1.66 1.02,2.71
100.1-200 NR 2.28 1.53,3.4
>200 NR 2.9 1.69,5
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-265 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Rahman et al. (2006a)
Study Type: case-
control
Location: Bangladesh
(Matlab)
Population: individuals
drinking water from
arsenic-contaminated
tube wells
n cases: 504
n control: 1830
Exposure Measures
Exposure Surrogate: drinking water
Exposure Description: average arsenic
exposure concentration; individuals
provided information on water
consumption history from 1970 (or birth
if after 1970); samples were obtained
from all functioning tube wells, with
village concentration used as proxy if
well samples unavailable; surface waters
assigned a concentration of 0 ng/L;
arsenic concentrations were imputed for
migrants
Population-Level Exposure:
10-300 ng/L range
Exposure Surrogate: drinking water
Exposure Description: individuals
provided information on water
consumption history from 1970 (or birth
if after 1970); reported information was
validated using household economic
surveys with information of sources of
drinking water; samples were obtained
from all functioning tube wells; if tube
well samples unavailable village
concentration was used as proxy; surface
Results
Stat Method: multivariate regression
water arsenic concentration by dietary pattern:
vegetable quartile 4, ug/L
Exp. Level n HR (CD
0.1-10 NR 1 n/a
10.1-50 NR 0.82 0.49, 1.36
50.1-100 NR 1.78 1.13,2.79
100.1-200 NR 1.96 1.35,2.85
>200 NR 2.39 1.43,3.97
Stat Method: multivariate regression
Outcome: as-related skin lesions
average arsenic exposure concentration
(quintiles; females), ug/L
Exp. Level n adjOR (Cl)
<10 12 1 n/a
10-49 15 1.66 0.65,4.24
50-149 65 3.06 1.39,6.74
150-299 84 4.08 1.86,8.93
> 300 56 6.88 3.06, 15.5
Stat Method: multivariate logistic regression
average arsenic exposure concentration
(quintiles;males), ug/L
Exp. Level n adiOR (Cl)
<10 13 1 n/a
10-49 38 3.25 1.43,7.38
50-149 59 2.28 1.04,4.98
150-299 110 5.41 2.52, 1.62
>300 52 9.56 4.20,21.8
Stat Method: multivariate logistic regression
Outcome: as-related skin lesions
cumulative arsenic exposure concentration
(females), ng/L-year
Exp. Level n adiOR (Cl)
<1000 22 1 n/a
1000-4999 78 1.94 1.1,3.42
5000-9999 87 4.5 2.54,7.99
>10000 45 9.19 4.77, 17.7
Stat Method: multivariate logistic regression
cumulative arsenic exposure concentration
(males), ug/L-year
Exp. Level n adiOR (Cl)
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
waters were assigned a concentration of
0 |jg/L; arsenic concentrations were
imputed for migrants
Population-Level Exposure:
1000-10000 ng/L-year range
<1000
1000-4999
5000-9999
>10000
37
75
119
41
NR
1
1.05
4.5
10.4
NR
n/a
0.65, 1.68
2.80, 7.22
5.27, 20.5
n/a
>300
Stat Method: multivariate logistic regression
Ranft et al. (2003)
Study Type: case-
control
Location: Slovakia
region not available
Population: Residents
of Prievidza District
living in vicinity of coal-
burning power plant
n cases: 210
n control: 201
Exposure Surrogate: soil
Exposure Description: arsenic
concentrations in soil and house dust
collected from random sample of
participants' households
Population-Level Exposure:
0.7-139 ng/g range
Outcome: nonmelanoma skin cancer
arsenic concentration in soil, ug/g
Exp. Level n stepwis (CD
e
multipl
e
regress!
on
means ratio NR 1.18 n/a
Stat Method: stepwise regression analysis
Exposure Surrogate: urine
Exposure Description: urinary arsenic
concentration; spot urine samples
provided at interview; population-level
exposure numbers reported are for
creatinine-corrected sum As
Population-Level Exposure:
6.07 ng/Lgeo mean, 1.79SD, 6.07-1.79
Outcome: nonmelanoma skin cancer
urinary arsenic concentration, u.g/L
Exp. Level n stepwis (CD
e
multipl
e
regressi
on
continuous 210 1.12 n/a
Stat Method: stepwise regression analysis
Seowetal. (2012)
Study Type: cohort
(prospective)
Location: Bangladesh
(Pabna)
Population: individuals
with arsenic-related
skin lesions
n total: 550
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration in water, water samples
collected from each participant's primary
drinking source and data collected on
drinking habits, water source, length of
use; baseline data collected 2001-2003;
samples collected again at follow up
(2009-2011)
Population-Level Exposure:
not available
Outcome: skin lesion recovery
loglO water arsenic concentration (decrease
between baseline and follow-up), u.g/L
Exp. Level n adjOR M
continuous NR 1.22 0.85, 1.78
Stat Method: logistic regression
loglO water arsenic concentration (baseline),
Exp. Level n adjOR (CD
continuous NR 0.59 0.41, 0.81
Stat Method: logistic regression
Outcome: skin lesion severity reduction
loglO water arsenic concentration (decrease
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
between baseline and follow-up), \JLQ/\.
Exp. Level n ad I Beta (CD
continuous NR -0.7 -2.18,0.78
Stat Method: linear regression GEE
loglO water arsenic concentration (baseline),
Exp. Level n ad i Beta (CD
continuous NR -1.34 -2.85,0.18
Stat Method: linear regression GEE
Exposure Surrogate: toenails
Exposure Description: arsenic
concentration in nail clippings collected
from each participant and sonicated to
remove contaminants; baseline data
collected 2001-2003; samples collected
again at follow up (2009-2011)
Population-Level Exposure:
not available
Outcome: skin lesion recovery
loglO toenail arsenic concentration (baseline),
Exp. Level n adjOR (CD
continuous NR 0.2 0.08, 0.44
Stat Method: logistic regression
loglO toenail arsenic concentration (decrease
between baseline and follow-up), u.g/g
Exp. Level n adjOR M
continuous NR 4.49 1.94, 11.1
Stat Method: logistic regression
Outcome: skin lesion severity reduction
loglO toenail arsenic concentration (baseline),
Exp. Level n ad i Beta (CD
continuous NR -0.09 -3.41, 3.22
Stat Method: linear regression GEE
loglO toenail arsenic concentration (decrease
between baseline and follow-up), u.g/g
Exp. Level n ad i Beta (CD
continuous NR -5.22 -8.61,-1.82
Stat Method: linear regression GEE
Xia et al. (2009)
Study Type: cross-
sectional
Location: China
(Bayingnormen, Shahai
village)
Exposure Surrogate: drinking water
Exposure Description: arsenic
concentration in drinking water;
exposure calculated from single well
water sample collected from each
household
Outcome: Skin lesions
drinking water arsenic concentration, ug/L
Exp. Level
0-5
5.1-10
10.1-20
20.1-50
50.1-100
100.1-300
NR
NR
NR
NR
NR
NR
M
n/a
1.47, 4.30
1.773, 4.525
2.78, 5.59
4.05, 8.97
5.77, 13.51
These draft development materials are for review purposes only and do not constitute Agency policy.
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-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Observational Epidemiology Studies for Health Effect Category: Skin Diseases
Reference and Study
Design
Exposure Measures
Results
Population: adults and
children living in
arseniasis-endemic
village
n cases: 11416
n control: n/a
Population-Level Exposure:
37.94 ng/L mean
>300 NR 7.94 2.73,23.12
Stat Method: logistic regression model
--: not reported; n: number of cases (when presented in Results column)
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Studies for Health Effect Category: Skin Diseases
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These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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http://dx.doi.org/10.1289/ehp.1205381
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Xia. Y: Wade. TJ: Wu. K: Li. Y: Nine. Z: Le. XC: He. X: Chen. B: Feng. Y: Mumford. JL. (2009). Well water
arsenic exposure, arsenic induced skin-lesions and self-reported morbidity in Inner Mongolia. Int J Environ
Res Public Health 6: 1010-1025. http://dx.doi.org/10.3390/iierph6031010
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 5-272 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
6 SUMMARY OF RISK OF BIAS EVALUATIONS FOR INORGANIC ARSENIC
ANIMAL STUDIES
6.1 Risk of Bias Overview - Developmental Effects including Neurodevelopmental
Study
Aaaarwal et al. (2007)
Ahmad etal. (2013)
Chattopadhvav et al. (2002)
Colomina etal. (1997)
Gandhi etal. (2012)
Markowski et al. (2012)
Martinez et al. (2008)
Martinez-Finley et al.
(2009)
Nagaraia and Desiraiu (1993)
Nagymaitenyi et al. (1985)
Ramsevetal. (2013c)
Primary (P) or
SuDDortins (SI
P
P
S
P
P
P
P
P
P
P
P
Selection
Randomization
+
-
-
+
-
++
-
-
-
-
-
Allocation
Concealment
+
-
-
+
-
+
-
-
-
-
-
a
|
O
£H
0
VI
&
a
g
0
U
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Confounding
Confounding
(Design)
+
++
-
++
-
++
+
-
+
+
+
Unintended
Exposure
+
-
+
+
+
+
+
+
+
+
+
Performance
Experimental
Conditions
+
++
+
++
+
++
++
++
+
+
+
Protocol
Deviations
+
+
+
+
+
+
+
+
+
+
+
Blinding (During
Study)
+
+
+
+
+
+
+
+
+
+
+
Att.
Missing Outcome
Data
++
++
-
++
+
-
-
-
+
-
Detection
«1
si i
li
ss«
-
+
-
++
++
+
++
+
-
+
Confounding
(Analysis)
+
+
n/a
+
+
+
+
+
-
+
+
Exposure
Characterization
+
++
-
+
-
+
+
++
-
-
+
Outcome
Assessment
+
+
-
-
++
++
+
+
-
-
+
SRB
Outcome
Reporting
++
-
++
++
+
++
+
++
-
++
+
Other
Internal Validity
++
++
-
++
+
++
+
++
+
-
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
6-1 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Study
Rodriauez et al. (2002)
Xi et al. (2009)
L. *"
0 <£
Primary (P
Supporting
P
P
Selection
Randomization
-
+
Allocation
Concealment
-
+
§
Comparison Gi
n/a
n/a
Confounding
Confounding
(Design)
+
-
Unintended
Exposure
+
+
Performance
Experimental
Conditions
+
++
Protocol
Deviations
+
+
60
3
If
P3 c/}
+
+
Att.
s
0
o
-» »
O
60
| |
S Q
+
-
Detection
Blinding
(Outcome
+
-
Confounding
(Analysis)
+
+
a
Exposure
Characterizatio
-
+
Outcome
Assessment
+
SRB
Outcome
Reporting
++
++
Other
Internal Validit
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
6-2 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
6.2 Risk of Bias Overview - Immune System and Lymphatic Effects
Study
Dasetal. (2012b)
Kozul et al. (2009)
NainandSmits(2012)
Ramsevetal. (2013b)
Sankaretal. (2013)
Stepnik et al. (2009)
Tokaretal. (201 Ob)
Waalkes et al. (2003)
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Primary (P) or
SiiDDOiiine (SI
P
P
P
P
P
P
P
P
P
P
Selection
Randomization
++
-
+
-
+
-
+
+
+
+
Allocation
Concealment
+
-
+
-
+
-
+
+
+
+
a
|
0
£H
0
VI
&
a
g
0
O
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Confounding
Confounding
(Design)
+
+
+
+
+
+
+
++
++
++
Unintended
Exposure
+
+
+
+
+
+
+
+
+
+
Performance
Experimental
Conditions
+
++
+
+
+
++
+
++
++
++
Protocol
Deviations
+
+
+
+
+
+
+
+
+
+
Blinding (During
Study)
+
+
+
+
+
+
+
+
+
+
Att.
Missing Outcome
Data
-
-
-
++
++
++
++
++
++
++
Detection
«1
si i
li
ss«
+
+
++
++
+
+
++
++
++
++
Confounding
(Analysis)
+
+
+
+
+
+
+
+
+
+
Exposure
Characterization
+
-
+
-
-
-
-
+
+
+
Outcome
Assessment
+
+
++
+
++
+
+
+
++
++
SRB
Outcome
Reporting
+
++
+
++
+
++
+
+
+
+
Other
Internal Validity
++
++
++
++
++
++
++
++
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
6-3 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
6.3 Risk of bias Overview - Liver Effects
Study
NainandSmits(2012)
Stepnik et al. (2009)
Tokaretal. (201 Ob)
TokaretaU20in
Tokaretal. (2012)
Waalkes et al. (2003)
Waalkes et al. (2004W
Waalkes et al. (2006a)
Waalkes et al. (2006b)
Primary (P) or
SuDDortins (SI
P
P
P
P
P
P
P
P
P
Selection
Randomization
+
-
+
-
+
+
+
+
+
Allocation
Concealment
+
-
+
-
+
+
+
+
+
Comparison Group
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Confounding
Confounding
(Design)
+
+
+
++
+
++
++
++
++
Unintended
Exposure
+
+
+
+
+
+
+
+
+
Performance
Experimental
Conditions
+
++
+
+
+
++
++
++
++
Protocol
Deviations
+
+
+
+
+
+
+
+
+
60
c
Q,
?
1?
PQ £
+
+
+
+
+
+
+
+
+
Att.
Missing Outcome
Data
-
++
++
++
++
++
+
++
++
Detection
«!
si i
11 1
ss«
++
+
++
++
++
++
++
++
++
Confounding
(Analysis)
+
+
+
+
+
+
+
+
+
Exposure
Characterization
+
-
-
+
+
+
-
+
+
Outcome
Assessment
++
+
+
++
++
+
++
++
++
SRB
Outcome
Reporting
+
++
+
+
+
+
++
+
+
Other
Internal Validity
++
++
++
++
++
++
++
++
++
April 2014
These draft development materials are for review purposes only and do not constitute Agency policy.
6-4 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
6.4 References for Risk of Bias Evaluations for Annimal
Toxicology Studies
Aggarwal. M: Wangikar. PB: Sarkar. SN: Rao. GS: Kumar. D: Dwivedi P: Malik. JK. (2007). Effects of low-
level arsenic exposure on the developmental toxicity of anilofos in rats. J Appl Toxicol 27: 255-261.
http://dx.doi.org/10.1002/iat. 1203
Ahmad. M: Wadaan. MAM: Farooq. M: Daghestani. MH: Samj AS. (2013). Effectiveness of zinc in modulating
perinatal effects of arsenic on the teratological effects in mice offspring. Biol Res 46: 131-138.
http://dx.doi.org/10.4067/S0716-97602013000200003
Chattopadhyav. S: Bhaumik. S: Nag Chaudhury. A: Das Gupta. S. (2002). Arsenic induced changes in growth
development and apoptosis in neonatal and adult brain cells in vivo and in tissue culture. Toxicol Lett 128:
73-84. http://dx.doi.org/10.1016/s0378-4274(01)00535-5
Colomina. MT: Albina. ML: Domingo. JL: Corbella. J. (1997). Influence of maternal stress on the effects of
prenatal exposure to methylmercury and arsenic on postnatal development and behavior in mice: A
preliminary evaluation. Physiol Behav 61: 455-459. http://dx.doi.org/10.1016/S0031-9384(96)00462-3
Das. TK: Mani. V: Kaur. H: Kewalramanj N: De. S: Hossain. A: Banerjee. D: Datta. BK. (2012). Effect of
vitamin E supplementation on arsenic induced oxidative stress in goats. Bull Environ Contam Toxicol 89:
61-66. http://dx.doi.org/10.1007/s00128-012-0620-0
Gandhi. DN: Panchal GM: Patel KG. (2012). Developmental and neurobehavioural toxicity study of arsenic on
rats following gestational exposure. Indian J Exp Biol 50: 147-155.
Kozul CD: Ely. KH: Enelow. RI: Hamilton. JW. (2009). Low dose arsenic compromises the immune response
to influenza A infection in vivo. Environ Health Perspect 117: 1441-1447.
http://dx.doi.org/10.1289/ehp.0900911
Markowskj VP: Reeve. EA: Onos. K: Assadollahzadeh. M: McKay. N. (2012). Effects of prenatal exposure to
sodium arsenite on motor and food-motivated behaviors from birth to adulthood in C57BL6/J mice.
Neurotoxicol Teratol 34: 221-231. http://dx.doi.0rg/10.1016/i.ntt.2012.01.001
Martinez-Finlev. EJ: Ali. AMS: Allan. AM. (2009). Learning deficits in C57BL/6J mice following perinatal
arsenic exposure: Consequence of lower corticosterone receptor levels. Pharmacol Biochem Behav 94: 271-
277. http://dx.doi.0rg/10.1016/i.pbb.2009.09.006
Martinez. EJ: Kolb. BL: Bell A: Savage. DP: Allan. AM. (2008). Moderate perinatal arsenic exposure alters
neuroendocrine markers associated with depression and increases depressive-like behaviors in adult mouse
offspring. Neurotoxicology 29: 647-655. http://dx.doi.0rg/10.1016/i.neuro.2008.05.004
Nagaraia. TN: Desiraiu. T. (1993). Regional alterations in the levels of brain biogenic amines, glutamate,
GAB A, and GAD activity due to chronic consumption of inorganic arsenic in developing and adult rats. Bull
Environ Contam Toxicol 50: 100-107. http://dx.doi.org/10.1007/BF00196547
Nagymajtenyi. L: Selypes. A: Berencsi G. (1985). Chromosomal aberrations and fetotoxic effects of
atmospheric arsenic exposure in mice. J Appl Toxicol 5: 61-63. http://dx.doi.org/10.1002/iat.2550050204
Nain. S: Smits. JE. (2012). Pathological, immunological and biochemical markers of subchronic arsenic toxicity
in rats. Environ Toxicol 27: 244-254. http://dx.doi.org/10.1002/tox.20635
Ramsey. KA: Foong. RE: Sly. PD: Larcombe. AN: Zosky. GR. (2013a). Early life arsenic exposure and acute
and long-term responses to influenza a infection in mice. Environ Health Perspect 121: 1187-1193.
http://dx.doi.org/10.1289/ehp.1306748
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 6-5 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Ramsey. KA: Larcombe. AN: Sly. PD: Zosky. GR. (2013b). In utero exposure to low dose arsenic via drinking
water impairs early life lung mechanics in mice. Pharmacol Toxicol 14: 13. http://dx.doi.org/10.1186/2050-
6511-14-13
Rodriguez. VM: Carrizales. L: Mendoza. MS: Faiardo. OR: Giordano. M. (2002). Effects of sodium arsenite
exposure on development and behavior in the rat. Neurotoxicol Teratol 24: 743-750.
http://dx.doi.org/10.1016/S0892-0362(02)00313-6
Sankar. P: Telang. AG: Suresh. S: Kesavan. M: Kannan. K: Kalaivanan. R: Sarkar. SN. (2013).
Immunomodulatory effects of nanocurcumin in arsenic-exposed rats. Int Immunopharmacol 17: 6570.
http://dx.doi.0rg/10.1016/i.intimp.2013.05.019
Stepnik. M: Stetkiewicz. J: Krainow. A: Domeradzka. K: Gradecka-Meesters. D: Arkusz. J: Stanczyk. M: Palus.
J: Dziubaltowska. E: Sobala. W: Gromadzinska. J: Wasowicz. W: Rydzynskj K. (2009). Carcinogenic effect
of arsenate in C57BL/6J/Han mice and its modulation by different dietary selenium status. Ecotoxicol
Environ Saf 72: 2143-2152. http://dx.doi.0rg/10.1016/i.ecoenv.2009.06.005
Tokar. EJ: Diwan. BA: Waalkes. MP. (2010). Arsenic exposure in utero and nonepidermal proliferative response
in adulthood in Tg.AC mice. Int J Toxicol 29: 291-296. http://dx.doi.org/10.1177/1091581810362804
Tokar. EJ: Diwan. BA: Waalkes. MP. (2012). Renal, hepatic, pulmonary and adrenal tumors induced by prenatal
inorganic arsenic followed by dimethylarsinic acid in adulthood in GDI mice. Toxicol Lett 209: 179-185.
http://dx.doi.0rg/10.1016/i.toxlet.2011.12.016
Tokar. EJ: Diwaa BA: Ward. JM: Delker. DA: Waalkes. MP. (2011). Carcinogenic effects of "whole-life"
exposure to inorganic arsenic in GDI mice. Toxicol Sci 119: 73-83. http://dx.doi.org/10.1093/toxsci/kfq315
Waalkes. MP: Liu. J: Ward. JM: Diwan. BA. (2006a). Enhanced urinary bladder and liver carcinogenesis in
male GDI mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen.
Toxicol Appl Pharmacol 215: 295-305. http://dx.doi.0rg/10.1016/i.taap.2006.03.010
Waalkes. MP: Liu. J: Ward. JM: Powell DA: Diwan. BA. (2006b). Urogenital carcinogenesis in female GDI
mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment. Cancer
Res 66: 1337-1345. http://dx.doi.org/10.1158/0008-5472.CAN-05-3530
Waalkes. MP: Ward. JM: Diwan. BA. (2004). Induction of tumors of the liver, lung, ovary and adrenal in adult
mice after brief maternal gestational exposure to inorganic arsenic: Promotional effects of postnatal phorbol
ester exposure on hepatic and pulmonary, but not dermal cancers. Carcinogenesis 25: 133-141.
http://dx.doi.org/10.1093/carcin/bggl81
Waalkes. MP: Ward. JM: Liu. J: Diwan. BA. (2003). Transplacental carcinogenicity of inorganic arsenic in the
drinking water: Induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. Toxicol Appl
Pharmacol 186: 7-17. http://dx.doi.org/10.1016/S0041-008X(02)00022-4
Xi. S: Sun. W: Wang. F: Jin. Y: Sun. G. (2009). Transplacental and early life exposure to inorganic arsenic
affected development and behavior in offspring rats. Arch Toxicol 83: 549-556.
http://dx.doi.org/10.1007/s00204-009-0403-5
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 6-6 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
7 EVIDENCE TABLES FOR INORGANIC ARSENIC
ANIMAL STUDIES
7.1 Summary of Observational Animal Studies for Health
Effect Category: Developmental Effects including
Neurodevelopmental
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
Results by Endpoint
(Aggarwal et al., 2007)
Dosing Design: reproductive/developmental
Chemical: Sodium Arsenite - NaAsO2
Species and Strain: rat, Wistar
Route of Exposure: oral - gavage
Administered Doses: Fl, combined (73-
90/group): 0,1 mg/kg /day
Dosing Description: PO dams dosed daily from
GD6 through GDIS
crown-rump length
Generation, Sex Dose(n) Response (cm±SE)
Fl, Combined 0(89) 3.74(±0.1)
1 (72) 3.54(±0.09)
no statistically significant effect on crown-rump length
observed up to 1 mg/kg/day exposure
fetal weight
Generation, Sex Dose(n) Response (g±SE)
Fl, Combined 0(89) 4.12(±0.08)
1(72) 4.05(±0.1)
no statistically significant effect on fetal weight observed
up to 1 mg/kg/day exposure
gross anomalies
Generation, Sex
Fl, Combined
Response (%)
8.89
32.88*
skeletal anomalies
Generation, Sex
Fl, Combined
Response (%)
12.5
21.05*
visceral anomalies
Generation, Sex Dose(n) Response (%)
Fl, Combined 0 (42) 0
1 (35) 0
no statistically significant effect on visceral anomalies
observed up to Img/kg/day exposure
(Ahmad et al., 2013)
Dosing Design: reproductive/developmental
Chemical: sodium arsenate - Na2HAsO4
Species and Strain: mice, Swiss Webster
Route of Exposure: oral - water
Administered Doses: Fl, combined (21/group): 0,
40 mg/kg body weight/day; Fl, male (NR): 0, 40
cliff avoidance
Generation, Sex
Fl, Combined
40 mg/kg-bw/day arsenic had significant (p<0.05 or
p<0.01) suppressive effect on mean cliff avoidance at each
observation (PND 1-21)
immobility duration
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-1 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
mg/kg body weight/day
Dosing Description: PO dams dosed daily from
GDO through PND15
(Gandhi etal., 2012)
Dosing Design: reproductive/developmental
Chemical: arsenic
Species and Strain: rat, Wistar
Route of Exposure: oral - gavage
Administered Doses: Fl, combined (20/group): 0,
1.5, 3, 4.5 mg/kg
Results by Endpoint
Generation, Sex Dose(n) Response
(seconds)
Fl, Male 0 (10) 73.5
40 (10) 208*
movement duration
Generation, Sex Dose(n) Response
(seconds)
Fl, Male 0 (10) 226.5
40 (10) 92.5*
number of rears
Generation, Sex Dose(n) Response
(median)
Fl, Male 0 (10) 15
40 (10) 5*
number of squares crossed
Generation, Sex Dose(n) Response
(median)
Fl, Male 0 (10) 371
40 (10) 128*
number of wall rears
Generation, Sex Dose(n) Response
(median)
Fl, Male 0 (10) 33
40 (10) 9*
number of washes
Generation, Sex Dose(n) Response
(median)
Fl, Male 0 (10) 6
40 (10) 7
righting reflex
Generation, Sex
Fl, Combined
40 mg/kg-bw/day arsenic had significant (p<0.05 or
p<0.01) suppressive effect on mean righting reflex at each
observation (PND 1-21)
rotating reflex
Generation, Sex
Fl, Combined
40 mg/kg-bw/day arsenic had significant (p<0.05 or
p<0.01) suppressive effect on mean rotating reflex at each
observation (PND 1-21)
cliff avoidance observed
Generation, Sex Dose(n) Response
(PNDiSE)
Fl, Combined 0 (20) 11(±0.3)
1.5 (20) 11(±0.25)
3 (20) 10.8(±1.27)
4.5 (20) 10.76(±1.24)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-2 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
Results by Endpoint
Dosing Description: PO dams dosed daily from
GD8 through PNDO
no statistically significant effect on cliff avoidance
observed up to 4.5 mg/kg
developmental milestones
Generation, Sex
Fl, Combined
no statistically significant effect on day of pinna
detachment, incisors eruption, fur development, eye
opening, ear opening, testes decent, or vaginal opening
observed up to 4.5 mg/kg
ear twitch observed
Generation, Sex
Fl, Combined
0(20)
1.5 (20)
3(20)
4.5 (20)
Response
(PNDiSE)
24.48(±0.18)
24.44(±0.2)
24.6(±0.91)
24.76(±0.92)
no statistically significant effect on ear twitch observed up
to 4.5 mg/kg
free fall righting observed
Generation, Sex
Fl, Combined
0(20)
1.5 (20)
3(20)
4.5 (20)
Response
(PNDiSE)
24.44(±0.25)
24.36(±0.88)
24.48(±0.26)
24.36(±0.29)
no statistically significant effect on free fall righting
observed up to 4.5 mg/kg
limb withdrawal reflexes observed
Generation, Sex
Fl, Combined
0(20)
1.5 (20)
3(20)
4.5 (20)
Response
(PNDiSE)
23.6(±0.91)
24(±0.18)
23.56(±0.17)
23.3(±1)
no statistically significant effect on limb withdrawal
reflexes observed up to 4.5 mg/kg
morphological anomalies
Generation, Sex
Fl, Combined
no statistically significant effect on morphological
anomalies observed up to 4.5 mg/kg
muscular grip strength
Generation, Sex
Fl, Combined
0(20)
1.5 (20)
3(20)
4.5 (20)
Response (sec
@9RPM±SE)
273.8(±1.5)
270.9(±1.1)
271.5(±1.3)
270.8(±2.5)
no statistically significant effect on muscular grip strength
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-3 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
(Markowskietal.,2012)
Results by Endpoint
observed up to 4.5 mg/kg
open field activity
Generation, Sex
Fl, Combined
no statistically significant effect on head elevation, hind
limb elevation, rearing, fecal boluses, urination, grooming,
sniffing, biting and licking, head bobbing, auditory startle,
pivoting, or gait abnormality observed up to 4.5 mg/kg
palmar grasp observed
Generation, Sex Dose(n) Response
(PNDiSE)
Fl, Combined 0 (20) 17.6(±0.25)
1.5 (20) 17.44(±0.28)
3 (20) 17.36(±0.9)
4.5 (20) 17.5(±0.6)
no statistically significant effect on palmar grasp observed
up to 4.5 mg/kg
startle reflex observed
Generation, Sex Dose(n) Response
(PNDiSE)
Fl, Combined 0 (20) 25.08(±0.33)
1.5 (20) 24.96(±0.37)
3(20) 25.12(±0.37)
4.5 (20) 25.04(±0.35)
no statistically significant effect on startle reflex observed
up to 4.5 mg/kg
surface righting reflex
Generation, Sex
Fl, Combined
no statistically significant effect on surface righting reflex
observed up to 4.5 mg/kg
T-maze
Generation, Sex Dose(n) Response (%)
Fl, Combined 0 (20) 100
1.5 (20) 99.91
3 (20) 99.54
4.5 (20) 99.56
no statistically significant effect on spontaneous activity in
the T-maze evaluation up to 4.5 mg/kg
tail pinch observed
Generation, Sex Dose(n) Response
(PNDiSE)
Fl, Combined 0 (20) 23.64(±0.92)
1.5 (20) 22.92(±1.37)
3 (20) 23.48(±0.23)
4.5 (20) 23.72(±0.8)
no statistically significant effect on tail pinch observed up
to 4.5 mg/kg
aberrant behaviors (shudder/spasm, intense grooming,
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-4 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
Results by Endpoint
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, C57BL/6J
Route of Exposure: oral - water
Administered Doses: Fl, combined (NR): 0, 8, 25,
80 ppm; Fl, female (NR): 0, 8, 25, 80 ppm; Fl,
male (NR): 0, 8, 25, 80 ppm
Dosing Description: PO dams exposed GD4
through GDIS or PNDO (whichever came first)
dorsoflexion)
Generation, Sex
Fl, Combined
all treated groups had a higher incidence of aberrant
behaviors from PND17-21
false alarm response
Generation, Sex
Fl, Combined
significant increase in the false alarm rate in the 8 ppm
animals during the first 4 sessions
grip strength
Generation, Sex
Fl, Female
all treated groups had a significant decrease in grip
strength
Generation, Sex
Fl, Male
all treated groups had a significant decrease in grip
strength
intertrial interval response
Generation, Sex
Fl, Combined
significant decrease in all treated groups from session 12
to 24
lever run rate
Generation, Sex
Fl, Combined
arsenic impacted lever run rate with higher-order sex-by-
RR-by-session-by-exposure interaction [P=0.03] and
earned food [P=0.01]
locomotor counts
Generation, Sex
Fl, Combined
no statistically significant effect on locomotor counts
observed up to 80 ppm at 2 months or puberty
response rate
Generation, Sex
Fl, Combined
arsenic impacted response rate with sex-by-session-by-
exposure interaction [P=0.03]
righting reflex
Generation, Sex
Fl, Combined
significant decrease in righting reflex in all treatment
groups
spontaneous activity
Generation, Sex
Fl, Combined
all treated groups had significantly less spontaneous
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-5 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
Results by Endpoint
activity
startle response
Generation, Sex
Fl, Combined
all treated groups had a significantly reduced acoustic
startle on PND 13
(Martinez etal., 2008)
Dosing Design: reproductive/developmental
Chemical: sodium arsenate - Na2HAsO4
Species and Strain: mice, C57BL/6J
Route of Exposure: oral - water
Administered Doses: Fl, combined (NR): 0, 0.05
ppm; Fl, female (NR): 0, 0.05 ppm; Fl, male (NR):
0, 0.05 ppm
Dosing Description: PO dams exposed daily 2
weeks before breeding through weaning (PND23)
forced swim task (total immobility times, sees)
Generation, Sex
Fl, Combined
total immobility time was significantly increased in arsenic
treated animals (0.05 ppm) compared to controls
(p<0.001)
latency to escape
Generation, Sex
Fl, Female
perinatal arsenic (0.05 ppm) caused a significant increase
in latency to escape in female offspring (p<0.0001)
Generation, Sex
Fl, Male
perinatal arsenic (0.05 ppm) caused a significant increase
in latency to escape in male offspring (p<0.0001)
(Martinez-Finley et al., 2009)
Dosing Design: reproductive/developmental
Chemical: sodium arsenate - Na2HAsO4
Species and Strain: mice, C57BL/6J
Route of Exposure: oral - water
Administered Doses: Fl, combined (NR): 0, 0.055
ppm
Dosing Description: PO males and females
exposed daily for 2 weeks before breeding; dams
continued treatment until weaning at PND23
8-way radial arm maze
Generation, Sex
Fl, Combined
significant effect of treatment (p<0.0001) in number of
entry errors for arsenic exposed animals over 3 days of
testing compared to controls at 0.055 ppm
novel object exploration
Generation, Sex
Fl, Combined
latency to approach novel object after acclimation period
was significantly slower (p<0.0001) in treated versus
control animals; number of entries to center in presence of
the novel object was significantly lower than control
(p<0.0006) at 0.055 ppm
whole brain weight; hippocampal wet weight
Generation, Sex
Fl, Combined
no statistically significant effect on whole brain weight or
hippocampal wet weight observed at 0.055 ppm
(Ramsey etal., 2013c)
Dosing Design: reproductive/developmental
Chemical: Sodium Arsenite - NaAsO2
Species and Strain: mice, C57BL/6
Route of Exposure: oral - water
Administered Doses: Fl, combined (NR): 0,10,
100 |jg/L
Dosing Description: PO dams treated daily from
GD8 through PNDO
birth length
Generation, Sex
Fl, Combined
Dose(n) Response
(mm±SD)
0(NR) 29.1(±1.74)
10 (NR) 28.8(±1.94)
100 (NR) 28.4(±1.9)*
significantly lower birth length in fetal mice at 100 ug As/L
(p <0.001) but not 10 ug As/L compared to control (p
>0.47)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-6 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
Results by Endpoint
birth weight
Generation, Sex
Fl, Combined
Dose(n)
0(NR)
10 (NR)
100 (NR)
Response (g±SD)
1.34(±0.16)
1.35(±0.19)
1.27(±0.18)*
significantly lower birth weight in fetal mice exposed to
100 ug As/L in utero compared to control (p <0.001), but
no significant difference in birth weight in fetal mice
exposed to 10 ug As/L compared to control (p >0.47)
(Rodriguez et al., 2002)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: rat, Sprague-Dawley
Route of Exposure: oral - water
Administered Doses: Fl, combined (29-
32/group): 0, 36.7 mg/L; Fl, male (13-15/group):
0, 0, 36.7, 36.7 mg/L
Dosing Description: PO dams exposed daily from
PND1 until weaning; Fl males dosed daily through
PND91 (Fl females not directly dosed)
body weight of pups
Generation, Sex Dose(n) Response (g±SE)
Fl, Combined 0 (11-12) 290.49(±18.34)
36.7 (10-11) 261.7(±18.33)*
body weight significantly reduced beginning at 4 weeks
and continuing until week 17 at 36.7 mg/L
eye opening
Generation, Sex
Fl, Combined
no statistically significant effect on eye opening observed
at 36.7 mg/L
learning tasks - delayed alternation
Generation, Sex
Fl, Male
significantly increased mean number of errors at 36.7 mg/L
(p<0.05) but no significant effect on latency
learning tasks - spontaneous alternation
Generation, Sex
Fl, Male
no statistically significant effect on spontaneous
alternation observed at 36.7 mg/L
motor coordination
Generation, Sex
Fl, Male
no statistically significant effect on motor coordination
observed at 36.7 mg/L
onset of reflexes: righting reflex, negative geotaxis,
pivoting, mid-air righting reflex, forelimb grip strength
Generation, Sex
Fl, Combined
no statistically significant effect on onset of reflexes
including righting reflex, negative geotaxis, pivoting, mid-
air righting reflex, and forelimb grip strength observed at
36.7 mg/L
pinna detachment
Generation, Sex
Fl, Combined
no statistically significant effect on pinna detachment
observed at 36.7 mg/L
spontaneous locomotor activity: total distance, vertical
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-7 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
(Rodriguez et al., 2002)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: rat, Sprague-Dawley
Route of Exposure: oral - water
Administered Doses: Fl, combined (22-
32/group): 0, 36.7 mg/L; Fl, male (11-15/group):
0, 36.7 mg/L
Dosing Description: PO dams exposed daily from
GDIS until weaning; Fl males exposed from
weaning until 13 wks of life (Fl females not
directly dosed)
Results by Endpoint
activity, horizontal activity, vertical movements
Generation, Sex
Fl, Male
no statistically significant effect on locomotor variables at
13 or 17 weeks at 36.7 mg/L
eye opening
Generation, Sex
Fl, Combined
significantly lower eye opening scores observed at 36.7
mg/L on PND 14 (p<0.05) on PND 14
learning tasks - delayed alternation
Generation, Sex
Fl, Male
significantly increased mean number of errors observed at
36.7 mg/L (p<0.05); no significant effect on latency
learning tasks - spontaneous alternation
Generation, Sex
Fl, Male
no statistically significant effect on spontaneous
alternation observed at 36.7 mg/L
mean body weight of pups
Generation, Sex Dose(n) Response (g±SE)
Fl, Combined 0 (11-12) 290.49(±18.34)
36.7 (10-11) 276.02(118.35)*
significantly reduced overall at 36.7mg/L but no significant
differences were observed at individual observation times
motor coordination
Generation, Sex
Fl, Male
no statistically significant effect on motor coordination
observed at 36.7 mg/L
onset of reflexes: righting reflex, negative geotaxis,
pivoting, mid-air righting reflex, forelimb grip strength
Generation, Sex
Fl, Combined
no statistically significant effect on the onset of reflexes
observed at 36.7 mg/L
pinna detachment
Generation, Sex
Fl, Combined
significantly more litters showed full pinna detachment at
36.7 mg/L on PND 12 (p<0.05)
spontaneous locomotor activity: total distance, vertical
activity, horizontal activity, vertical movements
Generation, Sex
Fl, Male
significantly increased vertical activity and vertical
movements at both 13 and 17 weeks at 36.7 mg/L
(p<0.05); no significant differences in total distance or
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-8 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
(Xietal., 2009)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: rat, Wistar
Route of Exposure: oral - water
Administered Doses: Fl, combined (12/group): 0,
10, 50, 100 mg/L
Dosing Description: PO dams treated daily GD6
through PND42; Fl treated daily PND28 through
PND42
Results by Endpoint
horizontal activity variables
air righting
Generation, Sex Dose(n) Response (%)
Fl, Combined 0 (64) 80.33
10 (69) 92.54*
50 (58) 73.21
100 (58) 68.63
auditory startle
Generation, Sex Dose(n) Response (%)
Fl, Combined 0 (64) 98.44
10 (69) 97.06
50 (58) 100
100 (58) 84.31*
avoidance test: learning session: latency of reaction
Generation, Sex Dose(n) Response
(secondsiSE)
Fl, Combined 0(12) 157.25(±107.93)
10 (12) 173.92(1132.58)
50 (12) 127.5(1129.04)
100 (12) 116(±136.02)
avoidance test: long memory session: latency of reaction
Generation, Sex Dose(n) Response
(secondsiSE)
Fl, Combined 0(12) 166.67(±46.19)
10(12) 139.58(173.19)
50 (12) 98.83(185.04)*
100(12) 125.08(181.14)
avoidance test: short memory session: latency of reaction
Generation, Sex Dose(n) Response
(secondsiSE)
Fl, Combined 0(12) 136.25(±65.2)
10 (12) 129.08(175.76)
50 (12) 115.83(180.25)
100 (12) 117.5(179.21)
cliff avoidance
Generation, Sex Dose(n) Response (%)
Fl, Combined 0(64) 55.1
10 (69) 68.97
50 (58) 51.79
100 (58) 56.6
forelimb hung
Generation, Sex Dose(n) Response (%)
Fl, Combined 0 (64) 93.75
10 (69) 97.01
50 (58) 98.25
100 (58) 100
negative geotaxis
Generation, Sex Dose(n) Response (%)
Fl, Combined 0 (64) 71.93
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-9 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
Results by Endpoint
10 (69) 69.23
50 (58) 84.21
100 (58) 63.04
postnatal body weight
Generation, Sex
Fl, Combined
body weight significantly decreased in 10, 50, and 100
mg/L arsenic-treated groups at PND 42, 16, and 12,
respectively (p<0.05)
rotarod test: remain time
Generation, Sex
Fl, Combined
no statistically significant effect on remain time on the bar
(at 9 and 18 rpm) observed up to 100 mg/L
square water maze: learning session: latency
Generation, Sex Dose(n) Response
(secondsiSE)
Fl, Combined 0 (12) 13(±4.81)
10 (12) 14.08(±6.42)
50 (12) 16.58(±8.72)
100 (12) 20.17(111.46)
square water maze: learning session: trained number
Generation, Sex Dose(n) Response
(secondsiSE)
Fl, Combined 0(12) 6.67(±1.61)
10(12) 8.67(±2.15)
50(12) 10.08(±3.12)*
100 (12) 11.67(±2.9)*
square water maze: memory session: latency
Generation, Sex Dose(n) Response
(secondsiSE)
Fl, Combined 0 (12) 12.08(±3.5)
10 (12) 11.75(±4.09)
50 (12) 14.33(±6.47)
100 (12) 13.08(±5.18)
square water maze: memory session: trained number
Generation, Sex Dose(n) Response
(secondsiSE)
Fl, Combined 0(12) 5.5(±1.83)
10(12) 6.92(±2.11)
50 (12) 8(±2.92)
100 (12) 8.08(±3.45)
tail hung
Generation, Sex Dose(n) Response (%)
Fl, Combined 0 (64) 89.06
10 (69) 92.65
50 (58) 93.1
100 (58) 70.77*
tail pinch
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-10 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Developmental Effects including
Neurodevelopmental
Reference and Dosing Protocol
Results by Endpoint
Generation, Sex
Fl, Combined
Dose(n)
0(64)
10 (69)
50 (58)
100 (58)
Response (%)
100
100
100
98.18
visual placing
Generation, Sex
Fl, Combined
Dose(n)
0(64)
10 (69)
50 (58)
100 (58)
Response (%)
83.33
68.85
84.62
60.87*
7.1.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Developmental Effects including
Neurodevelopmental
Aggarwal. M: Wangikar. PB: Sarkar. SN: Rao. GS: Kumar. D: Dwivedi P: Malik. JK. (2007). Effects of low-
level arsenic exposure on the developmental toxicity of anilofos in rats. J Appl Toxicol 27: 255-261.
http://dx.doi.org/10.1002/iat. 1203
Ahmad. M: Wadaan. MAM: Farooq. M: Daghestani. MH: Samj AS. (2013). Effectiveness of zinc in modulating
perinatal effects of arsenic on the teratological effects in mice offspring. Biol Res 46: 131-138.
http://dx.doi.org/10.4067/S0716-97602013000200003
Gandhi. DN: Panchal GM: Patel KG. (2012). Developmental and neurobehavioural toxicity study of arsenic on
rats following gestational exposure. Indian J Exp Biol 50: 147-155.
Markowskj VP: Reeve. EA: Onos. K: Assadollahzadeh. M: McKay. N. (2012). Effects of prenatal exposure to
sodium arsenite on motor and food-motivated behaviors from birth to adulthood in C57BL6/J mice.
Neurotoxicol Teratol 34: 221-231. http://dx.doi.0rg/10.1016/i.ntt.2012.01.001
Martinez-Finlev. EJ: Ali. AMS: Allan. AM. (2009). Learning deficits in C57BL/6J mice following perinatal
arsenic exposure: Consequence of lower corticosterone receptor levels. Pharmacol BiochemBehav 94: 271-
277. http://dx.doi.0rg/10.1016/i.pbb.2009.09.006
Martinez. EJ: Kolb. BL: Bell. A: Savage. DP: Allan. AM. (2008). Moderate perinatal arsenic exposure alters
neuroendocrine markers associated with depression and increases depressive-like behaviors in adult mouse
offspring. Neurotoxicology 29: 647-655. http://dx.doi.0rg/10.1016/i.neuro.2008.05.004
Ramsey. KA: Larcombe. AN: Sly. PD: Zosky. GR. (2013). In utero exposure to low dose arsenic via drinking
water impairs early life lung mechanics in mice. Pharmacol Toxicol 14: 13. http://dx.doi.org/10.1186/2050-
6511-14-13
Rodriguez. VM: Carrizales. L: Mendoza. MS: Fajardo. OR: Giordano. M. (2002). Effects of sodium arsenite
exposure on development and behavior in the rat. Neurotoxicol Teratol 24: 743-750.
http://dx.doi.org/10.1016/S0892-0362(02)00313-6
Xi. S: Sun. W: Wang. F: Jin. Y: Sun. G. (2009). Transplacental and early life exposure to inorganic arsenic
affected development and behavior in offspring rats. Arch Toxicol 83: 549-556.
http://dx.doi.org/10.1007/s00204-009-0403-5
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-11 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
7.2 Summary of Observational Animal Studies for Health
Effect Category: Immune System and Lymphatic Effects
Summary of Toxicology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Dosing Protocol
Results by Endpoint
(Dasetal., 2012b)
Dosing Design: chronic (>90 days)
Chemical: sodium arsenite - NaAsO2
Species and Strain: goat, not reported
Route of Exposure: oral - capsule
Administered Doses: female (6/group): 0, 50
mg/kg
Dosing Description: administered daily for 1 year
lymphocyte stimulation index (SI)
Sex
Female
0(6)
50(6)
Response
(unitlessiSE)
1.286(±0.03)
1.003(±0.01)*
significantly lower SI from 270 days onward
plasma total Ig concentration
Sex
Female
Dose(n) Response
(mg/mL±SE)
0 (6) 22.28(±0.83)
50 (6) 17.61(±0.78)*
significantly increased total Ig at 4 months; significant
declining trend at 9-12 months
(Kozuletal.,2009)
Dosing Design: subchronic (30 days to <90 days)
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, C57BL/6J
Route of Exposure: oral - water
Administered Doses: male (NR): 0,100 ppb
Dosing Description: animals (6-8/group) treated
for 5 weeks followed by intranasal inoculation
with sublethal dose of influenza virus
altered cellular numbers in BALF
Sex
Male
at day 7 post-infection, 100-ppb arsenic-exposed mice had
significant increase in number of cells, neutrophils, and
macrophages in BALF (p <0.001; Figure 4A)
dendritic cells migration capacity
Sex
Male
significant decrease for mice exposed at 100 ppb in
migration capability toward ADP in transwell assay (p
<0.001; Figure 7D)
total dendritic cells recovered in mediastinal lymph nodes
Sex
Male
decrease in number of dendritic cells in mediastinal lymph
nodes of 100-ppb exposed mice early in the course of
infection (day 3 post-infection) (p <0.01; Figure 7A)
viral liters
Sex
Male
arsenic exposure at 100 ppb significantly increased viral
titers on day 7 post-infection (p <0.05; Figure 2)
(Nain and Smits, 2012)
Dosing Design: chronic (>90 days)
Chemical: arsenite - As(OH)3
Species and Strain: rat, Wistar
Route of Exposure: oral - water
Administered Doses: male (6/group): 0, 0.4, 4, 40
antibody-mediated IgG in plasma
Sex
Male
0(6)
0.4 (6)
4(6)
40(6)
Response
(ug/mL±SE)
981(±144.7)
625(±104.6)*
396(±123.4)*
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-12 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Dosing Protocol
Results by Endpoint
Dosing Description: ad libitum for 18 weeks
antibody-mediated IgM in plasma
Sex
Male
0(6)
0.4 (6)
4(6)
40(6)
Response
(ug/mL±SE)
140(±5.9)
122(±13.8)
130(±25.2)
chemiluminescence
Sex
Male
0(6)
0.4 (6)
4(6)
40(6)
Response
(absorbanceiSE)
2853(±39.4)
3756(±413.9)
3275(±37.5)
(Ramsey etal.,2013b)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, C57BL/6
Route of Exposure: oral - water
Administered Doses: Fl, combined (NR): 0, 100
BALF: total cells, neutrophils, macrophages, and
lymphocytes
Dosing Description: dams exposed GD8 through
weaning; offspring exposed until PND49
Generation, Sex
Fl, Combined
significant effect of arsenic exposure at 3 days but not at
later time points up to 7 weeks for total cells and number
of macrophages in BALF; no other compound-related
effects for BALF parameters
IL-6, IFN-gamma, TNF-alpha, MCP-1, protein, viral titer
Generation, Sex
Fl, Combined
no statistically significant effect observed on viral titer at
100 ug/L
(Ramsey et al., 2013b)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, C57BL/6
Route of Exposure: oral - water
Administered Doses: Fl, combined (NR): 0, 100
BALF: total cells, neutrophils, macrophages, and
lymphocytes
Dosing Description: dams exposed GD8 through
weaning; offspring (infected with influenza at 1
week) exposed until PND49
Generation, Sex
Fl, Combined
significant effect of arsenic in flu-infected animals for total
cells in BALF and macrophages at 3 days post infection;
significant interaction between arsenic exposure and flu
treatment for total cells at 7 days post infection and for
neutrophils at 7 days post infection
IL-6, IFN-gamma, TNF-alpha, MCP-1, protein, viral titer
Generation, Sex
Fl, Combined
significant effect of arsenic exposure in flu-infected
animals for viral titer at 7 days post infection only
(Sankaretal., 2013)
Dosing Design: subchronic (30 days to <90 days)
Chemical: sodium arsenite - NaAsO2
Species and Strain: rat, Wistar
Route of Exposure: oral - water
Administered Doses: male (6/group): 0, 25 ppm
Dosing Description: ad libitum for 42 days
delayed-type hypersensitivity response (% increase in
skin thickness)
Generation, Sex
Male
Response (%±SE)
45(±3.41)
24.17(±3.27)*
secondary antibody production
Generation, Sex
Male
Response
0.731(±0.02)
0.498(±0.01)*
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-13 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Immune System and Lymphatic Effects
Reference and Dosing Protocol
(Stepnik et al., 2009)
Dosing Design: chronic (>90 days)
Chemical: sodium arsenate - Na2HAsO4
Species and Strain: mice, C57BL/6J/Han
Route of Exposure: oral - water
Administered Doses: female (100/group): 0, 50,
200, 500 ug/L
Dosing Description: animals on normal selenium
diet (low-selenium diet also evaluated) dosed
daily for 24 months
(Waalkes et al., 2006b)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, CD-I
Route of Exposure: oral - water
Administered Doses: Fl, female (35/group): 0, 85
ppm
Dosing Description: PO dams exposed daily GD8
through GDIS
Results by Endpoint
T cell stimulation index
Generation, Sex Dose(n) Response
(unitlessiSE)
Male 0 (6) 0.559(±0.04)
25 (6) 0.327(±0.03)*
significantly decreased splenocyte lymphocyte
proliferation as evidenced by decreased stimulation index
malignant lymphoma
Sex Dose(n) Response
(incidence)
Female 0 (83) 6/83
50 (90) 10/90
200 (85) 13/85
500 (90) 22/90*
malignant lymphoma showed clear arsenic concentration-
dependent increase of incidence; results similar for
animals fed a low-selenium diet
thymus, lymph node, spleen
Sex
Female
no significant association between lesion type and arsenic
exposure (up to 500 u.g/L) or selenium status
lymphoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Female 0 (33) 10/33
85 (34) 2/34*
7.2.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: : Immune System and Lymphatic
Effects
Das. TK: Mani V: Kaur. H: Kewalramanj N: De. S: Hossain. A: Banerjee. D: Datta. BK. (2012). Effect of
vitamin E supplementation on arsenic induced oxidative stress in goats. Bull Environ Contam Toxicol 89:
61-66. http://dx.doi.org/10.1007/s00128-012-0620-0
Kozul. CD: Ely. KH: Enelow. RI: Hamilton. JW. (2009). Low dose arsenic compromises the immune response
to influenza A infection in vivo. Environ Health Perspect 117: 1441-1447.
http://dx.doi.org/10.1289/ehp.0900911
Nain. S: Smits. JE. (2012). Pathological, immunological and biochemical markers of subchronic arsenic toxicity
in rats. Environ Toxicol 27: 244-254. http://dx.doi.org/10.1002/tox.20635
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 7-14 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Ramsey. KA: Foong. RE: Sly. PD: Larcombe. AN: Zosky. GR. (2013). Early life arsenic exposure and acute and
long-term responses to influenza a infection in mice. Environ Health Perspect 121: 1187-1193.
http://dx.doi.org/10.1289/ehp.1306748
Sankar. P: Telang. AG: Suresh. S: Kesavan. M: Kannan. K: Kalaivanan. R: Sarkar. SN. (2013).
Immunomodulatory effects of nanocurcumin in arsenic-exposed rats. Int Immunopharmacol 17: 6570.
http://dx.doi.0rg/10.1016/i.intimp.2013.05.019
Stepnik. M: Stetkiewicz. J: Krajnow. A: Domeradzka. K: Gradecka-Meesters. D: Arkusz. J: Stanczyk. M: Palus.
J: Dziubaltowska. E: Sobala. W: Gromadzinska. J: Wasowicz. W: Rydzynski. K. (2009). Carcinogenic effect
of arsenate in C57BL/6J/Han mice and its modulation by different dietary selenium status. Ecotoxicol
Environ Saf 72: 2143-2152. http://dx.doi.0rg/10.1016/i.ecoenv.2009.06.005
Waalkes. MP: Liu. J: Ward. JM: Powell DA: Diwan. BA. (2006). Urogenital carcinogenesis in female GDI
mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment. Cancer
Res 66: 1337-1345. http://dx.doi.org/10.1158/0008-5472.CAN-05-3530
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
7.3 Summary of Observational Animal Studies for Health
Effect Category: Liver Effects
Summary of Toxicology Studies for Health Effect Category: Liver Effects
Reference and Dosing Protocol
(Nain and Smits, 2012)
Dosing Design: chronic (>90 days)
Chemical: arsenite - As(OH)3
Species and Strain: rat, Wistar
Route of Exposure: oral - water
Administered Doses: male (6/group): 0, 0.4, 4, 40
ppm
Dosing Description: ad libitum for 18 weeks
(Stepnik et al., 2009)
Dosing Design: chronic (>90 days)
Chemical: sodium arsenate - Na2HAsO4
Species and Strain: mice, C57BL/6J/Han
Route of Exposure: oral - water
Administered Doses: female (100/group): 0, 50,
200, 500 ng/L
Dosing Description: animals on normal selenium
diet (low-selenium diet also evaluated) dosed
daily for 24 months
(Tokaretal., 2011)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, CD-I
Route of Exposure: oral - water
Administered Doses: Fl, female (30/group): 0, 6,
12, 24 ppm; Fl, male (30/group): 0, 6, 12, 24 ppm
Dosing Description: PO breeding pairs exposed
daily 2 weeks prior to breeding; dams continued
exposure through gestation and lactation and Fl
offspring continued on treatment until 2 years of
age
Results by Endpoint
liver histopathology (degree of vacuolization)
Sex Dose(n) Response
(gradeiSE)
Male 0 (6) 1.7(±0.21)
0.4 (6) 2(±0.58)*
4(6) 2.8(±0.17)*
40(6) 3.2(±0.31)*
liver adenoma or haemangioma
Sex Dose(n) Response
(incidence)
Female 0 (83) 0/83
50 (90) 2/90
200 (85) 1/85
500 (90) 3/90
liver focal nodular hyperplasia
Sex Dose(n) Response
(incidence)
Female 0 (83) 7/83
50 (90) 5/90
200 (85) 6/85
500 (90) 6/90
not significant in normal selenium group; for low-selenium
group, significant increase in focal nodular hyperplasia at
50ug/L
liver adenoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Female 0 (29) 1/29
6 (29) 1/29
12 (28) 2/28
24 (28) 1/28
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (29) 2/29
6 (29) 3/29
12 (28) 3/28
24 (28) 6/28
not significant
liver carcinoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Female 0 (29) 0/29
6 (29) 2/29
12 (28) 2/28
24 (28) 5/28*
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Liver Effects
Reference and Dosing Protocol
(Tokaretal., 2012)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, CD-I
Route of Exposure: oral - water
Administered Doses: Fl, male (50/group): 0, 85
ppm
Dosing Description: PO dams exposed daily from
GD8 through GDIS
(Waalkes et al., 2004b)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, C3H
Route of Exposure: oral - water
Administered Doses: Fl, female (25/group): 0,
42.5, 85 ppm; Fl, male (25/group): 0, 42.5, 85
ppm
Dosing Description: PO dams exposed daily from
GD8 through GDIS
Results by Endpoint
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (29) 0/29
6 (29) 4/29
12 (28) 6/28*
24 (28) 6/28*
liver total adenoma and carcinoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Female 0 (29) 1/29
6 (29) 3/29
12 (28) 4/28
24 (28) 6/28*
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (29) 2/29
6 (29) 6/29
12 (28) 7/28
24 (28) 10/28*
hepatic adenoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (49) 5/49
85 (45) 5/45
not significant
hepatic total tumors
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (49) 8/49
85 (45) 14/45
not significant; arsenic+DMA group significantly increased
compared with control, arsenic-only, and DMA-only groups
hepatocellular carcinoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (49) 3/49
85 (45) 9/45*
also significantly increased incidence for arsenic+DMA
group compared with control, DMA-only, and arsenic-only
groups
hepatocellular adenoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Female 0 (24) 2/24
42.5 (23) 3/23
85 (21) 3/21
not significant; similar results in animals treated with TPA
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (24) 10/24
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Liver Effects
Reference and Dosing Protocol
Results by Endpoint
42.5 (23) 12/23
85 (21) 19/21*
significant at 85 ppm; results similar for animals treated
with TPA
hepatocellular carcinoma
Generation, Sex
Fl, Female
0(24)
42.5 (23)
85 (21)
Response
(incidence)
1/24
3/23
1/21
not significant; similar results in animals treated with TPA
Generation, Sex
Fl, Male
Dose(n) Response
(incidence)
0 (24) 3/24
42.5 (23) 8/23
85 (21) 10/21*
significant at 85 ppm; results similar for animals treated
with TPA
hepatocellular tumors: multiplicity
Generation, Sex
Fl, Female
Dose(n) Response
(no./animal±SE)
0(24) 0.13(±0.07)
42.5(23) 0.41(±0.16)
85(21) 0.29(±0.14)
not significant; in animals treated with TPA, significant
increase in multiplicity at 85 ppm
Generation, Sex
Fl, Male
Dose(n) Response
(no./animal±SE)
0(24) 0.75(±0.16)
42.5 (23) 1.87(±0.45)*
85(21) 2.14(±0.27)*
significant increase at > 42.5 ppm; results similar for
animals treated with TPA
hepatocellular tumors: total
Generation, Sex
Fl, Female
Dose(n) Response
(incidence)
0 (24) 3/24
42.5 (23) 6/23
85 (21) 4/21
not significant; in animals treated with TPA, significant
increase in total tumor incidence at 85 ppm
Generation, Sex
Fl, Male
Dose(n) Response
(incidence)
0 (24) 12/24
42.5 (23) 14/23
85 (21) 19/21*
significant increase at 85 ppm; results similar for animals
treated with TPA
(Waalkes et al., 2006a)
Dosing Design: reproductive/developmental
liver adenoma
Generation, Sex
Response
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Liver Effects
Reference and Dosing Protocol
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, CD-I
Route of Exposure: oral - water
Administered Doses: Fl, male (35/group): 0, 85
ppm
Dosing Description: PO dams exposed daily from
GD8 through GDIS
(Waalkes et al., 2006b)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, CD-I
Route of Exposure: oral - water
Administered Doses: Fl, female (35/group): 0, 85
ppm
Dosing Description: PO dams exposed daily GD8
through GDIS
(Waalkes et al., 2003)
Dosing Design: reproductive/developmental
Chemical: sodium arsenite - NaAsO2
Species and Strain: mice, C3H
Route of Exposure: oral - water
Administered Doses: Fl, female (23-25/group): 0,
42.5, 85 ppm; Fl, male (21-24/group): 0, 42.5, 85
ppm
Dosing Description: PO dams exposed daily from
GD8 through GDIS
Results by Endpoint
(incidence)
Fl, Male 0 (35) 2/35
85 (35) 8/35*
liver carcinoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (35) 0/35
85 (35) 5/35*
liver total tumors
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (35) 2/35
85 (35) 11/35*
liver: total mesenchymal and epithelial tumors
Generation, Sex Dose(n) Response
(incidence)
Fl, Female 0 (33) 0/33
85 (34) 4/34
liver adenoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (24) 7/24
42.5 (21) 3/21
85 (23) 6/23
adenoma and carcinoma observed in some animals
resulting in a significantly increased nominal rate of
adenoma incidence (p<0.001) at the high-dose level
liver adenoma multiplicity (tumors/mouse)
Generation, Sex Dose(n) Response
(#/mouse±SE)
Fl, Male 0 (24) 0.71(±0.22)
42.5 (21) 1.43(±0.49)
85 (23) 3.61(±0.78)*
liver carcinoma
Generation, Sex Dose(n) Response
(incidence)
Fl, Male 0 (24) 3/24
42.5 (21) 8/21*
85 (23) 14/23*
liver carcinoma multiplicity (tumors/mouse)
Generation, Sex Dose(n) Response
(#/mouse±SE)
Fl, Male 0(24) 0.13(±0.07)
42.5(21) 0.42(±0.13)
85 (23) 1.3(±0.28)*
liver histological analysis: adenoma
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Summary of Toxicology Studies for Health Effect Category: Liver Effects
Reference and Dosing Protocol
Results by Endpoint
Generation, Sex Dose(n) Response
(incidence)
Fl, Female 0 (25) 5/25
42.5 (23) 3/23
85 (24) 3/24
liver tumor incidence and multiplicity unaltered by arsenic
exposure
liver histological analysis: carcinoma
Generation, Sex Dose(n)
Response
(incidence)
Fl, Female 0 (25) 0/25
42.5 (23) 1/23
85 (24) 1/24
liver tumor incidence and multiplicity unaltered by arsenic
exposure
liver total tumor multiplicity (tumors/mouse)
Generation, Sex Dose(n)
Fl, Male 0 (24)
42.5 (21)
85 (23)
Response
(#/mouse±SE)
0.87(±0.25)
1.81(±0.54)
4.91(±0.92)*
liver total tumors
Generation, Sex Dose(n)
Fl, Male 0 (24)
42.5 (21)
85 (23)
Response
(incidence)
10/24
11/21
20/23*
7.3.1 References for Summary of Observational Epidemiology Studies
for Health Effect Category: Liver Effects
Nain. S: Smits. JE. (2012). Pathological, immunological and biochemical markers of subchronic arsenic toxicity
in rats. Environ Toxicol 27: 244-254. http://dx.doi.org/10.1002/tox.20635
Stepnik. M: Stetkiewicz. J: Krajnow. A: Domeradzka. K: Gradecka-Meesters. D: Arkusz. J: Stanczyk. M: Palus.
J: Dziubaltowska. E: Sobala. W: Gromadzinska. J: Wasowicz. W: Rydzynski. K. (2009). Carcinogenic effect
of arsenate in C57BL/6J/Han mice and its modulation by different dietary selenium status. Ecotoxicol
Environ Saf 72: 2143-2152. http://dx.doi.0rg/10.1016/i.ecoenv.2009.06.005
Tokar. EJ: Diwan. BA: Waalkes. MP. (2012). Renal, hepatic, pulmonary and adrenal tumors induced by prenatal
inorganic arsenic followed by dimethylarsinic acid in adulthood in GDI mice. Toxicol Lett 209: 179-185.
http://dx.doi.0rg/10.1016/i.toxlet.2011.12.016
Tokar. EJ: Diwan. BA: Ward. JM: Delker. DA: Waalkes. MP. (2011). Carcinogenic effects of "whole-life"
exposure to inorganic arsenic in GDI mice. Toxicol Sci 119: 73-83. http://dx.doi.org/10.1093/toxsci/kfq315
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Waalkes. MP: Liu. J: Ward. JM: Diwan. BA. (2006a). Enhanced urinary bladder and liver carcinogenesis in
male GDI mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen.
Toxicol Appl Pharmacol 215: 295-305. http://dx.doi.0rg/10.1016/i.taap.2006.03.010
Waalkes. MP: Liu. J: Ward. JM: Powell. DA: Diwan. BA. (2006b). Urogenital carcinogenesis in female CD1
mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment. Cancer
Res 66: 1337-1345. http://dx.doi.org/10.1158/0008-5472.CAN-05-3530
Waalkes. MP: Ward. JM: Diwan. BA. (2004). Induction of tumors of the liver, lung, ovary and adrenal in adult
mice after brief maternal gestational exposure to inorganic arsenic: Promotional effects of postnatal phorbol
ester exposure on hepatic and pulmonary, but not dermal cancers. Carcinogenesis 25: 133-141.
http://dx.doi.org/10.1093/carcin/bggl81
Waalkes. MP: Ward. JM: Liu. J: Diwan. BA. (2003). Transplacental carcinogenicity of inorganic arsenic in the
drinking water: Induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. Toxicol Appl
Pharmacol 186: 7-17. http://dx.doi.org/10.1016/S0041-008X(02)00022-4
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
8 MODE OF ACTION (MOA) LITERATURE SEARCH
STRATEGY FOR THE TOXICOLOGICAL REVIEW
OF INORGANIC ARSENIC
8.1 Overview of Literature Search Strategy
1 The mode of action literature search strategy began with all references from initial
2 arsenic literature search that were not found in the health effects cluster (see Figure 3.1-
3 1). References from the health effects cluster had already been reviewed and references
4 discussing mode of action identified. The identified mode of action references from the
5 health effect cluster will be considered during evaluation of the mode of action literature.
6 For references not found in the health effects cluster (-24,000), a combination of
7 automated and manual selection process was used to identify relevant mode of action
8 literature. OmniViz reference visualization software was used to form clusters of
9 references using natural language processing. Natural language processing groups
10 references based on language similarity in the title and abstract. To identify references
11 relevant for mode of action, approximately 400 references were used as "seed"
12 references. "Seed" references are those previously identified by experts as relevant to
13 mode of action in peer reviewed inorganic arsenic human health risk assessments.
14 Clusters containing many seed items have a higher probability of relevance to the topics
15 discussed by the references in the seed. Those clusters with a smaller number of seeds
16 have a decreasing probability, and those with none have a low probability of relevance.
17 All the clusters that contain at least one seed reference were reviewed. While this
18 approach does not specifically identify individual references, it does identify groups of
19 references that have a higher probability of relevance.
20 The subset of mode of action clusters will be considered, along with references identified
21 from the original health effects cluster.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
9 INORGANIC ARSENIC MODE OF ACTION (MOA)
HYPOTHESIS SUMMARIES
9.1 Preamble
9.1.1 Background
1 The series of tables and summaries that follow provide a foundation for a discussion with
2 stakeholders attending a bimonthly meeting for the Integrated Risk Information System
3 (IRIS). As described in the inorganic arsenic assessment development plan (ADP), EPA
4 will use an adverse outcome pathway (AOP) framework to inform potential human health
5 effects associated with inorganic arsenic exposures. Information in an AOP framework
6 supports the use of mode of action (MOA) data as a basis for understanding adverse
7 effects (OECD. 2013). AOP and MOA analyses support hazard identification and dose-
8 response analysis decisions and are not in of themselves a requirement for organization of
9 the available health effects information. Each summary and accompanying table below
10 presents one of several hypothesized MOAs that may be relevant to understanding
11 adverse health outcomes following inorganic arsenic exposures in human populations1.
12 EPA defines the term MOA as "a sequence of key events and processes, starting with the
13 interaction of an agent with a cell, proceeding through operational and anatomical
14 changes, and resulting in cancer formation [or other adverse outcomes]" (U.S. EPA,
15 2005). In instances when data are available to establish 1) the initial interaction between
16 an agent and a cell (i.e., molecular initiating event), and 2) an adverse outcome relevant
17 to risk assessment, then a MOA may be similar to an AOP (OECD. 2013; Ankley et al..
18 2010). In instances when data are not available to establish both of these anchors, then
19 MOA may be used to organize data and identify data gaps. The MOA framework is used
20 consistently throughout these discussion materials in anticipation of subsequently
21 developing AOPs when sufficient data are available.
22 The hypothesized MOAs were selected based on available information from authoritative
23 reports and reviews on inorganic arsenic MOA (Cohen et al.. 2013; NRC. 2013; Jomova
24 etal.. 2011; Kitchin and Conolly. 2010; Prins. 2008). EPA understands that these MOAs
25 are not exhaustive; discussions during the IRIS bimonthly meeting may help to identify
1 Efforts to develop summaries and tables for hypothesized MOAs are ongoing; a subset of the MOA discussion
materials is available in the current draft.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 additional MOAs relevant for consideration in understanding adverse health effects of
2 inorganic arsenic, and provide insight on interactions between multiple MOAs that could
3 influence subsequent health effects. This approach anticipates that reviewers of these
4 materials will also identify additional literature to inform evaluations of MOAs relevant
5 to particular health outcomes in the IRIS assessment of inorganic arsenic. The following
6 summaries are not intended to provide a comprehensive presentation of available
7 information, or to present EPA's interpretation of the identified literature; rather these
8 summaries outline information from the identified literature on the main elements (i.e.,
9 molecular initiating events, key events, adverse outcomes) in a set of potentially key
10 MOAs as a foundation for further discussion. As these MOAs are refined, additional
11 documentation will be added based on information provided by reviewers of these
12 materials and the results of EPA's comprehensive literature search. More information on
13 the use of MOA data in the subsequent inorganic arsenic IRIS assessment is available in
14 the ADP.
9.1.2 Considerations relevant across all hypothesized MOAs
15 There are a number of cross cutting issues that need to be considered in the evaluation of
16 the various hypothesized MOAs. These include the metabolism of inorganic arsenic, and co-
17 toxic and interactive effects.
9.1.2.1 Inorganic arsenic Metabolism
18 The metabolism of inorganic arsenic (Figure 9-1) is relevant to all of the hypothesized
19 MOAs discussed below. However, to reduce redundancy in the presentations, the MOA
20 discussions will begin by identifying the specific metabolites (where known) that interact
21 with specific cellular molecules (where known) in the molecular initiating events for the
22 MOA. Specific metabolic pathways of inorganic arsenic will be discussed for each MOA
23 only to the extent that they are relevant to the evaluation of the MOA, to the explanation
24 or species differences in effects, or in the identification of potentially susceptible
25 populations [IRIS Handbook, Guidelines for carcinogen risk assessment (U.S. EPA.
26 2005). and Inorganic Arsenic ADP].
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Arsenatev Arsenate reductase, Glutathione S-transferase-d),
V « Glyceraldehyde phosphate dehydrogenase
(GAPDH)?; Nonenzymatic pathway
Arsenite111
-SAM
kSAH
Monomethylarsonic acid (MMAV)
V * Glutathione Stransferase-w
Monomethylarsonous acid (MMA111)
VSAM
^___, SAH
Methyltransferase (AS3MT) Dimethylarsink acid (DMAV)
Dimethylarsenous acid (DMA111)
Trimethyl arsine oxide (TMAOV)
\ «
Trimethyl arsine (IMA111)
Source: Modified from Sams etal. (2007).
Figure 9-1 Traditional metabolic pathway for inorganic arsenic in humans.
1
2
3
4
5
6
1
8
9
10
11
12
13
14
The reader may refer to recent reviews (Cohen etal.. 2013; Jomova et al.. 2011) for more
detailed information related to inorganic arsenic metabolism. Key elements of
mammalian inorganic arsenic metabolism that bear on internal exposures and dosimetry
include the following set of interrelated reactions:
Enzymatic or non-biological reductions of pentavalent arsenic species to As(III)
and other trivalent metabolites;
Oxidative methylation of trivalent species to pentavalent methylarsonic acid
(MMA[V]) and dimethylarsinic acid (DMA[V])
In rodents and humans, the net result of this "cascade" is to convert the bulk of inorganic
arsenic to methylated species through a series of redox reactions. As a result, internal
exposures after ingestion of inorganic arsenic tend to consist of mixtures of inorganic
arsenic and trivalent methylated species. The exact patterns of internal dose are species-
and target-organ specific, and vary based on exposure levels and duration, genetic
background. Other minor metabolites (substituted arsines and thiolated metabolites) may
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 also be formed under certain conditions, and are postulated to play a role in some aspects
2 of toxicity (Pinyayev et al., 2011). As noted above, the specifics of metabolic pathways
3 will be discussed only where investigators identify them as being important aspects of the
4 MOA. For example, the redox cascade has been implicated in the depletion of cellular
5 thiol compounds and in the generation of reactive oxygen species; thus, the implications
6 of these reactions are briefly noted as part of the relevant MOAs.
9.1.2.2 Co-toxic and interactive effects
7 As noted above, co-toxic and interactive effects between inorganic arsenic and other
8 chemicals or stressors are relevant to many of the MOA summaries that follow. Factors
9 that may generally impact susceptibility to inorganic arsenic exposure are noted here in
10 order to support a discussion on populations that may be at increased risk due to
11 cumulative or synergistic effects of inorganic arsenic and other chemicals or stressors.
12 These factors include: life stage, nutrition, genetics, sex, and pre-existing disease (NRC.
13 2013). In addition, smoking, alcohol consumption, and exposure to mixtures may also
14 increase vulnerability to the effects of inorganic arsenic (NRC. 2013). Inorganic arsenic
15 has also been found to interact with other metals, like cadmium (Huang et al.. 2009a).
16 and polycylic aromatic hydrocarbons (PAHs) (Fischer et al., 2005; Maier et al., 2002).
17 The potential interactions between inorganic arsenic exposure and smoking or other co-
18 exposures on individual responses have been assessed in epidemiological studies (Table
19 in Section 10.6). The synergistic interaction between smoking and inorganic arsenic has
20 been found to be greater than additive for skin lesions observed in Bangladesh (Chen et
21 al., 2006a). An interaction between smoking and bladder cancer was also observed in
22 New Hampshire (Karagas et al.. 2004). In addition, synergistic effects between fertilizer
23 use and inorganic arsenic exposure in well water were observed for skin lesions in
24 Bangladeshi men participating in the Health Effects of Arsenic Longitudinal Study
25 (HEALS) reported (Melkonian et al.. 2011). The HEALS study results further suggested
26 that men in this cohort, exposed to the same level of inorganic arsenic, with a history of
27 smoking and high fertilizer use may be more susceptible to skin lesions than those with
28 no smoking history or fertilizer use. Diets low in folate and other B vitamins have also
29 been associated with increased risks of skin lesions and hypertension (Pilsner et al.. 2009;
30 Chen et al.. 2007b: Mitra et al.. 2004).
31 As the assessment development process moves forward, a more systematic approach to
32 integrating information on factors that may have co-toxic and interactive effects with
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 inorganic arsenic will be undertaken. Input on this topic from stakeholders attending the
2 IRIS bimonthly meeting would thus useful for EPA.
9.2 Hypothesized MOA: Cytotoxicity and Regenerative
Proliferation
3 Relevant Health Effects: Bladder cancer, lung cancer, skin cancer
4 Cohen et al. (2013) have argued that the carcinogenic action of inorganic arsenic in the
5 bladder is due to a mode of action (MOA) that includes cytotoxicity to urothelial cells
6 followed by regenerative proliferation leading eventually to urothelial carcinoma. Cohen
7 et al. (2013) have further argued that this MOA may also apply to lung and skin cancers.
8 Prior to the molecular initiating events in this MOA, it is assumed that inorganic arsenic
9 will be transformed into active metabolites (see Preamble). Under this MOA, exposure of
10 sensitive tissue to the most toxic arsenic species, As(III) and MMA(III), and possibly
11 thiolated species, results in the following sequence of events (Figure 9-2):
12 Reaction with sulfhydryl groups of specific proteins in the target tissue,
13 Cytotoxicity caused by the reactive metabolites,
14 Regenerative proliferation (including hyperplasia) in tissues (e.g., urothelium), and
15 Development of tumors (Cohen et al.. 2013)
16 Cohen et al. (2013) propose that, following ingestion and metabolism of relatively large
17 amounts of inorganic arsenic, the molecular initiating event (MIE) under this MOA is
18 the reaction of arsenic species with protein thiol groups in epithelial cells. A number
19 of specific protein thiol targets have been identified, mostly by in vitro studies, including
20 tubulin, keratin, estrogen receptor-a (ERa), thioredoxin reductase, DNA repair associated
21 proteins including PARP-1, XPA, and XPD. In vitro studies with synthetic peptides also
22 indicate that inorganic arsenic species can react specifically with zinc finger motifs in
23 transcription factors and regulatory proteins (Wnek et al.. 2011; Kitchin and Wallace.
24 2008; Qin et al., 2008; Kitchin and Wallace. 2005). The specific protein interactions
25 responsible for the observed cytotoxicity and subsequent proliferation have not been
26 identified, however (Cohen et al.. 2013). Variations between species and tissue types in
27 the reactivity of different arsenic species with specific proteins could influence
28 subsequent biochemical responses; as noted above, this mode of action has been
29 investigated primarily in urothelial tissues but Cohen etal. (2013) suggest that it may also
30 apply to lung and skin cancers based on their evaluation of available in vitro, in vivo
31 animal and epidemiology data. As such, differences related to arsenic species and tissue
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1
2
may be factors of interest to consider in future research on this MOA in these or other
tissues according to (Cohen et al.. 2013).
iAs
Metabolism
Products
iAs(lll),
MMA(III),
Thiolated
species
+
MIE
Multiple
Sulfhydryl
Protein
Targets
(e.g.,
tubulin,
thioredoxin,
DNA repair
proteins
(PARP-1))
»
Biochemical
Responses
See text.
Possible
examples:
DNA
damage,
Reactive
oxygen
species
generation
*
Cellular
Response
Cytotoxicity,
Re-generative
Proliferation
+
Tissue/
Organ
Response
Cytotoxicity/
Necrosis,
Hyperplasia,
>
Individual
Response
Tumor
formation
(in animals)
»
Population
Response
^Incidence of:
Bladder Cancer,
Lung Cancer,
Skin Cancer
Abbreviations: Inorganic arsenic (iAs); Molecular Initiating Event (MIE); monomethylarsenous (MMA[III]);
Poly [ADP-ribose] polymerase 1 (PARP-1)
See Summary Text and Table for references; Figure based on Ankley et al. (2010).
Note: This Figure shows an overview of key events from the initial molecular interaction of arsenic species with sulfhydryl protein targets
through a possible population level response. As the assessment development process moves forward additional evidence may provide better
understanding of key events in the MOA and the level of evidence available to support connections between key events.
Figure 9-2 Hypothesized mode of action for Cytotoxicity and regenerative
proliferation.
4
5
6
7
8
9
10
11
12
As usually formulated by Cohen et al. (2013). the regenerative proliferation MOA is
silent with regard to the biochemical responses (i.e., molecular or genetic mechanisms)
underlying the progression from MIE to Cytotoxicity and subsequent proliferation to
carcinogenic transformation. While some studies suggest that the molecular or genetic
mechanisms in this MOA may include DNA strand breaks, altered transcription factor or
growth factor activity, and generation of reactive oxygen species (ROS) (Wnek et al..
2011: Wnek et al.. 2009: Eblin et al.. 2008: Eblin et al.. 2006: Simeonova et al.. 2002:
Simeonova et al.. 2000). other evidence from a short-term study suggests that mitigating
oxidative stress does not prevent regenerative proliferation, which implies that ROS is
not a necessary step in the MOA (Suzuki etal.. 2009). Additional studies were not
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 identified to further support or refute other possible biochemical responses; however,
2 Cohen et al. (2013) suggest that understanding underlying biochemical mechanisms (e.g.,
3 oxidative stress, epigenetic effects on DNA and histones), and the direct interaction of
4 arsenic species with cellular signaling pathways is of limited relevance because the dose-
5 response for the key cellular responses (cytotoxicity and proliferation) have been so well
6 established.
7 The first proposed key cellular response that Cohen etal. (2013) identify in this MOA is
8 epithelial cell cytotoxicity. Evidence of cytotoxicity comes from a wide range of in vitro
9 and in vivo studies. In vitro, the cytotoxicity of arsenic species (i.e., arsenite, MMA(III),
10 DMA(III), and thiol derivatives) has been demonstrated in a number of primary and
11 immortalized mammalian cell lines (Table in Section 10.1) (Suzuki et al.. 2010; Eblin et
12 al.. 2008; Bredfeldt et al.. 2006; Sens et al.. 2004; Drobnaet al.. 2003; Cohen. 2002;
13 Styblo etal.. 2000). Cytotoxicity, as measured by LC50 or IC50, varies greatly depending
14 on the arsenic species being evaluated and the cell lines employed. In vitro acute
15 cytotoxicity is greatest for the trivalent species (LC/IC50 values in the range of
16 approximately 1-20 uM for As [III], MMA[III], DMA[III]) and lower for the pentavalent
17 analogues (LC/IC50s on the order of 30-1500 uM). Acute cytotoxicity of trivalent arsenic
18 appears similar in primary cell lines and immortalized (UROTSA) cells. Limited data on
19 the thiol analogues such as DMMAT(V) suggest that its acute toxicity is similar to the
20 trivalent arsenicals (LC50 = 1.4-5.5 uM in urothelial and bronchioepithelial cells,
21 respectively).
22 Cytotoxicity and cellular necrosis has also been observed at the organ or tissue level in
23 vivo in a number of studies where rats and mice were exposed to inorganic arsenic in diet
24 and drinking water (Table in Section 10.1) (Arnold et al.. 2013; Yokohira et al.. 2011;
25 Suzuki etal..2010; Yokohira etal.. 2010; Suzuki et al.. 2008). Data suggest that female
26 rats are more sensitive to cytotoxic effects of inorganic arsenic than male rats or either
27 sex in mice (Suzuki et al.. 2008). Exposure via drinking also appears to elicit greater
28 effects on the bladder compared to dietary exposure in rats and mice (Suzuki etal.. 2008).
29 Evidence also indicates that cytotoxicity in As3mt knockout mice was generally similar
30 to those seen in the wild type and occurred at similar exposure levels as for As(III);
31 suggesting that methylation was not necessarily a key step in acute cytotoxicity, and that
32 unmethylated As(III) therefore likely played a role in the observed cytotoxic effects
33 (Yokohira et al.. 2011. 2010). In vitro studies of different cell lines also support a lack of
34 correlation between arsenic methylation capacity and cytotoxicity (Styblo et al.. 2000).
35 Finally, a 14-day study in F344 rats and WT and As3mt knockout C57BL/6 mice found
36 increasing incidence of elevated cytotoxicity scores in the urothelium over time (Arnold
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 et al.. 2013). In rats, one animal showed isolated foci of cytotoxicity in the urothelium
2 after only six hours of exposure, while larger numbers of rats (seven often) showed
3 elevated cytotoxicity scores by the end of the experiment (14 days). Cytotoxicity scores
4 were also elevated in both the wild type and AsSmt knockout mice beginning at
5 approximately 3 days of exposures.
6 Cohen et al. (2013) propose that the next key event in this MOA is increased cellular
7 (regenerative) proliferation at the organ or tissue level, which was observed in several
8 of the cytotoxicity studies just discussed (Table in Section 10.1). Simeonova et al. (2000)
9 observed urothelial hyperplasia and metaplasia in female C57BL/6 mice exposed to
10 0.01% sodium arsenite in drinking water for four weeks or longer. Hyperplasia was
11 accompanied by a "cobblestone" appearance of the urothelium, but not by necrotic
12 cytotoxicity. Simeonova et al. (2000) subsequently observed urothelial hyperplasia and
13 occasional squamous metaplasia in mice exposed to 50 and 100 ug/L As(III) for eight
14 weeks. Suzuki et al. (2008), reported simple urothelial hyperplasia occurring roughly in
15 parallel with increased cytotoxicity scores in rats and mice exposed to arsenite in food at
16 50-400 ppm or drinking water at 100 ppm for up to ten weeks. Subsequent studies with
17 female rats confirmed a dose-dependent increase in cytotoxicity and urothelial
18 hyperplasia following dietary exposures of 50 or 100 ppm for approximately 3-5 weeks
19 (Suzuki etal.. 2010: Suzuki et al.. 2009). Yokohira et al. (2010) also observed both
20 urothelial cytotoxicity and hyperplasia in C57BL/6 mice after as few as six days of
21 exposure to 150 ppm arsenite in diet or four weeks exposure to 25 ppm arsenite in
22 drinking water. Simultaneous occurrence of cytotoxicity and hyperplasia was confirmed
23 by SEM observations in one mouse exposed to 150 ppm in food. Arnold etal. (2013) also
24 found the incidence of both urothelial cytotoxicity and "mild simple hyperplasia"
25 increasing over time in female rats exposed to 100 ppm inorganic arsenic in water for 14
26 days. While the number of animals involved was limited, the slight lag (18 hrs) between
27 the earliest detectable increase in cytotoxicity scores and the occurrence of hyperplasia
28 supports the proposed MOA as requiring cytotoxicity as a precursor event to increased
29 (regenerative) proliferation. The focus on low, non-cytotoxic concentrations in in vitro
30 studies, and the use of transformed cell lines for evaluating indicators of proliferation
31 (e.g., reduced doubling time) complicates further substantiating the sequential
32 relationship of cytotoxicity and regenerative proliferation in this MOA (Bredfeldt et al..
33 2006: Sens etal.. 2004).
34 Cohen etal. (2013) define the apical individual response in this MOA as the
3 5 development of tumors subsequent to regenerative proliferation. A methylated
36 metabolite, dimethylarsinic acid [DMA(V)], has been found to lead to tumor
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1 development in rats but not mice (Arnold et al.. 2006) and the incidence of urothelial
2 hyperplasia was also elevated in exposed animals. In contrast to the results for DMA(V),
3 inorganic arsenic has generally not been found to be carcinogenic in conventional rodent
4 bioassays with adult animals (reviewed by Tokar et al., 2010a). Differences in outcomes
5 between exposures to inorganic arsenic and DMA(V) may arise due to metabolism or
6 distribution of the compound in rats, which may not be relevant to metabolism or
7 distribution in humans (Cohen et al., 2013). As discussed below, higher incidences of
8 tumors in human populations with high exposures to inorganic arsenic suggest that this
9 MOA is relevant for understanding adverse health outcomes in humans, and emphasizes
10 the importance of recent efforts to develop new rodent models of inorganic arsenic
11 carcinogenicity (Cohen etal.. 2013).
12 In contrast to data in adult animals, inorganic arsenic has been found to cause tumors in
13 rodents after exposures beginning in utero (Table in Section 10.1) (Tokar et al.. 2011;
14 Waalkes et al., 2004b; Waalkes et al., 2003). Early life exposures in mice to inorganic
15 arsenic in drinking water resulted in significantly increased incidences of tumors in
16 multiple tissues (Table in Section 10.1) in male and female offspring (Tokar et al., 2011;
17 Waalkes et al.. 2004b: Waalkes et al.. 2003). Dose-related increases in hyperplasia were
18 also seen in several tissues, including the bladder, ovaries, and uterus of the females
19 (Tokar etal. 2011).
20 Data from in utero exposure studies in animals that show an association between early
21 life exposures to inorganic arsenic and subsequent tumor development suggest that
22 developing children may be an important susceptible population for effects associated
23 with this MOA. Based on findings by Suzuki et al. (2008). females may also have greater
24 susceptibility to effects associated with this MOA, although no other data were identified
25 to support this possibility. Other factors that might contribute to individual susceptibility
26 related to this MOA may include exposures to other substances causing cytotoxicity in
27 the bladder or other target organs. As discussed above, variations in arsenic methylating
28 ability in rodents do not correlate in straightforward manner with cytotoxic responses in
29 the bladder. On the other hand, Chen et al. (Chen et al. (2003b): Chen et al. (2003a))
30 report that increased urinary MMA/DMA levels may be associated with increased risk of
31 skin and bladder cancer, respectively in heavily exposed human populations.
32 With regard to population responses, Cohen et al. also suggest that the available
33 epidemiological studies support the regenerative proliferative mechanism, in that
34 increased arsenic-related cancer risk has only clearly been demonstrated in populations
35 with exposure to relative high doses of inorganic arsenic (reviewed in Cohen et al.. 2013)
36 (Table in Section 10.1). This would be consistent with a situation where increased cancer
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 risk only occurred when internal concentrations of As(III) and/or other toxic metabolites
2 reached levels associated with cytotoxicity, followed by regenerative proliferation and
3 tumor development. However, very few epidemiological studies have been conducted
4 with sufficient statistical power to detect small elevations in risk at low exposures and
5 thus uncertainty is associated with the assertion of a threshold exposure below which
6 elevated cancer risks do not occur. A full review of the epidemiological literature related
7 to inorganic arsenic carcinogenicity is discussed separately in other documents prepared
8 for the inorganic arsenic IRIS assessment.
9.3 Hypothesized MOA: Effects Mediated by Endocrine
Signaling
Relevant Health Effects: Developmental Neurotoxicity, Male Infertility, Prostate Cancer
9 As discussed in the Preamble, inorganic arsenic metabolism leads to a number of
10 metabolites; however, limited data were identified linking specific metabolites to the
11 adverse health effects associated with the endocrine system. Nevertheless, several
12 adverse health effects following exposure to inorganic arsenic may result from events
13 mediated by the endocrine system (Goggin et al.. 2012; Davey et al.. 2008; Prins. 2008)
14 (Figure 9-3). The molecular initiating event (MIE) in this MOA is a topic of ongoing
15 research but based on literature reviewed for this summary may involve an interaction
16 between inorganic arsenic and an element of the transcription complex for gene
17 activation of nuclear hormone receptors. Specifically, inorganic arsenic may interact or
18 modulate one of the following elements: 1) the hormone binding domain of the hormone
19 receptor, 2) signaling pathways (e.g., mitogen activated protein kinases [MAPKs],
20 extracellular signal-regulated kinases [ERK 1/2]) responsible for posttranslational
21 modification of steroid hormone receptor proteins (e.g., coactivator phosphorylation), or
22 3) histone modifying proteins (i.e., acetylases, deacetylases, methylases) involved in
23 receptor activation (Barr et al.. 2009; Rosenblatt and Burnstein. 2009; Stoicaet al.. 2000).
24 Notably, the first MIE option, interaction with the hormone binding domain, may be
25 specific to estrogen receptor alpha (ERa), while the other possibilities may be more
26 broadly applicable across both steroid receptors (e.g., glucocorticoid receptor [GR],
27 progesterone receptor [PR], androgen receptor [AR], mineralocorticoids [MR]) and the
28 larger class of nuclear hormone receptors (e.g., thyroid hormone receptor [TR], retinoic
29 acid receptor [RAR]) (Davev et al.. 2008; Bodwell et al.. 2006; Stoicaet al.. 2000).
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1
2
3
4
5
6
7
8
9
10
11
Across receptor types, the literature indicates that the MIE is followed by a series of
biochemical responses that can be broadly characterized as altering gene activation and
subsequent cell signaling mediated by nuclear hormone receptors (Table in Section
10.2). In the case of ERa, inorganic arsenic may alter gene activation by inhibiting
binding of the natural ligand, estradiol (E2), to the receptor (Stoica et al., 2000). Low
levels of inorganic arsenic (1 nM) can then activate the receptor at levels approaching
that of E2 (Stoica et al.. 2000). Activation of ERa results in altered expression of genes
regulated by the receptor (e.g., vitellogenin, pS2, PR), which is measurable at the mRNA
and protein levels (Davey et al., 2007; Stoica et al., 2000). Importantly, inorganic arsenic
activation of ERa gene transcription is likely mediated by the receptor since treatment
with antiestrogen blocks gene transcription mediated by the receptor (Stoica etal.. 2000).
iAs
Metabolism
Products
Multiple
metabolism
products
likely relevant
MIE
Multiple
Possibilities:
Direct
hormone
receptor
interaction
Indirect
hormone
receptor
activation
modulation
»
Biochemical
Response
T-U
Hormone
receptor
activation
T-U
Receptor-
mediated
gene
expression
»
Cellular
Response
Cytotoxicity,
Proliferation
Altered cell
cycle
Altered
intracellular
distribution
of hormone
receptor
»
Tissue/
Organ
Response
Altered:
-HPA& HPG
activity
-Receptor
levels
-Reproductive
tissue weights
& hormone
levels
»
Individual
Response
Altered
learning &
behavior
(spatial
memory,
depressive-
like
behavior)
Population
Response
Associated
health
effects:
DNT
Male
infertility
Prostate
cancer
Abbreviations: Inorganic arsenic (iAs); molecular initiating events (MIEs); hypothalamic-pituitary-adrenal (HPA);
hypothalamic-pituitary-gondal (HPG); developmental neurotoxicity (DNT)
See Summary Text and Table for references; Figure based on Anklev et al. (2010).
Note: Figure hows a high-level summary of key events from the initial molecular interaction through a possible population level response. The
arrows link each key event (e.g., individual responses lead to population responses), but do not necessarily link each specific example response
(e.g., behavioral changes are not linked to male infertility). Of particular note for this MOA is that evidence at the individual level was only
identified for effects related to developmental neurotoxicity, even though population level responses indicate effects in other systems (i.e.,
reproductive effects). As the assessment development process moves forward additional evidence may provide better understanding of the key
events in this MOA and the connections between them.
Figure 9-3
Hypothesized mode of action for effects mediated by endocrine signaling.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 While the above sequence of biochemical responses is supported by one group of
2 investigators, others provide evidence that responses at the ERa receptor are similar to
3 those of other nuclear hormone receptors (e.g., GR, PR, TR, RAR) (Davey et al.. 2007;
4 Stoicaet al.. 2000). Under this second possible sequence of events, the MIE likely leads
5 to alterations in posttranslational modifications (e.g., phosphorylation) of coactivator
6 proteins (e.g., TIF2, GRIP1) that are critical for transcriptional activity at response
7 elements for each receptor (e.g., glucocorticoid receptor response elements [GREs]) (Barr
8 et al.. 2009; Rosenblatt and Burnstein. 2009): these modifications may result in impaired
9 interactions between coactivators (e.g., CARM1 and GRIP1) (Barr etal. 2009).
10 Alternatively, the MIE may lead to alterations in histone modifications necessary for
11 receptor-mediated gene activation (e.g., lower acetylation or methylation) (Barr et al..
12 2009). Ultimately, perturbations in the transcriptional complex impair receptor binding to
13 response elements, leading to changes in receptor-mediated gene activation (Barr et al..
14 2009; Rosenblatt and Burnstein. 2009). Changes in gene activation mediated by inorganic
15 arsenic through this MOA may result in either activation or suppression of gene activity.
16 Where low levels of inorganic arsenic (i.e., nanomolar range) may elevate hormone-
17 mediated gene activation, higher, non-cytotoxic concentrations may suppress hormone-
18 mediated gene activation (Davey et al.. 2008; Bodwell et al.. 2006; Bodwell et al.. 2004).
19 In addition to different outcomes resulting from low versus higher inorganic arsenic
20 exposure levels, differences in levels of hormone receptors may underlie different
21 responses across organ and tissue types (Bodwell et al.. 2006).
22 Differences in biochemical responses to inorganic arsenic may ultimately lead to changes
23 in cellular responses (e.g., cell proliferation, cell death) that vary by cell type based on
24 the factors noted above (e.g., receptor levels, ligand levels) (Rosenblatt and Burnstein.
25 2009: Davev et al.. 2008: Davev et al.. 2007: Stoicaet al.. 2000) (Table in Section 10.2).
26 Data from three transformed cell lines show variation in the LC50 for cytotoxicity
27 ranging from 3 to 15 (iM (Davey et al.. 2008: Davey et al.. 2007). While most evidence
28 suggests that cytotoxicity and proliferation elicited through this MOA are partially
29 mediated by the natural hormone ligand (E2) (Rosenblatt and Burnstein. 2009: Davey et
30 al.. 2008: Davev et al.. 2007: Stoica et al.. 2000): some evidence suggests that changes in
31 cell number elicited through ERa does not require the natural ligand, E2, and may be
32 mediated by alterations in cell cycle control (Davev et al.. 2007: Chow et al.. 2004:
33 Stoicaet al.. 2000). In addition to changes in cell number, inorganic arsenic mediated
34 changes in endocrine signaling may lead to alterations in intracellular hormone
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 distribution (i.e., shift from cytosol to nucleus) if exposure occurs early in life (e.g.,
2 during gestation and early postnatal development) (Goggin et al., 2012).
3 Changes at the cellular level can ultimately lead to tissue or organ system responses that
4 in this MOA include alterations in elements of the hypothalamic-pituitary-adrenal
5 (HPA) axis (e.g., intracellular receptor distribution, protein glycosylation), the
6 hypothalamic-pituitary-gonadal (HPG) axis (e.g., lower concentrations of
7 gonadotropins and sex steroid hormones), testicular toxicity, impaired
8 spermatogenesis, toxicity to the female reproductive system, and hormone-
9 dependent tissue remodeling (i.e., morphogenesis) (Goggin et al.. 2012; Chatterjee and
10 Chatterii. 2010; Davev et al.. 2008; Jana et al.. 2006; Sarkar et al.. 2003; Chattopadhyav
11 etal.. 1999) (Table in Section 10.2). Data supporting alterations in the HPA axis are
12 available from a developing animal model, suggesting that early life exposures to
13 inorganic arsenic may have particular effects at the individual level, as discussed below
14 (Goggin et al.. 2012). Still other studies have suggested endocrine-mediated effects of
15 inorganic arsenic exposure on male and female reproductive systems (e.g. decreased
16 reproductive tissue weight, sperm count, infertility, altered activity of ovarian and
17 testicular enzymes, and prostate cancer), which follows from alterations in elements of
18 the HPG axis noted above (Chatterjee and Chatterii. 2010; Rosenblatt and Burnstein,
19 2009: Prins. 2008: Jana et al.. 2006: Pant et al.. 2004: Sarkar et al.. 2003: Chattopadhvav
20 etal.. 1999). Changes in morphogenesis were observed in an amphibian model of thyroid
21 hormone (TH) activity that also has important implications for inorganic arsenic effects
22 on TH during the perinatal period of human development (6 months of gestation through
23 early postnatal development) (Goggin et al.. 2012).
24 Little evidence was identified to link tissue or organ level responses to individual
25 responses through this MOA; however, several studies suggest that alterations in GR
26 transcription and subsequent changes in HPA axis activity, such as those outlined above,
27 can lead to developmental neurotoxicity (e.g., impaired stress response, depressive-like
28 behaviors) following developmental inorganic arsenic exposure in mice (Goggin et al..
29 2012; Martinez-Finley et al.. 2011; Martinez-Finley et al.. 2009; Martinez et al.. 2008)
30 (Table in Section 10.2). Efforts to carry out a comprehensive literature search are
31 ongoing and may identify additional studies with data relevant to individual level
32 responses resulting from inorganic arsenic effects on the endocrine system.
33 No data were identified indicating the types of responses that might occur in susceptible
34 individuals through this MOA. Given the role of steroid receptors in this MOA,
35 differences in receptor or steroid levels across lifestages or physiologic conditions may
36 confer differences in response to inorganic arsenic exposures across individuals and
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 provide insight on potentially susceptible individuals (Bodwell et al.. 2006). The
2 influence of receptor levels is particularly important in considering developmental
3 inorganic arsenic exposures due to the critical role that TH, RAR and other nuclear
4 hormone receptors play during development coupled with evidence of developmental
5 neurotoxicity in animal models of inorganic arsenic exposure (Goggin et al., 2012;
6 Martinez-Finley et al.. 2011; Martinez-Finley et al.. 2009; Davey et al.. 2008; Martinez et
7 al., 2008). Thus, pregnant women and developing children may be particularly
8 susceptible to adverse outcomes from inorganic arsenic exposure.
9 Responses in susceptible individuals clearly influence responses observed at the
10 population level. To that end, findings in rodents suggesting that endocrine effects may
11 result in developmental neurotoxicity are concordant with findings in the epidemiology
12 literature that show a correlation between early life exposure to inorganic arsenic and
13 cognitive function ("Wasserman et al.. 2007). Other literature supports higher incidences
14 of male infertility and prostate cancer in populations exposed to inorganic arsenic,
15 although the connections between these observations and effects on the endocrine system
16 are less clear. Ongoing efforts to identify relevant literature may identify additional data
17 to connect inorganic arsenic effects on the endocrine system to population level
18 responses.
9.4 Hypothesized MOA: Effects Mediated By Epigenetic
Mechanisms
Relevant Health Effects: Bladder cancer, skin cancer, skin lesions
19 As detailed below, several studies were identified that indicate epigenetic mechanisms
20 may mediate some of the adverse health effects associated with exposure to inorganic
21 arsenic (Figure 9-4). There is a broad consensus in the literature that the depletion of
22 glutathione and S-adenosylmethionine (SAM) during cellular metabolism of inorganic
23 arsenic species are important molecular initiating events (MIEs) of this MOA (Martinez
24 et al.. 2011; Ren et al.. 2011; Reichard and Puga. 2010). In addition, inorganic arsenic
25 can also elevate levels of reactive oxygen species (ROS), which may in turn deplete
26 SAM, in conjunction with, or separately from SAM depletion that results from inorganic
27 arsenic methylation. Specifically, some evidence suggests that the depletion of
28 glutathione (GSH) due to elevated oxidative stress results in the shunting of S-adenosyl
29 homocysteine in order to replenish GSH, through the transsulfuration pathway, and away
30 from the synthesis of SAM, inducing a shortage of methylation cofactors (reviewed by
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 Reichard and Puga. 2010). Consistent with these findings and with multiple observations
2 of GSH depletion, some investigators interpret the downstream epigenetic changes
3 associated with inorganic arsenic exposure as mainly resulting from oxidative stress
4 effects [(Kitchin and Conolly. 2010); see Oxidative Stress MOA Summary)].
5 The depletion of SAM may lead to one of the most well-studied of arsenic-associated
6 epigenetic effects at the biochemical response level, namely, changes in DNA
7 methylation patterns. Like arsenic 3+ methyltransferase (AsSmt), DNA
8 methyltransferases (collectively, DNMTs) use SAM as a methyl donor. Therefore,
9 reduced cellular SAM levels as a result of increased AsSmt activity could lead to reduced
10 DNA methylation. Several studies have found reduced levels of DNMT activity or
11 expression in arsenic-exposed cell lines (Reichard et al.. 2007; Benbrahim-Tallaa et al..
12 2005; Zhao et al.. 1997). The observed changes in RNA expression levels suggest that
13 factors in addition to SAM depletion may be responsible for changes in DNMT activity
14 (Reichard and Puga. 2010).
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
iAs
Metabolism
Products
Multiple
metabolic
products
involved in
xJ/SAM
&T- ROS
^
MIE
Multiple
Possibilities:
^oxidative
stress
GSH, SAM
depletion
^
Biochemical
Response
Promoter
hyper-, hypo-
methylation
Histone
alterations
Global DNA
hypo-
methylation
t\4< miRNA
expression
,
Cellular
Response
Proliferation
Apoptosis
Differentiation
Trans-
formation
,
Tissue/
Organ
Response
Pre-
cancerous
skin lesions
Liver
steatosis
Vascular
effects
^
Individual
Response
Impaired
memory
(rodents)
^
Population
Response
Increased
incidence of:
Bladder
cancer
Skin cancer
Skin lesions
Hyper-
methylated
genes
associated
with diseases
Abbreviations: Inorganic arsenic (iAs); molecular initiating events (MIEs); glutathione (GSH); S-adenosylmethionine (SAM);
microRNA (miRNA)
See Summary Text and Table for references; Figure based on Anklevetal. (2010).
Note: Figure shows a high-level summary of key events from the initial molecular interaction through a possible population level response. The
arrows link each key event (e.g., individual responses lead to population responses), but do not necessarily link each specific example response
(e.g., impaired memory is not linked to skin cancer). Of particular note for this MOA is that evidence at the individual level was only identified
for effects related to impaired memory, even though population level responses indicate effects in other systems (e.g., bladder, skin). As the
assessment development process moves forward additional evidence may provide better understanding of the key events in this MOA and the
connections between them.
Figure 9-4 Hypothesized mode of action for epigenetic mechanisms underlying
associated health effects of inorganic arsenic exposures.
1
2
3
4
5
6
7
8
9
10
11
Sufficiently reduced DNMT activity would likely inhibit cells' ability to maintain normal
DNA methylation pattern and reduce the overall extent of DNA methylation. Global
DNA hypomethylation after inorganic arsenic exposure has indeed been observed in a
range of in vivo and in vitro studies (Pilsner etal.. 2012; Coppin et al.. 2008; Reichard et
al.. 2007; Benbrahim-Tallaa et al.. 2005; Chen et al.. 2004b; Sciandrello et al.. 2004; Xie
et al.. 2004; Chen etal.. 2001; Zhaoetal.. 1997) (Table in Section 10.3). Reduced
DNMT activity and SAM depletion were seen in some, but not all, of these studies. A
small number of studies have also reported global DNA hypermethylation in human
populations and animals (TVIajumdar et al.. 2010; Pilsner et al.. 2007; Zhong and Mass.
2001). but it is not clear whether these studies had sufficient resolution to resolve truly
"global" changes from promoter-specific changes, which are discussed below.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 In addition to non-specific reductions in DNA methylation, numerous studies have found
2 changes in specific gene promoter DNA methylation after inorganic arsenic exposure
3 (Ren et al.. 2011). DNA hypermethylation in the promoter regions of several tumor
4 suppressor genes has been reported in human cells (Smeester et al.. 2011; Chen et al..
5 2007a: Zhang et al.. 2007; Chanda et al.. 2006; Marsit et al.. 2006b). and in a number of
6 in vivo (Cm et al.. 2006a) and in vitro (Jensen et al.. 2008; Chai et al.. 2007; Fu and Shen.
7 2005; Mass and Wang. 1997) studies (Table in Section 10.3). Of note, hypermethylation
8 in the promoter regions of the tumor suppressor genes, Cdkn2a and Rassf 1 were
9 correlated with reduced mRNA expression in lung tissue of mice chronically exposed to
10 As(V) (Cui et al.. 2006a). indicating a role for epigenetic alterations in gene expression
11 levels related to malignant transformation. In agreement with most studies analyzing
12 global DNA methylation, hypomethylation has also been observed in Hras and ERa gene
13 promoter regions in livers of mice exposed to As(III) (Chen et al.. 2004b; Waalkes et al..
14 2004a: Okoji etal.. 2002). After 18.5 weeks of As(III) exposure in dietary methyl
15 deficient C57BL/6J mice, liver tissue exhibited steatosis and microgranulomas, along
16 with Hras promoter hypomethylation, highlighting an important link between inorganic
17 arsenic exposure and a dietary methyl deficient susceptible population (Okoji et al..
18 2002). Furthermore, ERa promoter hypomethylation was observed in combination with
19 increased expression of ERa and cyclin D1 (mRNA and protein; biomarkers of
20 hepatocellular lesions and carcinogenesis) in livers of mice chronically exposed to As(III)
21 (Chen et al.. 2004b). Taken together, the data suggest a general, but not entirely
22 consistent, pattern of 1) promoter methylation in tumor suppressor and apoptosis-related
23 genes, and 2) hypomethylation of proto-oncogenes and proliferation-related genes. In
24 addition, Jensen et al. [(Jensen et al. (2009b): Jensen et al. (2008))] have observed DNA
25 hypermethylation in promoter regions also subject to histone hypoacetylation (see
26 below). The mechanism by which the specificity of arsenic-associated promoter
27 methylation is established is not known (Ren et al.. 2011).
28 A second major epigenetic response to inorganic arsenic exposure that the literature
29 identifies is histone protein modifications. Histone proteins maintain the structure of
30 chromatin and play an important role in gene transcription and repression. The most
31 well-studied chemical modification of histones in response to inorganic arsenic exposure
32 are changes in acetylation and methylation patterns, but evidence also shows an
33 association between inorganic arsenic and increased histone phosphorylation (Ren et al..
34 2011). Changes in the acetylation pattern of H3 and H4 lysine residues after acute
35 inorganic arsenic exposure have been reported in the following cell lines: mouse
36 adenocarcinoma (Barr et al.. 2009). human bladder (Chu etal.. 2011; Jo et al.. 2009;
37 Jensen et al.. 2008). human lung (Li et al.. 2003). and human liver (Ramirez et al.. 2008)
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 (Table in Section 10.3). Most in vitro studies report decreased lysine acetylation after
2 inorganic arsenic exposure, which is in agreement with recent studies that described
3 decreased H3K9 acetylation in blood cells of humans exposed to inorganic arsenic
4 through drinking water (Arita et al.. 2012; Chervona et al.. 2012; Arita and Costa. 2009).
5 However, increased H3K14 acetylation and H3S10 phosphorylation associated with c-
6 Jun and c-Fos chromatin, along with increased expression of c-Jun and c-Fos, were
7 observed in human fibroblasts (Li et al.. 2003). c-Jun and c-Fos are important
8 transcriptional mediators of cellular differentiation, proliferation, and apoptosis. The
9 relevance of this finding for environmental exposures is questionable, however, because
10 this study used high and likely non-physiologic As(III) exposures (400 (JVI), whereas
11 other studies used less than 10 (iM As(III). Increased histone acetylation has been shown
12 to be associated with the inhibition of histone deacetylase activity; however the
13 underlying mechanism of this reduced enzyme activity is not known (Ramirez et al..
14 2008).
15 Results of other histone modification experiments have been quite variable. Both
16 increased and decreased methylation of H3 arginine and lysine residues were observed in
17 in vitro and in vivo lung and liver models. In contrast, increased H3K9 dimethylation has
18 been reported in human peripheral blood cells (Arita et al.. 2012; Chervona et al.. 2012).
19 mouse liver (Suzuki andNohara. 2013) and human lung adenocarcinoma cells (Zhou et
20 al.. 2008) after inorganic arsenic exposure. Of note, histone modifications associated with
21 inorganic arsenic exposure have been reported in connection with downstream effects,
22 including decreased p 16 expression in the absence of altered mRNA expression levels
23 (Suzuki andNohara. 2013) and increased HMT G9aprotein and mRNA levels (Zhou et
24 al.. 2008). Increased phosphorylation of H3S10 was linked with increased expression of
25 c-Jun and c-Fos and upregulation of caspase 10 (Li et al.. 2003). Taken together, studies
26 examining histone modifications indicate that inorganic arsenic exposure mediates
27 epigenetic alteration of DNA and histones, followed downstream alterations in gene
28 expressions and, as discussed below, some phenotypic changes in exposed cells.
29 An increasing body of evidence suggests that microRNA expression is altered in response
30 to inorganic arsenic exposure (Kaul et al.. 2014; Li et al.. 2012; Cao et al.. 2011; Marsit
31 et al., 2006a) (Table in Section 10.3). MicroRNAs, which generally suppress the
32 translation of mRNA into protein and enhance mRNA degradation, are both up- and
33 downregulated (often in the same model system) after inorganic arsenic exposure. Recent
34 evidence links altered microRNA expression to downstream effects and adverse events.
35 For example, the downregulation of hsa-miRNA-19a has been associated with cell
36 growth arrest and apoptosis (Cao et al.. 2011). More importantly, the upregulation of hsa-
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 miR-21 in response to As-induced ROS has been linked to carcinogenic transformation, a
2 likely epigenetic mediated MOA linked to changes in microRNA expression (Ling et al.,
3 2012). As discussed above, findings in different test systems are often inconsistent, and
4 the correlations of epigenetic changes with downstream effects of gene expression and
5 cell phenotype are just beginning to be elucidated.
6 Altered cellular phenotypes, including malignant transformation, have been associated
7 with epigenetic changes following inorganic arsenic exposure in several studies (Table in
8 Section 10.3). In addition to the transformation of embryonic lung fibroblasts noted
9 above (Ling et al.. 2012). the malignant transformation of p53 knocked down human
10 bronchial epithelial cells has been associated with downregulated hsa-miR-200b via
11 increased DNA promoter methylation (Wang et al.. 201 Ib). Jensen et al. (2009a; 2009b:
12 2008) also report epigenetic changes (parallel changes in DNA promoter methylation and
13 histone acetylation) in selected genes in parallel with the development of malignant
14 phenotype in human urothelial cells. Moreover, epigenetic alternations after inorganic
15 arsenic exposure have been reported in connection with tissue or organ system
16 responses, including skin lesions in humans (Banerjee et al., 2013; Pilsner et al.. 2009)
17 and liver effects in mice, such as steatosis, microgranulomas, and hepatocellular
18 carcinoma (Chen et al., 2004b; Waalkes et al., 2004a; Okoji et al.. 2002). Organ system
19 responses have been associated with both DNA hyper- (Banerjee et al.. 2013) and
20 hypomethylation (Pilsner et al., 2009; Chen et al., 2004b; Waalkes et al.. 2004a; Okoji et
21 al.. 2002).
22 While individual responses have been widely reported after inorganic arsenic exposure,
23 there are relatively few studies linking responses at the individual level to epigenetic
24 changes. As discussed below, there are some data connecting health effects associated
25 with inorganic arsenic exposures and epigenetic changes in population-based studies.
26 One study on response at the individual level in animals did evaluate inorganic arsenic
27 induced epigenetic changes in relation to cognitive function and found contextual
28 memory deficits in rats exposed during gestation and early postnatal development
29 (Martinez et al., 2011). Ongoing efforts to complete a comprehensive literature search
30 may identify additional studies that link inorganic arsenic exposure to epigenetic changes
31 and subsequent health effects.
32 Based on available mechanistic and in vivo studies, a range of factors affecting
33 individual variations in susceptibility may relate to epigenetic mechanisms underlying
34 adverse health effects of inorganic arsenic exposures (Table in Section 10.3). These
35 include dietary deficiencies, life stage susceptibility, gender, genetics, and smoking.
36 Several studies have investigated the relationships between dietary sufficiency and
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 epigenetic changes associated with inorganic arsenic exposure. Low folate status has
2 been associated with the development of skin lesions in Bangladeshi adults (Pilsner et al..
3 2007). as well as Hras promoter DNA hypomethylation, steatosis and microgranulomas
4 in livers of mice exposed to inorganic arsenic (Okoji et al.. 2002). While the proposed
5 epigenetic MOAs suggest that dietary intake of methionine and folate intake would
6 positively correlate with DNA methylation, conflicting evidence has been reported.
7 Associations between increases in DNA methylation and inorganic arsenic exposure were
8 only observed in individuals with adequate folate status (Pilsner et al.. 2007). Moreover,
9 Lambrou et al. found that the exposure-response relationship between inorganic arsenic
10 exposure and changes in DNA methylation in ALU retrotranspon elements (thought to be
11 involved in cancer and other diseases) varied depending on folate intake (Lambrou et al..
12 2012). Study subjects were elderly males from the Normative Aging Study whose arsenic
13 exposures had been relatively low. Evidence also suggests adverse effects related to
14 folate supplementation and subsequent high fetal exposure to reactive As metabolites,
15 where reduced fetal weights and altered fetal liver DNA methylation was observed after
16 in utero exposure from mouse dams fed a high folate diet (Tsang et al.. 2012).
17 In utero exposures to inorganic arsenic have been a major focus of efforts to identify
18 susceptible life stages for epigenetic effects of As exposure. Studies in rodents have
19 detected DNA hypomethylation (Martinez etal.. 2011; Waalkes et al.. 2004a) and
20 numerous DNA methylation changes at specific loci (Tsang etal.. 2012). Interestingly,
21 the analysis of cord blood of inorganic arsenic exposed mothers revealed the upregulation
22 of 12 miRNAs linked to cancer, diabetes, and immune response signaling pathways
23 (Rager etal.. 2014). Limited studies have attempted to evaluate the effect of gender on
24 epigenetic changes associated with inorganic arsenic exposure. In one study, DNA
25 methylation status differed between genders in mice exposed to As(III) independent of
26 cellular SAM levels (Nohara et al.. 2011). Another study reported a potential genetic
27 susceptibility related to epigenetic changes after inorganic arsenic exposure. In
28 peripheral blood samples of Argentinian women, an AS3MT haplotype associated with
29 efficient inorganic arsenic metabolism revealed increased methylation of the AS3MT
30 gene region and reduced AS3MT mRNA expression (Engstrom et al.. 2013). The
31 methylation status and expression of other genes on the same haplotype block as AS3MT
32 were also altered, being either upregulated or downregulated, and the authors suggested
33 that these genes may also be involved in inorganic arsenic metabolism or responses to
34 inorganic arsenic exposure.
3 5 The susceptible individual responses linked to genetic factors in different populations
36 may shed light on population responses associated with the epigenetic mechanisms of
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 inorganic arsenic-induced adverse health outcomes. In addition, changes in DNA
2 methylation patterns (hyper- or hypomethylation) have be identified in humans with skin
3 and bladder cancers (Chanda et al.. 2006: Marsit et al.. 2006b). Pilsner et al. (2009) found
4 a relationship between global DNA hypomethylation and the risk of inorganic arsenic-
5 induced skin lesions. Smeester et al. (2011) identified 182 genes whose promoter regions
6 were consistently hypermethylated in a Mexican population with arsenicosis symptoms
7 (skin lesions). Notably, they identified a network of 17 highly-methylated tumor
8 suppressor and related genes (the "suppressome"), and suggested that downregulation of
9 these genes increased the risk of inorganic arsenic-associated adverse effects. Future
10 research may strengthen existing evidence related to susceptible individuals, including
11 those with dietary methyl deficiencies or genetic polymorphisms, and reveal additional
12 factors that influence subsequent population level responses.
9.5 Hypothesized MOA: Immune Mediated Effects
Relevant Health Effects: Suppression of humoral immunity (i.e., decreased antibody
response), Suppression of innate immunity (decreased macrophage function),
Respiratory infection, Gastrointestinal infection, Contact hypersensitivity response
13 Several adverse health effects following exposure to inorganic arsenic may result from
14 events mediated by the immune system, including: suppression of humoral immunity
15 (decreased antibody response), suppression of macrophage function, and other aspects of
16 innate immunity (Figure 9-5). The molecular initiating event (MIE) for arsenic immune-
17 mediated effects is unknown, although available literature indicates that it likely includes
18 a pathway that leads to reactive oxygen species (ROS) generation and a pathway that is
19 unrelated to ROS. Because oxidative stress (and the generation of ROS) is covered in a
20 separate MOA, it will only be discussed briefly here with an indication as to where it may
21 play a role in immune-mediated effects. Specifically, there is evidence that apoptosis of
22 T-cells [e.g., (Gupta et al., 2003)1 as well as monocytes/macrophages [e.g., (Park et al..
23 2003)] is ROS dependent indicating that oxidative stress may contribute to effects on
24 both humoral and innate immunity. However, the molecular initiating events for most
25 immune and immune-mediated effects are unknown with evidence that some do not rely
26 on ROS production. For example recent studies by Bourdonnay et al. (2009) have
27 demonstrated that arsenic trioxide alters macrophage gene expression in human
28 macrophages (prepared from peripheral blood mononuclear cells (PBMC) from healthy
29 donors) through redox-sensitive signaling pathways that are independent of ROS
30 production.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 There are a number of biochemical responses within immune cells that are likely to
2 contribute to immune-mediated inorganic arsenic effects (Table in Section 10.4). First,
3 there is considerable evidence that inorganic arsenic exposure decreases the production of
4 cytokines by stimulated T-lymphocytes, particularly secretion of interleukin-2 (IL-2)
5 demonstrated at the protein and mRNA level. Inorganic arsenic not only decreased IL-2
6 secretion in culture conditions with T-cell superantigens (e.g., PHA or ConA), but more
7 importantly in studies where T-cells were stimulated with antibodies to CD3/CD28,
8 which mimic the biological function of natural antigens activating T-cells through T-cell
9 receptor engagement. Following activation, IL-2 stimulates survival of antigen-specific
10 T-cells, expansion of antigen-selected T-cells, differentiation, and development of
11 immunologic memory. Therefore, arsenic-induced inhibition of IL-2 as well as decreased
12 T-cell proliferation [e.g., (Vega et al.. 1999; Gonsebatt et al.. 1994)] suggests altered
13 biochemical responses that would contribute to reduced antibody responses. Evidence for
14 reduced IL-2 secretion includes populations with chronic inorganic arsenic exposure
15 (Biswas et al., 2008; Soto-Pena et al.. 2006) as well as in vitro arsenic exposure of cells
16 from healthy individuals (Morzadec et al.. 2012; Galicia et al.. 2003; Vegaet al.. 1999)
17 mouse in vivo and in vitro studies (Cho et al.. 2012; Soto-Pena and Vega. 2008; Conde et
18 al.. 2007). and from non-mammalian models including chickens (Das et al.. 2011).
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
iAs
Metabolism
Products
No evidence
on specific
metabolites
^
MIE
Unknown
(Hypotheses:
iAs species
-f ROS
-ROS-
independent
oxidative
stress
pathways)
^
Biochemical
Response
Examples:
sl/T-lymphocyte
cytokine
production
Altered cell
signaling (e.g.,
NF-kB pathway)
^
Cellular
Response
Examples:
sl/Monocyte/
macrophage
activity or #s
cytotoxicity,
-tNeutrophil
apoptosis
^
Tissue/
Organ
Response
sl/Thymus
^
Individual
Response
Examples:
si/ DTH
si/ Antibody
si/ Host
resistance
(to infection
^
Population
Response
Increased
incidence of:
Respiratory
infection
Disease/cold
fever
Infection-
related Gl
disease
Abbreviations: Inorganic arsenic (iAs); molecular initiating event (MIE); reactive oxygen species (ROS); delayed-type hypersensitivity (DTH)
See Summary Text and Table for references; figure based on Ankley et al. (2010).
Note: Figure shows a high-level summary of key events from the initial molecular interaction through a possible population level response. As
the assessment development process moves forward additional evidence may provide better understanding of the key events in the MOA and the
connections between them.
Figure 9-5
Hypothesized mode of action for effects mediated by the immune system.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
There is also consistent evidence that inorganic arsenic reduces T-cell secretion of other
cytokines including interferon-gamma (IFN-y) and less consistent evidence for reduced
IL-4, IL-5, IL-10, and IL-12. Together, evidence suggests that inorganic arsenic alters a
wide variety of immune cellular signals and pathways that relate to both innate and
humoral immunity. In general these cytokines have multiple roles that impact both innate
and humoral immune responses. For example, IFN-y is important for antigen presentation
by macrophages and reductions in IFN-y may therefore contribute to reduced antibody
response. IFN-y also directly inhibits viral replication and contributes to multiple aspects
of the innate immune system including natural killer (NK) cell activity and lysosome
activity of macrophages.
Other biochemical responses include altered cell signaling in NF-KB (Zheng et al.. 2012;
Lemarie et al.. 2006) and decreased transcription factor ERG2 (Bourdonnay et al.. 2009).
Lemarie et al. (2006) reported that arsenic trioxide induced apoptosis of human
peripheral blood derived monocytes during macrophage differentiation via a NF-KB-
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 dependent pathway. Bourdonnay et al. (2009) also reported arsenic trioxide-associated
2 inhibition of human macrophage differentiation. The authors suggest that the observed
3 effects on macrophages are likely to be mediated by reduced expression of EGR2, which
4 was independent of ROS production.
5 There are a number of studies reporting cellular phenotypic changes associated with
6 inorganic arsenic exposure that support a link between biochemical responses and tissue
7 or individual responses for immune-mediated arsenic effects. Many of the studies outline
8 effects on monocytes or macrophages including decreased recruitment in mice [e.g.,
9 (Patterson et al.. 2004)]. reduced differentiation in humans (Lemarie et al.. 2006). altered
10 morphology in mice and humans (Banerjee et al.. 2009; Bishayi and Sengupta. 2003).
11 and increased apoptosis in mice and humans (Lemarie et al.. 2006; Parketal.. 2003; de la
12 Fuente etal.. 2002). Phenotypic changes also included adverse changes in measures of
13 macrophage functional responses including decreased adhesion, reduced chemotaxis,
14 decreased phagocytosis of bacterial challenge, and reduced generation of ROS (Banerjee
15 et al.. 2009: Aggarwal et al.. 2008: Ghosh et al.. 2006: Arkusz et al.. 2005: Bishavi and
16 Sengupta. 2003; Sengupta and Bishavi. 2002). These cellular phenotypic changes were
17 associated with inorganic arsenic exposure in vitro to cells from healthy individuals [e.g.,
18 (de la Fuente et al.. 2002)1. experimental animals exposed to inorganic arsenic in drinking
19 water [e.g., catfish (Ghosh et al.. 2006); chickens (Aggarwal et al.. 2008) and mice
20 (Sengupta and Bishavi. 2002)1. and humans from inorganic arsenic-exposed populations
21 [e-g-, (Banerjee et al.. 2009)]. There are several studies that also reported increased
22 apoptosis of human neutrophils (Binet and Girard. 2008). human T-cells (Gupta et al..
23 2003). and mouse B-cells (Harrison and McCoy. 2001) following in vitro arsenic
24 exposure.
25 There are primary (i.e., bone and thymus) and secondary (spleen, lymph nodes, and
26 mucosal associated tissue) immune organs; however, immune cells are distributed
27 throughout the body and travel extensively through blood and lymph. Therefore there
28 may be important system-wide changes in local cell populations or function that are not
29 readily apparent when categorized at a tissue or organ response level. The one organ-
30 level arsenic-related response observed that is likely to contribute to immune-mediated
31 arsenic effects is decreased size of the thymus, which as the site of T-cell maturation is an
32 important part of humoral immunity. As a single parameter, thymus size is an immune
33 cell measure with low predictive value for immunotoxicity; however it may lend support
34 to altered immune function indicated by other assays (Luster et al.. 1992). particularly
35 immune functional measures such as T-cell mediated antibody response. Thymus size in
36 children from the Metlab region of Bangladesh was negatively associated with maternal
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 arsenic exposure determined at 8 and 30 weeks of gestation (Moore et al.. 2009; Raqib et
2 al., 2009). Decreased absolute, but not relative, thymus size was also reported in chickens
3 exposed to 3.7 ppm sodium arsenite in drinking water (Aggarwal et al.. 2008).
4 There are multiple inorganic arsenic-associated individual responses that represent
5 adverse functional immune changes as part of the immune-mediated arsenic effects.
6 Multiple studies report arsenic-associated suppression of the T-cell dependent antibody
7 response or response to a T-cell antigen such as sheep red blood cells (SRBCs) or
8 keyhole limpet hemocyanin (KLH). Male mice exposed to 1 or 50 ug/m3 arsenic trioxide
9 for 14 days, or 0.5-10 ppm sodium arsenite in drinking water had reduced T-cell
10 dependent antibody response to SRBC (Nain and Smits, 2012; Blakley et al., 1980). Male
11 Wistar rats exposed to sodium 0.4-40 ppm arsenite in drinking water had reduced IgG
12 antibody response to KLH, but no change in IgM response (Burchiel et al., 2009).
13 Arsenic-associated reductions in antibody response to SRBCs were also observed in
14 catfish as was decreased antibody response to antigen challenge with virus (F-strain RD-
15 F) in chickens (Aggarwal et al.. 2008; Ghosh et al.. 2007a).
16 Several studies report that inorganic arsenic exposure suppresses the delayed type
17 hypersensitivity (DTH) response. These hypersensitivity assays all require coordination
18 between multiple cytokine signals and two principal cell types: antigen presenting cells
19 (e-g-, macrophages or Langerhans cell) and T-cells. Sankar et al. (2013) reported that
20 exposure to 25 ppm sodium arsenite in drinking water for 42 days resulted in decreased
21 DTH to KLH measured by changes in footpad thickness in male Wistar rats.
22 Savabiesfahani et al. (1998) reported suppression of the related endpoint of decreased
23 phytohemagglutinin hypersensitivity response by rump skin fold thickness after exposure
24 of cotton rats to 5 or 10 ppm sodium arsenite. A decreased DTH response to DNCB or
25 PHA-P was also observed in chickens exposed to 3.7 ppm sodium arsenite for 60 days
26 (Aggarwal et al.. 2008). Inorganic arsenic exposure of mice at 50 mg/1 for 4 weeks was
27 associated with reduced contact hypersensitivity response following sensitization with
28 2, 4-dinitroflurobenzene (DNFB) (Patterson et al.. 2004).
29 Host resistance assays such as the response to viral challenge requires integration of
30 innate and adaptive immune response. For example, early reactions to viral challenge
31 include aspects of innate immunity such as recruitment of macrophages and neutrophils
32 to the lung to initiate phagocytosis, secrete cytokines and begin the process of antigen
33 processing and presentation for a strong humoral immune response. Mice exposed to 100
34 ppb sodium arsenite in drinking water displayed a significantly altered pattern of
3 5 neutrophil and macrophage recruitment into the lung as determined by bronchoalveolar
36 lavage fluid (BALF) with decreased neutrophils and macrophages through 3 days post
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 infection and increased numbers of macrophages and neutrophils 7 days post infection
2 (Kozul et al.. 2009). The resulting virus titers in inorganic arsenic exposed mice were
3 higher as were other signs of morbidity to respiratory influenza A (H1N1) virus.
4 Inorganic arsenic exposure is also associated with decreased bacterial clearance in
5 multiple animal models including mice (Bishayi and Sengupta. 2003). catfish (Ghosh et
6 al.. 2007a). and zebrafish (Navak et al.. 2007).
7 Suppression of host resistance assays, delayed-type hypersensitivity, and T-cell
8 dependent antibody response are considered among the best assays for determining
9 chemical immunotoxicity, particularly when there are indications that multiple functional
10 parameters are effected (WHO. 2012; U.S. EPA. 1998). and there is evidence that
11 inorganic arsenic exposure is associated with immune suppression by all three measures.
12 Few susceptible individual response factors have been identified that are likely to
13 contribute to immune-mediated inorganic arsenic effects. However, given the importance
14 for cytokine communication and coordination of immune function, gene polymorphisms
15 relating to cytokine function are logical candidates. Banerjee et al. (2011) reported an
16 association between polymorphisms in TNF-a (-308G/A) and IL-10 (-3575T/A)
17 promoters and inorganic arsenic-associated respiratory effects and conjunctivitis.
18 Individuals with GA/AA (-308 TNF-a) and TA/AA (-3575 IL10) genotypes were at
19 higher risk of developing inorganic arsenic-associated conjunctivitis and respiratory
20 effects, as well as inorganic arsenic-induced skin lesions. In a related study by the same
21 research group, Bhattacharjee et al. (2013) reported that polymorphisms in the NALP2
22 gene also modify risk of inorganic arsenic-associated respiratory disease.
23 Inorganic arsenic-associated increases in respiratory disease, incidence of colds or fever,
24 and diarrhea represent population level responses with a strong link to immune-
25 mediated inorganic arsenic effects. Increased relative risk of lower respiratory tract
26 infection for children of mothers with higher urinary arsenic levels was reported in
27 several studies of the Matlab region of Bangladesh (Rahman et al.. 2011; Raqib et al..
28 2009). A similar increase in relative risk of both upper and lower respiratory tract
29 infection and number of colds treated with prescription medications was reported in
30 children from a New Hampshire Birth Cohort correlated with maternal urinary arsenic
31 levels at 24-28 weeks of gestation (Farzan et al.. 2013). The Rahman et al. (2011) study
32 reported an increased relative risk of diarrhea in the children of arsenic-exposed mothers
33 in Bangladesh and the Farzan et al. (2013) study reported a non-significant arsenic-
34 associated increase in diarrhea symptoms lasting two or more days or requiring doctor
35 visit [RR=1.9 (95% CI: 0.9, 3.9) and RR=3.5 (95% CI: 0.8, 15.4)]. Although most of
36 these disease-related endpoints were in children, one of the Bangladesh cohorts reported
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 increased number of days with fever and increased number of days of diarrhea in the
2 pregnant mothers (Raqib et al.. 2009).
9.6 Hypothesized MOA: Oxidative Stress
Relevant Health Effects: Cardiovascular Disease, Diabetes, Liver Disease, Lung Cancer,
Bladder Cancer, Neurotoxicity, Non-Malignant Respiratory Disease, Pregnancy
Outcomes, Renal Disease, Skin Cancer, and Skin Lesions
3 As discussed in the Preamble, mammalian metabolism of inorganic arsenic involves a
4 cascade of oxidation-reduction reactions whose net results are (1) generation of trivalent
5 methylated species, (2) depletion of cellular thiols that are involved in maintaining
6 cellular redox balance, and (3) the generation of reactive oxygen species (ROS). Several
7 adverse health effects following exposure to inorganic arsenic may thus result from
8 events mediated by oxidative stress (Flora. 2011; Jomovaet al.. 2011; Kitchin and
9 Conolly. 2010) (Figure 9-6). The molecular initiating event (MIE) in this MOA is a
10 topic of ongoing research but likely includes one of the following: 1) intermediate arsine
11 species (e.g., dimethylarsine) react with molecular oxygen, 2) methylated arsenic species
12 react with ferritin, 3) arsenite oxidizes to arsenate, and 4) inorganic arsenic interacts with
13 complexes in the mitochondrial electron transport chain and/ or antioxidant enzymes
14 (e-g-, nicotinamide adenine dinucleotide phosphate-oxidase [NADPH oxidase]) (Li et al..
15 2014; Flora. 2011).
16 While multiple MIEs are possible for this MOA, each one will result in a biochemical
17 response that consists of perturbing the redox balance in the cell through: 1) generation of
18 ROS (e.g., superoxide, Fi2O2, hydroxyl radical), and 2) depletion of antioxidant defenses
19 (e-g-, glutathione [GSH], ascorbate, superoxide dismutase) (Flora. 2011; Jomova et al..
20 2011; Kitchin and Conolly. 2010; De Vizcaya-Ruiz et al.. 2009). Each set of responses,
21 ROS generation and redox depletion, can initially involve a separate set of reactions, but
22 both are intricately linked such that elevated ROS levels can deplete redox enzymes and
23 vice versa (Flora. 2011; Jomova et al.. 2011; Kitchin and Conolly. 2010). Moreover,
24 although the generation of ROS or depletion of antioxidant defenses may occur in
25 multiple tissue types, the subsequent redox response is likely tissue dependent due to
26 differences in constitutive levels of redox enzymes and peptides across cell types (e.g.,
27 higher constitutive glutathione levels in lung fibroblasts compared to keratinocytes)
28 (Snow et al.. 2005). In turn, while oxidative stress may be a MOA common to several
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1
2
adverse health effects, the context (i.e., cell type) in which oxidative stress occurs will
influence the health effect(s) that are ultimately observed.
iAs
Metabolism
Products
Trivalent
methylated
arsenic
species
Depleted
cellular redox
thiols
Generated
ROS
»
MIE
Multiple
Possibilities:
Examples:
As3* -> As5*
iAs species
react with:
°2
Ferritin
Respiratory
chain in
mitochondria
»
Biochemical
Response
tROS
Antioxidant
depletion
Followed by:
DNA damage,
changes in
gene
expression &
cell signaling,
etc.
*
Cellular
Response
Cytotoxicity,
Epithelial-
mesenchymal
transition
Malignant
trans-
formation
Others
(see Table in
Section 10.5)
»
Tissue/
Organ
Response
Tissue
remodeling
Inflam-
matory
response
Endocrine
signaling
changes
(see Table in
Section 10.5)
»
Individual
Response
Examples:
Insulin
resistance,
Hepatic
fibrosis,
Allergic lung
inflammation
(see Table in
Section 10.5)
»
Population
Response
-tOxidative
stress
biomarkers
Associated
diseases
(see Table in
Section 10.5)
Abbreviations: Inorganic arsenic (iAs); molecular initiating event (MIE); reactive oxygen species (ROS)
See Summary Text and Table for references; Figure based on Ankley et al. (2010).
Note: Figure shows key events from the initial molecular interaction through a possible population level response. Note that arrows link each key
event (e.g., individual responses lead to population responses), but do not necessarily link each specific example response (e.g., insulin resistance
is not linked to all of the diseases included in the Table in Section 10.5). As the assessment development process moves forward additional
evidence may provide a better understanding of the key events in this MOA and the connections between them.
Figure 9-6
Hypothesized mode of action for effects mediated by oxidative stress.
3
4
5
6
7
8
9
10
11
12
To that end, numerous biochemical responses can occur within cells following the
generation of ROS and depletion of antioxidant defenses, including changes in: protein
expression, enzyme activity, lipid oxidation, DNA damage, gene expression and cell
signaling (Table in Section 10.5). For instance, alterations in protein expression levels
have been observed in multiple tissue types. While observations of increased protein
expression levels related to antioxidant defense (e.g., Cu/Zn Superoxide dismutase
[SOD], nuclear factor [erythroid-derived 2]-like 2 [Nr£2]) (Zhao etal.. 2012: Zheng et al..
2012: Li etal.. 2011) and DNA repair (e.g., DNA polymerase (3) (reviewed in Snow et
al.. 2005) may occur across multiple cell types, other observations of elevated protein
levels may be specific to specific cells (e.g., Platelet endothelial cell adhesion molecule
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 [PCAM-1]) (Straub et al.. 2008). Cell-type specific changes in protein expression or other
2 biochemical responses once again highlight how one MOA may play a role in multiple
3 adverse health outcomes and provide insight in subsequent steps of the assessment
4 development process (see the Inorganic arsenic ADP for more information).
5 For many of the biochemical responses noted above, the concentration and duration of
6 inorganic arsenic exposure, and subsequent redox imbalance, may influence the ultimate
7 cellular response. Based on the literature reviewed, there appears to be a possible pattern
8 of generally adaptive cellular responses (e.g., increases in DNA base excision repair
9 genes and antioxidant enzymes) at relatively low exposures, whereas higher
10 concentrations may result in adverse cellular responses (e.g., decreases in DNA excision
11 repair proteins) (Snow et al.. 2005). The exposure at which disruption of cellular
12 homeostasis occurs varies greatly across cell lines, and thus the specific concentration
13 range that confers adaptive versus adverse cellular responses is a topic of ongoing
14 research (Clewell et al.. 2011; Flora. 2011; Gentry et al.. 2010). Similarly, the changes in
15 protein expression, enzyme activity, or DNA damage can be very time-dependent [e.g.,
16 elevated DNA repair enzyme activity at < 48 hrs of inorganic arsenic exposure, compared
17 to basal activity levels after72-120 hrs exposure (Snow et al.. 2005)] (Medeiros et al..
18 2012; Clewell etal.. 2011; Eblin et al.. 2008: Eblin et al.. 2006).
19 Separate from the consideration of exposure duration is the duration of a biochemical
20 response that inorganic arsenic may elicit in a cell. Two aspects of response duration are
21 important to examine. First, short-lived, reversible responses such as elevated ROS levels
22 likely lead to distinct outcomes from prolonged, irreversible responses such as DNA
23 damage or epigenetic alterations that persist after inorganic arsenic exposure is stopped
24 (Flora. 2011: Wnek et al.. 2009). Second, inorganic arsenic exposure may modulate the
25 natural duration of a response, thus turning an adaptive response to an adverse response.
26 For instance, evidence suggests that inorganic arsenic exposure may result in prolonged
27 activation of the Nrf2 transcription factor pathway compared to when the pathway is
28 activated by natural compounds (e.g., sulforaphane, tert-butylhyrdoquinone) (reviewed in
29 Lauetal.. 2013). The Nrf2 pathway is activated by oxidative stress and plays a key role
30 in antioxidant defense; however, prolonged activation of the Nrf2 pathway can lead to
31 sustained cell growth and is associated with cancer in several tissues (e.g., breast,
32 bladder, skin) (reviewed in Lau et al.. 2013). Recent data indicate that inorganic arsenic
33 exposure may mimic constitutive Nrf2 activation found in several tumor types (reviewed
34 in Lau etal.. 2013). The mechanism through which inorganic arsenic exposure leads to
35 subsequent activation of Nrf2 is an area of ongoing research; yet, evidence suggests that
36 unlike natural compounds, which activate Nrf2 by inhibiting its ubiquitination through
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 direct interaction with Keapl (Kelch-like ECH associated protein 1), inorganic arsenic
2 may activate Nrf2 through a Keap 1 -independent mechanism (reviewed in Lau et al..
3 2013). Further, data indicate that Nrf2 activators which act through interaction with
4 KEAP 1 can mitigate toxic effects of inorganic arsenic exposure both in vitro and in vivo
5 (Taoetal.. 2013; Zhao etal. 2012; Wang et al. 2007b). Data from multiple cell types
6 suggest that the Nrf2 pathway plays a critical role in antioxidant response to inorganic
7 arsenic exposure (see examples in the Table in Section 10.5) (reviewed in Lau et al..
8 2013). As discussed further below, data also suggest that individuals with genetic or
/ ' OO O
9 epigenetic alternations in the Nrf2 pathway may be more susceptible to inorganic arsenic
10 exposure. Together, data suggest that Nrf2 plays a critical, though complex, role in
11 inorganic arsenic mediated oxidative stress response and subsequent health effects.
12 Similar to observations of prolonged Nrf2 activation, data also suggest that inorganic
13 arsenic promotes stabilization of the transcription factor HIF-la; thus leading to
14 prolonged transcriptional activation of downstream targets (e.g., vascular endothelial
15 growth factor [VEGF]) (Li etal.. 2014). Downstream targets of HIF-1 a can play a key
16 role in malignant transformation and carcinogenesis by promoting angiogenesis,
17 dedifferentiation, and glycolysis (Li etal.. 2014). Prolonged HIF-la activation following
18 inorganic arsenic exposure is dependent on increases in ROS produced primarily by the
19 mitochondrial electron transport chain, possibly through inorganic arsenic activation of
20 NADPH oxidase at the cell surface (Li etal.. 2014). Together with data on Nrf2
21 activation, evidence that inorganic arsenic perturbs HIF-la transcriptional activity via
22 ROS production provides insight on how subsequent changes at the cellular or tissue/
23 organ levels may be quite distinct despite being initiated through a common MOA.
24 Biological responses such as those discussed above can lead to a several cellular
25 responses, such as cell death, malignant transformation, or epithelial-mesenchymal
26 transition (EMT) (Table in Section 10.5). For example, elevated levels of apoptosis
27 have been observed in multiple cell types across in vitro and in vivo models (e.g., Zhao et
28 al.. 2012; Zheng etal.. 2012). In contrast, EMT or other changes in cell membrane
29 structures represent phenotypic changes that are likely more unique to particular cell
30 types (i.e., epithelial cells). Importantly, manifestation of phenotypic changes in one cell
31 type (i.e., epithelial cells) may be informative for understanding adverse effects in
32 multiple tissue or organ systems. For instance, data from Straub et al. (2008) show lower
33 levels of membrane porosity due to elevated cell-junction protein expression (PECAM-1)
34 in liver sinusoidal epithelial cells, which may also have relevance for understanding
35 vascular remodeling in the cardiovascular system following inorganic arsenic exposures.
36 Other tissue or organ level responses associated with oxidative stress following inorganic
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 arsenic exposures include inflammatory response, endocrine signaling, and vascular
2 remodeling (Table in Section 10.5).
3 The types of organ or tissue level responses noted above are associated with adverse
4 health outcomes at the level of the individual response. Adverse health effects for which
5 there is evidence of association with oxidative stress response following inorganic arsenic
6 exposures include: bladder cancer, cardiovascular disease, diabetes, liver disease,
7 lung cancer, neurotoxicity, non-malignant respiratory disease, pregnancy outcomes,
8 renal disease, skin cancer, and skin lesions. The level of evidence supporting the
9 various steps of the oxidative stress MOA (i.e., from molecular initiating event to adverse
10 outcome) is variable. Based on an initial literature review, health outcomes with data
11 available across multiple points in the oxidative stress MOA include: cardiovascular
12 disease, lung inflammation, and skin disease (cancer or lesions). The identification of
13 additional literature in an ongoing literature search may provide more support across the
14 MOA for other health outcomes, or these may represent areas for future research.
15 Importantly, information on an oxidative stress MOA for one health effect may provide
16 insight on how this MOA could apply to other health effects. For instance, data suggest
17 that inorganic arsenic can activate the epidermal growth factor receptor (EGFR) through
18 the generation of ROS, and thus data showing EGFR activation in both an in vitro model
19 of human lung cells and serum samples from liver cancer patients may provide insight on
20 the role of this MOA in both lung and liver cancers [(Sung et al., 2012; Wuetal.. 1999).
21 reviewed in (Flora. 2011)]. In addition, multiple MOAs may be relevant for some health
22 outcomes such as hepatotoxicity, which is associated with inflammatory response and
23 metabolic changes as well as oxidative stress (reviewed in Flora. 2011): data also suggest
24 that the oxidative stress may act interdependently with a MOA involving sulfhydryl
25 protein binding in the development of bladder cancer following inorganic arsenic
26 exposures (Wnek et al., 2011). Finally, mechanisms involved in the oxidative stress
27 MOA [e.g., activation of mitogen activated protein kinase [MAPK] signaling pathway
28 (Ling etal.. 2012)1 may subsequently influence epigenetic mechanisms, and thus interact
29 with the epigenetic MOA (see Epigenetic Summary for details). Further research may
30 provide greater understanding of how the oxidative stress MOA interacts with other
31 MOAs in health outcomes associated with inorganic arsenic exposures.
32 Additional information on interactions between the oxidative stress MOA and other
33 factors may be particularly useful in identifying susceptible individual responses.
34 Current data support a key role for Nrf2 pathway activation (examples in the Table in
35 Section 10.5) (reviewed in Lau et al., 2013); where data suggest inorganic arsenic
36 exposure may lead to prolonged pathway activation that is similar to constitutive
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
1 activation of the pathway associated with skin squamous cell carcinoma in humans (Kim
2 et al., 2010 cited in, Zhao et al., 2012). In turn, individuals with mutations in the Nrf2
3 pathway (particularly Nrf2 or KEAP1) that confer constitutive activation of the pathway
4 may have higher levels of susceptibility following inorganic arsenic activation of the
5 pathway (Zhao et al., 2012). In addition, elevated levels of NADPH oxidase activity in
6 in vitro and in vivo liver models suggests that genetic or epigenetic alterations of this
7 enzyme could influence individual response to inorganic arsenic exposure (Straub et al.,
8 2008). Indeed, polymorphisms in the NADPH oxidase p22 subunit are hypothesized to
9 contribute to inorganic arsenic-related hypertension in Taiwan [(Hsueh et al., 2005) as
10 cited in (Straub et al.. 2008)]. Additional factors that may interact with this MOA include
11 diabetes, smoking, alcohol and co-exposures to cadmium (Table in Section 10.5). Future
12 research may identify other factors that influence individual susceptibility and subsequent
13 population level responses.
14 The prevalence of the genetic factors noted above in different populations may provide
15 insight on differences in population responses to inorganic arsenic exposure for health
16 outcomes like skin cancer or cardiovascular disease. Recent work demonstrates that
17 biomarkers of oxidative stress (e.g., malondialdehyde or other lipid peroxidation
18 products, 8-oxo-G, 8-Hydroxy-guanine or other oxidative DNA damage products) can
19 help connect population level responses to the occurrence of adverse health effects
20 mediated through this MOA (reviewed in Flora. 2011; De Vizcava-Ruiz et al., 2009).
21 Several studies have thus used biomarkers to confirm an association between inorganic
22 arsenic exposure and elevated oxidative stress [e.g., (Pi et al., 2002; Wu et al., 2001)1.
23 However, associations between disease in populations exposed to inorganic arsenic and
24 oxidative stress still primarily rely on observational population studies combined with
25 indicators of oxidative stress in in vitro and/or in vivo studies in cell or tissue types
26 relevant to the disease (e.g., cardiomyocytes for cardiovascular disease). Despite the
27 observed associations between oxidative stress biomarkers and population health
28 outcomes, a clear connection between inorganic arsenic-induced elevations in oxidative
29 stress and subsequent disease is still lacking and contributions from other MOAs cannot
30 be ruled out.
31
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
10 PRELIMINARY MECHANISTIC AND
SUSCEPTIBILITY DATA TABLES
10.1 Preliminary Data on Effects Mediated By Cytotoxicity
and Regenerative Proliferation
Relevant Health Effects: Bladder, lung, and skin cancer
Key Events
Observations
Organ system
Test System
Dose
(Exposure
Duration)3
References
Molecular Initiating events
Reactions with
GSH and other
non-protein
thiols
Reaction with
thiols/ dithiols in
specific proteins
Glutathione, cysteine,
lipoic acid conjugates
Inorganic arsenic
binding with tubulin,
keratin, ER-a and
related receptors,
PARP-1, thio-redoxin
reductase, AsSmt,
KEAP-1, many studies
of zinc finger proteins,
peptides; kB kinase;
EGFR, She; tyrosine
phosphatases,
ubiquitination
enzymes; XPA, XPD
(NER enzymes)
Reduced PARP
activity, restored by
co-incubation with Zn
Many
Not applicable
Urothelium
(Human)
Humans,
rodents, in
vitro
In vitro
binding of
As(lll)to
synthetic
peptides
UROtsa cells
Environmentally
relevant and higher
exposures
Kds =~1-30 ng/L
(\|/Kd with
^cysteine residues)
50 nM MMA(III)
(12-52wks)
(Cohen et al.. 2013)
(Kitchin and
Wallace, 2008,
2005), (Qin et al.,
2008)
(Wneketal.. 2011:
Wneketal.. 2009)
Biochemical Responses
See summary text
(Cohen etal.. 2013)
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Organ system
Test System
Dose
(Exposure
Duration)3
References
Cellular Responses
Cytotoxicity/
viability
Cytotoxicity/
viability
(continued)
24-hour viability
(mitochondrial
dehydrogenase assay)
24-hour viability
(mitochondrial
dehydrogenase assay)
Cell viability (light
microscopy);
95% mortality at low
exposure,
>99% mortality at two
highest exposures
Viability (MTT) assay
Viability N|/ 42%
(Trypan blue assay)
deduction, partially
abolished by ROS
scavengers
Viability \|/
(Trypan blue assay)
deduction, partially
abolished byNADPH
oxidase inhibitor, but
other antioxidants
Viability ]/
(Trypan blue assay)
Urothelium
(Human)
Multiple
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Urinary bladder
epithelium
(Rat)
Urinary bladder
epithelium
(Rat)
UROTSA,
other cell lines
Primary
human, rat
hepatocytes,
13 mam-
malian cell
lines
UROtsa cells
UROtsa cells
UROtsa cells
MYP3 rat cell
line
MYP3 rat cell
line
Arsenite IC50for
UROTSA = 17.8 |aM,
3.2 [iM for bronchial
cells, 10 [iM for rat
hepatocytes, >20
|Jv1 for human
hepatocytes,
keratinocytes
(24 hr)
IC50s(24hrs):
As(lll) = 1-100 |aM;
MMA(III):
0.4 - 5.5 nM;
DMA(III):
0.4 - >20 |aM;
most sensitive cell
line: MB4 (human
leukemia-derived)
lnMAs(lll)
(30 -48 days)
4, 8nMAs(lll)
(30 days)
IC50~5nMMMA(lll)
(24-72 hr)
"threshold" for
viability &
morphology
changes: ~2 |JV1
1 nM As(lll)
(24 hr)
luM As(lll)
(3 days)
LC50:
0.75nMAs(lll)
(3 days)
(Styblo et al., 2000)
(Styblo et al., 2000)
(Sens etal., 2004)
(Bredfeldtetal..
2006)
(Eblin etal., 2008)
(Suzuki etal., 2009)
(Suzuki etal. .2010)
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Proliferation
Malignant
transformation
Observations
Reduced doubling
time (43. 1 hr to 22.1
hr)
Reduced doubling
time (42 hrto27hr)
Reduced doubling
time (42 hrto21hr)
IMhymidine uptake
^S-phase cells
xl/Go/Gj cells
Colony formation in
soft agar, tumor
formation after
hetero-
transplantation
Colony formation in
soft agar
Differentiation to
squamous epithelium
with poorly defined
cell membranes,
multinucleate cells;
tumor formation after
hetero-
transplantation in
SCID mice;
^proliferate
biomarker (Ki-67) in
tumors
Organ system
Ureter epithelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Test System
1T1 human
cell line
UROtsa cells
UROtsa cells
UROtsa cells
UROtsa cells
UROtsa cells
UROtsa cells
UROtsa cells
Dose
(Exposure
Duration)3
8.3nMAs(lll)
(3 days)
lnMAs(lll)
(>60 days)
50nMMMA(lll)
(12weeks)
50 nM MMA(III)
(52 wks)
2 or 4 [iM sodium
arsenite
(48-72 hr)
2 or 4 \iM sodium
arsenite
(24 hr)
lnMAs(lll)
(60 days, followed
by repeated
passages in As-free
medium)
50 nM MMA(III)
(24 or 52 wks)
50 nM MMA(III)
(52 wks)
References
(Sens etal., 2004)
(Bredfeldtetal..
2006)
(Bredfeldtetal.,
2006)
(Simeonova et al.,
2000)
(Sens etal. .2004)
(Bredfeldtetal..
2006)
(Bredfeldtetal..
2006)
Tissue/ Organ Responses
Tissue
Cytotoxicity/
Necrosis
Mild-moderate
urothelial cytotoxicity
(observed by scanning
electron microscopy
[SEM])
Urothelium
(Rat; Mouse)
F344 rats,
C57BL/6 mice
100ng/LAs(lll) in
drinking water
(2 wks); or
50-400 ng/g in diet
(2-10 wks)
(Suzuki etal., 2008)
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Tissue
Cytotoxicity/
Necrosis
(continued)
Tissue
regeneration/
Hyperplasia
Observations
Urothelial
cytotoxicity,
(observed by SEM)
*Cytotoxicity reduced
by NADPH oxidase
inhibitor,
apocyanin(250 mg/L)
Urothelial
cytotoxicity, necrosis
(observed by SEM)
Urothelial
cytotoxicity, necrosis
(observed by SEM)
*cytotoxicity in KO
compared to WT in
same treatment
groups
Urothelial
cytotoxicity, necrosis
(observed by SEM)
*cytotoxicity in KO
compared to WT in
same treatment
groups
Mild-moderate
urothelial cytotoxicity
(observed by SEM)
*severity increased
overtime
Mild-moderate
urothelial hyperplasia
(male and female
rats, male mice)
Urothelial hyperplasia
*No effect of co-
exposure to NADPH
oxidase inhibitor
Organ system
Urothelium
(Rat)
Urothelium
(Rat)
Urothelium
(Mouse)
Urothelium
(Mouse)
Urothelium
(Rat)
Urothelium
(Mouse)
Urothelium
(Rat; Mouse)
Urothelium
(Rat)
Test System
F344 rats
(Female)
F344 rats
(Female)
Wild Type
(WT)
and arsenic
methyl-
transferase
(AsSmt) KO
mice (Female)
WT and AsSmt
KO mice
(Female)
F344 rats
(Female)
C57BL/6 WT
and AsSmt KO
mice
(Female)
F344 rats;
C57BL/6 mice
F344 rats
(Female)
Dose
(Exposure
Duration)3
100ppmAs(lll)in
diet
(20 days)
Dose-response ~10-
50 ppm As(lll) in
diet
(5 wks)
(NOEL: 1-10 ppm;
significant at < 50
ppm)
lOOppm As(lll)
in diet
(6 days), followed
by
50 ppm in drinking
water
(3 days)
10-25 ppm As(lll) in
drinking water
(4 wks)
100ppmAs(lll)in
drinking water
(6 hr-14 days)
25 ppm As(lll) in
drinking water
(6 hr-14 days)
100|ag/LAs(lll) in
water; 50-400 Mg/g
in diet
(2-10 wks)
100ppmAs(lll)in
diet
(20 days)
References
(Suzuki etal.. 2009)
(Suzuki etal., 2010)
(Yokohira et al.,
2010)
(Yokohira etal.,
2011)
(Arnold etal. .2013)
(Suzuki etal., 2008)
(Suzuki etal., 2009)
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Tissue
regeneration/
Hyperplasia
(continued)
Hyperplasia and
Metaplasia
Observations
Urothelial hyperplasia
Mild-moderate
hyperplasia,
*greater severity in
KO strain, but NOEL of
1 ppm in both strains;
Mild to moderate
bladder hyperplasia
(cancer bioassay)
Urinary bladder
hyperplasia
*observed at all
exposure levels in
males; only observed
in lowest exposure
group in females
Urothelial hyperplasia
*increased severity &
incidence overtime
Urothelial
hyperplasia,
occasional metaplasia
Organ system
Urothelium
(Rat)
Urothelium
(Mouse)
Urinary bladder
(Rat)
Urinary bladder
(Mouse)
Bladder
epithelium
(Rat)
Urinary Bladder
(Mouse)
Test System
F344 rats
(Female)
WT and AsSmt
KO mice
(Female)
F344 rats
CD-I mice
F344 rats
(Female)
C57/BL-6 mice
(Female)
Dose
(Exposure
Duration)3
-10-100 ppm As(lll)
in diet
(5 weeks)
(NOEL: 1-10 ppm;
significant at < 50
ppm)
50 ppm As(lll) in
drinking water
(6 days); or
10-25 ppmAs(lll) in
drinking water
(4 wks)
40 or 100 ppm
DMA(V) in feed
(2 yrs)
6, 12, 24 ppm
sodium arsenite
(2 weeks prior to
parental mating
through 2 years in
adulthood)
100 ppm As(lll) in
drinking water
(24hr-14days)
0.01% sodium
arsenite in drinking
water
(4 wks)
References
(Suzuki etal.. 2010)
(Yokohira et al..
2011)
(Arnold etal. ,2006)
(Tokar etal. .2011)
(Arnold etal. ,2013)
(Simeonova et al..
2000)
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Organ system
Test System
Dose
(Exposure
Duration)3
References
Individual Responses
Tumor
development
(animals)
Tumor
development
(animals)
(continued)
Urothelial cell
papillomas
*statistically
significant positive
trend if combine male
& female
Urothelial cell
carcinomas
*statistically
significant positive
trend in females if
male & female data
combined (low
incidence in males
precludes statistical
analysis
No increase in tumor
incidence
dose-related T" in:
hepatocellular
carcinomas, adrenal
tumors (male
offspring);
lung carcinomas,
ovarian tumors,
proliferative lesions of
oviduct and uterus
(female offspring)
Increased tumor
incidence of liver,
lung, gall bladder,
adrenal gland kidney
(male offspring);
Liver, lung, ovary,
uterus (female
offspring)
Urinary Bladder
(Rat)
Urinary Bladder
(Mouse)
Multiple Tissues
(Mouse)
Multiple Tissues
(Mouse)
F344 rats
B6C3F1 mice
C3H mice
CD-I mice
2-100 ppm DMA(V)
in feed
(2 yrs)
8, 40, 200, or 500
ppm DMA(V) in feed
(2 yrs)
42.5, 85 ppm
sodium arsenite in
drinking water
(gestation days 8-
18)
6, 12, 24 ppm
sodium arsenite
(2 weeks prior
parental to mating
through2 yrs in
adulthood)
(Arnold etal., 2006)
(Arnold etal., 2006)
(Waalkesetal.,
2004b; Waalkeset
al.. 2003)
(Tokar etal. .2011)
Susceptible Individuals
Reduced As
methylation
capacity
Subjects with lower
secondary
methylation indices
had higher risk of skin
and bladder cancer
Skin
Urinary bladder
(Human)
Human
Population
Cumulative
inorganic arsenic
intake 0-20 mg/L-
year
(Chenetal..2003b:
Chen etal., 2003a)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-6 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Cytotoxicity,
regenerative
proliferation
associated with
urinary calculi
UV-exposure
Observations
Observations of mild
cytotoxicity,
regenerative
proliferation after
exposure to calculi-
inducing substances
'MJV-induced DNA
strand breaks
^ UV-induced DNA
repair enzyme activity
Organ system
Urinary bladder
(Human)
Skin
(Human)
Test System
Animals and
human
population
HaCat cells
Dose
(Exposure
Duration)3
Drugs (humans) and
wax implants
(animals)
1 [iM sodium
arsenite
(24 hr)
2 [iM sodium
arsenite
(24 hr)
References
(Cohen. 2002)
(Qinetal.,2008)
Human Population Responses
Inorganic
arsenic-
associated
cancer risk
(bladder, lung,
skin)
Elevated risks of
bladder, lung, and
skin cancer in
chronically inorganic
arsenic-exposed
populations (multiple
epidemiological
studies); primarily
limited to populations
with water As levels
>100 Mg/L; limited
data suggest urinary
inorganic arsenic at
levels found to be
cytotoxic in rodents
are associated with
elevated risks.
Liver, prostate cancer
risk associated with
inorganic arsenic
(smaller number of
studies)
Multiple tissues
(Human)
Humans
Wide range of
exposure levels and
durations
Reviewed in:
(Cohen et al..
2013),
(Gibbet al., 2011),
(Schoen et al..
2004),
(NRC, 1999)
Exposure duration abbreviations: minutes (min), hours (hr), days (d), weeks (wks), years (yr)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-7 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
10.2Preliminary Data on Effects Mediated By Endocrine
Signaling
Relevant Health Effects: Developmental Neurotoxicity, Male Infertility, Prostate Cancer
Key Events
Observations Organ System
Test System
Dose
(Exposure
Duration)3
References
Molecular Initiating Events
Interaction
with hormone
binding
domain in
hormone
receptors
Modulate
signaling
pathways (e.g.,
mitogen
activated
protein kinases
[MAPKs,
extracellular
signal-
regulated
kinases
[ERK1/2])
responsible for
posttranslation
al modification
of coactivators
or steroid
hormone
receptors
^reporter activity
of ERa hormone
binding domain
*inhibited by
antiestrogen
Hypothesis
Kidney
(Monkey)
Not
applicable
(N/A)
COS-1 cells
N/A
1 [iM sodium
arsenite
(24 hr)
N/A
(Barret al..
2009;
Rosenblatt
and
Burnstein,
2009; Stoica
etal., 2000)
(Barret al..
2009;
Rosenblatt
and
Burnstein,
2009)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-8 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Modulate
histone
modifying
proteins (e.g.,
acetylases,
methylases)
responsible for
posttranslation
al modification
of coactivators
or steroid
hormone
receptors
Observations
Organ System
Hypothesis
N/A
Test System
N/A
Dose
(Exposure
Duration)3
N/A
References
(Barret al.,
2009:
Rosenblatt
and
Burnstein,
2009)
Biochemical Responses
Alterations in Nuclear Hormone Receptor Mediated Gene Activation
Androgen Receptor (AR)
\|/AR amino
and carboxyl
(N-C) termini
interaction
v|/AR
coactivator-
stimulated N-C
interaction
v|/AR
coactivator
recruitment to
chromatin
v|/AR
recruitment to
chromatin
xl/AR-mediated
gene
activation
xl/luciferase
activity in
mammalian
two-hybrid
assay
xl/luciferase
activity in
mammalian
two-hybrid
assay
\|/ immuno-
precipitation of
TIF2 at Prostate-
Specific Antigen
(PSA) promoter
xl/chromatin
immuno-
precipitation of
AR at PSA
promoter
\|/ androgen
response
element
luciferase
activity (ARE or
PSA)
Prostate
(Human)
Prostate
(Human)
Prostate
(Human)
Prostate
(Human)
Prostate
(Human)
PCS cells
(human
prostate
cancer cells)
PCS cells
(human
prostate
cancer cells)
LNCaP cells
(human
prostate
cancer cells)
LNCaP cells
PCS, LNCaP, or
LAPC4 cells
(human
prostate
cancer cells)
5 [iM arsenic
trioxide (ATO)
(24 hr)
5 \M ATO
(24 hr)
5 \M ATO
(24 hr)
5 \M ATO
(24 hr)
1-5 nM ATO
(48 hr)
(Rosenblatt
and
Burnstein,
2009)
(Rosenblatt
and
Burnstein,
2009)
(Rosenblatt
and
Burnstein,
2009)
(Rosenblatt
and
Burnstein,
2009)
(Rosenblatt
and
Burnstein,
2009)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-9 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
\|/androgen
response
element
luciferase
activity
vl/PSA mRNA
Organ System
Testes
(Mice)
Prostate
(Human)
Test System
TM4 mouse
Sertoli cells
LNCaP cells
Dose
(Exposure
Duration)3
2 [iM ATO
(48 hr)
2 [iM ATO
(48 hr)
References
(Rosenblatt
and
Burnstein,
2009)
(Rosenblatt
and
Burnstein,
2009)
Estrogen Receptor (ER)
Inhibition of
estradiol
binding to ERa
1^ERa
activation
Altered ER-
mediated gene
activation
N|/[3H]estradiol
binding *not
seen in work by
Chow et al.,
Chow et al.
(2004) using
ERa competitive
screening kit
No
N|/[3H]estradiol
binding
^estrogen
response
element
reporter
construct
activity in ERa
\|/vitellogenin
expression
(mRNA)
\|/Estrogen
Response
Element
expression
(luciferase
expression or
mRNA)
V|,GREBI basal
(mRNA)
Breast
(Human)
Breast
(Human)
Kidney
(Monkey)
Liver
(Chicken)
Breast
(Human)
Breast
(Human)
Human breast
cancer MCF-7
cells
Biochemical
assay
(screening kit)
COS-1 cells
Chick Embryo
Human breast
cancer MCF-7
cells
Human breast
cancer MCF-7
cells
Ki:0.5nM
sodium
arsenite
(18 hr)
100-200 nM
ATO
(not
specified)
1 nm-10 [iM
sodium
arsenite
(24 hr)
10-50
|amol/kg
As(lll)(4hr)
10 |amol/kg
E2
(3hr)
2.5 [iM As(lll)
(EC50)
(24 hr)
5[iM As(lll)
(EC50)
(24 hr)
(Stoica etal..
2000)
(Chow et al..
2004)
(Stoica et al..
2000)
(Davey et al..
2007)
(Davey et al..
2007)
(Daveyet al.,
2007)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-10 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Altered ER-
mediated gene
activation
(continued)
xl/ER-mediated
protein levels
Observations
v|/GREBl-E2
induced (mRNA)
\|/ERa basal
(mRNA)
\|/ERa basal
(mRNA
\|/ERa hormone
induced (mRNA)
*synergistic ]/
with E2
xl/Estrogen
Response
Element
expression
(luciferase
expression)
\|/c-myc protein
\|/c-myc protein
induced by E2
1spS2(mRNA)
*tblocked by
antiestrogen
\|/ERa protein
\|/ERa protein
\|/ERa hormone
induced protein
*synergistic ]/
with E2
^progesterone
receptor protein
*tblocked by
antiestrogen
Organ System
Breast
(Human)
Breast
(Human)
Breast
(Human)
Breast
(Human)
Breast
(Human)
Breast
(Human)
Breast
(Human)
Breast
(Human)
Breast
(Human)
Breast
(Human)
Test System
Human breast
cancer MCF-7
cells
Human breast
cancer MCF-7
cells
Human breast
cancer MCF-7
cells
Human breast
cancer
MCF-7 cells
Human breast
cancer MCF-7
cells
Human breast
cancer MCF-7
cells
Human breast
cancer MCF-7
cells
Human breast
cancer MCF-7
cells
Human breast
cancer MCF-7
cells
Human breast
cancer
MCF-7 cells
Dose
(Exposure
Duration)3
5 nM As(lll)
(EC50)
(24 hr)
5nM As(lll)
(EC50)
(24 hr)
2 \M ATO
(24 or 48 hr)
2 \M ATO
+ 10nM
estradiol
(24 or 48 hr)
2 \M ATO
(24 or 48 hr)
2 [iM ATO
+ 10nM
estradiol
(24 or 48 hr)
2 [iM ATO
(48 hr)
2 [iM ATO +
10 nM
estradiol
(48 hr)
l|aM sodium
arsenite
(24 hr)
0.1, 1, or 5
[iM sodium
arsenite
(24 hr)
2 |aM ATO
(48 hr)
2 |aM ATO +
10 nM 17(3-
estradiol
(48 hr)
1 [iM sodium
arsenite
(24 hr)
References
(Davey et al..
2007)
(Davey et al..
2007; Stoica
etal.. 2000)
(Chowetal..
2004)
(Chowetal.,
2004)
(Chowetal.,
2004)
(Chow et al.,
2004)
(Stoica et al..
2000)
(Stoica etal..
2000)
(Chowetal..
2004)
(Stoica etal.,
2000)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-11 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
\|/Vascular
Endothelial
Growth Factor
protein (mRNA
and protein)
Organ System
Uterus
(Rat)
Test System
Sprague-
Dawley rats
(Female)
Dose
(Exposure
Duration)3
4 |ag/ml
sodium
arsenite
(28 days)
References
(Chatterjee
and Chatterii,
2010)
Glucocorticoid Receptor (GR)
Altered
historic post-
translational
co-activator
protein activity
atGR-
regulated
promoter
Altered
historic post-
translational
modifications
atGR-
regulated
promoter
\|/chromatin
remodeling at
GR regulated
promoter
\|/GR binding
to
glucocorticoid
response
elements
(GREs)
J,
transcription
initiation at
GR-regulated
promoter
xl/protein
methyltransfera
se(CARMl)/
coactivator
(GRIP1)
interaction
\|/ acetylation
(H3K18ac)
\|/methylation
(H3R17me)
vl/ASacl
endonuclease
cleavage site
access
\|/GR binding to
GREs in H-Ras
and Raf-1
promoters
(chromatin
immuno-
precipitation)
*no \|/binding in
vitro
]/ reporter gene
mRNA initiation
^endogenous
GR-regulated
mRNA (serum
glucocorticoid
kinase [SGK])
initiation
Tumor
(Mouse)
Tumor
(Mouse)
Tumor
(Mouse)
Developing
Brain
(Mouse)
Tumor
(Mouse)
Tumor
(Mouse)
1470.2 cells
(mouse
adenocarcino
ma derived)
1470.2 cells
(mouse
adenocarcino
ma derived)
1470.2 cells
(mouse
adenocarcino
ma derived)
C57BL/6 mice
1470.2 cells
(mouse
adenocarcino
ma derived)
1470.2 cells
(mouse
adenocarcino
ma derived)
8 [iM sodium
arsenite
+ 5 nM
dexamethaso
ne (Dex)
(30 min)
8 [iM sodium
arsenite
+ 5 nM Dex
(15 min)
8 [iM sodium
arsenite
+ 5 nM Dex
(30 and 60
min)
50 ppb
sodium
arsenite
(2 weeks
prior to
gestation +
through
weaning)
8 [iM sodium
arsenite
+ 5 nM Dex
(120 min)
8 [iM sodium
arsenite
+ 5 nM Dex
(120 min)
(Barret al..
2009)
(Barret al..
2009)
(Barret al..
2009)
(Martinez-
Finleyet al..
2011)
(Barret al..
2009)
(Barret al..
2009)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-12 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
t/vl/GR
mediated gene
transcription
Observations
\|/ reporter gene
activity (MMTV-
chloramphenico
1 acetyl
transferase
[MMTV-CAT])
T" reporter gene
activity (G2T-
luciferase
construct)
\|/ reporter gene
activity (G2T-
luciferase
construct)
Organ System
Tumor
(Mouse)
Liver
(Rat)
Test System
1470.2 cells
(mouse
adenocarcino
ma derived)
EDR3 cells
(hepatoma
cell line)
Dose
(Exposure
Duration)3
0.5-8 [iM
sodium
arsenite
+ 100 nM
Dex
(4hr)
<1HM
sodium
arsenite
+ 50 nM Dex
(18 hr)
< 1-3 [iM
sodium
arsenite
+ 50nM Dex
(18 hr)
References
(Barret al..
2009)
(Bodwell et
al., 2006)
Mineralocorticoid Receptor (MR)
IVvl/MR-
mediated gene
transcription
T" reporter gene
activity (G2T-
luciferase
construct)
\|/ reporter gene
activity (G2T-
luciferase
construct)
Liver
(Rat)
EDR3 cells
(hepatoma
cell line)
<1HM
sodium
arsenite
+ 0.5 nM
aldosterone
(18 hr)
< 1-3 |aM
sodium
arsenite
+ 0.5nM
aldosterone
(18 hr)
(Bodwell et
al., 2006)
Progesterone Receptor (PR)
t/vl/PR-
mediated gene
transcription
T" reporter gene
activity (G2T-
luciferase
construct)
\|/ reporter gene
activity (G2T-
luciferase
construct)
Liver
(Rat)
EDR3 cells
(hepatoma
cell line)
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Altered TR
gene induction
Observations
\|/TR response
element-
luciferase (TRE-
luc)
1^0101
v|/DI01
1^0101
Organ System
Pituitary
(Rat)
Pituitary
(Rat)
Test System
GH3
rat pituitary
tumor cells
GH3
rat pituitary
tumor cells
Dose
(Exposure
Duration)3
0.5-2 [iM
As(lll) + 2 nM
Thyroid
Hormone (T3)
(24 hr)
0.1-1 [iM
As(lll)
+ 2 nM T3
(6hr)
2 nM As(lll)
+ 2nMT3
(6hr)
1-2 [iM As(lll)
+2 nM T3
(24 hr)
References
(Davey et al..
2008)
(Davev et al..
2008)
Retinoic acid Receptor (RAR)
Altered RAR-
mediated gene
activation
^Retinoic acid
inducible RAR
response
element) RARE)-
luciferase
expression
induced by all
trans-retinoic
acid (ATRA)
V|,RARE-
luciferase
expression
induced by
ATRA
tCYP26A
induced by
ATRA
v|/ CYP26A
induced by
ATRA
Embryo
(Human)
Embryo
(Human)
Embryo
(Human)
NTERA-2 (N2)
human
embryonic
carcinoma
cells
N2 cells
N2 cells
0.05-0.025
[iM As(lll)
(24 hr)
2.0|aMAs(lll)
(24 hr)
0.01 |aM
As(lll)
(24 hr)
< 0.025 |aM
As(lll)
(24 hr)
(Davev et al..
2008)
(Davev et al..
2008)
(Davev et al..
2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-14 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Organ System
Test System
Dose
(Exposure
Duration)3
References
Alterations in Cell Signaling Pathways Mediated by Hormone Receptors
Mitogen-
activated
protein kinase
(MARK)
pathway
alterations
vl/H-Ras & Raf-1
mRNA
*no \|/ in
protein
\|/phosphorylat
ed-ERK
Developing
Brain
(Mouse)
Developing
Brain
(hypothalamu
s; Mouse)
C57BL/6 mice
(Postnatal day
35)
C57BL/6 mice
(Postnatal day
35)
50 ppb
sodium
arsenite
(2 weeks
prior to
gestation +
through
weaning on
postnatal day
[PND] 23)
50 ppb
sodium
arsenite
(2 weeks
prior to
gestation +
through
weaning on
PND 23)
(Martinez-
Finlevet al..
2011)
(Martinez-
Finleyet al..
2011)
Cellular Responses
Cytotoxicity
Cytotoxicity
(continued)
\|/colony
forming ability
xl/colony
forming ability
(continued)
Breast
(Human)
Breast
(Human)
(continued)
Human breast
cancer MCF-7
cells
Human breast
cancer MCF-7
cells
Human breast
cancer
MCF-7 cells
15nM As(lll)
(LC50)
(24 hr); or
25nM As(lll)
(LC50)
+ 50 pM E2
(24 hr)
2 nM ATO
+ 10 nM 17(3-
estradiol
(IC50)
(72 hr)
*reduced
viability as
compared to
E2 alone
8 |aM ATO
(IC50)
(24 hr)
1-2 [iM ATO
(IC50)
(72 hr)
(Davev et al..
2007)
(Chow et al..
2004)
(Chowetal.,
2004)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-15 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Proliferation
Altered cell
cycle
Observations
^colony
forming ability
'T'cell number
*growth
inhibited by
antiestrogen
\|/cell number
21% v|/ Gl phase
cells
8%x|/ S phase
cells
12% v|/ G2/M
phase cells
26% t Gl phase
cells
8%x|/ S phase
cells
10% v|/ G2/M
phase cells
xl/Glcell cycle
proteins (cyclin
Dl and CDK4)
mRNA
Organ System
Embryo
Pituitary
(Rat)
Pituitary
(Rat)
Breast
(Human)
Prostate
(Human)
Breast
(Human)
Breast
(Human)
Uterus
(Rat)
Test System
Human breast
cancer MDA-
MB-231 cells
NTERA-2 (N2)
human
embryonic
carcinoma
cells
GH3 rat
pituitary
tumor cells
GH3 rat
pituitary
tumor cells
Human breast
cancer
MCF-7 cells
LNCaP, or
LAPCaP-Rl
cells
(human
prostate
cancer cells)
Human breast
cancer MCF-7
cells
Human breast
cancer
MCF-7 cells
Sprague-
Dawley rats
(Female)
Dose
(Exposure
Duration)3
17 [iM ATO
(IC50)
(24 hr)
4-8 [iM ATO
(IC50)
(72 hr)
3 nM As(lll)
(LC50)
(24 hr)
5-10 [iM
As(lll)(LC50)
(24 hr)
0.01-1 [iM
As(lll)
+ 10nM
thyroid
hormone (T3)
(24 hr)
1 [iM sodium
arsenite
(5 - 8 days)
5 [iM ATO
(3 days and 5
days)
2 \j.M ATO
(48 hr;
greater effect
at 72 hr)
2 [iM ATO
+ 10 nM 17(3-
estradiol
(48 hr)
*reduced
viability as
compared to
4 ng/ml
sodium
arsenite
(28 days)
References
(Chow et al..
2004)
(Davev et al.,
2008)
(Davev et al..
2008)
(Davev et al..
2008)
(Stoica et al..
2000)
(Rosenblatt
and
Burnstein,
2009)
(Chow et al..
2004)
(Chowetal.,
2004)
(Chatterjee
and Chatterii.
2010)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-16 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Altered
hormone
receptor
distribution
Observations
No change in
cytosolic MR
protein
\|/nuclear MR
protein
\|/ cytosolic GR
protein
xl/nuclear GR
protein
\|/ cytosolic GR
protein
^nuclear GR
protein
Organ System
Developing
Brain
(Hippo-
campus)
(Mouse)
Developing
Brain
(Hippo-
campus)
(Mouse)
Developing
Brain
(hypothalamu
s; Mouse)
Test System
C57BL/6 mice
(PND 35-40)
C57BL/6 mice
(PND 35-40)
C57BL/6 mice
(PND 31-40)
Dose
(Exposure
Duration)3
55 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through PND
23)
55 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through PND
23)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through
weaning on
PND 21)
References
(Martinez-
Finlevet al..
2009)
(Martinez-
Finleyet al..
2009)
(Goggin et al..
2012)
Tissue or Oman System Responses
Altered
hypothalamic-
pituitary-
adrenal(HPA)
axis activity
l^corticotrophin
releasing factor
^base-line
corticosterone
(CORT)
Developing
Brain
(hypo-
thalamus;
Mouse)
Plasma
(Mouse)
C57BL/6 mice
(PND 31-40)
C57BL/6 mice
(PND 35)
C57BL/6 mice
(PND 75-90)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through
weaning on
PND 21)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through
weaning on
PND 21 or 23)
(Goggin et al..
2012)
(Goggin et al..
2012)
(Martinez et
al., 2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-17 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Altered
hypothalamic-
pituitary-
gonadal (HPG)
axis activity
Altered
hypothalamic-
pituitary-
gonadal (HPG)
axis activity
(continued)
Observations
^plasma
corticosterone
Dose dependent
\|/ in: plasma
hormone levels
(luteinizing
hormone [LH],
follicle-
stimulating
hormone [FSH],
testosterone;
\|/in plasma LH,
FSH,
testosterone
xl/serum
estradiol levels
\|/ serum LH,
FSH levels
\|/ plasma
estradiol, LH,
FSH levels
*No effects
detected at 16
days of
exposure
Organ System
Plasma
(Rat)
Plasma
(Rat)
Plasma
(Rat)
Serum
(Rat)
Serum
(Rat)
Plasma
(Rat)
Test System
Albino rats
(Male)
Wistar rats
(Male)
Albino rats
(Male)
Sprague-
Dawley rats
(Female)
Sprague-
Dawley rats
(Female)
Sprague-
Dawley rats
(Female)
Dose
(Exposure
Duration)3
5 mg/kg/day
sodium
arsenite
(6 days/wk
for 4 wks)
5 or 6
mg/kg/day
sodium
arsenite
(26 days)
5 mg/kg/day
sodium
arsenite
(6 days/wk
for 4 wks)
0.4, 4, 40 or
80 Mg/ml
sodium
arsenite
(14 -56 days)
4 ng/ml
sodium
arsenite
(28 days)
0.4 ppm
sodium
arsenite
(16 or 28
days)
References
(Jana et al..
2006)
(Sarkar et al..
2003)
(Jana et al..
2006)
(Chatterjee
and Chatterii.
2010)
(Chatteriee
and Chatterii.
2010)
(Chattopadhy
avetal..
1999)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-18 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Testicular
toxicity
Impaired
Spermatogene
sis
Female
reproductive
toxicity
Observations
\|/in:
paired testicular
weights; and
testicular
testosterone;
Altered
testicular
enzyme levels;
germ cell
degeneration at
stage VII
* Effects
alleviated by co-
administration
of human
chorionic
gonadotrophin
** Effects
enhanced by co-
administration
of oestradiol
\|/ testicular
weights, sperm
count and
motility, altered
testicular
enzyme
activities
Dose dependent
\|/ in:
reproductive
organ weight;
epididymal
sperm count;
and
degeneration of
germ cells at
stage VII
\|/uterine
weight; altered
uterine
morphology
\|/uterine, ovary
and vagina
weights, ovarian
enzymes *No
effects detected
at 16 days of
exposure
Organ System
Male
reproductive
organs
(Rat)
Male
reproductive
organs
(Mouse)
Male
reproductive
organs
(Rat)
Female
reproductive
organs
(Rat)
Female
reproductive
organs
(Rat)
Test System
Albino rats
(Male)
Swiss albino
mice
(Male)
Wistar rats
(Male)
Sprague-
Dawley rats
(Female)
Sprague-
Dawley rats
(Female)
Dose
(Exposure
Duration)3
5 mg/kg/day
sodium
arsenite
(6 days/wk
for 4 wks)
53.39 nmol/L
sodium
arsenite
(365 days)
5 or 6
mg/kg/day
sodium
arsenite
(26 days)
4 |ag/ml
sodium
arsenite
(28 days)
0.4 ppm
sodium
arsenite
(16 or 28
days)
References
(Jana et al..
2006)
(Pantetal.,
2004)
(Sarkar et al..
2003)
(Chatteriee
and Chatterji,
2010)
(Chattopadhv
avetal..
1999)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-19 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Altered protein
glycosylation
Altered
receptor levels
Altered
receptor
sensitivity
Altered
neurotransmitt
er levels
Impaired
morphogenesis
Observations
v|/fully
glycosylated
11(3-
Hydroxysteroid
Dehydrogenase
Type 1
-f(trend) GR
mRNA
\|/corticotrophin
-releasing factor
receptor
xl/estrogen
receptor mRNA
and protein
^specific
binding to
serotonin
receptor (5HT-
1A)
T" dopamine
J,
noradrenaline
v|/5-HT
\lxT3-dependent
tail fin
resorption
Organ System
Developing
Brain
(hippo-
campus;
Mouse)
Adolescent
Brain
(hippo-
campus;
Mouse)
Adult Brain
(hippocampus
; Mouse)
Uterus
(Rat)
Adult Brain
(hippo-
campus;
Mouse)
Adult Brain
(hypothalamu
s, pituitary;
rat)
Tail
(Xenopus
laevis)
Test System
C57BL/6 mice
(PND 75- 90)
C57BL/6 mice
(PND 31-40)
C57BL/6 mice
(PND 75 -90)
Sprague-
Dawley rats
(Female)
C57BL/6 mice
(PND 75 -90)
Albino rats
(Male)
Ex-vivo
(Xenopus
laevis tails)
Dose
(Exposure
Duration)3
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through
weaning on
PND 21)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through
weaning on
PND 21)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through PND
23)
4 |ag/ml
sodium
arsenite
(28 days)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through PND
23)
5 mg/kg/day
sodium
arsenite
(6 days/wk
for 4 wks)
0.05-4 \M
As(lll)
+ 10 nM T3
(4 days)
References
(Goggin et al..
2012)
(Goggin et al..
2012)
(Martinez et
al., 2008)
(Chatterjee
and Chatterji,
2010)
(Martinez et
al., 2008)
(Jana et al..
2006)
(Davevet al..
2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-20 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Organ System
Test System
Dose
(Exposure
Duration)3
References
Individual Response
Impaired
spatial learning
and memory
Altered stress
response
Depressive like
behavior
Novel Object
Test
IMimeto
recognize
presence of
novel object
gentries in
presence of
novel object
8-way Radial
Arm Maze
gentry errors
^base-line
corticosterone
(CORT)
Blunted CORT
increase
following
stressor
Learned
Helplessness
Task
^latency to
escape in
Forced Swim
Test
^immobility
Mouse
Plasma
(Mouse)
Mouse
Mouse
C57BL/6 mice
(PND 35-40)
C57BL/6 mice
(PND 35)
C57BL/6 mice
(PND 75 -90)
C57BL/6 mice
(PND 75 -90)
55ppb
sodium
arsenate
(2 weeks
prior to
gestation
through PND
23)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through
weaning on
PND 21)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through PND
23)
50 ppb
sodium
arsenate
(2 weeks
prior to
gestation
through PND
23)
(Martinez-
Finlevet al..
2009)
(Goggin et al..
2012)
(Martinez et
al.. 2008)
(Martinez et
al.. 2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-21 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Susceptible Individuals
Developing
children
Indicators of
developmental
neurotoxicity in
rodents coupled
with lower
cogitative
performance in
epidemiology
studies
Population Level Response
Developmental
neurotoxicity
Male infertility
Prostate
Cancer
^performance
on Wechsler
Preschool &
Primary Scale of
Intelligence
Abnormal
sperm, \|/ sperm
count, sperm
mobility
^ male
infertility
1s prostate
cancer mortality
associated with
inorganic
arsenic
exposures
Organ System
Test System
Dose
(Exposure
Duration)3
References
See rows
above and
below for
animal and
epidemiologic
al data,
respectively
Rats or human
population
Varies
(Goggin et al..
2012:
Martinez-
Finleyet al.,
2009:
Martinez et
al., 2008;
Wasserman
etal., 2007)
Brain
(Human)
(Human &
animal
model)
Reproductive
system
(Human)
Prostate
(Human)
6-year-old
children
(Araihazar,
Bangladesh)
Human and
animal models
Human
population
Human
population
Mean 120.1
Mg/L in urine
(not
specified)
Varies
Varies
Varies
(Wasserman
etal.. 2007)
(Rosenblatt
and
Burnstein,
2009)
(Shen etal..
2013)
Reviewed in
(Prins. 2008)
Exposure duration abbreviations: minutes (min), hours (hr), days (d), weeks (wks), years (yr)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-22 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
10.3Preliminary Data on Effects Mediated by Epigenetic
Mechanisms
Relevant Health Effects: Bladder cancer, skin cancer, skin lesions
Key Events
Observations
Observation
Organ System
Test System
Observed in
Dose
(Exposure
duration)3
References
Molecular Initiating Events
xl/S-adenosyl-methionine
(SAM)
\|/SAM unrelated to
inorganic arsenic
methylation
'T'oxidative stress and
subsequent GSH
depletion
SAM depletion
associated with
methylation,
reduction of
inorganic arsenic
species
\|/SAM in cells with
low capacity to
methylate inorganic
arsenic;
^expression of
transsulfu ration
enzymes in
glutathione(GSH)
synthesis
^reactive oxygen
species (ROS);
^oxidation of GSH
transformation of
HELP cells via ^ROS
->ERK/NFKB
activation ->hsa-
miR-21
upregulation
Multiple
Prostate
(Human)
Multiple
Embryonic
lung
(Human)
Multiple
Transformed
prostate epithelial
cell line (RPWE-1)
Multiple
Embryonic lung
fibroblasts(HELF)
Multiple
5 [iM arsenite
(16 wks)
Multiple
1 [iM sodium
arsenite
(up to 30 cell
passages)
Reviewed in
(Reichard and
Puga. 2010).
(Martinez et al..
2011),(Ren et
al., 2011)
Coppin et al.,
2008
Reviewed in
(Reichard and
Puga, 2010)
Reviewed in
(Reichard and
Puga. 2010)
(Linget al..
2012)
Biochemical Responses
Altered DNA
methyltransferases
(DNMTs) activity
N|/ DNMT activity
(no change in
DNMTmRNA
expression),
associated with
hypomethylation
SAM depletion, \|/
expression of
DNMTland
DNMTS, global
hypomethylation
Prostate
(Human)
Skin
(Human)
Human prostate
epithelial cells
(RWPE-1)
Human HaCat
keratinocytes
5nMAs(lll)
(29 weeks)
up to 5 [iM
As(lll)
(3 days)
(Benbrahim-
Tallaa et al.,
2005)
(Reichard et al.,
2007)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-23 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Global DNA methylation
changes
Global DNA methylation
changes (continued)
Observations
Hypermethylation
only in folate
adequate
individuals
Hypermethylation
Hypomethylation
hypomethylation,
increased GSH and
decreased SAM
levels
hypomethylation,
decreased DNMT
activity with no
change in DNMT
mRNA expression
hypomethylation
hypomethylation
hypomethylation
(after 1 day) and
chromosomal
instability (8 weeks)
hypomethylation,
increased
expression of ERa
and cyclin GDI
mRNA and protein
hypomethylation,
gene expression
changes
Observation
Organ System
Blood
(Human)
Blood
(Human)
Skin/Blood
(Human)
Prostate
(Human)
Prostate
(Human)
Skin
(Human)
Liver
(Rat)
Lung
(Hamster)
Liver
(Mouse)
Liver
(Mouse)
Test System
Observed in
Peripheral blood
lymphocyte (PEL)
DNA
PEL DNA
PEL DNA in
individuals with skin
lesions
Human prostate
epithelial cells
(RWPE-1)
Human prostate
epithelial cells
(RWPE-1)
HaCaT keratinocytes
Rat liver epithelial
cells (TRL 1215)
Chinese hamster
cells (V79-CI3)
129/SvJ mice
HomozygousTg.AC
mice
Dose
(Exposure
duration)3
2-250 Mg/L
As(lll)
(>4 yrs)
250-500 Mg/L
As(lll)
(>6 months,
mean = 10 yrs)
2-250 Mg/L
(As[lll])
(>2 yrs)
5MMAs(lll)
(16 wks)
5 MM As(lll)
(29 wks)
0.2 MM
(4 wks)
125-500 nM
As(lll)
(18 wks)
10 MM As(lll)
(1 day -8 wks)
45ppmAs(lll)
(48 wks)
150 ppm
As(lll); 200
ppm As(V);
1500 ppm
MMA(V); or
1200 ppm
DMA(V)
(17 wks)
References
(Pilsner et al.,
2007)
(Majumdar et
al.. 2010)
(Pilsner et al.,
2009)
(Coppin et al.,
2008)
(Benbrahim-
Tallaa et al.,
2005)
(Reichard et al.,
2007)
(Zhao et al.,
1997)
(Sciandrello et
al., 2004)
(Chen etal.,
2004b)
(Xie etal. .2004)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-24 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Global DNA methylation
changes (continued)
Gene specific
methylation changes
Observations
hypomethylation;
correlation with c-
myc gene
expression, tumor
formation in nude
mice
hypo and
hypermethylation
Altered methylation
patterns in
repetitive DNA
elements (high in
Alu and low in LINE-
1 with higher
inorganic arsenic
exposure)
^Global
methylation
Hypomethylation
182
hypermethylated
genes (17 = tumor
suppressor); 1
hypomethylated
gene
Observation
Organ System
Liver
(Rat)
Kidney and
lung
(Human)
Blood
(Human)
Brain cortex
and
hippocampus
(Rat)
Brain cortex
(Rat)
Skin and
Blood
(Human)
Test System
Observed in
Rat liver epithelial
cells (TRL 1215)
kidney (UOK) and
lung epithelial type II
(A549) cell lines
elderly men; blood
leukocyte DNA
methylation
Wistar Rats
Wistar Rats
PEL DNA
(Zimapan, Mexico)
Dose
(Exposure
duration)3
125-500 nM
As(lll)
(18 wks)
As(lll)
(various)
0.02-1.45 Mg/g
toenail arsenic
(unspecified)
3 ppm sodium
arsenite; or
36 ppm
sodium
arsenite
(10 days prior
to gestation
through 1
month
postnatal
development)
3 ppm sodium
arsenite; or
36 ppm
sodium
arsenite
(10 days prior
to gestation
through 3 or 4
months
postnatal
development)
110 |ag As/L
(mean)
(>2 yrs)
References
(Chenetal.,
2001)
(Zhong and
Mass, 2001)
(Lambrou et al..
2012)
(Martinez et al..
2011)
(Martinez et al..
2011)
(Smeester et al..
2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-25 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Gene specific
methylation changes
(continued)
Observations
Aberrant DNA
methylation;
cellular
transformation
altered DNA
methylation of 455
promoters
(primarily
hypomethylation),
associated with
urinary iAs
DARK promoter
hypermethylation
p53, p!6 promoter
hypermethylation
(dose-dependent),
hypomethylation in
highest exposure
group
p!6 promoter
hypermethylation
RASSF1A, PRSS3
promoter
hypermethylation
DBC1, FAM83A,
ZSCAN12, C1QTNF6
promoter
hypermethylation
WNT5A promoter
hypermethylation
Observation
Organ System
Bladder
(Human)
Urine and
blood
(Human)
Bladder
(Human)
Blood
(Human)
associated
with skin
lesions
Blood
(Human)
Bladder
(Human)
Bladder
(Human)
Bladder
(Human)
Test System
Observed in
Human bladder cell
line(UROtsa)
Human Urine
(16 females in
Zimapan, Hildago,
Mexico)
Human bladder,
kidney, ureter
tumors from
urothelial carcinoma
patients
(Southwest Taiwan)
Human PEL
(West Bengal, India)
Human PEL in
patients with
arseniasis
(Guizhou Province,
China)
Human Bladder
tumors
(New Hampshire,
U.S.)
UROtsa urothelial
cells
UROtsa urothelial
cells
Dose
(Exposure
duration)3
50 nM
MMA(III)
(12, 24wks)
3.6-31.8 ng
Total As/mL in
urine
(10.7ng/mL
[mean])
(unspecified)
Unspecified
high doses
from well
water
(unspecified)
>50 Mg/L As in
drinking water
(<6 months)
highest group:
300-1000 As
Mg/L in
drinking water
(< 6 months)
Unspecified
doses from use
of
unventilated
coal stove with
high As
(unspecified)
>0.26 ng/g
toenail As
(unspecified)
lnMAs(lll),
or 50 nM
MMA(III)
(52 wks)
lnMAs(lll),
or 50 nM
MMA(III)
(52 wks)
References
(Wneketal.,
2010)
(Bailey et al..
2013)
(Chenetal.,
2007a)
(Chanda etal..
2006)
(Zhang etal..
2007)
(Marsit et al..
2006b)
(Jensen etal..
2008)
(Jensen etal..
2009b)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-26 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Gene specific
methylation changes
(continued)
Observations
DARK promoter
hypermethylation
and reduced
expression
p!6 promoter
hypermethylation
p53 promoter
hypermethylation
c-myc, c-Ha-ras
promoter
hypomethylation
p!6, RASSF1
promoter
hypermethylation,
\|/ expression of
plSand RASSF1,
increased
occurrence of lung
adenocarcinoma
p!6, RASSF1A, E-
cadherin, GSTP1
promoter
hypomethylation
c-Ha-ras promoter
hypomethylation in
dietary methyl
deficient mice,
steatosisand
microgranulomas
ERa promoter
hypomethylation
ERa promoter
hypomethylation,
T" expression of
ERa and cyclin GDI
mRNAand protein
Observation
Organ System
Bladder
(Human)
Immune
System
(Human)
Lung
(Human)
Embryo
(Hamster)
Lung
(Mouse)
Liver
(Human)
Liver
(Mouse)
Liver
(Mouse)
Liver
(Mouse)
Test System
Observed in
Uroepithelial cells
(SV-HUC-1)
Myeloma cells
(U266)
Lung
adenocarcinoma
cells (A549)
Syrian hamster
embryo cells
A/J mice
HepG2and Huh-7
liver cells
C57BL/6J mice
C3H mice (Adult
male with
hepatocellular
carcinoma [HCC]
after only in utero
exposure)
129/SvJ mice
Dose
(Exposure
duration)3
2,4,10 [iM
As(lll)
(2 days)
1,2 [iM As203
(3 days)
0.8-2 |aM
As(lll), or30-
300 [iM As(V)
(Iwk)
3-10 \M
As(lll),
or 50-150 [iM
As(V)
(2ds)
1, 10, 100 ppm
As(V)
(18 months)
2-10 [JVl As(lll)
(3 days)
2.6-14.6 Mg
As(lll)/gbody
weight/day
(18.5 wks)
85 ppm As(lll)
(gestational
day[GD]8-
18)
45 ppm As(lll)
(48 wks)
References
(Chalet al..
2007)
(Fu and Shen,
2005)
(Mass and
Wang, 1997)
(Takahashi et
al.. 2002)
(Cuietal..
2006a)
(Cuietal..
2006b)
(Okoji et al..
2002)
(Waalkesetal.,
2004a)
(Chenetal..
2004b)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-27 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Histone modification
Observations
hyper- and
hypomethylation of
VHL promoter
\|/ acetylation
(H3K18ac)
xl/methylation
(H3R17me)
T" histone
acetylation (H3;
lysine 14) and
phosphorylation
(H3; serine 10) at c-
jun and c-fos
chromatin,
increased
expression of c-jun
and c-fos
^ histone
HSacetylation
(H3K9); inhibition of
HDAC activity
\|/ histone
acetylation: H4K16,
H3K9, K14, K18, K23
N|/ H4; lysine 16
acetylation
\|/ H3 acetylation of
FAM83A, DCB1,
ZSCAN12, KRT7,
C1QTNF6, FGF5;
increased
acetylation of
KCNK10, NEFL
Observation
Organ System
Kidney
(Human)
Tumor
(Mouse)
Lung (Human)
Liver (Human)
Bladder
(Human)
Bladder
(Human)
Bladder
(Human)
Test System
Observed in
Human kidney cells
(UOK123, UOK109,
UOK121)
1470.2 cells (mouse
adenocarcinoma
derived)
Human fibroblasts
(WI-38 cells)
Human hepatoma
HepG2 cells
Human uroepithelial
cells (UROtsa)
Human bladder
epithelial cells
(UROtsa)
UROtsa and URO-
ASSC urothelial cells
Dose
(Exposure
duration)3
IC30, IC50, or
ICSO of each
cell line: 7-93
HMAs(lll)
(4 wks)
8 [iM sodium
arsenite
+ 5 nM Dex
(15 min)
400 [iM As(lll),
(up to 1 hr)
5-10|JVIAs(lll)
(1 day)
l-lOnMAs(lll)
or
0.3-3 |aM
MMA(III)
(up to 1 day)
150|aMAs(lll),
or 300 [iM
MMA(III)
(1 day)
1 HM As(lll),
or 50 nM
MMA(III)
(52 wks)
References
(Zhong and
Mass. 2001)
(Barr et al..
2009)
(Lietal., 2003)
(Ramirez et al..
2008)
(Chuetal.,
2011)
(Joetal., 2009)
(Jensen et al..
2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-28 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Histone modification
(continued)
Altered MicroRNA
expression
Observations
^permissive
transcription
histone
modifications
(DiMeK4; AcH3)
]/ repressive
transcription
histone
modifications
(TriMeK27, DiMeK9)
^ H3K27
trimethylation, T"
H3K9 dimethylation
and H3K4
trimethylation
(increase in HMT
G9a protein and
mRNA levels)
^ H3K4
trimethylation,
maintained after
inorganic arsenic
removal = inherited
through cell division
^ H2AX
phosphorylation
^ H3K9me2 and ^
H3K9acwith
increased urinary
inorganic arsenic;
other histone marks
correlated with
water inorganic
arsenic in gender
specific manner
t H3K9me2; ^
pl6INK4a
expression; no
change in promoter
DNA methylation
Upregulation of
hsa-miR-
22,34a,221,222 and
downregulation of
hsa-miR-210
Observation
Organ System
Bladder
(Human)
Lung
(Human)
Lung
(Human)
Skin
(Human)
Blood
(Human)
Liver
(Mouse)
Immune
system
(Human)
Test System
Observed in
UROtsa and URO-
ASSC urothelial cells
A549 human lung
adenocarcinoma
cells
A549 human lung
adenocarcinoma
cells
Melanoma cells
(RPMI7591)
Peripheral blood
mononuclear cells
(Bangladesh cohort
[n=40])
C57BI/6J mice
Human
immortalized
lymphoblast cells
(TK6 cell line)
Dose
(Exposure
duration)3
1 HM As(lll),
or 50 nM
MMA(III)
(52 wks)
0.1-10 [iM
As(lll)
(1 day)
0.1-1 [iM
As(lll)
(1 or 7 days)
1, 2.5, or 5 nM
As(lll)
(1 day)
91.5 Mg/L
urinary
inorganic
arsenic
(median)
(unspecified)
50 ppm
sodium
arsenite
(6 months)
<2nMAs(lll)
(6 days)
References
(Jensen et al..
2009b)
(Zhou et al..
2008)
(Zhou et al..
2009)
(Zvkova et al..
2006)
(Chervona et al..
2012); (Arita et
al.. 2012)
(Suzuki and
Nohara, 2013)
(Marsit et al..
2006a)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-29 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Altered MicroRNA
expression (continued)
Observations
downregulation of
miRNA-19a - cell
growth arrest and
apoptosis
upregulation of hsa-
miR-2909;
molecular
responses linked to
immune response
85 miRNA
upregulated, 52
downregulated;
predicted to be
involved in
regulating
phosphoproteins
and alternative
gene splicing
hsa-miR-21
upregulation
Observation
Organ System
Bladder
(Human)
Immune
system
(Human)
Vascular
system
(Human)
Embryonic,
lung
(Human)
Test System
Observed in
T24 human bladder
carcinoma cells
Peripheral blood
mononuclear cells
(PBMCs)
Umbilical vein
endothelial cells
(HUVECs)
Embryonic lung
fibroblast(HELF)
Dose
(Exposure
duration)3
4 [iM As203
(24 hr)
2 [iM sodium
arsenite
(48 hr)
20 [iM sodium
arsenite
(24 hr)
1 [iM sodium
arsenite
(up 30 cell
passages)
References
(Cao et al..
2011)
(Kauletal.,
2014)
(Lietal., 2012)
(Linget al.,
2012)
Cellular Phenotypic Changes
Malignant
transformation
transformation of
HELP cells via
increased ROS-
>ERK/NFKB
activation ->hsa-
miR-21
upregulation
transformation of
p53 knocked down
HBECs;
downregulated hsa-
miR-200b via
promoter
methylation
Altered H3 and H4
acetylation during
malignant
transformation
Embryonic,
lung
(Human)
Lung
(human)
Bladder
(Human)
Embryonic lung
fibroblast(HELF)
p53(low) human
bronchial epithelial
cells
UROtsa and URO-
ASSC urothelial cells
1 [iM sodium
arsenite
(up 30 cell
passages)
2.5 [iM sodium
arsenite
(16 wks)
lnMAs(lll),
or 50 nM
MMA(III)
(52 wks)
(Ling et al.,
2012)
(Wangetal.,
2011b)
(Jensen et al.,
2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-30 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Malignant
transformation
(continued)
Observations
Increase in
"permissive"
histone
modifications AcH3
and DiMeK4;
repressive
modifications
TriMeK27 and
DiMeK9 were
decreased -> non-
canonical WNT5A
signaling and
malignant
transformation
Genome-wide
changes in
promoter DNA
methylation,
increasing with
duration of
exposure, in parallel
with phenotypic
changes
(transformation)
Observation
Organ System
Bladder
(Human)
Bladder
(Human)
Test System
Observed in
UROtsa and URO-
ASSC urothelial cells
UROtsa and URO-
ASSC urothelial cells
Dose
(Exposure
duration)3
50 nM
MMA(III)
(24+ wks)
iMM As(lll),
or 50 nM
MMA(III)
(up to 52 wks)
References
(Jensen et al..
2009b)
(Jensen et al..
2009a)
Tissue/Organ Responses
Skin Lesions
Adverse liver effects
Development of
skin lesions
associated with
inorganic arsenic
exposure and PEL
hypomethylation
Risk of skin lesions
associated with
DARK and p!6
hypermethylation
Hepatic steatosis
with DNA
hypomethylation
Skin/Blood
(Human)
Skin and
blood
(Human)
Liver
(Mouse)
PEL DNA in
individuals with skin
lesions
(Araihazar,
Bangladesh)
PEL DNA in
individuals
(West Bengal, India)
129/SvJ mice
121 Mg/L
urinary As
(>2 yrs)
567.25 Mg/L
mean urinary
As(lll)(with
lesions)
Mean
urine As(lll)
495.48 Mg/L
mean
urinary As(lll)
(w/o lesions),
567.25 Mg/L
(with lesions)
45ppm As(lll)
(48 wks)
(Pilsner et al..
2009)
(Banerjee et al..
2013)
(Chenetal..
2004b)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-31 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Hepatocellular
carcinoma
Steatosis and
microgranulomas
with c-Ha-ras
promoter
hypomethylation in
dietary methyl
deficient mice
Observation
Organ System
Liver
(Mouse)
Liver
(Mouse)
Test System
Observed in
Adult male C3H mice
with HCC after only
in utero exposure
C57BL/6J mice
Dose
(Exposure
duration)3
85ppm As(lll)
(gestational
day [GD] 8-
18)
2.6-14.6 Mg
As(lll)/gbody
weight/day
(18.5 wks)
References
(Waalkesetal.,
2004a)
(Okoji et al..
2002)
Individual Responses
Contextual memory
deficits
^freezing behavior
*highest dose
group: significant at
all time points 2 -4
months of age
Lowest dose group:
significant at 1 time
point at 2 months
of age; all time
points 3 & 4 months
of age
Whole animal
(Rat)
Wistar Rats
3 or36ppm
sodium
arsenite,
(10 days prior
to gestation
through 1, 2, 3,
or 4 months
postnatal
development)
(Martinez et al..
2011)
Susceptible Individual response
Diet
(e.g., deficiencies in
methyl, folate,
methionine)
Altered DNA
methylation
patterns in
repetitive Alu and
LINE DNA elements
(high Alu
methylation
correlated with high
inorganic arsenic
exposure in low
folate condition,
and vice versa)
following low levels
of environmental
exposure
Hypermethylation,
modified by folate
development of
skin lesions
associated with low
folate
Blood
(Human;
Elderly men)
Blood
(Human)
Skin/Blood
(Human)
Blood leukocyte
DNA
in human cohort
study
PEL DNA
PEL DNA in
individuals with skin
lesions
0.02-1.45 Mg/g
toenail arsenic
(unspecified)
2-250 Mg/L
As(lll)
(>4 yrs)
2-250 Mg/L
As(lll)
(>2 yrs)
(Lambrou et al..
2012)
(Pilsner et al..
2007)
(Pilsner et al..
2009)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-32 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Life stage (in utero
exposure)
Observations
c-Ha-ras promoter
hypomethylation,
steatosis and
microgranulomas
5357 CpG islands
altered with high
maternal folate +
inorganic arsenic
global
hypomethylation
w/ high exposure,
PP1 promoter
hypomethylation,
reduced fear
memory
ERa promoter
hypomethylation,
HCC
12 miRNAs
upregulated (linked
to cancer, diabetes
and immune
response signaling
pathways)
5357 CpG islands
altered with high
maternal folate +
inorganic arsenic
Observation
Organ System
Liver
(Mouse)
Fetal liver
(Mouse)
Brain
(rat)
Liver
(Mouse)
Blood
(Human)
Fetal liver
(Mouse)
Test System
Observed in
C57BL/6J mice
CD-I mice
(Pregnant females)
Wistar rats
C3H mice
(Adult; male)
cord blood
(Mexican women's
cohort)
CD-I mice (Pregnant
females)
Dose
(Exposure
duration)3
2.6-14.6 Mg iAs
(lll)/gbody
weight/day
(18.5 weeks)
85ppm As(lll)
(GD 8-18)
+ High
maternal
folate intake
(11 mg/kg)
(GD5-18)
3 or 36 ppm
sodium
arsenite
(gestation to 4
months
postnatal
development)
85 ppm As(lll)
(GD8-18)
0.456-236 ng/L
inorganic
arsenic in
maternal
drinking water
inorganic
arsenic range
of 0.456-236
Mg/L; maternal
urine inorganic
arsenic range
of 6.2-319.7
|jg/L inorganic
arsenic in
maternal urine
(unspecified)
85 ppm As(lll)
(GD 8-18)
+ High
maternal
folate intake
(11 mg/kg) for
(GD5-18)
References
(Okoji et al..
2002)
(Tsang et al..
2012)
(Martinez et al..
2011)
(Waalkesetal..
2004a)
(Rager et al..
2014)
(Tsang et al..
2012)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-33 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Gender
Genetics
Observations
Males:
\|/DNA methylation;
V|,DNMTI
expression
(no change in SAM
content)
Females:
I^DNA methylation
in females
(no change in
DNMT1 levels)
\|/SAM content
AS3MT haplotype
associated with
efficient inorganic
arsenic metabolism,
methylation of
ASSMTgene region
and reduced AS3MT
mRNA expression
Observation
Organ System
liver
(Mouse)
Blood /Skin
(Human)
Test System
Observed in
C57BL/6J mice
Human peripheral
blood (Argentinian
women)
Dose
(Exposure
duration)3
50 ppm
sodium
arsenite +
methyl-
deficient diet
ad libitum
(5 months)
188 [ig/i mean
total urinary
arsenic
(unspecified)
References
(Nohara et al..
2011)
(Engstrom et al..
2013)
Population response
Hypermethylation of
genes related to diseases
associated with inorganic
arsenic (e.g., cancer,
heart disease, diabetes)
Inorganic arsenic
induced bladder cancer
risk
182
hypermethylated
genes related to
tumor suppression
(e.g., forkhead box
Fl [FoxFl], matrix
metallopeptidase
15 [MMP15])
Promoter
methylation
silencing of tumor
suppressor genes
(p!6, RASSF1A,
PRSS3) and soluble
Frizzled receptor
proteins (SFRPs) in
30-50% of bladder
cancer cases
Peripheral
blood
lymphocytes
(Human)
Bladder
tumors
(Human)
Females (n= 8) with
inorganic arsenical
skin lesions in
Zimapan, Hidalgo
State, Mexico;
compared to
females (n=8)
without lesions
Participants in
population-based
case-control of
bladder cancer in
New Hampshire,
U.S.
63.47 Mg/g
total arsenic in
urinary
creatinine
(average)
(unspecified)
< 0.26 Mg/g
toenail arsenic
(unspecified)
(Smeester et al..
2011)
(Marsit et al..
2006c; Marsit et
al., 2006b)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-34 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Inorganic arsenic-
induced skin cancer risk
Inorganic arsenic
induced skin lesions
Observations
Dose-related
increase in
hypermethylation
of p53 gene in
inorganic arsenic
exposed individuals
compared to
controls &
individuals with
inorganic arsenic-
induced skin cancer
patients
development of
skin lesions
associated with low
folate
Observation
Organ System
Blood
(Human)
Skin/Blood
(Human)
Test System
Observed in
Human subjects in
Kolkata, India
(individuals with
inorganic arsenic
associated skin
cancer & nonarsenic
cancer)
PEL
DNA in individuals
with skin lesions
Dose
(Exposure
duration)3
Controls:
<50 Mg/L
inorganic
arsenic in
drinking water
Exposed:
51-1000 ng/L
inorganic
arsenic in
drinking water
(9.5-19yrs)
2-250 ng/L
As(lll)(>2yrs)
References
(Chanda et al..
2006)
(Pilsner et al..
2009)
Abbreviations used for exposure durations: minutes (min), hours (hr), days (d), weeks (wks)
bExposure durations are characterized as "unspecified" when a study does not explicitly state the exposure duration
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-35 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
10.4Preliminary Data on Effects Mediated By the Immune
System
Relevant Health Effects: Suppression of humoral immunity (i.e., decreased antibody
response), Suppression of innate immunity (decreased macrophage function),
Respiratory infection, Gastrointestinal infection, Contact hypersensitivity response
Key Events
Observations
Organ
system
Test System
Dose
(Exposure
Duration)3
References
Molecular Initiating Events
Molecular initiating events for inorganic arsenic immunotoxicity are unknown.
There is some suggestion that generation of ROS may lead to some immune effects. For example, T-cell apoptosis
appears through a ROS-dependent pathway [e.g., (Gupta etal., 2003; Parketal., 2003)1
There is also evidence the effects on macrophages (and therefore many of the effects on the innate immune
system which are associated with macrophage function) are unrelated to increased production of ROS. For example arsenic
trioxide alters macrophage gene expression through a pathway independent of ROS production, and EGR2 may be one of
the molecular targets of inorganic arsenic (Bourdonnav et al.. 2009)
Biochemical Responses
xl/ATP-mediated
Ca(2+) signaling
\|/ production of
interleukin-2 (IL-
2), interferon-
gamma (IFN-
gamma)
^wound-induced
healing and peak
Ca(2+)
^wound-induced
total Ca(2+)
signaling
^wound-induced
healing, Ca(2+), and
# cells in Ca(2+)
wave
vl/IL-2, vUFNv, and
xl/IL-4 secreted
protein from
splenocytes in
culture, ConAor
anti-CD3 stimulated
Lung
(Human)
Lung
(Mice)
Lung
(Human)
Spleen
(Mice)
Immortalized
human
bronchial
epithelial
cells
(16HBE140-)
in vitro
C57BI6 male
mice ex vivo
Immortalized
human
bronchial
epithelial
cells
(16HBE140-)
in vitro
C57BI6 male
mice in vitro
[young or
aged mice (IL-
10 also N|/
from old
mice)]
0,130, or 330 nM
arsenic as sodium
arsenite
(4-5 wk)
50 ppb sodium
arsenite drinking
water
(4wk)
0.8 or 3.9 \M
sodium arsenite
(24 hr)
0, 0.03, 0.06, 0.13,
0.25, 0.50, 1, 2 |aM
Sodium arsenite
(48 hr)
(Sherwoo
detal..
2013)
(Sherwoo
detal..
2013)
(Sherwoo
detal..
2011)
(Cho et
al., 2012)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-36 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
\|/ production of
interleukin-2 (IL-
2), interferon-
gamma (IFN-
gamma)
(continued)
Observations
vl/IL-2, vUFNv, N!/ IL-
4 and vl/IL-12
secreted protein
from splenocytes in
culture, ConA or
anti-CD3/CD28
stimulated
vl/IL-2, vl/IFNv
secreted protein
and mRNA level
from splenocytes in
culture anti-
CD3/CD28
stimulated
\HL-2 secreted
protein levels from
PHA-stimulated
mononuclear cells;
no difference in
IFNv, IL-4, IL-10
xl/IL-2 secreted
protein levels from
PHA-stimulated
mononuclear cells
xl/IL-2 secreted
protein level PHA-
stimulated
mononuclear cells
\|/IL-2 at protein
and mRNA level
\|/IL-2 splenocytes
in culture, PHA-
stimulated
vl/IL-2, vUFNv, \HL-
4, vl/TNFa, vHL-10,
\|/IL-5 secreted
protein in culture,
ConA stimulated
xl/IL-2 secreted
Organ
system
Spleen
(Mice)
Primary T-
cells
(Human)
Primary
monocytes
differential
ed in 6
days into
macrophag
es
(Human)
Primary
mononucle
ar cells
(Human)
Primary
mononucle
ar cells
(Human)
Spleen
(Mice)
Primary T-
cells
(Human)
Spleen
Test System
Male
C57BI/6N
mice in vivo
Human T-cells
from PBMCs
from healthy
donors in
vitro
Human
monocytes
from PBMCs
from children
(6-10) living
in central
Mexico
chronically
exposed to As
in drinking
water
Human
PBMCs from
healthy
donors in
vitro
Human
PBMCs from
healthy
donors in
vitro
C57BI6
female mice
in vitro
Human T-cells
from PBMCs
from exposed
and
unexposed
donors
Chicken in
Dose
(Exposure
Duration)3
0, 0.01, 0.1, Img/kg
sodium arsenite i.g.
(30 days)
0, 0.25, 0.50, 1, 2
[iM Sodium arsenite
(6or24hr)
Low exposure
group:
Girls: 11.8 \ig/\
Boys: 15.6 [ig/\
urinary As (mean)
High exposure
group:
Girls: 88.2 \tg/\
Boys: 84.4 ng/l)
urinary As (mean)
(unspecified)
0, 0.01, 0.1, 1 [iM
Sodium arsenite
(24-48hr)
0, 0.01, 0.1, luM
Sodium arsenite
(24-48 hr)
0, 1, 10 [iM sodium
arsenite
(12, 24, 48 hr)
20 individuals with
skin lesions
compared to 18
unexposed
1 and 10 [iM
References
(Soto-
Pena and
Vega.
2008)
(Morzade
cetal..
2012)
(Soto;
Pena et
al.. 2006)
(Galicia et
al., 2003)
(Vega et
al.. 1999)
(Conde et
al.. 2007)
(Biswas et
al., 2008)
(Daset
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-37 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
^proliferation
of lymphocytes
^proliferation
of lymphocytes
(continued)
Cell signaling
change
Observations
protein from
splenocytes in
culture, and
bothvHL-2vHFNvat
mRNA level, ConA
stimulated
xl/ConA-stimulated
T-cell proliferation
in culture [3H] TdR
incorporation
xl/ConA-stimulated
T-cell proliferation
in culture [3H] TdR
incorporation
Slower proliferation
response to PHA- T-
cell in culture [3H]
TdR incorporation
xl/PHA-stimulated T-
cell proliferation in
culture [3H] TdR
incorporation
xl/PHA-stimulated T-
cell proliferation in
culture [3H] TdR
incorporation
NF-KB
(l^phosphorylated
p65)
Organ
system
(Chicken)
Primary T-
cells
(Human)
Spleen
(Rats)
Primary T-
cells
(Human)
Primary
mononucle
ar cells
(Human)
Primary
monocytes
differential
ed in 6
days into
macrophag
es
(Human)
Lung
(Mice)
Test System
vitro
Human T-cells
from PBMCs
from exposed
and
unexposed
donors
MaleWistar
rats in vivo
Human T-cells
from PBMCs
from exposed
(33
individuals
from an area
in Mexico)
and
unexposed
(30) donors
Human
PBMCs from
healthy
donors in
vitro
Human
monocytes
from PBMCs
from children
(6-10) living
in central
Mexico
chronically
exposed to As
in drinking
water
Nrf2-WTand
Nrf2-K0 mice
in vivo
Dose
(Exposure
Duration)3
sodium arsenite
(24, 48, 72 hr)
20 individuals with
skin lesions
compared to 18
unexposed
25 ppm sodium
arsenite in drinking
water
(42 days)
Exposed: 412 [ig/\
As in water
(7581364 |ag/l total
As in urine)
Unexposed: 37|jg/l
in water (37±37|jg/l
total As in urine)
0, 0.01, 0.1, l|aM
Sodium arsenite
(24-48 hr)
Low exposure
group:
Girls: 11.8 [ig/\
Boys: 15.6 [ig/\
urinary As (mean)
High exposure
group:
Girls: 88.2 [ig/\
Boys: 84.4 [ig/\)
urinary As (mean)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert dust]
(30 min/day/14d)
References
al., 2011)
(Biswas et
al.. 2008)
(Sankar et
al.. 2013)
(Gonseba
ttetal..
1994)
(Vega et
al., 1999)
(Soto-
Pena et
al., 2006)
(Zheng et
al., 2012)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-38 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
NF-KB (J, DNA
binding of p65 NF-
KB)
xl/enzymatic activity
of lysosomal
protease cathepsin
L
\lxtranscription
factor ERG2
tbasal
phosphorylation of
Lckand Fyn kinases
and 1*
phosphorylation of
Lck and Fyn after
stimulation by
antibodies to
CD3/CD28 in
splenocytes
Organ
system
Primary
monocytes
and pro-
monocyte
cell line
(Human)
Primary
lymphocyt
es
(Human)
Primary
monocytes
differential
ed into
macrophag
es
(Human)
Spleen
(Mice)
Test System
Human
monocytes
from PBMCs
from healthy
donors and
pro-
monocytic
U937 cell line
in vitro
Human
PBMCs from
blood of
healthy
volunteers
In vitro
Human
monocytes
from PBMCs
from healthy
donors in
vitro
Male
C57BI/6N
mice in vivo
Dose
(Exposure
Duration)3
0.25-1 [iM arsenic
trioxide
(1, 2, 3, 4, 6 days)
0, 1, 2, 3, 4, 5\M
arsenic trioxide
(48hr)
l|aM arsenic
trioxide
(48, 72 hr)
0, 0.01, 0.1, 1 mg/kg
sodium arsenite
intra-gastric
(30 days)
References
(Lemarie
etal..
2006)
(Gupta et
al.. 2003)
(Bourdon
nay etal..
2009)
(Soto-
Pena and
Vega.
2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-39 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Organ
system
Test System
Dose
(Exposure
Duration)3
References
Cellular Phenotypic Changes
N|/monocyte/
macrophage
activity or
number
N|/monocyte
recruitment to
peritoneal cavity
following
thioglycollate
stimulation
^differentiation
monocytes to
macrophages by
expression of
transferrin receptor
CD71
l^apoptosis of
splenic
macrophages
indicated by DNA
fragmentation
l^apoptosis of
monocytes,
macrophages by
Annexin V-Alexa568
(A5) and SG co-
staining
T" basal apoptosis
of monocytes,
macrophages by PI
staining and analysis
for hypodiploid cells
T" apoptosis of
monocytes,
macrophages by
DNA content assay,
Annexin V binding,
DNA fragmentation,
TUNEL
Macrophag
es
(Mice)
Primary
monocytes
and pro-
monocyte
cell line
(Human)
Spleen
(Mice)
Primary
monocytes
and pro-
monocyte
cell line
(Human)
Primary
monocytes
(Human)
Primary
monocytes
(Human)
Female balb/c
mice in vivo
Human
monocytes
from PBMCs
from healthy
donors and
pro-
monocytic
U937 cell line
in vitro
Male Swiss
albino mice in
vivo
Human
monocytes
from PBMCs
from healthy
donors and
pro-
monocytic
U937 cell line
in vitro
Human
monocytes
from children
chronically
exposed to As
and nearby
unexposed
children
Human
monocytes
from PBMCs
from healthy
donors in
vitro
50 mg/L sodium
metaarsenite in
drinking water
(4 wks)
0.25-1 [iM arsenic
trioxide
(1, 2, 3, 4, 6 days)
0.5 sodium arsenite
mg/kg bw/day
(15 days)
0.25-l|aM arsenic
trioxide
(1, 2, 3, 4, 6 days)
Urinary As range
from 94 to 240|ag/g-
creatinine exposed
children living in
town near gold
mine,
17-34|ag/g-
creatinine in nearby
unexposed children
0, 1, 5, 15,30, 50,
75, 100|JVI sodium
arsenite
(12, 36, 48, 72 hr)
(Patterso
n et al..
2004)
(Lemarie
etal..
2006)
(Sengupta
and
Bishayi,
2002)
(Lemarie
etal..
2006)
(deja
Fuente et
al., 2002)
(dela
Fuente et
al., 2002)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-40 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
\|/monocyte/
macrophage
activity or
number
(continued)
Observations
^macrophage cell
rounding,
\|/adhesion,
^phagocytosis of S.
typhimurium in 3h,
xl/NO'and 02"
following IPS
stimulation
overnight
Splenic
macrophages \|/NO"
and 02" after IPS
stimulation,
\|/macrophage
adhesion,
\|/chemotaxis,
^phagocytosis of
SRBCs
\|/macrophage
phagocytosis of A
hydrophila
^macrophage
abnormal
morphology,
\|/adhesion,
\|/chemotaxis
\|/ monocyte
/macrophage ROS
after PMA, J, NO"
after RD-F or IPS
stimulation
\|/ monocyte
/macrophage ROS
after PMA, ^ NO"
after IPS
stimulation
l^apoptosis of
monocytes,
macrophages by
Organ
system
Primary
monocytes
differential
ed in 6
days into
macrophag
es
(Human)
Spleen
(Mice)
Macrophag
es
(Catfish)
Spleen
(Mice)
Primary
monocytes
(Chicken)
Spleen and
peritoneal
macrophag
es
(Mice)
Primary
monocytes
and pro-
Test System
Human
monocytes
from PBMCs
from
individuals) in
West Bengal
India with
skin lesions
(n= 70)
chronically
exposed to As
in drinking
water
(Murshidabad
) and
unexposed
(n=64) (West
Midnapore
Male Swiss
albino mice in
vivo
Catfish in vivo
Male Swiss
albino mice in
vivo
Chicken
monocytes
from PBMCs
in vivo
Female
c57BL7J/Han
mice
Human
monocytes
pro-
Dose
(Exposure
Duration)3
Exposed individuals:
50 to 1,200 Mg/L
aresenic in drinking
water levels
Unexposed
individuals: levels 3
to 10 [ig/L inorganic
arsenic in drinking
water
0.5 sodium arsenite
mg/kg bw/day
(15 days)
42.42 [iM arsenic
trioxide
(21 days)
0.5 mg/kg bw
(intraperitoneal
injection) sodium
arsenite
(15 days)
3.7 ppm sodium
arsenite in drinking
water
(10, 20, 30, 40, 60
days)
0,0.5, 5, 50 sodium
hydrogen arsenate
(12 wks)
0, 0.5, 1, 2.5, 5[iM
tetraarsenic oxide
and diarsenic oxide
References
(Banerjee
etal..
2009)
(Sengupta
and
Bishavi.
2002)
(Ghosh et
al.. 2006)
(Bishavi
and
Sengupta,
2003)
(Aggarwal
etal..
2008)
(Arkusz et
al., 2005)
(Parket
al., 2003)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-41 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
l^neutrophil
apoptosis
I^T-lymphocyte
apoptosis
T" B-lymphocyte
apoptosis
\L-Langerhans
cell migration
Observations
Annexin V FITC
and PI staining
l^neutrophil
apoptosis
determined by
CD16 shedding
independent of
MAPKs
'T'T-cell apoptosis
determined by
TUNEL assay
'T'B-cell apoptosis
determined by
Annexin V assay
^activated
Langerhans cells in
cervical lymph
nodes of DNFB-
sensitized mice by
fluorescence-
activated sorting
Organ
system
monocyte
cell line
(Human)
Human
(Lung)
Primary
lymphocyt
es
(Human)
Lymphocyt
es
(Mice)
Immune,
Skin
(Mice)
Test System
monocytic
U937 cell line
in vitro
Human
neutrophils
from venous
blood of
healthy
volunteers
In vitro
Human
PBMCs from
blood of
healthy
volunteers
In vitro
Mouse B cell
lymphoma
line TA3
In vitro
Female balb/c
mice in vivo
Dose
(Exposure
Duration)3
(0, 2, 4, 6, 8, 10, 12
hr)
5 [iM arsenic
trioxide(.25-180
minutes)
0, 1, 2, 3, 4, 5 |aM
arsenic trioxide
(48 hr)
0, 0.8, 4, 20, 100,
500 [iM sodium
arsenite
(18 hr)
50 mg/l sodium
metaarsenite in
drinking water
(4 wks)
References
(Binet and
Girard,
2008)
(Gupta et
al., 2003)
(Harrison
and
McCoy.
2001)
(Patterso
n et al.,
2004)
Tissue/ Organ Responses
\|/Thymus size
\|/Thymus size
assessed
sonographically
^absolute, not
relative thymus
weight
Thymus
(Human)
Thymus
(Chicken)
Children in
Matlab region
of Bangladesh
cohort
Chickens in
vivo
Maternal arsenic
metabolites in urine
at weeks 8 and 30
of gestation
3.7 ppm sodium
arsenite in drinking
water
(10, 20, 30, 40, 60
days)
(Moore et
al., 2009;
Raqib et
al., 2009)
(Aggarwal
etal..
2008)
Individual Responses
xl/delayed-type
hypersensitivity
(DTH) response
V|,DTH to KLH by
footpad thickness
V|,DTH to 2,4-
dinitro-l-
chlorobenzene
(DNCB)orPHA-Pby
Immune
function
(Rats)
Immune
function
(Chicken)
MaleWistar
rats in vivo
Chickens in
vivo
25 ppm sodium
arsenite in drinking
water
(42 days)
3.7 ppm sodium
arsenite in drinking
water
(10, 20, 30, 40, 60
(Sankar et
al., 2013)
(Aggarwal
etal..
2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-42 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
\|/antibody
response
\|/antibody
response
(continued)
xl/host
resistance (to
infection)
Observations
skin thickness
\|/phytohemagglutin
in hypersensitivity
response by skin
thickness
^decreased
antibody response
by ELISA to
vaccination with
disease virus (F-
strain; RD-F)
\|/antibody
response by
agglutination to
bacterial (A.
hydrophila)
challenge;
^antigen-specific
plaque-forming cells
toSRBC
xl/antibody
response to SRBC by
RFC
xl/antibody
response for IgG at
day 14 to KLH by
ELISA; not
significant in IgM at
day5
xl/antibody
response to SRBC by
RFC
\|/ ability to
decrease bacteria
load (C. batmchus),
^tissue damage,
slower recovery,
^mortality
\|/ blood and splenic
clearance bacterial
(5. aureus)
challenge
^ability to clear
viral (snakehead
Organ
system
Immune
function
(Rats)
Immune
function
(Chicken)
Immune
function
(Catfish)
Immune
function
(Mice)
Immune
function
(Mice)
Immune
function
(Mice)
Immune
function
(Catfish)
Immune
function
(Mice)
Immune
function
Test System
Male cotton
rats
Chickens in
vivo
Catfish in vivo
Male
c57bl/6N
mice in vivo
MaleWistar
rats in vivo
Male white
Swiss cross
mice in vivo
Catfish in vivo
Male Swiss
albino mice in
vivo
Zebrafish in
Dose
(Exposure
Duration)3
days)
0, 5, 10 ppm sodium
arsenite
(6 wks)
3.7 ppm sodium
arsenite in drinking
water
(10, 20, 30, 40, 60
days)
42.42 [iM arsenic
trioxide
(150 days)
50 Mg/m3 and 1
mg/m3 nose only
inhalation arsenic
trioxide
(14 days)
0, 0.4, 4, 40 ppm
sodium arsenite in
drinking water
(18 wks)
0, 0.5, 2, 10 ppm
sodium arsenite in
drinking water
(3 wks)
42.42 [iM arsenic
trioxide
(150 days)
Sodium arsenite
(p.5 mg/kg bw (ip)
(15 days)
2 or lOppb sodium
arsenite in water
References
(Savabiea
sfahani et
al.. 1998)
(Aggarwal
etal.,
2008)
(Ghosh et
§L
2007a)
(Burchiel
etal.,
2009)
(Nain and
Smits,
2012)
(Blakley
etal..
1980)
(Ghosh et
§L
2007a)
(Bishavi
and
Sengupta.
2003)
(Nayaket
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-43 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
\|/contact
sensitization
response
Observations
rhabovirus) or
bacterial (E.
tarda)\oad
Respiratory
infection
T" influenza virus
titer and ^virus-
related morbidity
\|/Lymph node
proliferation; \|/ear
swelling to DNFB
Organ
system
(Zebrafish)
Immune
function
(Mice)
Immune,
Skin
(Mice)
Test System
vivo
Male C57bl/6j
mice in vivo
Female balb/c
mice in vivo
Dose
(Exposure
Duration)3
(4 days starting at 1
cell stage)
lOOppb sodium
arsenite in drinking
water
(5 wks)
50 mg/l sodium
metaarsenite in
drinking water
(4 wks)
References
al., 2007)
(Kozul et
al., 2009)
(Patterso
n et al..
2004)
Susceptible individual response
NALP2gene
polymorphism
(C/A +A/A) of
NLP2A1052E
SNPs
TNFaandlLlO
gene
polymorphism
(-308G/A and -
3575T/A)
NALP2 gene
polymorphism
modifies inorganic
arsenic-associated
respiratory disease
GA/AATNFa
genotype had
higher risk of
developing
inorganic arsenic-
induced
conjunctivitis and
respiratory effects;
TNFa (pro-
inflammatory
cytokine) and IL10
(anti-inflammatory
cytokine) gene
polymorphisms
modify serum TNFa
and IL10 levels
Immune/
Respiratory
(Human)
Immune/
Respiratory
/
eye
(Human)
Individuals
from West
Bengal all
with
inorganic
arsenic
exposure;
case-control
study divided
by presence
of inorganic
arsenic-
related skin
lesions
Individuals
from West
Bengal all
with
inorganic
arsenic
exposure;
case-control
study divided
by presence
of inorganic
arsenic-
related skin
lesions
Exposure assessed
by inorganic arsenic
content of drinking
water and urine
samples
Arsenic exposure
assessed in urine
(Bhattach
arjee et
al., 2013)
(Banerjee
etal..
2011)
Population Response
Respiratory
infection
T" relative risk of
lower respiratory
tract infection,
^relative risk of
Immune/
Respiratory
(Human)
Children in
Matlab region
of Bangladesh
MINIM
262 - 977 ng/L
maternal arsenic
metabolites in urine
(average)
(Rahman
etal..
2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-44 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Disease/cold
fever
Infection-
related Gl
disease
Observations
sever lower
respiratory tract
infection
l^acute respiratory
infection
T" relative risk of
lower and upper
respiratory tract
infection requiring
physician visitor
prescription
medication, and
^respiratory
symptoms,
T" days of fever
Scolds treated with
prescription
T" relative risk of
diarrhea
T" days of diarrhea
^diarrhea
symptoms lasting
two or more days or
requiring doctors
visit were
associated but not
significant
[RR=1.9(0.9,3.9) and
Organ
system
Immune/
Respiratory
(Human)
Immune/
Respiratory
(Human)
Immune
(Human)
Immune
(Human)
Immune/
gastro-
intestinal
(Human)
Immune/
gastro-
intestinal
(Human)
Immune/
Respiratory
(Human)
Test System
cohort
Children in
Matlab region
of Bangladesh
cohort
Children New
Hampshire
Birth Cohort
Pregnant
mothers in
Matlab region
of Bangladesh
cohort
Children New
Hampshire
Birth Cohort
Children in
Matlab region
of Bangladesh
MINIM
cohort
Pregnant
mothers in
Matlab region
of Bangladesh
cohort
Children New
Hampshire
Birth Cohort
Dose
(Exposure
Duration)3
compared to <39
Mg/L maternal
arsenic metabolites
in urine
152.4, 145.8 Mg/L
maternal arsenic
metabolites in urine
(mean) at weeks 8
and 30 gestation
6 |jg/L maternal
urinary As levels
(mean) at 24-28
weeks gestation
152.4, 145.8 Mg/L
maternal arsenic
metabolites in urine
(mean) at weeks 8
and 30 gestation
6 Mg/L maternal
urinary As
levels(mean) at 24-
28 weeks gestation
262 - 977 Mg/L
maternal arsenic
metabolites in urine
(average)
compared to <39
Mg/L maternal
arsenic metabolites
in urine
152.4, 145.8 Mg/L
maternal arsenic
metabolites in urine
(mean) at weeks 8
and 30 gestation
6 Mg/L maternal
urinary As levels
(mean) at 24-28
weeks gestation
References
(Raqib et
al., 2009)
(Farzan et
al., 2013)
(Raqib et
al., 2009)
(Farzan et
al., 2013)
(Rahman
etal..
2011)
(Raqib et
al.. 2009)
(Farzan et
al.. 2013)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-45 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
RR=3.5 (0.8,15.4)]
Organ
system
Test System
Dose
(Exposure
Duration)3
References
Abbreviations used for exposure durations: minutes (min), hours (hr), days (d), weeks (wks)
'Exposure durations are characterized as "unspecified" when a study does not explicitly state the exposure duration
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-46 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
10.5Preliminary Data on Effects Mediated By Oxidative
Stress
Relevant Health Effects: Cardiovascular Disease, Diabetes, Liver Disease, Lung Cancer,
Bladder Cancer, Neurotoxicity, Non-Malignant Respiratory Disease, Pregnancy
Outcomes, Renal Disease, Skin Cancer, and Skin Lesions
Key Events
Observations
Organ system
Test System
Dose
(Exposure
Duration)
References
Molecular Initiating Events
Reaction with 02
(intermediate
arsine species;
e.g.,
dimethylarsine)
Reaction with
ferritin
(Methylated-As)
Oxidation of As(lll)
to As(V)
Reactions with
NADPH oxidase
Reactions with
mitochondrial
respiratory chain
l^free radicals
(e.g., Dimethylarsenic peroxyl
radical [(CH3)2AsOO],
superoxide anion)
Redox-active Fe release
H202 formation followed by
Fenton reaction (hydroxyl
radical formation)
xl/ROSwith NADPH inhibitor
xl/ROSwith mitochondrial
respiratory chain inhibitor
Biochemical Responses
Generation of
reactive oxygen
species
\|/dichlorofluorescein
diacetate (peroxides)
Multiple
(See Review
Article)
Multiple
(See Review
Article)
Multiple
(See Review
Article)
Liver
(Human)
Liver
(Human)
Multiple
(See Review
Article)
Multiple
(See Review
Article)
Multiple
(See Review
Article)
Human
immortalized
liver cell line
HL-7702
Human
immortalized
liver cell line
HL-7702
Multiple
(See Review Article)
Multiple
(See Review Article)
Multiple
(See Review
Article)
Diphenylene-
iodonium chloride
(DPI)
(30 min
pretreatment) +
5 [iM arsenite
(2hr)
Rotenone
(30 min
pretreatment) +
5 [iM arsenite
(2hr)
Reviewed in
(Flora, 2011)
Reviewed in
(Flora, 2011)
Reviewed in
(Flora, 2011;
Jomova and
Valko, 2011)
(Lietal.,
2014);
Reviewed in
(Flora, 2011)
(Lietal.,
2014);
Reviewed in
(Flora. 2011)
Skin
(Human)
HaCaT
transformed
keratinocytes
0.5 [iM trivalent
arsenic (As[lll])
(24 hr)
(Snow et al..
2005)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-47 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Generation of
reactive oxygen
species (continued)
Observations
tH202
I^Superoxide
I^Superoxide
T" 2',7'-dichlorofluorescein-
diacetate (DCFH-DA)
tH202
*co-treatment with anti-
oxidants prevents T"
Dose dependent 'T'CM-
H2DCFDA fluorescence
(general ROS indicator)
* co-treatment with anti-
oxidants mitigates T"
*latent ^ with MMA(III)
compared with As(lll) (no T"
at 10 min)
tCM-H2DCFDA
* co-treatment with anti-
oxidants mitigates T"
Time-dependent 'T'CM-
H2DCFDA fluorescence
*significant T" only at 12
weeks
Organ system
Lung
(Human)
Lung
(Rat)
Liver
(Mouse)
Liver
(Human)
Liver
(Rat)
Kidney
(Rat)
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Test System
WI38 human
diploid lung
fibroblast
Lung Epithelial
Cells (LECs)
Liver Sinusoidal
Endothelial
Cells (SECs)
Human
immortalized
liver cell line
HL-7702
Wistar Rats
(Male, albino)
(liver
microsomes)
Wistar Rats
(Male, albino)
(kidney
microsomes)
UROtsa cells
UROtsa cells
UROtsa cells
Dose
(Exposure
Duration)
0.5 [iM trivalent
arsenic (As[lll])
(24 hr)
< 1 [iM sodium
arsenite
(30 min)
2.5-5 [iM arsenite
(30 min)
5 [iM arsenite
(2hr)
100 ppm sodium
arsenite
(30 days)
100 ppm sodium
arsenite
(30 days)
1-100 [iM NaAs02
(10 min)
50500nMMMA(lll)
(30 min)
10 [iM NaAs02
(10 min)
500nMMMA(lll)
(10 min)
50nMMMA(lll)
(4 - 12 weeks)
References
(Lietal..
2011)
(Straub etal..
2008)
(Lietal.,
2014)
(Ramanathan
etal., 2003)
(Ramanathan
etal.. 2003)
(Eblinetal..
2006)
(Eblinetal..
2008)
(Wneketal.,
2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-48 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Mitochondrial
Activity Changes
Alteration in
glutathione and
other non-
enzymatic
antioxidant levels
Alteration in
glutathione and
other non-
enzymatic
antioxidant levels
(continued)
Depletion of
micronutrients
Enzyme Activity
Changes
Observations
l^colocalization of ROS &
mitochondria staining
V|,GSH
V|,GSH
\|/ Ascorbic acid
xl/a-tocopherol
*co-treatment with anti-
oxidants prevents ]/
tGSH
\|/ascorbate
xl/ Fe(ll)
xl/SOD dismutase
\|/catalase
\|/SOD dismutase
\|/catalase
xl/glutathione reductase
Organ system
Liver (Human)
Brain (Mouse)
Brain (Rat)
Lung
(Rat)
Liver (Rat)
Kidney
(Rat)
Pancreas
(Rat)
Pancreas
(Rat)
Lung
(Rat)
Liver (Human)
Brain (Mouse)
Brain (Rat)
Test System
Human
immortalized
liver cell line
HL-7702
Swiss Mice
(Male albino)
Sprague
Dawley Rats
(Male)
Lung Epithelial
Cells (LECs)
Wistar Rats
(Male, albino)
(liver
microsomes)
Wistar Rats
(Male, albino)
(kidney
microsomes)
Wistar Rats
(Male)
INS-1(832/13)
cells
(Rat p-cells)
Lung Epithelial
Cells (LECs)
Human
immortalized
liver cell line
HL-7702
Swiss Mice
(Male albino)
Sprague
Dawley Rats
(Male)
Dose
(Exposure
Duration)
5 [iM arsenite
(2hr)
0.5 or 1 As203
mg/kg (45 days)
0.05, 0.10, 0.30, 3.0
ppm Na3As04(40
days)
2 [iM sodium
arsenite
(<30min)
100 ppm sodium
arsenite
(30 days)
100 ppm sodium
arsenite
(30 days)
1.7 mg/kg
NaAs+302
(every 12 hr/
90 days)
0.25 -0.5 [iM
arsenite
(96 hr)
2 [iM sodium
arsenite
(2-8 hr)
5 [iM arsenite
(12 hr)
0.5 or 1 mg/kg
As203 (45 days)
0.05, 0.10, 0.30, 3.0
ppm Na3As04
(40 days)
References
(Lietal..
2014)
(Rao and
Avani, 2004)
(Chaudhuri
etal., 1999)
(Lietal.,
2011)
(Ramanathan
etal., 2003)
(Ramanathan
etal., 2003)
(Izquierdo-
Vega etal..
2006)
(Fu etal.,
2010)
(Lietal.,
2011)
(Lietal.,
2014)
(Rao and
Avani, 2004)
(Chaudhuri
etal., 1999)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-49 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Enzyme Activity
Changes
(continued)
Protein expression
and/or level
changes
Observations
1^DNA ligase
\|/ DNA ligase
Racl-GTPase activation
NADPH Oxidase activation
(Nox2-based)
^ NADPH Oxidase
(inferred)
'tPropyl hydroxylase (PHDs)
(inactivates HIF-la)
l^haem oxygenase
xl/Cytochrome P450
xl/Cyto chrome b5
vl/NADPH-cyt P450 reductase
*1V\I/ mitigated by
antioxidants
xl/thioredoxin reductase
(TrxR)
\|/poly(ADP-ribose)
polymerase-1 (PARP-1)
*T* activity if MMA(III)
exposure is discontinued for
2 weeks prior to
measurement in cells
previously exposed for 4 or 8
weeks
Western Blot:
I^Base excision repair
proteins
(DNA polymerase (3, DNA
ligase 1)
Organ system
Lung (Human)
Liver (Mouse)
Liver (Human)
Liver (Rat)
Kidney (Rat)
Pancreas (Rat)
Urothelium
(Human)
Skin
(Human)
Test System
WI38 human
diploid lung
fibroblast
C57BL/6 Tac
Mice
(In-vivo and ex-
vivo liver
sinusoidal
endothelial
cells [SECs])
Human
immortalized
liver cell line
HL-7702
Wistar Rats
(Male, albino)
(liver
microsomes)
Wistar Rats
(Male, albino)
(kidney
microsomes)
Wistar Rats
(Male)
UROtsa cells
Human
Keratinocyte
Cells (HaCaT)
Dose
(Exposure
Duration)
0.5-lnMAs(lll)
(24 to 120 hr)
SorlOuM As(lll)
(24 to 120 hr)
In vivo: 250 ppb
sodium arsenite
(5wk)
Ex vivo: 2.5 [iM
sodium arsenite
(8hr)
5 [iM arsenite
(12 hr)
100 ppm sodium
arsenite
(30 days)
100 ppm sodium
arsenite
(30 days)
1.7 mg/kg NaAs+302
(every 12 hr/
90 days)
50 nM MMA(II)
(4-12 weeks)
O.l-lnMAs(lll)
(24 hr)
References
Reviewed in
(Snowet al..
2005)
(Straub etal..
2008)
(Li etal.,
2014)
(Ramanathan
etal., 2003)
(Ramanathan
etal., 2003)
(Izquierdo-
Vega etal..
2006)
(Wneketal..
2011)
Reviewed in
(Snow et al..
2005)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-50 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Protein expression
and/or level
changes
(continued)
Observations
\|/ Base excision repair
proteins
Western Blot:
I^Base excision repair
proteins
(DNA polymerase P,
DNA ligase 1)
\|/ Base excision repair
proteins
mRNA & Western Blot:
I^NRFl
1^NRF2
Western Blot:
1^Nrf2
Western Blot:
I^Cu/Zn SOD, thioredoxin
*mitigated by antioxidants
Immunofluorescence:
tPECAM-1
Western Blot:
^HIF-la
Western Blot:
tVEGF
Organ system
Lung (Human)
Skin
(Human)
Lung (Mouse)
Lung (Rat)
Liver (Mouse)
Liver (Human)
Liver (Human)
Test System
WI38 human
diploid lung
fibroblast
Immortalized
human
keratinocyte
cells
(HaCaT)
Mice
(unspecified
strain; wild
type and Nrf2-
knockout)
Lung Epithelial
Cells (LECs)
C57BL/6 Tac
Mice
(In-vivo and ex-
vivo liver
sinusoidal
endothelial
cells [SECs])
Human
immortalized
liver cell line
HL-7702
Human
immortalized
liver cell line
HL-7702
Dose
(Exposure
Duration)
5-10nMAs(lll)
(24 hr)
0.1-1 nM As(lll)
(24 hr)
5- 10nM As(lll)
(24 hr)
>5 [iM inorganic
arsenite (As[lll])
(6hr)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert background
dust]
(30min/day/14
days)
2 [iM sodium
arsenite
(16 weeks)
In vivo: 250 ppb
sodium arsenite
(5wk)
Ex vivo: 1-5 [iM
sodium arsenite
(8hr)
5 [iM arsenite
(12 hr)
1 5 [iM arsenite
(12 hr)
References
Reviewed in
(Snowet al..
2005)
(Zhao et al..
2012)
(Zheng et al..
2012)
(Lietal.,
2011)
(Straub etal..
2008)
(Lietal.,
2014)
(Lietal.,
2014)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-51 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Protein expression
and/or level
changes
(continued)
Observations
Western Blot:
1^Nrf nuclear fraction
* 1s ARE luciferase activity;
^expression of downstream
targets mRNA (e.g., Hmoxl,
NAD(P)H, catalase)
Western Blot:
tHsp70
(stress protein)
Western Blot:
l^metallothionein
(stress protein)
mRNA & Western Blot:
tPARP-1
*no effect on expression if
MMA(III) exposure is
discontinued for 2 weeks
prior to measurement in cells
previously exposed for 4 or 8
weeks
Western blot:
^ Cox-2
*levels normalize by 24 hr
**co-treatment with SOD or
melatonin block induction;
no effect of catalase
mRNA:
^ Cox-2
*levels normalize by 24 hr
**co-treatment with
catalase, SOD or melatonin
block induction
Organ system
Pancreas
(Rat)
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Test System
INS-1(832/13)
cells
(Rat p-cells)
UROtsa cells
UROtsa cells
UROtsa cells
UROtsa cells
Dose
(Exposure
Duration)
0.25 -0.5 |aM
arsenite
(96 hr)
1 |aM NaAs02
(30 min)
10 [iM NaAs02
(30-240 min)
50 nM - 5 |aM
MMA(III)
(30 -240 min)
1 |aM NaAs02
(240 min)
10 [iM NaAs02
(30-240 min)
50 nM - 5 |aM
MMA(III)
(30 -240 min)
50nMMMA(lll)
(4-12 weeks)
1 [iM sodium
arsenite
(4 hr); or
50 nM MMA(III)
(4hr)
1 [iM sodium
arsenite
(4 hr); or
50nMMMA(lll)
(4hr)
References
(Fu etal..
2010)
(Eblinetal..
2006)
(Wneketal.,
2011)
(Eblinetal.,
2008)
(Eblinetal..
2008)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-52 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Cell membrane
disruption
Cell membrane
disruption
(continued)
DNA,
chromosomal
damage
Observations
Western blot:
vl/MnSOD
*no change in Mn SOD with
As(lll) treatment; very little
change in catalase with
either As(lll) or MMA(III)
treatments
Western blot:
-Ku/Zn SOD
*<], after 24 hr MMA(III)
exposure
^Lipid peroxidation
^Lipid peroxidation
(continued)
Oxidative DNA damage
(l^anti-8-Oxo-dG staining)
Organ system
Urothelium
(Human)
Urothelium
(Human)
Brain (Mouse)
Brain (Rat)
Liver
(Mouse)
Liver (Rat)
Kidney (Rat)
Pancreas (Rat)
Lung (Mouse)
Test System
UROtsa cells
UROtsa cells
Swiss Mice
(male albino)
Sprague
Dawley Rats
(Male)
BALB/c Mice
(Male)
Wistar Rats
(Male, albino)
(liver
microsomes)
Wistar Rats
(Male, albino)
(Kidney
microsomes)
Wistar Rats
(Male)
Mice
(unspecified
strain; wild
type and Nrf2-
knockout)
Dose
(Exposure
Duration)
50nMMMA(lll)
(1 to 24 hr)
1 [iM sodium
arsenite
(0.5-24hr)
50nMMMA(lll)
(0.5 -4 hr)
0.5 or 1 mg/kg
As203 (45 days)
0.05, 0.10, 0.30, 3.0
ppm Na3As04(40
days)
3.2 mg/L
Asflll/AsfV)
(6 months)
100 ppm sodium
arsenite
(30 days)
100 ppm sodium
arsenite
(30 days)
1.7 mg/kg
NaAs+302
(every 12 hr/
90 days)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert background
dust]
(30 min/day/14
days)
References
(Eblinetal..
2008)
(Eblinetal.,
2008)
(Rao and
Avani. 2004)
(Chaudhuri
etal., 1999)
(Santra etal.,
2000)
(Ramanathan
etal., 2003)
(Ramanathan
etal., 2003)
(Izquierdo-
Vega etal..
2006)
(Zheng et al.,
2012)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-53 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Gene expression
changes
Gene expression
changes
(continued)
Observations
Oxidative DNA damage
(^ 8-OHdG staining)
Oxidative DNA damage
(l^anti-S-Oxo-dG levels
measured by HPLC/ECD)
xl/anti-8-Oxo-dG levels
measured by HPLC/ECD
^DNA single-strand breaks
(comet assay and flow
cytometry)
1^NRF2& ARE dependent
genes (HMOX-1, NQol, GCLC,
GCLM, SRX)
-T-Nrf2 targets (NQ01, yGCS,
HO-1)
Altered gene expression
related to:
oxidative stress (^HMOXl);
protein folding (x|/FKB5)
Thioredoxin reductase
CMXNRDI)
Metallothinonine regulation
CMVIT1E)
DNA damage sensing
(v|/DDB2)
Thioredoxin CMXN)
Cell adhesion/growth
CM.GALS8)
Immune response (\|/THBD)
Organ system
Blood
(Human)
Urothelium
(Human)
Urothelium
(Human)
Skin
(Human)
Lung (Mouse)
Urothelium
(Human)
Test System
Human
Population
UROtsa cells
UROtsa cells
Immortalized
human
keratinocyte
cells (HaCaT)
Mice
(unspecified
strain; wild
type and Nrf2-
knockout)
Human
uroepithelial
cells from
kidney donor
ureter
segments
Dose
(Exposure
Duration)
10.88 to 19.05
Mg/gCr urinary
arsenic
(40-70 yrs)
1 - 10 nM NaAs02
(30 min)
50nMMMA(lll)
(30)
50nM-5|aM
MMA(III)
(60 min)
1 - 10 nM NaAs02
(60 min)
50 nM MMA(II)
(4-12 weeks)
1.25-40 [iM
inorganic arsenite
(As[lll])
(6hr)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert background
dust]
(30min/day/14
days)
6nMAs(lll)
+MMAV+DMAV
(24 hr); or
6nMAs(lll)
+MMA3++DMA3+
(24 hr)
References
(Peietal..
2013)
(Eblinetal.,
2006)
(Wneketal..
2011)
(Zhao et al.,
2012)
(Zheng et al.,
2012)
(Yager etal.,
2013; Clewell
etal., 2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-54 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Gene expression
changes
(continued)
Cell signaling
changes
Observations
Alterations in genes related
to: inflammatory signaling,
epithelial-to-mesenchymal
transition, cell cycle control,
and apoptosis/survival
signaling
^adaptive gene response
(delay apoptosis,
preinflammatory)
Altered gene expression
related to:
Oxidative stress,
proteotoxicity, inflammation,
and proliferative signaling,
DNA repair, cell cycle, G2/M
checkpoint control, and
induction of apoptosis
Altered apoptotic gene
expression
760 Alternations in gene
expression, generally related
to:
Oxidative stress (e.g., NQ01)
Lipid metabolism (e.g.,
ALDH2)
Inflammatory response (e.g.,
IL8, MAPK1)
176 alternations in gene
expression, generally related
to:
Oxidative stress (e.g., TNF)
Lipid metabolism (e.g., AKT3)
Inflammatory response
(e.g., IL8, IL6)
Genes in ERK 1/2 MARK- &
NF-KB signaling pathways
Organ system
Urothelium
(Human)
Various
Various
Various
Urothelium
(Human)
Urothelium
(Human)
Urothelium
(Human)
Test System
Human
uroepithelial
cells from
kidney donor
ureter
segments
Various
Various
Various
UROtsa cells
UROtsa cells
UROtsa cells
Dose
(Exposure
Duration)
0.06 [iM inorganic
arsenic and
trivalent or
pentavalent
metabolites
(24 hr)
<0.01 [iM various
arsenic species
(various exposure
durations)
0.1-10 [iM various
arsenic species
(various exposure
durations)
10 - 100 [iM
various arsenic
species
(various exposure
durations)
IHMMMA(III)
(24 hr)
1 [iM DMA(III)
(24 hr)
lnMMMA(lll)or
DMA(III)
(24 hr)
Transcription Factors (e.g., Nrf2, HIF-la, NF-KB)
References
(Clewell et
al.. 2011)
(Gentry et
al., 2010)
Review
(Gentry et
al., 2010)
Review
(Gentry et
al.. 2010)
Review
(Bailey etal.,
2012)
(Bailey etal.,
2012)
(Bailey etal.,
2012)
Reviewed in
(Flora, 2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-55 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
(Numerous;
examples provided
here see review
article for details)
Observations
NF-KB (tp-p65)
Organ system
Lung (Mouse)
Test System
Mice
(unspecified
strain; wild
type and Nrf2-
knockout)
Dose
(Exposure
Duration)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert background
dust]
(30min/day/14
days)
Mitogen-activated protein kinases (MAPKs)
Erk
(Ras, Raf, MEK, ERK
activation)
Lung (Rat)
Lung Epithelial
Cells (LECs)
100 [iM B[a]P
(24hr)
2 [iM sodium
arsenite
(16wks)
Tyrosine phosphorylation
'T'p- Epidermal Growth
Factor Receptor
Lung (Human)
Transformed
human
bronchial cells
(BEAS)
500 [iM sodium
arsenite
(20 min)
References
(Zheng et al..
2012)
Reviewed in
(Flora, 2011)
(Lietal..
2011)
Reviewed in
(Flora, 2011)
(Wuetal.,
1999)
Cellular Responses
Cytotoxicity/
viability,
proliferation,
apoptosis
Cytotoxicity/
viability,
proliferation,
1s Cytotoxicity
^apoptosis
\|/cell viability
*T" mitigated by natural
Nrf2-inducer
tTUNEL labeling
^proliferation
Skin
(Human)
Lung
(Human)
Lung (Mouse)
Lung (Rat)
Immortalized
human
keratinocyte
cells (HaCaT)
Human
bronchial
epithelium
cells
(16HBE14o)
Mice
(unspecified
strain; wild
type and Nrf2-
knockout)
Lung Epithelial
Cells (LECs)
>10|aMAs(lll)
(24 hr)
<1HM As(lll)
(48 hr)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert background
dust]
(30 min/day/14
days)
2 [iM sodium
arsenite
(24 hr)
(Zhao et al..
2012)
(Tao et al.,
2013)
(Zheng et al..
2012)
(Lietal.,
2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-56 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
apoptosis
(continued)
Epithelial-
mesenchymal
transition
Cell matrix
changes
Functional
Changes
Malignant
transformation
Observations
l^cell viability
xl/cell viability
*reduced Nrf2 expression
sensitizes cells to viability
change; activation of Nrf2
mitigates effects
]/ cell viability
*co-treatment with
antioxidants other than
catalase prevents ]/
No ]/ cell viability
Colony formation,
^epithelial protein markers
l^mesenchymal protein
markers
*mitigated by antioxidant
treatment
\|/ porosity
\|/insulin production
xl/glucagon production
xl/insulin secretion in
response to glucose
^insulin secretion in
response to potasium
chloride
l^multinucleated cells,
morphological changes
(confocal microscopy)
tumor formation in in vivo
xenografts
Organ system
Bladder
(Human)
Bladder
(Human)
Lung (Rat)
Liver (Mouse)
Pancreas
(Rat)
Pancreas
(Rat)
Urothelium
(Human)
Test System
Human bladder
urothelium cell
line(UROtsa)
Human bladder
urothelium cell
line(UROtsa)
Lung Epithelial
Cells (LECs)
C57BL/6 Tac
Mice
(In-vivo and ex-
vivo liver
sinusoidal
endothelial
cells [SECs])
Wistar Rats
(Male)
INS-1(832/13)
cells
(Rat p-cells)
UROtsa cells
Dose
(Exposure
Duration)
5-10|JVIAs(lll)
(24 hr)
20-80 |aM As(lll)
(24 hr)
1 [iM sodium
arsenite,
(24 hr)
50nMMMA(lll)
(24 hr)
100|JVIB[a]P
(24hr)
2 [iM sodium
arsenite
(16wks)
In vivo: 250 ppb
sodium arsenite
(5wk)
Ex vivo: 1-5 [iM
sodium arsenite (8
hr)
1.7 mg/kg
NaAs+302
(every 12 hr/
90 days)
0.25 -0.5 [iM
arsenite
(96 hr)
0.05 [iM MMA(III)
(24 -52 weeks)
References
(Wang et al..
2007b)
(Eblinetal..
2008)
(Lietal..
2011)
(Straub et al..
2008)
(Izquierdo-
Vegaetal..
2006)
(Fu etal.,
2010)
(Bredfeldt et
al., 2006)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-57 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Organ system
Test System
Dose
(Exposure
Duration)
References
Tissue/ Organ Responses
Tissue remodeling
Inflammatory
response
Vascular
remodeling
Endocrine
signaling changes
T" Alveolar septa thickening,
collagen deposition,
fibroblast proliferation,
pneumocyte hyperplasia;
T" inflammatory cells in BAL
fluid
-T-TNF-a, IL-6 in BAL fluid
tTh2cytokines(IL-3, IL-4)
't'chemokines (TGF-(3, MCP-
1)
*T" mitigated by natural
Nrf2-inducer
^ TNF-a, IL-1P, IFNy
Sinusoidal capillarization
\|/ nutrient/ waste exchange
^fasting serum glucose
'T'blood insulin
Lung (Mouse)
Lung (Mouse)
Placenta
(Human)
Liver (Mouse)
Pancreas (Rat)
Mice
(unspecified
strain; wild
type and Nrf2-
knockout)
Mice
(unspecified
strain; wild
type and Nrf2-
knockout)
Human
Population
C57BL/6 Tac
Mice
(In vivo and
ex vivo liver
sinusoidal
endothelial
cells [SECs])
Wistar Rats
(Male)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert background
dust]
(30 min/day/14
days)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert background
dust]
(30 min/day/14
days)
>60 [ig/L urinary
arsenic at
gestational week 30
In vivo: 250 ppb
sodium arsenite
(5wk)
Ex vivo: 8 hr
1.7 mg/kg
NaAs+302
(every 12 hr/90
days)
(Zheng et al.,
2012)
(Zheng et al.,
2012)
(Ahmed et
al., 2011)
(Straub et al.,
2008)
(Izquierdo-
Vega et al..
2006)
Individual Responses
Diabetes
(Inferred from
insulin resistance)
Liver disease
Insulin resistance
Hepatic fibrosis
Blood (Rat)
Liver (Mouse)
Wistar Rats
(Male)
BALB/c Mice
(Male)
1.7 mg/kg
NaAs+302 (every 12
hr/
90 days)
3.2 mg/L
(15 months)
(Izquierdo-
Vega et al..
2006)
(Santra etal.,
2000)
Reviewed in
(Flora, 2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-58 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Non-malignant
respiratory disease
Observations
Allergic lung inflammation
Susceptible individual response
KEAP1 and/or
NRF2 mutations
NADPH oxidase
p22 subunit
polymorphisms
Diabetics
Alcohol
T" NRF2 activity in skin
cancer patients
^hypertension risk in
individuals with
polymorphisms & high
inorganic arsenic exposure
xl/thioredoxin reductase
(TrxR)
Ethanol may augment
oxidative stress and induction
of angiogenic factors that
would promote tumor
growth
Organ system
Lung (Mouse)
Test System
Mice
(unspecified
strain; wild
type and Nrf2-
knockout)
Dose
(Exposure
Duration)
0.48 mg/m3
synthetic dust [10%
arsenic trioxide +
inert background
dust]
(30min/day/14
days)
References
(Zheng et al..
2012)
Skin
Cardio-
vascular
system
Pancreas
(Rat)
Cardiovascular
system
Human
population
Human
population
Wistar Rats
(Male)
Human
microvascular
endothelial
(HMVEC) cells
Not applicable
0.7- 0.93 mg/L
median inorganic
arsenic in well
water
(>6 months)
1.7 mg/kg NaAs+302
(every 12 hr/
90 days)
l-5uM arsenite in
presence or
absence of 0.1%
EtOH. 24 hour
experiments
(Kimetal..
2010) cited
in (Zhao et
al., 2012)
(Hsuehetal.,
2005); Cited
in (Straub et
al.. 2008)
(Izquierdo-
Vegaetal.,
2006);
Schulze et al.
(2004)
(Kleiand
Barchowsky,
2008)
Population Response"
Elevated oxidative
stress
Elevated oxidative
stress
Cardiovascular
disease
'T'superoxide in plasma
(chemiluminescence method)
xl/Plasma antioxidants
'T'serum lipid peroxides
xl/non-protein sulfhydryl
levels in whole blood
Peripheral vascular disease,
ischemic heart disease, acute
myocardial infarction,
atherosclerosis, hypertension
Plasma
(Human)
Blood
(Human)
Cardiovascular
system
Human
Population
(Taiwan)
Human
population
(Inner
Mongolia,
China,)
Human
population
9.60 |ag/L
Average arsenic
blood levels
(Average age: 64
years)
0.41 mg/L
Average arsenic
blood levels
(average: 18 years)
Varies
(Wuetal..
2001)
(Pietal..
2002)
Cited by
(Straub et al.,
2008)
Reviewed in
(Flora, 2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-59 Draft: Do Not Cite or Quote
-------
Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Bladder cancer
Diabetes
Liver Cancer
Liver disease
Lung Cancer
Neurotoxicity
Non-malignant
respiratory disease
Pregnancy
outcomes
Renal disease
Skin Disease
(Bowmen's
Disease, cancer)
Observations
Elevated incidence of bladder
cancer in populations
exposed to relatively high
inorganic arsenic
concentrations (>100 [ig/i in
drinking water)
Multiple measures (e.g.,
insulin resistance)
l^serum Epidermal Growth
Factor Receptor in liver
cancer patients
Portal hypertension,
noncirrhotic liver fibrosis
Hepatic fibrosis, portal
hypertension
Inferred from EGFR activation
in BEAS cells and tEGFR in
serum of liver cancer patients
Peripheral neuropathy
Allergic lung inflammation
preeclampsia, pre-term birth,
chorioamnionitis, brain white
matter damage, chronic lung
disease in preterm infants
Urinary cancer
Renal insufficiency, necrosis,
failure
l^oxidative DNA adducts
(8-OHdG)
l^skin lesions
Organ system
Bladder
Endocrine
system
Serum
Liver
Liver
Lung
Nervous
system
Lung
Placenta
(Human)
Kidney
Skin
Test System
Human
population
Human
population
Human Case
Controls
Human
population
Human
population
Human
population
Human
population
Human
population
Human
population
Human
population
Human
population
Dose
(Exposure
Duration)
Varies but generally
>100 |ag/L in
drinking water
Various
Average 0.5 -0.6
mg/L inorganic
arsenic in drinking
water
Various
Various
Various
Various
Various
Various
Various
Various
References
Reviewed in
(Cohen et al..
2013)
(Maulletal..
2012): cited
in (Fu et al.,
2010)
(Sung et al.,
2012)
Cited in
(Straub et al..
2008)
(Santra et al.,
1999);
Reviewed in
(Flora, 2011)
(Sung et al..
2012; Wu et
al., 1999)
Cited by (Rao
and Avani,
2004)
Cited in
(Zheng et al.,
2012)
Cited in
(Ahmed et
al.. 2011)
Reviewed in
(Flora, 2011)
(Peietal.,
2013)
Reviewed in
(Yuetal.,
2006)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-60 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Observations
Organ system
Test System
Dose
(Exposure
Duration)
References
aNote: Associations between disease in populations exposed to inorganic arsenic and oxidative stress relies primarily on observational
population studies combined with indicators of oxidative stress in in vitro and/or in vivo studies in cell or tissue types relevant to the disease
(e.g., cardiomyocytes for cardiovascular disease). Data directly linking inorganic arsenic exposure to disease through an oxidative stress MOA
were not identified at the population level, although biomarkers of oxidative stress in populations exposed to inorganic arsenic have been
identified.
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-61 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
10.6Preliminary Data on Potential Interactions between
Inorganic Arsenic Exposure and Other Chemicals or
Stressors
Key Events
Observations
Organ system
Test System
Dose
(Exposure Duration)3
References
Susceptible Individuals
Smoking
Co-exposures
Multiple
epidemiological studies
have found smoking
interacts with inorganic
arsenic exposure to
increase lung and
bladder cancer risk
Synergistic interaction
of smoking
andinorganic arsenic
ingestion with skin
lesions
Synergistic interaction
between inorganic
arsenic exposure and
smoking in mortality
from heart disease
Interaction between
smoking and bladder-
cancer risk (^ odds
ratio in ever smokers
compared to never
smokers; greater T" in
odds ratio for smokers
with shorter duration of
As exposure compared
to smokers with longer
exposure duration)
Synergistic effects
between fertilizer use
and inorganic arsenic
levels in drinking water
for skin lesions; longer
duration of fertilizer
use associated with
higher hazard ratio
Lung
Urinary bladder
(Human)
Skin
(Human)
Heart disease
(Human)
Bladder
(Human)
Skin
(Human)
Human
Population
Human
population
Bangladesh
Human
population
(New
Hampshire)
Human
population
(Bangladesh)
Variable
Variable
25.3-114 ppb
>0.330 Mg/gtoenail
As cone.
(Inorganic arsenic:
16.5 yrs [average];
Smoking: <15yrsor
< 15 yrs)
>50 ng/L total
arsenic in water
(As: 10 yrs [mean];
Fertilizer: <10yrs)
>10 |ag/L total
arsenic in water
(As: 10 yrs [mean];
Fertilizer: >10yrs)
(Cohen et al..
2013) review
(Chen etal..
2006a);
(Melkonian et
al., 2011)
(Chen etal..
2011b)
(Karagaset al..
2004)
(Melkonian et
al..2011)
These draft development materials are for review purposes only and do not constitute Agency policy.
April 2014 10-62 Draft: Do Not Cite or Quote
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Key Events
Diet
Observations
Cd and As have
cumulative effects on
renal tubule leakage
Low vegetable fiber,
low calcium, low folate
and low animal protein
may increase risk of
skin lesions
Poor nutritional status
(low body weight)
associated with
increased risk of skin
lesions
Lower body-mass index
associated with
increased risk of skin
lesions
Lower dietary intake of
folate and other
B vitamins led to a
stronger positive
association between
exposure and
hypertension
Development of skin
lesions associated with
low folate
Non-toxic inorganic
arsenic exposure leads
to enhanced inorganic
arsenic accumulation
when combined with
Se-deficiency; could
affect fetal brain
development
Organ system
Kidney
Skin
(Human)
Skin
(Human)
Skin
(Human)
Hypertension
(Human)
Skin/Blood
(human)
Brain
(Developing
Mouse)
Test System
Humans
Human
Population
(West Bengal,
India)
Human
Population
(West Bengal,
India)
Human
Population
(Bangladesh)
Human
population
(Bangladesh)
Peripheral
blood
lymphocyte
DNAin
individuals
with skin
lesions
Pregnant ICR
mice
Dose
(Exposure Duration)3
Mean concentration
of
Cd: 1.21.ppband
As: 5.7ppb
<500 ng/L total
arsenic
(unspecified)
<73.0 Mg/kg/day
total arsenic
(unspecified)
Variable
<864 ppb
2-250 Mg/LAs(lll)(>2
years)
58 |amol/kg/day
sodium arsenite
+/-Se-deficient diet
References
(Huang et al..
2009a)
(Mitraetal.,
2004)
(Mazumder et
al., 1998)
(Milton etal..
2004); (Ahsan et
al., 2006)
(Chen etal..
2007b)
(Pilsner etal..
2009)
(Mivazaki etal..
2005)
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
10.7References for Mode of Action Hypothesis Summaries
and Preliminary Adverse Outcome Pathway Tables
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Raqib. R. (2011). Arsenic-associated oxidative stress, inflammation, and immune disruption in human
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V: van Geen. A: Howe. GR: Graziano. JH. (2006). Arsenic exposure from drinking water and risk of
premalignant skin lesions in Bangladesh: Baseline results from the Health Effects of Arsenic Longitudinal
Study. Am JEpidemiol 163: 1138-1148. http://dx.doi.org/10.1093/aie/kwj 154
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The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human
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Clin Immunol 29: 582-594. http://dx.doi.org/10.1007/sl0875-009-9304-x
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Banerjee. N: Nandv. S: Kearns. JK: Bandvopadhyav. AK: Das. JK: Maiumder. P: Basu. S: Banerjee. S: Sau. TJ:
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Modifications of DAPK and p!6 Genes Contribute to Arsenic-Induced Skin Lesions and Non-
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Molecular events associated with arsenic-induced malignant transformation of human prostatic epithelial
cells: Aberrant genomic DNA methylation and K-ras oncogene activation. Toxicol Appl Pharmacol 206:
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Giri. AK. (2013). Association of NALP2 polymorphism with arsenic induced skin lesions and other health
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Binet F: Girard. D. (2008). Novel human neutrophil agonistic properties of arsenic trioxide: involvement of p38
mitogen-activated protein kinase and/or c-jun NH2-terminal MAPK but not extracellular signal-regulated
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activity in arsenic and lead intoxicated mature Swiss albino mice. Toxicology 184: 31-39.
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Biswas. R: Ghosh. P: Banerjee. N: Das. JK: Sau. T: Banerjee. A: Roy. S: Ganguly. S: Chatterjee. M: Mukherjee.
A: Giri. AK. (2008). Analysis of T-cell proliferation and cytokine secretion in the individuals exposed to
arsenic. HumExp Toxicol 27: 381-386. http://dx.doi.org/10.1177/0960327108094607
Blaklev. BR: Sisodia. CS: Mukkur. TK. (1980). The effect of methylmercury, tetraethyl lead, and sodium
arsenite on the humoral immune response in mice. Toxicol Appl Pharmacol 52: 245-254.
http://dx.doi.org/10.1016/0041-008X(80)90111-8
Bodwell JE: Gosse. JA: Nomikos. AP: Hamilton. JW. (2006). Arsenic disruption of steroid receptor gene
activation: Complex dose-response effects are shared by several steroid receptors. Chem Res Toxicol 19:
1619-1629. http://dx.doi.org/10.1021/tx060122q
Bodwell JE: Kingslev. LA: Hamilton. JW. (2004). Arsenic at very low concentrations alters glucocorticoid
receptor (GR)-mediated gene activation but not GR-mediated gene repression: Complex dose-response
effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain.
Chem Res Toxicol 17: 1064-1076. http://dx.doi.org/10.1021/tx0499113
Bourdonnav. E: Morzadec. C: Fardel O: Vernhet L. (2009). Redox-sensitive regulation of gene expression in
human primary macrophages exposed to inorganic arsenic. J Cell Biochem 107: 537-547.
http://dx.doi.org/10.1002/icb.22155
Bredfeldt TG: Jagadish. B: Eblin. KE: Mash. EA: Gandolfi. AJ. (2006). Monomethylarsonous acid induces
transformation of human bladder cells. Toxicol Appl Pharmacol 216: 69-79.
http://dx.doi.0rg/10.1016/i.taap.2006.04.011
Burchiel SW: Mitchell LA: Lauer. FT: Sun. X: Mcdonald. JD: Hudson. LG: Liu. KJ. (2009). Immunotoxicity
and biodistribution analysis of arsenic trioxide in C57B1/6 mice following a 2-week inhalation exposure.
Toxicol Appl Pharmacol 241: 253-259. http://dx.doi.0rg/10.1016/i.taap.2009.09.019
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Cao. Y: Yu. SL: Wang. Y: Quo. GY: Ding. Q: An. RH. (2011). MicroRNA-dependent regulation of PTEN after
arsenic trioxide treatment in bladder cancer cell line T24. Tumor Biology 32: 179-188.
http://dx.doi.org/10.1007/sl3277-010-0111-z
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and hypermethylation of DAPK promoter in SV-40 immortalized human uroepithelial cells. Toxicol Lett
173: 48-56. http://dx.doi.0rg/10.1016/i.toxlet.2007.06.006
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D_. (2006). DNA hypermethylation of promoter of gene p53 and p!6 in arsenic-exposed people with and
without malignancy. Toxicol Sci 89: 431-437. http://dx.doi.org/10.1093/toxsci/kfi030
Chatterjee. A: Chatterji U. (2010). Arsenic abrogates the estrogen-signaling pathway in the rat uterus. Reprod
Biol Endocrinol 8: 80. http://dx.doi.org/10.1186/1477-7827-8-80
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induces hepatic global and individual gene hypomethylation: Implications for arsenic hepatocarcinogenesis.
Carcinogenesis 25: 1779-1786. http://dx.doi.org/10.1093/carciiVbghl61
Chen. H: Liu. J: Zhao. CO: Diwan. BA: Merrick. BA: Waalkes. MP. (2001). Association of c-myc
overexpression and hyperproliferation with arsenite-induced malignant transformation. Toxicol Appl
Pharmacol 175: 260-268. http://dx.doi.org/10.1006/taap.2001.9253
Chen. WT: Hung. WC: Kang. WY: Huang. YC: Chai. CY. (2007a). Urothelial carcinomas arising in arsenic-
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Chen. Y: Graziano. JH: Parvez. F: Hussain. I: Momotai. H: van Geen. A: Howe. GR: Ahsan. H. (2006).
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Cho. Y: Ahn. KH: Back. MJ: Choi. JM: Ji. JE: Won. JH: Fu. Z: Jang. JM: Kim. DK. (2012). Age-related effects
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induced gene expression changes in primary human uroepithelial cells. Toxicol Lett 205: S43-S43.
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Cohen. SM. (2002). Comparative pathology of proliferative lesions of the urinary bladder. Toxicol Pathol 30:
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arsenic [Review]. CritRev Toxicol 43: 711-752. http://dx.doi.org/10.3109/10408444.2013.827152
Conde. P: Acosta-Saavedra. LC: Govtia-Acevedo. RC: Calderon-Aranda. ES. (2007). Sodium arsenite-induced
inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells.
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Coppin. JF: Qu. W: Waalkes. MP. (2008). Interplay between cellular methyl metabolism and adaptive efflux
during oncogenic transformation from chronic arsenic exposure in human cells. J Biol Chem 283: 19342-
19350. http://dx.doi.org/10.1074/ibc.M802942200
Cui X: Wakai T: Shirai Y: Hatakevama. K: Hirano. S. (2006a). Chronic oral exposure to inorganic arsenate
interferes with methylation status of p!6INK4a and RASSF1A and induces lung cancer in A/J mice. Toxicol
Sci 91: 372-381. http://dx.doi.org/10.1093/toxsci/kfi 159
Cui. X: Wakai. T: Shirai. Y: Yokoyama. N: Hatakevama. K: Hirano. S. (2006b). Arsenic trioxide inhibits DNA
methyltransferase and restores methylation-silenced genes in human liver cancer cells. Hum Pathol 37: 298-
311. http://dx.doi.0rg/10.1016/i.humpath.2005.10.013
Das. S: Pan. D: Bern. AK: Rana. T: Bhattacharya. D: Bandvapadvav. S: De. S: Sreevatsava. V: Bhattacharya. S:
Das. SK: Bandvopadhavav. S. (2011). Sodium arsenite mediated immuno-disruption through alteration of
transcription profile of cytokines in chicken splenocytes under in vitro system. Mol Biol Rep 38: 171-176.
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Davev. JC: Bodwell JE: Gosse. JA: Hamilton. JW. (2007). Arsenic as an endocrine disrupter: Effects of arsenic
on estrogen receptor-mediated gene expression in vivo and in cell culture. Toxicol Sci 98: 75-86.
http://dx.doi.org/10.1093/toxsci/kfm013
Davev. JC: Nomikos. AP: Wungjiranirun. M: Sherman. JR: Ingram. L: Batki. C: Lariviere. JP: Hamilton. JW.
(2008). Arsenic as an endocrine disrupter: arsenic disrupts retinoic acid receptor-and thyroid hormone
receptor-mediated gene regulation and thyroid hormone-mediated amphibian tail metamorphosis. Environ
Health Perspect 116: 165-172. http://dx.doi.org/10.1289/ehp.10131
de la Fuente. H: Portales-Perez. D: Baranda. L: Diaz-Barriga. F: Saavedra-Alanis. V: Lavseca. E: Gonzalez-
Amaro. R. (2002). Effect of arsenic, cadmium and lead on the induction of apoptosis of normal human
mononuclear cells. ClinExp Immunol 129: 69-77. http://dx.doi.0rg/10.1046/i.1365-2249.2002.01885.x
De Vizcava-Ruiz. A: Barbier. O: Ruiz-Ramos. R: Cebriaa ME. (2009). Biomarkers of oxidative stress and
damage in human populations exposed to arsenic [Review]. Mutat Res Genet Toxicol Environ Mutagen 674:
85-92. http://dx.doi.0rg/10.1016/i.mrgentox.2008.09.020
These draft development materials are for review purposes only and do not constitute Agency policy.
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
Drobna. Z: Jaspers. I: Thomas. DJ: Srvblo. M. (2003). Differential activation of AP-1 in human bladder
epithelial cells by inorganic and methylated arsenicals. FASEB J 17: 67-69. http://dx.doi.org/10.1096/fj.02-
0287fie
Eblin. KE: Bowen. ME: Cromev. DW: Bredfeldt TG: Mash. EA: Lau. SS: Gandolfi. AJ. (2006). Arsenite and
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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Draft Development Materials for the IRIS Toxicological Review of Inorganic Arsenic
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