c/EPA
EPA/635/R-14/218
Preliminary Materials
www. ep a. go v/ir is
Preliminary Materials for the Integrated Risk Information System (IRIS)
Toxicological Review of Hexavalent Chromium Part 2:
Human, Toxicokinetic, and Mechanistic Studies
[CASRN 18540-29-9]
September 2014
NOTICE
This document is comprised of preliminary 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. It is being circulated for review of its technical
accuracy and science policy implications.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
DISCLAIMER
This document is comprised of preliminary materials for review purposes only. 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.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
CONTENTS
ABBREVIATIONS v
PREFACE vii
1. METHODS FOR IDENTIFYING AND SELECTING STUDIES 1-1
1.1. Draft Literature Search and Screening Strategy 1-1
1.2. Selection of Critical Studies in Early Stages of Draft Development 1-7
1.2.1. General Approach 1-7
1.2.2. Selection of Human Studies for Evidence Tables for Hexavalent Chromium 1-8
1.2.3. Preliminary Evidence Tables 1-10
1.2.4. Study Characteristics that Will Be Considered in the Evaluation and Synthesis of
the Critical Studies for Hexavalent Chromium 1-10
2. PRELIMINARY EVIDENCE TABLES 2-1
2.1. Data Extraction for Preliminary Epidemiology Evidence Tables 2-1
2.2. Gastrointestinal Effects 2-2
2.3. Hepatic Effects 2-4
2.4.Hematological Effects 2-8
2.5.lmmunological Effects 2-10
2.6. Reproductive and Developmental Effects 2-17
2.7.Noncancer Respiratory Effects- Pulmonary Function 2-25
2.8. Noncancer Respiratory Effects - Nasal Pathology and Histopathology 2-31
2.9. Lung Cancer 2-38
2.10. Cancers Associated with Oral Exposure 2-44
3. PRELIMINARY TOXICOKINETIC STUDY INFORMATION 3-1
4. PRELIMINARY MECHANISTIC STUDY INFORMATION 4-1
REFERENCES R-l
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
TABLES
Table 1-1. Database search strategy for hexavalent chromium 1-5
Table 1-2. Summary of additional search strategies for hexavalent chromium 1-7
Table 1-3. Inclusion criteria used to identify epidemiology studies of health-related endpoints of
hexavalent chromium 1-9
Table 1-4. General and outcome-specific considerations for chromium study evaluation 1-16
Table 2-1. Evidence pertaining to gastrointestinal (Gl) effects following exposure to hexavalent
chromium 2-2
Table 2-2. Evidence pertaining to hepatic effects following exposure to hexavalent chromium 2-4
Table 2-3. Evidence pertaining to hematological effects following exposure to hexavalent
chromium 2-8
Table 2-4. Evidence pertaining to immunological effects following exposure to hexavalent
chromium 2-10
Table 2-5. Evidence pertaining to reproductive and developmental effects following exposure to
hexavalent chromium 2-17
Table 2-6. Evidence pertaining to noncancer respiratory effects (pulmonary function) following
exposure to hexavalent chromium 2-25
Table 2-7. Evidence pertaining to noncancer respiratory effects (nasal pathology and
histopathology) following exposure to hexavalent chromium 2-31
Table 2-8. Evidence pertaining to lung cancer following inhalation exposure to hexavalent
chromium 2-38
Table 2-9. Evidence pertaining to cancer following oral exposure to hexavalent chromium 2-44
Table 3-1. Preliminary categorization of in vivo hexavalent chromium toxicokinetic studies 3-2
Table 3-2. Preliminary categorization of in vitro and ex vivo hexavalent chromium studies
primarily focused on toxicokinetics in the Gl tract and blood 3-6
Table 3-3. Preliminary categorization of in vitro studies primarily examining distribution and
reduction mechanisms 3-7
Table 3-4. Human biomonitoring and biomarker studies 3-8
Table 3-5. Physiologically-based pharmacokinetic models for hexavalent chromium 3-8
FIGURES
Figure 1-1. Literature search approach for hexavalent chromium 1-4
Figure 3-1. Relationship between ex vivo reduction models, in vivo gastric models, and whole-
body PBPK models 3-9
Figure 4-1. Summary of in vivo and in vitro mechanistic outcomes by mechanistic category 4-4
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
ABBREVIATIONS
ACP acid phosphatase
ADAFs age-dependent adjustment factors
ADME adsorption, distribution, metabolism,
elimination
ALP alkaline phosphatase
ALT alanine aminotransferase
AST aspartate aminotransferase
ATSDR Agency for Toxic Substances and
Disease Registry
BAL bronchoalveolar lavage
CalEPA California Environmental Protection
Agency
CASRN Chemical Abstracts Service Registry
Number
CBC complete blood count
CCA chromated copper arsenate
CPSC Consumer Product Safety Commission
Cr VI hexavalent chromium
Cr III trivalent chromium
E2 estradiol
EPA Environmental Protection Agency
FDA Food and Drug Administration
FEF forced expiratory volume
FEV forced expiratory flow
FRN Federal Register Notice
FSH follicle-stimulating hormone
FVC forced vital capacity
GD gestation day
GGT yglutarnyl transferase
GH growth hormone
GI gastrointestinal
GPT glutamic-pyruvate transaminase
HCT hematocrit
HERO Health and Environmental Research
Online
Hb hemoglobin
HSDB Hazardous Substances Data Bank
IARC International Agency for Research on
Cancer
Ig immunoglobulin
INF inter fer on
IPCS International Programme on Chemical
Safety
IRIS Integrated Risk Information System
LDH lactate dehydrogenase
LH luteinizing hormone
LOD limit of detection
LOQ limit of quantitation
MCH mean corpuscular hemoglobin
MCHC mean corpuscular hemoglobin
concentration
MCLG maximum contaminant level goal
MCV mean cell volume
MEFR maximum expiratory flow rate
MetHgb methemoglobin
MMAD mass median aerodynamic diameter
MMD mass median diameter
MRL minimum reporting level
NAS National Academy of Sciences
NATA National-Scale Air Toxics Assessment
NCEA National Center for Environmental
Assessment
NIOSH National Institute for Occupational
Safety and Health
NJ DEP New Jersey Department of
Environmental Protection
NOAEL no-observed-adverse-effect level
NPDWR National Primary Drinking Water
Regulation
NPL National Priorities List
NRC National Research Council
NTP National Toxicology Program
OPP Office of Pesticides Program
OR odds ratio
ORD Office of Research and Development
OSHA Occupational Safety and Health
Administration
P4 progesterone
PBPK physiologically-based pharmacokinetic
PEF peak expiratory flow
PND postnatal day
PNW postnatal week
RBC red blood cell
RCRA Resource Conservation and Recovery
Act
RED reregistration eligibility decision
RfC reference concentration
RfD reference dose
RR relative risk
RTF Research Triangle Park
SD standard deviation
SDH sorbitol dehydrogenase
SMR standard mortality rate
SRBC sheep red blood cells
T testosterone
TRI Toxic Release Inventory
TSCATS Toxic Substances Control Act
Submission database
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
UCMR3 Third Unregulated Contaminant
Monitoring Rule
VC vital capacity
VCL curvilinear velocity
VSL straight line velocity
WBC white blood cell
WHO World Health Organization
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
2 PREFACE
3 This draft document presents the second of two sets of preliminary materials for an
4 assessment of hexavalent chromium (Cr VI) prepared by EPA's Integrated Risk Information System
5 (IRIS) Program. The first set of preliminary materials released in April 2014, "Preliminary
6 Materials for the Integrated Risk Information System (IRIS) Toxicological Review of Hexavalent
7 Chromium Part 1: Experimental Animal Studies" ("Part 1 Preliminary Materials") presented the
8 planning and scoping summary, problem formulation information, and a summary of the
9 experimental animal evidence for the health effects of hexavalent chromium. This second set of
10 preliminary materials presents updated information on the literature search and screening
11 strategy, approaches for the selection of human studies of hexavalent chromium for hazard
12 identification, presentation of critical human studies in evidence tables, and a preliminary summary
13 of toxicokinetic and mechanistic studies pertinent to the assessment of hexavalent chromium. This
14 material is being released for public review and comment prior to a public meeting, providing an
15 opportunity for the IRIS Program to engage in early discussions with stakeholders and the public
16 on data that may be used to identify adverse health effects and characterize dose-response
17 relationships.
18 The preliminary materials are responsive to the National Research Council (NRC) 2011
19 report Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde (NRC,
20 2011). The IRIS Program's implementation of the NRC recommendations is following a phased
21 approach that is consistent with the NRC's "Roadmap for Revision" as described in Chapter 7 of the
22 formaldehyde review report. The NRC stated that "the committee recognizes that the changes
23 suggested would involve a multi-year process and extensive effort by the staff at the National
24 Center for Environmental Assessment and input and review by the EPA Science Advisory Board and
25 others." Phase 1 of implementation has focused on a subset of the short-term recommendations,
26 such as editing and streamlining documents, increasing transparency and clarity, and using more
27 tables, figures, and appendices to present information and data in assessments. Phase 1 also
28 focused on assessments near the end of the development process and close to final posting. Phase 2
29 of implementation is focused on assessments that are in the beginning stages of assessment
30 development The IRIS hexavalent chromium assessment is in Phase 2 and represents a significant
31 advance in implementing the NRC recommendations. In the development of this assessment, many
32 of the recommendations are being implemented in full, while others are being implemented in part
33 Achieving full and robust implementation of certain recommendations will be an evolving process
34 with input and feedback from the public, stakeholders, and independent external peer review.
35 Phase 3 of implementation will incorporate the longer-term recommendations made by the NRC,
36 including the development of a standardized approach to describe the strength of evidence for
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 noncancer effects. In May 2014, the NRC released their report reviewing the IRIS assessment
2 development process. As part of this review, the NRC reviewed current methods for evidence-
3 based reviews and made several recommendations with respect to integrating scientific evidence
4 for chemical hazard and dose-response assessments. In their report, the NRC states that EPA
5 should continue to improve its evidence-integration process incrementally and enhance the
6 transparency of its process. The committee did not offer a preference but suggests that EPA
7 consider which approach best fits its plans for the IRIS process. The NRC recommendations will
8 inform the IRIS Program's efforts in this area going forward. This effort is included in Phase 3 of
9 EPA's implementation plan.
10 The literature search and screening strategy, which describes the processes for identifying
11 scientific literature, screening studies for consideration, and identifying pertinent sources of health
12 effects data, is responsive to NRC recommendations regarding the development of a systematic and
13 transparent approach for identifying the scientific literature for analysis. The preliminary materials
14 also describe EPA's approach for the selection of critical studies to be included in the evidence
15 tables, as well as the approach for evaluating methodological features of studies that will be
16 considered in the overall evaluation and synthesis of evidence for each health effect The
17 development of these materials is in response to the NRC recommendation to thoroughly evaluate
18 critical studies with standardized approaches that are formulated and based on the type of research
19 (e.g., observational epidemiology or animal bioassays). In addition, NRC recommendations for
20 standardized presentation of key study data are addressed by the development of the preliminary
21 evidence tables and exposure-response arrays for primary health effect information.
22 EPA welcomes all comments on the preliminary materials in this document, including the
23 following:
24 • the clarity and transparency of the materials;
25 • the approach for identifying pertinent studies;
26 • the selection of critical studies for data extraction to preliminary evidence tables;
27 • any methodological considerations that could affect the interpretation of or confidence
28 in study results; and
29 • any additional studies published or nearing publication that may provide data for the
30 evaluation of human health hazard or dose-response relationships.
31
32 The preliminary evidence tables should be regarded solely as representing the data on each
33 endpoint identified as a result of the literature search strategy and approach to selecting critical
34 studies. Similarly, the tables of toxicokinetic and mechanistic studies should be regarded as
35 representing inventories of studies on these topics identified as a result of the literature search
36 strategy. These studies do not reflect any conclusions as to hazard identification or dose-response
37 assessment
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 After obtaining public input and conducting additional study evaluation and data
2 integration, EPA will revise these materials to support the hazard identification and dose-response
3 assessment in a draft Toxicological Review that will be made available for public comment
4
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
l.METHODS FOR IDENTIFYING AND SELECTING
STUDIES
2 The NRG [2011] recommended that EPA develop a detailed search strategy utilizing a
3 graphical display documenting how initial search findings are narrowed to the final studies that are
4 selected for further evaluation on the basis of defined inclusion and exclusion criteria. Following
5 these recommendations, a literature search and screening strategy were used to identify literature
6 characterizing the health effects of hexavalent chromium. This strategy consisted of a search of
7 online scientific databases and other sources, casting a wide net in order to identify all potentially
8 pertinent studies. In subsequent steps, references were screened to exclude papers not pertinent
9 to an assessment of the health effects of hexavalent chromium, and remaining references were
10 sorted into categories for further evaluation. Section 1.1 describes the literature search and
11 screening strategy in detail and updates the literature search and screening strategy presented in
12 the Part 1 Preliminary Materials.
13 The NRG [2011] further recommended that after studies are identified for review by
14 utilizing a transparent search strategy, the next step is to summarize the details and findings of the
15 most pertinent studies in evidence tables. The NRC suggested that such tables should provide a link
16 to the references, and include details of the study population, methods, and key findings. This
17 approach provides for a systematic and concise presentation of the evidence. The NRC also
18 recommended that the methods and findings should then be evaluated with a standardized
19 approach. The approach that was outlined identified standard issues for the evaluation of
20 epidemiological and experimental animal studies. Section 1.2 describes the approach taken for
21 selecting studies to be included in preliminary evidence tables of the epidemiology literature for
22 hexavalent chromium. Section 2 presents the selected studies in preliminary human evidence
23 tables arranged by health effect
24 1.1. Draft Literature Search and Screening Strategy
25 The literature search for hexavalent chromium was conducted in four online scientific
26 databases, including PubMed, Toxline, Web of Science, and TSCATS, in January 2013; the search was
27 repeated in July 2013 and in February 2014. The detailed search approach, including the search
28 strings and number of citations identified per database, is presented in Table 1-1. This search of
29 online databases identified 9,708 citations (after electronically eliminating duplicates]. The
30 computerized database searches were also supplemented by a manual search of citations from
31 other regulatory documents (Table 1-2]; 108 citations were obtained using these additional search
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 strategies. In total, 9,816 citations were identified using online scientific databases and additional
2 search strategies.
3 These citations were screened using the title, abstract, and in limited instances, full text for
4 pertinence to an evaluation of the health effects of hexavalent chromium exposure. The process for
5 screening the literature is described below and is shown graphically in Figure 1-1.
6 • 169 references were identified as potential sources of chronic health effects data and
7 were considered for data extraction into evidence tables.
8 • 1,774 studies were identified as supporting studies; these included 126 studies
9 describing physiologically-based pharmacokinetic (PBPK) models and other
10 toxicokinetic information, 806 studies providing genotoxicity and other mechanistic
11 information, 735 dermal, acute, short-term, injection, and intratracheal instillation
12 exposure studies, and 107 human case reports. While still considered sources of health
13 effects information, studies investigating dermal, acute, short-term, injection, and
14 intratracheal instillation exposures and case reports are generally less pertinent for
15 characterizing health hazards associated with chronic oral and inhalation exposure.
16 Therefore, information from these studies was not considered for extraction into the
17 preliminary evidence tables. Nevertheless, these studies will still be evaluated as
18 possible sources of supporting health effects information.
19 • 468 references were identified as secondary sources of health effects information (e.g.,
20 reviews and other agency assessments); these references were kept as additional
21 resources for development of the Toxicological Review.
22 • 781 references were kept for further review. This category includes conference
23 abstracts that did not provide enough material to evaluate pertinence and foreign
24 language studies.
25 • 6,624 references were identified as not being pertinent to an evaluation of the health
26 effects of hexavalent chromium and were excluded from further consideration (see
27 Figure 1-1 for exclusion categories). The majority of studies categorized as not being
28 pertinent were excluded based on one or more of the following criteria:
29 o study did not evaluate chromium
30 o extraction or remediation studies
31 o physical or chemical property studies
32 o analytical methods for measuring chromium levels without exposure data
33 o chromium not evaluated for effects (e.g., used in sample preparation)
34 o bacterial metabolism studies; or
35 o interaction studies (i.e., independent effects of chromium not evaluated).
36 The literature will be regularly monitored for the publication of new studies and a formal
37 updated literature search and screen will be conducted after the IRIS bimonthly public meeting
38 discussing these preliminary materials. The documentation and results for the literature search
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 and screen can be found on the Health and Environmental Research Online (HERO) website
2 [http://hero.epa.gov/index.cfm?action=landing.main&project id=2233].1
3
1 HERO (Health and Environmental Research Online) is a database of scientific studies and other references
used to develop EPA's risk assessments aimed at understanding the health and environmental effects of
pollutants and chemicals. It is developed and managed in EPA's Office of Research and Development (ORD)
by the National Center for Environmental Assessment (NCEA). The database includes more than 1,400,000
scientific articles from the peer-reviewed literature. New studies are added continuously to HERO.
Note: The HERO database will be regularly updated as additional references are identified during assessment
development and as more appropriate tags are assigned to individual studies already in the HERO database
for hexavalent chromium. Therefore, the numbers of references (by tag) displayed on the HERO webpage for
hexavalent chromium may not match the numbers of references identified in Figure 1-1.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Pubmed
n = 4,863
Database Searches
(see Table 1-1 for keywords and limits)
Web of Science
n = 4,964
Toxline
(incl. TSCATS)
n = 5,299
(After duplicates removed electronically)
n = 9,708
TSCATS 2
n = 55
Additional Search Strategies
(see Table 1-2 for methods and results)
n = 108
Combined Dataset
(After all duplicates removed)
n = 9,816
Manual
Screening For Pertinence
(Title/Abstract/Full Text)
Excluded (not pertinent) (n = 6,624)
304 Non peer-reviewed
123 Exposure
306 Ecology
881 No toxicology keywords
5010 Other not pertinent
J~
Sources of Health Effects
Data (n = 169)*
110 Human health effects
studies
60 Animal studies
"One study (LJet al.2OOO)is
categorized in animal and human.
<.....
^
>
1
Kept for Further Review (n = 781)
628 Foreign language
153 Abstract only
A
Supporting Studies
(n = 1,774)
126
806
626
35
74
107
PBPK/ADME
Mechanistic studies
(including Genotoxicity)
Dermal studies
Acute/short-term
studies
Injection or
intratracheal studies
Human case reports
Secondary Sources of
Health Effects
Information (n = 468)
231 Reviews
30 Other agency
assessments
46 Other studies
161 Other Cr compounds
(e.g., metal
chromates)
2
3
4
Figure 1-1. Literature search approach for hexavalent chromium.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Table 1-1. Database search strategy for hexavalent chromium
Database
(Search Date)
Keywords
Limits
PubMed
(1/29/2013)
(7/19/2013)
(2/5/2014)
hexavalent chromium OR (hexavalent AND
chromium) OR CRVI OR CR VI OR Chromium VI
OR "Chromic acid" OR "Calcium chromate" OR
"Potassium dichromate" OR "Potassium
chromate" OR "Sodium chromate" OR "lead
chromate" OR "zinc chromate" OR "strontium
chromate" OR "ammonium dichromate" OR
13765-19-0[RN] OR 1333-82-0[RN] OR 7789-00-
6[RN] OR 7778-50-9[RN] OR 7775-ll-3[RN] OR
7789-12-0[RN] OR 13530-65-9[RN] OR 7738-94-
5[rn] OR 18540-29-9[rn] OR 7758-97-6[RN] OR
11119-70-3[rn] OR 11103-86-9[rn] OR 13530-
65-9[rn] OR 7788-98-9[rn] OR 77898-09-5[rn]
OR 7789-06-2[rn]
None
Web of Science
(1/29/2013)
(7/19/2013)
(2/5/2014)
Topic = (hexavalent chromium OR (hexavalent
AND chromium) Chromium VI OR CrVI OR Cr VI
OR "Chromic acid" OR "Calcium chromate" OR
"Chromic trioxide" OR "Potassium dichromate"
OR "Potassium chromate" OR "Sodium
chromate" OR "Sodium dichromate dehydrate"
OR "lead chromate" OR "zinc chromate" OR
"strontium chromate" OR "ammonium
dichromate" OR "ammonium chromate" OR
13765-19-0 OR 1333-82-0 OR 7789-00-6 OR
7778-50-9 OR 7775-11-3 OR 7789-12-0 OR
13530-65-9 OR 7738-94-5 OR 18540-29-9 OR
7758-97-6 OR 11119-70-3 OR 11103-86-9 OR
13530-65-9 OR 7788-98-9 OR 77898-09-5 OR
7789-06-2)
Refined by: Research Areas = Toxicology,
Biochemistry molecular biology, Public
environmental occupational health,
Dermatology, Cell biology, Oncology, Life
sciences biomedicine other topics, Allergy,
Veterinary sciences, Developmental
biology, Immunology, Reproductive
biology, Pathology, Physiology, Urology
nephrology, Hematology, Neurosciences
neurology, Respiratory system,
Cardiovascular system cardiology,
Obstetrics gynecology, Infections diseases,
Gastroenterology hepatology, Microscopy
Web of Science
(1/29/2013)
(7/19/2013)
(2/5/2014)
Topic = (hexavalent chromium OR (hexavalent
AND chromium) Chromium VI OR CrVI OR Cr VI
OR "Chromic acid" OR "Calcium chromate" OR
"Chromic trioxide" OR "Potassium dichromate"
OR "Potassium chromate" OR "Sodium
chromate" OR "Sodium dichromate dehydrate"
OR "lead chromate" OR "zinc chromate" OR
"strontium chromate" OR "ammonium
dichromate" OR "ammonium chromate" OR
13765-19-0 OR 1333-82-0 OR 7789-00-6 OR
7778-50-9 OR 7775-11-3 OR 7789-12-0 OR
13530-65-9 OR 7738-94-5 OR 18540-29-9 OR
7758-97-6 OR 11119-70-3 OR 11103-86-9 OR
13530-65-9 OR 7788-98-9 OR 77898-09-5 OR
7789-06-2)
AND
cancer* OR carcinogen* OR chronic OR
Refined by: Research Areas = Chemistry,
Environmental sciences ecology,
Spectroscopy, Pharmacology pharmacy,
Water resources, Genetics heredity,
Science technology other topics,
Biophysics, Food sciences technology,
Endocrinology metabolism, Research
experimental medicine, Nutrition
dietetics, Zoology, General internal
medicine, Construction building
technology, Parasitology, Medical
laboratory technology, Education
educational research,
Otorhinolaryngology, Rheumatology,
Anatomy morphology, Emergency
medicine, Mycology, Sport sciences,
Psychiatry
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Database
(Search Date)
Keywords
Limits
subchronic OR genotox* OR inhalation
absorption OR oral absorption OR mice OR
mouse OR Mutagenicity OR pharmacokinetic
OR rat OR rats OR (toxic* NOT (fish OR
bacteria* OR microorganism* OR plant*) OR
tumor*
Toxline (includes
TSCATS)
(1/29/2013)
(7/19/2013)
(2/5/2014)
18540-29-9 OR 7789-09-5 OR 13765-19-0 OR
1333-82-0 OR 7758-97-6 OR 7789-00-6 OR
7778-50-9 OR 7775-11-3 OR 7789-12-0 OR
7789-06-2 OR 13530-65-9 OR 7788-98-9 OR
7738-94-5 OR 13530-68-2
Not PubMed; synonyms included
TSCATS2
(1/29/2013)
(7/19/2013)
(2/5/2014)
18540-29-9
None
1
2
3
4
5
a For Web of Science, results were obtained by searching the research areas noted in the "Limits" column using the
italicized terms in the "Keywords" column (starting with 'Topic = (hexavalent chromium...)"), and subsequent
filtering in EndNote using the additional keywords in normal text (starting with "cancer* OR ...").
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Table 1-2. Summary of additional search strategies for hexavalent chromium
Approach used
Manual search
of citations from
reviews
conducted by
other
international
and federal
agencies
Source(s)
ATSDR (Agency for Toxic Substances
and Disease Registry). (2012).
Toxicological profile for chromium.
Atlanta, GA: US Department of Health
and Human Services, Public Health
Service.
U.S. EPA (2010). Toxicological review
of hexavalent chromium (external
review draft). (EPA/635/R-10/004A).
Washington, DC.
OSHA (Occupational Safety & Health
Administration). (2006). Occupational
exposure to hexavalent chromium.
Final rule. Fed Reg 71: 10099-10385.
IPCS (International Programme on
Chemical Safety). (2013). Inorganic
chromium (VI) compounds. (78).
Geneva, Switzerland: World Health
Organization.
NIOSH (National Institute for
Occupational Safety and Health).
(2013). Occupational exposure to
hexavalent chromium. (DHHS (NIOSH)
Publication No. 2013-128).
Department of Health and Human
Services, Centers for Disease Control
and Prevention.
Date
performed
1/2013
1/2013
5/2014
5/2014
5/2014
Number of additional citations
identified
40
59
3
5
1
2
3
4 1.2. Selection of Critical Studies in Early Stages of Draft Development
5 1.2.1. General Approach
6 In response to the NRC recommendations, each study retained after the literature search
7 and screen is evaluated for aspects of its design, conduct, or reporting that could affect the
8 interpretation of results and the overall contribution to the synthesis of evidence for determination
9 of hazard potential. Much of the key information for conducting this evaluation can generally be
10 found in the study's methods section and in how the study results are reported. Importantly, the
11 evaluation at this stage does not consider study results, or more specifically, the direction or
12 magnitude of any reported effects.
13 To facilitate the evaluation outlined above, evidence tables are constructed that
14 systematically summarize the important information from each study in a standardized tabular
15 format as recommended by the NRC [2011]. In general, the evidence tables may include all studies
This document is a draft for review purposes only and does not constitute Agency policy,
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1 that inform the overall synthesis of evidence for hazard potential. At this early stage of study
2 evaluation the goal is to be inclusive. Exclusion of studies may unnecessarily narrow subsequent
3 analyses by eliminating information that might later prove useful. Premature exclusion might also
4 give a false sense of the consistency of results across the database of studies by unknowingly
5 reducing the diversity of study results. However, there may be situations in which the initial review
6 of the available data will lead to a decision to focus on a particular set of health effects and to
7 exclude others from further evaluation. This situation could occur, for example, with a chemical
8 with a large database that has a few well-developed areas of research, but many other areas that
9 consist of sparse data, offering a very limited basis for drawing conclusions regarding hazard. In
10 this case, EPA will focus on the more developed areas of research for hazard identification. For
11 hexavalent chromium, the identification of the health effects that will serve as the focus of this
12 health assessment was discussed in Problem Formulation in the Part 1 Preliminary Materials.
13 Additionally, a study can be excluded at this stage if flaws in its design, conduct, or reporting
14 are so great that the results would not be considered credible. Such study design flaws are
15 discussed in a number of EPA's guidelines (see http://www.epa.gov/iris/backgrd.html] or
16 summarized in the draft Preamble to the IRIS Toxicological Review ("Preamble")2. An example of
17 these flaws includes studies where a control or referent group is lacking. Studies with flaws in their
18 design, conduct, or reporting are not included in evidence tables.
19 For larger databases, such as that for hexavalent chromium, additional criteria could
20 facilitate a more efficient review of the database and help to focus on the more informative studies
21 in evaluating the potential for hazard. These criteria could be specific to each type of study or a
22 particular endpoint, and may consider factors such as those discussed in EPA's guidelines or
23 summarized in the draft Preamble. The inclusion criteria used to identify the critical epidemiology
24 literature for hexavalent chromium are discussed in Section 1.2.2.
25 1.2.2. Selection of Human Studies for Evidence Tables for Hexavalent Chromium
26 After the literature search was manually screened for pertinence (Figure 1-1; Sources of
27 Chronic Health Effects Data), 110 human studies were identified as sources of health effects data
28 and considered for data extraction to evidence tables. As discussed in the Problem Formulation for
29 hexavalent chromium in the Part 1 Preliminary Materials, the hazard identification in the IRIS
30 Toxicological Review will focus on the following health effects that may be associated with chronic
31 exposure: respiratory, gastrointestinal (GI) tract, hepatic, immunological, hematological,
32 reproductive, developmental, lung cancer associated with inhalation exposure, and GI cancer
33 associated with oral exposure. These represent the health effects for hexavalent chromium with
34 well-developed areas of research. A screen of the literature published after the publication of the
2 See the draft Preamble in the Toxicological Review of Ammonia (revised external review draft) at
http://cfpub.epa.gov/ncea/iris drafts/recordisplay.cfm?deid=254524 or the Toxicological Review of
Trimethylbenzenes (revised external review draft) at
http://cfpub.epa.gov/ncea/iris drafts/recordisplay.cfrn?deid=254525.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 ATSDRf2012] Toxicological Profile and other recent reviews [IPCS. 2013: NIOSH. 2013] did not
2 identify other health effect categories that should be added to those already identified.
3 The specific inclusion criteria for each health-related endpoint are summarized in Table 1-3.
4 Studies with noncancer endpoints were included in the evidence tables if they included a measure
5 of one or more primary health effect endpoints identified in Problem Formulation. Inhalation
6 studies examining lung cancer incidence or mortality risk with dose-response data or usable
7 exposure data were included in the lung cancer table (either as a table entry or notation regarding
8 related studies within a table entry) consistent with the criteria in Table 1-3. Oral studies that
9 provided data on cancer incidence or mortality risk of the GI tract or related sites, including oral
10 cavity, stomach, colon, liver, pancreas, or urinary tract, were included in the oral exposure cancer
11 table.
12 An additional 11 studies were not included in evidence tables because they were meta-
13 analyses (n = 5) or were only published in a language other than English (n = 6). Meta-analyses are
14 not considered primary source studies, but are reviewed to assess the completeness of EPA's
15 literature search. The non-English language studies will be reviewed individually to determine
16 their potential contribution to the health assessment of hexavalent chromium.
17 Table 1-3. Inclusion criteria used to identify epidemiology studies of health-
18 related endpoints of hexavalent chromium
Noncancer inclusion criteria
1. Is the study population humans?
AND
2. Is exposure to chromium:
• measured in air, water, or biological tissue;
• based on knowledge of industrial hygiene (occupational settings); or
• based on knowledge of specific contamination sites or accidental exposure?
AND
3. Does the study compare a health effect in higher versus lower or no exposure groups?
AND
4. Does the study include a measure of one or more primary health effect endpoints relating to:
• hepatic effects (e.g., liver enzymes, mortality due to liver cirrhosis)
• GI tract effects (e.g., mortality due to diseases of the digestive system)
• hematological effects (e.g., red blood cell counts)
• immune effects (e.g., serum immunoglobulin levels, lymphocyte subpopulations, cytokines)
• respiratory effects (e.g., nasal ulcerations, pulmonary function)
• reproductive and developmental effects (e.g., steroidal or gonadotropin hormones, sperm parameters,
pregnancy outcomes including spontaneous abortion, neonatal mortality)
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Inhalation exposure - lung cancer inclusion criteria
1. Is the study population humans?
AND
2. Is exposure to chromium measured in air or biological tissue?
AND
3. Does the study examine quantitative measures of chromium exposure in relation to lung cancer incidence or
mortality risk?
AND
4. Does the study estimate lung cancer risk at lower exposures than used in exposure-response modeling in the
previous EPA assessment?
Oral exposure - cancer inclusion criteria
1. Is the study population humans?
AND
2. Is exposure to chromium:
• measured in water or biological tissue; or
• based on knowledge of specific contamination sites or accidental exposure?
AND
3. Does the study compare cancer risk in higher versus lower or no exposure groups?
AND
4. Does the study examine oral cavity, liver, Gl tract, pancreas or urinary tract cancer incidence or mortality
risk?
2 1.2.3. Preliminary Evidence Tables
3 The evidence tables present data from studies related to a specific outcome or endpoint of
4 toxicity. At a minimum, the evidence tables include the relevant information for comparing key
5 study characteristics such as study design, exposure metrics, and dose-response information.
6 Evidence tables will serve as an additional method for presenting and evaluating the suitability of
7 the data to inform hazard identification for hexavalent chromium during the analysis of hazard
8 potential and utility of the data for dose-response evaluation. The complete list of references
9 considered in preparation of these materials can be found on the HERO website at:
10 http://hero.epa.gov/index.cfm?action=landing.main&project id=2233.
11 1.2.4. Study Characteristics that Will Be Considered in the Evaluation and Synthesis of the
12 Critical Studies for Hexavalent Chromium
13 Several considerations will be used in EPA's evaluation of hexavalent chromium
14 epidemiology studies, including aspects of the study design affecting the internal or external
15 validity of the results (e.g., population characteristics and representativeness, exposure and
16 outcome measures, confounding, data analysis), focusing on specific types of bias (e.g., selection
17 bias; information bias due to exposure misclassification), and other considerations that could
18 otherwise influence or limit the interpretation of the data. A study is externally valid if the study
19 results for the study population can be extrapolated to external target populations. An internally
20 valid study is free from different types of biases, and is a prerequisite for generalizing study results
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 beyond the study population. These issues are outlined in the IRIS Preamble, and are described
2 below.
3
4 Study population
5 Evaluation of study population characteristics, including key socio-demographic variables
6 and study inclusion criteria, can be used to evaluate external validity (i.e., generalizability) and to
7 facilitate comparison of results across different study populations. Some aspects of the selection
8 process may also affect the internal validity of a study, resulting in a biased effect estimate.
9 The general considerations for evaluating issues relating to the study population include
10 adequate documentation of participant recruitment, including eligibility criteria and participation
11 rates, missing data, and loss to follow-up. This information is used to evaluate internal study
12 validity related to selection bias. Different types of selection bias that may occur include the
13 healthy worker effect, differential loss to follow up, Berkson bias (relating to selection of
14 participants in hospital-based case-control studies), and participation bias. It is important to note
15 that low participation rates, or differences in participation rates between exposed and non-exposed
16 groups or between cases and controls, is not evidence of selection bias. Rather, selection bias arises
17 from a differential pattern of participation with respect to both the exposure and the outcome, i.e.,
18 patterns of participation that would result in a biased effect estimate. This could occur, for
19 example, if people with high exposure and the outcome of interest are more likely to participate
20 than people with low exposure and the outcome.
21 Most of the available hexavalent chromium studies examined health outcomes among
22 occupationally exposed workers. EPA will consider the implications of this type of study population
23 with respect to the generalizability of the observed effects. EPA will also consider whether
24 reported effect estimates are impacted by a healthy worker or healthy worker survivor effect.
25 These types of selection biases may result in an underestimation of risk among occupational
26 populations if their health is compared to that of a less healthy general population. Information to
27 be used to assess the potential influence of these types of bias on observed results include data on
28 the duration of work or exposure prior to recruitment into the study, literature pertaining to the
29 susceptibility of specific outcomes to these biases, and analytic approaches used to assess or
30 address these biases.
31
32 Exposure measures
33 General considerations for evaluating exposure include: (1) how exposure can occur (e.g.,
34 exposure sources, routes and media), (2) appropriate critical exposure period(s) for the outcomes
35 under study, (3) variability in the exposure metrics of interest (e.g., temporal and spatial variability
36 for environmental measures or inter-individual variability for biomonitoring data) that can impact
37 the choice of exposure metric (e.g., cumulative, average, or peak exposure), (4) analytical
38 methodology employed (e.g., choice of biological matrix, sampling protocol, quantification
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 approach, etc.), (5) choice of exposure surrogate evaluated (e.g., constituent chemical or
2 group/mixture), and (6) classification of individuals into exposure categories. These
3 considerations help determine how accurate and precise the exposure estimates are, and how likely
4 measurement error is with respect to the exposure metrics used. Nondifferential misclassification
5 of exposure categories, for example, can also result from measurement error and is expected to
6 predominantly result in attenuated effect estimates [Blair etal.. 2007).
7 Chromium exposure can occur in a variety of occupational settings, including production of
8 chromium metal and metal alloys, chromium electroplating, stainless steel welding, and production
9 or use of chromium pigments and other compounds containing chromium [OSHA, 2006]. The
10 studies identified through EPA's literature search reflect this array of occupational settings, and
11 generally include one or more measures of exposure (e.g., air monitoring or blood or urine
12 samples). EPA will consider the distribution of exposure in evaluating individual studies and when
13 comparing results among groups of studies. One consideration is the contrast of exposure levels
14 (i.e., the difference between "high" and "low"); a study with a very narrow contrast may not have
15 sufficient variability to detect an effect that would be seen over a broader range. Another
16 consideration is the absolute level of exposure, as different effect estimates may be expected in
17 studies examining different exposure levels even if they had similar exposure contrasts.
18
19 Primary outcome measures
20 The general considerations for evaluating issues relating to accuracy, reliability, and
21 biological relevance of outcomes include adequate duration of exposure and follow-up in order to
22 evaluate the outcomes of interest, and use of appropriate ascertainment methods to classify
23 individuals with regard to the outcome (e.g., high sensitivity and specificity). Issues relating to
24 assessment of the specific primary health effects are discussed below and summarized in Table 1-4.
25
26 Hepatic, hematologic. and immune effects
27 Most of the measures used in the categories of hepatic, hematologic and immune effects are
28 serologic or urinary parameters related to enzymes, differential blood cell counts, and other
29 measures of target organ function or damage. Details of the laboratory procedures used to measure
30 these parameters, including their normal reference range (by sex and age), are important
31 considerations in the interpretation of these measures. With respect to the immune system
32 measures, EPA will evaluate these as a set, examining evidence of dysregulation, rather than
33 focusing on one specific marker.
34 In addition to assessing whether reported parameters are outside normal physiological
35 range, EPA will also consider evidence of smaller changes in the distribution of a parameter that
36 may represent an effect on a population level [e.g., as is the case for early childhood exposure to
37 lead and decrements in intelligence as measured by IQ (U.S. EPA. 2013]].
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 The studies assessing hepatic, hematologic and immune effects typically include several
2 related measures (e.g., several measures of Thl cytokines, or several measures of liver enzymes).
3 EPA recognizes that the interpretation of consistency across studies can be difficult when different
4 findings are seen among a set of related outcome measures (e.g., several studies, each with different
5 liver enzyme measures; one measure is elevated in each study but the specific enzyme that is
6 elevated differs among the studies). In general, EPA does not consider this type of variability in
7 observed effects to be evidence of a lack of consistency. Expert professional judgment will be used
8 to evaluate and clarify, if possible, any inconsistencies.
9
10 Reproductive and pregnancy outcomes
11 The chromium literature includes studies of reproductive and gonadotropin hormone levels
12 in men and studies of semen parameters that can be indicative of reduced fertility. The details of
13 the laboratory procedures, including information on the basic methods, level of detection, and
14 coefficient of variation, are important considerations for hormone assays and measures of semen
15 parameters. The World Health Organization (WHO) laboratory methods for analysis of sperm
16 counts and semen parameters (see, for example, WHO, 1999) are generally recognized as standards
17 in this field. EPA will consider studies that reference these methods, regardless of which revision
18 used, to be reliable measures.
19 Expectant mothers can encounter pregnancy loss either through a stillbirth (fetal death
20 after 20 gestational weeks) or from a spontaneous abortion also known as a miscarriage (fetal
21 death during the first 20 gestational weeks). Pregnancy loss can occur even before a clinically
22 recognized pregnancy; early pregnancy (or "subclinical") loss, determined by measurement of
23 human chorionic gonadotropin, is very common, accounting for approximately 20% of pregnancies
24 (Wilcoxetal.. 1988). Spontaneous abortions, particularly those occurring in the first trimester, may
25 not require medical intervention and thus medical records may not be a reliable source for this
26 outcome (Slamaetal.. 2014). In addition to medical records, interview data can be used to
27 ascertain pregnancy losses at later stages of gestation. However, these ascertainment methods are
28 more prone to measurement error since they are subject to maternal recall. Validation studies
29 indicate that recall of previous spontaneous abortions is relatively complete, particularly for losses
30 that occurred after the 8th week of gestation (>80% of recorded spontaneous abortions were
31 recalled) fWilcox and Horney. 19841
32 Infant birth weight, a common health outcome in reproductive epidemiological studies, is
33 dependent on both gestational duration and fetal growth rate. Gestational duration can be
34 measured as a continuous outcome or dichotomous outcome such as preterm birth. Preterm births
35 include infants delivered earlier than 37 gestational weeks. Infants born between 32 and 36
36 gestational weeks are considered moderate preterm births, while those delivered earlier than 32
37 gestational weeks are classified as very preterm births. Different measures of fetal growth
38 restriction are often examined in epidemiological studies. In addition to the continuous measure of
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 birth weight, another commonly used measure is the categorical variable of low birth weight
2 (defined as <2500 g). Small for gestational age (defined as birth weight < the 10th percentile for the
3 gestational birth weight distribution) is considered a better measure of fetal growth rate as it takes
4 into consideration gestational duration, and would be preferred over a measure of birth weight in a
5 study that includes preterm births. Birth weight and gestational duration can also be examined as
6 continuous variables, often in analysis that excludes preterm or low birth weight births, so that the
7 focus of the analysis is on variability within the "normal" range. EPA considers analyses of these
8 various indices for both outcomes (fetal growth and gestational age) to be informative with respect
9 to hazard identification, but will consider each separately as they address different issues. EPA
10 considers birth weight obtained from medical records to be a reliable source as this is a very
11 accurate and precise measurement.
12 Although more prone to measurement error than birth weight measures, gestational age
13 can be estimated from several approaches. Some of these include ultrasonography, estimates based
14 on date of last menstrual period based on maternal recall, or from clinical examination based on
15 antenatal or newborn assessments (which may include an ultrasound). Menstrual dating of
16 gestational age dependent on maternal recall of the last menstrual period can be subject to
17 considerable measurement error in some cases, so ultrasonography-based estimates may be
18 considered more accurate (Savitz etal., 2002: Taipale and Hiilesmaa, 2001).
19
20 Respiratory effects (noncancer)
21 Pulmonary function
22 The American Thoracic Society has published guidelines for equipment performance
23 requirements, validation, quality control, test procedures, and reference equations for each type of
24 spirometric measurement (Miller etal.. 2005). as well as the interpretation of testing results
25 (Pellegrino etal., 2005). Lung function varies by race or ethnic origin, gender, age, and height, and
26 is best compared when normalized to the expected lung function based on these variables
27 (Pellegrino etal.. 2 005: Hankinson etal.. 1999). Some measures (e.g., FEVi and PEF) exhibit diurnal
28 variation (Chan-Yeung, 2000: Lebowitz etal., 1997): thus time of day of the lung function measures
29 should also be considered.
30
31 Cancer
32 Studies of cancer risk in relation to chromium exposure typically examine cancer diagnosis
33 ascertained using cause of death data from death certificates. EPA will examine evidence pertaining
34 to the accuracy of cause of death data (from underlying or multiple causes of death fields) for
35 specific cancers. An additional issue is the validity of mortality data as a representation of cancer
36 incidence; mortality data for cancer types with a high survival rate may underrepresent disease
37 incidence, require additional considerations with respect to determining appropriate time windows
38 of exposure, and may lead to biased risk estimates if survival is related to exposure. Five-year
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 survival rates for lung cancer and stomach cancer, the primary cancers evaluated in this health
2 assessment for hexavalent chromium, are low (17% and 2 8%, respectively, for lung and stomach
3 cancer, based on U.S. Surveillance, Epidemiology and End Results data [http://seer.cancer.gov/: last
4 accessed August 14, 2014), and EPA does not consider use of mortality data to be a limitation in
5 studies of these endpoints.
6 In 1998, EPA classified hexavalent chromium as a "known human carcinogen by the
7 inhalation route of exposure" based on consistent evidence that inhaled chromium causes lung
8 cancer in humans and hexavalent chromium causes cancer in animals. The same conclusion has
9 been reached by other federal, state, and international health agencies. Accordingly, and as
10 discussed in the Problem Formulation in the Part 1 Preliminary Materials, this assessment plans to
11 adopt this conclusion and focus its review of the lung cancer evidence on identifying studies that
12 might improve the quantitative dose-response analysis. Although the considerations with respect
13 to selection of study population, confounding, and analysis are important, considerable focus will
14 be placed on evaluation of issues relating to exposure measurement, and the exposure range
15 encompassed in a study. EPA will consider the extent to which exposure estimates are supported
16 by ambient monitoring and/or biological monitoring, ability to capture changes in exposure over
17 time, and the potential for measurement or assignment of exposure to be influenced by knowledge
18 of outcome (e.g., lung cancer mortality).
19
20 Confounding
21 The general considerations for evaluating issues relating to potential confounding include
22 consideration of which factors may be potential confounders (i.e., those strongly related to both the
23 exposure and the outcome under consideration, and are not intermediaries on a causal pathway),
24 adequate control for these potential confounders in the study design or analysis, and where
25 appropriate, quantification of the potential impact of mismeasured or unmeasured confounders.
26 Uncontrolled confounding by factors that are positively associated with both the exposure and
27 health endpoint of interest, and those that are inversely associated with both exposure and health
28 endpoint, will result in an upward bias of the effect estimate. Confounding by factors that are
29 positively associated with either exposure or the health endpoint, and inversely associated with the
30 other axis, will result in a downward bias of the effect estimate.
31
32 Potential confounding by other worksite exposures
33 EPA will review literature pertaining to potential co-exposures in the occupational settings
34 included in these preliminary materials, and the literature pertaining to the relation between any of
35 these exposures and the outcome(s) examined. For co-exposures that are known or likely to be
36 associated with the outcome, EPA will review the study details to determine the extent to which
37 potential confounding was addressed in the design or analysis.
38
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 Potential confounding by other factors
2 Age and sex are considered important explanatory factors for most types of outcomes to be
3 considered in this assessment; race or ethnicity may also influence some measures (such as some
4 hematological parameters). Some of the health effects under consideration may also have strong
5 associations with other risk factors. For example, smoking is a very strong risk factor for lung
6 cancer, and is also, to a lesser degree, associated with various measures of immune function.
7 Alcohol consumption is a known contributing factor to the development of liver cirrhosis. In
8 evaluating the potential for confounding by any of these factors, EPA will review evidence
9 pertaining to comparison of these factors with respect to the chromium exposed workers and the
10 referent group used in a particular study.
11
12 Data Analysis
13 The general considerations for evaluating issues relating to data analysis include adequate
14 documentation of statistical assumptions and analytic approach (including addressing skewness of
15 exposure or outcome variables), consideration of sample size and statistical power, and use of
16 appropriate statistical methods for the study design.
17 Table 1-4. General and outcome-specific considerations for chromium study
18 evaluation
General considerations
Study population
Study population and setting: geographic area, site, time period, age and sex
distribution, other details as needed (may include race/ethnicity, socioeconomic
status)
Recruitment process; exclusion and inclusion criteria, knowledge of study
hypothesis; knowledge of exposure and outcome
For worker populations - duration of work, incidence or prevalence sampling
Participation rates: Total eligible; participation at each stage and for final analysis
group and denominators used to make these calculations
Length of follow-up, loss to follow-up
Comparability: Participant characteristic data by group, data on non-participants
Exposure
Industrial hygiene measures
Biological matrix or target tissue/organ (e.g., urine)
Level of detection (LOD) or level of quantitation (LOQ)
Exposure distribution (e.g., central tendency, range), proportion < LOD
Contrast between "exposed" and "referent" comparisons
Analysis
Consideration of data distribution including skewness of exposure and outcome
measures
Consideration of influence of "tails" in analysis based on continuous exposure
measure
Consideration of values below LOD or LOQ
Presentation of effect estimates, rather than statement regarding presence or
absence of statistical significance
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Outcome-specific considerations
Hepatic, hamate-logical,
immune
Measures - Type of assay
Sensitivity/detection limits, coefficient of variation
Consideration of - Age, sex, smoking history
confounding
Relevant exposure - Up to 6 months preceding blood or urine sample collection for assays
timewindow(s)
Steroidal and
gonadotropin
hormones (adults; sex-
specific)
Measures - Type of assay
Sensitivity/detection limits, coefficient of variation
Consideration of - Age, smoking, body mass index (consider if these are related to exposure)
confounding
Relevant exposure - Up to 6 months preceding hormone sample collection
time window(s)
Sperm parameters
Measures - Type of assay (e.g., WHO protocol)
Consideration of - Age, smoking, body mass index, abstinence time (consider if these are related to
confounding exposure)
Relevant exposure - Up to 6 months preceding semen sample collection; could also consider cycle-
time window(s) specific (or lagged cycle-specific) window
Spontaneous abortion - Human chorionic gonadotropin measures, maternal (or paternal) report of
Measures pregnancy history (interview or questionnaire), medical records (based on
maternal report), hospitalization records
Consideration of - Age, gravidity, maternal smoking (consider if these are related to exposure)
confounding
Relevant exposure - Up to 3 months preceding conception, conception cycle, and gestational period
timewindow(s)
Respiratory (noncancer)
- pulmonary function
Measures - Standard protocol
Consideration of - Age, sex, height, smoking
confounding
Relevant exposure - Up to 6 months preceding pulmonary function measures
timewindow(s)
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Cancer
Measures
Consideration of
confounding
Relevant exposure
time window(s)
- Accuracy and validity of mortality cause of death data
available)
Lung cancer: smoking
- 5-20 years before death
[or incidence data, if
1
2
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
2 2. PRELIMINARY EVIDENCE TABLES
3 2.1. Data Extraction for Preliminary Epidemiology Evidence Tables
4 The evidence tables present data from studies related to a specific health effect. At a
5 minimum, the evidence tables include the relevant information for comparing key study
6 characteristics such as study design, exposure metrics, and dose-response information. Evidence
7 tables will serve as a method for presenting and evaluating the suitability of the data for the
8 analysis of hazard potential and utility of the data for exposure-response evaluation. For each
9 study listed, key information on the study design, including characteristics that inform study
10 quality, and study results pertinent to evaluating the health effects of hexavalent chromium
11 exposure are summarized in preliminary evidence tables.
12 The complete list of references considered in preparation of these materials can be found on
13 the HERO website at:
14 http://hero.epa.gov/index.cfm?action=landing.main&project id=2233.
15
16
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.2. Gastrointestinal Effects
2
3
Table 2-1. Evidence pertaining to gastrointestinal (GI) effects following
exposure to hexavalent chromium
Reference and Study Design
Results
Birket al. (2006) (Germany)
cohort study
Population: Exposed: male chromate prodcution workers from
two plants; worked at least 12 months after each plant
converted to a no-lime process (n = 901); Leverkusen n = 593,
began work in 1958 or later, mean duration 9 yrs; Uerdingen (n
= 308, began work in 1964 or later, mean duration 11 yrs
Referent: external analysis (compared with regional rates); also
included analysis by exposure level
Outcome: cause on death certificate based on ICD9
Exposure Assessment: Cumulative exposure using job exposure
matrix developed based on work histories and urinary Cr
measurements (most collected from routine medical
examinations; (n=7000 from 1958-1998 in Leverkusen and n =
5400 from 1964-1995 in Uerdingen). Personal air samples (n =
252 from 1985-1998 in Leverkusen and n = 215 from 1986-
1994 in Uerdingen) and area air samples (n = 3422 from 1973-
1998) in Leverkusen and n = 1161 from 1978-1995 in
Uerdingen) were available for part of the study period.
Exposure mean: varied over time (general decline from 1960s
through 1990s). Mean concentration in air: 8.83 and 8.04 ng
Cr/m3 in Leverkusen and Uerdingen, respectively. Range of
concentration in urine: from 15-50 ng/L up to 1970 to 1-<10
Hg/L in 1987-1998 in Leverkusen; from 5-30 ng/L up to 1970 to
1-<10 ng/L in 1987-1996 in Uerdingen.
Mean Length of Follow-Up: 16 yrs for Leverkusen plant; 19 yrs
for Uerdingen plant
Smoking data available for more than 90% of cohort
Reported Endpoint: diseases of the digestive
system; ICD9
Exp. Group
cases
SMR
0.52
chromate 6
workers
Stat Method: SMR calculated using German
national rates
95% Cl
0.19-1.13
Haves et al. (1979) (United States)
cohort (retrospective) study
Population: Exposed: male chromium chemical production
workers hired as hourly employees between 1945 and 1974 (n
= 1803); employed greater than 90 days
Referent: compared to age, race, and cause-specific rates for
Baltimore City males for the appropriate time periods
About 11.5% lost to follow-up
Outcome: cause on death certificate based on ICD8 codes 520-
577
Exposure Assessment: average air concentrations are available
in Braver et al. (1985); new milling and roasting plant
constructed in 1950 led to reduction in exposures; analysis did
not differentiate between periods of employment
Reported Endpoint: deaths due to diseases of
the digestive system; ICD8 (520-577)
Exp. Group cases SMR 95% Cl
workers 23 0.64 0.40-0.95
Stat Method: SMRs using city referent rates
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results
old plant (1945-1949; n = 555): 795 ng/m3 CrO3;
413 ng/m3 Cr VI
old plant (1950-1959; n = 354): 143 ng/m3 CrO3;
74ng/m3CrVI
new plant (1950-1959; n = 219 plus unknown n for 1957): 60
u.g/m3 CrO3; 31 u.g/m3 Cr VI
Luippoldetal. (2005) (United States)
cohort (retrospective) study
Population: Exposed: male and female chromate production
employees exposed to low-level hexavalent chromium at two
plants (Plant 1 = North Carolina; Plant 2 = Texas) (n = 617);
average duration of employment was 12.4 years at Plant 1 and
7.8 years for Plant 2; age at first exposure was similar for both
plants (28.9 years and 31.3 years for Plants 1 and 2,
respectively); mean time since first exposure: 20 years for Plant
land 10 years for Plant 2
Referent: compared with national and state-specific mortality
reference rates; results only provided using state-specific rates
Outcome: cause on death certificates (pre-1979) and in the
National Death Index-Plus (post-1979) based on ICD9 codes
520-579
Exposure Assessment: job-exposure matrices created based on
personal air-monitoring measurements and plant personnel
records
5230 personal air samples 1974-1988 in Plant 1; 1200 personal
air samples 1980-1998 in Plant 2; annual geometric means
range 0.36-4.36 ng/m3 Cr VI
Length of Follow-Up: follow-up for 60% of Plant 1 employees
was >20 years; maximum follow-up for Plant 2 employees was
18 years; end of the study follow-up period was December 31,
1998
Reported Endpoint: deaths due to diseases of
the digestive system; ICD8 (520-577)
Exp. Group cases SMR 95% Cl
chromate 1 0.43 0.01-2.41
workers
Stat Method: SMRs using state referent rates
1
2
3
SMR: standard mortality rate; 95% Cl: 95% confidence interval
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.3. Hepatic Effects
2
3
Table 2-2. Evidence pertaining to hepatic effects following exposure to
hexavalent chromium
Reference and Study Design
Results by Endpoint
Birketal. (2006) (Germany)
cohort study
Population: Exposed: male chromate prodcution workers from
two plants; worked at least 12 months after each plant
converted to a no-lime process (n = 901); Leverkusen n = 593,
began work in 1958 or later, mean duration 9 yrs; Uerdingen (n
= 308, began work in 1964 or later, mean duration 11 years
Referent: external analysis (compared with regional rates); also
included analysis by exposure level
Outcome: cause on death certificate based on ICD9
Exposure Assessment: Cumulative exposure using job exposure
matrix developed based on work histories and urinary Cr
measurements (most collected from routine medical
examinations; (n = 7000 from 1958-1998 in Leverkusen and n =
5400 from 1964-1995 in Uerdingen). Personal air samples (n =
252 from 1985-1998 in Leverkusen and n = 215 from 1986-
1994 in Uerdingen) and area air samples (n = 3422 from 1973-
1998) in Leverkusen and n = 1161 from 1978-1995 in
Uerdingen) were avaiable for part of the study period.
Exposure mean: varied over time (general decline from 1960s
through 1990s). Mean concentration in air: 8.83 and 8.04 ng
Cr/m3 in Leverkusen and Uerdingen, respectively. Range of
concentration in urine: from 15-50 ng/L up to 1970 to 1-<10
Hg/L in 1987-1998 in Leverkusen; from 5-30 ng/L up to 1970 to
1- <10 ng/L in 1987-1996 in Uerdingen.
Mean Length of Follow-Up: 16 yrs for Leverkusen plant; 19 yrs
for Uerdingen plant
Smoking data available for more than 90% of cohort
Reported Endpoint: cirrhosis of the liver; ICD9
Exp. Group
cases
chromate
workers
SMR
0.4
0.08-1.16
Stat Method: SMR calculated using German
national rates
Moulin etal. U993a) (France)
cohort (retrospective) study
Population: Exposed: male welders (n = 2721) with at least 1
year of employment (mean year of birth 1940; mean duration of
employment 19.5 years) and an internal comparison group of
manual workers (n = 6683) employed in 13 factories in France;
smoking habits of 87% of total study population known; not
statistically different between welders and nonwelders (both
about 53%)
Referent: compared with national death rates for the male
population
Loss To Follow-Up: 122 (4.5%) welders and 221 (3.3%)
nonwelders lost to follow-up
Reported Endpoint: liver cirrhosis deaths; ICD8
(571)
welders by duration of employment
cases
Exp. Group
<10 years 1
10-19 years
>20 years
2
17
SMR
0.64
0.58
2.03
welders by time since first employment
cases
Exp. Group
<10 years 1
10-19 years 2
>20 years 17
SMR
0.86
0.58
1.94
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Outcome: cause determined from French national file of causes
of death managed by the French National Institute for Medical
Research and Health using ICD8 code 571; records of hospitals
and of general practitioners also used
Exposure Assessment: based on duration of employment and
time since first employment; data collected from personnel
registers of 13 factories
Length of follow-up: approximately 11-13 years
Stat Method: SMRs using national referent rates
Moulin etal. U993b) (France)
cohort (retrospective) study
Population: Exposed: stainless steel producing workers (n =
4227); males with at least 3 years of employment between 1
January 1968 and 31 December 1984 at UGINE SA plant, died in
France, and with complete data
Referent: compared to national death rates for the male
population; males
59 workers lost to follow-up
Outcome: cause on death certificate based on ICD8 code 571
Exposure Assessment: based on job histories in different
workshops in the plant from company records
Length of Follow-Up: <17 years
Reported Endpoint: liver cirrhosis deaths; ICD8
(571)
Exp. Group cases SMR
production 55 1.74
95% Cl
1.31-2.26
workforce
excluding
office and
administrati
on
Stat Method: SMRs using national referent rates
Moulin etal. (1990) (France)
cohort (retrospective) study
Population: Exposed: male ferrochromium and stainless steel
plant workers (n = 1717) employed at least 1 year between
January 1,1952, and December 31,1982 (when production of
ferrochromium was occurring); smoking habits of 67% of cohort
members known from medical records; of these, 67.2% of
exposed and 70.4% of nonexposed were current smokers
Referent: compared with French general population (n = 552)
About 32 workers lost to follow-up
Outcome: cause ascertained from general practitioners or from
hospital records using ICD8 code 571
Exposure Assessment: exposure based on individual job
histories at the factory; data available as "exposed" or
"nonexposed" with "exposed" meaning to have been employed
for at least 1 year in the workshops producing ferrochromium or
in the workshops producing stainless steel
Length of follow-up: follow-up for mortality occurred from the
date of first employment to December 31,1982
Reported Endpoint: liver cirrhosis deaths; ICD8
(571)
Exp. Group cases SMR 95% Cl
nonexposed 2 0.52 0.06-1.88
workers
exposed
workers
6 0.77 0.28-1.68
Stat Method: SMRs using national death rates
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Saraswathvand Usharani (2007) (India)
cross-sectional study
Population: Exposed: chrome platers from a chrome plating unit
(n = 130); males and females (98% male) from Coimbatore,
Tamilnadu, India; continuously employed in the factory (8
hours/day/week) <= 8 years; average age = 33.4 years
Referent: residents from the same area as workers and not
known to be exposed to chromium or other metals at work or
residents who live in the vicinity of the factory (n = 130) used as
reference group; non-white males (100% male); average age =
31 years
Outcome: liver enzymes measured in blood
Exposure Assessment: based on employment as a chrome plater
in a factory and duration of exposure (i.e., 8-15 or 16-25 years
of exposure); no measurements of chromium reported
Reported Endpoint:
[ALT] (IU/L)
alanine aminotransferase
Exp. Group
reference
exposed 8-
15 years
exposed
16-25 years
n mean SD p-value
130 22 1.69 n/a
73 34.34 2.5 <0.01
57 43.28 1.72 <0.01
Reported Endpoint:
(IU/L)
alkaline phosphatase [ALP]
Exp. Group
reference
exposed 8-
15 years
exposed
16-25 years
n mean SD p-value
130 60.84 5.67 n/a
73 70.15 6.24 <0.01
57 83.72 7.63 <0.01
Reported Endpoint:
[AST] (IU/L)
aspartate aminotransferase
Exp. Group n
reference 130
exposed 8- 73
15 years
exposed 57
16-25 years
Stat Method: t-test
mean SD p-value
19.18 2.14 n/a
32.92 3.71 <0.01
38.62 4.04 <0.01
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Khan et al. (2013) (Pakistan)
cross-sectional study
Population: Exposed: male tannery workers (n = 120) from
Sialkot, Pakistan; working for more than 5 years; selected
randomly by employer records after informed consent; excluded
any worker with chronic illness including diabetes mellitus,
hepatitis, renal failure, contact dermatitis or with any
orthodontic/orthopedic implant; average age = 33 years
Referent: male residents from the same area (n = 120) used as
reference group; methods of recruitment not reported
Outcome: liver enzymes measured in blood
Exposure Assessment: blood and urine
median (interquartile range)
Exposed:
blood 569 (377-726) nmol/L
urine 131 (46-313) nmol/L
(r = 0.741, p< 0.01)
Referent:
blood 318 (245-397) nmol/L
urine 13 (3-26) nmol/L
Reported Endpoint: alanine aminotransferase
[ALT] (U/L)
Exp. Group
unexposed
workers
exposed
workers
ri mean SD p-valu
120 27.63 11.26 n/a
120 33.82 12.23 0.001
Reported Endpoint: alkaline phosphatase [ALP]
(U/L)
Exp. Group
unexposed
workers
n
120
120
mean SD
186 38
exposed
workers
Stat Method: t-test
197
65
0.222
1
2
3
4
5
n = total in group; n/a: not applicable; SMR: standard mortality rate; SD: standard deviation; 95% Cl: 95%
confidence interval
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.4. Hematological Effects
2
3
Table 2-3. Evidence pertaining to hematological effects following exposure to
hexavalent chromium
Reference and Study Design
Results by Endpoint
Khan et al. (2013) (Pakistan)
cross-sectional study
Population: Exposed: male tannery workers (n =
120) from Sialkot, Pakistan; median (range)
duration of employment: 9 (5-21) years; selected
randomly by employer records after informed
consent; excluded any worker with chronic illness
including diabetes mellitus, hepatitis, renal
failure, contact dermatitis or with any
orthodontic/ orthopedic implant; average age =
33 years
Referent: male residents from the same area (n =
120) used as reference group; methods of
recruitment not reported
Outcome: standard complete blood count (CBC)
Exposure Assessment: blood and urine
median (interquartile range)
Exposed:
blood 569 (377-726) nmol/L
urine 131 (46-313) nmol/L
(r = 0.741, p< 0.01)
Referent:
blood 318 (245-397) nmol/L
urine 13 (3-26) nmol/L
Parameter (mean
±SD)
red blood cells
[RBC] (x 1012/L)
hemoglobin [Hb]
(g/L)
platelet count (x
109/L)
Stat Method: t-test
unexposed
workers
(n = 120)
5.27±0.42
14.55±1.2
290.26±76.27
exposed
workers
(n = 120)
5.18±0.49
12.52±1.82 0.001
246.5±64.12 0.001
Song et al. (2012) (China)
cross-sectional study
Population: Exposed: chromate production
factory workers (n = 100); males and females
(74% male) with no past or present medical
history of liver disease, renal dysfunction,
diabetes, cardiovascular disorder or other chronic
diseases; no dietary supplements containing
elements or vitamins; no radiation exposure in
the past year; and employment in the present job
for at least one year; median (range) duration of
employment: 13.03 (1-33) years; excluded
workers who might be exposed to a little Cr III
and iron; average age = 37.9 years
Referent: no occupational exposure to chromate
or other toxic metals and lived more than 20
kilometers away from the factory in the same city
(n = 50); average age = 38.1 years
Outcome: standard complete blood count (CBC)
Parameter (mean
±SD)
red blood cells
[RBC] (x 1012/L)
hemoglobin [Hb]
(g/L)
unexposed
(n = 50)
4.73±0.43
144.76±12.55
exposed
(n = 100) p-value
4.78±0.75 0.596
148.77±27.16 0.218
Stat Method: Mann-Whitney U-test
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Exposure Assessment: 8-hour personal exposure
samples collected for all participants; air samples
collected at multiple sites
median (range)
Exposed:
air 16.96 (0.31-145.95) u.g/m3
Referent:
air 0.06 (0.01-0.34) u.g/m3
1
2
3
n = total in group; SD: standard deviation
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.5. Immunological Effects
2
3
Table 2-4. Evidence pertaining to immunological effects following exposure to
hexavalent chromium
Reference and Study Design
Qian et al. (2013) (China)
cross-sectional study
Population: Exposed: male chromate production
workers (n = 106) aged 25-50 years old with no
medical history of allergy, asthma, or allergic
rhinitis; no skin infections, fever, or other clinical
disease; >=1 year of employment in the factory
with >=3 months in the same work location;
workers split into two groups: Group 1 (50
workers) used to examine cytokine production;
Group 2 (56 workers) used to analyze humoral
immunity; same activity pattern and occupational
hazards among groups; smoking status and
alcohol intake information collected mean ± SD
years working for Group 1: 17.4 ± 7.7; Group 2
mean not provided
Referent: nonexposed males living approximately
20 km from the factory (n = 50); average age =
39.4 ± 8.5 years
Significantly more workers in Group 1 smoked
and consumed alcohol compared with referents;
Group 2 and referents were similar.
Outcome: cytokines and levels of immunoglobulin
and complement measured in serum
Exposure Assessment: air samples from six
representative areas in each workshop; blood
samples collected from workers at the end of 5
consecutive working days and from reference
group after completion of the questionnaire;
urine sample collected from all subjects and
normalized to creatinine
median (quartile)
Group 1:
air (mean ±SD) 14.38±18.08 ng/m3
blood 14.8 (13.9) ug/L
urine 10.86 (8.79) ng/g creatinine
Group 2:
air (mean ±SD) 28.55±29.70 ng/m3
blood 16.2 (15.1) ug/L
urine 16.28 (12.35) ng/g creatinine
Results by Endpoint
blood chromium concentration, u.g/L
reference exposeda'b
Parameter (n = 50)
serum IgG (g/l) 12.41±2.05 10.94±2.45b
(mean ± SD)
serum IgA (g/l) 2.82±1.15 2.35±0.88b
(mean ± SD)
serum IgM (g/l) 0.97±0.43 1.17±0.49b
(mean ± SD)
serum IgE (g/l) 81.87 55.19b
(median, quartile) (237.08) (157.41)
serum C3 (g/l) 0.91±0.13 1.20±0.24b
(mean ± SD)
serum C4 (g/l) 0.23±0.05 0.32±0.07b
(mean ± SD)
serum IL-2 (pg/ml) 1.25±0.18 1.24±0.11a
(mean ± SD)
serum IL-4 (pg/ml) 1.42±0.29 1.37±0.20a
(mean ± SD)
serum TNF-gamma 1.50 1.60a
(pg/ml) (0.33) (0.32)
(median, quartile)
serum IL-6 (pg/ml) 2.45 2.05a
(median, quartile) (1.15) (0.73)
serum IL- 10 (pg/ml) 1.82±0.34 1.68±0.38a
(mean ± SD)
serum IFN-gamma 3.46±0.91 3.06±0.73a
(pg/ml) (mean ±SD)
serum IL-17A 7.56±2.90 6.08±1.92a
(pg/ml) (mean ±SD)
serum IFN- 3.48±0.92 3.13±0.58a
gamma/IL-4
(mean ± SD)
a Group 1 (n = 50)
bGroup2(n = 56)
Stat Method: two sample t-test or Mann-Whitney U
chi-square test
p-value
0.026
0.043
0.246
0.610
0.001
0.001
0.811
0.311
0.880
0.021
0.045
0.032
0.004
0.026
test and
blood chromium concentration, ug/L
corr coeff
Parameter (n=156)
p-value
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Referent:
blood 1.74 (1.29) ng/L
urine 0.92 (0.51) u.g/g creatinine
Boscolo et al. (1997) (Italy)
cross-sectional study
Population: Exposed: male plastic factory workers
aged 34.8 ± 6.1 years old (n = 15); 9 smokers;
occupational exposure period of 3.9 ± 1.9 years
(range: 14 months-11 years)
Referent: residents living in the same area with
similar age and smoking habits as workers; not
occupationally exposed to toxic agents (n = 15)
Outcome: lymphocyte subpopulations and
immunoglobulins measured in blood
Exposure Assessment: pre-shift serum and urine
chromium levels measured
median (25th-75th percentiles)
Exposed:
serum 0.26 (0.19-0.50) ng/L
urine 0.45 (0.28-0.88) ng/L or 0.20 (0.14-
0.43) ng/g creatinine
Referent:
serum 0.22 (0.07-0.44) ng/L
urine 0.17 (0.13-0.42) ng/LorO.12 (0.10-
0.17) ng/g creatinine
ambient air chromate concentration range = 0.1-
5.7 ng/m3
Results by Endpoint
serum IgG (g/l) -0.325
serum IgA (g/l) -0.231
serum C3 (g/l) 0.352
serum C4 (g/l) 0.276
serum IFN-gamma -0.245
(Pg/ml)
serum IL-17A(pg/ml) -0.244
urine chromium concentration, u.g/g
serum IL- 10 (pg/ml) -0.25
Stat Method: Pearson and Spearman correlations;
0.002
0.031
0.001
0.01
0.045
0.016
0.04
blood or
urine levels used as continuous variable for correlation
coefficient calculation
Exp. Group
Parameter (median, reference exposed
25th-75th percentiles) (n = 15) (n = 15)
IgA (mg/dl) 277 (186- 193 (182-
292) 282)
IgG (mg/dl) 1151 (942- 1240 (991-
1276) 1296)
IgM (mg/dl) 79 (58- 118 (75-
111) 140)
CD5+-CD19+ (103/ul) 35 (26-52) 51 (27-55)
CD5-CD19+ (103/ul) 258 (248- 133 (117-
408) 209)
total CD19+ (103/ul) 330 (260- 180 (150-
460) 280)
CD3+ (103/nl) 1890 1630
(1680- (1035-
2170) 1995)
CD3-CD25+ (103/nl) 165 (128- 116 (89-
230) 134)
CD3-HLADR+ (103/nl) 475 (368- 398 (237-
585) 488)
CD4+-CD45RO- (103/nl) 530 (430- 350 (255-
560) 460)
CD4-CD45RO+ (103/nl) 590 (500- 470 (355-
710) 650)
total CD25+ (103/nl) 540 (360- 360 (265-
600) 452)
total CD4+ (103/nl) 1140 (970- 870 (585-1
1240) 135)
total CD8+ (103/nl) 810 (570- 710 (435-
870) 795)
total HLA-DR+ (103/nl) 657 (518- 488 (394-
p-value
NS
NS
NS
NS
<0.001
<0.001
NS
<0.05
<0.05
<0.01
NS
NS
<0.05
NS
NS
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
CD16+-56+ (103/u.l)
lymphocytes (103/nl)
820)
490 (290-
730)
2730
(2300-
3090)
689)
460 (300-
610
2340
(1490-
2915)
NS
NS
total leukocytes
NS
6776 6764
(5680- (5940-
8190) 7180)
Stat Method: Mann-Whitney test; Bravais-Pearson correlation
coefficient was used to test for trend, but trends were assessed
in reference group separate from exposed subjects
Verschooretal. (1988) (Netherlands)
cross-sectional study
Population: Exposed: chrome-plating workers
(aged 39 ± 12 years; employed 8 ± 6 years),
stainless steel welders (aged 41 ± 9 years;
employed 16 ± 8 years), and boilermakers (aged
38 ± 10 years; employed 8 ± 6 years) (total n = 75)
Referent: employees (aged 35 ± 12 years) in a
truck factory located in the same area as the two
chrome-plating companies, cutters working in the
same company as the stainless steel welders, or
employees from a construction factory located in
the neighborhood of the stainless steel welders
(total n = 63)
Welder and referent subgroups did not differ
from each other with respect to smoking habits.
Outcome: serum immunoglobulin G measured in
blood
Exposure Assessment: end-of-shift serum
chromium and urine chromium measured;
chrome-plating workers and stainless steel
welders exposed to water-soluble Cr VI;
boilermakers exposed to metallic Cr
geometric mean (range)
Chrome platers:
serum 0.6 (0.2-1.3) ng/L
urine 9 (1-34) ng/g creatinine
Welders:
serum 0.2 (0.04-2.9) ng/L
urine 3 (1-62) ng/g creatinine
Boilermakers:
serum 0.2 (0.07-0.7) ng/L
urine 1 (0.3-1.5) ng/g creatinine
Reported Endpoint: serum immunoglobulin G (IgG) (g/l)
Exp. Group
reference
chrome platers
welders
boilermakers
ri
63
21
38
16
mean
11.6
11.6
11.1
11.1
SD
2.4
3.2
2.6
2.8
Stat Method: ANOVA; correlation analysis using serum
chromium
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Referent:
serum
urine
0.2(0.1-0.9) ug/L
0.4 (0.1-2) u.g/g creatinine
Mignini et al. (2009) (Italy)
cross-sectional study
Population: Exposed: male shoe, hide, and
leather industry workers aged 39.7 ± 4.3 years old
(n = 40); average exposure period (±SD) within
shoe industry and in tanneries 7.4 ± 3.7 years;
smokers excluded
Referent: nonsmoking staff of the same age range
as the exposed subjects (n = 44)
Outcome: lymphocyte subpopulations and
cytokine levels measured in blood
Exposure Assessment: levels of chromium
measured in the air, serum, and urine; exposed
group separated into "greater" and "less"
exposure groups based on urine levels;
approximate mean levels in urine based on visual
inspection of the figures:
greater exposed: 0.6
less exposed: 0.4
referent: 0.15
Reported Endpoints: neutrophils, macrophages, lymphocytes,
lymphocyte subpopulations (CD4+, CD8+, CD19+, CD16+/CD56+,
CD4/CD8)
Authors stated there was no difference between exposed and
reference groups for neutrophils, macrophages, lymphocytes,
or lymphocyte subpopulations (CD4+, CD8+, CD19+,
CD16+/CD56+, and CD4/CD8). (Reported in figures only.)
Stat Method: Duncan Multiple Range, Newman-Keuls, or Mann-
Whitney test
Reported Endpoints: peripheral blood mononucleatic cells, IL-
12, lymphocyte proliferation, IL-6, IL-2
Authors stated the high-exposure group showed decreased
peripheral blood mononucleatic cells and IL-12 and increased
lymphocyte proliferation, IL-6, and IL-2. (reported in figures
only)
Stat Method: Duncan Multiple Range, Newman-Keuls, or Mann-
Whitney test
Tanigawa et al. (1998) (Japan)
cross-sectional study
Population: Exposed: male workers (retired or
currently employed) in manufacturing of chromic
acid, sodium dichromate, and potassium
dichromate at a chemical plant, aged 41-65
(mean 57) years old (n = 19; 7 current smokers);
chromate workers exposed for 7-39 (mean 19)
years; exposure terminated at 1-39 (mean 18)
years before the study
Referent: nonexposed male volunteers including
13 current smokers, aged 50-65 years (mean 57
years), who worked at the same factory (n = 33)
Outcome: lymphocyte subpopulations measured
in blood
Exposure Assessment: based on job description
stratified by smoking status
Reported Endpoint: I cells
Parameter (mean ±
SD)
CD3+ T lymphocytes
(cells/mm3)
CD4+ T lymphocytes
(cells/mm3)
CD8+ T lymphocytes
(cells/mm3)
Exp. Group
nonexposed chromate
workers; workers;
nonsmokers nonsmokers
CD3+ T lymphocytes
(cells/mm3)
CD4+ T lymphocytes
(cells/mm3)
CD8+ T lymphocytes
(cells/mm3)
(n = 20)
1840±650
1250±450
670±480
nonexposed
workers;
smokers
(n = 13)
2110±530
1660±570
540±280
(n = 12)
1150±640
870±510
330±200
chromate
workers;
smokers
(n = 7)
1140±380
790±260
470±250
<0.001
<0.01
NS
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Stat Method: Student's t test or Welch's t test
Kuo and Wu (2002) (Taiwan)
cross-sectional study
Population: Exposed: male and female workers in
five chromium electroplating plants in central
Taiwan (n = 10); post-treatment workers (n = 17);
for entire study population, average age 37 years
old; work duration 72.9 months; 42% smokers
Referent: male and female administrative
workers not exposed to chromium or any other
metals (n = 19)
Outcome: immunological parameters measured
in blood
Exposure Assessment: personal sampler affixed
to workers' collars for the duration of one shift;
urinary chromium measured at end of shift
High:
urine >6.41 ng/g creatinine
Moderate:
urine 1.14-6.40 ng/g creatinine
Referent:
urine <1.13 ng/g creatinine
airborne Cr concentration, mg/m
corr coeff (n = 46)
0.05
-0.008
-0.06
Parameter
B-cells (%)
T-cells (%)
T4 (%) (anti-Leu4 CD3-FITC
+ anti-Leu3a CD4-PerCP)
T4/T8 ratio -0.01
T8 (%) (anti-Leu3a CD4- -0.08
PerCP + anti-Leu2a CD8-
FITC)
IL-6 (ng/ml) -0.004
IL-8(ng/ml) 0.13
TNF-alpha (ng/ml) -0.12
Stat Method: Pearson correlation
NS
NS
NS
NS
NS
urinary chromium level, ug/g creatinine
Reported Endpoint:
Parameter low moderate p^ high Q^
(adjBetaiSE) (ref, n = (n = 17) value (n = 10) value
19)
0 - <0.05 -4.29±2.23 <0.1
2.87±1.41
0 - NS -8.82±4.93 <0.1
7.81±8.55
0 - NS -0.23±4 NS
0.03±2.54
B-cells (%)
T-cells (%)
T4 (%) (anti-
Leu4 CD3-
FITC + anti-
LeuSa CD4-
PerCP)
T4/T8 ratio
T8 (%) (anti-
LeuSa CD4-
PerCP + anti-
Leu2a CD8-
FITC)
IL-6 (ng/ml)
IL-8 (ng/ml)
0 0.07±0.19 NS 0.53±0.3 <0.1
0
NS -6.49±3.59 NS
1.78±2.28
0 0.38±0.26 NS 0.69±0.26 <0.0
1
0 16.24±19. NS 38.74±20. <0.0
5 15
0
-0.63±1.3 NS -0.85±1.34 NS
TNF-alpha
(ng/ml)
Stat Method: linear regression model; adjusted for age, gender
and smoking
Khan et al. (2013) (Pakistan)
Reported Endpoint: white blood cells [WBC] (10/L)
Exp. Group
mean
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
cross-sectional study
Population: Exposed: male tannery workers (n =
120) from Sialkot, Pakistan; median (range)
duration of employment: 9 (5-21) years; average
age 33 years old; selected randomly by employer
records after informed consent; excluded any
worker with chronic illness including diabetes
mellitus, hepatitis, renal failure, contact
dermatitis or with any orthodontic/ orthopedic
implant; smoking status information not indicated
Referent: male residents from the same area (n =
120); methods of recruitment not reported
Outcome: WBC count measured in blood
Exposure Assessment: blood and urine
median (interquartile range)
Exposed:
blood 569 (377-726) nmol/L
urine 131 (46-313) nmol/L
(r = 0.741, p< 0.01)
Referent:
blood 318 (245-397) nmol/L
urine 13 (3-26) nmol/L
unexposed workers 120 7.56 1.25 n/a
exposed workers 120 8.79 1.82 0.001
Stat Method: t-test
Wang et al. (2012) (China)
cross-sectional study
Population: Exposed: male chromate production
plant workers who weigh or pack chromate aged
38.66 ± 6.07 years; exposed to sodium
dichromate for at least 6 months (n = 86); mean
(range) work duration time: 12.01 ± 0.84 (1-33)
years
Referents: healthy residents from housekeeping
company (including salesman, meter checker,
repairman, etc.) living in same city without
occupational exposure to chromate or other
chemicals (n = 45) used as reference group;
matched to exposed by socioeconomic and
demographic status such as age, smoking,
drinking; average age 39.64±10.3 years
Outcome: WBC count measured in blood
Exposure Assessment: post-shift urine samples
collected from exposed workers after 5
consecutive work days; analysis performed 3
hours after sample collection
Reference:
urine 1.53+/-2.09 ng/g creatinine
Reported Endpoint: white blood cell count [WBC] (10/L)
Exp. Group
reference
chromate-exposed
workers
n
45
86
mean
6.17
6.96
1.72 0.025
Stat Method: Mann-Whitney test
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
2
3
Reference and Study Design
Exposed:
urine 18.68+/-14.60 u.g/g creatinine
Results by Endpoint
adjBeta: adjusted Beta; NS: not significant; n/a: not applicable; SE: standard error; SD: standard deviation
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.6. Reproductive and Developmental Effects
2
3
Table 2-5. Evidence pertaining to reproductive and developmental effects
following exposure to hexavalent chromium
Reference and Study Design
Results by Endpoint
Hormones
Li et al. (2001) (China)
cross-sectional study
Population: Exposed: male electroplating
factory workers working at electroplating
factory for 1-15 yr (n = 21)
Referent: compared with workers from the
same factory without exposure to any harmful
chemicals (n = 22)
Outcome: hormones measured in serum
Exposure Assessment: chromium measured in
serum and seminal fluid (nmol/mL)
Exposed:
serum: 1.4+/-0.01 x 10"3 (n = 21)
seminal fluid: 7.55 +/- 0.06 x 10-3 (n = 18)
Referent:
serum: 1.26 +/- 0.02 x 10"3 (n = 13)
seminal fluid: 6.38 +/-1.06 x 10"3 (n = 4)
Reported Endpoint: hormone levels
Parameter
Exp. Group
reference exposed
(n = 21) (n = 20)
2.41±0.08
follicle
stimulating
hormone (FSH)
(mean ± SE, x
10"3 lU/mL)
luteinizing
hormone (LH)
(mean ± SE, x
10"3 lU/mL)
Stat Method: not reported
7.34±0.34
6.85±0.3
6.33±0.16
NS
Bonde and Ernst (1992) (Denmark)
cross-sectional study
Population: Exposed: male tungsten inert gas
stainless steel welders and manual metal arc
and/or metal active gas mild steel welders (n =
60); smoking most prevalent among the
highest exposed (73.6%)
Referent: compared with non-welding metal
workers and electricians (n = 47)
Outcome: hormones measured in serum
Exposure Assessment: pre-shift blood samples
obtained from 86 subjects (5 plants only);
post-work shift spot urine samples collected
and those with urinary chromium levels
at/below the median (<1.07 nmol/mmol
creatinine) comprised reference group that
contained 100% of electricians, 16% of
stainless steel welders, 46% of mild steel
welders, and 48% of non-welding metal
workers
high: >1.78 nmol/mmol creatinine
medium: 1.07-1.78 nmol/mmol creatinine
Reported Endpoint: hormone levels
pre-shift blood chromium concentration, nmol/L
Parameter n adiBeta
107
-0.02
107
107
-0.05
-0.001
NS
follicle stimulating
hormone [FSH]
(IU/L)
luteinizing
hormone [LH]
(IU/L)
testosterone
(nmol/L)
Stat Method: linear regression; chromium entered in model as a
continuous variable; adjustment factors included age, alcohol
drinking, race/ethnicity, smoking status, shift work, use of Finnish
bath, fertility problems, history of urogenital disorder, fever,
abstinence period, occupation
NS
NS
urinary chromium concentration, nmol/mmol creatinine
Exp. Group
1.07-1.78
Parameter
follicle
stimulating
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
low: <1.07 nmol/mmol creatinine
hormone [FSH]
(meaniSD, IU/L)
luteinizing 6.7±2.8 6.8±2.4 6.8±3.0 NS
hormone [LH]
(mean ±SD, IU/L)
testosterone 16.4±5.6 18.7±7.3 21.0±7.8 NS
(mean ± SD,
nmol/L)
Stat Method: linear regression; chromium entered in model as a
continuous variable
Hiollundetal. (1998) (Denmark)
cohort (prospective) study
Population: Exposed: male welders 20-35
years old who were first-pregnancy planners
(couples without earlier reproductive
experience who intended to discontinue
contraception in order to become pregnant)
recruited 1992-1994 from members of the
union of metal workers and 3 other trade
unions (n = 126); enrolled couples
discontinued birth control and were followed
up to 6 menstrual cycles or until a pregnancy
was achieved
Referent: first-pregnancy planners who were
nonmetal workers (n = 200) or metal workers
without welding during the past 3 months (n =
68)
Among the 3 exposure groups, 23-35% were
smokers
Outcome: hormones measured in serum
Exposure Assessment: questionnaire on
current and previous welding exposure,
including type and welding method, average
daily duration of welding, and welding with or
without application of local exhaust
ventilation; at entry, each male provided
blood sample and semen sample
Reported Endpoint: hormone levels
Exp. Group
non-welder
Parameter
reference
(n = 200)
3.3 (2.3-4.9) 3.5 (2.4-4.4)
welder
(n = 126)
3.2 (2.5-4.3)
follicle stimulating
hormone (FSH)
(IU/L) (median, 25th-
75th percentile)
luteinizing hormone 3.3(2.6-4.5) 3.1(2.5-4.7) 3.3(2.6-4.6)
(LH) (median, 25th-
75th percentile)
testosterone/SHBG 0.48(0.38- 0.49(0.39- 0.47(0.37-
(units) (median, 0.59) 0.65) 0.62)
25th-75th percentile)
Authors stated that hormone measurements were not significantly
different in exposed vs. reference groups.
Stat Method: analysis of covariance using SAS GLM procedure
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Sperm parameters
Li et al. (2001) (China)
cross-sectional study
Population: Exposed: male electroplating
factory workers working at electroplating
factory for 1-15 yr (n = 21)
Referent: compared with workers from the
same factory without exposure to any harmful
chemicals (n = 22)
Outcome: sperm parameters (sample
collected after 5 days abstinence)
Exposure Assessment: chromium measured in
serum and seminal fluid (nmol/mL)
Exposed:
serum: 1.4+/-0.01 x 10"3 (n = 21)
seminal fluid: 7.55 +/- 0.06 x 10-3 (n = 18)
Referent:
serum: 1.26 +/- 0.02 x 10"3 (n = 13)
seminal fluid: 6.38 +/-1.06 x 10"3 (n = 4)
Reported Endpoint: sperm parameters
Parameter
sperm counts
(mean ±SE,
106/ml)
sperm motility 81.92±0.41
(meaniSE, %)
liquefaction time 30.9±0.86
(mean ±SE, min)
Stat Method: not reported
Exp. Group
reference exposed
88.96±3.4 47.05±2.13
69.71±0.93
32.81±0.76
<0.05
NS
Bonde and Ernst (1992) (Denmark)
cross-sectional study
Population: Exposed: male tungsten inert gas
stainless steel welders and manual metal arc
and/or metal active gas mild steel welders (n =
60); smoking most prevalent among the
highest exposed (73.6%)
Referent: compared with non-welding metal
workers and electricians (n = 47)
Outcome: sperm parameters (3 samples at 1-
month intervals between samples; collected
after 3 days abstinence); parameters of
repeated samples from each individual were
averaged
Exposure Assessment: pre-shift blood samples
obtained from 86 subjects (5 plants only);
post-work shift spot urine samples collected
and those with urinary chromium levels
at/below the median (<1.07 nmol/mmol
creatinine) comprised reference group that
contained 100% of electricians, 16% of
stainless steel welders, 46% of mild steel
welders, and 48% of non-welding metal
workers
high: >1.78 nmol/mmol creatinine
medium: 1.07-1.78 nmol/mmol creatinine
Reported Endpoint: sperm parameters
pre-shift blood chromium concentration, nmol/L
Parameter n
sperm concentration 107
(million/mL)
proportion of motile 107 0.04 NS
sperms (%)
sperm penetration rate 107 0.02 NS
(cm/hr)
proportion of normal sperm 107 0.07 NS
forms (%)
Stat Method: linear regression; chromium entered in model as a
continuous variable; adjustment factors included age, alcohol
drinking, race/ethnicity, smoking status, shift work, use of Finnish
bath, fertility problems, history of urogenital disorder, fever,
abstinence period, occupation
urinary chromium concentration, nmol/mmol creatinine
Parameter
Exp. Group
1.07-1.78
(mean ±SD)
total sperm count
(million/ejaculation)
sperm concentration
(million/mL)
proportion of motile
50.7±20.9
51.6±16.4 54.8±11.9 55.2±14.6
NS
NS
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
low: <1.07 nmol/mmol creatinine
sperms (%)
sperm penetration 3.69±0.79 3.61±0.68 3.75±0.56 NS
rate (cm/hr)
proportion of 56.8±20.5 61.0±17.1 65.8±17.8 NS
normal sperm forms
(%)
Stat Method: linear regression; chromium entered in model as a
continuous variable
Danadevi et al. (2003) (India)
cross-sectional study
Population: Exposed: male welders aged 21-
41 years old employed in a welding plant and
exposed to welding fumes for 2-21 years (n =
57)
Referent: compared with subjects matched for
age, lifestyle, and economic status who were
not exposed to known harmful chemicals (n =
57)
Forty-five (40.7%) men in the study population
were smokers
Outcome: sperm parameters (2 samples at
weekly intervals between samples; collected
after 3 days abstinence)
Exposure Assessment:
28 welders and 27 referents randomly
selected for blood analysis; blood sampled on
the morning of the 4th day of the workweek
mean ±SD
Exposed:
blood 131.0 ± 52.6
Referent:
blood 17.4 ± 8.9
Reported Endpoint: sperm parameters
Parameter
Exp. Group
reference welders
(mean ±SD)
sperm count (x 106/mL)
rapid linear progressive
motility (%)
nonspecific aggregation
14.0 ± 12.0 49.0 ± 22.0
<0.001
sperm vitality (%)
normal morphology (%)
head defects (%)
mid-piece defects (%)
tail defects (%)
80.4 ± 6.8 67.6 ± 22.8 <0.001
69.0 ± 8.0 37.0 ± 14.3 <0.001
16.4 ±5.6 38.3 ±9.7 <0.001
9.8 ±3.8 19.5 ±9.2 <0.001
4.8 ±0.8 5.2 ±4.9 NS
Additional analysis evaluated the relationship between blood
chromium and semen parameters in the control group and welders
using simple regression analysis. There was significant positive
correlation between percentage of tail defects and blood chromium
in male welders; significant negative correlation occurred between
blood chromium in male welders and sperm count, sperm motility,
including other measures of motility not shown, and sperm vitality;
smoking did not show an effect on semen parameters in welders or
referents.
Stat Method: Mann-Whitney U test
Hiollundetal. (1998) (Denmark)
cohort (prospective) study
Population: Exposed: male welders 20-35
years old who were first-pregnancy planners
(couples without earlier reproductive
experience who intended to discontinue
contraception in order to become pregnant)
recruited 1992-1994 from members of the
union of metal workers and 3 other trade
unions (n = 126); enrolled couples
discontinued birth control and were followed
up to 6 menstrual cycles or until a pregnancy
was achieved
Reported Endpoint: sperm parameters
Exp. Group
reference non-welder welder
Parameter
(n = 200)
sperm count per ejaculate 136
148
(n = 126)
144
(10s) (median, 25th and 75th (55-252) (75-241) (77-300)
percentiles)
sperm density (106/mL)
(median, 25th and 75th
percentiles)
sperm density <20xl06/mL
(% of subjects)
motile sperm (%) (median,
50 52.5
(24-80.5) (27-99)
21
62
17.7
65
56.0
(27-98)
15.1
67
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Referent: first-pregnancy planners who were
nonmetal workers (n = 200) or metal workers
without welding during the past 3 months (n =
68)
Among the 3 exposure groups, 23-35% were
smokers
Outcome: sperm parameters; monthly
samples obtained during follow-up (maximum
of 6 menstrual cycles)
Exposure Assessment: questionnaire on
current and previous welding exposure,
including type and welding method, average
daily duration of welding, and welding with or
without application of local exhaust
ventilation; at entry, each male provided
blood sample and semen sample
25th and 75th percentiles) (53-69) (55-74) (56-72)
straight line velocity (VSL) 24.8 25.9 24.6
(nm/s) (median, 25th and (18-32) (18-31) (19-29)
75th percentiles)
curvilinear velocity (VCL) 74.1 70.7 68.9
(nm/s) (median, 25th and (62-82) (61-81) (57-77)
75th percentiles)
normal morphology (%) 40.0 40.5 42.5
(median, 25th and 75th (34-45) (34-45) (34-48)
percentiles)
normal morphology <30% 19.0 13.9 10.5
(% of subjects)
Authors stated that sperm parameters were not significantly
different in exposed vs. reference groups.
Stat Method: analysis of covariance using SAS GLM procedure
Other reproductive and developmental endpoints
Hiollundetal. (1995) (Denmark)
cohort (retrospective) study
Population: Exposed: married metal workers
in steel manufacturing companies (n = 1483
pregnancies; maternal mean age of the 2
exposed groups about 28 years old); worked
for a minimum of 1 year from 1964-1984
Referent: married subjects reporting no
welding used as reference group (1037
pregnancies; maternal mean age: 28.8 ± 5.3
years old)
Paternal smoking similar among groups (~59-
63%)
Outcome: spontaneous abortions among
spouses (identified through Danish population
register with dates of marriage and divorce)
obtained through hospital discharge records
(Danish In-patient Hospital Register), 1977-
1987
Exposure Assessment: questionnaire filled out
in 1986 recording first and last year worked in
a particular type of welding
Reported Endpoint: spontaneous abortion; ICD8
Exp. Group cases
reference 94
mild-steel welding 54
stainless steel 62
welding
Stat Method: logistic regression
OR
1
0.96
0.78
95% Cl
n/a
0.68-1.4
0.55-1.1
Hiollundetal. (2000) (Denmark)
cohort (prospective) study
Population: Exposed: male first-pregnancy
planners (couples without earlier reproductive
experience who intended to discontinue
contraception in order to become pregnant)
recruited 1992-1994 from members of the
union of metal workers and 3 other trade
Reported Endpoint: spontaneous abortion/miscarriage
Exp. Group cases adjRR 95% Cl
no welding 48 1 n/a
(reference)
mild-steel welding 13 1 0.5-2.1
stainless steel 10 3.5 1.3-9.1
welding
Stat Method: Cox regression; adjusted for center, female age, female
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
unions (77 pregnancies);; enrolled couples
discontinued birth control and were followed
up to 6 menstrual cycles or until a pregnancy
was achieved
Referent: subjects reporting no welding (203
pregnancies)
Outcome: early loss based on human
chorionic gonadotrophic hormone analysis in
10 daily urine samples, with an elevation (>1.0
IU/1) followed by decline; clinical loss based on
June 1996 interview or questionnaire about
pregnancy outcome for all clinically-diagnosed
pregnancies
Exposure Assessment: questionnaire on
current and previous welding exposure,
including type (stainless steel, mild steel, or
other metal) and welding method, average
daily duration of welding, and welding with or
without application of local exhaust
ventilation
body mass index, menstrual cycle length, male and female smoking,
caffeine and alcohol consumption, reproductive disease
Hiollundetal. (2005) (Denmark)
cohort (retrospective) study
Population: Exposed: IVF-treated women in a
couple with male metal workers (n = 319 [91
stainless steel welders, 128 mild steel welders,
100 non-welding metalworkers]); 181 male
metal workers with historical stainless steel
welding (n = 61, <1 yr; n = 57, 1-5 yr; n = 63,
6+ yr); information for subject recruitment
available from the Danish In Vitro Fertilization
Register (DIVF) covering all IVF treatments
after 1993
Referent: nonexposed pregnancies (n = 2925
with or without outcome)
Smoking information obtained through
questionnaire
Outcome: information on pregnancy survival
until clinical detection collected from the DIVF
register; outcome information collected from
national health registers
Exposure Assessment: questionnaires used to
identify metal welders, exposure duration,
and welding type
Reported Endpoint: spontaneous abortion/miscarriage; ICD10
historical stainless steel welding
Exp. Group cases
nonexposed reference 830
pregnancies
<1 year 16
1-5 years 15
6+ years 13
0.93
0.94
0.68
Exp. Group cases
nonmetal workers 830
metal workers-no 32
welding
metal workers-mild 32 0.95
steel welding
metal workers- 16 0.59
stainless steel welding
Stat Method: Cox regression; adjusted for center, male and female
smoking, male and female coffee consumption, male and female
alcohol consumption, male and female age, number of transferred
embryos
95% Cl
n/a
0.48-1.79
0.55-1.6
0.38-1.25
95% Cl
n/a
0.82-1.67
0.66-1.36
0.36-0.98
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Bonde et al. (1992) (Denmark)
cohort (retrospective) study
Population: Exposed: male production
workers employed at Danish stainless steel (n
= 1317; mean age: 29.5 ± 4.8 years old) or
mild steel (n = 924; mean age: 29.6 ± 4.8 years
old) manufacturing companies for a minimum
of 1 year between April 1964 and December
1984 who fathered children 1973-1986
considered at risk based on paternal welding
exposure
Referent: compared with members of
company cohort, excluding metal workers,
who fathered children considered not at risk
based on paternal welding exposure (n =
1328; mean age: 30.3 ± 5.3 years old)
Paternal smoking similar among groups (~64-
69%)
Outcome: history of spontaneous abortion
collected by midwives for women with a
pregnancy ending in live birth after 1977;
other pregnancy outcomes for all pregnancies
in relevant time period collected from Danish
Medical Birth Register with linkage to in-
patient register (for congenital malformations)
and death certificates (for neonatal mortality)
Exposure Assessment: self-questionnaire
reporting first and last year worked for each
welding type and welding methods used
Length of Follow-Up: 0-20 years
Reported Endpoint: spontaneous abortion/miscarriage
Exp. Group cases
not at risk (reference) 23
at risk from mild steel 12
welding
at risk from stainless 38
steel welding
Stat Method: logistic regression; adjusted for maternal age,
birthplace, marital status, and paternal smoking and drinking habits
2.0
95% Cl
n/a
0.5-2.4
1.1-3.5
Reported Endpoint: preterm birth/delivery (>3 weeks preterm)
Exp. Group cases OR 95% Cl
not at risk (reference) 52 1 n/a
at risk from mild steel 26 0.71 0.44-1.45
welding
at risk from stainless 67 1.32 0.91-1.91
steel welding
Stat Method: logistic regression
Reported Endpoint: birth weight <= 2500 g
Exp. Group cases OR 95% Cl
not at risk (reference) 84 1 n/a
at risk from stainless 83 1.01 0.74-1.38
steel welding
at risk from mild steel 52 0.89 0.63-1.28
welding
Stat Method: logistic regression
Reported Endpoint: all malformations; ICD8: 740-759
95% Cl
n/a
0.62-1.06
Exp. Group cases
not at risk (reference) 87
at risk from stainless 75
steel welding
at risk from mild steel 37 0.57 0.41-0.80
welding
Stat Method: Poisson regression, the influence of some confounders
assessed using logistic regression models; adjusted for age of
parents, maternal parity, degree of specialization of hospital
department, paternal alcoholic beverage consumption and smoking
habits, occupational status of the mother, living area
Reported Endpoint: neonatal mortality
Exp. Group cases OR 95% Cl
not at risk (reference) 11 1 n/a
at risk from stainless 11 0.99 0.43-2.30
steel welding
at risk from mild steel 2 0.26 0.06-1.18
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
welding
Stat Method: logistic regression
1
2 cases = number of cases calculated from information provided by study authors
3 adjBeta: adjusted Beta; adjOR: adjusted odds ratio; adjRR: adjusted relative risk; NS: not significant; n = total in
4 group; n/a: not applicable; OR: odds ratio; SE: standard error; SD: standard deviation; 95% Cl: 95% confidence
5 interval
6
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.7. Noncancer Respiratory Effects - Pulmonary Function
2
3
Table 2-6. Evidence pertaining to noncancer respiratory effects (pulmonary
function) following exposure to hexavalent chromium
Reference and Study Design
Results by Endpoint
Lung: function
Huvinen et al. (2002b) (Finland)
cohort (prospective) study
Population: Exposed: workers in the furnace
department of the ferrochromium plant and
steel melting shop (n = 104; mean age 48 ±
6.9 years old)
Referent: compared with workers from the
cold rolling mill whose exposure to
chromium or dust in general was extremely
low (n = 81; mean age 45.6 ± 7 years old)
Loss To Follow-Up: 5 subjects lost to follow-
up because they left the company (2) or died
from cardiac infarction (3)
Outcome: diffusing capacity measured by
experienced lab technicians
Exposure Assessment: subjects categorized
by job classification; personal air samples
from 1987 (n = 72) and 1999 (n = 10)
collected
1987: median = 0.0005 mg/m3, maximum =
0.0066 mg/m3
1999: median = 0.0003 mg/m3, maximum =
0.0007 mg/m3
stationary samples provided similar medians
Reported Endpoint:
diffusing capacity of the lung for carbon
monoxide (TLCO) (mean percentage of predicted values)
Exp. Group
unexposed never
smokers
Cr VI exposed
never smokers
unexposed ever
smokers
Cr VI exposed ever
smokers
n mean SD p-value
27 112.1 11.7 n/a
41 112.1 13.9 NS
52 102.1 11.8 n/a
63 109 17.5 <0.05
Stat Method: Student's t-test
Lung: spirometry
Kuo et al. (1997) (Taiwan)
cross-sectional study
Population: Exposed: male and female
Taiwanese chromium electroplating factory
workers from 9 factories (n = 155); workers
were from 3 factories that used chromium
(mean age 36.3 years old), 6 that used
nickel-chromium (mean age 39.6 years old)
Referent1 compared with workers from 2
zinc electroplating factory workers (n = 34;
mean age 36.9 years old)
Outcome: respiratory function test using
machine operated by worker
Exposure Assessment: end of shift urine
Reported Endpoint:
Exp. Group
zinc workers
nickel-chromium
workers
chromium workers
Reported Endpoint:
Exp. Group
zinc workers
nickel-chromium
workers
chromium workers
Reported Endpoint:
forced expiratory volume in 1 sec [FEV1] (mL)
n reg. coeff p-value
34 n/a n/a
129 -311.5 <0.05
26 -368 <0.05
forced vital capacity [FVC] (mL)
n reg. coeff p-value
34 1 n/a
129 -404.2 <0.01
26 -556.4 <0.01
maximum expiratory flow rate [MEFR] (L/sec)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
samples; average urinary chromium
concentrations (ng/g creatinine): 3.7 (zinc
workers), 7.3 (nickel-chromium workers),
and 41 (chromium workers)
Results by Endpoint
Exp. Group n reg. coeff p-value
zinc workers 34 1 n/a
nickel-chromium 129 0.37 NS
workers
chromium workers 26 0.38 NS
Reported Endpoint: peak expiratory flow in 1 second [PEF] (L/sec)
Exp. Group n reg. coeff p-value
zinc workers 34 1 n/a
nickel-chromium 129 1.47 NS
workers
chromium workers 26 0.21 NS
Reported Endpoint: peak expiratory flow in 25 seconds [PEF25]
(L/sec)
Exp. Group n reg. coeff p-value
zinc workers 34 1 n/a
nickel-chromium 129 0.17 NS
workers
chromium workers 26 0.13 NS
Reported Endpoint: peak expiratory flow in 50 seconds [PEF50]
(L/sec)
Exp. Group n reg. coeff p-value
zinc workers 34 1 n/a
nickel-chromium 129 0.1 NS
workers
chromium workers 26 0.15 NS
Reported Endpoint: peak expiratory flow in 75 seconds [PEF75]
(L/sec)
Exp. Group n reg. coeff p-value
zinc workers 34 1 n/a
nickel-chromium 129 0.01 NS
workers
chromium workers 26 0.03 NS
Reported Endpoint: vital capacity [VC] (mL)
Exp. Group n reg. coeff p-value
zinc workers 34 1 n/a
nickel-chromium 129 -296.2 <0.05
workers
chromium workers 26 -462.9 <0.01
Stat Method: Multiple regression comparing lung function of
chromium, nickel, and zinc workers (Cr workers' result minus Zn
workers' result or Ni-Cr workers' result minus Zn workers' result)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Lindbergand Hedenstierna (1983) (Sweden)
cross-sectional study
Population: Exposed: male and female
employees in chrome plating industry (n =
104); employed in the chrome plating
industry at 1 of 13 companies; working on
the day of study; 40 nonsmokers and 64
smokers
Referent: male auto mechanics (excluding
painters or welders) (n = 119) and office
employees (n = 19) used as reference group
nonsmokers and 67 smokers
Outcome: spirometry; means reported for
low, mixed, and high for Monday and
Thursday am and used as a reference
Exposure Assessment: personal air samples
for 84 participants on 13 different days,
personal air samples for 11 participants over
a week, and 5 stationary air samples over 19
days; median exposure time was 4.5 years
low exposure: <2 ng Cr Vl/m
mixed exposure: <2 ng Cr Vl/m3 and other
acids and metallic salts
high exposure: >2 ng Cr Vl/m3
Results by Endpoint
Reported Endpoint: CV%
Exp. Group n mean SD p-value
nonsmokers
reference 52 11.65 6.13 n/a
exposed 17 15.2 8.1 NS
smokers
reference 67 12.43 5.52 n/a
exposed 24 17.1 7.9 NS
Stat Method: multiple linear regression
Reported Endpoint: FEF25-75 (L/sec)
Exp. Group n mean SD p-value
nonsmokers
reference 52 4.16 1.44 n/a
exposed 26 4.71 1.6 NS
smokers
reference 67 4.36 1.33 n/a
exposed 48 4.45 1.36 NS
Stat Method: multiple linear regression
Reported Endpoint: FEF25_75 (L/sec) on Thursday afternoon
Exp. Group n mean SD p-value
low 10 4.54 1.45 NS
mixed 15 4.64 1.26 NS
high 6 4.59 1.53 <0.05
FEF25-75 observed on Monday and Thursday morning were reference
values; authors stated FEF25.75 significantly decreased on Thursday
afternoon compared with Monday morning and Thursday morning
in high exposure group.
Stat Method: multiple linear regression
Reported Endpoint: FEV1.0 (L)
Exp. Group n mean SD p-value
nonsmokers
reference 52 4.08 0.85 n/a
exposed 26 4.54 0.92 NS
smokers
reference 67 4.38 0.92 n/a
exposed 48 4.31 0.85 NS
Stat Method: multiple linear regression
Reported Endpoint: FEVj 0 (L) on Thursday afternoon
Exp. Group n mean SD p-value
low 10 4.43 0.97 NS
mixed 15 4.06 0.95 NS
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Huvinen et al. (2002b) (Finland)
cohort (prospective) study
Population: Exposed: workers in the furnace
department of the ferrochromium plant and
steel melting shop (n = 104; mean age 48 ±
6.9 years old)
Referent: compared with workers from the
cold rolling mill whose exposure to
chromium or dust in general was extremely
Results by Endpoint
high 6 4.92 1.29 <0.05
FEV10 observed on Monday and Thursday morning were reference
values; authors stated FEV10 significantly decreased on Thursday
afternoon compared with Monday morning and Thursday morning
in high exposure group.
Stat Method: multiple linear regression
Reported Endpoint: FVC (L)
Exp. Group n mean SD p-value
nonsmokers
reference 52 5.2 1 n/a
exposed 26 5.61 0.99 NS
smokers
reference 67 5.66 1.02 n/a
exposed 48 5.27 0.9 NS
Stat Method: multiple linear regression
Reported Endpoint: FVC (L) on Thursday afternoon
Exp. Group n mean SD p-value
low 10 5.35 1.24 NS
mixed 15 4.73 1.22 <0.01
high 6 5.75 1.58 <0.01
FVC observed on Monday and Thursday morning were reference
values; authors stated FVC significantly decreased on Thursday
afternoon compared with Monday morning and Thursday morning
in high and mixed exposure groups.
Stat Method: multiple linear regression
Reported Endpoint: phase III, % N2/L
Exp. Group n mean SD p-value
nonsmokers
reference 52 1.49 1.33 n/a
exposed 17 1.09 0.57 NS
smokers
reference 67 1.34 0.54 n/a
exposed 24 1.63 0.97 NS
Stat Method: multiple linear regression
Reported Endpoint: FEV% (FEVLO/FVC x 100)
Exp. Group n mean SD p-value
unexposed never 27 99.8 5.8 n/a
smokers
Cr VI exposed 41 97.9 7.2 NS
never smokers
unexposed ever 52 95.2 8.7 n/a
smokers
Cr VI exposed ever 63 97.8 7.8 NS
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
low (n = 81; mean age 45.6 ± 7 years old)
Loss To Follow-Up: 5 subjects lost to follow-
up because they left the company (2) or died
from cardiac infarction (3)
Outcome: spirometry by experienced lab
technicians
Exposure Assessment: subjects categorized
by job classification; personal air samples
from 1987 (n = 72) and 1999 (n = 10)
collected
1987: median = 0.0005 mg/m3, maximum =
0.0066 mg/m3
1999: median - 0.0003 mg/m3, maximum -
0.0007 mg/m3
stationary samples provided similar medians
Bovet et al. (1977) (Switzerland)
cross-sectional study
Population: Exposed: male chromium
electroplating workers (n = 44) employed in
one of 17 chromium electroplating plants;
the three exposure groups did not
significantly differ by age, exposure time, or
smoking status
Outcome: wedge bellows spirotest using
Kory et al., 1961 or Bates et al., 1962
standards
Exposure Assessment: based on urinary
measurements taken at end of morning or
end of afternoon:
low exposure: <6.0 ng/g creatinine
medium exposure: 6.1—15 ng/g creatinine
high exposure: 15.1 ng/g creatinine
Results by Endpoint
smokers
Reported Endpoint
Exp. Group
unexposed never
smokers
Cr VI exposed
never smokers
unexposed ever
smokers
Cr VI exposed ever
smokers
Reported Endpoint
Exp. Group
: forced expiratory volume
n mean
27 92.3
41 91.9
52 88.5
63 87.9
: forced vital capacity (FVC]
n mean
unexposed never 27 92.4
smokers
Cr VI exposed 41 94.2
never smokers
unexposed ever 52 92.9
smokers
Cr VI exposed ever 63 89.6
smokers
Stat Method: Student's t-test
in 1 second (FEV10)
SD p-value
10.5 n/a
11.3 NS
13.6 n/a
14.1 NS
(D
SD p-value
8.5 n/a
12 NS
11.5 n/a
11.5 NS
Reported Endpoint: forced expiratory flow 25%-75% (FEF25-75) (% of
the standards of Bates)
urinary chromium concentration
Exp. Group n mean
low (<6.0)
medium (6.1-15)
high (>15.1)
Reported Endpoint
(% of the standards
Exp. Group
low (<6.0)
medium (6.1-15)
high (>15.1)
Reported Endpoint
Exp. Group
26 106.98
12 90.73
6 78.23
: forced expiratory volume
of Kory)
n mean
26 95.64
12 92.73
6 81.93
SD
27.15
22.00
19.28
in one second (FeVJ
SD
10.63
13.72
14.87
: vital capacity (% of the standards of Kory)
n mean
low (<6.0) 26 95.77
medium (6.1-15) 12 97.98
high (>15.1) 6 89.85
Stat Method: not reported
Parameter
n
SD
9.96
13.19
14.22
F value p-value
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
<0.03
forced expiratory flow 25%-75% (FEF25.75) 44 3.90
(% of the standards of Bates)
forced expiratory volume in one second 44 3.45
(FeVJ (% of the standards of Kory)
vital capacity (% of the standards of Kory) 44 1.04
Authors noted that there was a significant effect of chromium on
FeViandFEF25.75.
Stat Method: univariate ANOVA
<0.05
0.36
1
2
3
NS: not significant; n/a: not applicable; SD: standard deviation; reg coeff: regression coefficient
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.8. Noncancer Respiratory Effects - Nasal Pathology and
2 Histopathology
3 Table 2-7. Evidence pertaining to noncancer respiratory effects (nasal
4 pathology and histopathology) following exposure to hexavalent chromium
Reference and Study Design
Results by Endpoint
Clinical observation
Huvinen et al. (2002b) (Finland)
cohort (prospective) study
Population: Exposed: workers in the furnace
department of the ferrochromium plant and
steel melting shop (n = 104; mean ± SD age
48 ± 6.9 years old)
Referent: compared with workers from the
cold rolling mill whose exposure to
chromium or dust in general was extremely
low (n = 81; mean ± SD age 45.6 ± 7 years
old)
Loss To Follow-Up: 5 subjects lost to follow-
up because they left the company (2) or died
from cardiac infarction (3)
Outcome: self-reported (questionnaire)
Exposure Assessment: subjects categorized
by job classification; personal air samples
from 1987 (n = 72) and 1999 (n = 10)
collected
1987: median = 0.0005 mg/m3, maximum =
0.0066 mg/m3
1999: median = 0.0003 mg/m3, maximum =
0.0007 mg/m3
stationary samples provided similar medians
Reported Endpoint: rhinitis >3/12 months
percent
Exp. Group difference 95% Cl
Cr VI exposed group 0.4 -13.3-14.1
Stat Method: Fisher's exact test
Lung: nonneoplastic lesions
Huvinen et al. (1996) (Finland)
cross-sectional study
Population: Exposed: male stainless steel
production workers (n = 109; mean ± SD age
43.3 ± 6.9 years old); minimum of 8 years of
employment in the same department
Referent: compared with male cold rolling
mill workers (n = 95; mean ± SD age 40.7 ±
7.1 years old)
Outcome: lesions determined by chest
radiography
Exposure Assessment: subjects grouped into
4 categories according to exposure to
different chromium compounds; personal
Reported Endpoint: lung: nonneoplastic lesions
Exp. Group
reference Cr VI exposed
Parameter (n = 95) (n = 109) p-value
bilateral pleural 0 4.6 NS
plaques (% of total)
changes in visceral 1.1 0.9 NS
pleura (% of total)
small opacities (% of 12.8 12 NS
total)
unilateral pleural 3.2 4.6 NS
plaques (% of total)
Stat Method: chi-square test
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
and stationary air samples collected during
1987 exposure study; Cr VI at low
concentrations throughout the steel
smelting shop; it exceeded the detection
limit in only some personal samples;
generally below detection in the cold rolling
mill
mean Cr VI concentration in urine for 44
workers: 0.03 nmol/L (1993) and 0.04
Hmol/L (1987)
Results by Endpoint
Nasal cavity: gross pathology
Huvinen et al. (2002a) (Finland)
cross-sectional study
Population: Exposed: male stainless steel
production workers (n = 29); never smokers
with a minimum of 14 years employment in
the same department
Referent: compared with workers from the
cold rolling mill (n = 39) whose exposure to
chromium or dust in general was extremely
low (total dust content = 0.3-0.5 mg/m3)
Outcome: questionnaire for nasal
symptoms; physical exam including anterior
rhinoscopy and rigid nasoendoscopy
Exposure Assessment: subjects divided into
4 groups based on type of chromium
exposure; Cr VI group comprised 29 workers
from the steel melting shop (median Cr VI air
concentration = 0.5 ng/m3)
Reported Endpoint: nasal epithelium
Exp. Group
referent steel melting shop
Parameter [RR (95% Cl)l (n = 39
atrophic nasal epithelium 1
infected nasal epithelium 1
livid/endemic nasal epithelium 1
total atypical nasal epithelium 1
Stat Method: likelihood-based risk ratio
[ (n = 29)
2.7 (0.36-20.2)
1.5 (0.64-3.7)
3.7 (1.3-10.6)
2.4(1.4-4.1)
Nasal cavity: nonneoplastic lesions
Lindbergand Hedenstierna (1983) (Sweden)
cross-sectional study
Population: Exposed: male and female
employees in chrome plating industry (n =
104); employed in the chrome plating
industry at 1 of 13 companies; working on
the day of study; 40 nonsmokers and 64
smokers
Referent: male auto mechanics (excluding
painters or welders) (n = 119) and office
employees (n = 19) used as reference group
for lung function and nose and throat
measurements, respectively (n = 138) ; 52
nonsmokers and 67 smokers
Outcome: visual inspections conducted prior
to interviews
Reported Endpoint: atrophy
8-hr mean air concentration Cr VI u.g/m3
Exp. Group n
<= 1.9 19
2-20 24
highest air concentration Cr VI u.g/m3
Exp. Group n
0.2-1.2 10
2.5-11 12
20-46 14
cases p-value
4 NR
8 <0.05
cases p-value
1 n/a
8 NR
0 NR
Reported Endpoint: perforation only
8-hr mean air concentration Cr VI u.g/m3
Exp. Group n
<= 1.9 19
cases p-value
0 NR
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Exposure Assessment: personal air samples
for 84 participants on 13 different days,
personal air samples for 11 participants over
a week, and 5 stationary air samples over 19
days; median exposure time was 4.5 years
low exposure: <2 u.g Cr Vl/m3
mixed exposure: <2 u.g Cr Vl+/rn3 and other
acids and metallic salts
high exposure: >2 ng Cr Vl/m3
2-20 24 3
highest air concentration Cr VI ng/m3
Exp. Group n cases
0.2-1.2 10 0
2.5-11 12 0
20-46 14 3
Reported Endpoint: subjective irritation
8-hr mean air concentration
Exp. Group
<= 1.9
2-20
n
19
24
highest air concentration Cr VI ng/m3
Exp. Group n
0.2-1.2 10
2.5-11 12
20-46 14
cases
4
11
cases
0
8
4
Reported Endpoint: ulceration
8-hr mean air concentration
Exp. Group n
<= 1.9 19
2-20 24
highest air concentration Cr VI ng/m3
Exp. Group ri
0.2-1.2 10
2.5-11 12
20-46 14
cases
0
8
NR
cases p-value
0 n/a
0 NR
7 NR
Stat Method: chi-square test with Yate's correction. Number of
ulceration cases at the highest exposure value compared with
controls was not discussed separately from the data reported as 8-
hr mean value of exposure.
Lin et al. (1994) (Taiwan, Province of China)
cross-sectional study
Population: Exposed: male and female
chromium electroplating workers from 7
chromium electroplating factories (n = 79;
aged 15-64 years old)
Referent: compared with male and female
workers from 3 aluminum electroplating
factories (n = 40; aged 14-65 years old)
Outcome: condition based on
otolaryngologist exam
Exposure Assessment: based on job
Reported Endpoint: nasal septum abnormality
Exp. Group
Cr office
workers Cr other
Parameter
nasal
septum
perforation
nasal
septum scar
formation
p-value
for trend
10
<0.001
0.043
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
category; air and urine samples analyzed for
Cr
geometric mean air concentrations:
Al electroplating factory workers (n = 15):
0.1 ng/m3
Cr electroplating office, outdoor workers (n
= 14): 2.4 u.g/m3
Cr electroplating workers in other process
fields (n = 25): 11.2 u.g/m3
Cr electroplating workers near electroplating
tanks (n = 23): 89.7 u.g/m3
mean +/- SD urine levels:
Al electroplating factory workers (n = 40):
0.13 +/- 0.09 u.g/g creatinine
Cr electroplating office, outdoor workers (n
= 19): 1.9 +/-1-7 u.g/g creatinine
Cr electroplating workers in other process
fields (n = 29): 3.5 +/-1.6 u.g/g creatinine
Cr electroplating workers near electroplating
tanks (n = 30): 11.9 +/- 8.7 u.g/g creatinine
0
16
48
nasal
septum
ulcer
Stat Method: Mantel extension test for trend
68
<0.001
Kitamuraetal. (2003) (Korea)
cross-sectional study
Population: Exposed: male chromium
plating workers aged 19-53 years old (n =
27) with signs and symptoms of olfactory
irritation, but without nasal septum
perforation or ulcer
Referent: compared with healthy male clerks
working at the same factory (n = 34)
Outcome: rhinoscopy examination by
otolaryngologist
Exposure Assessment: based on job title;
blood and urine Cr levels measured
plating workers blood Cr: 1.29 (0.16-3.69)
Hg/dL; urinary Cr: 2.88 (0.01-8.37) ng/g
creatinine
referent blood Cr: 0.55 (0.04-1.95) ng/dL;
urinary Cr: 2.26 (0.01-10.18) ng/g creatinine
air concentrations in plating factories
Cr VI: 0.013, 0.033, 0.0054, and 0.0047
mg/m3
Cr III: 0.059, 0.021, 0.0063, and 0.0047
mg/m3
Reported Endpoint: inflammation of nasal mucosa
Exp. Group
Cr plating
reference workers
Parameter (%)
inflammation of nasal
mucosa
obstruction or adhesion of
the olfactory cleft
Stat Method: chi-squared test
46
<0.01
Kuo et al. (1997) (Taiwan)
Reported Endpoint: nasal obstruction
Exp. Group
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
cross-sectional study
Population: Exposed: male and female
Taiwanese chromium electroplating factory
workers from 9 factories (n = 155); workers
were from 3 factories that used chromium
(mean age 36.3 years old), 6 that used
nickel-chromium (mean age 39.6 years old)
Referent: compared with workers from 2
zinc electroplating factory workers (n = 34;
mean age 36.9 years old)
Outcome: condition based on
otolaryngologist exam
Exposure Assessment: end of shift urine
samples; average urinary chromium
concentrations (ng/g creatinine): 3.7 (zinc
workers), 7.3 (nickel-chromium workers),
and 41 (chromium workers)
zinc workers 34 0
nickel-chromium workers 129 17.8 0.01
chromium workers 26 15.4 0.01
Reported Endpoint: nasal septum perforation
Exp. Group r\
zinc workers 34
nickel-chromium workers 129
chromium workers 26
Reported Endpoint: nasal septum ulcer
Exp. Group ri
zinc workers 34
nickel-chromium workers 129
chromium workers 26
Reported Endpoint: paranasal sinusitis
Exp. Group r\
zinc workers 34
nickel-chromium workers 129
chromium workers 26
Stat Method: chi-squared test or analysis of variance; Mantel
extension test for trend
Rovle (1975) (United Kingdom)
cross-sectional study
Population: Exposed: male and female
chromium platers (n = 997; mean age 42.9);
exposed to chromic acid >=3 months;
employed at 1 of 54 plating plants whose
principal industry was chromium plating
Referent: compared with male and female
manual workers in the same area (n = 1117;
mean age 43.6)
Outcome: self-reported (questionnaire)
Exposure Assessment: questionnaire used to
record number of years a worker was
exposed to chromic acid during chromium
plating; air and dust analyses recorded in 42
of 54 plants (1969-1970); Cr air levels
generally <0.03 mg/m3; dust levels generally
between 0.3 and 97.0 mg/g
Reported Endpoint: nasal effects
years CrO3 exposure
Parameter (%)
nasal ulcers
nose bleeding
nasal perforations
Exp. Group
<1 1J5
(n = 234) (n = 394)
13.1
19
6
14.5
0.5
3.6
>5
(n = 369)
16.8
16
8.7
p-value for
trend
0.001
NS
0.001
Stat Method: not reported
PHS (1953) (United States)
cohort (retrospective) study
Population: Exposed: male workers in 6
plants directly involved in the manufacture
of chromates and bichromates from
Reported Endpoint: perforation of nasal septum
time worked in industry
Exp. Group
<6 months
6 months-3 years
n
41
117
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
chromite ore (n = 897)
Referent: none
Outcome: information obtained from
medical records
Exposure Assessment: exposure based on
time worked in industry
Gibb et al. (2000b) (United States)
cohort (retrospective) study
Population: Exposed: male workers in a
chromate production plant in Baltimore, MD
(n = 2307); first employed between August
1, 1950 and December 31, 1974
Referent: none
Outcome: physician findings reported in
clinic and first records
Exposure Assessment: airborne Cr VI
measurements taken 1950-1985 based on
job title to provide worker exposure
estimates; short-term airborne dust samples
collected in workers' breathing zones 1950-
1964; mid-1960s-1985, 24-hour
measurements from fixed-site monitors and
observations of time spent near each
monitor used; 1977-1985, full-shift personal
samples collected based on job title; plant
closed 1985
Length of Follow-Up: 18 years
Cohen et al. (1974) (United States)
cross-sectional study
Population: Exposed: white male and female
electroplate workers aged 18-63 years old in
the nickel-chrome department (n = 37)
Referent: compared with randomly-chosen
workers employed in other areas of the
plant not significantly exposed to chromic
acid (n = 15)
Outcome: self-reported (questionnaire)
Exposure Assessment: air samples collected
from the breathing zones of several exposed
workers in the nickel-chrome department
and referents, mean Cr VI — 0.0029 (ND—
0.0091) and 0.0003 (0.0001-0.0004) in
nickel-chrome plating area and referent
areas, respectively
Results by Endpoint
3- 10 years 370
>10 years 369
Stat Method: not reported
55.4
69.6
Reported Endpoint: ulcerated nasal septum
ambient airborne chromium
Parameter cases adiRR
0.1 mgCrO3/m3 increase 1451 1.2
p-value
0.0001
Authors stated that ambient airborne hexavalent chromium
exposure was significantly associated with occurrence of ulcerated
nasal septum.
Stat Method: Cox proportional hazards model adjusted
year at hire and age at hire
for calendar
Reported Endpoint: nasal ulceration
non-exposed
Parameter (%) (n = 15)
nasal mucosa (grade 0) 93
shallow erosion of septal mucosa 0
(grade 1)
ulceration and crusting of septal 0
mucosa (grade 2)
avascular, scarified areas of septal 0
mucosa without erosion or ulceration
(grade 3)
perforation of septal mucosa (grade 7
4)
exposed
(n = 37)
5
22
32
30
11
Stat Method: Fisher's exact test (results not provided)
1
2
cases = number of cases calculated from information provided by study authors
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 f difference in percent of respiratory symptoms between referents and Cr VI exposed subjects
2 adjRR: adjusted relative risk; NS: not significant; NR: not reported; n/a: not applicable; SD: standard deviation; RR:
3 relative risk; 95% Cl: 95% confidence interval
4
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.9. Lung Cancer
2
3
Table 2-8. Evidence pertaining to lung cancer following inhalation exposure to
hexavalent chromium
Reference and Study Design
Results by Endpoint
Studies of Baltimore chromate production plant (after improvements to production facilities)
Gibb et al. (2000a) (United States)
cohort study
Population: Exposed: male chromate production
workers in Baltimore, MD (n = 2357); first
employed between August 1,1950, and December
31,1974, after improvements made to chromium
production processes. Mean duration 3.1 years;
median 5 months.
Referent: external analysis (compared with
Maryland state rates); internal analysis across
exposure levels
Outcome: National Death Index (1979-1992);
Social Security data 1977-1978; information
through 1977 obtained from Hayes et al. (1979);
cause on death certificate based on ICD8
Exposure Assessment: Cumulative exposure using
job exposure matrix developed based on work
histories and approximately 70,000 routinely
collected exposure measurements taken
beginning in 1950; measurement protocols
changed overtime: short term (10-20 minutes)
breathing zone samples used high volume air
sampling pump and impinger from 1950 to 1961;
fixed site samples (24 1-hour samples per day)
from 154 areas and estimation of time spent in
specific areas used beginning in the 1960s;
reduced to 27 areas and 8 3-hour samples in 1979;
full-shift personal samples beginning in 1977; dust
samples collected about 3 years after plant closed
at or near 26 of the 27 fixed sites; air analyzed for
trivalent/hexavalent ratio.
Also includes information on smoking status at
beginning of employment for 93% of cohort.
Five-year lag used for all models.
Mean Length of Follow-Up: 30 years
Related studies: earlier analyses of related
cohorts: Hayes etal. (1979) and Braver et al.
(1985); subsequent analyses of exposure-
response: OSHA (2006); Park and Stayner (2006);
and Park etal. (2004).
Reported Endpoint: lung cancer mortality; ICD8
cumulative Cr exposure (mg CrOjm -yrs)
Exp. Group cases RR
each 10-fold 122 1.38
increase
p-value
0.0001
Stat Method: Cox proportional hazard models using age as the
time variable and adjusting for smoking status.
cumulative Cr exposure quartiles (mg CrOjm -yrs)
Exp. Group
0-0.00149
0.0015-0.0089
0.009-0.0769
0.077-5.25
cases
26
28
30
38
RR
1
1.83
2.48
3.32
Stat Method: Cox proportional hazard models using age as the
time variable, median value in each exposure quartile, and
adjusting for smoking status.
Additional analyses indicated associations with hexavalent
chromium (RR 1.55 per 10-fold increase) but not with trivalent
chromium (RR0.17 per 10-fold increase).
OSHA (2006) includes additional modeling of these data using:
different numbers of exposure categories (e.g., 5, 6,10);
Baltimore city rather than Maryland state reference rates;
different lag periods; estimates of cumulative smoking (pack-
years).
Park and Stayner (2006) examined evidence of non-linearity
using these data: the potential value of two-stage modeling
was evaluated and found to provide little improvement in
model fit; additional modeling of departure from linearity
using a one-stage model and second-degree fractional
polynomials; and other measures to examine intensity
thresholds and effects of different assumptions regarding
exposure half-life.
Park et al. (2004) used these data to estimate excess lifetime
risk of lung cancer. At the (then) OSHA permissible exposure
limit (PEL) of 0.10 mg/m3, the excess lifetime risk was 255 (95%
Cl 109-416) per 1,000.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Studies of Ohio chromate production plant
Proctor et al. (2004) (United States)
cohort study
Population: Exposed: male chromate production
workers in Painesville, OH, who worked at least 12
months beginning in January 1940 or later (n =
482); mean duration not reported; 45% <5 years in
exposed job
Referent: external analysis (compared with Ohio
state rates); internal analysis across exposure
levels
Outcome: National Death Index; cause on death
certificate based on ICD9 code 162
Exposure Assessment: Cumulative exposure and
highest average monthly exposure using job
exposure matrix developed based on work
histories and approximately 800 area air samples
collected from 23 surveys conducted in 1943-
1981.
Also includes information on smoking status at
beginning of employment for 35% of cohort
Five-year lag used for all models.
Mean Length of Follow-Up: 30 years
Related studies: Proctor et al. (2003) (additional
exposure assessment details); Crump et al.
(2003); Luippold et al. (2003); Mancuso (1997,
1975) (previous studies of an earlier cohort:
workers hired 1931-1937, with exposure based on
1949 industrial hygiene survey)
Reported Endpoint: lung cancer mortality; ICD9 (162)
cumulative hexavalent chromium exposure (mg/m - yrs)
Exp. Group
0-0.19
0.2-0.48
0.49-1.04
1.05-2.69
2.7-23
cases
3
8
4
16
20
SMR
0.67
1.8
0.91
3.7
4.6
Stat Method: SMRs using state referent rates
highest monthly hexavalent chromium exposure (mg/m )
Exp. Group cases SMR
<0.052 4 1
0.053-0.16 4 1.7
0.209-0.212 9 1.9
0.27-0.42 5 1.9
0.47-0.57 20 2.9
0.58-4.1 9 6.9
Stat Method: SMRs using state referent rates
Crump et al. (2003) includes additional modeling of these data
(e.g., using relative risk and additive risk models with
additional exposure categories for cumulative exposure).
Studies of modern production facilities
Birket al. (2006) (Germany)
cohort study
Population: Exposed: male chromate prodcution
workers from two plants; worked at least 12
months after each plant converted to a no-lime
process (n = 901); Leverkusen n = 593, began work
in 1958 or later, mean duration 9 yrs; Uerdingen (n
= 308, began work in 1964 or later, mean duration
11 years
Referent: external analysis (compared with
regional rates); also included analysis by exposure
level
Outcome: cause on death certificate based on
ICD9
Exposure Assessment: Cumulative exposure using
job exposure matrix developed based on work
Reported Endpoint: lung cancer mortality; ICD9 (162)
Exp. Group n SMR 95% Cl
chromate workers 22 1.48 0.93-2.25
Stat Method: SMR calculated using German national rates
cumulative Cr in urine (ng/L-yr)
Exp. Group
>200
>200 (adjusting for
peak exposure)
Peak exposure (one or
more measure >40
Hg/L, adjusting for
cumulative exposure)
8
8
NR
OR
6.9
3.7
3.4
95% Cl
2.6-18.2
1.2-11.2
0.9-12.1
Authors state risk unchanged after controlling for smoking.
Stat Method: logistic regression
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
histories and urinary Cr measurements (most
collected from routine medical examinations; (n =
7000 from 1958-1998 in Leverkusen and n = 5400
from 1964-1995 in Uerdingen). Personal air sam
pies (n =252 from 1985-1998 in Leverkusen and n
=215 from 1986-1994 in Uerdingen) and area air
samples (n = 3422 from 1973-1998) in Leverkusen
and n= 1161 from 1978-1995 in Uerdingen) were
avaiable for part of the study period.
cumulative Cr in urine (ug/L-yr) 10-year lag
Exposure mean: varied overtime (general decline
from 1960s through 1990s). Mean concentration
in air: 8.83 and 8.04 ng Cr/m3 in Leverkusen and
Uerdingen, respectively. Range of concentration
in urine: from 15-50 ng/L up to 1970 to 1-<10
Hg/L in 1987-1998 in Leverkusen; from 5-30 ng/L
up to 1970 to 1-<10 ng/L in 1987-1996 in
Uerdingen.
Mean Length of Follow-Up: 16 years for
Leverkusen plant; 19 years for Uerdingen plant
Smoking data available for more than 90% of
cohort
Related studies: Korallus et al. (1993) (earlier study
of both plants); Industrial Health Foundation
(2002) [see table entry below; this report provides
more extensive details regarding the study
population, exposure measures, and analysis than
found in Birketal. (2006)1
Exp. Group
0-39.9
40-99.9
100-199.9
>200
SMR
0.93
0.78
1.31
2.05
95% Cl
0.34-2.01
0.16-2.28
0.43-3.07
0.88-4.04
Similar results seen with 0- and 10-year lags.
Stat Method: SMRs calculated using North Rhine-Westphalia
referent population rates
Luippold et al. (2005) (United States)
cohort study
Population: Exposed: male and female chromate
production workers from two plants (n = 617),
worked at least 12 months: Castle Hayne, NC (n =
430, began work 1971 or later, mean duration 12
years) and Corpus Christi, TX (n = 187, began work
1980 or later, mean duration 8 years)
Referent: external analysis (compared with state
rates)
Outcome: cause on death certificates (pre-1979)
and in National Death Index-Plus (post-1979)
based on ICD9 code 162
Exposure Assessment: Cumulative exposure using
job exposure matrix developed based on work
histories and personal air-monitoring
measurements (n = 5461 from 1974-1992 and
1995-1998 in the North Carolina plant; n = 1249
from 1980-1982,1986-1988, and 1990-1998 in
the Texas plant). Additional area samples available
for other years in the study period.
Reported Endpoint: lung cancer mortality; ICD9 (162)
occupation
Exp. Group cases SMR
chromate workers 3 0.84
Stat Method: SMRs using state referent rates
95% Cl
0.17-2.44
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
exposure range: 0.36-4.36 ng/m
Mean Length of Follow-Up: 20 years for North
Carolina plant; 10 years for Texas plant
Smoking data available for 89% of cohort
Related studies: Pastides et al. (1994) (North
Carolina plant; earlier -10 year mean follow-up);
Industrial Health Foundation (2002) [see table
entry below; this report provides more extensive
details regarding the study population, exposure
measures, and analysis than found in Luippold et
al. (2005)1
Industrial Health Foundation (2002) (United
States; Germany)
cohort study
[This is the original analysis of the 4 plants that
were subsequently published as separate papers
by Birk et al. (2006) and Luippold etal. (2005) for
two plants in Germany and two plants in the
United States, respectively. Details from this
report pertaining to the cohorts, exposure
measures, and analysis are provided in the table
entries above for Birk et al. (2006) and Luippold et
al. (200511
Population: Exposed: chromate production
workers in four plants (two in Germany, n = 901
and two in United States (n = 617) (total n = 1518);
worked 1 year or more in plants using low- or no-
lime chromium production processes
Referent: external analysis (compared German
national rates and U.S. state rates); internal
analysis across exposure levels
Outcome: cause on death certificate (ICD not
reported)
Exposure Assessment: Cumulative and peak
exposure measures developed based on work
histories and job exposure matrix based on urinary
Cr measures (German plants) and personal air
monitoring levels (U.S. plants); for internal analysis
combining all plants, air exposure levels for the
U.S. plants were converted to urinary exposure
levels using a published conversion factor (0.77);
this value was somewhat smaller than the
conversion factor derived from limited parallel
data from the German plants (0.85 for Leverkusen
plant and 0.92 for Uerdingen)
Mean Length of Follow-Up: 16 years for
Leverkusen plant; 19 years for Uerdingen plant; 20
Reported Endpoint: lung cancer mortality; ICD9 (162)
cumulative Cr exposure (ug/L-yr)
Exp. Group cases SMR 95% Cl
<40 9 0.89 0.41-1.7
40-99.9 3 0.78 0.16-2.3
100-<200 5 1.31 0.43-3.1
>200 8 2.05 0.88-4.0
Stat Method: SMRs calculated using North Rhine-Westphalia
and state referent population rates
Exp. Group
<40
40-<200
>200
cases
3
9
9
95% Cl
(referent)
0.6-6.9
2.4-27.1
Stat Method: logistic regression; adjusted for smoking and
limited to age at first exposure >35 yrs (only 1 death among
those exposed before age 35)
Exp. Group adjOR 95% Cl
High cumulative 3.8 1.2-11.5
(>200 ng/L-yrs)
Ever peak (>40 ng/L) 3.1 0.9-11.3
Stat Method: logistic regression; adjusted for smoking and
limited to German cohort (22 of the 25 deaths occurred in
Germany; Germany had higher cumulative exposures; and
individual data allowed assessment of "peak" exposure)
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
years for North Carolina plant; 10 years for Texas
plant
Smoking data available for 93% of German
workers and 89% of U.S. workers
Davies et al. (1991) (United Kingdom)
cohort study
Population: Exposed: male chromate production
workers at three facilities, two of which
implemented process and hygiene improvements
at factories (allowing comparison of "prechange"
and "postchange" workers) (n = 2607); worked at
least Ifull year with some of the work occurring
between January 1,1950, and June 30,1976
Referent: local and national death rates adjusted
for social class and area differences
Outcome: cause on death certificate based on
ICD9 codes 162 and 239.1
Exposure Assessment: based on job history,
duration of service, start of employment, and
implementation of process and hygiene
improvements that started in 1955; no exposure
estimates provided
Mean Length of Follow-Up: not reported
Reported Endpoint: lung cancer mortality; ICD9 (162 and
239.1)
Exp. Group
Rutherglen prechange
(starting dates 1945-
1958)
Rutherglen postchange
(starting dates 1959-
1966)
Eaglescliffe prechange
(starting dates 1945-
1960)
Eaglescliffe
postchange (starting
dates 1961-1976)
cases
41
52
SMR
1.60
0.97
1.95
1.09
<0.001
NS
<0.001
NS
Stat Method: SMRs using area mortality data, adjusted for
class and area; Poisson distribution used to test statistical
significance (results also provided using national rates, but
with little difference)
Authors noted several cases of lung cancer among postchange
workers at young ages (<50 years) and seven additional lung
cancers among postchange workers in Eaglescliffe identified
after the end of the follow-up period (Dec 1, 1988).
Studies of stainless steel welders
Gerin et al. (1993) (9 European countries)
cohort study
Population: Exposed: male stainless steel workers
in IARC multicenter historical cohort study from
135 companies in 9 European countries (n =
11,092)
Referent: compared with expected deaths
Outcome: method not reported
Exposure Assessment: Cumulative dose estimated
based on each subject's exposure history
constructed including dates of starting and
stopping employment; the base metal welded and
the welding process; changes in exposure over
time; and information on the history of the
welding practice over time by company (based on
average concentrations of welding fumes for each
Reported Endpoint: lung cancer mortality
cumulative hexavalent Cr exposure in ever stainless steel
welders (mg-years/m3)
Exp. Group
<0.05
0.05-0.5
0.5-1.5
1.5+
cases
0
7
9
5
SMR
0
1.30
1.93
1.41
95% Cl
0-12.7
0.52-2.68
0.88-3.66
0.46-3.29
Stat Method: SMRs using expected relative risks
cumulative hexavalent Cr exposure in predominantly stainless
steel welders (mg-years/m3)
Exp. Group cases SMR 95% Cl
<0.05 0 0 0-28.4
0.05-0.5 3 2.08 0.43-6.09
0.5-1.5 4 2.00 0.55-5.12
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
welding situation)
Results by Endpoint
1.5+ 5 1.48
Stat Method: SMRs using expected relative risks
0.48-3.45
1
2
3
4
adjOR: adjusted odds ratio; NR: not reported; NS: not significant; n/a: not applicable; SMR: standard mortality rate;
RR: relative risk; 95% Cl: 95% confidence interval
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 2.10. Cancers Associated with Oral Exposure
2
3
Table 2-9. Evidence pertaining to cancer following oral exposure to
hexavalent chromium
Reference and Study Design
Stomach: neoplastic lesions
Several papers based on mortality data for a
population in northeastern China
Zhang and Li (1997)a; (1987)
Beaumont et al. (2008)
Koraor at 3! l">nOCt\
ecological studies
Population' Exposed1 males and females from 5
agricultural villages 1-5 miles east of
ferrochromium alloy plant near JinZhou city in the
LiaoNing Province. Groundwater contaminated by
Cr VI up to 20 mg/L (n ~ 10,000) between 1960 and
1978; reporting of a yellowing of the water by local
residents in 1964 is what led to the investigation
and identification of this contamination by the local
health department.
Referent: Original study by Zhang and Li (1987) and
Beaumont et al. (2008) : comparison was area
including the industrial town of TangHeZi and 3
agricultural villages near TangHeZi with no
groundwater hexavalent chromium pollution.
Kerger et al. (2009) presented results using
TangHeZi only, and using the other villages
excluding TangHeZi from the referent group.
Outcome: cause on death records
Exposure Assessment: comprehensive well survey
(21-170 wells per village tested) in 1965; periodic
testing through 1979
a Zhang and Li (1997) was retracted in 2006 by
Journal of Occupational and Environmental
Medicine because "financial and intellectual input
to the paper by outside parties was not disclosed"
(Brandt-Rauf, 2006).
Linos et al. (2011) (Greece)
ecological study
Population' Exposed1 male and female adult
residents of industrial area of Greece (Oinofita
region) who were registered as permanent
residents of Oinofita in the municipality records (n
= 5842); legally registered citizens of the
municipality at any time during the follow-up
period (1/1/1999-31/12/2009)
Results by Endpoint
Reported Endpoint: stomach cancer deaths
Reference and Comparison Group RR 95% Cl
Beaumont etal. (2008) (four 1.82 1.11-2.91
areas)
Roaiimnnt ot al OflflR^ l\ ianNina 1 fiQ 1 19 9 AA
Province)
Kerger et al. (2009) (agricultural 1.22 0.74-2.01
villages, excludes TangHeZi)
Kerger et al. (2009) (TangHeZi, 2.07 1.25-3.44
excludes agricultural villages)
[Other differences in the analytic approach and results
among these studies will be presented in greater detail in the
draft Toxicological Review.]
Reported Endpoint: stomach cancer deaths; ICD9 (151)
Exp. Group cases SMR 95% Cl p-
value
total 6 1.21 0.44-2.63 0.755
male 4 1.16 0.32-2.96 0.909
female 2 1.33 0.16-4.81 0.886
Stat Method: SMRs using Voiotia mortality statistics
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
Referent: compared with mortality statistics of the
entire Voiotia prefecture (similar geographical,
population density, socioeconomic, and ethnic
origin characteristics)
Outcome: cause on death certificate based on ICD9
code 151
Exposure Assessment: measurements of Cr VI in
groundwater from Oinofita municipality
November 2007-February 2008: levels above 10
in 35 out of 87 samples with maximum of 156
September 2008-December 2008: 41-53 ng/L in 3
samples of public drinking water
July 2007-July 2010: 13 measurements above 10
Hg/Lwith maximum of 51 ng/L
(other potential contaminants not measured)
Oral, liver, and other Gl tract and urinary tract cancers
Linos et al. (2011) (Greece)
ecological study
Population: Exposed: male and female adult
residents of industrial area of Greece (Oinofita
region) who were registered as permanent
residents of Oinofita in the municipality records (n
= 5842); legally registered citizens of the
municipality at any time during the follow-up
period (1/1/1999-31/12/2009)
Referent: compared with mortality statistics of the
entire Voiotia prefecture (similar geographical,
population density, socioeconomic, and ethnic
origin characteristics)
Outcome: cause on death certificate based on ICD9
code 151
Exposure Assessment: measurements of Cr VI in
groundwater from Oinofita municipality
November 2007-February 2008: levels above 10
in 35 out of 87 samples with maximum of 156
September 2008-December 2008: 41-53 ng/L in 3
samples of public drinking water
July 2007-July 2010: 13 measurements above 10
Hg/Lwith maximum of 51 ng/L
(other potential contaminants not measured)
Reported Endpoint: lip, oral cavity and pharynx cancer
deaths; ICD9 (140-149)
Exp. Group cases SMR 95% Cl
total 3 3.44 0.71-10.1
male 3 4.69 0.97-13.7
female 0 n/a n/a
Reported Endpoint: colon cancer deaths; ICD9 (153)
Exp. Group cases
total 6
male 1
female 5
SMR 95% Cl p-value
0.84 0.31-1.82 0.844
0.28 0.01-1.54 0.249
1.40 0.45-3.26 0.578
Reported Endpoint: liver primary cancer deaths; ICD9 (155.0)
Exp. Group cases
total 6
male 4
female 2
SMR 95% Cl p-value
11.0 4.05-24.0 <0.001
8.12 2.21-20.8 0.003
39.5 4.79-143 0.002
Reported Endpoint: pancreas cancer deaths; ICD9 (157)
Exp. Group Exp.
Group
total 6
male 4
female 2
Exp. Group
0.85
0.88
0.80
Exp. Group Exp.
Group
0.31-1.85 0.882
0.24-2.25 1.000
0.10-2.88 1.000
Reported Endpoint: bladder cancer deaths; ICD9 (188)
Exp. Group cases SMR
total 3 0.82
male 2 0.65
95% Cl p-value
0.17-2.40 1.000
0.08-2.36 0.821
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference and Study Design
Results by Endpoint
female 1 1.68 0.04-9.38
Reported Endpoint: kidney and other genitourinary
deaths; ICD9 (184, 187, 189)
Exp. Group cases SMR 95% Cl
total 6 2.04 0.75-4.43
male 1 0.63 0.02-3.51
female 5 3.68 1.19-8.58
Stat Method: SMRs using Voiotia mortality statistics
0.896
organ
p-value
0.158
1.000
0.025
1
2
3
4
5
adjBeta: adjusted Beta; n/a: not applicable; SMR: standard mortality rate; RR: relative risk; 95% Cl: 95% confidence
interval
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
2 3.PRELIMINARY TOXICOKINETIC STUDY
3 INFORMATION
4 Studies relevant to the absorption, distribution, metabolism, or excretion (ADME) of
5 hexavalent chromium identified through the literature search for this chemical are summarized in
6 Tables 3-1 to 3-5. These tables summarize key study design features; they do not include an
7 extraction of detailed study information or results, and as such, do not represent evidence tables.
8 The purpose of these tabulations is to elicit early discussions with stakeholders and the public on
9 potential issues related to these studies, and to provide an opportunity for identifying other
10 relevant studies not captured in the literature search.
11 Table 3-1 presents a summary of studies that contain primary in vivo toxicokinetic data in
12 rats, mice, and humans following hexavalent chromium exposure. These tables indicate whether
13 studies contained concurrent data for trivalent chromium exposure, as these data are informative
14 in directly assessing differences between hexavalent and trivalent chromium kinetics. Table 3-1
15 also indicates whether a study has been used quantitatively or qualitatively in the development of
16 physiologically-based pharmacokinetic (PBPK) models.
17 Table 3-2 presents a summary of studies that contain in vitro or ex vivo data related to
18 absorption and/or reduction in the GI tract or blood. These studies primarily focus on quantitative
19 analysis of kinetics.
20 Table 3-3 presents a summary of studies related to the distribution and reduction of
21 hexavalent chromium in a variety of systems. These studies differ from those in Table 3-2 in that
22 the experiments primarily focused on mechanisms by modifying the enzymes or transport carriers
23 in the systems tested. Tables 3-1 to 3-3 include only those studies pertaining primarily to
24 hexavalent chromium toxicokinetics, and do not include studies that primarily address hexavalent
25 chromium toxicity.
26 Table 3-4 presents a summary of studies related to human biomonitoring of hexavalent
27 chromium in industrial or volunteer populations that focus primarily on data on biomarkers of
28 exposure as opposed to human health effects.
29 Table 3-5 identifies papers that present PBPK models for hexavalent chromium. Figure 3-1
30 illustrates how toxicokinetic data from multiple sources are utilized in PBPK models, and how these
31 models may be applied in dose-response assessment.
32
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
2
Table 3-1. Preliminary categorization of in vivo hexavalent chromium
toxicokinetic studies
Reference
Species
Tissue matrices and notes
Crlll
control3
PBPK
useb
Intravenous (IV) injection
Cavallerietal. (1985)
Cikrtand Bencko (1979)
Danielsson et al.
(1982)
Liu etal. (1994)
Liu etal. (1996)
Norseth etal. (1982)
Merrittetal. (1989)
Richelmi etal. (1984)
Rat
Rat
Mouse
Mouse
Rat
Hamster
Rat
Bile, whole blood, and plasma. 2 hour time course data.
Total body burden, urine, feces, liver, kidneys, plasma, and Gl
tract wall. 24 hour time course data.
Fetus, placenta, liver, kidney, serum. Injection to pregnant
mice at day 13 or 16 of gestation. Spot sample 1 hour after
injection.
Blood, liver, heart, spleen, kidney, and lung. Kinetics of
pentavalent chromium (Cr V) following Cr VI reduction. 60
minute time course data.
Bile and liver. 2 hour time course data.
Urine, plasma, RBC, kidney, spleen, liver, and lung. Monthly
or weekly injections. 5 week post exposure time course data
Blood. In vivo Cr VI measurement of reduction and capacity.
Spot sample at 1 minute post exposure.
N
Y
Y
N
Y
N
N
Y
Y
N
N
N
N
Y
Intraperitoneal (IP) injection
Afolaranmi and Grant
(2013)
Balakin etal. (1981)
Brvson and Goodall
(1983)
Bulikowski et al. (1999)
Doker etal. (2010)
Manzo etal. (1983)
Ogawaetal. (1976)
Sankaramanivel et al.
(2006)
Rat
Rat
Mouse
Rat
Mouse
Rat
Mouse
Rat
Liver, kidney, heart, brain, lung, spleen, testes, blood, urine,
and feces. Effect of ascorbic acid. Spot sample 24 hours post
exposure.
Liver, whole body (excluding liver), wall of cecum, chime of
cecum, urine, and feces. Spot sample 30 minutes post
exposure. This is a chelation study that included a Cr Vl-only
group.
Total body burden, urine, and feces. 21-day time course
data.
Skin. Injections over 30 days. Micronutrient interaction
study with Cr Vl-only groups.
Liver, kidney, brain, lung, heart, and testis. Effect on other
essential metals analyzed. Spot sample at 12 hours post
exposure.
Bile, plasma, liver, urine, feces, stomach, small intestine, and
large intestine. Detection in Gl tissues post exposure. 2 hour
time course data.
Urine, feces, whole body. Spot sample data at 48 hours post
exposure.
Bone (vertebrae, femur, and calvaria). IP injections once per
day for 5 days.
N
Y
Y
N
N
Y
Y
N
N
N
N
N
N
Y
N
N
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference
Suzuki (1988b)
Uenoetal. (1995)
Species
Rat
Mouse
Tissue matrices and notes
Plasma, whole blood. 60 minute time course data.
Liver. Total Cr and pentavalent (Cr V). 12-hour time course
data.
Crlll
control3
N
N
PBPK
useb
N
N
Subcutaneous injection
Pereiraetal. (1999)
Yamaguchietal. (1983)
Mouse
Rat
Liver, kidney, and spleen. Multiple injections (once per week
for varying number of weeks). Spot sample at 1 week after
last exposure.
Urine, feces, lung, liver, kidney, brain, heart, spleen, testis,
muscle, hair, blood. 30-day time course data.
N
Y
N
N
Oral
Collins etal. (2010)
(National Toxicology
Program studies)
Iranmanesh et al. (2013)
Finlev etal. (1997)
Kerger etal. (1997)
Kerger etal. (1996)
Paustenbach et al.
(1996)
Kirmanetal. (2012)
Saxenaetal. (1990)
Sutherland etal. (2000)
Thomann etal. (1994)
Rat,
Mouse
Rat
Human
Rat,
Mouse
Rat,
Mouse
Rat
Rat
Urine, feces, erythrocytes, plasma, liver, kidney, glandular
stomach, and forestomach (2-year study). Blood, kidney, and
femur (21-day study only). No mouse urinary data for chronic
Cr III study. Chronic Cr Ill/Cr VI data at multiple sacrifice
times (after 2-day washout period). Time course (2-day)
gavage data (urine/feces only) for Cr III only.
Liver, kidney, intestine, spleen, and testicle. Drinking water
exposure for 60 days. Spot sample after 7-day washout
period. This is a chelation study that included a Cr Vl-only
group.
Human toxicokinetic volunteer studies. Urine, plasma, and
RBC. Multiple exposure scenarios (i.e., single and repeated
doses). Time course data over multiple days before, during
and after exposure.
Oral cavity, stomach, duodenum, jejunum, ileum, plasma, red
blood cell (RBC), and liver. Spot sample at end of 90-day
exposure period.
Oral (drinking water) study in pregnant rodents. Maternal
blood, placenta, and fetus.
Bone, kidney, liver, and testes. Exposure for 44 weeks, with
spot samples 4-6 days post-exposure (no time course data).
Blood, liver, kidney, spleen, bone, and total carcass. 6 week
exposure followed by 140 days post exposure. Time course
data of pre and post exposure periods.
Y
N
Y
N
N
N
N
Y
N
Y
Y
N
N
Y
Intratracheal
Bragt and van Dura
(1983)
Rat
Urine, feces, blood, heart, lungs, spleen, kidneys, liver,
pancreas, testes, and bone marrow (femur).
50-day post exposure time course data for whole body
retention and blood. 10-day time course data for urine and
feces. Spot sample data for other tissues at 50 days post
exposure. 3 different Cr VI formulations.
N
Y
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference
Edel and Sabbioni (1985)
Perraultetal. (1995)
Gaoetal. (1993)
Vanoirbeek et al. (2003)
Wiegand etal. (1987)
Wiegandetal. (1984a)
Species
Rat
Sheep
Rat
Rat
Rabbit
Tissue matrices and notes
Lung, trachea, kidney, liver, spleen, pancreas, epididymus,
testes, brain, heart, thymus, femur, skin, fat, muscle,
stomach, small intestine, large intestine, blood, plasma, RBC,
lung lavage, urine, and feces. Spot sample in tissues at 24
hours post exposure. 7-day time course data of excretion.
Bronchoalveolar lavages (BAL), lung. Exposure and analysis
of particulate forms. 30-day time course data for BAL; spot
sample for lung at day 30.
Blood, plasma, urine, and lymphocytes. 72-hour time course
data.
Lung, liver, plasma, RBC, urine. Spot tissue samples at 2 and
7 days post exposure. 7-day time course data of urinary
excretion.
Blood, plasma, RBC, liver, kidneys, urine, lung, and trachea.
4-hour post exposure time course data.
Crlll
control3
Y
Y
Y
Y
Y
PBPK
useb
Y
N
N
N
N
Inhalation
Cohen etal. (1997)
Kalliomaki etal. (1983)
Kalliomaki etal. (1983)
Suzuki etal. (1984)
Rat
Rat
Rat
Lung (and lung fluids/subcompartments), liver, kidney, and
spleen. Exposure for 5 hours/day, 5 days a week. Spot
samples at 2 or 4 weeks (24 hours post exposure)
Blood, liver, kidneys, stomach, spleen and lung. Welding arc
fumes (with chromium concentration measurement).
Exposures vary in hours per day or number of days exposed.
Spot samples at 24 hours post exposure. 106-day time
course data for elimination study.
Lung, whole blood, plasma, RBC, kidney, spleen, heart, liver,
and testis. Aerosolized Cr III and Cr VI. Exposure for 2 or 6
hours. 7-day time course data.
N
N
Y
N
N
N
Multiple routes
Cooganetal. (1991)
Febel etal. (2001)
Kargacinetal. (1993)
Mutti etal. (1979)
Rat
Rat
Rat,
Mouse
Rat
RBC, WBC. Oral and IV injection. Spot samples at 1 hour, 24
hours, and 7 days post exposure.
Oral and intrajejunal injection. Urine, feces, jejunum, liver,
portae, hepatica, and cava caudalis. Spot sample data (at 60
minutes for intrajejunal injection, and 3 days for oral
exposure).
Oral and IP injection. Single and repeated exposures. Liver,
kidney, spleen, femur, lung, heart, muscle, and blood. Spot
sample data at 4 and 8 weeks for chronic drinking water, 4
and 14 days for repeated IP injections. Spot 24/72 hour data
for single IP exposures.
Subcutaneous injection, oral exposure. Urine, spleen, liver,
renal cortex, renal medulla, lung, and bone. 48 hour (single
exposure) and 12 week (repeated exposure) time course
N
Y
N
N
N
N
Y
Y
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference
Mivai (1980)
Mivaietal. (1980)
Savatoetal. (1980)
Susaetal. (1988)
Species
Rat,
Mouse
Rat
Mouse
Tissue matrices and notes
data.
Inhalation, intratracheal. Lung, plasma, RBC, spleen, kidney,
duodenum, testes, urine, and feces. Long-term (30+ day)
time course data.
Oral gavage and IV injection. Blood, brain, skull, thyroid,
lung, heart, liver, spleen, pancreas, kidney, adrenal, stomach,
intestine, bone, muscle, testis, urine, and feces. 30-day time
course data of feces/urine and body retention. 5-day time
course data for tissues.
Liver, kidney, spleen, testes, urine and feces. Spot sample 24
hours post exposure. 3-day time course data for urine and
feces. This is a chelation study that included Cr Vl-only
groups.
Crlll
control3
Y
Y
N
PBPK
useb
N
Y
N
1
2
3
4
5
aNotes (yes/no) if study also collected data for Cr III kinetics.
bNotes (yes/no) whether data from a study were used qualitatively or quantitatively in a published PBPK model.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
2
3
Table 3-2. Preliminary categorization of in vitro and ex vivo hexavalent
chromium studies primarily focused on toxicokinetics in the GI tract and
blood
Reference
Species
Test system
Notes
PBPK
use3
Gastric systems
De Flora et al. (1987)
De Flora et al. (1997)
Gammelgaard et al.
(1999)
Kirmanetal. (2013)
Proctor et al. (2012)
Shrivastava et al.
(2003)
Skowronski et al.
(2001)
Human
Human
Rat
Human
Rat,
Mouse
Rat
N/A
Gastric juice
Intestinal
bacteria, gastric
juice
Artificial gastric
juice; small
intestine
Gastric juice
(fasted)
Gastric juice and
contents
Crypt, mid and
upper villus,
intestinal loop
Artificial gastric
juice
Hourly gastric juice samples via nasogastric tube. Cr VI
reduction capacity estimated for fed and fasted humans.
Orcadian effects also observed.
Reduction and mutagenic activity of Cr VI analyzed at 60
min. Reducing capacities derived for intestine and other
tissues (blood, RBC, lung fluids/bacteria, saliva).
1st order reduction rate half-life derived; permeability
parameters through rat jejunum derived.
2nd-order reduction kinetics for human gastric juice
derived. pH-dependent model derived.
2nd-order reduction kinetics derived. Reduction
capacities estimated for both species.
Cr VI reduction in various tissue types. Capacity and
time needed to reduce Cr VI analyzed.
Oral bioaccessibility study. Examined Cr VI reduction in a
simulated soil matrix/gastric juice environment.
Y
Y
N
Y
Y
N
N
Reduction and/or uptake in RBCs
Aasethetal. (1982)
Afolaranmi et al.
(2010)
Alexander and Aaseth
(1995)
Beyersmann et al.
(1984)
Branca etal. (1989)
Cooganetal. (1991)
Corbett etal. (1998)
Kortenkamp et al.
(1987)
Richelmi etal. (1984)
Human
Human
Human,
Rat
Human
Human
Human,
Rat
Human
Human
Rat
RBC
Plasma, RBC,
whole blood
Human RBC, rat
liver cells
RBC
Human RBC
RBC, WBC, whole
blood
Plasma, blood
RBC
RBC, plasma
Reduction rate of Cr VI in RBC, and trapping of reduced
Cr III observed.
Distribution into different blood components (RBC and
plasma) observed.
Cellular uptake and reduction analyzed. Effect of pH and
anion carrier inhibitors observed.
RBC permeability and reduction analyzed.
Reduction of Cr VI in RBC observed.
Uptake kinetics, and distribution in cells examined.
Reduction in plasma quantified in fed/fasted individuals.
Cellular uptake rates analyzed.
Reduction of Cr VI in RBC and plasma observed.
Y
N
N
N
N
N
Y
N
Y
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Reference
Wiegandetal. (1985)
Species
Human,
Rat
Test system
RBC
Notes
Uptake into RBC analyzed.
PBPK
use3
Y
1
2
3
4
Notes (yes/no) whether data from a study were used qualitatively or quantitatively in a published PBPK model.
5
6
Table 3-3. Preliminary categorization of in vitro studies primarily examining
distribution and reduction mechanisms
Liver
Lung
RBC
Other
Human
Jannettoetal. (2001)
Myers and Myers (1998)
Pratt and Myers (1993)
Harris etal. (2005)
Petrillietal. (1986)
Petruzzellietal. (1989)
Wong etal. (2012)
Ottenwalder et al. (1987)
Ottenwaelder et al. (1988)
Wiegandetal. (1984b)
Wiegand and Ottenwaelder (1985)
Rat
Aiyar etal. (1992)
Alexander etal. (1982)
Alexander etal. (1986)
De Flora et al. (1985)
Garcia and Jennette (1981)
Gruber and Jennette (1978)
Gunaratnam and Grant (2001)
Mikalsen etal. (1989)
Mikalsen etal. (1991)
Ohta etal. (1980)
Rossi and Wetterhahn (1989)
Rossi etal. (1988)
Standeven and Wetterhahn (1991)
Ueno etal. (1990)
Wiegandetal. (1986)
De Flora et al. (1985)
Suzuki (1988a)
Suzuki and Fukuda (1990)
Berndt (1976) (kidney)
Standeven and Wetterhahn (1991) (kidney)
Debetto et al. (1988) (thymocytes)
Arslan et al. (1987) (thymocytes)
Miscellaneous systems
Denniston and Uyeki (1987), Ortega et al. (2005), Sehlmeyer et al. (1990): Chinese hamster ovary
Dillon et al. (2002): Chinese hamster lung
Krepkiv et al. (2003): Rabbit liver metallothionein
O'Brien et al. (1992): Glutathione and other thiols (not specific tc
Kitagawa et al. (1982): Bovine RBCs.
a particular tissue or species).
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Table 3-4. Human biomonitoring and biomarker studies
Reference
Gargasetal. (1994)
Goldoni et al. (2006)
Lukanova et al. (1996)
Muttamara and Leong (2004)
Nomivama etal. (1980)
Pierre et al. (2008)
Siogrenetal. (1983)
Welinder etal. (1983)
Biomarker and industry/exposure notes
Urine / Human volunteer study of ingested chromite ore processing residue in soil
Exhaled breath / Chrome plating
Lymphocytes, RBCs, urine /Chrome plating
Blood, urine / Chromium alloy factory
Urine / Population from geographic areas of known chromium pollution
Urine / Chrome plating
Urine / Stainless steel welding
2
3
4
5
Table 3-5. Physiologically-based pharmacokinetic models for hexavalent
chromium
Reference
Species
Notes
O'Flaherty (1996)
O'Flaherty (1993)
O'Flaherty et al. (2001)
Rat
O'Flaherty and Radike
(1991)
Calibrated to data from exposure via IV injection, gavage, inhalation, and drinking
water (all data are from studies dated 1985 and earlier). Background Cr III
exposure incorporated. Single compartment lumped model for Gl kinetics. Model
not readily extendable to the mouse.
O'Flaherty et al. (2001)
Human
Kirmanetal. (2012)
Rat,
Mouse
Incorporates new data, including those from experiments designed by the
authors. Only data for drinking water and dietary routes incorporated. Total
concentrations in control groups subtracted from exposure groups to account for
background Cr III levels. Multi-compartment Gl model, with reduction kinetics
based on the model by Proctor et al. (2012).*
Kirmanetal. (2013)
Human
6
7
8
9
10
*EPA has developed a revised ex vivo reduction model (Schlosser and Sasso, In Press), which follows the same
basic principles as Proctor et al. (2012) and Kirman etal. (2013) (i.e., binary reaction with depleting reducing
agent), but with a different reaction scheme and pH function. As shown in Figure 3-1, a new reduction model can
be incorporated into pre-existing Gl tract models.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Ex vivo
reduction
model
Whole-body model
Gl:
A
\7
Stomach Duodenum Jejunum lleum
Cr(VI)
—>
Gastrointestinal tract model
•Can estimate
absorption of Cr(VI)
•More complex and
data intensive
•Can estimate in vivo
reduction of Cr(VI)
•Must make assumptions
about absorption
2
3
4
5
Figure 3-1. Relationship between ex vivo reduction models, in vivo gastric
models, and whole-body PBPK models.
These models can be used to estimate the internal dose to the tissues where toxicological responses are observed,
and perform animal-human extrapolation3.
Thompson et al. (2014) used PBPK modeling to estimate the average lifetime daily internal dose (mg hexavalent
chromium absorbed per L small intestine segment) for the duodenum, jejunum, and ileum of mice from the NTP 2-
year bioassay. Incidence data for all three segments were pooled for internal dose-response modeling. The
corresponding human internal dose for interspecies extrapolation was the lifetime daily mg/L hexavalent
chromium absorbed in the whole small intestine. The mass of hexavalent chromium escaping stomach reduction
(per L small intestine) was considered as an alternative to the human hexavalent chromium absorption dose
metric, and requires only the gastrointestinal tract model.
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
2 4. PRELIMINARY MECHANISTIC STUDY
3 INFORMATION
4 The systematic literature search for hexavalent chromium also identified studies evaluating
5 mechanisms of action considered potentially relevant to effects observed following exposure to
6 hexavalent chromium. Studies were included if they evaluated mechanistic events following
7 exposure to: hexavalent chromium; the reductive intermediate oxidation states penta- and
8 tetravalent chromium; trivalent chromium (if relevant to hexavalent chromium effects); or
9 otherwise contained information relevant to the mechanistic understanding of hexavalent
10 chromium toxicity. Reviews or analyses that do not contain original data are not included here, but
11 may be considered in later stages of assessment development
12 The diverse array of mechanistic studies presented here includes investigations of the
13 cellular, biochemical, and molecular mechanisms underlying toxicological outcomes. For this
14 preliminary evaluation, information reported in each study was extracted into a database (in the
15 form of an Excel spreadsheet) that will facilitate future evaluation of mechanistic information. This
16 information is being made available to provide an opportunity for stakeholder input, including the
17 identification of relevant studies not captured here.
18 The information extracted from each study and included in the database corresponds to the
19 column headings in the spreadsheet, and is as follows: link to HERO record (contained within a URL
20 that links to the study abstract in the HERO database), author(s), year, title, source, link to abstract
21 in PubMed (if any), molecular formulation, oxidation state, in vitro/in vivo, species/test system, cell
22 type, endpoint, assay, and mechanistic category. The database supports sorting capabilities, e.g.,
23 data can be organized by assay. The database is available through HERO at
24 http://hero.epa.gov/index.cfm?action=reference.details&reference id=2444793. To access this
25 database, click on the link at the top of the web page and select "download" and then "ok" to view
26 the spreadsheet in Excel. This spreadsheet may also be saved to your desktop by downloading and
27 selecting "save." The resulting inventory of hexavalent chromium mechanistic studies consists of
28 3,235 discrete measures from 806 studies. Table 4-1 presents a summary of the mechanistic
29 outcomes recorded in the database from each study identified.
30 The mechanistic categories developed here are not mutually exclusive and are designed to
31 facilitate the analysis of similar studies and experimental observations in a systematic manner.
32 This process will allow the identification of mechanistic events that contribute to mode(s) of action
33 (MOAs) and/or adverse outcome pathways (AOPs) following hexavalent chromium exposure. The
34 mechanistic categories assigned to each mechanistic outcome reported by an individual study are
35 as follows: 1) mutation, including investigations of gene and chromosomal mutation; 2) DNA
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 damage, including indicator assays of genetic damage; 3) alterations of DNA repair; 4) oxidative
2 stress; 5) changes in cell death and division (this captures a broad range of assays, but it is useful to
3 consider them together as observations resulting from cell cycle alterations); 6) pathology, which
4 includes morphological evaluations pertaining to the dysfunction of organs, tissues, and cells;
5 7) epigenetic effects, which are observations of heritable changes in gene function that cannot be
6 explained by changes in the DNA sequence; 8) receptor-mediated and cell signaling effects;
7 9) immune system effects; 10) cellular and molecular ADME; 11) cellular differentiation and
8 transformation; 12) cellular energetics; and 13) "other," to capture those mechanistic outcomes not
9 easily assigned to a defined category. The ADME category above includes studies conducted to
10 investigate the mechanism of carcinogenicity of hexavalent chromium, specifically, intracellular
11 reduction and the formation of DNA-reactive intermediates and oxygen radicals; as such, these
12 studies would typically not be included in the toxicokinetic studies identified in Section 3.
13 Information summarized in Table 4-1 and Figure 4-1 and detailed in the mechanistic
14 database can be used to ascertain the breadth and scope of available mechanistic studies. At this
15 preliminary stage, study results are not presented. Additionally, the inclusion of a study in the
16 spreadsheet does not reflect conclusions reached as to mechanistic study quality or relevance.
17 After the epidemiological and experimental studies on each health effect have been synthesized,
18 mechanistic studies will be reviewed and findings synthesized to evaluate potential MOAs and/or
19 AOPs, which can be used to inform hazard identification and dose-response assessment, specifically
20 addressing questions of human relevance, susceptibility, and dose-response relationships.
21
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1
2
Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Table 4-1. Summary of mechanistic outcomes evaluated following exposure to
hexavalent chromium
Mechanistic
category
Mutation
DNA damage
Alterations of DNA
repair
Oxidative stress
Changes in cell death
and division
Pathology
Epigenetic effects
Receptor-mediated
and cell signaling
effects
Immune system
effects
Cellular and molecular
ADME
Cellular differentiation
and transformation
Cellular energetics
Other
Number of mechanistic outcomes
Mammals
Humans
In vivo
14
30
2
10
3
0
3
0
0
15
0
0
8
In vitro
35
235
33
175
303
4
40
37
33
36
10
18
7
Mice
In vivo
27
18
0
76
15
23
1
1
4
10
4
0
5
In vitro
11
26
1
54
39
0
1
4
5
2
9
0
0
Rats
In vivo
8
29
1
215
52
69
1
9
15
52
1
6
6
In vitro
2
19
0
89
103
4
1
3
1
21
6
17
8
Hamsters
In vivo
0
4
0
0
1
0
0
0
0
0
0
0
0
In vitro
63
122
5
10
114
0
2
0
0
23
26
8
0
Total Outcomes
Total
mechanistic
outcomes/
number of
studies
311/144
769/300
54/28
728/206
703/256
110/36
54/22
60/25
63/27
213/106
59/26
58/30
52/17
3235
3
4
5
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
Mechanistic Outcomes
In vivo
I In vitro
Mutation
DNA damage
DNA repair
Oxidative stress
Cell death and division
Pathology
Epigenetic effects
Receptor-mediated and cell signaling effects
Immune effects
ADME
Differentiation and transformation
Cellular energetics
Other
100 200 300 400 500 600 700
Total outcomes reported in mechanistic database
800
2
3
4
5
6
Figure 4-1. Summary of in vivo and in vitro mechanistic outcomes by
mechanistic category.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1
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1 O'Flaherty. ET. (1993). A pharmacokinetic model for chromium. Toxicol Lett 68: 145-158.
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49 http://dx.doi.org/10.1080/15287399509531958
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Preliminary Materials for the IRIS Toxicological Review ofHexavalent Chromium
1 Petrilli, FL: Rossi, GA: Camoirano, A: Romano, M: Serra, D: Bennicelli, C: De Flora, A: De Flora, S.
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