v>EPA
United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA-600/8-83-021A
June 1983
External Review Draft
Research and Development
Health Assessment
Document for
Inorganic Arsenic
Review
Draft
\
(Do Not
Cite or Quote;
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
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REVIEW DRAFT EPA-600/8-83-021A
DO NOT CITE OR QUOTE Exiemal Review Draft
HEALTH ASSESSMENT DOCUMENT FOR
INORGANIC ARSENIC
June, 1983
NOTICE
This document is a preliminary draft. It has not been formally released
by EPA and should not at this stage be construed to represent Agency policy.
It is being circulated for comment on its technical accuracy and policy
implications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
RESEARCH TRIANGLE PARK, NORTH CAROLINA 27711
013AS1/E June 1983
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The authors of this document are:
Dr. Paul Mushak
University of North Carolina
Chapel Hill, North Carolina
Dr. Magnus Piscator
Karolinska Institute
Stockholm, Sweden
Donna J. Sivulka
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
The cancer risk assessment and portions of the
section on carcinogenicity were prepared by:
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, D.C.
Project Manager:
Donna J. Sivulka
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
11
013AS1/E June 1983
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Participating members of the CAG are listed below:
(Principal authors and contributors to carcinogencity
sections of this document are designated by *).
Roy Albert, M.D. (Chairman)
Elizabeth Anderson, Ph.D.
Larry D. Anderson, Ph.D.
Steven Bayard, Ph.D.
David Bayliss, M.S.
Chao W. Chen, Ph.D.
Margaret Chu, Ph.D.*
Herman J. Gibb, M.S., M.P.H.*
Bernard H. Haberman, D.V.M., M.S.
Charalingayya B. Hiremath, Ph.D.
Robert McGaughy, Ph.D.
Dharm V. Singh, D.V.M., Ph.D.
Todd W. Thorslund, Sc.D.*
Kenny S. Crump, Ph.D. (consultant)*
Science Research Systems, Inc.
Ruston, Louisiana
m
013AS1/E June 1983
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DISCLAIMER
This report is an internal draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
iv
013AS1/E June 1983
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PREFACE
The Office of Health and Environmental Assessment, in consultation
with other Agency and non-Agency scientists, has prepared this health
assessment to serve as a "source document" for Agency-wide use. Speci-
fically, this document was prepared at the request of the Office of Air
Quality Planning and Standards.
In the development of this assessment document, the scientific
literature has been inventoried, key studies have been evaluated, and
summary/conclusions have been prepared such that the toxicity of arsenic
is qualitatively and where possible, quantitatively, identified. Observed
effect levels and dose-response relationships are discussed where appro-
priate in order to place adverse health responses in perspective with
observed environmental levels.
013AS1/E June 1983
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TABLE OF CONTENTS
LIST OF TABLES x
LIST OF FIGURES \\"\ xii
1. INTRODUCTION 1-1
2. SUMMARY AND CONCLUSIONS 2-1
2.1 BACKGROUND INFORMATION 2-1
2.1.1 Chemical/Physical Aspects of Arsenic 2-1
2.1.2 The Environmental Cycling of Arsenic 2-3
2.1.3 Levels of Arsenic in Various Media 2-4
2.1.3.1 Levels of Arsenic in Ambient Air 2-4
2.1.3.2 Levels of Arsenic in Drinking Water 2-5
2.1.3.3 Arsenic in Food 2-5
2.1.3.4 Arsenic in Soils 2-6
2.1.3.5 Other Sources of Arsenic 2-6
2.2 ARSENIC METABOLISM 2-6
2.2.1 Routes of Absorption 2-6
2.2.1.1 Respiratory Absorption 2-6
2.2.1.2 Gastrointestinal Absorption 2-7
2.2.1.3 Transplacental Transfer 2-7
2.2.2 Biotransformation of Inorganic Arsenic In Vivo 2-7
2.2.3 Distribution of Arsenic in Man and Animals 2-9
2.2.4 Arsenic Accumulation 2-10
2.2.5 Arsenic Excretion 2-10
2.3 ARSENIC TOXICOLOGY 2-10
2.3.1 Acute Toxicity 2-10
2.3.2 Chronic Toxicity 2-11
2.3.2.1 Carcinogenesis/Mutagenesis of Inorganic
Arsenic 2-11
2.3.2.1.1 Human Epidemiology of Arsenic
Carcinogenesis 2-12
2.3.2.1.2 Experimental Studies of Arsenic
Carcinogenesis 2-18
2.3.2.1.3 Arsenic Mutagenesis 2-18
2.3.2.2 Chronic Neurological Effects of Arsenic
Exposure 2-19
2.3.2.3 Cardiovascular Effects of Arsenic Exposure 2-20
2.3.2.4 Other Systemic Effects of Arsenic 2-20
2.3.3 Factors Affecting Arsenic Toxicity 2-21
2.4 ARSENIC AS AN ESSENTIAL ELEMENT 2-21
2. 5 HUMAN HEALTH RISK ASSESSMENT FOR ARSENIC 2-22
2.5.1 Exposure Aspects of Arsenic 2-22
2.5.2 Effect/Response Aspects of Arsenic 2-23
2.5.2.1 Relevant Health Effects 2-23
2.5.2.2 Dose-Effect/Dose-Response Relationships 2-25
2.5.3 Populations at Special Risk to Health Effects of
Arsenic 2-27
VI
013AS1/B June 1983
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TABLE OF CONTENTS
(continued)
3. BACKGROUND INFORMATION 3-1
3.1 CHEMICAL/PHYSICOCHEMICAL ASPECTS 3-1
3.2 ENVIRONMENTAL CYCLING OF ARSENIC 3-4
3.3 LEVELS OF ARSENIC IN VARIOUS MEDIA 3-8
3.3.1 Levels of Arsenic in Ambient Air 3-9
3.3.2 Levels of Arsenic in Drinking Water 3-15
3.3.3 Arsenic in Food 3-16
3.3.4 Arsenic in Soils 3-19
3.3.5 Other Sources of Arsenic 3-21
4. ARSENIC METABOLISM 4-1
4.1 ROUTES OF ARSENIC ABSORPTION 4-1
4.1.1 Respiratory Absorption 4-1
4.1.2 Gastrointestinal Absorption 4-8
4.1.3 Transplacental Passage 4-10
4.2 BIOTRANSFORMATION PROCESSES IN VIVO 4-11
4.2.1 Biomethylation of Inorganic Arsenic in Humans and
Experimental Animals 4-12
4.2.1.1 Human Studies 4-12
4.2.1.2 Animal Studies 4-15
4.2.2 In Vivo Oxidation/Reduction of Inorganic Arsenic in
Mammalian Systems 4-15
4.2.3 Chemical Stability of Trivalent and Pentavalent In-
organic Arsenic to Oxidation-Reduction 4-19
4. 3 DISTRIBUTION OF ARSENIC IN MAN AND ANIMALS 4-20
4.4 ARSENIC ACCUMULATION 4-23
4.5 ARSENIC EXCRETION IN MAN AND ANIMALS 4-24
5. ARSENIC TOXICOLOGY 5-1
5.1 ACUTE TOXICITY OF ARSENIC IN MAN AND ANIMALS 5-1
5.2 CHRONIC TOXICITY OF ARSENIC IN MAN AND ANIMALS 5-2
5.2.1 Carcinogenicity/Mutagenicity of Arsenic 5-2
5.2.1.1 Clinical Aspects of Human Arsenic
Carcinogenesis 5-16
5.2.1.2 Epidemiological Aspects of Human Arsenic
Carcinogenesis 5-18
5.2.1.2.1 Cancer of the Lung 5-18
5.2.1.2.2 Cancer of the Skin and Pre-
cancerous Skin Lesions 5-56
5.2.1.2.3 Other Cancers 5-76
5.2.1.3 Experimental Studies of Arsenic
Carcinogenesis 5-78
5.2.1.4 Quantitative Carcinogen Risk Estimates 5-86
5.2.1.4.1 Introduction 5-86
5.2.1.4.2 Unit Risk for Air 5-89
5.2.1.4.2.1 Methodology for
Quantitative Risk
Estimates 5-89
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013AS1/B June 1983
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TABLE OF CONTENTS
(continued)
5.2.1.4.2.2 Risk Estimates from
Epidemiologic
Studies 5-93
5.2.1.4.2.3 The Lee-Feldstein
(1982) Study 5-94
5.2.1.4.2.4 The Higgins et al.
(1982) Study 5-104
5.2.1.4.2.5 The Brown and Chu
Estimates from the
Anaconda Data 5-110
5.2.1.4.2.6 The Enter!ine and
Marsh (1982) Study.... 5-120
5.2.1.4.2.7 The Ott et al.
(1974) Study 5-129
5.2.1.4.2.8 Discussion 5-134
5.2.1.4.3 Unit Risk for Water 5-136
5.2.1.4.4 Relative Potency 5-143
5.2.1.5 Summary and Conclusions of the
Carcinogenicity of Arsenic 5-147
5.2.1.5.1 Qualitative Summary 5-147
5.2.1.5.2 Quantitative Summary 5-149
5.2.1.5.3 Conclusions 5-150
5.2.1.6 Arsenic Mutagenesis 5-150
5.2.2 Non-Carcinogenic Chronic Effects 5-156
5.2.2.1 Neurotoxic Effects 5-156
5.2.2.2 Cardiovascular Effects 5-161
5.2.2.3 Teratogenesis and Developmental Effects 5-165
5.2.2.3.1 Animal Studies 5-165
5.2.2.3.2 Human Studies 5-168
5.2.2.4 Hematological Effects 5-169
5.2.2.5 Hepatic Effects 5-171
5.2.2.6 Renal Effects 5-172
5.2.2.7 Respiratory Effects 5-172
5.2.2.8 Immunosuppressant Effects 5-173
5.3 FACTORS AFFECTING ARSENIC TOXICITY 5-173
6. ARSENIC AS AN ESSENTIAL ELEMENT 6-1
7. HUMAN HEALTH RISK ASSESSMENT FOR ARSENIC 7-1
7.1 AGGREGATE EXPOSURE LEVELS TO ARSENIC IN THE U.S. POPULATION... 7-1
7.2 SIGNIFICANT HUMAN HEALTH EFFECTS ASSOCIATED WITH AMBIENT
EXPOSURES 7-4
7.2.1 Acute Exposure Effects 7-4
7.2.2 Chronic Exposure Effects 7-5
7.3 DOSE-EFFECT/DOSE-RESPONSE RELATIONSHIPS 7-7
7.3.1 General Considerations 7-7
7.3.2 Effects and Dose-Response Relationships 7-8
7.3.2.1 Respiratory Cancer 7-9
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013AS1/B June 1983
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TABLE OF CONTENTS
(continued)
7.3.2.2 Skin Cancer 7-9
7.3.2.3 Non-cancerous Skin Lesions 7-10
7.3.2.4 Peripheral Neuropathological Effects and
Cardiovascular Effects 7-10
7.4 POPULATIONS AT SPECIAL RISK TO ARSENIC EXPOSURE 7-11
8. REFERENCES 8-1
IX
013AS1/B June 1983
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LIST OF TABLES
Table Page
3-1 Physical Properties of Arsenic and Arsenic Compounds 3-2
3-2 Cumulative Frequency Distribution of NASN Individual 24-Hour
Ambient Air Arsenic Levels 3-10
3-3 Primary Copper Smelters in the United States 3-13
3-4 Levels of Arsenic by Food Class in Adult Food Composites from
20 U.S. Cities 3-17
3-5 Levels of Arsenic by Food Class in Infant and Toddler Food
Composites from 10 U.S. Cities 3-18
3-6 A Comparison of Arsenic Levels in Arsenic-Treated and
Uncontaminated Soils in North America 3-20
5-1 Summary of Case Reports and Epidemiologic Studies of Cancer
or Precancerous Lesions in Persons Exposed to Arsenic 5-3
5-2 Observed and Expected Deaths Due to Respiratory Malignancies,
By Exposure Category 5-21
5-3 Observed and Expected Deaths for Selected Causes in Retrospective
Cohort Analysis (1940-1973) 5-23
5-4 Observed and Expected Deaths and Standardized Mortality Ratio for
Selected Causes of Death of 527 Males of Cohort Under Study 5-28
5-5 Observed and Expected Respiratory Cancer Deaths and Standardized
Mortality Ratios by Arsenic Exposure Index 5-29
5-6 Observed and Expected Respiratory Cancer Deaths and Standardized
Mortality Ratios by Intensity and Duration of Exposure to Arsenic... 5-29
5-7 Respiratory Cancer Deaths and SMRs By Cumulative Arsenic
Exposure Lagged 0 and 10 years, Tacoma Smelter Workers 5-31
5-8 Respiratory Cancer Deaths and SMRs by Duration of Exposure and
Latency, Tacoma Smelter Workers 5-33
5-9 Respiratory Cancer Deaths and SMRs by Duration and Intensity
of Exposures, Tacoma Smelter Workers 5-34
5-10 1965 Smelter Survey Atmospheric Arsenic Concentrations 5-38
5-11 Observed and Expected Deaths from Respiratory Cancer, with
Standardized Mortality Ratios (SMR), by Cohort and Degree of
Arsenic Exposure, 1938-63 5-39
5-12 Mortality for All Causes and Respiratory Cancer from 1938 to 1978
by Time-Weighted Average (TWA) Arsenic Exposure as of Entrance into
Cohort 5-46
5-13 Mortality for All Causes and Respiratory Cancer by Ceiling Arsenic
Exposure as of Entrance into Cohort 5-47
5-14 Respiratory Cancer Mortality by Method of Analysis and TWA
Arseni c Category 5-49
5-15 Respiratory Cancer Mortality by Method of Analysis and Ceiling
Arsenic Category 5-50
5-16 Prevalence of Skin Cancer (per 1000) by Age and Arsenic
Exposure (ppm) 5-57
5-17 Results of Total Arsenic Analysis and Arsenite and Arsenate
Determination in the Yenshei Water Samples 5-61
5-18 Lane County Water Arsenic Levels 1974-1978 5-67
5-19 Age Specific Death Rates for Utah and Three Mi Hard County
Communities 5-71
5-20 Summary Table of Experimental Studies of Arsenic Carcinogenesis 5-79
013AS1/B June 1983
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LIST OF TABLES (continued)
No. Page
5-21 Observed and Expected Deaths Due to Selected Causes,
With Standardized Mortality Ratios (SMRs) Among Smelter
Workers, 1938-1977 5-95
5-22 Description of Length of Employment Groups, With Numbers of
Smelter Workers, Numbers of Deaths, Person-Years at Risk,
and Duration of Smelter Employment (Based on Total Work
Experience Through September 30, 1977) 5-96
5-23 Observed and Expected Deaths from Respiratory Cancer, With
Person-Years of Follow-Up, By Cohort and Degree of Arsenic
Exposure 5-97
5-24 Dose-Response Data from Lee-Feldstein (1982) Used for Risk
Assessment 5-100
5-25 Summary of Quantitative Risk Analyses 5-103
5-26 Respiratory Cancer Mortality 1938-1978 from Cumulative Exposure
to Arsenic for 1800 Men Working at the Anaconda Copper Smelter 5-106
5-27 Observed and Expected Lung Cancer Deaths and Person-Years By
Level of Exposure, Duration of Employment and Age at Initial
Employment 5-112
5-28 Arsenic Exposures: 1965 Smelter Survey Atmospheric Arsenic
Concentrations 5-115
5-29 Observed and Expected Number of Respiratory Cancer Deaths for Each
Cel 1 in the Low-Exposure Group of Table 5-27 5-118
5-30 Cells from Table 5-29 Combined Within Rows to Obtain Cells With
Three or More Expected Respiratory Cancer Deaths 5-119
5-31 Cells from Table 5-29 Combined Within Columns to Obtain Cells
With Three or More Expected Respiratory Cancer Deaths 5-119
5-32 Observed Deaths and SMRs for 2802 Smelter Workers Who Worked a
Year or More 1940-64, Followed Through 1976, By Cause of Death 5-121
5-33 Data From Table 8 of Enter!ine and Marsh (1982), With Person-
Years of Observation Added 5-124
5-34 Data From Tab! e 4 of Ott et al. (1974) 5-131
5-35 Combined Unit Risk Estimates for Absolute-Risk Linear Models 5-135
5-36 Age-Exposure-Specific Prevalence Rates for Skin Cancer 5-138
5-37 Data Utilized to Obtain Predictor Equation and Figure 5-12 5-141
5-38 Relative Carcinogenic Potencies Among 52 Chemicals Evaluated by
the Carcinogen Assessment Group As Suspect Human Carcinogens 5-145
5-39 Chromosomal Effects of Inorganic Arsenic in Man and Animals 5-151
5-40 Summary of Studies Investigating Arsenic-Induced Mutagenic Effects.. 5-153
5-41 Prevalence of Blackfoot Disease (per 1000) by Age and Arsenic
Exposure (ppm) 5-162
7-1 Routes of Daily Human Arsenic Intake 7-2
XI
013AS1/B June 1983
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LIST OF FIGURES
Figure Page
3-1 The Generalized Geochemical Cycle for Arsenic 3-5
3-2 Biological Cycling of Arsenic 3-7
3-3 NASN Annual Average Arsenic Concentrations 3-11
4-1 Arsenic Retention in Rat Lungs Following Intratracheal
Instillation of a Single Dose 4-4
4-2 Lung Concentrations of Arsenic in Hamsters Given Weekly
Intratracheal Instillations of Arsenic Trioxide, Arsenic
Trisulfide or Calcium Arsenate 4-7
5-1 Comparison of Census Tracts Experiencing Exposure to the Fisher
Formation and Exhibiting High Skin Cancer Occurrence 5-68
5-2 Relative Risks and 90% Confidence Limits for Data of
Lee-Feldstein (1982) 5-101
5-3 Absolute Risks and 90% Confidence Limits for Data of
Lee-Feldstein (1982) 5-102
5-4 Relative Risks and 90% Confidence Limits for Data of Higgins
(1982) 5-108
5-5 Absolute Risks and 90% Confidence Limits for Data of Higging
(1982) 5-109
5-6 Relative Risks and 90% Confidence Limits for Zero-Lag Data of
Enter!line and Marsh (1982) 5-125
5-7 Relative Risks and 90% Confidence Limits for 10-Year Lag Data of
Enterl ine and Marsh (1982) 5-126
5-8 Absolute Risks and 90% Confidence Limits for Zero-Lag Data of
Enterl i ne and Marsh (1982) 5-127
5-9 Absolute Risks and 90% Confidence Limits for 10-Year Lag Data of
Enterl ine and Marsh (1982) 5-128
5-10 Relative Risks and 90% Confidence Limits for Data of Ott et al.,
1974, with Highest Exposure Group Omitted 5-132
5-11 Relationship Between Transformed Prevalence and log ppm Arsenic in
Water, log age. 5-142
5-12 Histogram Representing the Frequency of Distribution of the Potency
Indices of 52 Suspect Carcinogens Evaluated by the Carcinogen
Assessment Group 5-144
xn
013AS1/B June 1983
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ACKNOWLEDGMENTS
The following individuals attended a review workshop on an early draft
of this document and submitted valuable comments:
Dr. Thomas Clarkson
Department of Environmental Health Sciences
University of Rochester
Rochester, New York
Dr. Annemarie Crocetti
New York Medical College
New York, New York
Dr. Philip Enterline
Department of Biostatisties
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, Pennsylvania
Dr. Paul Hammond
Kettering Laboratory
University of Cincinnati
Cincinnati, Ohio
Dr. Dinko Kello
Institute for Medical Research
Zagreb, Yugoslavia
Dr. Paul Mushak
ithology
ina
Ur. fdU I HUblldK.
Department of Pathology
University of North Caroline
Chapel Hill, North Carolina
Dr. Magnus Piscator
Karolinska Institute
Department of Environmental Hygiene
Stockholm, Sweden
Dr. Samuel Shibko
Division of Toxicology
U.S. Food and Drug Administration
Washington, D.C.
In addition, there are several scientists who contributed valuable
information and/or constructive criticism to interim drafts of this report.
XI 11
013AS1/B June 1983
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Of specific note are the contributions of: Gerald Akland, Gary Evans, Warren
Galke, Lester Grant, Victor Hasselblad, Casey Jason, Kantharajapura S. Lavappa,
Charles Nauman, and Terry Risher.
xiv
013AS1/B June 1983
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1. INTRODUCTION
This report evaluates health effects associated with arsenic exposure,
with particular emphasis being placed on the delineation of health effects
thought to be of most concern in regard to exposure to inorganic arsenic of
the general U.S. population. Organic arsenic compounds are considered only in
so far as certain forms of the element arise via transformation of arsenic in
man and other species, or arise by environmental transformation.
This report is organized into chapters which provide a cohesive discus-
sion of all aspects of inorganic arsenic and delineate a logical linking of
this information to human health risk. The chapters include: an executive
summary (Chapter 2) of the information contained within the text of later
chapters; background information on the chemical and environmental aspects of
arsenic, including levels of arsenic in media with which U.S. population
groups come into contact (Chapter 3); arsenic metabolism, where factors of
absorption, biotransformation, tissue distribution, and excretion of inorganic
arsenic are discussed with reference to the element's toxicity (Chapter 4);
arsenic toxicology, discussing the various acute, subacute, and chronic health
effects of inorganic arsenic in man and animals, including discussion of
selected dose-effect and dose-response relationshops, (Chapter 5); arsenic as
an essential element, which deals with the current status of inorganic arsenic
as a required nutrient in at least some species of animals (Chapter 6); and a
human health risk assessment for arsenic, where key information from the
preceding chapters is placed in an interpretive and quantitative perspective
highlighting those health effects likely of most concern for U.S. populations,
(Chapter 7).
013AS5/B 1-1 June 1983
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This report is not intended to be an exhaustive review of all the arsenic
literature, but is focused upon those data thought to be most useful and
relevant for human health risk assessment purposes. Particular emphasis is
placed on delineation of health effects and risks associated with exposure to
airborne arsenic, in view of the most immediate use intended for the present
report, i.e., to serve as a basis for decision making regarding the regulation
of arsenic as a hazardous air pollutant under pertinent sections of the Clean
Air Act, as amended in 1977. Health effects associated with the ingestion of
arsenic or with exposure via other routes are also discussed, providing a
basis for possible use for multimedia risk assessment purposes, as well. The
background information provided at the outset on sources, emissions, and
ambient concentrations of arsenic in various media is presented in order to
provide a general perspective against which to view the health effects evalua-
tions contained in later chapters of the document. More detailed exposure
assessments, taking into account even more recent, up-to-date emission and
ambient concentration data are to be prepared separately for use in subsequent
EPA regulatory decision making regarding arsenic.
013AS5/B 1-2 June 1983
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2. SUMMARY AND CONCLUSIONS
As a toxic agent, inorganic arsenic possesses several properties that are
not shared with many environmental pollutants. The element exists in various
chemical states, e.g., tri- and pentavalent inorganic arsenic and methylated
organic arsenic, with each having differing toxicological potential. In man,
experimental animals and other organisms, arsenic undergoes a variety of
transformations, the full significance and mechanisms of which are as yet not
well understood. Furthermore, there appears to be a nutritional requirement
for low levels of arsenic in certain experimental animals and this may also be
the case for man. All of these factors complicate the analyses of the toxico-
logical effects and the risk for human health associated with environmental
exposure to arsenic compounds. The following chapter summarizes these factors
as they are presented in-depth in the ensuing document text.
2.1 BACKGROUND INFORMATION
2.1.1 Chemical/Physical Aspects of Arsenic
It is the various compounds of arsenic which have been of most importance
in the extensive history of the toxicology of the element, the zero-valent
metallic form being of minor toxicological interest.
Arsenic is encountered as a component of sulfidic ores of metals such as
copper, cobalt and nickel. The smelting of these ores is associated with
arsenic release into the environment. Arsenic trioxide, As203, a toxicologi-
cally significant form, is a smelter product arising from air roasting of
these sulfidic ores.
Arsenic trioxide, white arsenic, is only sparingly soluble in water and
other solvents which do not promote chemical transformation. The compound
dissolves in acidic or alkaline aqueous media to yield either the free acid or
013AS5/A 2-1 June 1983
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salts, with these being soluble in a number of solvents. The oxide readily
sublimes (135°C) and this factor is of importance in considering analytical
methods for measuring levels of the compound.
The pentavalent arsenic pentoxide, ASpOj-, may be prepared by nitric acid
oxidation of the trioxide or the element itself. This form has high solubi-
lity in water (63 g/100 g water), forming the strongly oxidizing arsenic acid,
H3As04 (E° = 0.56V).
Stability of the valency forms of arsenic in solution are dependent on
the nature of the medium. Oxygenated media and higher pH favor the penta-
valent form, while reducing and/or acidic media favor the trivalent state.
The acids of both valency forms of arsenic readily form alkali and alka-
line metal salts with the former being much more soluble than the latter.
Organic ester derivatives of arsenic are quite labile to hydrolysis and this
chemical behavior has biochemical/toxicological implications in the postulated
role of arsenate ion in interfering with phosphorylation reactions.
Arsine (arsenic trihydride, AsH3) is the most poisonous of the arseni-
cal s, being a strong hemolytic agent, and it can be formed under certain
restricted conditions, i.e., reduction of the oxy compounds in the presence of
a strong hydrogen source.
Mono- and dimethyl arsenic arise by both environmental and i_n vivo trans-
formation processes.
In high-temperature processes, arsenic is released as a vapor which is
then adsorbed or condensed onto small particles. Such adherence to particles
of 1-2 urn or less may result in enhanced health risk from the agent since
particles in this size range are inhaled and deposited in the deepest part of
the respiratory tract.
013AS5/A 2-2 June 1983
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Arsenic compounds tend to form insoluble complexes with soils and sedi-
ments. In the case of soils, the interaction occurs with amorphous aluminum
or iron oxides.
2.1.2 The Environmental Cycling of Arsenic
Primary smelting, biocide use and glass manufacturing constitute some of
the major inputs of arsenic into the various environmental compartments. Of
an estimated total release of approximately 10,000 short tons annually in the
U.S., smelter activity accounts for about 50 percent, biocide (pesticide,
fungicide, herbicide) use contributes 32 percent, and glass production con-
tributes about 7.0 percent with the remaining amount being released from
various other sources.
The atmosphere is a major conduit for arsenic emitted from anthropogenic
sources to the other environmental compartments via wet and dry precipitation
processes. Dry and wetfall onto soils may be followed by movement through
soils either into groundwater or surface water. Passage of arsenic into
surface waters may be followed by transfer to sediments.
Such cycling is made complex by chemical and biological transformations
which have been reported as occurring in the various environmental compart-
ments.
Trivalent arsenic in the atmosphere or in aerated surface waters can
undergo oxidation to the pentavalent state, while pentavalent arsenic in media
which are below pH 7.0 and contain oxidizable material can react to form the
trivalent form via reduction.
Biological transformations of arsenic have been documented as occurring
via both sedimentary bacteria and suspended marine algae. Several different
hypotheses have been advanced to explain the biological cycling of arsenic.
013AS5/A 2-3 June 1983
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Reduction and methylation of inorganic arsenic occurs only to a limited
extent in soils, one report noting a conversion of only 1-2 percent over a
period of months.
With reference to the relative amounts of the annual environmental burden
of arsenic, it has been calculated for 1974 that land is the major sink for
arsenic, approximately 90 percent, with the atmosphere accounting for 7-8
percent and the smallest quantity appearing in waters.
2.1.3 Levels of Arsenic in Various Media
Available data on levels of arsenic in various media with which man
interacts are generally in the form of total arsenic content, with limited
information available for identifying specific chemical forms of arsenic in
the media.
2.1.3.1 Levels of Arsenic in Ambient Air—Based on the comprehensive data for
U.S. air levels of arsenic obtained by the U.S. EPA's National Air Sampling
Network, air levels of arsenic in the U.S. generally do not exceed 0.1 ug/m3.
Generally, airborne arsenic is adhered to particulate matter. Although
the immediate areas around smelters may contain some arsenic in the vapor
form, data is available to indicate rapid adherence to particulate matter when
sampling 2-3 km from these emission sites.
The specific chemical forrn(s) of airborne arsenic is still unclear.
Generally, in most urban/suburban areas, arsenic is mainly in the form of a
mixture of inorganic arsenic in the tri- and pentavalent states. Only in
areas where methylated arsenic is used agriculturally or where biotic trans-
formation can occur has methylated arsenic been found in air samples.
013AS5/A 2-4 June 1983
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2.1.3.2 Levels of Arsenic in Drinking Water—The most comprehensive survey of
community drinking water supplies for arsenic content was reported in 1970,
involving 18,000 systems. More than 99 percent of the sites sampled contained
less than the 10 ppb (0.01 mg/liter) detection limit, measured as total
arsenic.
Well waters in the western U.S. and Alaska, however, may have much higher
levels owing to geochemical enrichment. In Lane County, Oregon, recent ana-
lyses report levels up to 2.2 ppm (2.2 mg/liter), while the highest figure in
Alaska was 10 ppm (10 mg/liter), representing both natural and mining residue
contributions.
It is reasonable to assume that the chief chemical form of arsenic in
most public water supplies would be the pentavalent inorganic form, owing to
both aeration and chlorination. Similarly, well waters in Alaska and the
western U.S. are reported to mainly contain pentavalent inorganic arsenic.
2.1.3.3 Arsenic in Food—The most recent data base for the arsenic content of
foods is the 1975-1976 survey carried out by the U.S. Food and Drug Adminis-
tration. Shellfish and other marine foods have the highest levels on a food
category basis. Overall, the total dietary intake of arsenic in 1975-1976
was approximately 50 |jg (elemental arsenic), representing an increase from the
preceding years. Whether this increase represents a trend or merely reflects
random variation in sampling from year to year is still to be determined.
The chemical forms of arsenic in foods are varied and complex. Crusta-
ceans and other marine life store arsenic in complex organoarsenical forms
which, based on recent reports, are assimilated by man and generally excreted
intact. Toxicologically, these forms are comparatively inert.
013AS5/A 2-5 June 1983
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2.1-3.4 Arsenic in SoiIs—Background soil arsenic levels range from less than
1 ppm to over 40 ppm, the latter reflecting agricultural practices as well as
air fallout.
Soil arsenic is usually bound to clay surfaces, and its mobility is a
function of soil pH, phosphate levels, iron and aluminum content, and soil
type. The mobile fraction, usually in the pentavalent form, is of concern in
terms of movement to plants and water. Little reductive methylation occurs in
most soils.
2.1.3.5 Other Sources of Arsenic—Limited data on arsenic content of tobacco
suggests that more recent values range from around 1.5 ppm or less, while in
the past (1945) values up to 40 ppm were measured. This decrease reflects
reduced use of arsenical biocides in tobacco production.
2.2 ARSENIC METABOLISM
2.2.1 Routes of Absorption
Major routes of absorption of arsenic in the general population are
inhalation and ingestion, either by direct intake of food and water or secon-
dary to inhalation and swallowing. Arsenic uptake through the skin appears to
be a minor route of exposure. Factors affecting the extent of absorption
include chemical forms, particle size, and solubility.
2.2.1.1 Respiratory Absorption—Limited data from human subjects suggest that
about 40 percent of inhaled arsenic is deposited in the lungs, of which 75-85
percent is absorbed over several days, yielding a net absorption of
approximately 30 percent of the inhaled amount.
Several studies of smelter workers also confirm that significant absorp-
tion of inhaled arsenic occurs, as judged by rapidly rising urine arsenic
levels when exposure first occurs. Furthermore, the levels excreted are
correlated with workplace air levels.
013AS5/A 2-6 June 1983
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Animal data also indicate respiratory tract absorption when exposure
occurs by inhalation of aerosols or by intratracheal instillation.
2.2.1.2 Gastrointestinal Absorption—Based on a number of reports using human
subjects, soluble inorganic arsenic is almost totally absorbed from the gas-
trointestinal tract. Similar data has been obtained for such experimental
animal species as the rat, pig, and monkey.
Less soluble forms of arsenic, such as arsenic trioxide in suspension,
lead to considerably lower absorption while insoluble arsenic triselenide
passes through the human GI tract with negligible absorption.
2.2.1.3 Transplacental Transfer—Transplacental transfer of arsenic in man
appears to occur based on autopsy data and on one report showing that newborn
cord blood levels approximate those of the mothers. Measurable levels of
arsenic in fetal tissue have been determined by the fourth month of gestation,
increasing to month seven.
In animals, inorganic arsenic appears to rapidly cross the placenta!
barrier where it is distributed in embryonic tissue.
2.2.2 Biotransformation of Inorganic Arsenic In-Vivo
An understanding of inorganic arsenic metabolism in man and other species
is complicated by recently revealed biotransformations, processes discovered
because of the development of analytical techniques which permit the chemical
speciation of arsenic into its various forms. These processes not only relate
to pharmacokinetic parameters such as tissue distribution and excretion, but
also figure in the toxicology of the element. The two processes of signifi-
cance for consideration here are the methylation of inorganic arsenic and
oxidation-reduction interconversion of inorganic arsenic.
An extensive recent literature documents the i_n vivo methylation of
inorganic arsenic to mono- and dimethyl arsenic (the latter being the major
013AS5/A 2-7 June 1983
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methylated metabolite) in every mammalian system studied to date, including
man.
While the quantitative features of this phenomenon may vary among spe-
cies, one can generally state that: 1) dimethyl arsenic is the major trans-
formation product; 2) methylation represents a route of detoxification, the
methylated forms being not only much less toxic but also more rapidly ex-
creted; 3) the methylating capacity of a given system can persist over a range
of inorganic arsenic exposure but at some point can be overwhelmed; and 4)
retrospective assessment of early data on arsenic metabolism must be reviewed
in light of the current knowledge about biomethylation. In man, dimethyl
arsenic represents approximately 75-90 percent of total arsenic excretion,
with monomethyl arsenic being excreted in lesser amounts.
The demonstration of interconversion of the two valency forms of arsenic
claimed in earlier literature must be considered in light of the biomethyla-
tion phenomenon, and only more recent studies addressing this problem using
chemical speciation techniques can be considered reliable. Invariably, the
giving of inorganic penta- or trivalent arsenic to experimental animals or
human volunteers leads to predominantly methylated forms, with any inorganic
arsenic being present in small amounts. Two recent studies using similar
speciation methods and human subjects, offer conflicting data regarding the vr\
vivo reduction of pentavalent to trivalent arsenic. In one study, no increase
in urinary output of trivalent arsenic was seen when pentavalent arsenic was
given, while the second report notes levels of trivalent arsenic in urine
which are claimed to only arise from i_n vivo reduction. The former study used
one subject, the latter three subjects. Thus, in vivo reduction of inorganic
arsenic remains to be confirmed.
013AS5/A 2-8 June 1983
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Even with sophisticated analytical methods permitting chemical speciation
in biological media, the lability of arsenic in dosing solution to oxidation-
reduction requires careful assessment of the actual form being administered.
2.2.3 Distribution of Arsenic in Man and Animals
Blood is the main vehicle for transport of arsenicals following absorp-
tion, and from which arsenic is cleared relatively rapidly to tissues in all
species except the rat. In the rat, arsenic-erythrocyte interaction tends to
preclude rapid movement to tissues, with a biological half-time of up to 90
days, versus a corresponding time of several days in all other species.
Arsenic movement from blood appears to conform to a three-compartment model
which must reflect in part the biomethylation of inorganic arsenic noted
above.
Exposure of various experimental animals to either tri-or pentavalent
inorganic arsenic leads to initial accumulation of the element in liver,
kidney, spleen, aorta, and skin. In most species, arsenic clearance from soft
tissue is relatively rapid except for the skin, where the high sulfhydryl
group content probably promotes tight arsenical binding.
In man, tissue partitioning data is mainly available from autopsy data.
Heart, kidney, liver and lung have highest levels on a concentration basis, but
skin and excretory/storage organs such as nails and hair have the highest
absolute amounts. Brain tissue has levels only slightly below those of other
soft tissues.
Recent data on valency and exposure level effects on tissue distribution
of arsenic indicate that levels of arsenic in kidney, liver, bile, brain,
skeleton, skin, and blood are 2- to 25-fold higher for the trivalent form than
for the pentavalent state, and are greatly increased at higher dosing. The
difference is held to be due to the relative methylating capacity of either
form as well as the level of exposure.
013AS5/A 2-9 June 1983
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2.2.4 Arsenic Accumulation
The long-held view of arsenic as an element which accumulates in the body
was mainly based on the behavior of arsenic in the rat, an anomalous model
which does not reflect the case with other species. For other species, inclu-
ding man, long-term accumulation does not generally occur in psysiologically
active compartments in the body.
In man, the only evidence for tissue accumulation is autopsy data for
retired workers with a history of metal smelter exposure which indicates lung
arsenic levels 8-fold higher than in a control population. This suggests the
existence of a very insoluble form of arsenic in smelter ambient air.
2.2.5 Arsenic Excretion
Renal clearance appears to be the major route of excretion of absorbed
arsenic in man and animals. Biliary transport of the element leads to enteric
reabsorption, with little carriage in feces.
In man, inorganic arsenic is excreted rather rapidly, and in several
studies in which continuous exposure resulted in the acquisition of steady
state, around 60 percent of a given dose was excreted within one day.
The pattern of renal excretion reflects the j_n vivo biotransformation
capacity for inorganic arsenic, one study noting that trivalent arsenic was
excreted more slowly than an equivalent dose of the pentavalent form, and
higher doses of both forms were cleared relatively more slowly than lower
doses.
2.3 ARSENIC TOXICOLOGY
2.3.1 Acute Toxicity
Acute symptoms of arsenic poisoning are similar in both man and experi-
mental animals. With oral exposure, the acute symptoms include severe gastro-
intestinal damage resulting in vomiting and diarrhea and general vascular
013AS5/A 2-10 June 1983
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collapse leading to shock, coma, and death. Other acute effects are muscular
cramps, facial edema, and cardiovascular reactions. Airborne exposure at high
levels also results in severe irritation of nasal mucosa, larynx, and bronchi.
Sequalae of acute contact with inorganic arsenic include peripheral nervous
system disturbances with slow recovery and reversible effects on the hema-
topoietic system.
Levels of exposure associated with acute arsenic toxicity vary with the
valency form of the element, the trivalent state being approximately 4-fold
more toxic than pentavalent arsenic. Oral ID™ values for trivalent arsenic
vary from 15 to 293 mg/kg b.w. in rats and from 10-150 mg/kg in other test
species.
While a number of outbreaks of acute arsenic poisoning have been des-
cribed, few data exist on actual doses andi type of arsenical involved. One
report has estimated the human lethal dose to be anywhere from 70 to 180 mg
for arsenic trioxide.
2.3.2 Chronic Toxicity
Two categories of chronic arsenic toxicity can be discerned from the
available literature: 1) the carcinogenicity/mutagenicity of arsenic; and 2)
various non-carcinogenic chronic effects.
2.3.2.1 Carcinogenesis/Mutagenesis of Inorganic Arsenic—The current status
of inorganic arsenic as a human and experimental animal carcinogen has been
extensively and critically reviewed by public agencies such as the National
Institutes of Occupational Safety and Health, scientific bodies such as the
National Academy of Science and the International Agency for Research on
Cancer, and in a number of individual assessments.
At present, the collective evidence for an etiological role of inorganic
arsenic in human cancers is strongest for cancers of the skin and lung.
013AS5/A 2-11 June 1983
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In man, chronic oral exposure to arsenic induces a sequence of changes in
skin epithelium, proceeding from hyperpigmentation to hyperkeratosis charac-
terized as keratin proliferation of a verrucose nature, and leading in some
cases to late onset skin cancers. The skin cancers can be histopathologically
characterized as either squamous carcinomas in the keratotic areas or basal
cell carcinomas.
Arsenic-associated skin cancers, regardless of type of exposure, differ
from those having an ultraviolet light etiology in that they occur on un-
exposed areas such as the palms and soles and occur as multiple lesions. The
latency period for such lesions has been reported to range from 13 to 50 years
for arsenical medicinally induced skin cancer. The most reliable study of
skin cancer associated with arsenic-contaminated drinking water found the
human latency period to be 24 years.
Lung cancers associated with occupational exposure to arsenic appear to
be mainly of the poorly differentiated and small-cell undifferentiated epi-
dermoid carcinoma type, although well-differentiated epidermoid carcinoma and
acinar-type adenocarcinoma have also been noted. The latency period for such
lung cancer due to occupational arsenic exposure at smelters has been reported
to range from 13 to 50 years.
While other visceral cancers have also been claimed to be associated
with arsenic exposure, the data base for such association is less conclusive
than for cancers of skin and lung.
2.3.2.1.1 Human Epidemiology of Arsenic Carcinogenesis. Disease-producing
inorganic arsenic exposures have been demonstrated in both occupational and
non-occupational populations for copper smelters, metallurgical processing
plants, contaminated drinking water, accidental food poisoning, the manu-
facture and agricultural uses of pesticides and therapeutic uses of arsenical
drugs.
013AS5/A 2-12 June 1983
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Major health end points strongly associated with arsenic exposures in-
clude general mortality, lung cancer mortality, skin cancer, peripheral vascu-
lopathy, hyperkeratosis and dermatitis. Of these, cancer of the lung and skin
have received the most attention. Furthermore, epidemiological reports re-
lating to arsenic exposures have a wide geographical distribution, with
studies in the United States, Europe, Asia and South America.
Lung Cancer
An excess mortality in respiratory cancer has been noted among smelter
workers and among workers engaged in the production and use of arsenical pes-
ticides. In a number of these studies, the levels of exposure are uncertain
and there is simultaneous exposure to agents such as other metals and sulfur
dioxide. Furthermore, some of these studies did not take into account the
effects of cigarette smoking.
A proportionate mortality study of an English factory which manufactured
arsenite as a sheep dip powder found that workers at the facility had a pro-
portion of lung cancer deaths twice that for other workers in the geographic
area. Of the total factory group, the chemical workers, who were the most
closely associated with the arsenite production, accounted for all of the
lung cancer deaths and had a higher proportion of deaths from all cancers than
the total factory population. Air exposure information was limited, high
3
levels up to 4 mg As/m having been reported only for 1945-1946. The outcome
of the earlier English study has been supported by studies of two facilities
in the United States. At one facility manufacturing lead-, calcium-, and
magnesium arsenate and copper acetoarsenite over the period 1919-1956, the
ratio of observed-to-expected lung cancer deaths among workers was evaluated
on the basis of exposure level, giving ratios ranging up to 7:1 in the highest
exposure category.
013AS5/A 2-13 June 1983
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The second U.S. facility, in Baltimore, MD, has been the subject of two
occupational studies. At this operation, production of lead-, calcium-, and
sodium arsenate was started in the early 1950s. Air levels of arsenic were
not available. In the most recent report --a followup of workers employed
from 1946 to 1974 — statistically significant increases in lung cancer deaths
were found predominantly in arsenical production workers employed before 1946
and with more than 25 years of employment. Information on smoking history was
not obtained.
Occupational exposure to arsenic also occurs in smelters. Several re-
ports have centered on workers at a copper smelter in the State of Washington.
In the most recent publication concerning cancer deaths at this facility, an
increase in overall mortality, a significant increase in cancer deaths, and a
highly signficant increase in deaths from lung cancer were noted. Although
cigarette smoking was not taken into account, a clear lung cancer dose response
by arsenic exposure was found.
Other U.S. studies have been done at smelter sites in Utah and Montana.
In the Utah study, smelter workers showed a 3-fold increase in the lung cancer
death rate compared to the general population of the state. Exposure to
sulfur dioxide, and copper, as well as arsenic, were found to be signifi-
cantly higher for the lung cancer cases. Differences in smoking habits could
not explain the excess lung cancer mortality. Smelter workers at the Montana
smelter were found to follow a lung cancer dose response by arsenic exposure.
Differences in smoking habits could not explain the differences in lung cancer
mortality. There was found to be little association, if any, between sulfur
dioxide exposure and lung cancer mortality.
013AS5/A 2-14 June 1983
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Excess lung cancer mortality has also been reported for workers in for-
eign smelters. Several reports have concerned the smelter facility in Sweden.
In this operation, it was found that arsenic exposure was associated with in-
creases in lung cancer deaths, the ratio being 4.6 for a work history of more
than 17 years. Sulfur dioxide exposure was not found to be associated with
lung cancer, nor could the results be explained by differences in smoking
habits. A study of smelter workers in Japan has also reported a positive
association between smelter employment and lung cancer. Workers in the high-
est exposure and longest follow-up category were reported to have a 25-fold
increase in lung cancer mortality.
Several studies suggest that populations surrounding arsenic-emitting
sources are at a greater risk of lung cancer. One study found that lung can-
cer in counties with smelters was significantly higher than in counties with-
out smelters. Another study found an association between residence in an area
surrounding an arsenic pesticide plant and lung cancer mortality even after
controlling for employment at the pesticide plant. Two lung cancer mortality
studies of populations in the vicinity of smelters are inconclusive with
regard to lung cancer risk in the general population because lung cancer
deaths of workers at the smelters were included in the analyses. It should be
noted that none of these studies addressed the effects of population migration,
however.
Skin Cancer and Precancerous Lesions
All of the occupational studies on arsenic were mortality studies. Be-
cause skin cancer is rarely fatal, the occupational studies, in general, did
not find excesses of skin cancer. The English study referred to in the pre-
ceding section, however, did note that cancer deaths among those factory
013AS5/A 2-15 June 1983
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workers with skin cancer was 13.6 percent compared to a figure of 1.3 percent
in the reference population.
Most of the available information on the association of arsenic with skin
cancer has involved non-occupational populations in geographical areas as
diverse as Taiwan, Argentina, and northern Europe, and has involved arsenic in
drinking water or medicinal preparations.
In Taiwan, exposure started in 1910-1920 with the availability of water
from deep wells. In the most comprehensive study of this group, 37 villages
with a population of 40,421 were surveyed in 1965 and the prevalence rate of
skin cancer categorized by arsenic exposure and age. The prevalence rate of
skin cancer increased with both well water arsenic and age. The greatest
prevalence rate was in the >-60-years age group (192.0/1,000 subjects) exposed
to well water with an arsenic content of > 0.6 ppm. There was a similar
ascending gradient for hyperkeratosis, an apparent precondition for the later
onset of skin cancer.
In Cordoba, Argentina, arsenical waters have also been reported to be
associated with increased rates of skin cancer among the population using this
water. In the various reports on this area, it has been noted that over 81
percent of persons with "arsenical-type" skin epitheliomas presenting them-
selves at a particular dermatology clinic came from areas where high levels of
arsenic were known to be present in the water supplies and where arsenicism
among individuals was known to occur. Lack of information on the size of the
populations in each geographic area limit the conclusions that can be drawn
from the study, however.
In Antofagasta, Chile, the presence of a relatively high level of arse-
nic, 0.6 ppm, in the public drinking water from 1958 to 1970 was shown in a
013AS5/A 2-16 June 1983
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number of epidemic "logical surveys to have resulted in a high number of skin
lesions including hyperkeratosis, a recognized precondition for skin cancer.
In one report of cases seen and diagnosed from 1968 to 1971 in Antofagasta,
the author reported 457 patients with various cutaneous lesions including leu-
koderma, melanoderma, hyperkeratosis, and squamous-cell carcinoma; all had
high arsenic content in the hair. The number of cases for each diagnosis was
not specified.
An investigation of the population having contact with well waters con-
taining elevated levels of arsenic in an area of Oregon did not yield any
evidence for skin cancer associated with such exposure, nor did a similar
study in Utah. The population sample sizes of the Oregon and Utah studies
were too small to detect the increase in skin cancer prevalence that would be
predicted from the Taiwanese study, however.
The chronic ingestion of trivalent arsenic present in the medicinal
preparation, Fowler's Solution, has been shown to be associated with the
typical arsenic dermatopathology, including skin cancer. In one detailed
study of patients with a history of Fowler's Solution use, 21 cases of skin
cancer and 106 cases of hyperkeratoses were found among 262 subjects. Both
the hyperkeratosis and skin cancer prevalence rates were found to increase as
the total ingested amounts of the arsenical increased. The minimal latency
period for hyperkeratosis was 2.5 years while the minimal latency period for
skin cancer was 6 years, with an average of 14 years.
Internal neoplasms associated with arsenic exposure have been reported in
subjects exposed to medicinal arsenic as well as in such occupational groups
as vintners and smelter workers.
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2.3.2.1.2 Experimental studies of arsenic carcinogenesis. In summary, arse-
nic carcinogenicity in test animals, using different chemical forms, routes of
exposure, and various experimental species, has not been documented. Part of
the difficulty may lie in the selection of an appropriate animal model. The
absence of skin cancers in the experimental animals used could be accounted
for by their skin being poor models of human skin. Rat results must be con-
sidered suspect because the rat is anomalous in how it handles arsenic meta-
bolically.
In mice, exposure to inorganic arsenic by various routes yielded negative
results.
Some data exist to suggest that inorganic arsenic may be a co-carcinogen,
particularly with benzo(a)pyrene.
2.3.2.1.3 Arsenic mutagenesis. Both i_n vivo and i_n vitro mutagenic responses
have been documented for tri- and pentavalent arsenic and these have taken the
cytological form of both chromosomal and point mutation disturbances.
In a recent, detailed study of Swedish smelter workers, chromosomal
responses consisting of gaps, chromatid aberrations, and chromosomal aberra-
tions were ranked with respect to degree of arsenic exposure as well as such
factors as age, employment period, and smoking habits. The frequency of all
aberrations was higher in all worker categories than in the control group.
However, the correlation between frequency of aberrations and arsenic exposure
was not very good. No isolated effect of smoking was noted.
Chromosomal aberrations were studied in cultured lymphocytes from sub-
jects treated with arsenic, mainly for psoriasis. The incidence of aberra-
tions in the form of secondary constrictions, gaps and broken chromosomes were
very significantly higher than in a control group of psoriatic and eczemous
patients.
013AS5/A 2-18 June 1983
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Both arsenate and arsenite appear to impair DNA repair processes in E.
coli and human epidermal cells after UV irradiation, while arsenate has been
cited as inhibiting human lymphocyte transformation by retarding thymidine
uptake into DNA.
Exposure of cells in culture to varying levels of arsenic produces the
same chromosomal changes that are seen in subjects exposed to arsenic. The
magnitude of these effects is greater for trivalent arsenic than for the
pentavalent form.
2.3.2.2 Chronic Neurological Effects of Arsenic Exposure—Both peripheral and
central nervous system effects have been documented in man and animals exposed
to inorganic arsenic.
Peripheral nervous system effects have been noted in workers occupation-
ally exposed to arsenic and in individuals accidentally exposed to foodstuff
arsenic. Some of these effects follow an insidious course, appearing months
or years after onset of exposure. Effects are of both the sensory and motor
types, sensory deficits manifesting themselves first. The resulting poly-
neuropathies tend to follow a slow course of recovery over months or years.
More subtle neurological effects, such as neuromuscular disturbances and
altered nerve conduction velocity have also been reported by various inves-
tigators.
While there are documented cases of central nervous system effects in
children due to acute or subacute exposure, chronic arsenic intoxication as a
factor in such abnormalities as hearing impairment has not been confirmed.
Few useful animal models exist for the central and peripheral nervous
system effects seen in humans. One study has reported evidence of CMS func-
tional deficits in rats exposed to arsenic trioxide aerosol, while a second
013AS5/A 2-19 June 1983
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report claims impaired behavioral responses in rats given arsenic trioxide by
mouth. Since rats handle arsenic differently than all other species, the
significance of these data is not clear.
2.3.2.3 Cardiovascular Effects of Arsenic Exposure—Cardiovascular effects
associated with chronic arsenic intake include the Blackfoot Disease seen in
Taiwanese consuming well water having elevated arsenic. This is a peripheral
vascular disease leading to gangrene of the extremities. Since ergotamine-
like compounds were also present in the waters, the conclusive role for arsenic
is not clear. Peripheral vascular changes have been documented among German
vintners who were exposed occupationally to arsenic pesticides as well as ar-
senic in wine.
2.3.2.4 Other Systemic Effects of Arsem'c--Non-cancerous respiratory effects
of inorganic arsenic are mainly seen with occupational exposure and with
arsenic trioxide. In one study of smelter workers, those handling refined
arsenic showed nasal septum perforation and rhinopharyngolaryngitis while
workers in roaster, furnace and converter areas showed tracheobronchitis and
pulmonary insufficiency.
Teratogenic effects of arsenic compounds at relatively high exposure
levels have been demonstrated in a number of animal species, including ham-
sters, rats, and mice. Generally, such effects have been observed after
parenteral administration of either arsenite or arsenate. Oral exposures of
animals to these same arsenic compounds at lower doses, by contrast, have not
been shown to produce any notable effects on reproduction and development.
There is little evidence that inorganic arsenic is a human teratogen.
Hepatic effects have been noted in a number of studies dealing with
chronic intake of arsenic. These disturbances take the form of cirrhosis and
portal hypertension. One complicating factor in occupational exposure assess-
ment has been the effect of alcohol consumption.
013AS5/A 2-20 June 1983
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Chronic exposure to arsenic via well water contaminated by arsenic,
medicinals, or in the workplace, produces a reversible anemia. Rats, mice,
and cats fed either arsenite or arsenate show reduced hemoglobin production
via disturbance of the ALA-synthetase and heme synthetase steps in the heme
biosynthetic pathway.
Renal effects seen with arsenite or arsenate exposure in either man or
animals have been poorly characterized.
2.3.3 Factors Affecting Arsenic Toxicity
The most widely recognized and studied interactive behavior of arsenic is
with selenium, the pair being antagonistic in effect in all animal species
studied. Dietary arsenic supplementation is known to protect against selenium
toxicity, while selenium protects against either tri- or pentavalent arsenic.
Arsenite shows a protective effect for selenite toxicity in cell cultures but
the reverse does not appear to be the case.
Little data exists for interactive relationships between arsenic and
other elements. One report notes that cadmium and arsenic given simultane-
ously by the oral route retarded weight gain in young adult rats to a greater
extent than either element given alone.
2.4 ARSENIC AS AN ESSENTIAL ELEMENT
Inorganic arsenic appears to be an essential element in certain animal
species—rats, goats, chicks, and minipigs--based on the observation of
detrimental effects using diets deficient in the element.
In rats, arsenic-deficient diets in pregnant dams are associated with
slow growth, enlarged spleens, erythrocyte dysfunction in post-weaning off-
spring, and greater perinatal mortality.
013AS5/A 2-21 June 1983
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In studies using goats and minipigs, diets having less than 50 ppb As
produced effects in the adult animals as well as in their offspring. Morta-
lity of adult goats was increased as was the mortality of both kids and pig-
lets. In chicks, arsenic deprivation influenced the effects of dietary ar-
ginine, manganese, and zinc, the fluctuations of which variously affected
metabolic activity.
Remaining to be independently demonstrated are a physiological role for
arsenic, the existence of any specific carrier in the body, or arsenic essen-
tiality in man.
2.5 HUMAN HEALTH RISK ASSESSMENT FOR ARSENIC
This portion of the summary contains the data summarized earlier, placed
in a perspective of the possible quantitative risk posed to the general popula-
tion of the United States by arsenic exposure. Categories of consideration
include (1) levels of arsenic in media relevant to the U.S. population; (2)
those effects relevant to the general population; (3) indicators of exposure,
specifically "internal dose" measures; (4) dose-effect and dose-response
relationships which can be determined from available information; and (5) the
identification of groups within the general population who may be at increased
risk for the health effects of arsenic.
2.5.1 Exposure Aspects of Arsenic
Arsenic exposure in the general population of the United States occurs
via inhalation and ingestion of water and food.
Respiratory intake of arsenic on a daily basis is approximately 0.12 ug,
of which 0.03 ug would be absorbed, assuming 30 percent absorption and based
3
on a 1981 national average air value of 0.006 ug/m of air and a daily venti-
lation rate of 20 m .
013AS5/A 2-22 June 1983
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Since much of the U.S. drinking water supply is below the 10 ug/liter
level, daily consumption of water at a rate of 2 liters would lead to an
intake < 20 ug.
Based on FDA figures from 1975 to 19/6, daily arsenic intake from food is
approximately 50 ug (elemental arsenic) for adults. If one assumes at least
80 percent absorption of this daily intake, approximately 40 ug is the ab-
sorbed amount. It should be noted, however, that arsenic in certain foods is
known to be in a chemically complex form that is relatively resistant to
metabolism and toxicologically inert and, consequently, is rapidly excreted
intact. Therefore, the amount of absorbed food arsenic considered to be
toxicologically significant is relatively small compared to total arsenic
intake.
Cigarette smoking contributes about 6 ug/pack of cigarettes in mainstream
smoke, of which approximately 2.0/ug pack would be absorbed.
Thus, the aggregate absorbed amount is approximately < 60 ug for non-
smokers. However, the actual amount of toxicologically significant arsenic
taken in daily would probably be closer to 20 ug or less.
2.5.2 Effect/Response Aspects of Arsenic
2.5.2.1 Relevant Health Effects—General population concerns are with effects
arising from long-term exposure to moderate levels of arsenic.
One can rank health effects germane to the general population as follows:
1. Respiratory tract cancer.
2. Skin cancer.
3. Non-cancerous skin lesions.
4. Peripheral neuropathological effects.
5. Cardiovascular changes.
Cancer of the respiratory system is clearly associated with exposure to
arsenic via inhalation. This association has been especially noted among
013AS5/A 2-23 June 1983
-------
workers engaged in the production and usage of pesticides and among smelter
workers. The latency period for lung cancer due to occupational arsenic expo-
sure has been reported to range from 13 to 50 years.
Cancer of the skin has been found as a dose-dependent effect in a Tai-
wanese population with lifetime exposure to well water arsenic as well as
among people who were treated with large doses of arsenite for skin disorders.
Arsenic-associated skin cancers occur on areas of the body generally unexposed
to the ultraviolet light of the sun, such as the palms of hands and soles of
feet. The latency period for skin cancer has been reported to range from 13
to 50 years for arsenical medicinally-induced cancer. In the Taiwanese drink-
ing water study, the latency period was reported to be about 24 years.
The International Agency for Research on Cancer (IARC) has concluded that
there is sufficient evidence that inorganic compounds are both lung and skin
carcinogens in humans.
Hyperkeratosis and hyperpigmentation, sometimes with precancerous changes,
have been a common finding in persons ingesting arsenic. These skin lesions,
like the manifest cancer, develop on surfaces usually unexposed to sunlight.
Peripheral nervous system effects range from sensory-motor deficits with
higher exposure to changes in electromyography and nerve conduction velocity
at long-term, low levels of contact with arsenic.
Vascular effects, such as Blackfoot Disease (peripheral vasculopathy)
have been noted in a Taiwanese population having life-long arsenic exposure;
however, these effects may have been confounded by the presence of ergotamine-
like compounds. Peripheral vascular changes have also been found in German
vintners exposed occupationally to arsenic pesticides as well as arsenic in
wine.
013AS5/A 2-24 June 1983
-------
2.5.2.2 Dose-Effect/Dose-Response Relationships—The general question of how
to define and employ a dose factor in attempts at quantitative assessments of
human health risk for any toxicant is highly dependent upon 1) the available
information on the body's ability to metabolize the agent, and 2) the assess-
ment of the relative utility of various internal indices of exposure.
The time period over which a given total intake occurs is highly impor-
tant. For example, intake of one gram of arsenic over a period of years would
be quite different pathophysiologically from assimilating this amount at one
time, the latter probably having a lethal outcome. This time-dependent beha-
vior is related in part to the relative ability of the body to detoxify inor-
ganic arsenic by methylation as a function of both dose and time.
In cases of acute and sub-acute exposure, indicators of internal exposure
such as bood or urine arsenic levels are probably appropriate for assessing
the intensity of exposure.
With chronic, low-level exposure, however, the available data would indi-
cate that the total amount assimilated is probably more important than an
indicator concentration without knowledge of the total exposure period. An
added problem is the background level of arsenic found in some indicators due
to dietary habit. Therefore, in low-level chronic exposures, arsenic levels
in blood or urine would only be moderately increased over background levels.
Hair arsenic levels cannot be employed as reliable indicators of exposure
because no methods exist for distinguishing external contamination levels from
those accumulated via absorption and metabolic distribution.
Given the above limitations concerning the use of blood, urinary or hair
arsenic concentrations as internal indices of cumulative, long-term low-level
arsenic exposure, the dose-effect/dose-response relationships summarized below
013AS5/A 2-25 June 1983
-------
are done so mainly in terms of external arsenic exposure levels via either
inhalation or ingestion.
From available data, the Carcinogen Assessment Group (CAG) of the U.S.
Environmental Protection Agency (EPA) has estimated carcinogenic unit risks
for both air and water exposures to arsenic. The quantitative aspect of
carcinogen risk assessment is included here because it may be of use in
setting regulatory priorities, evaluating the adequacy of technology-based
controls, and other aspects of the regulatory decision-making process. How-
ever, the imprecision of presently available technology for estimating cancer
risks to humans at low levels of exposure should be recognized. At best,
the linear extrapolation model used (see Section 5.2.1.4) provides a rough
but plausible estimate of the upper limit of risk—that is, with this model
it is not likely that the true risk would be much more than the estimated
risk, but it could be considerably lower. The risk estimates presented
below should not be regarded, therefore, as accurate representations of
true cancer risks even when the exposures involved are accurately defined.
The estimates presented may, however, be factored into regulatory decisions
to the extent that the concept of upper-risk limits is found to be useful.
The air estimates were based on data obtained in five separate studies
involving three independently exposed worker populations. Linear and quadra-
tic response models in both the absolute and relative form were fitted to the
worker data. It was found that for the models that fit the data at the
p = .01 or better level, the corresponding unit risk estimates ranged from
-4 -2
1.05 x 10 to 1.36 x 10 . However, linear models were found to fit better
than quadratic models and absolute models fit better than relative models.
The CAG also felt that exposure to trivalent arsenic was more representative
of low environmental exposure than pentavalent arsenic. Restricting their
unit risk estimates to those obtained from linear absolute models where exposure
013AS5/A - 2-26 June 1983
-------
-3 -3
was to trivalent arsenic gave a range of 1.25 x 10 to 7.6 x 10 . A weighted
average of the five estimates in this range gave a composite estimate of 4.29 x
ID'3.
The unit risk estimates for water were based on an extensive drinking
water study which was conducted in a rural area of Taiwan. An association
between arsenic in well water and skin cancer was observed in the study popu-
lation. Using the male population, who appeared to be more susceptible, the
CAG estimated that the unit risk associated with drinking water contaminated
-4
with 1 ug/£ of arsenic was 4.3 x 10 .
To compare the air and water unit risks, the CAG converted the exposure
units in both cases to mg/kg/day absorbed doses, which resulted in unit risk
estimates of 50.1 and 15.0, respectively.
The potency of arsenic compared to other carcinogens was evaluated by
+3 -1
noting that an arsenic potency of 2.25 x 10 (mMol/kg/day) lies in the
first quartile of the 52 suspect carcinogens that have been evaluated by the
CAG.
The U.S. EPA is presently examining information from studies on both
patient and general populations which have been exposed to arsenic via
medicinals or drinking water, respectively, in order to determine whether
quantitative dose-response relationships can be established for non-cancerous
skin lesions.
While the qualitative evidence for peripheral neurological effects and
cardiovascular changes in arsenic exposed populations is well-established, the
data are insufficient for determining quantitative dose-response relationships
at the present time.
2.5.3 Populations at Special Risk to Health Effects of Arsenic
From a Japanese study, which reported on the poisoning of children ex-
posed to arsenic in infant milk formula, young children may be considered at
013AS5/A 2-27 June 1983
-------
risk for acute exposure to arsenic. From the clinical reports published at
the time of the mass poisoning, as well as those from follow-up studies, a
number of signs of central nervous system involvement were noted at both the
time of the episode and much later, with the follow-up studies showing behav-
ioral problems, abnormal brain wave patterns, marked cognitive deficits, and
severe hearing loss.
Because children consume more water per body weight than do adults, the
daily intake of arsenic via drinking water per kilogram body weight would be
greater in children. This might have implications regarding chronic exposure
effects in children. However, it should be noted that serious health effects
due to chronic exposure of arsenic in drinking water have not been found at a
greater frequency in children than adults.
Individuals residing in the vicinity of certain arsenic emitting sources,
e.g., certain types of smelters, may be at risk for increased arsenic intake
because of both direct exposure to arsenic in air and indirect exposure via
arsenic secondarily deposited from air onto soil or other human exposure
media. The relative contribution from such indirect exposures to increased
risk would be difficult to define, however.
A less-defined group at risk would be cigarette smokers due to some arse-
nic in tobacco, but it is not clear just what the quantitative increase in
risk would be.
013AS5/A 2-28 June 1983
-------
3. BACKGROUND INFORMATION
3.1 CHEMICAL/PHYSICOCHEMICAL ASPECTS
Compounds of arsenic in various chemical forms have most prominently
figured in the extensive history of the toxicology of the element. The
physical properties for several of these compounds are presented in Table 3-1.
In contrast, the element in the metallic, zero-valent form is of minor
toxicological interest.
Geochemically, arsenic is encountered as a component of sulfidic ores,
occurring as the arsenides and diarsenides of metals such as nickel, cobalt,
and copper, and is present in rocks and soils at trace levels. Smelting of
commercially important metal ores, therefore, often has associated with it the
release into the environment of significant quantities of certain arsenic
compounds. For example, arsenic trioxide, As^O.,, a major form of the element
in terms of its toxicological history, is a smelter product arising from air
roasting of metallic arsenides or arsenic-containing sulfides.
Arsenic trioxide, white arsenic, is only slightly soluble in water and
other solvents which do not promote chemical transformation. Its solubility
in solvents which mimic physiological media may not necessarily be the same as
for simple solvents, e.g., gastric juice versus water. Arsenic trioxide
sublimes, the process becoming pronounced at 135°C. This property appears to
have been overlooked through the years in considering analytical methods for
measuring levels of the compound. Dissolution of the trioxide in aqueous
media leads to formation of arsenous acid, H^AsOo, while alkaline treatment
leads to formation of the arsenite ion, AsO(OH) ~, with both the acid and the
salt being freely soluble in a number of solvents.
013AS1/D 3-1 June 1983
-------
TABLE 3-1. PHYSICAL PROPERTIES OF ARSENIC AND ARSENIC COMPOUNDS
o
1 — '
00
3=
oo
00
1
IX)
Chemical name
Arsanilic acid
Arsenic
Arsenic pentoxide
Arsenic sulphide
Arsenic trioxide
Arsine
Calcium arsenate
Dimethylarsinic
acid
Lead arsenate
Atomic/
mol ecular
weight
217.07
74 92
229.84
246.04
197.84
77.95
398.08
138.00
347.12
Melting
point
(°C)
232
817 (28 atm)
(triple-point)
315 (dec.)
300
312.3
-113.5
200
720 (dec. )
Boi 1 ing
point
(°C)
—
613 (sublimes)
---
707
465
55 (dec 230)
---
—
Density
(9/cm3)
1.9571*°
5.727"1
4.32
3.43
3.738
2.695 (gas)b
1.689849 (liq
3.62
5.79
Crystal system
monoclinic needles from
water or ethanol
hexagonal , rhombic
amorphous
yellow or red monoclinic
needles (change from yellow
to red at ~170°C)
amorphous or vitreous
colourless gas
.)
amorphic powder
prism
monoclinic leaves
CAS
Number
98-50-0
7440-38-2
1303-28-2
1303-33-9
1327-53-3
7784-42-1
7778-44-1
75-60-5
7784-40-9
Methanearsonic
acid, disodium
salt
Methanearsonic
acid, monosodium
183.9
132-139
crystal 1ine
144-21-8
salt
Potassium arsenate
Potassium arsenite
Sodium arsenate
dodecahydrate
Sodium arsenite
Sodium cacodylate
161.9 115-119
180.04 288
254.8
423.93 86.6
129.91
159.98 200
— cyrstalline
2.867 tetrahedral
— powder
1.752-1.804 trigonal or hexagonal prism
1.87 powder
— cyrstalline
2163-80-6
7784-41-0
13464-35-2
7631-89-2
7784-46-5
124-65-2
.Vapour pressure 0.653 (200°C)
Specific gravity (air = 1)
Source: Adapted from International Agency for Research on Cancer (1980).
c»
GO
-------
Arsenic pentoxide, As?05, may be readily prepared by nitric acid oxida-
tion of elemental arsenic or the trioxide. Compared to the trioxide, the
pentoxide has considerable solubility in water (63.0 g/100 g water), presumably
dissolving to form the relatively strong arsenic acid, H-jAsO.. In acid media,
arsenic acid has oxidizing potential (E°=0.56V).
The relative stability of solutions of arsenic or arsenous acids to
oxidation-reduction is of considerable importance in terms of valency-dependent
arsenic toxicity. In oxygenated media, one would expect the pentavalent form
to dominate, while reducing media would favor the trivalent state.
Arsenous and arsenic acids both form mono-, di- and tri-metal salts, the
alkali-metal salts such as potassium and sodium arsenite being freely soluble
in water and the alkaline salts such as calcium or magnesium arsenite being
slightly soluble.
While tri-organic esters of the tri- and pentavalent arsenic acids are
known, they are labile to hydrolysis and one would expect the mono- and di-
organic derivatives to be even more so. This behavior has implications in the
postulated role of arsenate ions in interfering with phosphorylation reac-
tions.
Arsine (arsenic trihydride, AsH3) is a strong hemolytic toxicant and
probably the most poisonous of the arsenicals. Although generally a minor
factor in the environmental chemistry of arsenicals, it can form under certain
restricted conditions, i.e., via reduction in the presence of a strong hydro-
gen source.
Mono- and dimethyl arsenic, in the form of methyl arsonous and methyl
arsonic, dimethylarsinous and dimethylarsinic (cacodylic) acids occur both in
the environment and are formed via i_n vivo transformation in many mammalian
013AS1/D 3-3 June 1983
-------
species, including man; such organic arsenic compounds are also of commercial
significance. For instance, both methylarsonic and dimethylarsinic acids,
usually in the form of the mono- or dialkali salts, are employed as herbicides
which, when released into the environment, may undergo reduction to the cor-
responding labile arsine compounds, CH.AsH, (methylarsine) and (CH0)0 AsH (di-
•3 L- 6 £.
methylarsine) (Arsenic. NAS, 1977). Like the trivalent inorganic arsenic,
methylarsonous acid can interact with thiol groups (as can cacodylic acid) to
form the CH3-As(-S-)2 and (CH3)2-As-S groups respectively. The physical forms
of arsenic in the environment depend on its mode of emission and subsequent
interactions with other materials.
Arsenic, along with other trace metals, can be mobilized in association
with airborne particles derived from high-temperature sources such as fossil-
fueled power plants, metallurgical smelters and blast furnaces.
Arsenic compounds form insoluble complexes with soils and sediments.
With soils, the interaction involves clay surfaces containing amorphous alu-
minum or iron oxides (Woolsen, 1976).
3.2 ENVIRONMENTAL CYCLING OF ARSENIC
Inorganic arsenic is real eased into the environment from a number of
anthropogenic sources which include primary copper, zinc and lead smelters,
glass manufacturers (specifically those that add arsenic to the raw materials)
and arsenic chemical manufacturers. Figure 3-1 presents a generalized scheme
for the geochemical cycling of arsenic through various compartments of the
environment. The atmosphere is a major conduit for arsenic emitted from
anthropogenic sources to the balance of the cycle via wet and dry precipita-
tion processes. The rate of movement of arsenic from the atmosphere is not
known at present.
013AS1/D 3-4 June 1983
-------
O
I—'
CO
CO
I
en
c.,
c
3
in
UD
CD
CO
INHALATION OF OUST
I AND GASEOUS FORMS
. OF ARSENIC
1
1
1
1
ATMOSPHERE
t
1
1
1
BIOSPHERE
PLANTS T~^ ANIMALS
DEGRADATION
DEGRADATION ABSORPTION "«£bsS-
AND AND QfrNrifr
SOLUTION ADSORPTION 'bVfc.
I I X
VAPORIZATION
PRECIPITATION
HYDROSPHERE
WATER T"" SEDIMENTS
1 1
CHEMICAL PRECIPITATION SOLUTION I
AND SEDIMENTATION MECHANIC
OF SOLIDS , WEATHERI
I 1
OUST
• CHEMICAL
PRECIPITATION
LITHOSPHERE
ROCKS
ARSENIC -BEARING
DEPOSITS
PRECIPITATION
SOLUTION
\HO
AL
NG
SOLUTION AND
MECHANICAL
WEATHERING
PEOOSPHERE
SOILS
GLACIAL MATERIALS
i
PRECIPITATION AND
CONSOLIDATION OF SOLIDS
Figure 3-1. The generalized geochemical cycle for arsenic.
Source: Union Carbide (1977).
-------
Dry and wet fall onto soils may be followed by movement through soils
either into ground water or surface water. Passage of arsenic into surface
waters may then be followed by further transfer to sediments.
Complicating an understanding of the environmental cycling of arsenic are
the existence of chemical and biochemical transformations which occur within
the cycle.
Trivalent arsenic in the atmosphere can undergo oxidation to the penta-
valent state. Such conversion can also occur in aerated surface waters. On
the other hand, pentavalent arsenic in an aqueous medium which is somewhat
acidic is an oxidant, and in the presence of oxidizable material it will react
to form trivalent arsenic (NAS, 1977).
One hypothesis of the biological cycling of arsenic is presented in a
generalized scheme set forth in Figure 3-2. In this scheme Wood (1974),
proposes that sedimentary bacteria link arsenate to arsenite, which in turn
may be altered to form methyl- and dimethyloxy arsenicals. Further action of
bacteria and molds transform these intermediates to di-and tri-methyl arsine.
These volatile products pass into the hydrosphere and then into the atmosphere,
where oxidative transformation to dimethyl-arsinic acid and, further, to
inorganic arsenic occurs.
More recent reports by Andreae and co-workers (Andreae and Klump, 1979;
Andreae, 1979; 1980; 1982) dispute this hypothesis with respect to marine
environments. In analyses performed by Andreae and other workers, no volatile
organoarsenic compounds were found to be formed in seawater, negating the
hypothesis suggesting that reductive bromethylation resulting in volatile
compounds serves as a contributing source to the atmospheric cycle of arsenic.
013AS1/D 3-6 June 1983
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AIR
DIMETHYLARSINE
TRIMETHYLARSINE
HO
11 BACTERIA " BACTERIA
O O
II
BACTERIA
HO — AsT—CHr
II
O
ARSENATE
SEDIMENT
ARSENITE
METHYLARSENIC
ACID
DIMETHYLARSINIC
ACID
Figure 3-2. The proposed biological cycle for arsenic.
Source: Wood (1974)
013AS1/D
3-7
June 1983
-------
While the authors did note the occurrence of biomethylation, the observed
products were non-volatile, water-soluable methlylated oxoacids of low toxi-
city. Further, the site of biotransformation was reported to be planktonic
algae residing in the photic zone rather than sedimentary bacteria. Similarly
the authors noted that methylated species were not found in a number of rain
samples collected along the Pacific coast between 1976-1978. Such species
would be expected if significant ocean-to-atmosphere transfer by biomethylation
reactions was occurring. Andreae suggested that a global mass balance could
be constructed for the atmospheric arsenic cycle which derived its major input
from anthropogenic rather than biogenic sources.
Reduction and methylation of inorganic arsenic occurs only to a limited
extent in soils, 1-2 percent over a period of months having been reported in
one study (Woolson, 1976).
In terms of the relative amounts of arsenic partitioned among the various
environmental compartments, Suta (1980) has calculated that land is the major
sink for arsenic, accounting for approximately 90 percent of the dissipation
for the year 1974. The atmosphere accounts for 7-8 percent dissipation with
the least quantity appearing in waterborne effluents.
3.3 LEVELS OF ARSENIC IN VARIOUS MEDIA
As was noted in the previous section, geochemical and biological cycling
mechanisms contribute to arsenic burden in various media. Such burdening of a
given medium is augmented from specific sources, e.g., agro chemicals contain-
ing arsenic applied to agricultural lands.
Available information on the arsenic content of media with which man
interacts, is generally in the form of total amounts of element, with limited
data available for assessing specific chemical form. Since the toxicity of
arsenicals varies with chemical form, any supporting data for determining
chemical states will be discussed in this report, however fragmentary.
013AS1/D 3-8 June 1983
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3.3.1 Levels of Arsenic in Ambient Air
The most comprehensive data for ambient air levels of arsenic in the U.S.
are those of the National Air Sampling Network conducted by the U.S.EPA.
Measurements from this network are summarized in Table 3-2. All values were
determined from nuclear activation analysis of individual 24-hour high volume
particulate samples. As shown in Table 3-2, the number of observations avail-
able is considerably different from year to year. This is due to changes in
the participation of state and local agencies operating the individual sites
and, for the year 1981, only about half the samples collected have been ana-
lyzed and reported into the network data base at this time. Thus, direct
comparison of the summary statistics from year to year may be of limited
utility.
A closer examination of the NASN data by site indicates that in areas not
influenced by copper smelters, maximum 24-hour concentrations do not exceed
0.1 Mg/m3. There are only two exceptions of approximately 600 site/years
represented in the table where there were observations above 0.1 ug/m3 --
Omaha, Nebraska, and Charleston, West Virginia. The site in Charleston ceased
operation after 1978, therefore, it is difficult to interpret the single value
above 0.1 [jg/m3. Repeated observations above 0.1 ug/m3 have occurred at the
site in Omaha, Nebraska.
Using the NASN data base, U.S. annual arithmetic mean arsenic concentra-
tions are plotted in Figure 3-3. The plot suggests considerable variability
over the five-year period with no clear direction of trend. Perhaps the most
striking feature in the data is the relatively low annual arsenic level ob-
served in 1980. A partial explanation for this observation may be the strike
which ideled most of the nation's copper smelters from June through September
of 1980 (Eldred et al., 1983).
013AS1/D 3-9 June 1983
-------
TABLE 3-2. CUMULATIVE FREQUENCY DISTRIBUTION OF NASN
INDIVIDUAL 24-HOUR AMBIENT AIR ARSENIC LEVELS
Year
1977
1978
1979
1980
1981
Minimum
Detection
Limit
.004
.006
.005
.007
.007
Number
of
Observations
5385
1679
1263
2934
688
Percentile3
30
0
.006
.005
0
0
50
0
.006
.005
0
0
70
.004
.008
.005
0
0
99
.048
.075
.077
.037
.058
Arithmetic
Mean (SD)
.0049
.0109
.0091
.0026
.0059
.0165
.0253
.0192
.0113
.0275
Percentile values indicate the percentage of stations below the given air level
Values in
Source: National Arsenic Data Base, OAQPS/OANR, U.S. Environmental Protection
Agency (Akland, 1983).
013AS1/D
3-10
June 1983
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0.011
1978
1979
1980
Figure 3-3. NASN annual average arsenic concentrations.
Source: National Arsenic Data Base, OAQPS/OANR,
U.S. Environmental Protection Agency
(Akland, 1983).
3-11
June 1983
-------
The locations of these primary copper smelters in the U.S. are listed in
Table 3-3. Examination of the NASN data by individual sites shows that the
highest arsenic levels are consistently recorded in areas of Arizona, Montana,
Tennessee, Texas, and Washington which are impacted by the copper smelting
industry. Thus, the closure of many of these plants for a substantial period
in 1980 may have had the effect of depressing the nationwide average concen-
tration of arsenic in ambient air for that year. Unfortunately, the possible
effect of the 1980 copper smelter strike cannot explain the low arsenic levels
observed in that year nationwide. Even urban areas in the northeast, which
would not be affected, exhibited lowered concentrations and the possibility
that the analytical methodology may have systematically affected results
cannot be ruled out.
Several factors of importance in assessing these data concern the parti-
tioning of arsenic between particulate-bound fractions and vapor material as
well as the lability of arsenic on air sampling filters. Non-particulate
arsenic would chiefly be a problem in the immediate area of smelter emissions,
adhesion to particulates increasing with residence time and distance from the
emission source. Thompson (1976) has noted that all of the arsenic in the air
in regions of smelters is adhered to particulates when sampled 2-3 kilometers
from the operation. Lao et al. (1974) have cautioned about the hazard of
arsenic loss, chiefly as the trioxide, from samplers at levels of 1.0 micro-
grams or less. Walsh et al. (1977), however, could not remobilize particulate
arsenic once trapped in samplers. Whatever the hazard, the NASN values are
internally consistent, remote areas having the lowest values and regions of
smelter operations having the highest levels.
An important consideration in assessing the significance of air exposure
of arsenic to health risk is the chemical form or forms of arsenic in the
013AS1/D 3-12 June 1983
-------
TABLE 3-3. PRIMARY COPPER SMELTERS IN THE UNITED STATES
Location
Company
1. Anaconda, Montana
2. Tacoma, Washington
3. Garfield, Utah
4. El Paso, Texas
5. McGill, Nevada
6. Hidalgo, New Mexico
7. Hurley, New Mexico
8. Hayden, Arizona
9. Hayden, Arizona
10. Miami, Arizona
11. Morenci, Arizona
12. Ajo, Arizona
13. Douglas, Arizona
14. San Manuel, Arizona
15. Copper Hill, Tennessee
16. White Pine, Michigan
Anaconda Company
Asarco, Inc.
Kennecott Copper Corp.
Asarco, Inc.
Kennecott Copper Corp.
Phelps Dodge Corp.
Kennecott Copper Corp.
Kennecott Copper Corp.
Asarco, Inc.
Inspiration Consolidated Copper Corp.
Phelps Dodge Corp.
Phelps Dodge Corp.
Phelps Dodge Corp.
Magma Copper Company
Cities Services Company
Copper Range Company
Source: National Arsenic Data Base, OAQPS/OANR, U.S. Environmental Protection
Agency (Akland, 1983).
013AS1/D
3-13
June 1983
-------
ambient air of the United States. Work by Johnson and Braman (1975), as well
as that of Attrep and Anirudhan (1977), indicate that methylated arsenic,
possibly in significant amounts, has been found in air samples, but its pre-
sence can likely be ascribed to either biotic activity or the use of methy-
lated arsenics as herbicides. This is not in total agreement with Andreae
(1982) who suggests that methylated atmospheric arsenic is due predominantly
to anthropogenic sources based upon his studies of marine environments.
Methylated forms become a minor factor in suburban and urban areas.
It is not clear from the available data what forms of inorganic arsenic
are in most air samples: trivalent, pentavalent or mixtures of these two
oxidation forms. Crecelius (1974) found that rain water samples for an urban
area of the Western U.S. contained only about one-third (35 percent) trivalent
arsenic. In a study conducted at various sites along the Pacific coast,
Andreae (1980) observed wide variations in the ratio of arsenite to arsenate
in rain. He attributed this variability to emissions of predominantly penta-
valent arsenic from the sea surface and trivalent arsenic from industrial
emissions (particularly those from a copper smelter in the Northwest), and by
redox reactions during the residence of arsenic in atmospheric particulates
and hydrometeors. Caution should be exercised, however, in interpreting any
extrapolations from washout samples to original air composition, given the
lability of inorganic arsenic to oxidation or reduction depending on aeration,
acidity of the rain sample, and presence of oxidizable matter.
In summary, then, one can assume that methylated arsenic is of minor
concern in suburban and urban/industrial air samples, and that the major
inorganic portion is a variable mixture of the trivalent and pentavalent
forms.
013AS1/D 3-14 June 1983
-------
3.3.2 Levels of Arsenic in Drinking Water
The maximum permissible concentration of arsenic in U.S. drinking water
supplies is 0.05 mg/liter or 50 ppb (U.S. Public Health Service, 1962), al-
though this value is currently under review (EPA, 1980). In their survey of a
large number of community water supplies (18,000), McCabe et al. (1970) found
that more than 99 percent of the sites sampled contained less than the 10 ppb
(0.01 mg/liter) detection limit measured as total arsenic.
Notable exceptions to the generally favorable picture for U.S. population
exposure to drinking water arsenic are isolated well water sources associated
with geochemical enrichment by arsenic found mainly in the Western U.S. and
Alaska (Arsenic.NAS, 1977; Whanger et al. , 1977; Harrington et al. , 1978;
Southwick et al., 1980; 1982). Whanger et al. (1977) have noted that well
water arsenic levels in Lane County, Oregon, have ranged up to 2.2 ppm
(one well) with levels generally increasing with well depth. Harrington et
al. (1978) also noted that an area of Fairbanks, Alaska, had well water levels
ranging as high as 10 ppm, representing geochemical input as well as contamina-
tion by residues from prior gold-mining activity. Southwick et al., (1981)
reported levels ranging from 0.18-0.27 ppm in desert communities in Utah.
As with arsenic in air, it is important to take into account available
information regarding the chemical forms of arsenic in the potable water
supplies. It is reasonable to assume that the chief form of arsenic in most
municipal water supplies, particularly surface reservoirs, would be penta-
valent arsenic due to aeration and chlorination. Similarly, the major form of
arsenic in well waters relatively enriched in arsenic have been analyzed and
also appear to be predominantly in the pentavalent inorganic state (Whanger et
al., 1977; Harrington et al., 1978; Southwick et al., 1981). The chemical
013AS1/D 3-15 June 1983
-------
character of arsenic-rich well water in the U.S. versus other regions of the
world will be taken up elsewhere.
3.3.3 Arsenic in Food
Perhaps the most useful body of data for assessment of the contribution
of food arsenic to the total exposure picture in the U.S. is the recent survey
carried out in August, 1975 to July, 1976 by the U.S. Food and Drug Adminis-
tration (Johnson et al. , 1981a,b). In Table 3-4 are summarized the average
arsenic levels in various adult food classes for the period noted above;
values are expressed analytically as arsenic trioxide. Corresponding average
arsenic levels in food classes of 6-month old infants and 2-year old toddlers
are summarized in Table 3-5.
In comparing the mean levels in comparable food categories, it appears
that for children and adults, meat, fish and poultry constitute the greatest
dietary source of arsenic. Within this category, shellfish and other marine
foods contain the highest levels of arsenic (Jelenik and Cornelieussen, 1977).
For infants, grain and cereal products constitute the only known source of
arsenic intake from the categories measured.
Johnson et al. (1981a) have calculated that the total adult daily intake
of arsenic (as As203) for August, 1975 to July, 1976 was approximately 65 pg.
(Corresponding elemental content can be obtained by multiplying by 0.75.
Thus, the intake of elemental arsenic would be 50 (jg.) This represents an
increase over the 1974 value of 21 ug reported by Jelenik and Corneliussen
(1977). Differences in the two years can primarily be accounted for by in-
creases in the arsenic content of meat, fish and poultry; grains and ceral
products; beverages; and dairy products. Johnson et al. (1981a) did not
discuss whether the apparent increase in arsenic levels in certain categories
represented a trend or merely reflected random variation from year to year.
It should be noted, however, that arsenic mean levels in all food categories
013AS1/D 3-16 June 1983
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TABLE 3-4. LEVELS OF ARSENIC (As203) BY FOOD CLASS IN
ADULT FOOD COMPOSITES FROM 20 U.S. CITIES
(AUGUST, 1975 - JULY, 1976)
Food Class Composite No. of Positive Composites As, ppm Mean (Range)
Dairy products
Meat, fish and poultry
Grain and cereal products
Potatoes
Leafy vegetables
Legume vegetables
Root vegetables
Garden fruits
Fruits
Oils, fats and shortening
Sugar and adjuncts
Beverages (including
drinking water)
1
17
8
NDb
ND
1
1
1
ND
1
ND
1
0. 004(0. 08)a
0.19(0.03-0.46)
0.02(0.03-0.10)
0.004(0.07)
0.004(0.07)
0.005(0.10)
0.002(0.04)
0.008(0.15)
aMean values are based on 20 composites for every food class.
bND = not detected
Source: Adapted from Johnson et al. (1981a).
013AS1/D 3-17 June 1983
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TABLE 3-5. LEVELS OF ARSENIC (As203) BY FOOD CLASS IN
INFANT AND TODDLER FOOD COMPOSITES FROM
10 U.S. CITIES (AUGUST, 1975 - JULY, 1976)
Food Class Composite
No. of Positive Composites
As, ppm Mean (Range)
InfantToddler
Water
Whole milk, fresh
Other dairy and substitutions
Meat, fish and poultry
Grain and cereal products
Potatoes
Vegetables
Fruits and fruit juices
Oils and fats
Sugar and adjuncts
Beverages
ND
ND
ND(I) 7(T)
3(1) 2(T)
ND
ND
ND
ND(I)
ND(I)
ND
0.092 (0.06-0.29)
0.018(0.04-0.09) 0.008(0.03-0.05)
0.003(0.03)
0.004(0.04)
dND = not detected
Mean values are based on 10 composites for every food class.
Source: Adapted from Johnson et al. (1981a).
013AS1/D
3-18
June 1983
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generally declined over the years 1967-1974. Therefore, data collected over
the past few years (1977-present) but, as yet, unanalyzed, should be closely
examined in order to determine whether the increases seen in 1975-1976 have
actually constituted the beginning of a new trend.
In no other medium is the issue of chemical forms of arsenic more complex
and simultaneously more important than that in food, given the fact that the
diet is a major, if not the main, source of arsenic for most of the U.S.
population. As will be pointed out in a later section, arsenic in crustaceans
and other marine life is present in the form of various chemically complex
organoarsenicals, which appear to be not only resistant to metabolism but are
rapidly excreted intact. Comparatively speaking, then, these forms are re-
garded as being toxicologically inert.
3.3.4 Arsenic in Soils
Soil arsenic levels are mainly of concern in this section to the extent
that arsenic mobility and transformation in this medium allow for passage of
the element to ground water, air and the food chain (via plant uptake). This
area has been reviewed in some detail (Arsenic. MAS, 1977; Wool son, 1977;
Walsh et al., 1977).
Background levels of arsenic in soils range from less than 1 ppm to above
40 ppm and the relative enrichment of this background level with agricultural
practices is secondary to fallout from air in the regions of industrial ac-
tivity and can be of the order of 100 times. In Table 3-6 are listed some
comparative values for uncontaminated soils versus soils contaminated by the
repeated use of defoliants and insecticides containing arsenic (Walsh and
Keeney, 1975).
Arsenic in soils is usually bound to clay surfaces containing amorphous
aluminum or iron oxides, the degree of immobilization (adsorption) being a
013AS1/D 3-19 June 1983
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TABLE 3-6. A COMPARISON OF ARSENIC LEVELS IN ARSENIC-TREATED AND UNCONTAMINATED
SOILS IN NORTH AMERICA
Sampling
site
Colorado
Florida
Idaho
Indiana
Maine
Maryland
New Jersey
New York
North Carolina
Nova Scotia
Ontario
Oregon
Washington
Wisconsin
Total As content,
uncontaminated
soil
1.3 - 2.3
8
0 - 10
2-4
9
19 - 41
10.0
3 - 12
4
0 - 7.9
1.1 - 8.6
2.9 - 14.0
3-32
6-13
8-80
4 - 13
2.2
ppm
treated
soil3
13 - 69
18 - 28
138-204
56 - 250
10 - 40
21 - 238
92 - 270
90 - 625
1 - 5
10 - 124
10 - 121
17 - 439
4 - 103
106 - 830
106 - 2553
48
6-26
Crop
Orchard
Potato
Orchard
Orchard
Blueberry
Orchard
Orchard
Orchard
Tobacco
Orchard
Orchard
Orchard
Orchard
Orchard
Orchard
Orchard
Potatoe
aT, , ., . ...
As pesticide or defoliant. Soils treated experimentally are not included.
Source: Walsh and Keeny (1975).
013AS1/D
3-20
June 1983
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function of soil type, soil pH, phosphate levels, levels of iron or aluminum
as well as residence in soil. Soil-adsorbed arsenic is rather inert to trans-
formation or movement and it is the soluble fraction which is of interest,
usually in the pentavalent form. Pentavalent arsenic arises from both soil
aeration and degradation of methylated arsenic herbicides. Little reductive
methylation of arsenic occurs in typical soils compared to sediments, Wool son
(1976) observing that only 1-2 percent conversion of arsenate occurred over a
period of months.
Transfer of soil arsenic to plants entails the soluble, labile fraction
of arsenic and the site of uptake is the root system where highest levels are
found. Edible portions of most food plant classes are low. This is also the
case for terrestrial flora, but marine plant life such as algae accumulate
considerable levels of arsenic (Irgolic et al., 1977).
3.3.5 Other Sources of Arsenic
Small and McCants (1962) found an average of 1.5 ppm arsenic in tobacco
residues taken from U.S. tobacco grown in soils having average arsenic levels
of 3 ppm. Of the total arsenic content of cigarette tobacco, 10-15 percent is
in mainstream smoke (Thomas and Collier, 1945) in an unidentified form. In
the past, levels of up to 40 ppm arsenic were detected in U.S. cigarettes
(Holland and Acevedo, 1966) owing to arsenical use as pesticides. Lower
current levels probably reflect curtailed use of arsenic as a pesticide in
tobacco growing. '
While current levels of arsenic may be lower in tobacco than had been the
case, past exposure of cigarette smokers remains a health factor in consider-
ing respiratory cancer risk given the long clinical induction period (decades)
for this health effect (see Chapter 5).
013AS1/D 3-21 June 1983
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4. ARSENIC METABOLISM
4.1 ROUTES OF ARSENIC ABSORPTION
The significance of various routes of arsenical intake for man and various
other animal species is dependent upon the physical and chemical form of the
arsenical, the mode of exposure, and the animal species under study. The
major routes that are of significance to general public health are inhalation
and ingestion, either via direct intake of food and water or secondary intake
via the inhalation of arsenic in a form and size where it is eventually swal-
lowed. Inhalation is probably of more significance in occupational settings,
while oral intake is the major exposure route for the population at large.
Percutaneous absorption of arsenic, while poorly studied, appears to be a
relatively minor route of exposure except under certain occupational exposure
conditions.
4.1.1 Respiratory Absorption
Some quantitative and qualitative information about the respiratory
deposition and absorption of arsenic by human subjects have been reported.
Holland and co-workers (1959) used a group of hospital patients (lung cancer)
to assess the deposition and absorption of inhaled arsenic using arsenite-
containing cigarettes labeled with arsenic-74 as well as arsenite-containing
aerosols. Deposition amounted to approximately 40 percent and more than
three-fourths (75 to 85 percent) of the deposited arsenic was absorbed from
the lungs within 4 days. While it may be argued that the health status of
these subjects may have influenced the extent of absorption, it is never-
theless reasonable to infer that relatively rapid and extensive absorption of
arsenic from the human lung likely occurs.
013AS1/A 4-1 June 1983
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A study of a group of workers (Pinto et al., 1976) exposed to airborne
arsenic in a copper smelter in 5-day test periods demonstrated average urinary
arsenic excretion values ranging from 38 to 539 ug/liter to be associated with
averages of air levels of arsenic ranging from 3 to 295 (jg/m (overall 53 ug
3
As/m ). Urinary arsenic was correlated with workplace air exposure (0.53, p
<0.01). Either direct pulmonary absorption or swallowing of larger parti cu-
late matter was evident as seen from elevations of urinary arsenic within 24
hours.
In a later study of copper smelter workers in which urinary excretion of
arsenic was determined as total levels and chemically- variant forms, Smith
et al. (1977) studied control subjects and individuals from low, medium, and
high arsenic exposure groups. In that study, the variations in concentrations
of all arsenic forms isolated in urine--trivalent, pentavalent, methyl, and
dimethyl arsenic—were directly correlated with levels of airborne exposure
(the relevant issue of arsenic biotransformation HI vivo being discussed
elsewhere in this section). An important feature of the Smith et al . (1977)
report was the observation of a difference in the tightness of the correlation
between excretion and exposure as a function of particle size. Both smaller
clearly respirable (<5 pm) and larger less-respirable (>5 urn) arsenic parti-
cles correlated well with excretion levels, but the less-respirable arsenic-
excretion relationship was seen to be much stronger than that for the finer
mode particles. According to the authors, this is due to the swallowing of
the large particle fraction and significant absorption from the GI tract.
Some animal data have also been reported on arsenic absorption via the
respiratory tract. Bencko and Symon (1970) observed that hairless mice breath-
' 3
ing a solid aerosol of fly ash containing 180 pg As/m for several weeks had
013AS1/A 4-2 June 1983
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increases in tissue arsenic values. Since the particle size was determined to
be only less than 10 urn, Part of this intake may have occurred via the GI
tract. Increases in tissue arsenic in two exposure groups also occurred when
rats were exposed to arsenic trioxide (condensation aerosols: 1.0, 3.7, and 46
o
ug/m ) for 90 days (Rozenshtein, 1970).
Relatively rapid absorption of pentavalent arsenic (arsenate solution)
was noted by Dutkiewicz (1977) when rats were exposed intratracheally (arsenate
solution labeled with arsenic-74; 0.1 and 4.0 mg/kg). Arsenic tissue distri-
bution dynamics were similar for intratracheal and companion intravenous
exposure studies, indicating that the rate of intratracheal arsenic uptake
more closely resembles that from parenteral administration than do oral or
percutaneous exposures.
The pulmonary retention of arsenic compounds with different solubilities
has recently been studied by two research groups.
Inamasu et al. (1982) gave 61 male Wistar rats single intratracheal
instillations of arsenic trioxide or calcium arsenate suspended in phosphate
buffer (pH 6.9). Controls (19) were given instillations of the phosphate
buffer solution. The total dose of arsenic administered to each animal was
about 2 mg in 0.2 ml suspensions.
Four to five of the arsenic exposed animals were killed at intervals from
15 minutes to 168 hrs after instillation. The average amounts of arsenic
recovered in lungs of rats at 15 minutes after the instillation of calcium
arsenate and arsenic trioxide were 1146 ug and 620 jjg, respectively. After
24 hrs, almost all of the deposited arsenic trioxide had disappeared from the
lungs, whereas only about 50 percent of the calcium arsenate had been cleared
as shown in Figure 4-1.
013AS1/A 4-3 June 1983
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100
50
10
UJ
fc
cc
o
z
UJ
0.1
TTM r
CALCIUM ARSENATE
ARSENIC TRIOXIDE
JLI I
-i
CONTROL LEVEL
0 3 6 12 24 48
TIME AFTER INSTILLATION, hours
96
168
Figure 4-1. Arsenic retention in rat lungs following intratracheal instil-
lation of a single dose. Percentage values are based on the average
amount of arsenic present in rat lungs at 15 minutes after instillation of
arsenic trioxide (--•--) or calcium arsenate (—*—). Vertical bars: means ±
S.D.
Source: Inamasu et al. (1982).
4-4
June 1983
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Of the small remaining amount of arsenic trioxide, most gradually dis-
appeared over the next several days declining to a level of 5.6 ug at 168 hrs
after instillation, a level slightly higher than that seen in the controls
(1.3 (jg). In contrast, calcium arsenate remained at about the same level
168 hrs after instillation as was observed after 24 hrs (768 ug), clearly
demonstrating a much higher level of retention compared to arsenic trioxide.
In the study by Pershagen et al. (1982), male Syrian golden hamsters were
given four weekly intratracheal instillations of suspensions of arsenic triox-
ide, arsenic trisulfide and calcium arsentate in doses of 0.3, 0.5 and 0.5 mg
as arsenic, respectively. The suspensions were made in 0.9 percent NaCl, and
sulfuric acid was added accordingly to equalize the acidity of the three
different suspensions. Twenty animals were assigned to each treatment group.
Five animals in each group were killed immediately after the first instilla-
tion. Two to five animals were then killed one week after two or four instil-
lations and two weeks after four instillations.
The mortality was highest among the animals exposed to arsenic trioxide.
In this group, 9 of the remaining 11 animals not sacrificed for tissue analy-
sis had died by the week following the third instillation. In contrast, at
the second instillation, two animals died in the group receiving arsenic
trisulfide but no further deaths occured in this group. A total of three
animals receiving calcium arsenate died during the first week following the
fourth instillation. Aside from those animals specifically sacrificed for
tissue analysis, no other deaths occurred in this group either.
In the lungs, the amount of arsenic was 386,755 and 866 mg/kg wet weight
immediately following instillation of arsenic trioxide, arsenic sulfide and
calcium arsenate, respectively. One week after the second instillation the
013AS1/A 4-5 June 1983
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amounts were 0.81, 9.2 and 579 mg/kg, respectively. In Figure 4-2 it can be
seen that after the fourth instillation the differences between arsenate
exposed animals and the other groups was even more pronounced. Examination of
the lungs revealed severe lung damage only among animals exposed to calcium
arsenate. In all groups, areas with epithelial hyperplasia and metaplasia
were seen.
Although different species and different time intervals were used in the
above studies, the results were very consistent, i.e. arsenic trioxide was
rapidly cleared from the lungs, whereas calcium arsenate was very slowly
eliminated. The differences appear to be related to the relative solubility
of the compounds, calcium arsenate having the lowest solubility. The doses in
these two experiments were of the same magnitude, but the lung damage reported
by Pershagen et al. among the arsenate-exposed animals might have influenced
the clearance mechanisms. In addition, the possibility of higher acidity in
the suspensions used by Pershagen et al. may also have had an influence.
The large differences in retention of arsenic compounds demonstrated in
these two studies are of great interest in relation to the association between
airborne arsenic and lung cancer. These differences in retention might ex-
plain the relatively high concentration of arsenic found in deceased smelter
workers whose last exposure to arsenic occurred many years prior to death
(Brune et al. , 1980) (see Section 4.4). These workers were thought to be
exposed to arsenic trioxide, but it may be that the retained fraction noted in
the lungs was another arsenic compound of less solubility.
013AS1/A 4-6 June 1983
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1000
o>
£
O)
z
ID
100
10
I I I I
I I
0* 1* 2» 3* 4 5
WEEK ("instillation)
Figure 4-2. Lung concentrations of arsenic in hamsters
given weekly intratracheal instillations of arsenic tri-
oxide (•), arsenic trisulfide (•), or calcium arsenate (*)
(bars indicate ±1 S.D.). Animals at Week 0 were killed
immediately following the first instillation; other
animals were killed either 1 or 2 weeks after an
instillation.
Source: Pershagen et al. (1982).
4-7
June
1983
-------
4.1.2 Gastrointestinal Absorption
In both man and experimental animals, factors which govern the absorption
of arsenic from the gastrointestinal tract include the chemical form of the
element, its physical characteristics, and dosing level. It can be stated
that soluble arsenicals will be generally more extensively absorbed than the
insoluble forms. On the other hand, one should be cautious in extending
correlations of simple water solubility to the chemical milieu existing in the
GI tracts of various species.
Taken collectively, the reports of Coulson et al. (1935), Ray-Bettley and
O'Shea (1975), Crecelius (1977), Mappes (1977), and Buchet et al. (1981a,b)
demonstrate that very substantial absorption of soluble inorganic trivalent
arsenic from the GI tract into the blood stream typically occurs. Greater
than 95 percent of inorganic arsenic taken orally by man appears to be ab-
sorbed, with less than 5 percent of the administered amount appearing in feces
(Coulson et al., 1935; Ray-Bettley and O'Shea, 1975).
Consistent with the above observations, Mappes (1977) observed that daily
oral intake of an aqueous solution of around 0.8 mg trivalent arsenic resulted
in a daily urinary excretion of 69 to 72 percent of the daily dose in one
subject. Also, Crecelius (1977) reported that ingestion of 50 ug trivalent
and 13 |jg pentavalent inorganic arsenic in a wine sample led to the appearance
of 80 percent of all the ingested arsenic in urine within 61 hours. Crecelius
(1977), however, reported that ingestion of well water mainly containing
identified pentavalent inorganic arsenic led to urinary clearance of half the
intake within approximately 3 days.
More recently, Buchet et al. (1981b) found that daily arsenic excretion
in human volunteers exposed to the dose range 125-1000 yg/day amounted to 60
013AS1/A 4-8 June 1983
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percent of the dose. Steady state was achieved within 5 days after arsenic
dosing began.
In contrast to the relatively high absorptive rate for soluble inorganic
arsenic, Mappes (1977) reported that insoluble arsenic triselenide (As2$e3),
when taken orally, passes through the GI tract with negligible absorption.
Arsenic intake via the diet of non-occupationally exposed populations
requires that one consider the issue of bioavailability. Arsenic in food-
stuffs is probably incorporated into the matrix of these commodities in a
variety of ways.
The so-called "shrimp" arsenic present in crustaceans and other fish
appears to represent a complex organic form of the element which has prompted
considerable recent study (LeBlanc and Jackson, 1973; Westoo and Ryda'lv, 1972;
Munro, 1976; Edmonds et al., 1977; Penrose et al., 1977; Crecelius, 1977;
Edmonds and Francesconi, 1977). In brief, the results of such studies indi-
cate that the arsenic present in shellfish and other marine foods appears to
be extensively absorbed and rapidly excreted intact as a complex organoarseni-
cal by man and animals, and, as such, does not appear to pose a particular
health threat to man.
Studies of the oral intake and absorption of arsenicals in experimental
animals have also been conducted and generally confirm the findings derived
from the above human studies. More specifically, soluble inorganic arsenic,
delivered as either trivalent or pentavalent solutions, is almost completely
absorbed from the GI tract of rats (Coulson et al. , 1935), with 88 percent
absorption being observed for arsenic trioxide solution (Urakabo et al. , 1975;
Dutkiewicz, 1977) and 70 to 90 percent for arsenate solution. Similar obser-
vations have been made for pigs (Munro et al. , 1974), with 90 percent of
013AS1/A 4-9 June 1983
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arsenic trioxide solution being absorbed, and monkeys (Charbonneau et al.,
1978a), with 98 percent of arsenic trioxide being absorbed. Also, Charbonneau
et al. (1978b) fed arsenic-containing fish (Atlantic grey sole) to adult
female monkeys as a homogenate (1 mg fish arsenic/kg body weight) and noted
that about 90 percent of the intake was absorbed, of which about 75 percent
appeared in urine after 14 days. In a related study, swine and adolescent
monkeys were seen to absorb approximately 70 and 50 percent, respectively. On
the other hand, arsenic trioxide in suspension given orally to rabbits and
rats was reported to result in only about 40 and 30 percent absorption, respec-
tively (Ariyoshi and Ikeda, 1974).
4.1.3 Transplacental Passage
Potential fetal exposure to toxic elements via the mother is a matter of
major importance given the potential sensitivity of i_n utero development to
deleterious impacts of exogenous toxic agents.
In a study of maternal-newborn blood groups for arsenic, Kagey et al.
(1977) reported that cord blood levels approximate those of mothers in 101
subject sets. Tissue analysis (Kadowaki, 1960) of fetus arsenic in a pre-
sumably healthy Japanese population indicated measurable element levels by at
least month four of gestation which increased to month seven. Of importance
here is the observation that brain levels, as well as those of bone, liver,
and skin, were the highest of all tissue tested.
Complicating the issue is the chemical nature of the tissue arsenic
assayed in either of the two studies noted above, in as much as precise chemi-
cal speciation was not attempted. Also, the Japanese study presumably did not
select material in a manner such that dietary histories could be discerned.
Thus, questions can be raised regarding implications of these data for feto-
toxicity.
013AS1/A 4-10 June 1983
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Transplacental transfer of arsenic has also been demonstrated in experi-
mental animals. Transplacental transfer of arsenate administered parenterally
in hamsters has been demonstrated by Perm's laboratory (Perm, 1977; Hanlon and
Perm, 1977). The movement was rapid, with embryonic tissues showing levels
close to those in maternal blood 24 hours after dosing. Trivalent arsenic
exposure results in transplacental passage in pregnant rats. Arsenic was
detected in newborn rats when the dams received arsenic trioxide in the diet.
4.2 BIOTRANSFORMATION PROCESSES IN VIVO
An understanding of the metabolism of inorganic arsenic by man and a
number of other species is substantially complicated by a series of newly-
revealed biotransformations, including methylation of inorganic arsenic. It
is thus appropriate to discuss i_n vivo transformation processes at this point,
since much of the data dealing with blood transport, tissue distribution and
subsequent excretion is much better understood in light of these findings.
A major factor in the determination of transformation processes for
arsenic in man and other animals was the evolution of appropriate analytical
methods within the decade which permit chemical speciation of chemically
variant forms of arsenic with reference to both oxidation-state lability and
inorganic versus organo-substituted arsenic.
These procedures involve different analytical approaches and include
selective reduction of various arsenic forms to the hydride, and subsequent
analysis by colorimetry (Lakso et al., 1979), emission spectrometry (Braman
and Foreback, 1973; Crecelius, 1977), atomic absorption spectrometry (Edmonds
and Francesconi, 1977; Buchet et al. 1980), and gas-liquid chromatography
(Andreae, 1977; Talmi and Bostick, 1975). Alternatively, inorganic arsenic
(III) or (V) and methylated forms can be directly measured by ion-exchange
chromatographic techniques (Tarn et al. 1978; Henry and Thorpe, 1980).
013AS1/A 4-11 June 1983
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There are a number of points germane to consideration of i_n vivo trans-
formations of arsenic: 1) biomethylation of inorganic arsenic; 2) oxidation-
reduction of inorganic arsenic i_n vivo; 3) the relative chemical stability of
inorganic arsenic to oxidation-reduction as it affects experimental dosing and
chemical speciation in biological media.
4.2.1 Biomethylation of Inorganic Arsenic in Humans and Experimental Animals
An extensive literature has recently appeared documenting the i_n vivo
methylation of inorganic arsenic to mono-and dimethyl arsenic (the latter
being the major methylated metabolite) in every mammalian system studied to
date, including man.
While the quantitative features of this phenomenon may vary among species,
one can generally state that 1) dimethyl arsenic is the major transformation
product; 2) methylation represents a route of detoxification of the more toxic
inorganic forms; 3) dimethyl arsenic is a terminal metabolite, formed rela-
tively rapidly and rapidly excreted; 4) that while the iji vivo methylating
capacity of a given system may persist over a range of inorganic arsenic
exposure, at some point the body burden of the unmethylated fraction is enough
to induce toxic effects, evidenced by the extensive literature dealing with
inorganic arsenic toxicity; and 5) retrospective assessment of earlier data
dealing with arsenic metabolism, including distribution and excretion, must be
viewed in light of current knowledge about biomethylation in different species.
4.2.1.1 Human Studies—Using a method that permits the determination of tri-
and pentavalent inorganic arsenic as well as mono- and dimethylarsenic acids
via selective reduction, volatilization, and helium-arc emission detection,
Braman and Foreback (1973) analyzed the urinary excretion of arsenic in four
human subjects. About 66 percent of the total urine arsenic concentration
013AS1/A 4-12 June 1983
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(22.5 ppb) was present as dimethylarsinic acid and 17 percent as pentavalent
inorganic arsenic. Trivalent inorganic arsenic and methylarsonic acid were •
present in equal amount, approximately eight percent each.
Crecelius (1977) reported the urinary excretion of form-variable arsenic
when a human subject ingested arsenic-rich wine (50 ug trivalent and 13 ug
pentavalent). About 80 percent of the arsenic ingested with the wine was
excreted within 61 hours. Of the total excreted, 63 percent was in the form
of dimethyl arsenic acid, 18 percent was monomethyl arsenic acid, and approxi-
mately 9 percent each was in the two inorganic forms.
Consumption of well water containing 200 ug of arsenate by a subject in
the same study showed urinary trivalent arsenic at near background levels with
an elevation in pentavalent form as well as significant excretion of dimethyl-
arsenic. Of the total amount ingested, about 50 percent was recovered in
urine by 3 days. Arsenic as contained in canned crab tissue was also studied
in this experiment. It has been established that arsenic is present in marine
foods in an organic form which is excreted intact.
The study of Smith et al. (1977), using basically the same speciation/
analysis techniques noted in the previous study and involving urinary profiles
for a group of copper smelter workers, also confirmed transformation processes
i_n vivo. In controls, as well as in three study groups that varied as to
intensity of airborne trivalent arsenic oxide exposure, dimethyl arsenic was
the dominant species in urine, followed by methyl arsenic, trivalent arsenic
and pentavalent arsenic, in descending order.
In another smelter worker study, Buchet et al. (1980a) assessed the
distribution of arsenic and metabolites in urine samples in different groups
according to the degree of inorganic arsenic exposure. Total urinary arsenic
013AS1/A 4-13 June 1983
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in exposure groups ranged from 74 to 934 pg/liter, of which 75 percent repre-
sented methylated forms (mono- and dimethyl), with dimethyl arsenic predomi-
nating. Control subjects showed a somewhat higher level of methylated arsenic
in urine, approximately 90 percent, suggesting some dependency of the extent
of methylation on the level of exposure.
A number of recent studies have described in more detail the biomethyla-
tion of inorganic arsenic using human volunteers.
Buchet et al. (1981a) followed the urinary excretion of inorganic and
methylated arsenic in 3-5 volunteers ingesting single amounts of arsenic at a
dose of 500 ug, in the form of either arsenite, monomethyl or dimethyl arsenic.
After 96 hours, 46 percent of the dose in subjects given arsenite (trivalent
arsenic) was excreted, 25 percent in the inorganic form and 75 percent as
methylated metabolite. Of the latter, one-third was monomethyl arsenic and
two-thirds was the dimethylated form. Dimethyl arsenic was excreted intact,
75 percent of the ingested amount appearing in urine by 96 hours. With mono-
methyl arsenic, excretion reached 80 percent by 96 hours, with around 13
percent of the urine level representing conversion to the dimethyl form.
In a follow-up report, these workers (Buchet et al. 1981b) monitored the
urinary excretion of various arsenical forms in 4 human subjects undergoing
repeated ingestion (5 days) of trivalent inorganic arsenic as a meta arsenite
salt at 4 levelS--125, 250, 500 or 1000 |jg As. By 14 days, the percent of
methylated forms of total forms ranged from 74-93 percent over the intake
range. From this study, it would appear that the methylating capacity of the
human subject was unaffected up to the 500-ug As level, at which point some
decrease in methylated arsenic as a percentage of total was observed.
013AS1/A 4-14 June 1983
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Yamauchi and Yamamura (1979) reported their results with 3 volunteer
subjects who ingested an arsenic-rich extract (prepared from a particular kind
of seaweed) containing 2.88 ppm total arsenic. Of the total amount, 86 percent
was pentavalent inorganic arsenic, 7 percent was trivalent inorganic arsenic
and 7 percent was dimethyl arsenic. These volunteers ingested the preparation
as a single dose at a level of 10 ug/kg body weight, for total amounts of 650,
680, and 760 ug in the three subjects. By 48 hours, urine levels of total
arsenic amounted to 36 percent of the dose. Of the excreted amount, dimethyl
and monomethyl arsenic accounted for 47.4 and 25.3 percent, respectively.
4.2.1.2 Animal Studies--To date, biomethylation processes involving inorganic
arsenic and experimental animals have been documented in dogs (Lakso and
Peoples, 1975; Charbonneau et al. 1978a; Tarn et al. 1979a), mice (Vahter,
1981), rabbits (Marafante et al. 1980; Bertolero et al. 1981), the bovine
(Lakso and Peoples, 1975), and the rat (Odanaka et al. 1978). While the level
of methylated forms of arsenic in most experimental species resembles that in
man, approximately 80 percent, there is a greater amount of the dimethyl- and
a lesser amount of monomethyl arsenic.
Vahter (1981) has shown (1) that the degree of biomethylation is dose-
dependent, at least in mice, falling off in relative percentage with increas-
ing level of dosing; (2) that this dependency probably accounts for the obser-
vation of dose-dependent retention in mice; and (3) methylation occurs to a
greater extent with trivalent arsenic than with the pentavalent form, although
retention, relative to total dose, is greater with the trivalent form.
4.2.2 In Vivo Oxidation/Reduction of Inorganic Arsenic In Mammalian Systems
Oxidation of trivalent inorganic arsenic to the pentavalent state has
been claimed in dogs (Ginsberg, 1965), rats (Winkler, 1962), mice (Bencko
et al. 1976), and humans (Mealey et al. 1959). An important factor in consider-
013AS1/A 4-15 June 1983
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ing these studies critically is the fact that none of the reports considered
the presence of methylated arsenic, which may well have affected the analy-
tical techniques employed and the analytical data obtained. Secondly, except
for the Bencko et al. (1976) study, it is not clear that careful attention was
paid to the oxidation state composition of dosing media or the effect of
sample handling on oxidation state stability. In the Mealey et al. (1959)
report, the analytical method involved acidification of urine with hydro-
chloric acid and extraction of the presumed "trivalent" arsenic into benzene,
leaving the presumed "pentavalent" form in the aqueous phase. Since Mushak et
al. (1977) have shown that methylarsonic and dimethylarsinic (cacodylic) acid
behave like the pentavalent inorganic form in this extraction procedure, it is
probable that the "arsenate" fraction was mainly methylated arsenic.
In the study of Crecelius (1977), where chemical speciation techniques
were employed, it does not appear that ingestion of a sample containing mainly
arsenite (trivalent form) is associated with excretion of pentavalent in-
organic arsenic as the chief inorganic form. After 61 hours, 80 percent of
the ingested amount appeared in urine, with the two inorganic forms each
constituting minor fractions, mono- and dimethyl arsenic being the main forms.
Evidence for the u\ vivo reduction of pentavalent to trivalent inorganic
arsenic has been claimed in several early reports. Lanz et al. (1950) reported
some reductive conversion (10-15 percent) of arsenate to arsenite in rats,
using as a method the precipitation from urine of arsenate as a mixed salt and
analysis of the supernatant for arsenic (III). The accuracy of this method
for partitioning trace arsenic levels is questionable. Furthermore, at the
time of this study, the presence of methylated arsenic was not known. There-
fore, it is not possible to accept this author's conclusions since unprecipi-
tated arsenic could also have consisted of methylated forms.
013AS1/A 4-16 June 1983
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Ginsberg (1965) reported that 14 percent of urinary and 6 percent of
plasma arsenic in dogs receiving intravenous infusion of arsenate was in the
form of trivalent arsenic. In this study, trivalent was presumably separated
from pentavalent arsenic by chelation-extraction using ethyl xanthate. Based
on current knowledge that methylated arsenic was present, it is difficult to
accept the data without knowledge of the behavior of mono- and dimethyl arse-
nic in this analytical method.
In the recent report of Tarn et al. (1979b) using dogs dosed with arsenate,
a small amount of trivalent inorganic arsenic was detected in urine, using
ion-exchange and thin-layer chromatographic techniques. These authors did not
independently determine the extent of artifactive interconversion between the
two forms using these techniques.
In a recent study by Vahter (1981), in which mice and rats were adminis-
74
tered As-labeled trivalent or pentavalent arsenic, the author reported that
increases in retention with dose were less pronounced for the pentavalent form
than for the trivalent form due to the fact that elimination of pentavalent
arsenic seemed to be less dependent on methylation. Nevertheless, increases
in retention with pentavalent arsenic were observed. Vahter discussed the
possibility that the observed dose-related increase in retention after expo-
sure to pentavalent arsenic may have been partly due to i_n vivo reduction of
the pentavalent to trivalent form. Noting the work of McBride et al. (1978),
whose studies indicated that certain microorganisms required reduction of
pentavalent arsenic to trivalent before methylation could proceed, Vahter
suggested that a similar mechanism might have been functioning in both the
mice and rats. Evidence to support this hypothesis was presented in the
author's observation that trivalent arsenic seemed more readily methylated
than pentavalent.
013AS1/A 4-17 June 1983
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Two recent studies using human subjects and identical chemical speciation
techniques for arsenic appear to offer conflicting data regarding pentavalent
arsenic reduction.
Crecelius (1977) noted that ingestion of a sample of well water tested as
having 200 ug As only in the pentavalent form resulted in a urinary level of
trivalent arsenic which was virtually the same as background concentration
before taking the arsenic sample. Urine was collected for approximately 3
days, during which time about 50 percent of the dose was excreted.
Yamauchi and Yamamura (1979) fed a preparation of seaweed containing 86
percent pentavalent arsenic and 7 percent each of trivalent inorganic and
dimethyl arsenic to 3 human subjects as one dose at a total dosing of 650,
680, and 760 ug total arsenic. By 48 hours, based on their method which was
the Braman et al. (1977) procedure, 36 percent of the original dose appeared
in urine, with 75 percent present as methylated forms and about 17 percent
present as trivalent arsenic (6.3 percent of the total amount ingested). The
authors calculated that the amount of trivalent inorganic arsenic was greater
than could be ascribed to the small amount ingested originally and they stated
that the fraction represented ij} viyo reduction of pentavalent arsenic. Since
the mean intake was approximately 700 ug, the 7 percent present as trivalent
inorganic arsenic amounted to 49 ug, of which 36 percent or 18 ug would have
been expected to appear in urine in some form. Using 75 percent methylation,
only approximately 4-5 ug would have been present as the trivalent form, when
in fact a mean value of 43.4 was found (range: 36-51 ug). Since the Braman
et al. (1977) method is a reasonably accurate speciating technique and there
is little evidence that samples were handled in a way to promote artifactive
formation of trivalent arsenic after excretion, the data cannot be readily
questioned on this basis.
013AS1/A 4-18 June 1983
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The different results obtained by Crecelius (1977) and Yamauchi and
Yamamura (1979) may be related to the relative amounts of arsenic assimilated.
The Japanese study used amounts about 3-fold greater than that reported by
Crecelius. Furthermore, only one subject was used in the Crecelius (1977)
investigation.
4.2.3 Chemical Stability of Trivalent and Pentavalent Inorganic Arsenic
to Oxidation-Reduction
In aerated water, trivalent inorganic arsenic will undergo extensive
oxidation to the pentavalent form, particularly when present at low levels
(Feldman, 1979).
The pH of aqueous solutions appears to be the major factor in the rela-
tive stability of either valency form. Buchet et al. (1980) found that tri-
valent arsenic in solutions at pH of 7.0 or 9.6 were oxidized to the extent of
70-90 percent within one week, compared to 25 percent conversion at pH 4.8.
Vahter and Norin (1980) also noted rapid oxidation of As (III) in aqueous
solution at room temperature, while storage at 4°C showed little conversion.
Pentavalent inorganic arsenic, on the other hand, is stable at neutral or
alkaline pH but undergoes reduction with decreasing pH (Durrant and Durrant,
1966).
In studies directed to j_n vivo transformations of inorganic arsenic,
urine levels are commonly used and some data exist regarding valency stability
of arsenic in urine.
Buchet et al. (1980) found that trivalent inorganic arsenic in urine at
pH 7.0 or less was relatively stable, with only 10 percent oxidation occurring
by 7 days. At pH 9.5, 50 percent of oxidation occurred within one day.
013AS1/A 4-19 June 1983
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4.3 DISTRIBUTION OF ARSENIC IN MAN AND ANIMALS
Blood is the main vehicle for transport of arsenicals from absorption
sites to the tissues, with the hemokinetic character of arsenic being depen-
dent on the animal species studied.
It is readily apparent from the literature that the rat constitutes an
anomalous model for studies of the fate of inorganic arsenicals i_n vivo and
this includes the clearance behavior of rat blood-borne arsenic (Hunter et
al., 1942; Ducoff et al., 1948; Lanz et al., 1950; Ariyoshi and Ikeda, 1974;
Klaassen, 1974; Tsutsumi and Kato, 1975; Dutkiewicz, 1977). In the case of
the rat, arsenic in blood is only slowly cleared following exposure, with
about 80 percent of the total blood arsenic content localized in the erythro-
cyte. The half-times of blood clearance for inorganic arsenic in the rat
(trivalent or pentavalent) is of the order of 60 to 90 days (Lanz et al. ,
1950; Ariyoshi and Ikeda, 1974).
Arsenic in the blood of other species—man (Ducoff et al., 1948; Mealey
et al., 1959; Tarn et al., 1979b), mice (Lanz et al., 1950; Crema, 1955),
rabbit (Hunter et al. , 1942; Ducoff, 1948; Klaassen, 1974), dog (Lanz et al.,
1950; Hunter et al., 1942), and primates (Hunter et al., 1942; Klaassen,
1974)—whether given as the pentavalent form or as the trivalent form, is
rapidly cleared. Normal blood arsenic values for individuals in the U.S. and
Europe are in the range of 1-5 |jg total arsenic/liter whole blood (Bergstromn
and Wester 1969; Damsgaard et al. , 1973; Kagey et al., 1977 and Valentine
et al., 1979). According to Kagey et al. (1977), cigarette smokers showed
mean blood arsenic levels approximately 50 percent higher than non-smokers.
It is reasonable to assume that human background blood levels reflect mainly
dietary arsenic, much of which would likely be in various organo-arsenical
forms that are extensively absorbed and rapidly cleared.
013AS1/A < 4-20 June 1983
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Clearance of arsenic in dog and man was found to fit a three-compartment
model by Charbonneau et al. (1978a) and Tarn et al. (1979b) with half-times of
1, 5, and 35 hours, respectively. When contrasted with the work of Tarn et al.
(1978), which reported the time-dependent jn vivo methylation of arsenic and
excretion in dogs, the various components presumably relate to initial excre-
tion of inorganic arsenic, followed by clearance of dimethyl arsenic.
The tissue partitioning of arsenic in man has been studied using both
autopsy and dosing data. Kadowaki (1960) found (measurements in ppm, wet
weight) that nails (0.89), hair (0.18), bone (0.07-0.12), teeth (0.08) and
skin (0.06) generally housed the highest absolute amounts of arsenic, while
heart, kidney, liver and lung contained somewhat lower levels (0.04-0.05).
Brain tissue (0.03) had an arsenic level only slightly lower than other soft
tissues. Liebscher and Smith (1968), analyzing tissue samples (ppm dry weight)
from non-exposed sources in Scotland, observed lung to have the highest levels
(0.09), with liver and kidney levels (0.03) not materially different from
other soft tissue. Like the Kadowaki study, hair (0.46), nails (0.28) and
skin (0.08) had the highest absolute values; however, bone and teeth (0.05)
did not contain levels appreciably different from some other tissues (pectoral
muscles, 0.06; ovary, 0.05; and pancreas, 0.05).
In addition to the autopsy studies by Kadowaki (1960) and Liebscher and
Smith (1968), Larsen et al. (1979) have recently reported on a detailed study
of the topographical distribution of arsenic in normal human brain tissue.
Arsenic is distributed throughout all brain regions, with white matter showing
higher levels than gray matter.
In looking at tissue distribution of arsenic in experimental animals,
exposure of various species to either tri-or pentavalent arsenic leads to the
013AS1/A 4-21 June 1983
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initial accumulation of the element in liver, kidney, lung, spleen, aorta, and
skin (Hunter et al., 1942; Ducoff et al., 1948; Lanz et al., 1950; Peoples,
1964; Ariyoshi and Ikeda, 1974; Cikrt and Bencko, 1974; Klaassen, 1974; Tsutsumi
and Kato, 1975; Urakabo et al., 1975; Dutkiewicz, 1977; Sabbioni et al. , 1979;
Marafante et al., 1980). With the exception of the rat, a species in which
metabolism of arsenic is only a very limited model for study of this element
(vide supra), clearance from soft tissue is rather rapid except for the skin,
where the high sulfhydryl group content may promote tight trivalent arsenical
binding. As also seen with human tissue, arsenic is apparently lodged in
brain of experimental animals exposed to arsenic, with slow clearance reported
(Crema, 1955).
Recently, Vahter and Norin (1980) compared the dependency of dose and
valency form of inorganic arsenic on tissue compartmentalization of arsenic in
mice. Unlike most of the earlier reports, these workers used chemical specia-
tion techniques (ion-exchange chromatography) to verify that their dosing
media contained purely tri- or pentavalent arsenic. Using single oral dosing
at 0.4 or 4.0 mg/kg levels and radioisotopic tri- or pentavalent arsenic,
levels of arsenic in kidney, liver, bile, brain, skeleton, skin and blood were
always greater (2-10 fold) in terms of percent total dose for the trivalent
form than for the pentavalent form, and most pronounced at the higher dose.
These workers ascribe much of this difference to relative methylating effi-
ciency as a function of exposure level and valence form.
In a similar study using Golden Hamsters exposed to injected tri- or
pentavalent radioisotopic arsenic, with care taken to assure valence purity,
Ckirt et al. (1980) found that levels of arsenic in liver, kidneys, gut wall
and bile were always greater, 2-25 fold, with trivalent arsenic exposure.
013AS1/A 4-22 June 1983
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4.4 ARSENIC ACCUMULATION
The long-held view of arsenic as an element that accumulates in the body
was mainly based on the behavior of arsenic in the rat, an animal model which
in retrospect was the least helpful in understanding the fate of the toxicant
In vivo f°r other mammalian species and man.
Based on current arsenic elimination data for all mammalian species
studied other than the rat (vide supra), one concludes that marked long-term
accumulation of arsenic generally does not occur in physiologically vital
components of the body. This is in contrast to, say, long-term lead accumula-
tion in bone or cadmium accumulation in renal cortex. Autopsy tissue data for
human subjects of different ages is not conclusive regarding possible long-
term tissue accumulation. Kadowaki (1960) did observe higher mean levels of
arsenic in skin and kidney samples of subjects approximately 50 years of age
versus infant values, but dietary histories of the subjects were not available
to allow for differentiation of increases in arsenic levels due to current
versus past exposures for the older subjects. Deposition in hair is really
excretory in nature, not accumulative.
Brune et al., (1980) have reported that lung tissue from retired smelter
workers from the Ronnskar smelter in Sweden, on autopsy, had median values for
arsenic which were about 8 times higher than that for a control group. Kidney
and liver values, however, were not significantly different between smelter
worker groups and controls. Arsenic accumulation in the lung of smelter
workers even after several years of retirement and removal from workplace
exposure (interval of 2-19 years) suggests that a very insoluble form of
arsenic exists in smelter ambient air and is inhaled by these workers.
013AS1/A 4-23 June 1983
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Lindh et al., (1980) measured the arsenic in autopsy femur samples of 7
occupationally exposed workers. The time between retirement and death ranged
from 0-21 years. A control sampling from 5 autopsy cases was included. Using
both neutron activation analysis and proton-induced X-ray emission (PIXIE)
techniques, no clear evidence of significant arsenic accumulation in bone was
seen. The scatter of levels was wide in the worker group, 0.006-0.21 parts-per-
million, with a median of 0.014 ppm, versus a range of 0.005-0.007 in the
control samples.
4.5 ARSENIC EXCRETION IN MAN AND ANIMALS
Renal clearance appears to be the major route of excretion of absorbed
arsenic in man and animals, biliary transport of the element leading to enteric
reabsorption with little carriage in feces.
Recent data for normal or background levels of arsenic in urine of human
subjects in the U.S. reveal values of less than 20 ug/liter (20 parts per
billion). If seafood has been consumed, such values can rise considerably to
levels of 1,000 ug/liter Or higher (Westbo and Rydalv, 1972; Pinto, 1976).
In a study designed to assess the utility of urine arsenic measurement in
occupational exposure settings, Mappes (1977) reported excretion data for both
single and multiple daily dosing for a human subject ingesting arsenite solu-
tion. By 3 hours, renal excretion was maximal, with about one-quarter of the
single dose appearing in the urine by day 1 post-exposure. With successive
arsenite ingestion (0.8 mg As), daily urinary clearance after 5 days was about
two-thirds of daily intake.
Buchet et al. (1981b), in their study of human subjects ingesting arsenite
in amounts ranging from 125-1000 ug/day for 5 days, calculated a steady state
occurring within 5 days. With steady state, 60 percent of daily intake is
excreted daily. This figure is in good agreement with that of Mappes (1977)
cited above.
013AS1/A 4-24 June 1983
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Crecelius (1977) noted that following ingestion of arsenic in wine [50 [ig
As (III), 13 M9 As (V)] approximately 80 percent of the dose was excreted
within 61 hours. Oral ingestion of arsenic (V) in well water (200 ug), however,
led to about 50 percent urinary excretion by 3 days post-ingestion. Mealey et
al. (1959) measured urine arsenic in patients given trivalent arsenic by
intravenous administration, with approximately 60 percent of the dose amount
appearing in the urine within 24 hours. Hunter et al. (1942) noted that a
group of human subjects given arsenic via parenteral administration exhibited
considerable variance in the urinary clearance of arsenic, ranging from 30 to
80 percent after 4 to 5 days.
As might be predicted from the ijn vivo behavior of arsenicals in the rat,
urinary excretion of arsenic in this species is very slow (due to erythrocyte
retention) on the order of two to five percent of the arsenic intake by several
days post-dosing (Coulson et al., 1935; Ariyoshi and Ikeda, 1974). Urakabo et
al. (1975) calculated a half-time of 84 days for arsenic in the rat.
Slow clearance of arsenic from the rat gave rise to the widely-held
assumption for many years that arsenic was one of the elements that accumu-
lated in the body. Other species excrete arsenic rapidly. Mice, rabbits,
swine, dogs, and monkeys clear the majority of injected trivalent arsenic
within 24 hours, with excretion usually being >7Q percent within that time
period (Ducoff et al., 1948; Crema, 1955; Munro et al., 1974; Lakso and Peo-
ples, 1975; Tarn et al., 1978; Charbonneau et al., 1978a). Other studies also
indicate rapid urinary clearance of arsenic given in the pentavalent form to
species other than the rat (DuPont et al., 1942; Ginsberg and Lotspeich, 1963;
Peoples, 1964; Lakso and Peoples, 1975).
013AS1/A 4-25 June 1983
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Several studies have compared the relative rates of elimination of radio-
74
labeled ( As) trivalent and pentavalent inorganic arsenic (Vahter and Norin,
1980; Vahter, 1981) where precautions were taken to assure the purity of the
respective dosing solutions as to valency state. Whole body retention of
trivalent inorganic arsenic in mice was 2-3 times greater than that of arsenate
while retention times for both forms were dose-dependent, increasing with
increasing exposure. In these studies, the animals received single oral doses
of either form at a level of 0.4 or 4.0 mg As/kg. Differences in elimination
rates appeared to relate to the relative degree of methylation of inorganic
arsenic to the rapidly excreted methylated forms, chiefly dimethyl arsenic.
Biliary transport of arsenic has been reported for a number of species.
Bile-excreted arsenic is reabsorbed. Cikrt and Bencko (1974) noted that the
rat had a higher biliary excretion rate for the trivalent than for the penta-
valent form (approximately 10:1). Klaassen (1974) noted that the biliary
excretion rate was much greater for the rat than for either the rabbit or the
dog.
Ckirt et al., (1980) monitored biliary exretion in the Golden Hamster
using penta- or trivalent inorganic arsenic. Significant differences in
biliary excretion rates and cumulative excretion were seen between the two
forms, being much greater for the trivalent form. However, fecal and urine
arsenic content was greater with pentavalent arsenic administration. Biliary
transport data for man are not available.
Deposition of arsenic in such organs as hair and nails can be considered
an excretory mechanism for arsenic. Although hair analysis has had a long
history in arsenic's chemical and forensic literature, for reasons of both
analytical convenience and the possibility of establishing an exposure history
013AS1/A 4-26 June 1983
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from sectional analysis, many questions remain unanswered. The relationship
between arsenic deposition in hair and various exposure parameters has not
been well defined on a quantitative basis nor are the physiological mechanisms
well understood. The chemical nature of hair arsenic is also largely unknown.
013AS1/A 4-27 June 1983
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5. ARSENIC TOXICOLOGY
The acute and chronic toxicity of arsenic will largely depend on the
chemical form and physical state of the compound involved. Inorganic tri-
valent arsenic is generally regarded as being more acutely toxic than
inorganic pentavalent arsenic which in turn is more toxic than methylated
forms of arsenic (NAS, 1977; Pershagen and Vahter, 1979; WHO, 1981). The
so-called "fish arsenic" is regarded as nontoxic. It is thus necessary to
always specify, if possible, arsenic compounds when discussing effects and
constructing dose-effect and dose-response relationships. In addition,
factors like particle size and solubility must be taken into account.
Trivalent compounds with low solubility, e.g., arsenic sulfide, will have low
oral toxicity but may be retained in the lung (Brune et al., 1980).
5.1 ACUTE TOXICITY OF ARSENIC IN MAN AND ANIMALS
In animal experiments the oral LD5Q has been found to vary from 15 to 293
mg/kg body weight in rats and from 10-150 mg/kg in other animals (Dieke and
Richter, 1946; Harrison et al., 1958). The lower values refer to experiments
with soluble arsenic compounds. Franke and Moxon (1936) found that the LD75
48 hours after i.p. administration, was 4-5 mg As/kg body weight for sodium
arsenite and 14-18 mg/kg for sodium arsenate.
Acute effects seen in animals after oral exposure are similar to effects
seen in human beings and include gastroenteritis, diarrhea and cardiovascular
effects (Nelson et al., 1971; Selby et al., 1977).
A large number of acute arsenic poisonings are described in the litera-
ture, but few data exist on actual doses and type of compound. Vallee et al.
(1960) estimated the lethal dose to be on the order of 70 to 180 mg for arsenic
013AS2/A 5-1 June 1983
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trioxide. Acute symptoms are due to severe gastrointestinal damage, resulting
in vomiting and diarrhea and general vascular injury which may lead to shock,
coma or even death. Other acute symptoms are muscular cramps, facial edema,
and cardiovascular reactions (Holland, 1904; Done and Peart, 1971).
Acute symptoms have also been seen after airborne exposure to high con-
centrations of arsenic trioxide, causing severe irritation of nasal mucosa,
larynx, and bronchi (Holmqvist, 1951; Pinto and McGill, 1953).
Reversible effects on the hematopoietic and cardiovascular systems and
peripheral nervous disturbances with slow recovery have also been noted (Ohta,
1970; Heyman et al., 1956; Jenkins, 1966; Nagamatsu and Igata, 1975: O'Shaugh-
nessy and Kraft, 1976; Hamamoto, 1955; Chhuttani et al., 1967).
Over the years, a number of large-scale poisonings have occurred due to
contamination of beer (Kelynack et al., 1900), soy sauce (Mizuta et al.,
1956), dried infant milk (Tokanehara et al., 1956), and well water (Yoshikawa
et al., 1960). These episodes mainly caused subacute and chronic symptoms and
will be discussed in the following sections.
5.2 CHRONIC TOXICITY OF ARSENIC IN MAN AND ANIMALS
5.2.1 Carcinogenicity/Mutagenicity of Arsenic
The case for the association of inorganic arsenic with skin and lung
cancer as well as other visceral carcinomas has been extensively reviewed
(Arsenic. NAS, 1977; IARC, 1973 and 1980; NIOSH, 1975; Hernberg, 1977; Sunder-
man, 1976, Pelfrene, 1976; Kraybill, 1978; Wildenberg, 1978; Pershagen and
Vahter, 1979; WHO, 1981). The literature on arsenic carcinogenicity in humans
is summarized in Table 5-1.
013AS2/A 5-2 June 1983
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TABLE 5-1. SUMMARY OF CASE REPORTS AND EPIOEMIOLOGIC STUDIES OF CANCER OR PRECANCEROUS
o
1 — »
53 Study
Media Population
Air Smelter
Workers-
Tacoma ,
Washington
(Analysis of
deaths for
1946-60)
LESIONS IN PERSONS EXPOSED TO ARSENIC
Author(s)
Pinto and
Bennett
(1963)
Type of
Study
Proportionate
Mortality
Results
No difference
in lung cancer
proportionate
mortal ity
between exposed
and unexposed
workers.
Highlights and Deficiencies
Workers leaving the plant
before retirement were not
included. In the classification
of workers by exposure, the
"non-exposed" group apparently
were exposed since they also
had high levels of arsenic in
the urine.
en
i
CO
Smelter
Workers-
Tacoma,
Washington
(follow-up from
1950-71)
Smelter
Workers-
Tacoma,
Washington
(follow-up
from 1949-73)
Mil ham and Cohort 40 observed
Strong lung cancer
(1974) deaths versus
18 expected
(P <0.001)
Pinto et al. Cohort 32 observed
(1977) respiratory
cancer deaths,
versus 10.5
expected,
(P <0.05); Dose
response seen by
urinary arsenic
levels and by
duration and
intensity of
exposure.
Urinary arsenic levels of
persons living around the
smelter decreased with
distance from the smelter.
Study consisted of only
pensioners.
c
3
fD
i-D
co
00
-------
TABLE 5-1. (continued)
GO
3=-
GO
Media
Study
Population
Author(s)
Type of
Study Results
High! ights
and Deficiencies
01
Air Smelter
workers-
Tacoma,
Washington
(Follow-up
from 1941-1976)
Smelter Workers-
Anaconda, Montana
(Followup from
1938 to 1963)
Smelter
Workers-
Anaconda, Montana
(Followup from
1964 to 1977)
Enterline and Cohort 104 respiratory
Marsh cancer deaths
(1982) observed versus
52.5 expected
(P <0.01). Dose
response found by
intensity and
duration of exposure.
Lee and Cohort 147 respiratory
Fraumeni cancer deaths
(1969) observed versus
4.47 expected
(P <0.01). Dose
response found by
intensity and
duration of exposure.
Lubin (1981) Cohort 146 respiratory
cancer deaths versus
88.7 expected
(P <0.01).
Short-term high intensity
arsenic exposures appeared to
have a greater effect than did
long-term low intensity
exposures; SO^ exposure was
found to have little or no
effect.
A dose-response was found
between exposure to sulfur
dioxide and respiratory cancer
mortality. Exposure to sulfur
dioxide could not be separated
from exposure to arsenic,
however.
Exposure to sulfur dioxide was
not found to have an independent
effect on cancer risk.
c:
3
CD
CO
CO
-------
TABLE 5-1. (continued)
o
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en
i
en
Study
Media Population
Air Smelter
Workers-
Anaconda,
Montana
(Followup
from 1938
to 1977)
Sample of 1800
of the Smelter
Workers-
Anaconda, Montana
(Followup from
1938-1977)
Lung cancer
from the
parish
where the
Ronnskar
smelter is
located
Lung cancer
deaths in the
city of
Saganoseki-
Machi , Japan.
Author(s)
Lee-Feldstein
(1982)
Welch et al.
(1982)
Axel son
et al.
(1978)
Kuratsune
et al.
(1974)
Type of
Study Results
Cohort 302 respiratory
cancer deaths
observed versus
105.8 expected
(P <0.01). Dose
response found by
duration and
exposure.
Cohort 24 respiratory cancer
deaths versus 4.6 expected
(P <0.01) in the heavy
exposure category. Dose-
response found by intensity
(both time-weighted average
and ceiling level
categories) of exposure.
Case- For smelter workers, the
control lung cancer mortality
odds ratio was 4.6; there
also was a significantly
(P <0.02) elevated risk
of leukemia and myeloma
among smelter workers.
Case- 58% of lung cancer cases
control were found to be former
smelter workers versus
15.8% in the controls.
Highlights and Deficiencies
Analysis of lung cancer
mortality by S02 exposure
found that S02 did not
play an important role in
the respiratory cancer
process.
Exposure to sulfur dioxide
did not appear to be
associated with lung
cancer.
The cause of death listed
on the death certificate
was validated using
detailed pathologic
analysis.
C_i
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TABLE 5-1. (continued)
Media
Study
Population
Author(s)
Type of
Study Results
Highlights
and Deficiencies
Air
Copper
smelters in
Saganoseki-
machi, Japan
Tokudome
and Kuratsune
(1976)
Cohort
Smelter
Workers in
Magna, Utah
Rencher et al.
(1977)
Proportionate
mortality and
cohort.
en
i
cr>
Residents
living near
a smelter
in El Paso,
Texas
Rom et al.
(1982)
Case-
control
29 Trachea, lung,
and bronchus cancer
deaths versus 2.44
expected (P <0.01);
3 observed colon cancer
deaths versus 0.59
expected (P <0.05).
A lung cancer dose
response was seen by
length of employment
and level of exposure.
7 percent of the deaths
were lung cancer deaths
compared to 0 to 2.2
percent for other factory
workers and 2.7 percent
for the State; the lung
cancer death rate was
found to be 10.1 per
10,000 versus 2.1 and
3.3 per 10,000 for mine
workers and the State
respectively.
No association was
found between
lung cancer and
distance from the
plant.
The latent period ranged
from 13 to 50 years, with
an average of 37.6 years.
Effects of migration,
smoking and occupation were
not considered.
c
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TABLE 5-1. (continued)
Media
Study
Population
Author(s)
Type of
Study Results
Highlights
and Deficiencies
Air
Residents of Newman et al.
Deer Lodge (1976)
and Silver Bow
Counties,
Montana
All counties
in the United
States with
smelters
Residents
near a
smelter
in Utah
Blot and
Fraumeni
(1975)
Lyon et al.
(1977)
Residents near Pershagen
Ronnskarverken etal.
smelter in (1977)
northern Sweden
Ecological There was an increase
Correlation found in the incidence
of lung cancer among
men. In one of the
cities there was also
an increase in lung
cancer among women.
Ecological Average lung cancer
Correlation mortality rates were
significantly elevated
for both males and
females in 36 counties
with smelters processing
copper, lead, or zinc ores.
Case- No association
Control between cancer
and distance from
the smelter was
found.
Ecological A significantly higher
Correlation mortality rate for
lung cancer was noted
for men in the exposed
area. The increase was
no longer significant
when occupational cases
were excluded, however.
No adjustment was made for
cancer cases which may be
occupational.
Lymphoma cases which may
have an association with
arsenic exposure were used as
controls. Effects of smoking,
migration, and occupation were
not considered.
When excluding occupational
cases of lung cancer from
the study population, lung
cancer cases for a
comparable occupational
group were not excluded
from the comparison
population.
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TABLE 5-1. (continued)
o
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CO
CO
Media
Study
Population
Author(s)
Type of
Study
Results
Highlights
and
Deficiencies
Air
Population Matanoski
surrounding an et al.
arsenical (1976, 1981)
pesticide
facility
Ecological
Correlation
Arsenical
sheep dip
manufacturing
workers
Hill and
Fanning
(1948)
Proportionate
mortality
en
oo
The lung cancer
mortality for males in
the census tract in
which the plant was
located was 3-4 times
higher than the control
tracts (P <0.05).
29.3 percent of
deaths were due
to lung cancer
versus 12.9 percent
of deaths among
workers in the same
geographic area who
were not exposed to
arsenic (P <0.05).
The excess in cancer
deaths was mainly
due to an excess in
lung cancer and skin
cancer.
The difference in the lung
cancer mortality rate in
the index tract could not
be explained by occupation.
c
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oo
TABLE 5-1. (continued)
Air
CJI
i
Media
Study
Population
Author(
1)
Type
Stud
of
y
Results
Highl
ights
and
Deficiencies
Arsenical
pesticide
manufacturing
workers
Ott et al.
(1974)
Proportionate
Mortality and
Cohort
Retirees of
an arsenical
pesticide
plant in
Baltimore,
Maryland
(follow-up
from 1960-
1972
Baetjer
et al. (1975)
Proportionate
mortality
and Cohort
16.2% and 3.5% of
deaths in the exposed
group were from cancer
of the respiratory
system and from
lymphatic and hemato-
poietic cancers,
except leukemia,
respectively versus
5.7 and 1.4% in the
controls; the cohort
mortality study found
20 respiratory cancer
deaths and 5 deaths
of the lymphatic and
hematopoietic tissues
versus 5.8 and 1.3
expected respectively
(Both significant at
P <0.01).
The proportionate
mortality ratio (PMR)
was 6.58 for
respiratory cancer
(P <0.05); for cause- '
specific mortality the
observed-to-expected
ratios were 16.67 for
respiratory cancer and
50 for lymphatic cancer
(Both with P <0.05).
A respiratory cancer
mortality dose response was
not found below an average
dosage of 3890 mg of
arsenic, but above that
dosage there was a good
dose response. It should
be noted, however, that
all of the respiratory
cancer at or below 3890 mg
had less than one year of
exposure. Thus, it is
unlikely that those deaths
were due to arsenic
exposure.
The cohort study was
limited to pensioners only.
_
3
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GO
—I
Study
Media Population
Air Retirees of
an arsenical
pesticide
plant in
Baltimore,
Maryland
(follow-up
1946-1977)
Wenatchee
Valley orchard
workers in the
state of
Washington
German
vintners
Author(s)
Mabuchi et al .
(1979)
Nelson et al.
(1973)
Roth (1958)
TABLE 5-1.
Type of
Study
Cohort
Cohort
Proportional
mortality
(continued)
Results Highlights and Deficiencies
12 observed lung cancer
deaths versus 3.6
expected, (P <0.05);
A dose response by
duration of employment
was seen for those with
exposure of high intensity.
No difference was found
between the cohort and
the state of Washington
for overall cancer
mortality or for lung
cancer mortality.
Of 47 autopsies among
vintners with chronic
I
O
Water
Residents of
a section of
Taiwan with
high levels
of arsenic in
the drinking
water
Tseng et al.
(1968);
Tseng (1977)
Sample of Borgono and
inhabitants Grieber
of Antofagasta, (1972)
Chile
arsenic intoxication,
64% of the deaths were
due to cancer, 60% to
lung cancer; 6 of the 47 and
13 of the 47 were reported
to have liver and skin
tumors, respectively.
Cross- A skin cancer
sectional prevalence rate
of 10.6/1000 for
those drinking
wel1 water was
found compared
to 0/1000 for
a control area.
The skin cancer
rate followed a
dose-response by
arsenic concentration
in the water.
Cross- Abnormal skin
Sectional pigmentation and
hyperkeratosis were
found in Antofagasta
where high arsenic
levels in the water
were reported. No
skin cancers were
reported, however.
00
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o
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TABLE 5-1. (continued)
en
I
Study
Media Population Author(s)
Type of
Study Results
Highlights and Deficiencies
Water Residents of Bergoglio
certain (1964)
departments
in the province
of Cordoba,
Argentina
exposed to
high levels
of arsenic in
the water
Patients at Arguello
a dermatology et al.
clinic in
eastern
Argentina
Proportionate The proportion
mortality of cancer
deaths was
higher than
for the province
as a whole
(23.84% versus
15.3% P <0.05).
Of the cancer
deaths, respir-
atory cancer
was reported to
be 35% and skin
cancer 2.3%.
Case The largest
Reports proportion of cases
in the clinic (82%)
came from areas with
the highest incidence
of chronic endemic
regional arsenical
intoxication.
The data is apparently not
age-adjusted. No compar-
ison is made of the per-
centage of respiratory and
skin cancer deaths in the
affected departments with
the respective proportion
for Cordoba Province.
The study was not
population-based.
Therefore, it cannot be
said that the incidence
of skin cancer is
significantly increased
in these areas.
Residents in an Morton et al. Cross-
area of Lane (1976) sectional
County, Oregon
The prevalence of
skin cancer was not
found to be associated
with arsenic concentra-
tions in the water.
The sample size was
relatively small.
C_.
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TABLE 5-1. (continued)
CO
3=
CO
Media
Water
Study
Population Author(s)
Two persons Astrup
1 iving in an (1968)
area of Taiwan
with endemic
high levels
of arsenic in
the water supply.
Type of
Study
Case reports
Results
Both individuals
had developed
blackfoot disease.
Highlights and Deficiencies
Milk
A group of
children in
Japan
Yamashita
et al. (1972)
Cohort
en
i
Arsenical
medicinals
Patients
being treated
with arsenical
medicinals
Hutchinson
(1888)
Arsenical
medicinals
Patients being
treated for
skin diseases
and various
internal
disorders with
arsenical
medicinals
Neubauer
(1947)
Case
Reports
Case
Reports
Hyperpigmentation and
depigmentation were
found to be prevalent
in about 15 percent of
the survivors
approximately 15 years
after exposure.
Six patients treated
with arsenical
medicinals exhibited
the keratotic lesions
associated with
arsenical poisoning.
143 individuals with
epitheliomas and who had
taken arsenical
medicinals.
There was no comparison
group.
3
fD
i-D
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o
I—"
CO
CO
Media
Study
Population
TABLE 5-1. (continued)
Author(s)
Type of
Study
Results
Highlights and Deficiencies
en
i
Arsenical
medicinal
Arsenical
medicinal
Arsenical
medicinal
(Fowler's
Solution)
Arsenical
medicinals
(Fowler1s
Solution)
Patients
treated with
Fowler's
solution (an
arsenical
medicinal) by
a private
practitioner
Patients
treated with
arsenical
medicinals
Male patient
27 cases
exposed to
arsenic either
via arsenical
drugs or via
occupation
Fierz
(1965)
Cohort
Reymann
et al.
(1978)
Cohort
Regelson
et al. (1968)
Sommers and
McManus
(1953)
Case
Report
Case
Reports
106 of the 262 patients
reporting for physical
examination reported
hyperkeratosis; 21
cases of skin cancer
were also found. The
response increased with
increasing dose.
Of 389 persons treated
with arsenical
medicinals, 41 internal
malignant neoplasms
were found to occur
versus 44.6 expected.
No increase in internal
malignant neoplasms
was found by dose.
Hemangi oendothe1i a 1
sarcoma of the liver.
Skin carcinoma were
reported in all cases;
visceral cancers were
reported for some of
the cases.
Less than 45% of the cohort
presented themselves for
physical examination, and
the author himself reported
that the patients reporting
for examination were not a
representative sample.
Furthermore, no controls
were used.
There was no control group.
Internal organs presumably
includes the lung, and
there was no control for
smoking, a major confounder
with regard to lung cancer.
CO
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TABLE 5-1. (continued)
CO
3=
Media
Arsenical
Medicinal
Study
Population
Male patient
Author(s)
Nurse (1978)
Type of
Study
Case
Report
Results
Adenocarcinoma
of the kidney
Highlights and Deficiencies
Patient treated with a variety
of other drugs before developing
kidney cancer.
Arsenical 2 male patients Knoth (1966)
Medicinal 1 female patient
I
H-"
-P»
Arsenical
medicinals
occupational
exposure
and air
(occupa-
tional)
exposure
16 vintners
who were
arsenical
pesticide
users; patient
who took arsenical
medicinals
Braun (1958)
Case Female developed
Reports mammary carcinoma
and skin cancer;
1 male patient
developed a
reticulosarcoma of
the glans penis;
1 male developed
skin cancer.
Case reports Skin and visceral
cancers were reported
among the vintners; skin,
lung cancers were reported
for one patient taking an
arsenical medicinal
skin cancer was reported
for the other patient
who took an arsenical
medicinal.
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TABLE 5-1. (continued)
en
i
Media
Arsenical
medicinals
(Fowler's
Solution)
Study
Population
2 male
patients
Author(s)
Morris
et al.
(1974)
Type of
Study
Case
Reports
Results
One patient developed
skin pigmentation, skin
tumors, carcinoma of the
larynx, and a probable
bronchial carcinoma; the
other developed skin
pigmentation and keratosis.
Both developed noncirrhotic
portal hypertension.
Highlights and Deficiencies
Arsenical
medicinal
(Fowler's
Solution)
Arsenical
medicinal s
(Fowler's
Solution)
Arsenical
medicinal
(Fowler1 s
Solution)
Female
patient
4 male patients
and 1 female
patient
1 male patient
Prystowsky
(1978)
Popper et al.
(1978)
Lander et al .
Case
Report
Case
Reports
Case
Report
Woman developed
nasopharyngeal cancer
developed palmar and
keratosis.
; also
plantar
The cases developed
angiosarcoma of the liver.
The patient developed
angiosarcoma.
c:
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This subsection will first focus on clinical pathophysiological aspects
of arsenic carcinogenesis, followed by pertinent epidemiological studies of
arsenic-induced carcinogenesis. Experimental studies of arsenic-induced
carcinogenesis will also be presented as will data dealing with arsenic muta-
genesis.
5.2.1.1 Clinical Aspects of Human Arsenic Carcinogenesis--In man, chronic
exposure to arsenic induces a characteristic sequence of changes in skin
epithelium, proceeding from hyperpigmentation to hyperkeratosis which may be
histologically described as showing keratin proliferation of a verrucose
nature with derangement of the squamous portions of the epithelium or may even
be described in some cases as squamous cell carcinomas.
Late onset skin cancers, associated with arsenic exposure, appear to be
of two histopathological types: squamous carcinomas in the keratotic areas
and basal cell carcinomas. In one study dealing with skin cancer after pro-
longed use of Fowler's solution (Neubauer, 1947), the ratio of types was
approximately 1:1.
Arsenic-associated skin cancers differ from those of ultraviolet light
etiology by occurring on areas generally not exposed to sunlight, e.g. palms
and soles, and occurring as multiple lesions (Arsenic. NAS, 1977; Pershagen
and Vahter, 1979; WHO, 1981; Tseng, 1977; Sunderman, 1976). This appears to
be the case for medicinal (Neubauer, 1947), environmental (Tseng et al. ,
1968), and occupational (Roth, 1958; Braun, 1958) exposure. The time lag
between initiation of exposure and occurrence of skin cancer has been reported
to range from 13 to 50 years for arsenical medicinally induced skin cancer.
The minimal latency period for skin cancer in the most reliable epidemiologic
study of arsenic-contaminated drinking water was reported to be 24 years.
013AS2/A 5-16 June 1983
-------
The amount of data on the histological classification of lung tumors
associated with occupational arsenic exposure is limited. Newman et al.
(1976) report that arsenic-associated lung cancers are usually the poorly
differentiated type of epidermoid bronchogenic carcinoma. These investigators
studied worker groups with diagnosed lung cancer in copper-mining and smelting
communities in Montana. Of 25 smelter workers, 4 had well-differentiated
epidermoid carcinoma, 10 poorly differentiated epidermoid carcinoma, 7 small-
cell undifferentiated epidermoid carcinoma and 3 acinar-type adenocarcinoma.
Copper miners and "non-copper" control individuals had lung cancer profiles
which were similar to each other.
The time period between initiation of exposure and the occurrence of
arsenic-associated lung cancer was found in a couple of studies to be on the
order of 35-45 years (Lee and Fraumeni, 1969; Tokudome and Kuratsune,1976).
Recently, a latency period of <20 years was reported by Enter!ine and Marsh
(1980; 1982) based upon their studies of copper smelter workers in Tacoma,
Washington. Tokudome and Kuratsune (1976) found that the latent period for
lung cancer ranged from 13 to 50 years.
The association of other visceral cancers with arsenic exposure has been
noted in a number of reports and has been reviewed elsewhere (WHO, 1981;
Arsenic. NAS, 1977; NIOSH, 1976; IARC, 1973). For example, hemangiosarcoma of
the liver, a rare form of cancer, has been diagnosed in workers exposed to
arsenic and in non-occupationally arsenic-exposed individuals (Roth, 1958;
Regelson et al., 1968; Lander et al., 1975). Morris et al. (1974) have postu-
lated that the peculiar hepatic fibrosis associated with arsenic-induced
portal hypertension is a precursor state for subsequent progression to hepatic
angiosarcoma. Popper et al. (1978) have noted that the hepatic fibrosis and
hypertension seen in humans with Thorotrast, vinyl chloride or arsenic exposure
013AS2/A 5-17 June 1983
-------
are also induced by agents which presumably also have a role in hepatic
angiosarcoma.
Other cancers noted in arsenic-exposed subjects include: lymphomas and
leukemia (NIOSH, 1976; Ott et al., 1974); renal adenocarcinoma (Sommers and Mc-
Manus, 1953; Nurse, 1978); and nasopharyngeal carcinoma (Prystowsky et al., 1978).
Pelfrene (1976) has criticized the reports of internal malignant neoplasms
associated with arsenic exposure on the basis of the relative rarity of their
detection in large-scale studies of chronic arsenic exposure such as that of
Tseng (1968, 1977). More recently, Reymann et al. (1978) reported on a study
of a group of patients who took arsenic medicinally in the 1930s. An increase
in internal cancers was observed only in a subpopulation of female patients
treated for multiple basal cell carcinomas and patients with arsenic keratoses,
when compared with the expected incidence of malignant internal neoplasms
based on the Danish Cancer Registry.
5.2.1.2 Epidemiological Aspects of Human Arsenic Carcinogenesis
5.2.1.2.1 Cancer of the lung. A large number of reports are available on
possible associations between occupational exposure to arsenic and cancer of
the respiratory system. As is common in studies of this type, exposure data
are very uncertain and the arsenic exposure is not always clearly defined
regarding the physicochemical properties of the arsenic compounds. The picture
is often confused by simultaneous exposure to other agents, especially sulfur
dioxide and metals. Data on smoking are often lacking or incomplete.
An excess mortality in respiratory cancer has especially been noted among
workers engaged in the production and usage of pesticides, and among smelter
workers.
In 1948, Hill and Faning presented data on proportional mortality rates among
British workers exposed to a mixture of ingredients—including sodium arsenite,
powdered sulfur and soda ash—used in the manufacture of a sheep-dip powder.
013AS2/A 5-18 June 1983
-------
Between 1910 and 1943, 75 deaths had occurred among workers in the sodium
arsenite factory and 1,216 deaths had occurred among workers in the same area
but without known exposure to arsenic. Proportionate mortality analysis
showed that of the deaths among factory workers, 29.3 percent had died from
cancer, whereas the corresponding figure for the other workers was 12.9 per-
cent. The excess in cancer deaths among the factory workers was mainly due to
an excess in lung cancer, 31.8 percent of all cancer deaths compared with 15.9
percent; and in skin cancer, 13.6 percent compared with 1.3 percent.
Among the factory workers, chemical workers, who were the workers most
closely associated with arsenite production, had a higher proportion of cancer
deaths than did the factory workers as a group. Furthermore, all lung cancer
deaths had occurred among the chemical workers.
Arsenic in the air of the sodium arsenite factory was determined in
3
1945-46 (Perry et al., 1948) and concentrations up to 4 mg As/m were found by
sampling for 10 minutes. No data were given on the age of the deceased, and
smoking habits were not recorded. The data do not allow any conclusions about
exposure before 1943. Nevertheless, this study indicated that there might be
an increased risk for respiratory cancer in the manufacture of arsenic-containing
pesticides, and studies in two United States plants have given further
support.
Ott et al. (1974) studied the mortality of workers in one of these two
chemical plants. From 1919 to 1956 one unit formulated and packaged insecti-
cides containing arsenic in the form of lead arsenate, calcium arsenate,
copper acetoarsenite, and magnesium arsenate. During this period, the pro-
portions of the different compounds varied. The main product was lead arsenate.
The size of the workforce was about 30 in 1928 and 100 in 1948. Turnover was
high with less than 25 percent of the men remaining with the unit for more
013AS2/A 5-19 June 1983
-------
than one year. Arsenic concentrations in air in 1943 were between 0.18 and 19
3 3
mg As/m in the packaging area; in 1952 concentrations were 1.7-40.8 mg As/m
and 0.26-7.5 mg/m in the drum dryer area and packaging area, respectively.
By combining job classifications and air arsenic data, four exposure classifi-
cations were obtained with estimated arsenic exposures (8-hr TWA) of 5, 3, 1,
3
and 0.1 mg/m . The total dosage was then calculated for each individual by
3
multiplying air levels with the number of days at work and assuming that 4 m
were inhaled during a working day.
Mortality was studied by analysis of proportionate mortality and by a
retrospective cohort analysis. Nearly 2,000 employees in the factory had died
between 1940 and 1972. One hundred seventy-three were identified as having
worked one or more days in the arsenical production unit and who then either
worked for the company until death or died after retirement.
Ott et al. (1974) after adjusting for age and year of death compared the
differences in proportionate mortality between the study group and the controls.
Among the exposed, respiratory cancer accounted for 16.2 percent of the deaths
compared with 5.7 percent in the controls (p < 0.001). There was also a signifi-
cant increase (p < 0.05) in deaths from lymphatic and hematopoietic cancers,
except for leukemia. Table 5-2 shows the observed to expected ratios for re-
spiratory cancer in relation to exposure. (In the original table, dosage esti-
3
mates were based on 4 m inhaled per 8 hr and expressed as the natural logarithms.
3
In the present table, dosage is expressed in mg and is based on 10 m inhaled
air.) There is no tendency towards a dose-response relationship at total expo-
sures from 105 to 3890 mg, but a sharp increase is noted at higher dosages.
Furthermore, Blejer and Wagner (1976) reported that of the 173 deaths, 138 had
occurred among workers with less than one year of exposure. In that group, 16
deaths were due to respiratory cancer. As seen in Table 5-2, 15 of those deaths
013AS2/A 5-20 June 1983
-------
TABLE 5-2. OBSERVED AND EXPECTED DEATHS DUE TO RESPIRATORY MALIGNANCIES,
BY EXPOSURE CATEGORY
TWA Concentra-
tion x months
of exposure
<1
1-1.9
2-3.9
4-5.9
6-11.9
12-23.9
24-59.9
60-95.9
96+
Average
dosage
mg
105
316
630
1050
1991
3890
8833
16257
74332
No. of
total
deathst
26
17
24
22
27
18
13
13
13
Respiratory Malignancy Deaths
Ob-
served*
1 (1)
2 (2)
4 (4)
3 (3)
3 (3)
2 (2)
3 (1)
5 (0)
5 (0)
Expected
1.77
1.01
1.38
1.36
1.70
.97
.77
.79
.72
Ratio Observed
Katl° Expected
.6
2.0
2.9
2.2
1.8
2.1
3.9
6.3
7.0
tn = 173, 138 workers had less than one year of exposure.
*Number in brackets shows respiratory cancer deaths in workers
exposed less than one year.
Source: Modified from Ott et al. (1974), and Blejer and Wagner (1976).
013AS2/A
5-21
June 1983
-------
occurred in the six groups with average total exposures estimated to be from
105 to 3890 mg. There are no quantitative data on other compounds that these
workers might have been exposed to during their total time with the company;
however, it is known that in addition to the arsenic-containing insecticides,
the plant processed and packaged several other products, the most important of
which were powdered sulfur and dry lime sulfur.
The retrospective cohort analysis was based on a roster of 603 workers
who had worked for at least one month in the actual unit between 1940 and
1973. Workers leaving the company before retirement as well as workers who
had been exposed to asbestos were not included in the analysis. It was stated
that virtually all men with at least one year of exposure had been identified.
Person-years, by 10-year age groups, for five calendar year groups were calcu-
lated and expected number of deaths were calculated by using United States
white male mortality data. Table 5-3 shows that by this analysis a significant
increase (p < 0.01) in deaths due to respiratory cancer was found among
exposed workers. There was also a significant increase (p < 0.01) in the
number of deaths due to malignant neoplasms in lymphatic and hematopoietic
tissues, except leukemia.
A chemical plant in Baltimore has been subjected to two studies concern-
ing the working environment and one study concerning the outer environment.
This plant started producing arsenic acid in the early 1900s and in the early
1950s production of arsenical pesticides started. Lead arsenate, calcium
arsenate and sodium arsenate were among the compounds produced. Production
terminated in 1974 (Matanoski et al., 1976). The plant also produced chlori-
nated hydrocarbons and organic phosphates. Data on air concentrations of
arsenic are lacking.
013AS2/A 5-22 June 1983
-------
TABLE 5-3. OBSERVED AND EXPECTED DEATHS FOR SELECTED CAUSES IN
RETROSPECTIVE COHORT ANALYSIS (1940-1973)
Observed
deaths
Expected
deaths
(U.S. white
male)
Ratio of
observed
to expected
deaths
All causes 95
Malignant neoplasms, total 35
Respiratory system 20
Digestive organs & peritoneum 7
Lymphatic & hematopoietic
tissues except leukemia 5
All other sites 3
Diseases of cardiovascular system 41
Emphysema, chronic bronchitis,
& asthma
All external causes
All other causes
4
9
6
113.5
19.4
5.8
6.3
1.3
6.0
58.5
2.8
12.7
20.1
.84
1.80
3.45t
1.11
3.85t
.50
.70
1.43
.71
.30
t p < 0.01
Source: Ott et al. (1974).
013AS2/A
5-23
June 1983
-------
In the first study, Baetjer et al. (1975) reported on both the propor-
tionate mortality and age-specific death rates of workers who had retired
between 1960 and 1972 and generally had at least 15 years' employment. Seven-
teen of 22 deaths among male white workers and two of five among female workers
were due to malignant neoplasms. The female deaths did not appear to be
related to occupational exposure, whereas, the male deaths did. Of the 17
malignant neoplasms in males, 10 were in the respiratory tract, 3 were lympho-
sarcomas, and the remaining 4 were of other tissues. The proportionate mor-
tality analysis, based on mortality data for the city of Baltimore, showed an
observed/expected ratio of 6.58 for respiratory cancer (p <.05) and 15.79 for
cancer of the lymphatic and hematopoietic system (0.1 < p < 0.05). The age-
specific death rate analysis showed that deaths from respiratory cancer were
16.67 times the expected and that for lymphosarcomas, the observed number
was 50 times that of the expected number. The authors reported that observed
and expected rates for non-cancer deaths did not differ significantly (p <
0.05).
In a second study (Mabuchi et al., 1979), a follow-up was made of workers
employed from 1946 to 1974. Since exposure data were lacking, an attempt was
made to classify workers according to exposure to arsenicals and non-arsenicals.
A roster of 3,141 workers was obtained. Since 2,189 workers had been employed
for less than 4 months, a 20 percent random sample was drawn from that popula-
tion and together with the remaining 952 workers constituted the study popula-
tion: 1,050 males and 343 females, mainly white. Exposure assessments were
made, and the workers were categorized into one of six exposure groups.
Of the study population, 240 had died: 197 males and 43 females. Ex-
pected deaths were calculated from the city of Baltimore statistics. The
observed/expected ratios for lung cancer were analyzed by exposure, year of
013AS2/A 5-24 June 1983
-------
first employment, and duration of employment. A statistically significant
increase in lung cancer mortality (SMR = 336, p < 0.05) was found among "pre-
dominantly arsenical production" workers. There was a clear lung cancer mor-
tality dose-response among these workers by duration of exposure. Those
employed 15-24 years and 25+ years both had statistically significant (p <
0.05) lung cancer SMRs (1365 and 2750, respectively). Interestingly, statis-
tically significantly elevated SMRs were only found in "predominantly arsenical
production" workers, but not in workers engaged entirely in arsenical produc-
tion. Further analysis revealed that the proportion of workers engaged en-
tirely in arsenical production for 5 years or more was relatively low (1
percent), while the proportion of workers exposed predominantly, but not
entirely, to arsenic for 5 years or more was much higher (29 percent). This
difference in duration of exposure may have accounted for the absence of
excess lung cancer mortality among the purely high arsenic exposed workers.
Data on smoking were not obtained.
Occupational exposure to arsenical pesticides has been common among
vintners and agricultural workers. Exposure has mainly been to lead arsenate.
In a study of orchard workers, Nelson et al. (1973) did not find an excess of
lung cancer compared with the state of Washington. This study was evaluated
by NIOSH (1975), and it was concluded that the study by Nelson et al. did not
accurately depict the cancer mortality of persons exposed to lead arsenate.
Several studies in Germany indicate that workers exposed to arsenic
trioxide when spraying vineyards had a high mortality in cancer, especially
lung cancer. In one report (Roth, 1958), it was stated that of 47 autopsies
among vintners with chronic arsenic intoxication, 30 (64 percent) were due to
cancer, and 18 to lung cancer (60 percent of all cancer deaths). The author
did not state how the cases were selected, nor were controls used in the study.
013AS2/A 5-25 June 1983
-------
Occupational exposure to arsenic also occurs in smelters where exposure
is predominantly to arsenic trioxide. Several studies have been done on
mortality among workers at the copper smelter in Tacoma, Washington. Pinto
and Bennet (1963) reported on the proportionate mortality of 229 workers from
1946 to 1960. Workers leaving the plant before retirement were not included.
The proportionate mortality of the smelter workers was compared with that of
males in the state of Washington in 1958. Of all cancer deaths, the respec-
tive proportions of lung cancer were 41.9 and 23.7 percent. The authors then
classified the smelter workers according to arsenic exposure and did not find
any difference between exposed and non-exposed. However, the "non-exposed"
had elevated arsenic levels in urine, suggesting possible exposure. More
extensive studies have since been published, showing an increase in lung
cancer among arsenic-exposed workers (Milham and Strong, 1974; Pinto et al.,
1977; Pinto et al., 1978; Enterline and Marsh, 1980; Enterline and Marsh,
1982).
Milham and Strong (1974) examined county records from 1950 to 1971 to
find the number of deaths due to respiratory cancer among county residents
employed at the smelter. Expected number of cases were calculated for the
smelter population by using the 1960 age-cause specific mortality statistics
for white males in the United States. Forty deaths were observed and 18 were
expected.
The two papers by Pinto et al. (1977, 1978) refer to the same study and
the following is based on the 1978 paper.
The cohort studied consisted of 527 men who were living pensioners on
January 1, 1949 or who became pensioners before January 1, 1973. Complete job
histories were obtained for 525 men. The average duration of employment was
013AS2/A 5-26 June 1983
-------
28 years, ranging from 7 to 54 years and beginning in 1910. Death certifi-
cates were obtained for all 324 men who had died during the observation period
(1949-1973). Expected numbers of deaths were calculated from statistics of
the state of Washington.
An exposure index was constructed by using data on urinary levels of
arsenic obtained in 1973. Mean urinary concentrations were calculated for 32
departments, and the individual exposure index was obtained by multiplying
urinary arsenic level with years of work in a department. If an individual
had worked in more than one department, the index values were added. By
dividing the exposure index by the total number of years in the smelter, an
index of intensity of exposure was obtained, i.e., the average urinary level.
These indices were created to enable interdepartmental comparisons and did not
reflect past exposure since air analysis in the 1930s to 1940s indicated that
exposure might have been 5-10 times higher at that time. It may have been
still higher in 1910.
Data were also obtained on smoking habits from all men still alive and
from relatives of men who had died since January, 1961. Table 5-4 (Pinto et
al., 1978) shows that there was a significant increase (p < 0.05) in deaths
from all causes, in cancer deaths in general, and, specificially, in deaths
from respiratory cancer. Almost all of the excess mortality could be explained
by the increase in lung cancers which could not be explained by smoking.
Table 5-5 shows respiratory cancer deaths in relation to exposure index
(a value which reflects both the duration and intensity of exposure). An
increase in SMR with exposure is seen. Table 5-6 shows that both duration and
intensity of exposure contributed to the excess in respiratory cancer. As
stated above, the urine values are relative and do not reflect the actual
exposure.
013AS2/A 5-27 June 1983
-------
TABLE 5-4. OBSERVED AND EXPECTED DEATHS AND STANDARDIZED MORTALITY RATIO
FOR SELECTED CAUSES OF DEATH OF 527 MALES OF COHORT UNDER STUDY*
Cause of death
All Causes
Cancer
Digestive
Respiratory
Lymph, etc.
Urinary
All Other Cancers
Stroke
Heart Disease
Coronary Heart Disease
All Other Heart Disease
Respiratory Disease
All Other Causes
Disease
Classification!
140-205
150-159
160-164
200-203, 205
180,181
330-334
400-443
420
480-493, 500-502
Observed
324
69
20
32
2
3
12
43
144
120
24
11
57
Expected
288.7
46.5
16.4
10.5
2.1
3.3
14.2
38.0
132.3
110.2
22.1
10.8
61.8
SMR
112.2+
148.4+
122.0,
304.8+
95.2
90.9
84.5
113.2
108.8
108.9
108.6
101.8
92.2
*Cohort consisted of living male pensioners from a copper-smelting plant who were
living January 1, 1949, and whose causes of death were noted through December 31,
1973.
fNumbers from rubrics of 7th Revision of International Classification of Diseases.
+P<.05
Source: Pinto et al. (1978).
013AS2/A 5-28 June 1983
-------
TABLE 5-5. OBSERVED AND EXPECTED RESPIRATORY CANCER DEATHS AND
STANDARDIZED MORTALITY RATIOS BY ARSENIC EXPOSURE INDEX
Exposure index
Under 2,000
2,000-2,999
3,000-5,999
6,000-8,999
9,000-11,999
12,000 and over
Mean index
1,514
2,513
4,317
7,473
10,135
14,712
Respiratory Cancer Deaths
No. of men
36
109
205
109
38
29
Observed
1
4
11
7
4
5
Expected
0.9
2.1
3.9
2.3
0.7
0.6
SMR
111.1
190.5
282.0*
304.3*
571.4*
833.3*
*p <.05
Source: Pinto et al. (1978).
TABLE 5-6. OBSERVED AND EXPECTED RESPIRATORY CANCER DEATHS AND STANDARDIZED
MORTALITY RATIOS BY INTENSITY AND DURATION OF EXPOSURE TO ARSENIC
Intensity of Duration of exposure
exposure less than 25 years 25 years and more
(|jg/liter urine) Observed Expected SMR Observed Expected SMR
50-199
200-349
350 and over
2
4
3
2.1
1.5
0.5
95.2
266.7
600.0*
10
8
5
3.6
2.2
0.6
277.8*
363.6*
833.3*
*P<.05
Source: Pinto et al. (1978).
013AS2/A
5-29
June 1983
-------
It was also shown that the main excess occurred in ages 65-74 years,
whereas at higher ages the lung cancer rate was closer to expected rates.
More recently, Enterline and Marsh (1980; 1982) conducted additional
studies on workers at this same copper smelter in Tacoma. A cohort of 2802
males who worked a year or more during the period 1940-1964 were identified.
Since a one-year work exposure was required for eligibility into the cohort,
actual followup did not start until 1941 and extended through 1976. In the
cohort the vital status of 51 could not be verified, leaving 2751 persons. In
that group 1061 deaths had occurred. There was a significant increase in
total cancer mortality which wholly depended on an increase in deaths from
lung cancer. Arsenic exposure was estimated for each man on the basis of a
representative average urinary arsenic level for workers in a given department.
Using this representative value, an individual value was calculated for each
man for each year of employment in a given department and a total exposure
estimate per individual was made by summing values across all jobs and all
years of employment.
This method of estimating exposure differed from earlier methods employed
by Enterline and coworkers (Pinto et al. , 1977; 1978) in that estimates of
historic exposure, based upon simple linear interpolations and extrapolations
of actual data from 1948-52 and 1973-75, were used to characterize exposure by
department, rather than by 1973 urinary measurements. Use of this new method of
analysis partially helped to eliminate exposure underestimates of workers
employed in the early years of the smelter operation. However, the present
method did not totally eliminate this bias because urinary arsenic levels were
only determined for workers starting in 1948. For workers exposed prior to
1948 (approximately 80 percent of the present study cohort), urinary arsenic
values for 1948-52 were assumed to apply. Furthermore, the average urinary
arsenic level for some departments may have been based on only a few samples,
013AS2/A 5-30 June 1983
-------
thereby limiting the usefulness of the departmental average as a representative
measure of any given worker's urinary arsenic level. The authors did note
that in areas of the smelter where arsenic levels were reported to be high,
workers tended to be measured more often for urinary arsenic. Thus, averages
for those areas were, in fact, more representative.
Using this time-weighted measure of exposure, a life table method for
accumulative dose, a 10-year lag period and a standard population of mortality
rates in the state of Washington, the authors reported that SMRs for respira-
tory cancer ranged from 155 in the lowest exposure category to 246 in the
highest category. Table 5-7 shows the relationship between the time-weighted
estimates of arsenic exposure lagged 0 and 10 years and respiratory cancer.
TABLE 5-7. RESPIRATORY CANCER DEATHS AND SMRs
BY CUMULATIVE ARSENIC EXPOSURE LAGGED 0 AND
10 YEARS, TACOMA SMELTER WORKERS
Cumulative
Exposure (ug/As/1)
(urine-years)
<500 ( 302)
500-1500 ( 866)
1500-3000 ( 2173)
3000-5000 ( 4543)
7000+ (13457)
0 Lag
Observed
Deaths
8
18
21
26
31
Lag
SMR
202.0
158.4
203.2**
184. 1**
243.4**
10 Year
Observed
Deaths
10
22
26
22
24
Lag
SMR
155.4
176.6*
226.4**
177.6*
246.2**
* p<.05
**p<.01
()Mean of class interval
Source: Enterline and Marsh (1982).
This relationship was much weaker than that previously reported by Pinto et
al. (1977; 1978). Enterline and Marsh noted that results from the two sets of
studies were not totally comparable due not only to the differences in the
exposure estimates noted above, but also to differences in followup periods.
013AS2/A
5-31
June 1983
-------
In earlier reports, the followup started after exposure stopped at retirement,
whereas in the present study, followup started at varying points in the work
experience of the workers allowing for followup and dose accumulation to pro-
ceed concurrently. When the authors analyzed a subsample of the present
study cohort, consisting of 582 workers retired at age 65 and over (parallel-
ing the experimental design of the earlier studies), a stronger dose-response
relationship was, in fact, observed.
Table 5-8 shows the respiratory cancer deaths and SMRs by duration of
exposure and time since first exposure. In this particular study, it would
appear that neither duration of exposure nor long latent periods made strong
contributions to excess respiratory cancer. The authors suggested that this may
have been due to the high SMRs observed shortly after termination of employment
but not noted thereafter; thus, for workers with less than 10 years of exposure
the SMR is highest 10-19 years after date of hire, for workers employed 10-19
years the SMR is highest 20-29 years after date of hire, etc. When the authors
reanalyzed the data according to a method which followed workers only from the
point of termination or retirement, both duration of exposure and intensity of
exposure contributed more strongly to respiratory cancer mortality (Table 5-9).
The difference in the two analyses led the authors to suggest that the weak dose-
response relationship observed in the first analysis may have resulted from a
tendency for workers in high exposure jobs to leave employment more quickly than
those in low exposure.
In studying the interactive effects of sulfur dioxide, the authors did
not find significant differences in respiratory cancer incidence in two depart-
ments which both had high arsenic exposures (7500 ug/m3) but differing S02
exposures, one having low to moderate exposures (520 ppm) and the other having
013AS2/A 5-32 June 1983
-------
o
I—>
co
to
ro
en
i
CO
CO
TABLE 5-8. RESPIRATORY CANCER DEATHS AND SMRs BY DURATION OF EXPOSURE
AND LATENCY, TACOMA SMELTER WORKERS
Latency (Years)
Duration
(years)
<10
10-19
20-29
30+
Total
<10 10-19 20-29 30+ Total
Observed Observed Observed Observed Observed
Deaths SMR Deaths SMR Deaths SMR Deaths SMR Deaths
1 55.6 10 265.4* 17 210.1** 12
6 156.4 8 278.0* 4
13 197.0* 13
20
1 55.6 16 210.4* 38 216.3** 49
137.9
137.9
265.3**
221.3**
191.8**
40
18
26**
20
104
SMR
178.9**
187.2*
226. 1*
221.3**
198.1**
* p < .05
**p < .01
Source: Enterline and Marsh (1982).
=3
fD
00
CO
-------
o
H-•
CO
00
no
en
i
CO
TABLE 5-9. RESPIRATORY CANCER DEATHS AND SMRs BY DURATION
AND INTENSITY OF EXPOSURES, TACOMA SMELTER WORKERS
Intensity estimate
Duration of
exposure
(years)
<10
10-19
20-29
30+
Total
Lowt
No. at
risk
687
149
225
159
1220
Observed
deaths
15
7
10
9
41
Expected§
deaths
8.83
2.61
3.59
2.98
18.01
SMR
169.9
268.2*
278.6**
302.0**
227.7**
No. at
risk
824
168
171
165
1328
High++
Observed
deaths
25
11
16
11
63
Expected§
deaths
12.26
3.42
2.77
3.17
21.62
SMR
203.9**
321.6**
577.6**
347.0**
291.4**
* p < 0.05.
** p < 0.01.
t low = <290 [jg/As/A urine (mean 163).
++ high = >290 ug/As/£ urine (mean 477).
§ Based on Washington State white males.
Source: Enter!ine and Marsh (1982).
00
CO
-------
essentially none. Because the respiratory cancer SMRs were quite similar in
the two departments, the authors suggested that SOp exposure did not play an
important role in respiratory cancer excess at that particular smelter.
In discussing their overall study results, Enterline and Marsh noted
that, in this particular case, a dose response was not observed when dose was
measured in terms of cumulative dose. The results seen in Table 5-8 suggest
that short exposures seemed to have a disproportionately greater effect than
long exposures and that effects of early exposure tended to diminish with
time. Table 5-9 suggests that short high-intensity exposures may have a
greater effect than longer term more low-level exposures. The fact that
different results are obtained when different exposure/followup methods are
employed suggest that choice of experimental design has a possible influence
on results. The possibility that some workers may have simply been more
susceptible than others may also have accounted for the dose-response relation-
ships observed in this study.
The authors did suggest that if the responses were, in fact, due to
arsenic, the role of arsenic in this particular situation may have been as
promoter rather than initiator. If this were the case, the significance of
cumulative exposure to arsenic as a measure of dose would be questionable in
regard to the induction of respiratory cancer as observed in this study. The
role of arsenic as an initiator as well as a promoter cannot be ruled out,
however. Until further research is done, the authors' conclusions from this
study remain speculative.
Mortality of workers in a smelter in Magna, Utah, was studied by Rencher
et al. (1977). Average hourly air concentrations of arsenic in 12 work areas
3
were between zero and 22 mg/m in 1975 (NIOSH, 1975). However, exposure
013AS2/A 5-35 June 1983
-------
before 1959 had likely been higher, since a processing of ore with a rela-
tively low arsenic content began in that year. In the period 1959 to 1969,
965 deaths had occurred among all current or former employees, and death
certificates were obtained for virtually all deceased. The proportionate
mortality for smelter workers was compared with that for mine workers, concen-
trator workers, refinery, and office workers, and for the population above 20
years of age for the entire state of Utah in 1968. Among the smelter workers,
7 percent of the deaths were due to respiratory cancer, whereas the percentage
for the other factory employees varied from 0 to 2.2 percent and was 2.7
percent for the state. Data on smoking were obtained for all smelter workers
and for subsamples of the other employee groups and indicated that nonsmoking
smelter workers had the same percentage of deaths from lung cancer as mine and
concentrator workers who smoked. By applying life-table methods, age-adjusted
death rates were obtained. For smelter workers a death rate for lung cancer
of 10.1 per 10,000 was obtained compared with 2.1 and 3.3 per 10,000 for mine
workers and the state population, respectively. Causes of death were compared
with a cumulative exposure index obtained by multiplying number of days spent
in each department by the average exposure level and then summing. The average
exposure to arsenic as well as sulphur dioxide, sulphates, lead, and copper
were found to be higher for the lung cancer cases than for other causes of
death.
In addition to these studies, a large study by Lee and Fraumeni (1969)
involving 8,047 white males was conducted at an Anaconda Copper Smelter in
Montana from 1938 to 1956.* Data were obtained on time, place, and duration
*While the original Lee and Fraumeni study reported on the mortality
experience of male smelter workers in unidentified states, subsequent analyses
of these workers indicate that they were employed solely at the Anaconda smelter
in Montana.
013AS2/A 5-36 June 1983
-------
of employment for each individual, all subjects having worked at least 12
months in the smelter during the indicated study period. Follow-up was from
1938 to 1964. Death certificates were obtained, and the life-table method was
used to compute the expected number of deaths, using mortality rates of the
State of Montana. The smelter workers were classified into 5 cohorts based on
total years of smelter work and the time period in which the years were worked:
(1) 15 or more worked before 1938; (2) 15 or more years worked between 1938
and 1963; (3) 10-14 years; (4) 5-9 years; and (5) 1-4 years. An attempt was
also made to classify the workers according to exposure to arsenic and sulphur
dioxide. Exposure to arsenic for more than 12 months had occurred among 5,185
men. These workers were divided into three groups; heavy, medium, and light
exposures. This division was based on exposure times and place at work.
Arsenic concentrations in air were primarily determined from a 1965 survey by
Public Health Service officials (NIOSH, 1975). These air data are shown in
Table 5-10.
According to a former Public Health official associated with this survey,
actual measurements were collected during two different periods—one in 1965
and one "about five to six years earlier"--and at several locations within
given departments (Archer, 1983; personal communication). It is impossible,
however, to determine how the values listed in Table 5-10 are distributed over
these different time periods and locations. Further, it is also impossible to
determine the number of hours sampled at a given location. Therefore, the
arithmetic means used by Lee and Fraumeni to characterize heavy, medium and
light exposures, can only be viewed as very rough estimates of arsenic exposure,
their primary value being in their relative scale of measurement.
In Table 5-11 it is seen that heavy and medium exposures resulted in
significant increases in SMR for respiratory cancer. The SMR was highest
(800) in workers belonging to cohort 1 (more than 15 years of smelter work
013AS2/A 5-37 June 1983
-------
TABLE 5-10. 1965 SMELTER SURVEY ATMOSPHERIC
ARSENIC CONCENTRATIONS (mg As/m3)
Median: 0.185
"Heavy exposure area" as classified by Lee and Fraumeni
Arsenic Roaster Area Mean- 1 47
O0~ 0.20
0.10 0.22
0.10 0.25
0.10 0.35
0.10 1.18
0.10 5.00
0.17
12.66
"Medium exposure area" as classified by Lee and Fraumeni
Reverberatory
Treater Buildi
Area
0.03
0.22
0.23
0.36
0.56
0.63
0.66
0.76
0.78
0.78
0.80
0.83
ng and Arsenic
0.93
1.00
1.27
1.60
1.66
1.84
1.94
2.06
2.76
3.40
4.14
8.20
Loading
Mean:
Median:
1.56
0.88
~O8~
0.10 0.62
0.10 3.26
0.11 7.20
Mean:
Median:
1.50
0.295
"Light exposure areas" as classified by Lee and Fraumeni
Copper Concentrate Transfer System Mean: 0.70
OS Median: 0.65
0.65
1.20
Samples from Flue Station
(TTD
0.24
Reactor Bui 1 din
001
0.002
0.002
0.002
0.003
0.009
0.010
Mean:
Median:
Mean:
Median:
0.17
0.17
0.004
0.002
Source: National Institute of Occupational Safety and Health (1975).
013AS2/A
5-38
June 1983
-------
TABLE 5-11. OBSERVED AND EXPECTED DEATHS FROM RESPIRATORY CANCER, WITH STANDARDIZED
MORTALITY RATIOS (SMR), BY COHORT AND DEGREE OF ARSENIC EXPOSURE, 1938-63
Cohort
All cohorts
combined
1
2
3-5+
Number of persons i
arsenic category*
Respiratory
cancer
mortality
Observed
Expected
SMR
Observed
Expected
SMR
Observed
Expected
SMR
Observed
Expected
SMR
n
Heavy
18
2.7
667t
8
1.0
soot
6
0.9
667t
4
0.9
444§
402
Maximum exposure to
arsenic (12 or more
months)*
Medium
44
9.2
478t
22
3.3
667t
12
2!2
545. t
10
3.8
263§
1,526
Light
45
18.8
239t
14
5.6
250t
9
2.9
310t
22
10.3
214t
3,257
*The remaining 2,862 men in the study worked less than 12 months in their
category of maximum arsenic exposure and had an SMR of 286t-
tSignificant at the 1% level.
+Cohorts 3, 4, and 5 were combined, since observed and expected deaths
were small for each cohort alone.
§Significant at the 5% level.
Source: Lee and Fraumeni (1969).
013AS2/A
5-39
June 1983
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before 1938), and then decreased to 263 among workers with 1-14 years of
smelter work. Among the workers with light exposure, the SMR was 250, 310,
and 214 in cohorts 1, 2, and 3-5, respectively. Among the smelter workers
with less than 12 months exposure to arsenic, the SMR was 286.
Lee and Fraumeni also looked at factors that possibly had confounding
effects on their study results. Smoking histories were not recorded; however,
based upon information obtained from other studies, Lee and Fraumeni concluded
that smoking alone could not have accounted for the excess respiratory cancer
mortality of the magnitude observed in their study.
In contrast to smoking, the authors did note a positive relationship
between exposure to sulfur dioxide and respiratory cancer mortality; however,
they found it difficult to separate the relationship of arsenic from sulfur
dioxide. Most of the work areas having heavy arsenic exposure were also areas
having medium sulfur dioxide exposure; conversely, all work areas with heavy
sulfur dioxide exposure were areas of medium arsenic exposure. The authors
did note, however, that persons with the heaviest exposure to arsenic and
moderate or heavy exposure to sulfur dioxide were those most likely to die of
respiratory cancer in this particular instance.
Since the Lee and Fraumeni study, additional research has been conducted
on the employees of the Anaconda smelter. Lubin et al. (1981) studied 5403 of
these employees. These workers had all been employed for 12 months or more
between January 1, 1938 and December 31, 1956 and were known to be alive as of
December 31, 1963. Essentially, this cohort was equivalent to the surviving
members from the Lee and Fraumeni cohort.
Exposure was from date hired to December 31, 1963; follow-up was from
1964 to 1977. Classification of exposure categories was similar to that of
Lee and Fraumeni. However, unlike the study of Lee and Fraumeni, a cumulative
013AS2/A 5-40 June 1983
-------
arsenic exposure index was calculated for each worker. This index was derived
by, first, weighting the three exposure categories and then multiplying the
number of years an individual worked in a given category by this weight and
summing over categories. The weights were derived from mean airborne dust
concentrations taken during 1943 to 1958, which averaged 11.3, 0.58 and 0.29
mg As/m3 in the respective heavy, medium and light categories. These values
differed from those used by Lee and Fraumeni to group departments (Table 5-9).
It should be noted that the exposure estimates used by Lee and Fraumeni were
based upon more recent monitoring data primarily collected in 1965. Lubin
et al. reduced weights in the heavy category by a factor of 10 in order to
account for the wearing of respirators as was observed "at least in recent
years." SMRs were calculated by comparisons to U.S. white males.
The mortality experience of workers during the years 1964 to 1977 was
similar to that of the workers studied by Lee and Fraumeni during the period
1938-1963. Excess deaths from respiratory cancer corresponded to areas of
highest arsenic levels. The authors noted an overall strong gradient in risk
associated with the indices of cumulative arsenic exposure. However, the
authors also noted that this gradient was less clear when weighting of the
high exposure category was reduced ten-fold to account for respirator usage.
According to Welch et al. (1982), however, respirator usage was not common
prior to 1964.
Some study differences were noted by Lubin et al. between their respec-
tive study and that of Lee and Fraumeni. Differences in excess respiratory
cancer—65 percent in the more recent period versus a three-fold excess in the
earlier period—were partially attributed to differences in respiratory cancer
rates observed between the two comparison populations. Respiratory cancer
rates in the general populace have increased in recent years; therefore,
013AS2/A 5-41 June 1983
-------
comparisons to recent populations will produce lower relative risks than
comparisons to past general populations in which the rates of respiratory
cancer were lower. The authors also noted that the comparison populations
differed in composition. Lee and Fraumeni used white males in the State of
Montana as their standard population, whereas Lubin et al. used U.S. white
males. As noted in this study, as well as elsewhere (Welch et al., 1982;
Higgins et al., 1982), death rates for specific causes of death (inclusive of
respiratory cancer) have been reported to be lower in Montana. Finally, the
authors suggested the possibility that individuals most susceptible to lung
cancer contracted the disease in the earlier period and were, thus, lost to
the study follow-up due to death.
In looking at S02 exposures, the authors were unable to totally separate
the possible interactive effects of SO^ with arsenic. However, they did note
that after controlling for arsenic, no significant increase in mortality could
be associated with heavy or medium S02 exposures, whereas the association with
arsenic exposure persisted after controlling for S02- This finding is consis-
tent with that of other researchers studying smelter populations (Enter!ine
and Marsh, 1982; Welch et al., 1982; Higgins et al., 1982).
In an update of the earlier study co-authored with Fraumeni, Lee-Feldstein
(1982) observed the mortality experience of the same Anaconda workers (with
the exception of two women) from 1938 to 1977. The workers (8045) were assigned
to one of five cohorts on the basis of total years of employment. Cohort 1
worked 25 + years; cohort 2, 15-24 years; cohort 3, 10-14 years; cohort 4, 5-9
years, and cohort 5, 1-4 years. SMRs were calculated by comparison to the
combined white male populations in the States of Idaho, Wyoming and Montana.
013AS2/A 5-42 June 1983
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Of the thirteen specific causes of death considered, tuberculosis,
digestive and respiratory cancer, vascular lesions of the CNS, diseases of the
heart, emphysema, and cirrhosis of the liver showed a significant excess of
observed deaths over that expected; however, only excesses in respiratory
cancer showed a positive gradient with length of employment when comparing
cohorts 1 through 5. The ratio of observed to expected mortality from
respiratory cancer was approximately 5.1, 4.5 and 2.3 in the heavy, medium and
light arsenic-exposure groups, respectively. This was in accord with the
earlier results of Lee and Fraumeni, except that the ratio of observed
respiratory cancer deaths to that expected in the heavy exposure category in
the earlier study was 7. The results of this study continued to support those
of the earlier studies.
In still another study of this Anaconda smelter, Higgins et al. (1982)
reported on a sample of 1800 workers. Compared to the 8047 workers studied by
Lee and Fraumeni, the cohort of Higgins et al. included all the workers origi-
nally designated in Lee and Fraumeni's heavy exposure category (277) and a
random sample (20 percent) of the remaining known workers. The date of entry
into the study cohort ranged from 1938 to 1956, providing the individual had
one year of work experience. Unlike other studies on these workers, smoking
histories on the 1800 workers were obtained either by direct questioning or by
proxy respondent. SMRs were based on comparisons to standard populations both
in the State of Montana as well as white males in the United States.
From industrial hygiene records for the period 1943 to 1965, estimates of
airborne arsenic concentrations within 35 smelter departments were provided.
A total of 818 samples were collected from 18 departments and departmental
averages were calculated from these measurements. The remaining 17 depart-
ments were estimated by analogy with those that were known. The departments
013AS2/A 5-43 June 1983
-------
were then grouped into four categories in which arsenic exposure was charac-
terized as low (< 100 ug/m ), medium (100-499 pg/m3), high (500-4999 ug/m3) or
very high (> 5000 pg/m ).
Workers were assigned to these categories based upon estimations of both
time-weighted average (TWA) arsenic exposure levels and ceiling levels. TWA
values were individually calculated based upon the time that a worker spent in
a given department and the average arsenic concentration estimated for that
department. This quantity was summed across all departments the individual
worked in and was divided by total time worked to yield a TWA. TWA arsenic
exposures were calculated at entry into the study cohort and at the beginning
of January, 1964, corresponding to the end of the follow-up period used by Lee
and Fraumeni. TWA differences between these two periods could have increased,
decreased, or remained the same depending on the work history of an individual
worker. In contrast, ceiling levels were defined as the highest level to
which an employee was exposed for a period of 30 days or more. Ceiling levels
were calculated at entry into cohort, at the beginning of 1964 and at the
beginning of 1978. Unlike a TWA value, a worker's ceiling level could only
increase or remain the same from point of entry into the cohort.
Data were analyzed according to five different exposure/follow-up methods
which varied in the amount of overlap allowed between exposure and follow-up
periods. Method I, the primary method used by the authors, included each
worker's arsenic exposure up to the date he entered the cohort. Follow-up was
from entry to 1978; thus, there was no overlap of the two periods. Method
IV—exposure from date hired to 1964, follow-up from 1964 to 1978--also had no
overlap. Methods II and V had complete overlap—exposure from date hired to
1964, follow-up from 1938 to 1964 and exposure from date hired till termina-
tion, follow-up from 1938 to 1978, respectively. Method III had partial
013AS2/A 5-44 June 1983
-------
overlap—exposure from date hired to 1964, follow-up from 1938 to 1978.
Except where specifically noted, results were given according to Method I.
The results of the study supported the thesis that exposure to arsenic
was strongly related to respiratory cancer mortality in workers at the Ana-
conda Smelter. SMRs for the total cohort for all causes of death were identi-
cal when compared to either the State of Montana or U.S. white males (both
SMRs = 133, significant at 0.01 level); however, SMRs for specific causes were
somewhat higher when compared to Montana than when compared to the U.S. Expo-
sure to arsenic appeared to be the principle factor in the observed increased
risk for respiratory cancer, the study cohort having 3 times the expected
death rate for white men living in Montana. Exposure to other occupational
contaminants, such as sulfur dioxide and asbestos, did not appear to account
for respiratory cancer excess, while smoking explained only a small fraction
of the excess.
Of particular note were the differing respiratory cancer results obtained
under the two categories of arsenic exposure (Tables 5-12 and 5-13). The SMR
for men in the lowest TWA category was elevated, although not significantly
so, whereas the SMRs in the other TWA categories were significantly elevated.
Mortality for respiratory cancer by ceiling arsenic exposure showed that SMRs
were only signficantly elevated in the high and very high categories, whereas
they were close to expectation in the two lower exposure categories. Date of
hire showed a definite relationship to mortality from respiratory cancer.
Workers that were employed in the early years of the smelter operation—from
1884 to 1938, but particularly prior to 1923, when a selective floatation proc-
ess which markedly improved fume and dust recovery was introduced--had higher
SMRs, indicating that the overall higher arsenic exposures in the early years
were associated with higher death rates from respiratory cancer. Age at hire
013AS2/A 5-45 June 1983
-------
TABLE 5-12. MORTALITY FOR ALL CAUSES AND RESPIRATORY CANCER FROM 1938 TO 1978
BY TIME-WEIGHTED AVERAGE (TWA) ARSENIC EXPOSURE
AS OF ENTRANCE INTO COHORT
Ceiling
Arsenic
3
(pg/m ) N
<100
100-
500-
5000-
* Signi
** Signi
Source:
547
542
565
146
ficant at .05
ficant at .01
Higgins et al
Person-
Years
13152
14157
13460
3552
level
level
. (1982).
Respiratory
All Causes Cancer
Obs Exp SMR Obs Exp SMR
219 196.7 111* 11 7.9 138
216 178.0 121** 22 7.3 303**
292 184.7 158** 29 7.7 375**
89 56.1 159** 18 2.6 704**
013AS2/A
5-46
June 1983
-------
TABLE 5-13. MORTALITY FOR ALL CAUSES AND RESPIRATORY CANCER
BY CEILING ARSENIC EXPOSURE
AS OF ENTRANCE INTO COHORT
Ceiling
Arsenic
(ug/m3)
<100
100-
500-
>5000
Respiratory
Person- All Causes Cancer
N Years Obs Exp SMR Obs Exp SMR
445 10591 165 152.1 108 8 6.2 129
276 7083 80 80.5 99 4 3.4 116
833 20757 416 288.5 144** 41 11.8 348**
246 5889 155 94.4 164** 27 4.1 662**
* Significant at .05 level
** Significant at .01 level
Source: Higgins et al. (1982).
013AS2/A
5-47
June 1983
-------
did not seem to have a confounding effect, although the authors did note that
the SMRs for respiratory cancer showed more fluctuation with age than did all
causes of death.
Tables 5-14 and 5-15 show comparisons of TWA and ceiling respiratory
cancer mortality as analyzed by the different exposure/follow-up methods. The
'. *"
authors noted that, while there was some variation in the SMRs derived from
the different methods, the same basic pattern of increasing TWA and ceiling
SMRs with increasing arsenic exposures could be seen for each method. Of
particular significance were the results shown in Table 5-15. The SMRs for
the low and medium ceiling categories were lower when each man's ceiling was
calculated as of 1964 (method III) and as of his lifetime (method V), than
when calculated as of entry into the cohort (method I). The authors inter-
preted these results to indicate that workers exposed only to arsenic concen-
3
trations below 500 ug/m would probably experience little mortality due to
respiratory cancer.
A number of criticisms have been made of this study (48 FR 1864), a few
of which bear mentioning at this point.
The representativeness of the exposure estimates as they relate to over-
all exposure conditions in the smelter and specifically to the cohort's TWA
and ceiling exposures has been criticized. The authors noted that individual
worker exposure estimates, based upon area measurements rather than personal
samples, would not likely have great precision. Furthermore, estimates of
analogy—as in 17 of the departments—weaken the reliability of overall exposure
estimates, although areas that were thought to be "problem" areas of high expo-
sure were areas that were generally measured. The extent to which respirator
usage was an effective protective measure is also unknown. In interviews with
former workers, however, indications were that the use of respirators was not
widespread or regular during the period prior to 1964. Collectively, the problems
013AS2/A 5-48 June 1983
-------
o
i—"
co
GO
no
UD
TABLE 5-14. RESPIRATORY CANCER MORTALITY BY METHOD OF ANALYSIS
AND TWA ARSENIC CATEGORY
TWA
Arsenic
(ng/m3)
<100
100-
500-
^5000
N
547
542
565
146
Ia
Obs
11
22
29
18
METHOD OF
II]
Exp
7.9
7.3
7.7
2.6
SMR
138
303**
375**
704**
N
522
580
515
183
Obs
5
28
29
18
ANALYSIS
r D
Exp
7.9
7.8
7.1
2.7
SMR
63
359**
408**
673**
N
354
410
313
111
IV
Obs
4
16
9
9
c
Exp
4.8
5.1
4.2
1.6
SMR
84
313**
216*
573**
*Signifleant at .05 level
**Significant at .01 level
aExposure from date hired to cohort entry. Follow-up from cohort entry to 1978.
Exposure from date hired to 1964.
'Exposure from date hired to 1964.
Source: Higgins et al. (1982).
Follow-up from cohort entry to 1978.
Follow-up from 1964 to 1978.
Cj
=5
ro
_i
^•0
co
-------
TABLE 5-15. RESPIRATORY CANCER MORTALITY BY METHOD OF ANALYSIS
AND CEILING ARSENIC CATEGORY
1 — »
to
3»
£2 Ceiling
Arsenic
(ug/m3)
<100
100-
500-
^5000
Ia
N
445
276
833
246
Obs
8
4
41
27
Exp
6.2
3.4
11.8
4.1
SMR
129
116
348**
662**
N
275
218
970
337
METHOD OF ANALYSIS
III IVC
Obs
3
2
41
34
Exp
4.0
2.5
13.8
5.2
SMR
75
79
298**
652**
N
178
152
656
202
Obs
3
0
20
15
Exp
2.3
1.6
8.7
3.0
SMR
130
-
230**
496**
N
267
210
969
354
Vd
Obs
3
2
41
34
Exp
3.9
2.4
13.7
5.5
SMR
77
83
300**
617**
*Significant at .05 level
**Significant at .01 level
en
o
Exposure from date hired to cohort entry. Follow-up front cohort entry to 1978.
Exposure from date hired to 1964.
Exposure from date hired to 1964.
Exposure from date hired to 1978.
Follow-up from cohort entry to 1978.
Follow-up from 1964 to 1978.
Follow-up from cohort entry to 1978.
Source: Higgins et al. (1982).
oo
CO
-------
regarding exposure estimates probably tended to affect results such that
exposure values were underestimated from 1884 to 1938, were reasonable for
1938 to 1964, and were overestimated for the period after 1964.*
Of even greater importance is the classification of a limited number of
workers (approximately 22 percent of the total Anaconda cohort) into the
various ceiling categories. While classifying workers according to exposure
levels, irrespective of duration, may have some plausibility, i.e., measures
of .exposure other than cumulative exposure might possibly correlate better
with respiratory cancer, the fact that Higgins et al. drew such conclusions on
small sample sizes has been questioned. (This issue is discussed in greater
detail in Section 5.2.1.4.) By analyzing risk according to ceiling category,
a significant proportion of workers in the low and medium TWA categories were
placed in high ceiling categories -- 21 and 60 percent, respectively -- result-
ing in small sample sizes in the two lower exposure categories. (This can be
seen by comparing the sample sizes in Tables 5-12 and 5-13.) The risk of lung
cancer mortality as predicted using a linear dose-response model (see Quanti-
tative Section 5.2.1.4 of this chapter) cannot be detected given these small
sample sizes.
In order to address this issue, Higgins et al. are presently undertaking
a study of the entire Anaconda cohort; however, results of this study will not
be forthcoming till 1984. In the interim, the authors' conclusions drawn from
this study remain speculative.
In foreign smelters, an excess in lung cancer mortality has also been
found. The Ronnskar smelter in Sweden, which has been processing arsenic-rich
'Requests by the U.S. EPA for the actual exposure data have been granted by
I. Higgins. Further discussion of this data is intended pending receipt of
the information.
013AS2/A 5-51 June 1983
-------
ores since the 1920s, has been the subject of several studies. Axelson et al.
(1978) made a case-control study of mortality from respiratory cancer in
relation to employment at that smelter. In the parish surrounding the smelter,
369 deaths have been recorded in the registers for men aged 30-74 years during
the years 1960 to 1976. Causes of death were obtained in all cases. Smoking
habits were obtained from medical files. Cases were defined as subjects who
died of malignant'tumors of the lung, other cancers, cardiovascular disease,
cerebrovascular disease, and cirrhosis of the liver. The control group was
made up of persons from the same parish who died from causes other than the
above, excluding 44 persons with diabetes, mental deficiency and unclear
diagnoses. Attempts were made to assess exposure and four exposure groups
were constructed, based on intensity and duration of exposure and time between
initiation of exposure and death. It was found that exposure to arsenic was
associated with a significant increase in deaths from lung cancer. For the
three exposure groups with at least 3 months of exposure occurring 5 years
prior to death, the lung cancer mortality ratio was 4.6. In these groups,
there was an increase with exposure intensity. For the fourth group in which
exposure was essentially nonexistent; or, first exposure was for periods less
than 3 months and/or death occurred within 5 years of this first exposure, the
sample size was too small to detect risk in this exposure group that would be
predicted by a linear dose-response model.
The influence from other agents, including sulfur dioxide, to these other
agents did not seem to be associated with lung cancer. In 83 percent of the
lung cancer cases there was a history of smoking. It was not stated how the
smelter employee differed from the other cases. A study of smoking habits by
Pershagen (1978) showed that the excess lung cancer mortality could not be
explained by smoking habits.
013AS2/A 5-52 June 1983
-------
Because a high lung cancer mortality rate was noted among males in Saganoseki-
machi, Japan for the period 1967-69, Kuratsune et al. (1974) did a case-control
study of lung cancer cases in that town. The nineteen cases of lung cancer
for the period 1967-69 were compared with nineteen controls randomly selected
from deaths of diseases other than cancer of the lung, skin, or bladder for
the 1967-69 period. Smoking and drinking habits, residential and occupational
histories, and exposure to atomic bomb radiation were the factors compared.
Fifty-eight percent of lung cancer cases were found to be former smelter
workers vs. 15.8 percent in the controls (p <0.01). The relative risk was
reported to be 9.0 (confidence limits not reported). The author did not
indicate that confounding variables were controlled for in the estimate of the
relative risk. No difference was found between the cases and controls for
smoking habits, residential history, drinking habits, or atomic bomb radiation.
Tokudome and Kuratsune (1976) did a cohort study of 2765 male workers
including 839 copper smelter workers at the metal refinery in Saganoseki-machi,
Japan. Deaths which occurred between 1949 and 1971 were analyzed in the
study. The expected number of deaths was calculated using mortality data for
Japanese males. A significantly increased mortality was noted for lung cancer
(SMR = 1189; observed = 29; expected = 2.44; p <0.01) and colon cancer (SMR =
508; observed = 3; expected = 0.59; p <0.05). A dose response was demonstrated
between lung cancer mortality and the degree of exposure measured by length of
employment and level of exposure. A very high excess mortality from lung
cancer (SMR = 2500; 10 observed; 0.4 expected; p <0.01) was found among smelter
workers who had worked in the heaviest exposure category and who had been
employed over 15 years before 1949. The latent period in this study ranged
from 13 to 50 years.
013AS2/A 5-53 June 1983
-------
Studies have also been performed to see if there is any increase in lung
cancer among residents in areas surrounding smelters. Lyon et al. (1977)
compared the incidence of lung cancer and lymphoma in Utah residents from
1970-1975 in relation to the distance of these residents from a smelter and
found no association. It should be noted that distance from the smelter was
based on address at the time of diagnosis; nothing regarding the length of
time lived near the smelter was factored into the analysis. Furthermore, use
of lymphoma cases as controls is questionable since lymphomas may also be
associated with arsenic (Ott et al., 1974). Thus, the conclusion of the study
that there was no association between lung cancer and distance from the smelter
is questionable.
In a more recent study, Rom et al. (1982) compared lung cancer with
breast and prostate cancer in residents living near a non-ferrous smelter in
El Paso, Texas. The study period ranged from 1944-1973. Similar to methods
used by Lyon et al. (1977), comparisons were made in relation to distance from
the smelter. Breast and prostate cancer were chosen as control cancers because
they have no known association with arsenic exposure. The authors reported
that the distribution of lung cancer cases (575) and control cancer cases
(1490) was roughly the same for the different distances studied. No associa-
tion between lung cancer and distance from the smelter was found, nor were
there any associations for race, age or sex. However, the authors did note
that they were unable to control for such factors as smoking, occupation and
migration, and were unable to obtain environmental exposure measurements over
most of the years studied.
In Montana, the studies by Newman et al. (1976) showed that there was an
increase in the incidence of lung cancer among men in cities where copper
013AS2/A 5-54 June 1983
-------
smelters are located. In one of the cities there was also an increased inci-
dence of lung cancer among women. It was not stated to what extent occupa-
tional exposure had caused the increase, and there was no control for smoking.
In the Blot and Fraumeni study (1975), the cancer mortality in 71 counties
with smelters and refineries was studied from 1950 to 1969. Comparisons were
made with the remaining 2,985 counties in 48 states. In 36 counties with
smelters processing copper, lead, or zinc ores, lung cancer mortality was
significantly higher both among males (p < 0.01) and females (p < 0.05). For
all 36 counties with these industries the median SMR was 112 for males and 110
for females. Although occupational cancers were included in the analyses and,
therefore, contributed to some of the excess risk, the number of workers in
the smelter industry generally comprised a small fraction of the total popula-
tion (less than 1 to 3 percent); thus, it was unlikely that occupational
exposures alone accounted for the observed excess mortality in males or the
increased risk for females, Although this study is suggestive of a lung
cancer effect in populations surrounding smelters, it is unknown if the lung
cancer cases were even exposed to arsenic. Thus, the results, although sug-
gestive, are inconclusive.
In the Baltimore, Maryland area, Matanoski et al. (1976; 1981) studied
cancer mortality in areas near the earlier mentioned pesticide facility. They
found an excess of all cancers and respiratory cancers among males in the area
nearest to the factory but not among females. Soil arsenic levels generally
corresponded to lung cancer and all cancer incidences, with the highest average
of arsenic in the soil (63 ppm) reported in the area with the greatest cancer
risk. The authors were unable to account for the differences noted between
males and females, but suggested that smoking may have contributed to these
differences. Other environmental factors and/or occupational exposure may
013AS2/A 5-55 June 1983
-------
have also influenced cancer mortality excess. Further environmental sampling
of arsenic and conducting community surveys were recommended to address these
unknown factors.
Pershagen et al. (1977) studied cancer deaths in the area surrounding the
Ronnskar smelter in Sweden. From 1961 to 1975 there was a significant excess
of respiratory cancers in the male population (SMR = 250) compared to resi-
dents in an area without known emissions of arsenic but in which the same age
distribution and occupational profiles applied. When the occupationally
exposed cases were excluded, significant increases in respiratory cancers were
no longer detected (SMR 173); however, the male population still showed a
tendency to excess lung cancers. No similar occupational group was excluded
from the comparison population, however. There was no tendency to an increase
in lung cancer among women.
5.2.1.2.2 Cancer of the skin and precancerous skin lesions. An elevation in
the proportionate mortality of skin cancer was reported by Hill and Faning
(1948) for factory workers manufacturing sodium arsenite and by Roth (1957,
1958) for German vintners. In addition, an increased incidence of skin cancer
has been reported after long-term oral exposure to arsenic.
In Taiwan a large population had long-term exposures to inorganic arsenic
in drinking water. Exposure started in 1910-20 when water was obtained from
deep wells, 100-200 m. below the surface. Already in the 1920s vascular
changes began to appear and in the 1950s the first epidemiological studies
were conducted. The arsenic content of the water varied from 0.01 to 1.82
mg/1 (Chi and Blackwell, 1968; Astrup, 1968, and Tseng et al., 1968; Tseng,
1977), generally being 0.4 - 0.6 mg/1, whereas water from shallow wells or
other surface waters generally contained from near zero to 0.15 mg As/1.
013AS2/A 5-56 June 1983
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Tseng et al. (1968), and Tseng (1977) have reported the results from a
large scale epidemiologic survey of arsenic-related diseases in an area with
high arsenic concentrations in drinking water. The population at risk was
103,514 persons. Thirty-seven villages with a population of 40,421 were
surveyed house-to-house. Examinations were made with special attention to
pigmentation, hyperkeratosis, and cancer of the skin. Four hundred twenty
eight cases of arsenical skin cancer were found resulting in a rate of
10.6/1000. No cases were under 20 years of age. The prevalence rate increased
markedly with age except for females >70. Over 10 percent of the people >59
were affected by skin cancer. The overall male/female ratio was 2.9:1, with
males having a higher rate in all age groups >29.
The villages were divided into 4 exposure levels: <0.3, 0.3-0.6, >0.6,
and undetermined, based on their water arsenic content. There was a clear cut
ascending gradient of prevalence from low to high in each of 3 age groups
(Table 5-16).
TABLE 5-16. PREVALENCE OF SKIN CANCER (per 1000)
BY AGE AND ARSENIC EXPOSURE (ppm)
Arsenic content
of drinking water
(ppm)
<.3
0.3 - 0.6
>0.6
20-39
1.3
2.2
11.5
Age
40-59
4.9
32.6
72.0
>60
27.
106.
192.
1
2
0
Source: Adapted from Tseng, et al. (1968).
013AS2/A 5-57 June 1983
-------
Hyperpigmentation (melanosis) was found in 18.4 percent of the total
population, 19.2 percent for males and 17.6 percent for females. Usually the
prevalence was higher for males than females. The rates increased steadily
with age for males and did likewise for females until a peak was reached at
50-59, followed by a gradual decline.
The overall prevalence rate for keratosis was 7.1 percent - 7.5 percent
for males and 6.8 percent for females. Males had higher rates in the greater
than 49 year group. The prevalence increased for both males and females up to
age 70 and then declined.
As was the case for skin cancer, the prevalence rates for hyperpigmenta-
tion and keratosis suggested that positive correlations existed between these
conditions and the arsenic content of the water in the artesian wells; the
greater the arsenic content, the higher the prevalence.
In the total survey of 40,421 people, 7418 cases of hyperpigmentation,
2868 of keratosis, 428 of skin cancer, and 360 of blackfoot disease (Section
5.2.2.2) were found. Many of these occurred in combination in the same indi-
vidual .
The data were examined by comparing expected (based on overall rates) and
observed rates for various combinations of the 4 end points. The obtained
ratios indicated quite strongly that a common underlying cause existed for the
4 conditions, presumably chronic arsenicism.
A control population of 7500 persons from nonendemic areas was examined
in the same way as the arsenic exposed persons. 4978 people lived on Matsu
Island; its water supply was from shallow wells and no arsenic was detectable
by the analytic methods used in the main series. The remaining portion of
control population members came from 5 villages on Taiwan whose water source
013AS2/A 5-58 June 1983
-------
was shallow wells with arsenic levels between 0.001-0.017 mg/£ (ppm). No
cases of melanosis, keratosis, or skin cancer were observed in the entire
control population.
Although age of onset of the conditions was difficult to assess, some
information on latency was obtained. "We know from the study that the young-
est cancer patient was 24, the youngest with hyperpigmentation was 3, and the
youngest with keratoses was 4". This meant that hyperpigmentation could
occur in patients who were exposed from birth for at least 3 years, keratosis
for 4 years, and cancer for 24 years (Tseng et al., 1968).
While the Taiwanese data collected in the late 1960's strongly implicated
arsenic as the etiological source of the observed diseases, recent findings
have called to question the hypothesis of arsenicism as sole causative source
in the induction of cardiovascular effects. The discovery by Lu et al. (1977b;
1978) of fluorescent compounds identified as alkaloids—either lysergic acid,
dihydrolysergic acid or a derivative of ergotamine tartfate--has opened the
possibility that other toxic mechanisms may have been involved. Ergotamine-
like compounds in combination with high alkalinity, characteristic of these
waters, have been shown to cause gangrene (Lu et al. , 1977a,b; 1978). Whether
these compounds have a confounding effect on skin cancer is presently unknown.
In addition, recent analyses by Irgolic (1982) on a limited number of
samples have shown the water samples to contain predominantly pentavalent
arsenic and no organic arsenicals. Samples taken from two wells in the,Yenshei
Province of Taiwan were collected in plastic cubitainers. Two samples each of
unpreserved water and water preserved either by addition of 0.1 weight percent
of ascorbic acid or by acidification of 0.1 M HN03 were sent to the U.S. for
analysis a few days after collection. Treatment of samples by HNO, or ascorbic
013AS2/A 5-59 June 1983
-------
acid was done immediately upon collection (Irgolic, 1983; personal communica-
tion). Samples were analyzed during a two-week period after arrival in the
U.S.; the total time lapse between collection and analyses ranging from one to
three weeks. The results of the analyses can be seen in Table 5-17. Addi-
tional water samples collected from other parts of Taiwan also contained
pentavalent arsenic. However, these samples were less reliable in that the
collection period was unknown, and, upon arrival in the U.S., these samples
had a yellowish hue with some flocculated matter present (Irgolic, 1982).
Several questions still remain to be answered in regard to water-usage
patterns of the Taiwanese. For instance, it is not clear how quickly the
water drawn from the wells was consumed; nor is it clear how much of the water
was consumed in tea or other beverages where cooking preparations, such as
boiling, would have altered the chemical form of the arsenic. These questions
need to be answered in light of the possible affect these answers might have
on interpreting the observed skin cancer incidence.
Chi and Blackwell (1976) conducted a case-control study in the area of
Taiwan studied by Tseng et al. The authors compared a variety of factors
between 353 cases of blackfoot disease and 353 controls matched for sex and
age. Socioeconomic status, occupation, cigarette smoking, diet, and consump-
tion of deep well water which was arsenic-contaminated were the factors
compared. Two factors were found to be significantly different between the
cases and controls. Significantly (P < 0.01) more cases than controls were
found to consume deep well water and to have a lower socioeconomic status.
Though the author concluded that the primary contributing cause of blackfoot
013AS2/A 5-60 June 1983
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TABLE 5-17. RESULTS OF TOTAL ARSENIC ANALYSES AND ARSENITE
0 MNU HKOtlNrtlt Utl tKmiNHI iUINO ilN 1 nt rclNOnti WttICK iHrifLCCr
h— '
co
Ascorbic
Sample Acid 0.1%
Well I
—
Well II
en
i _
01
TOTAL ARSENIC, ppm
0.1 M Un-
HN03~ preserved HGa
+ - 0.84+0.02
0.88+0.01
+ 0.8510.01
+ - 1.0510.08
1.1610.03
+ 1. 1110.02
ICPb
0.7310.01
0.7210.01
0.7310.01
0.9510.01
0.9610.01
0.9810.01
Arsenite, ppm
by HG
0.024+0.001
0.02210.001
-
0.02410.01
Arsenate, ppm
by HG
0.85+0.01
0.83+0.08
-
1.08+0.02
^Average + average deviation of at least three determinations per sample.
aHG = Hydride generation technique.
ICP = Inductively coupled argon plasma emission spectrometry.
Source: Irgolic (1982).
CO
CO
-------
disease was consumption of deep well water, the socioeconomic differences
cannot be completely discounted.
Other studies have also explored the relationship of arsenic to skin
cancer and various skin lesions. Similar chronic effects as seen in Taiwan
have been reported in other countries.
In Antofagasta, Chile, a new water supply was obtained in 1958. In the
1960s, physicians began noticing dermatological manifestations and even deaths,
especially among children. In an investigation of skin pigmentation in 27,088
school children from the provence of Antofagasta, an overall incidence of 12
percent was reported. It was discovered that the drinking water contained 0.8
mg As/1. Borgono and Greiber (1972) compared 180 inhabitants of Antofagasta
with a community without exposure to arsenic via drinking water. Abnormal
skin pigmentation was reported to be present in 80 percent and hyperkeratosis
in 36 percent of the Antofagasta inhabitants whereas none were found in the
control group (p < .05).
In 1970, a water treatment plant was installed and there was a consider-
able drop in arsenic. According to Borgono et al. (1977), there were no skin
lesions in children born since the water treatment began. However, it should
be noted that in this more recent study the sample size of children born since
the water treatment plant began was small (306) and no comparison population
was studied. Therefore, any conclusions associating the lack of dermatological
manifestations with the decrease in arsenic must take into account the small
sample size. In regard to skin cancer, the follow-up may not have been long
enough to detect a difference.
013AS2/A 5-62 June 1983
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In addition to the work of Borgono and co-workers, Zaldivar and Guillier
published a series of papers on the Antofagasta situation (Zaldivar, 1974;
Zaldivar, 1977; Zaldivar and Guillier, 1977). The first of these (Zaldivar,
1974) describes a study on a total of 457 patients (208 males and 249 females)
bearing cutaneous lesions (leukoderma, melanoderma, hyperkeratosis, and squa-
mous cell carcinoma). The cases were collected both by the author and the
local hospital during the period 1968 to 1971. Children 0 to 15 years of age
accounted for 69.2 percent of the male cases and 77.5 percent of the female
cases. The average incidence/100,000 for cases with cutaneous lesions in 1968
to 1969 were 145.5 and 168.0 for males and females, respectively. By 1971 the
incidence rates had dropped to 9.1 and 10.0 for males and females, respec-
tively. The decline in morbidity was so rapid that caution should be exer-
cised before concluding that the arsenic was the cause of the skin lesions.
The existence of arsenical waters in an eastern area of the province of
Cordoba, Argentina, has been known for many decades (Arguello et al. , 1938;
Bergoglio, 1964). Effects noted on the population from this area include
hyperpigmentation, keratosis, and skin and respiratory cancer. A large area
of the province, mainly in the east and somewhat to the south, is the focal
point for chronic endemic regional arsenical intoxication (CERAI) (Arguello et
al., 1938). This CERAI is due to the ingestion of well water coming from the
uppermost sheet of underground water - the principal source of arsenic - as
well as due to the ingestion of arsenic from the wells, which varies within
wells throughout the region. The concentration also varies with rainfall.
Vanadium is also elevated in areas with high arsenic content. A later report
(Bergoglio, 1964) indicates that progress had been made in improving the
hygienic condition of the drinking water.
013AS2/A 5-63 June 1983
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Arguello et al. (1938) summarized the early history of investigations
(1913 to mid-1938) into the health outcomes associated with the ingestion of
arsenic contaminated water. They also reported the results of an investiga-
tion of a large series of epitheliomas collected from mid-1932 to September
1938 at the dermatosyphilology clinic of a medical school in the arsenic-
contaminated area. The series consisted of 323 cases of epithelioma of which
39 or 12.1 percent were cases with clinical evidence of CERAI.
Patients exhibiting CERAI had characteristic cutaneous lesions, repre-
sented by the symmetrical pal mo-plantar keratoderma and melanoderma, although
the latter symptom was seen less frequently. Foot and hand keratoderma were
seen in 100 percent of the CERAI patients. Appearance usually occurred 2 to 3
years after the onset of intoxication. A prodrome of the keratosis is the
appearance of an erythema in the same location, and a subjective crawling
sensation and local fever. Otherwise, it is a state of dryness which precedes
the keratosis.
Arguello et al. (1938) also reported that most patients also had hyper-
hidrosis and abnormalities of pigmentation. The melanoderma appeared early in
the process and was variable among patients. It was described as small dark
spots ranging in diameter from 1 to 10 mm. They had a tendency to coalesce
and appeared predominantly on the trunk in the areas not exposed to the sun.
Atropy may be associated with telangiectasia and loss of color, or leukoderma,
between the hyperpigmented areas (the "raindrop" appearance cited by Reynolds,
1901).
Geographically, the largest proportion of cases in the clinic came from
the areas with the highest incidence of CERAI. Because the authors' data are
not population based, however, it cannot be stated that the incidence of skin
013AS2/A 5-64 June 1983
-------
cancer is significantly increased in these areas. The authors reported that
the hands and feet are the locations of choice for the arsenical epitheliomas
(38.5 percent vs 3.9 percent) compared to the nonarsenical epithelioma. An
example of this can be seen in the head where 81.6 percent of the nonarsenical
epitheliomas occur versus 15.4 percent for arsenical epithelioma.
Bergoglio (1964) did a proportionate mortality study of residents of
certain departments (counties) in the Province of Cordoba, Argentina where
endemip arsenic levels in the water supply are reported to be very high. The
proportion of cancer deaths was higher in those departments than for the
province as a whole (23.84% versus 15.3% P <0.05). Of the cancer deaths,
respiratory cancer constituted 35% and skin cancer 2.3%. From the description
by the author, it can probably be inferred that this data is not age-adjusted.
No comparison is made of the percentage of respiratory and skin cancer deaths
in the affected departments with the respective proportion for Cordoba Province.
Morton et al. (1976) investigated the relationship of skin cancer morbi-
dity and the ingestion of arsenic-contaminated drinking water in Lane County,
Oregon. The southcentral region of Lane County is underlaid by an arsenic
rich stratum called the Fisher formation which is known to produce high arsenic
levels in waters from wells drilled into the land. An extensive search of the
pathology records of medical providers in Lane County, Oregon, was conducted
in 1972 for the occurrence of skin cancer during the years 1958 to 1971.
Cases were thoroughly screened to eliminate duplications and were then coded
to 1970 census tract numbers according to the residential address at the time
of diagnosis. Water samples were obtained in all census tracts at selected
points in all municipalities and water districts in the county, as well as
from single family water sources. The single family water sources were neither
013AS2/A 5-65 June 1983
-------
randomly nor uniformly distributed throughout the county but instead were
heavily concentrated in the regions believed to have water arsenic problems.
Water samples collected during 1968 to 1974 were compiled into mean concen-
trations for each census tract and census tract region. The authors stated
that it seemed reasonable to assume that the samples were representative of
the earlier time periods as well.
The skin cancer data were expressed in four sets of rates because of the
availability of 4 sets of population estimates. Overall mean annual incidence
rates for the entire 1958 to 1971 period used mean population estimates based
on all four sets of denominators. Census tract regions were devised to simplify
analysis and presentation. Table 5-18 presents the water arsenic level obtained.
As can be readily seen the South rural area had a much greater arsenic exposure
than any of the other sections of the county. Figure 5-1 contrasts the parts
of the county underlaid by the Fisher formation, and subsequent higher arsenic
levels, with the parts of the county experiencing higher squamous cell skin
cancer. Relatively little concordance is noted. A multiple regression analysis
performed by the author demonstrated essentially no relation between skin
cancer and water arsenic. It should be noted that water arsenic levels in
this study varied from 0 to 2150 ppb. The authors point out that the Lane
County water arsenic levels were much lower than those reported for Taiwan and
Antofagasta. In particular only 5 percent of the Lane County samples con-
tained 100 or more ppb of arsenic in contrast to 48 percent of the samples in
that range in the Taiwan data.
013AS2/A 5-66 June 1983
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TABLE 5-18. LANE COUNTY WATER ARSENIC LEVELS 1974-1978
Arsenic, p.p.b.
Geographic region mean*
range
1970 Population served
by water districts
Sol
no of samplesnumber% of area residents
Rural
North
East
South
Midwest
Coast
Urban
NE Springfield
SW Springfield
S Eugene
W Eugene
NW Eugene
N Eugene
Core Eugene
16.5+
7.6
11.8
33.0
9.7
4.7
4.8
3.9
6.0
5.3
6.5-
3.8
3.8
4.0
0-2150
0-24
0-70
0-2150
0-107
<1-13
0-860
0-8
0-30
0-750
0-860
<1~8
0-8
-------
vn
oo
FISHER FORMATION
URBAN
EUGENE - SPRINGFIELD
RURAL
LANE COUNTY
HIGH RISK |>X +t,.0/2 Sy
j | VERY HIGH RISK |>~X+2t,.0/2 Sy.x/vAN|
URBAN
EUGENE - SPRINGFIELD
RURAL
LANE COUNTY
Figure 5-1. Comparison of census tracts experiencing exposure to the Fisher formation and
exhibiting high skin cancer occurrence.
Source: Morton et al. (1975).
OO
-------
Similar findings were reported by Southwick et al. (1981) in a study
conducted on residents of West Mi Hard County, Utah. As an area in which
naturally occurring arsenic in public drinking water had been reported, West
Millard provided an "excellent "opportunity to study the effects of arsenic
exposure on a homogeneous, stable population with a predominantly 'Mormon
lifestyle1" (Southwick et al., 1981). The exposed communities of Hinckley and
Deseret had average arsenic concentrations of 0.18 mg/1 and 0.27 mg/1, respec-
tively (based upon monthly water samples taken between May 1976 to May 1977).
The control community of Delta had average arsenic concentrations of 0.02
mg/1. All drinking water in the study communities came from wells and the
predominant species of arsenic was reported as the pentavalent form (85%).
All study participants from the exposed communities were required to be
five years of age or older and to have been residents of Hinckley or Deseret
for at least the previous five years. Control participants were selected at
random from age and sex categories matched to the exposed participants.
Control participants were required to have lived their entire lives either in
Delta or communities where arsenic in drinking water did not exceed the national
standard of 0.05 mg/1.
Physical examinations were conducted to detect signs and symptoms associ-
ated with chronic arsenic poisoning. A total of 250 people participated in
these examinations (145 exposed, 105 control); not all of these participated
in each part of the examination, however. No explanation was provided by the
authors as to the differences in participation rate for different parts of the
examination. Urine and hair samples were collected from 94 and 74 percent of
the participants, respectively. Dermatological examinations were conducted on
249 individuals. Neurological and hematological examinations were also
013AS2/A 5-69 June 1983
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conducted and are discussed in Section 5.2.2.1 and 5.2.2.4, respectively. In
addition, the incidence of cancer and vascular diseases in the study popu-
lation was compared to other counties in the State of Utah.
The study results showed a clear relationship between the amount of
arsenic consumed in drinking water and the amount measured in hair and urine.
Differences between exposed and control populations were statistically signif-
icant.
Of the 249 participants examined for dermatological signs of arsenic
toxicity (palmar and plantar keratosis and hyperkeratosis, tumors, diffuse
pigmentation, arterial insufficiency), only 12 showed such signs and no parti-
cipant had more than one sign. The 12 individuals were not clustered among
the more heavily exposed and when the dermatological signs were regressed
against annual arsenic dose and the log of the dose, no significant associa-
tions were found.
Age adjusted cancer incidence rates showed Hinckley to have a somewhat
lower cancer incidence than Delta. Cancer death rates, 1956 to 1976, showed
Hinckley to have the highest rate (138 per 100,000) when compared to 42 other
Utah communities. However, this was based on an estimate of population distri-
bution in 1960, since census data were only available for 1970. Table 5-19
shows age specific death rates for Utah and three Mi Hard County communities.
(Fillmore is the County seat; comparisons to Deseret were not made due to the
community's small population). Between 1956 and 1976, 14 cancer deaths were
reported for Hinckley. All of these deaths occurred in individuals 45 years
or older and the cancers were types most frequently reported for Utah: lung,
breast, large intestine, prostate, stomach, leukemia, kidney, uterus, bone and
connective tissue. Hinckley had generally lower death rates for cardiac and
013AS2/A 5-70 June 1983
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TABLE 5-1S. AGE SPECIFIC DEATH RATES FOR UTAH
AND THREE MILLARD COUNTY COMMUNITIES
(DEATHS/100,000/YEAR)
Community
Characteristics
CANCER
State
Fill more
Delta
Hinckley
CARDIOVASCULAR
State
Fil Imore
Delta
Hinckley
CEREBROVASCULAR
State
Fil Imore
Delta
Hinckley
ARTERIOSCLEROSIS
State
Fil Imore
Delta
Hinckley
AGE GROUP SIZE
State
Fil Imore
Delta
Hinckley
Age Groups and (Number of Deaths)
0-4
7 (158)
0
0
0
1 (25)
0
0
0
1 (24)
0
0
0
0
0
0
0
119,004
157
202
40
5-14
6 (274)
14 (1)
0
0
0.4 (18)
0
0
0
0.5 (23)
0
0
0
0.07 (3)
0
0
0
224,417
347
400
108
15-24
6 (223)
0
22 (1)
0
1 (34)
0
0
0
1 (36)
0
0
0
0.2 (7)
0
0
0
175,607
202
224
57
25-44
19 (875)
17 (1)
61 (4)
0
18 (840)
17 (1)
30 (2)
0
4 (201)
0
0
0
0.5 (21)
0
0
0
227,502
293
330
79
45-64
149 (4749)
196 (13)
189 (11)
390 (6)
275 (8788)
392 (26)
344 (20)
325 (5)
52 (1651)
60 (4)
34 (2)
0
13 (406)
15 (1)
17 (1)
65 (1)
159,613
332
291
77
65+
558 (7680)
706 (25)
986 (29)
1053 (8)
2079 (28587)
1638 (58)
1599 (47)
1316 (10)
797 (10965)
1017 (36)
1088 (32)
789 (6)
202 (2781)
311 (11)
272 (8)
395 (3)
68,759
177
147
38
Death rates from 1956-1975 for cancer, cardiovascular disease, cerebrovascular disease,
and arteriosclerosis, showing numbers of deaths and the average size of the age group.
Source: Southwick et al. (1981).
013AS2/A
5-71
June 1983
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vascular diseases than did the control community of Delta. The authors noted
that no unusual death patterns likely to be associated with arsenic exposure
were seen in Hinckley.
Certain weaknesses exist with this study; most notably, that of a small
study population from which to derive meaningful statistical analyses. Further-
more, children and adults were not treated separately. In regard to sample
size, the authors felt that the small sample size was somewhat compensated by
the homogeneity and stability of the predominantly non-smoking population.
Data on food consumption were also missing which might have influenced urinary
arsenic levels. This, in turn, may have resulted in overstating the strength
of the dose-response relationship for urinary arsenic and arsenic in drinking
water. It should also be noted that some participants were reported to have
an average water consumption greater than 8£, which seems very high, even
taking into account the hot summers. In reporting on the lack of arsenic-
related effects in this study population compared to others (Tseng et al.,
1968; Borgono and Greiber, 1972; Borgono et al. , 1977; Zaldivar, 1977; Zaldivar
and Guiller, 1977), the authors did note that populations in Taiwan and Anto-
fagasta were exposed to considerably higher concentrations of arsenic in their
drinking water.
Interestingly, the importance attached to the fact that no adverse effects
were seen in this group of individuals exposed to drinking water arsenic
levels four times that allowed by the Interim Primary Drinking Water Regula-
tions (0.05 mg As/1), is somewhat compromised by the very characteristics of
the population that make it useful for epidemiological study. The fact that
this study population is so homogeneous and stable and, therefore, lends
itself to a relatively well-controlled statistical analysis, also makes it
013AS2/A 5-72 June 1983
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less useful in terms of being representative of the overall population of the
U.S. For this reason, any generalizations that might be drawn from this study
population are subject to limitations.
In addition to exposures via drinking water, food exposures and thera-
peutic exposures have also caused skin lesions and cancers. Hyperpigmentation
and depigmentation of the skin were found to be common among the survivors of
the Morinaga milk poisoning in 1955. A follow-up study conducted on the
exposed children when they were 17-20 years of age showed the prevalence of
lesions to be 15 percent (Yamashita et al., 1972). It is not known if any
skin cancers have developed.
Hutchinson (1888) first reported on a possible association of skin cancer
with the use of arsenical medicines. Prior to that, the association between
these arsenical agents and keratotic lesions had been recognized. In his
classic paper, Hutchinson reported on 6 patients with case histories who
exhibited the keratotic lesions associated with arsenical poisoning. He felt
that the clinical series supported two principal conclusions:
1. Prolonged internal use of arsenic may seriously affect the
nutrition of the skin and that use may produce warty or
corn-like indurations.
2. Continued use of arsenic may result in a tendency for
these "arsenic corns" to grow downward and pass into
epithelial cancer.
Neubauer (1947) later compiled a series of reports on 143 cases of medi-
cinal arsenical epitheliomas. He excluded five categories of cases reported
in the literature to keep the series consistent with regard to diagnosis of
case and history of arsenical use. Seventy-one percent of the patients being
treated with arsenical medicine were patients suffering from skin diseases,
013AS2/A 5-73 June 1983
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especially psoriasis (54 percent). In contrast, only a small percentage of
the cases reported came from patients treated with arsenic for various internal
disorders. In nearly all cases the drugs used were inorganic and almost all
were trivalent. The most commonly used arsenical was potassium arsenite. No
externally applied arsenic-related skin cancer case was reported in the series.
The elapsed time from the beginning of administration of the arsenical
drug to the beginning of the epitheliomatous growth was variable, but averaged
18 years regardless of the type of lesion. In cases with keratosis, the
latent period to the onset of keratosis was about half the latent period to
the onset of the epithelioma, i.e., about 9 years. Thirty-three percent of
the patients were 40 or younger. Of the 143 patients, 13 had or developed
miscellaneous cancers at other sites, but such cases were not reported syste-
matically.
Fierz (1965) reported a follow-up study of patients treated with arsenic
by a private practitioner. An accurate assessment of the total arsenic intake
in terms of the amount of Fowler's Solution administered was available to the
investigator from patient records. The follow-up examination was conducted
under the auspices of a local polyclinic. Fourteen hundred fifty patients
were identified as having received arsenic treatment, and invitations were
mailed for them to come for a free follow-up medical examination. During the
period March 1963 to April 1964, 262 patients presented themselves for exami-
nation. Two hundred eighty patients were not located while 100 patients
actively refused to participate. Only patients under 65 years of age were
invited to participate in the study. The author admits that the patients
reporting for examination were not a representative sample. In fact, he
categorizes them into three groups which range the spectrum of likely biases.
There were patients satisfied with the results of the arsenic treatment and
013AS2/A 5-74 June 1983
-------
wishing to express thanks, patients in whom disturbing side effects were
occurring, and finally patients who were still suffering from the initial
disease and who were eager to get a consultation.
Arsenic treatment was prescribed for individuals suffering primarily from
three main skin diseases: psoriasis (64 patients), neurodermatitis (62), and
chronic eczema (72). In addition, treatment was also prescribed for 64 patients
suffering from assorted skin diseases other than those listed above.
Fierz noted that the arsenic treatment showed good success. Of the 64
cases of psoriasis, 55 reported a favorable effect while taking the drops.
Forty-eight of 62 patients with neurodermatitis reported a favorable effect.
This effectiveness was the cause for the patients' reliance on the drug.
Upon examination, 106 of 262 patients (40.4 percent) reported hyper-
keratoses, although frequently a detailed examination was necessary to find
the changes. Hyperkeratoses were round, superficially verrucose papules, 1 to
3 mm in diameter. The number and the exact presentation of the hyperkeratoses
varied from case to case.
In the series, 21 cases of skin cancer were found comprising 8 percent of
the total subjects. As was in the case of hyperkeratosis, some variability
was observed in the expression of the skin cancers. Multiple basal cell
carcinoma was the most frequent histologic type observed, occurring in 48
percent of the cancer patients. The basal cell carcinomas appeared morpho-
logically as polycyclic, sharply bounded erythemas with slight infiltration.
In 13 of the 21 cancer cases, multiple carcinomas were observed, a much higher
proportion than had been observed with other causes of skin cancer. Of the 21
patients with carcinomas, 16 showed distinctly developed arsenic warts on the
palms and soles simultaneously with the skin tumors.
013AS2/A 5-75 June 1983
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Both hyperkeratosis and skin cancer were found to vary with increasing
arsenic intake. Above 400 ml of Fowler's solution, more than 50 percent of the
patients studied showed hyperkeratosis. As the dose increased there was a cor-
responding increase in the simultaneous occurrence of hyperkeratosis of the palms
and soles. Only 2/15 cases of hyperkeratosis with intakes of up to 250 ml had
a simultaneous presentation, while 16/27 had a simultaneous presentation with
intake of 250 to 500 ml.
As with the hyperkeratosis, skin cancer increased with increasing arsenic
doses. Below 500 ml only basal cell carcinomas were found; spindle cell carci-
nomas were only found above that dose. The latency period for hyperkeratosis was
at a minimum 2.5 years; skin cancer, however, had a minimum latency period of 6
years with a mean latency period of 14 years. Knoth (1966) also reported on two
patients treated with aresenical medicinals and who developed skin cancer.
Roth (1958) reported that of 47 autopsy cases of vintners with chronic
arsenic intoxication, 13 had skin tumors.
5.2.1.2.3 Other cancers. Whereas there are many studies suggesting that
there is an association between inhalation exposure and respiratory cancer and
oral exposure and skin cancer, there are no consistent data with regard to
cancer in internal organs.
Reymann et al. (1978) have investigated the relationship between the
intake of arsenic for medicinal purposes and subsequent internal neoplasms.
Study subjects were identified by examining the files of a dermatology clinic
in Denmark for the years 1930 to 1939. Two rosters of study subjects were
generated: 1) persons treated with arsenic for multiple basal cell carcinoma,
Bowen's disease, psoriasis, Verruca planus, and Lichen planus, and 2) persons
with keratoses from the first roster plus 30 other persons identified as
having keratoses. The first roster of 413 persons comprised the basic study
013AS2/A 5-76 June 1983
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population; 24 persons were excluded for various reasons resulting in a final
study population of 389 persons. The malignancy history of both populations
were traced through the years 1943-1974 in the Danish Cancer Registry. For
each person a length of observation period was determined and an expected
number of internal malignant neoplasms were determined using the former data.
In the main study population, 41 cases were observed versus 44.6 cases
expected. Therefore, no increased incidence of internal malignancies was
noted in the arsenic-treated patients. However, examination of the data by
individual skin disease categories showed that only women with multiple basal
cell carcinoma had a significantly higher incidence of internal cancer. The
same trend, although not significant, was observed in female patients exhibit-
ing verruca pi anus. Next, an analysis was made of a possible dose-response
relationship using duration of treatment as the exposure variable. The cate-
gories were low, medium and high, based on <1 month, 1-3 month, and >3 month
duration of standard dose administration (6-8 mg As,,CL). No relationship
between dose and internal organ cancer was noted for the total population or
by sex. In addition, the form of arsenic administered did not seem to affect
the incidence of internal cancer, nor was any effect noted due to period of
observation. Reymann et al. did not provide a definition of the term "internal
cancer". It is presumed that the authors included lung cancer in their defi-
nition. If so, the authors did not provide any adjustment for smoking.
Regardless, the sample size of 389 persons is probably too small to detect an
excess in the incidence of internal cancer, even if lung cancers were excluded.
The keratosis group was not analyzed in the same way. Eight of the 19
men with keratosis died before 1974. Four of these were due to cancer of the
internal organs. Expected deaths were 1.9. Similarly, 5 deaths due to cancer
of the internal organs were observed in the 34 women with keratosis compared
013AS2/A 5-77 June 1983
-------
with 3.3 expected. Together there were 9 deaths due to cancer of the internal
organs compared to 5.2 expected. Although the figure is almost doubled it is
still not significant. On the average, the patients with keratosis received
higher doses of arsenic than the other patients.
Hemangioendothelioma and reticulosarcoma of the liver has been reported by
Roth (1958) to occur among German vintners exposed occupationally to arsenic.
The same type of malignancy occurrence has also been reported in isolated cases
by several authors (Pershagen and Vahter, 1979). Higgins et al. (1982) reported
increased mortality for cirrhosis of the liver and urinary cancer in workers
at the Anaconda Montana smelter.
Knoth (1966) reported on two patients who had been treated with arsenical
medicinals and developed tumors at sites other than the skin or lung. One of
the patients was a 61-year old woman who had been treated with an arsenical
medicinal and developed mammary carcinoma. The other case was that of a 53-
year old male who had been treated with an arsenical medicinal for cirrhosis
vulgaris and developed a reticulosarcoma of the glans penis.
In the studies by Ott et al. (1974), an increased proportionate mortality
due to malignant neoplasms of lymphatic and hematopoietic tissues was found.
Axelson et al. (1978) found an increased risk of leukemia and myeloma in a
case-control study of workers exposed at a smelter.
5.2.1.3 Experimental Studies of Arsenic Carcinogenesis--Arsenic carcinogeni-
city in test animals has not been generally observed. The literature on
experimental inorganic arsenic carcinogenesis, as summarized in Table 5-20 and
as reviewed by scientific bodies (NAS, 1977; NIOSH, 1975; IARC, 1973 and 1980)
and individuals (Sunderman, 1976; Wildenberg, 1978; Pershagen and Vahter, 1979),
supports this conclusion.
In view of the presently recognized anomalous metabolizing of inorganic
arsenic by rats, studies which used rats as the experimental subjects have not
013AS2/A 5-78 June 1983
-------
o
h- '
CO
rv> Route
;C-
Oral
Oral
Oral
Oral
Oral
Oral
i
UD Oral
Oral
Oral
Oral
TABLE 5-20. SUMMARY TABLE OF
Species (Strain)
Mice (C57B16)
Mice (Swiss)
Mice (Swiss)
Mice (NMRI)
Mice (C3H/St, female)
Rats (not specified)
Rats (Bethesda Blacks)
Rats (Osborne-Mendal)
Rats (Long Evans)
Rats (Wistar)
Compound
As2°3
AS2°3
NaAsp£
As203
NaAs02
Pb3(As04)2
As2°3
NaAsO,,
NaAs02
Pb (AsO ).
Na^AsO/* ^
Pb3(As04)2
EXPERIMENTAL STUDIES OF ARSENIC CARCINOGENESIS
Vehicle Results*
Tap water
or 12% aqueous
ethanol
Drinking water
Drinking water
Drug (Psor- +(?)
Intern) or
Fowler's solu-
tion
Drinking water
Not specified
Tap water
or aqueous
ethanol (12%)
Diet
Drinking water
Diet
Diet
+ NDEA Diet
IDEA Diet
Reference
Huepert &
Payne, 1962
Baroni et al. ,
1963
Kanisawa &
Schroeder, 1967
Knoth, 1966/67
Schrauzer &
Ishmael, 1974
Fairhall &
Miller 1941
Hueper & Payne,
1962
Byron et al . ,
1967
Kanisawa &
Schroeder, 1969
Kroes et al. ,
1974
Remarks
Shortened life
span of treated
(aq. ethanol) vs.
Control
Shortened life
span, low dose
Significance cannot
be determined, un-
complete reporting
by author
Poor survival
in treated
Reduced survival
at highest dose
Low dose
High mortality and
2 tumors (incidence
not reported
observed in lead
arsenate group)
3
O>
i-D
CO
CO
-------
TABLE 5-20. (continued)
0
!~^ Route
j=
1X0 Oral
Inhalation
Intratracheal
instillation
Intratracheal
Instillation
tn Intratracheal
Co Instillation
0
Skin painting
(application)
Skin painting
(application)
Skin painting
(application)
Species (Strain)
Dog
Mice (not specified)
Rats (Wistar King)
male
Rats (Wistar King)
male
Rats (BDIX)
Mice (not specified)
Mice (S)
Mice (Rockland
all-purpose)
Compound
NaAsO, or
Na3As64
NaAs02
(1) As20,
(2) Copper ore
(3.95%
Arsenic)
(3) Flue dust
As203
Ca3(As04)2
KAsO? and
As2°3
KAs02
followed by
croton oil
in acetone
(1) KAs02
followed by
croton oil in
benzene
Vehicle Results*
Diet
Aqueous aerosol
Not specified
Aqueous
solution
Bordeaux +
mixture
(contains
CuS04 & Ca(OH)2)
Ethanol
Methanol
80% ethanol
Reference
Byron et al . ,
1967
Berteau et al . ,
1978
Ishinishi et al . ,
1977
Ishinishi et
al., 1976
Ivankovic et
al . , 1979
Leitch &
Kennaway 1922
Salaman &
Roe 1956
Boutwell, 1963
Remarks
Weight loss, early
mortality, short
duration of experi-
ment
Reported in an
abstract form, high
incidence in controls
One tumor observed
in treated, not sig-
nificant
One tumor observed
in treated, not sig-
nificant
Results cannot be
attributed to arsenic
alone
Neubauer (1947)
failed to confirm
this observation
As reviewed by
IARC (Vo. 23, 1980)
As reviewed by
IARC (Vol. 23, 1980)
UD
co
CO
-------
TABLE 5-20. (continued)
013AS2/A
<_n
i
CO
C_i
c
3
0>
to
00
GO
Route
Skin painting
(application)
Skin painting
(application)
S.C. injection
Subcutaneous
implant
Subcutaneous
injection
i.v. injections
Intramuscullary
injection
Intramuscullary
injection
Oral
Oral
Species (Strain)
Mice (Rockland
all-purpose)
Mice (Swiss)
Mice (Swiss) female
Progeny
Rats (random-bred)
male albino
Rats (random-bred)
male albino
Mice (Swiss)
female
Rats (Osborne-Mendel)
Rabbits
Mice (Swiss)
Mice (STS)
Compound
(2) OMB A
followed by
KAs02 in 80%
ethanol
(1) Na3As04
(2) Na3As04
followed by
croton oil
and DMBA
Na AsO
Na^AsO*
Ca3(As04)2
Ca3(As04)2
Na3As04
Arsenic
Arsenic
As20 &
croton oil
OMBA or urethan
Arsanilic acid
or KAsO? followed
by DMBA (skin)
then croton oil
(skin) in benzene
Vehicle Results*
acetone Not carcino-
genic
Water containing
Tween 60
Water con- No promotional
tainig activity
Tween 60 observed
Water +
Water +
Paraffin
pellets
Sunflower oil
Water +
Metallic
Metallic
Drinking water
Diet
Reference Remarks
Boutwell , 1963
Baroni et al . ,
1963
Osswald & Goerttler,
1971
Arkhipov, 1968 As reviewed by
I ARC (Vol. 23, 1980)
Arkhipov, 1968
Osswald &
Goerttler, 1971
Hueper, 1954
Hueper, 1954
Baroni et al . ,
1963
Boutwell, 1963 As reviewed by
I ARC (Vol. 23, 1980)
(*) + statistically significant excess tumors observed over controls
- no statistically significant excess tumors of treated vs. control or no tumors observed
-------
been discussed in the text, but have been presented in Table 5-20. Studies on
other animal models have generally resulted in negative findings. A few of
these are discussed below, but most have also been summarized in Table 5-20.
In a study by Baroni et al. (1963), Swiss mice were given either arsenic
trioxide dissolved in drinking water (concentration of 100 mg/£) ad libitum
for the duration of the 70-week experiment; or, sodium arsenate in a concen-
tration of 15.8 gm/£ in a 2.5 percent solution of Tween 60 in water, applied
twice weekly for the duration of the experiment. Each compound was tested
alone, in combination with skin applications of croton oil (to test for initi-
ating action), and after initiation with a single skin application of
7,12-dimethylbenz(a) anthracene or with administration of urethan by stomach
tube (to test for promoting action). All tests failed to show any carcino-
genic activity of the two compounds under the given experimental conditions.
Kanisawa and Schroeder (1969) treated Swiss mice with sodium arsenite
(equivalent to 5 pg/ml As) in drinking water for the 30-month duration of
their study. In the treated animals, the authors noted 6 malignant and 11 com-
bined malignant and benign tumors out of 103 animals versus 15 malignant and
50 combined malignant and benign tumors out of 170 control animals; thus, the
results were negative for showing any carcinogenic effect of sodium arsenite
in this study.
In a study of Leitch and Kennaway (1922; as reported in IARC, 1980), 100
mice were given skin applications of a solution of potassium arsenite in
ethanol containing 1.8 percent arsenic trioxide (later reduced to 0.12 percent
due to a high death rate), thrice weekly for 3 months. Of the 33 mice that
lived for 3 months, only one developed a metastasizing squamous cell carcinoma.
In certain animal systems, positive carcinogenic responses have been
reported, however. For example, Osswald and Goerttler (1971) exposed pregnant
013AS2/A 5-82 June 1983
-------
Swiss mice to daily parenteral dosing of sodium arsenate (0.5 mg/kg, solution
of 0.005 percent arsenale salt) for a total of 20 injections. Part of the
offspring groups received 20 injections of the same level subcutaneously at
weekly intervals. Leukemia or lymphoma was seen in 46 percent of the mothers
(11/24) at the end of 2 years versus none in the controls. Of the treated
offspring, 41 percent (17/41) of the males and about half of the females
(24/50) developed leukemia versus only 3 of 55 male and female control off-
spring (approximately 6 percent). IARC (1973) has criticized this study for
the absence of exposure of controls to the appropriate vehicle solution.
Knoth (1966) noted significant frequency of tumors in 30 mice exposed to
Fowler's solution orally (one drop/week, 20 weeks, approximately 5.3 mg As
total),including adenocarcinomas of the skin, lung, and lymph nodes. The ab-
sence of experimental details makes critical assessment of this study difficult.
Some recent animal studies have employed different exposure conditions
than have been employed in the past. Berteau et al. (1978) have exposed a
tumor-susceptible strain of female mice to a respirable aerosol of inorganic
arsenic (1 percent aqueous solution of sodium meta-arsenite, 20 to 40 minutes
daily, 5 days/week, 55 weeks total). The 30 exposed mice showed neither gross
nor histological evidence of neoplasia.
In a two-part study, Ishinishi et al. (1977) examined the carcinogenic
and co-carcinogenic effects of various arsenic compounds on male Wistar-King
rats. In the first part of the study, arsenic trioxide, an arsenic-containing
copper ore (containing 3.95 percent arsenic) or metal refinery flue dust
(containing 10.5 percent arsenic) were administered to 51 rats via 15 weekly
intratracheal instillations. The rats were observed over their lifespan. Of
the 25 surviving rats, one adenocarcinoma was seen in the group receiving flue
dust. One lung metastasis from osteosarcoma of the femur and one adenoma was
013AS2/A 5-83 June 1983
-------
reported in the group exposed to the copper ore. No malignant tumors were
reported in the group receiving arsenic trioxide; however, one adenoma was
reported for this group. All groups displayed squamous cell metaplasia in the
airway and osteometaplasia in the alveolus of the lung.
In the second part of the study, 87 rats were instilled with each of the
above compounds suspended in a saline solution containing benzo[a]pyrene
(B[a]P) or with B[a]P, alone. Control rats (23) were instilled with the
saline solution. Of the 34 surviving exposed rats, one adenocarcinoma was
seen in the group receiving B[a]P plus copper ore. All exposed groups had
squamous cell carcinomas of the lung. Of particular interest to the authors,
was the noted co-carcinogenic effect of arsenic trioxide with B[a]P; rats in
this group exhibited a 43 percent incidence rate (3/7) for squamous cell
carcinomas. This compared with a 14 percent (1/7) incidence rate in animals
given B[a]P, alone. No benign or malignant tumors were seen in the 7 surviv-
ing control rats. Again, squamous cell metaplasia or osteometaplasia were
seen in all groups.
The results indicated a positive interaction between arsenic trioxide and
B[a]P; however, the authors noted that the numbers of surviving animals were
too small to permit drawing any firm conclusions from the study.
In another study (1980), Ishinishi et al. gave 30 male adult Wistar rats
intratracheal instillations of arsenic trioxide in suspension for 15 weeks.
Of the 19 rats that survived, only one malignant squamous cell carcinoma was
observed over lifetime. No tumors were found in the controls.
Ivankovic and co-workers (1979) exposed rats, via intratracheal instilla-
tion, to a pesticide mixture corresponding to that used in the past for vine-
yard treatment and consisting of a mixture of copper (II) sulfate, calcium
hydroxide and calcium arsenate. Of 25 rats exposed to ca. 0.07 mg arsenic, 10
013AS2/A 5-84 June 1983
-------
died from lung necrosis or pneumonia. In the survivors, 9 animals (60 percent)
showed multi-focal bronchogenic adenocarcinomas and bronchiolar/alveolar cell
carcinomas.
This study appears to offer experimental evidence that the vineyard
pesticide mixture, employed as such, could have been carcinogenic to vine
dressers working with the material. One difficulty with this study is an
ambiguity regarding its full significance for the general issue of arsenic
inducing carcinogenic effects by itself. Clearly, the high mortality rate, 40
percent, and the known toxicity of Bordeau mixture (copper sulfate plus calcium
hydroxide) to animals (Pimentel and Marques, 1969) and man (Villar, 1974,
Pimentel and Marques, 1969) suggest carcinogenesis; however, it is impossible
to clearly ascribe such activity to arsenic alone given the presence of other
compounds within the mixture. In their studies, Ivankovic et al. (1979) did
not include animal groups exposed to calcium arsenate alone or to Bordeau
mixture alone.
Recently, both Inamasu et al. (1982) and Pershagen et al. (1982) have
studied the effects of intratracheal instillation of calcium arsenate (see
Section 4.1.1 for complete discussion). Inamasu et al. gave single intra-
tracheal instillations of arsenic trioxide or calcium arsenate to male Wistar
rats. Pershagen et al. instilled male Syrian golden hamsters with four weekly
suspensions of arsenic trioxide, arsenic trisulfide and calcium arsenate. The
results of both studies showed that arsenic trioxide was rapidly cleared from
the lungs, whereas calcium arsenate was slowly eliminated. The differences in
clearance appeared to be related to solubility, with the less soluble calcium
arsenate exhibiting the slowest clearance.
These recent findings might help to explain the differences noted above
in the earlier studies of Ishinishi et al. (1977; 1980) and Ivankovic et al.
013AS2/A 5-85 June 1983
-------
(1979). In regard to the Ivankovic study, it may be that the calcium arsenate,
of itself, contributed to the high mortality rate observed in the exposed
rats.
Schrauzer and co-workers (Schrauzer and Ishmael, 1974; Schrauzer et a!.,
1977; Schrauzer et al. , 1978) have reported experimental results using oral
arsenic and the tumorigenic effect of the agent on spontaneous mammary adeno-
carcinomas in an inbred strain of mice (C3H/St Mice). These workers noted
that while arsenic retards the overall incidence of tumor formation (10 or 80
ppm As), it stimulates the growth of tumors that otherwise occur. When these
animals were exposed to only 2 ppm As (arsenite) in drinking water, compared
to levels of 10 or 80 ppm, there was no effect on frequency of tumors, although
the same enhanced tumor growth was seen as before with levels of 10 or 80 ppm
As (Schrauzer et al. , 1978). Furthermore, a higher incidence of multiple
tumors of the mammary gland was observed, as was the abolishing of the anti-
carcinogenic effect of selenium in this system when both elements were given
together.
5.2.1.4 Quantitative Carcinogen Risk Estimates
5.2.1.4.1 Introduction. This quantitative section deals with the unit risk for
arsenic in air and water and the potency of arsenic relative to other carcino-
gens that the Carcinogen Assessment Group (CAG) of the U.S. Environmental Pro-
tection Agency has evaluated. The unit risk estimate for an air pollutant is
defined as the lifetime cancer risk occurring in a population in which all
individuals are exposed continuously from birth throughout their lifetimes to
o
a concentration of 1 (jg/m of the agent in the air they breathe. The unit risk
estimate for water is defined similarly, but with a water concentration of 1
Unit risk estimates are used for two purposes: (1) to compare several agents
with each other in terms of carcinogenic potency, and (2) to give a crude
013AS2/A 5-86 June 1983
-------
indication of the human health risks that might be associated with exposure to
these agents, if the actual exposures are known.
The data used for quantitative estimates can be of two types: (1) life-
time animal studies, and (2) human studies where cancer risk has been asso-
ciated with exposure to the agent. It is assumed, unless evidence exists to
the contrary, that if a carcinogenic response occurs at the dose levels used
in a study, then responses at all lower doses will occur with an incidence
that can be determined by an appropriate extrapolation model.
There is no solid scientific basis for any mathematical extrapolation
model that relates carcinogen exposure to cancer risks at the extremely low
concentrations which must be dealt with in evaluating environmental hazards.
For practical reasons, such low levels of risk cannot be measured directly
either by animal experiments or by epidemiologic studies. It is necessary,
therefore, to depend on current knowledge of the mechanisms of carcinogenesis
for guidance as to the correct risk model to use.
At the present time, the dominant view is that most cancer-causing agents
also cause irreversible damage to DNA--a position supported by the fact that a
large proportion of agents that cause cancer are also mutagenic. There is
reason to expect that the quanta! type of biological response, which is char-
acteristic of mutagenesis, is associated with a linear non-threshold dose-
response relationship. Indeed, there is substantial evidence from mutagenesis
studies with both ionizing radiation and a wide variety of chemicals that this
type of dose-response model is the appropriate one to use in estimating cancer
risks from environmental exposures. This is particularly true at the lower
end of the dose-response curve. At higher doses, there can be an upward
curvature, probably reflecting the effects of multistage processes on the
mutagenic response. The linear non-threshold dose-response relationship is
013AS6/A 5-87 June 1983
-------
also consistent with the relatively few epidemiologic studies of cancer re-
sponses to specific agents that contain enough information to make the evalu-
ation possible (e.g., radiation-induced leukemia, breast and thyroid cancer,
skin cancer induced by arsenic in drinking water, liver cancer induced by
aflatoxins in the diet). There is also some evidence from animal experiments
that is consistent with the linear non-threshold model (e.g., the initiation
stage of the two-stage carcinogenesis model in rat liver and mouse skin).
Because its scientific basis, although limited, is the best of any of the
current mathematical extrapolation models, the linear non-threshold model has
been adopted here as the primary basis for risk extrapolation at low levels of
exposure.
The quantitative aspect of carcinogen risk assessment is included here
because it may be of use in setting regulatory priorities, evaluating the
adequacy of technology-based controls, and other aspects of the regulatory
decision-making process. However, the imprecision of presently available
technology for estimating cancer risks to humans at low levels of exposure
should be recognized. At best, the linear extrapolation model used here
provides a rough but plausible estimate of the upper limit of risk—that is,
with this model it is not likely that the true risk would be much more than
the estimated risk, but it could be considerably lower. The risk estimates
presented below should not be regarded, therefore, as accurate representations
of true cancer risks even when the exposures involved are accurately defined.
The estimates presented may, however, be factored into regulatory decisions to
the extent that the concept of upper-risk limits is found to be useful.
013AS6/A 5-88 June 1983
-------
5.2.1.4.2 Unit Risk for Air
5.2.1.4.2.1 Methodology for quantitative risk estimates. The methodologies
used to arrive at quantitative estimates of risk must be capable of being
implemented using the data available in existing epidemiologic studies of
exposure to airborne arsenic. In order to extrapolate from the exposure
levels and temporal exposure patterns in these studies to those for which risk
estimates are required, it will be assumed that the age-specific mortality
rate of respiratory cancer per year per 100,000 persons for a particular
5-year age interval i can be represented using either of two models:
a.(D) = a.[l + a'Dk] (1)
(a relative or multiplicative risk model), or
a.(D) = a. + 100,OOOa'Dk (2)
(an absolute or additive risk model). With either model, a- is the age-
specific mortality rate per year of respiratory cancer in a control population
not exposed to arsenic, a1 is a parameter representing the potential of air-
borne arsenic to cause respiratory cancer, and D is some measure of the ex-
posure to arsenic up to the ith age interval. For example, D might be the
cumulative dose in ug/m3 years, the cumulative dose neglecting exposure during
the last 10 years prior to the ith age interval, or the average dose in ug/m3
over some time period prior to the ith age interval. The forms to be used for
D will be constrained by the manner in which dose was treated in each indi-
vidual epidemiologic study. The parameter k determines the shape of the
013AS6/A 5-89 June 1983
-------
dose-response curve. Attention will be given particularly to the values k = 1
and k = 2. If k = 1, the age-specific incidence rates vary linearly with the
dose level (a linear model), and if k = 2 they vary quadratically. At low
exposures the extra lifetime probability of respiratory cancer mortality will
vary correspondingly (e.g., linearly for k = 1 and quadratically for k = 2).
The dose-response data available in the epidemiologic studies for esti-
mating the parameters in these models consists primarily of a dose measure D.
J
for the jth exposure group, the person-years of observation Y-, the observed
J
number of respiratory cancer deaths 0., and the number E. of these deaths
J J
expected in a control population with the same sex and age distribution as the
exposure group. The expected number E. is calculated as
J
j = Y...a./100,000, (3)
where Y-. is the number of person-years of observation in the ith age category
and the jth exposure group (Y- = ,-Y-.)- This is actually a simplified repre-
sentation, because the calculation also takes account of the change in the
age-specific incidence rates with absolute time. The expected number of
respiratory cancer deaths for the ith exposure group is
E(0.) = * Yj.a^l + a'D.jk)/100,000
a'D.k) (4)
J
013AS6/A 5-90 June 1983
-------
under the relative risk model, and is
E(0.) = * Y..(a. +100,OOOa'D-k)/100,000
= Ej * a'YjDjk (5)
under the absolute risk model. Consequently, with either model, E(O-) can be
J
expressed in terms of quantities typically available from the published epi-
demiologic studies. Note that person-years of observation are not required if
the multiplicative model is used.
Making the reasonable assumption that 0. has a Poisson distribution, the
J
parameters a1 and k can be estimated from the above equations using the method
of maximum likelihood. Once these parameters are estimated, the age-specific
mortality rates for respiratory cancer can be estimated for any desired ex-
posure pattern.
To estimate the corresponding additional lifetime probability of respira-
tory cancer mortality, let b-,,..., b-,g be the mortality rates, in the absence
of exposure, for all cases per year per 100,000 persons for the age intervals
0-4, 5-9,..., 80-84, and 85+, respectively; let a-,,...,a-,o represent the
corresponding rates for malignant neoplasms of the respiratory system. The
probability of survival to the beginning of the ith 5-year age interval is
estimated as
FI [1 - 5b 7100,000]. (6)
J
013AS6/A 5-91 June 1983
-------
Given survival to the beginning of age interval i, the probability of dying of
respiratory cancer during this 5-year interval is estimated as
53^100,000. (7)
The probability of dying of respiratory cancer given survival to age 85
is estimated as a-,g/b-,g. Therefore, the probability of dying of respiratory
cancer in the absence of exposure to arsenic is estimated as
17 i-1
(1 - 5b. /100,000)]
(8)
Pn = I [5a. /100,000) FI (1 - 5b. /100,000)]
i=l X j=l J
17
+(a18/blg) n (i - 5/100,000)
=l J
Here the mortality rates a- apply to the target population for which risk
estimates are desired, and consequently will be different from those in
(l)-(5), which applied to the epidemiologic study cohort. If the 1976 U.S.
mortality rates (male, female, white, and non-white combined) are used in this
expression, then P~ = 0.0451.
To estimate the probability P™ of respiratory cancer mortality when
exposed to a particular exposure pattern EP, the formula (8) is again used,
but a. and b- are replaced by a-(D-) and b.(D-), where D. is the exposure
measure calculated for the ith age interval from the exposure pattern EP. For
example, if the dose measure used in (1) is cumulative dose to the beginning
of the ith age interval in ug/m3-years, and the exposure pattern EP is a
lifetime exposure to a constant level of 10 ug/m3, then D. = (i-l)(5)(10),
013AS6/A 5-92 June 1983
-------
where the 5 accounts for the fact that each age inverval has a width of 5
years. The additional risk of respiratory cancer mortality is estimated as
PEP - PO. (9)
If the exposure pattern EP is constant exposure to pg/m3, then P™ - PQ is
called the "unit risk."
This approach can easily be modified to estimate the extra probability of
respiratory cancer mortality by a particular age due to any specified exposure
pattern. It is also clear that the applications of the approach are not
limited to respiratory cancer.
5.2.1.4.2.2. Risk estimates from epidemiologic studies. Prospective studies
of the relationship between mortality and exposure to airborne arsenic have
been conducted for the Anaconda, Montana smelter (Lee and Fraumeni, 1969;
Lee-Feldstein, 1982; Higgins et al., 1982; Brown and Chu, 1983 a, b, c); and
the Tacoma, Washington smelter (Pinto et al., 1977; Enterline and Marsh,
1982).
The study of Lee-Feldstein (1981) reported on an additional 14 years of
follow-up of the cohort of 8047 studied by Lee and Fraumeni (1969), and used
essentially the same methods of analysis as the earlier study. Therefore it
will not be necessary to consider the Lee and Fraumeni study in any detail in
this report. Higgins et al. (1982) followed for an additional 14 years a
sample of 1800 men from the cohort studied by Lee and Fraumeni, but used
different exposure classifications and different methods of analysis.
Brown and Chu (1983 a, b, c), in a series of papers, arranged the Ana-
conda smelter data in such a manner that a mathematical model could be derived
from it to account for the effect of the timing of exposure as predicted by
the multistage model.
013AS6/A 5-93 June 1983
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Whereas Pinto et al. (1977) studied a cohort from the Tacoma smelter
consisting of 527 followed only after retirement, the study by Enter!ine and
Marsh (1982) involved 2802 men and included follow-up prior to retirement.
Consequently, the Enterline and Marsh study appears to provide a stronger
basis for quantitative risk assessment than the Pinto et al. study.
In addition to studies of copper smelter workers, there have also been
studies of workers exposed to arsenicals in the production or use of pesti-
cides. Ott et al. (1974) studied the mortality experience of workers exposed
to lead arsenate and calcium arsenate.
5.2.1.4.2.3 The Lee-Feldstein (1982) study. This study included 8047 white
males who were employed as smelter workers for 12 months or more before 1957,
and whose mortality experience was observed from 1938 through 1977. Alto-
gether, the study involved 192,476 person-years of follow-up and 3550 deaths,
including 302 from respiratory cancer (Table 5-21). Expected numbers of
cancer deaths were calculated on an age-adjusted basis using the combined
mortality experience of the white male population of Idaho, Wyoming, and
Montana. As Table 5-21 indicates, malignant neoplasms of the digestive and
respiratory tracts had SMRs of 125 and 285, respectively, both of which were
significant at the 1% level (SMR = [observed/expected][100]).
Workers were categorized both by duration of employment and level of
exposure to airborne arsenic in order to determine the effect of these param-
eters upon mortality. For each year of the study period, workers were as-
signed to one of five groups on the basis of total years of smelter employment
completed (Table 5-22). Work areas in the smelter were divided into heavy,
medium, or light exposure areas. Based upon this division, workers were
categorized into heavy, medium, or light exposure groups, as determined by
their maximum exposure for 12 or more months. The results for respiratory
cancer based upon these categorizations are given in Table 5-23.
013AS6/A 5-94 June 1983
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TABLE 5-21. OBSERVED AND EXPECTED DEATHS DUE TO SELECTED CAUSES,
WITH STANDARDIZED MORTALITY RATIOS (SMRs)
AMONG SMELTER WORKERS, 1938-77
Number of deaths
Cause of Death List No.a Observed Expected
Tuberculosis
Respiratory
Other
Malignant neoplasms
Digestive
Respiratory
Other 140-148,
177-181,
Vascular lesions of
central nervous
system
Diseases of heart
Influenza and pneumonia
Emphysema (1963-77 only)
Cirrhosis of liver
Accidents
Motor vehicle 810-825,
Other 800-802,
001-019
001-008
010-019
140-199
150-159,
160-164°
165-170
190-199
330-334
400-443
480-483,
490-493
527
581
800-962
830-835
840-862
Suicide and homicide 963-964, 970-979
All other causes
Total
980-985
Residual
aSeventh revision of International Lists
53
47
6
609
167
302
140
262
1366
88
90
76
288
106
182
83
606e
3522
of Diseases
27.93
25.51
2.42
370.74
133.58
105.81
131.35
211.56
1056.55
76.05
34.58
36.53
280.27
115.55
164.72
86.08
548.50
2728.79
and Causes
SMRb
190°
184C
248
164^
125^
285C
107
124C
129C
116
260C
208C
103
92
110
98
129C
of Death.
SMR = (observed/expected) x 100.
Significant at 1% level. Bailar and Ederer (1964)
Among the 302 deaths from respiratory cancer, the site was lung and
bronchus (162,163) in 289 cases, larynx (163) in 9, mediastinum (164)
in 3 and (160) in 1.
Includes 19 emphysema deaths occurring in the years preceding 1963, for which
emphysema death rates are not available from individual states.
Source: Lee-Feldstein (1982).
013AS6/A
5-95
June 1983
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TABLE 5-22. DESCRIPTION OF LENGTH OF EMPLOYMENT GROUPS, WITH NUMBERS OF SMELTER
WORKERS, NUMBERS OF DEATHS, PERSON-YEARS AT RISK, AND
DURATION OF SMELTER EMPLOYMENT (BASED ON TOTAL
WORK EXPERIENCE THROUGH SEPT. 30, 1977)
Length of
employment group
1 (25 or more years)
2 (15 to 24 years)
3 (10 to 14 years)
4 (5 to 9 years)
5 (1 to 4 years)
TOTAL
Number of.
persons
1899
1138
678
1082
3248
SW5
Number of
deaths
1169
586
328
433
1006
3527
Number of
person-years
of follow up
27,053
26,556
19,734
30,854
88,279
192,476
Employees in all cohorts were living on Jan. 1, 1938.
Group assignment of each person here was based on his status at the
termination of employment or on September 30, 1977 (whichever date was
earlier).
Represents cumulative follow-up experience over the study period, 1938-77,
with a total of 67,569 person-years of follow-up in the period 1964-77.
Individuals were initially counted at risk upon completing 1 year of employ-
ment or on Jan. 1, 1938, if employed at least a full year before that date.
In each calendar year of the study period, employees were counted in the group
reflecting their cumulative work experience to date.
Source: Lee-Feldstein (1982).
013AS6/A
5-96
June 1983
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TABLE 5-23. OBSERVED AND EXPECTED DEATHS FROM RESPIRATORY CANCER,
WITH PERSON-YEARS OF FOLLOW-UP, BY COHORT AND
DEGREE OF ARSENIC EXPOSURE
Maximum Exposure to Arsenic (12 or more months)'
Heavy
Years of Exposure Obs/Exp P-Y
25 years+ 13/2.5 2400
15-24 9/1.3 2629
Less than 15 years 11/2.4 6520
Medium
Obs/Exp P-Y
49/7 6837
13/4.0 6509
31/9.3 24594
Light
Obs/Exp P-Y
51/16.3 14573
16/8.6 12520
69/31 78245
The 1562 men who worked less than 12 months in their category of maximum
arsenic exposure were not included in this table.
Observed/Expected.
£
Person-years of follow-up furnished by Dr. Lee-Feldstein (personal communi
cation).
Source: Adapted from Lee-Feldstein (1982).
013AS6/A
5-97
June 1983
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Exposures to airborne arsenic were estimated from 702 samples collected
at 56 sampling stations during the years 1943-1958 (Morris, 1975). Morris
estimated that airborne levels averaged 11.27, 0.58, and 0.27 mg/m3 in the
heavy, medium, and light exposure areas, respectively. Respirators were used
with varying degrees of faithfulness in the high exposure areas; consequently,
average individual exposures in these areas were probably much less than 11.27
mg/m3. A rough estimate is that use of respirators reduces the exposure
levels by a factor of 10 (OSHA, 1978).
The Lee-Feldstein (1982) study has a number of features which support its
use in making quantitative estimates of respiratory cancer risk from airborne
arsenic. It was aOarge study that involved observations of a considerable
number of respiratory cancer deaths. A substantial amount of follow-up was
conducted of persons who had been exposed for 15 years or more. Estimates of
exposure levels and work histories are available for estimating individual
exposures and for determining dose response.
It would have been more appropriate for making quantitative estimates of
risk to have categorized workers by their individual cumulative or average
exposures, rather than by their maximum exposures for 1 year or more. In
developing the quantitative estimates, it will be assumed that a worker's
average exposure during work hours was equal to the exposure for the category
to which he was assigned. However, because these assignments were based upon
maximum exposures for at least a 12-month period, this approach tends to
overestimate exposures, and consequently, to underestimate the carcinogenic
potency of arsenic.
013AS6/A 5-98 June 1983
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Because smoking is also an important risk factor for respiratory cancer,
it would have been very useful to have smoking histories for the workers.
Higgins et al. (1982) collected some limited smoking data for this cohort.
Higgins suggest that the smelter workers smoked somewhat more than the average
U.S. white male population, but the difference was not enough to have a major
effect upon the outcome of the study.
Development of risk estimates: The data from the Lee-Feldstein (1982)
study used in the risk assessment are listed in Table 5-24. The relative risk
(observed/expected) from this table are graphed in Figure 5-2, and the abso-
lute risks ([observed-expected/ person-years) in Figure 5-3. It is clear from
these graphs that the risk for the high-exposure group exposed for greater
than 25 years is not commensurate with the risks for the other groups. Be-
cause of this, and also because the exposures in the high exposure groups are
much more uncertain than those of the other groups, it was decided to estimate
risk using only the low and medium exposure groups. Results of applying
chi-square goodness-of-fit tests of the relative and absolute risk models with
k = 1 and k = 2 are recorded in Table 5-25. The maximum likelihood estimates
of the carcinogenic potency parameter a1 are also listed in this table. The
maximum likelihood fits of these models are graphed in Figures 5-2 and 5-3.
All of the fits are poor (p less than 0.0001) with the exception of that for
the absolute-risk model; this latter fit is marginally acceptable (p = 0.025).
The unit risk (additional risk of respiratory cancer death from lifetime
exposure to 1 (jg/m3 airborne arsenic) obtained from the absolute-risk model
with k = 1 is also listed in Table 5-25. This risk was estimated by applying
(2), (8), and (9) with D- based upon a constant exposure of 1 ug/m3.
013AS6/A 5-99 June 1983
-------
TABLE 5-24. DOSE-RESPONSE DATA FROM LEE-FELDSTEIN (1982) USED FOR RISK ASSESSMENT
Cohort
1
(25 + years
(of exposure)
2
(15-25
years of
exposure)
3
(less than
15 years of
exposure)
Maximum
Exposure
to Arsenic
Heavy
Medium
Light
Heavy
Medium
Light
Heavy
Medium
Light
Cumulative
Exposure
(ug/m3-years)
36064
18560
9280
22250
11600
5800
5973
3074
Person-Years
of .
Observation
2400
6837
14573
2629
6509
12520
6520
24594
Observed
Deaths
13
49
51
9
13
16
11
31
Expected
Deaths
2.5
7.0
16.3
1.3
4.0
8.6
2.4
9.3
Exposures are in ug/m3-years estimated as (air concentration)(duration).
For light, medium, and heavy exposures, air concentration was estimated as
290, 580, and 1127 ng/m3, respectively (OSHA, 1978). Duration was estimated
as follows (cf. Table 5-22):
Cohort 1: Persons in this cohort had at least 25 years' exposure. If
all had worked continuously throughout follow-up, average
duration would have been 25 + 27053/1899 = 39 years. There-
fore the mid-point (39 + 25)/2 = 32 years was used.
Cohort 2: The mid-point of the employed interval, i.e., (15 + 25)/2 = 20
years was used.
Cohort 3: A weighted average of the mid-points of the employment intervals,
i.e. ,
(3) (88279)
U -"""• --"+'-'-"-- -T--I- -linn -Ji
(7.5X30854) + (12.5)(19734) _
88279 + 30854 + 19734
years.
Furnished by Dr. Lee-Feldstein.
013AS6/A
5-100
June 1983
-------
12
10-
Q ^
S 6
0)
cc
4-
• Cohort 1
O Cohort 2
A Cohorts 3-5
Dose-response data
is from Table 5-24.
Fit is by relative risk
model, heavy exposures
omitted.
0
I
8000
16000 24000
Cumulative Dose (yug/m3-years)
I
32000
r
40000
Figure 5.2. Relative risks and 90% confidence limits for data of Lee-Feldstein (1982).
5-101
June 1983
-------
8-
• - Cohort 1
O~ Cohort 2
A- Cohorts 3-5
6-
k = 2
O
O
O
4-
o
(A
2-
Dose-response data
is from Table 5-24.
Fit is by absolute risk
model, heavy exposures
omitted.
I
8000
I I
16000 24000
Cumulative Dose (Afg/m3- years)
32000
40000
Figure 5-3. Absolute risks and 90% confidence limits for data of Lee-Feldstein (1982).
5-102
June 1983
-------
0
I—1
CO
oo
1— >
en
i
j— J
o
CO
TABLE 5-25. SUMMARY OF QUANTITATIVE RISK ANALYSES
Exposed
Population
Anaconda
smelter
workers
ASARCO
smelter
workers
Dow pesticide
manufacture workers
Study and
Data Source
Lee-Feldstein
Table 5-24 (heavy
exposure omitted)
Higgins et al.
Table 5-24
Brown & Chu
Table 5-27
Enterline & Marsh
Table 5-21
(zero lag)
Enterline & Marsh
Table 1 (10-year
lag) 5-21
Ott et al.
Table 5-34 (high
exposure omitted)
Model
absolute risk
relative risk
absolute risk
relative risk
absolute risk
absolute risk
relative risk
absolute risk
relative risk
relative risk
k
1
2
1
2
1
2
1
2
1
1
2
1
2
1
2
1
2
1
2
Results
Carcinogenic
Potency (a')a
2.48(-7)
2.09(-11)
3.00(-4)
2.09(-8)
2.36(-7)
1.74(-11)
3.17(-4)
2.18(-8)
9.45(-16)
6.04(-7)C
1 43(-10)
4i6(-4)
1.01(-7)
8.85(-7)
2 Ol(-lO)
5.13(-4)
1.06(-4)
9.2(-4)
1.58(-7)
of Goodness-of-Fit Test
x2 (d.f.)
12.7(5)
60(5)
28(5)
79(5)
1.2(3)
10.3(3)
2.57(3)
15.4(3)
7.01(7)
5.5(4)
20.7(4)
11.6(4)
23.4(4)
7.0(4)
26.1(4)
14.5(4)
28.9(4)
5.0(7)
9-4(7)
p-value
0.025
0.00001
0.00004
0.00001
0.75
0.017
0.46
0.0015
0.41
0.24
0.0003
0.02
0.00011
0.14
0.00003
0.006
0.00002
0.66
0.23
K
"unit" risk"
2.80(-3)
lack of fit.
lack of fix.
lack of fit
4.90(-3)
1.05(-4)
4.03(-3)
lack of fit
1.25(-3)
6.81(-3)
lack of fit
5.44(-3)
lack of fit
7.60(-3)
lack of fit
lack of fit
lack of fit
1.36(-2)
7.68(-4)
Potencies are in different units, depending upon model used (see text), and consequently are not comparable.
Additional lifetime risk of respiratory cancer mortality from lifetime environmental exposure to 1 ug/m3 arsenic.
c6.04(E-7) means 6.04 x 10-7.
p-value of chi-square goodness-of-fit test is less than 0.01.
c
3
fD
CO
CO
-------
Specifically,
D1 = 4.56[(i-l) + 2.5] (10)
was used, which represents the cumulative exposure in ug/m3 resulting from a
constant exposure to ug/m3 from birth to the mid-point of the ith 5-year age
interval. The factor 4.56 is needed to account for the fact that the workers
in the occupational study used to estimate the carcinogenic potency of arsenic
were only exposed during work hours. Assuming that workers were exposed for
an average of 8 hours per day, 240 days per year, an environmental exposure to
1 ug/m3 for 1 year is equivalent to an occupational exposure to
(1 ug/m3)(24 hours/8 hours)(365 days/240 days) = 4.56 ug/m3 (11)
for 1 year.
5.2.1.4.2.4 The Higgins et al. (1982) study. Higgins et al. conducted
additional independent follow-up through 1977 of a sample of 1800 men from the
Anaconda smelter cohort studied by Lee and Fraumeni (1969). The sample in-
cluded all of the men classified in the heavy exposure category by Lee and
Fraumeni (1969), as well as a random sample of 20% of the remaining cohort.
There were 80 deaths from respiratory cancer in the sample. Expected numbers
were based upon the mortality rates of Montana white males, except for "all
respiratory diseases"; U.S. white males were the referenced population for the
latter category.
Higgins et al. also reviewed the industrial hygiene data and calculated
average concentrations for the period 1943-1965 for 18 departments. No
measurements were available for 17 departments, and average concentrations
were estimated for these. These estimates were coupled with work histories
013AS6/A 5-104 June 1983
-------
updated through 1978 to obtain exposure measures for each individual in the
study. Three types of individual exposure measures were considered: ceiling,
time-weighted average (TWA), and cumulative. Ceiling exposures were esti-
mates, in ug/m3, of the highest exposure a man experienced for 30 days or
more. TWA exposures were estimates, in units of ug/m3, of the time-weighted
average exposures during the period of employment. Cumulative exposures were
estimates of total exposure in units of ug/m3-years.
Higgins et al. investigated 5 combinations of follow-up and time period
during which exposure was assessed: I. Exoosure was assessed up to the date a
worker entered the study and follow-up was from entry into the study through
1978; II. Exposure was assessed up to 1964 and follow-up was also through
this date; III. Exposure was assessed through 1964 and follow-up was through
1978; IV. Exposure was assessed through 1964 and follow-up was from 1964
through 1978; V. Exposure was assessed through 1978 and follow-up was also
through 1978. These different methods were considered principally because of
the perceived difficulties of overlapping exposure and follow-up periods.
Thus, with methods I and IV, exposure and follow-up periods were disjoint,
whereas with methods II and V they coincided.
The analyses based upon ceiling exposures are not considered suitable for
quantitative risk assessment because it seems extremely unlikely that respira-
tory cancer risk would be a function of peak exposures for any 30-day period,
regardless of the other exposures that might have been experienced. This is
also the case with the TWA analyses, because the exposures were averaged only
over the period of employment, without regard to the duration of employment.
If either of these dose measures were appropriate, it would mean, for example,
3
that exposure to 500 ug/m for 1 month would produce the same risk as exposure
3
to 500 ug/m for 30 years—which seems highly unlikely.
013AS6/A 5-105 June 1983
-------
Thus, the analyses of Higgins et al. which appear to be most appropriate
for developing quantitative estimates are those based upon cumulative expo-
sure. This particular type of analysis was applied only to method V and
applied only in Higgins (1982). The results of this analysis for lung cancer
are listed in Table 5-26.
TABLE 5-26. RESPIRATORY CANCER MORTALITY 1938-1978 FROM
CUMULATIVE EXPOSURE TO ARSENIC FOR 1800 MEN WORKING AT
THE ANACONDA COPPER SMELTER3
Cumulative
Exposure
|jg/m3-years
0-500.
(250)D
500-2000
(1250)
2000-12000
(7000)
2; 12000
(16000)
Person-Years
of Observation
13845.9
10713.0
11117.8
9015.5
Observed
Deaths
4
9
27**
40**
Expected
Deaths
5.8
5.7
6.8
7.3
aFrom Higgins (1982), Table 6.
Numbers in parenthesis indicate assumed average exposures.
**
Significant at 0.01 level.
Information on the smoking habits of 80.6% of the 1800 men was obtained
from questionnaires administered directely to those still living and to close
friends or relatives of those who were deceased. Sixteen percent of the
smelter workers were "non-smokers" compared with 24-36% of U.S. males from
1955 through 1978. Thus it appears that the smelter workers smoked somewhat
more than the average U.S. male. However, no confounding was detected between
013AS6/A 5-106 June 1983
-------
arsenic exposure and smoking; 15.1% of those in the "heavy" exposure group
were non-smokers, versus 16.3% in the other exposure groups. Significant
increases in respiratory cancer were observed even among non-smokers exposed
to high levels of arsenic.
Development of risk estimates: The relative risks (observed/expected)
from Table 5-26 are graphed in Figure 5-4, and the absolute risks ([observed-
expected]/person-years) in Figure 5-5. Results of applying chi-square goodness-
of-fit tests of the relative- and absolute-risk models with k = 1 and k = 2
are recorded in Table 5-25. The maximum likelihood estimates of the car-
cinogenic potency parameter a' are also listed in Table 5-25. The maximum
likelihood fits of those models are graphed in Figures 5-4 and 5-5. The fits
for k = 1 are both excellent, with the absolute-risk model providing a slightly
better fit than the relative-risk model (p = 0.75 vs. p = 0.42). The fits for
k = 2 are much less adequate (p = 0.017 for the absolute-risk model and p = 0.004
for the relative-risk model).
The unit risks (defined as the additional risk of respiratory cancer
death from lifetime exposure to 1 ug/m3 airborne arsenic) obtained from the
absolute- and relative-risk models with k = 1 are also listed in Table 5-25.
These risks were estimated by applying (1) or (2), (8), and (9) with D.
based upon a constant exposure of 1 pg/m3. Specifically,
Di = (4.56)(72) (12)
was used, which represents the average lifetime cumulative exposure in ug/m3
resulting from a constant exposure to 1 ug/m3. Average lifetime exposure is
used because it seems most commensurate with the treatment of exposure by
Higgins et al.; in their analysis all of the person-years attributable to a
013AS6/A 5-107 June 1983
-------
7-
Dose-response data
is from Table 5-26.
Fit is by relative risk model.
4000 8000
Cumulative Dose
(jug/m3- years)
12000
16000
Figure 5-4. Relative risks and 90% confidence limits for data of Higgins (1982).
5-108
June 1983
-------
Dose response data
is from Table 5 26
Fit is by absolute
risk model
4000 8000 12000 16000
Cumulative Dose
(/vg/m3- years)
Figure 55. Absolute risks and 90% confidence limits for data of Higgins (1982)
5-109
June 1983
-------
single worker were placed into a single exposure category based upon total
lifetime exposure, and consequently person-years of observation were placed
into exposure categories according to exposures which had not yet occurred. It
would have been more appropriate for purposes of quantitative risk assessment
had exposures been related to each 5-year age interval (as was done in the
analysis of Enterline and Marsh, 1982) rather than to the total observation
period of an individual. The factor 4.56 converts from occupational to envi-
ronmental exposures and is explained at equation (11).
5.2.1.4.2.5 The Brown and Chu estimates from the Anaconda data.
Development of Risk Estimates. As noted by Whittemore (1977) and Day and
Brown (1980), the multi-stage theory for the carcinogenic process predicts
that the carcinogenic response is a function of the following factors:
(1) exposure rate
(2) duration of exposure
(3) age at initial exposure
(4) time since cessation of exposure.
Brown and Chu (1983a) discuss in detail the ways in which these factors
influence the age-specific carcinogenic rate at various stages of the car-
cinogenic process.
Using the updated Anaconda copper smelter workers cohort originally
studied by Lee and Fraumeni (1969) and recently extended through 1977 by
Lee-Feldstein (1982), Brown and Chu (1983b) concluded that airborne arsenic
most probably acted on a late stage of the carcinogenic process. As a result,
they hypothesized that the carcinogenic risk from arsenic exposure could be
quantified by assuming a multistage model in which only the penultimate stage
is affected by exposure. Under this assumption, the risk may be expressed in
the form
013AS6/A 5-110 June 1983
-------
r(d, to) = C[(d) + t' -t0 (13)
where d is the duration of exposure, t is the age at initial exposure, and C,
k are unknown parameters. The parameter C depends upon the exposure rate, and
the parameter k upon the time effect of exposure.
Brown and Chu (1983b) noted a deviation from this model on the part of
workers who left employment at the copper smelter before the age of 55. As a
result, the mortality experience of that group after leaving employment was
not included in the analysis.
In order to estimate the unknown parameters C and k, the basic mortality
data were arranged in the three-way table reproduced as Table 5-27. The three
classifications used in this table are as follows:
(1) Level of exposure, corresponding to Lee and Fraumeni (1969)--
classified into heavy, medium, and light exposure groups;
(2) Duration of employment, classified into the following five sub-
groups; 0-9, 10-19, 20-29, 30-39, and 40+ years;
(3) Age at initial employment, classified into the following five sub-
groups; 20, 20-29, 30-39, 40-49, and 50+ years.
For each of the 3 x 5 x 5 = 75 cells in the table, the following three
variables were given:
Obs = observed number of respiratory cancer deaths;
Exp = expected number of respiratory cancer deaths (based upon the U.S.
white male age-specific calendar-time-specific respiratory cancer
mortality rates); and
Pyr = person-years of observation.
A single individual could supply information for more than one cell as
his duration of employment increased over the follow-up period. The person-
year weighted average duration of employment, and age at initial employment,
were calculated for each cell.
013AS6/A 5-111 June 1983
-------
TABLE 5-27. OBSERVED AND EXPECTED LUNG CANCER DEATHS AND
PERSON-YEARS BY LEVEL OF EXPOSURE, DURATION OF EMPLOYMENT, AND
AGE AT INITIAL EMPLOYMENT
Age at
Initial
Employment
0-9
Duration
10-19
of Employment (years)
20-29
30-39
40+
High Exposure Level Group
<20 Obs
Exp
Pyr
20-29 Obs
Exp
Pyr
30-39 Obs
Exp
Pyr
40-49 Obs
Exp
Pyr
50+ Obs
Exp
Pyr
Medium Exposure
<20 Obs
Exp
Pyr
20-29 Obs
Exp
Pyr
30-39 Obs
Exp
Pyr
40-49 Obs
Exp
Pyr
50+ Obs
Exp
Pyr
0
0.001
206
0
0.008
624
0
0.030
398
0
0.083
210
0
0.066
78.0
Level Group
0
0.010
1801
0
0.035
2636
0
0.167
1939
0
0.167
1190
1
0.262
295
0
0.009
408
0
0.051
637
0
0.077
207
0
0.054
80.0
0
0.027
23.2
0
0.039
1763
0
0.118
1622
0
0.473
1137
0
0.414
448
0
0.076
71.2
0
0.065
588
2
0.164
495
3
0.106
155
0
0.034
49.1
0
0.0
0.0
1
0.171
1500
2
0.331
1099
1
0.329
438
1
0.098
98.9
0
0.011
14.5
3
0.249
499
0
0.277
308
0
0.053
59.1
0
0.007
6.88
0
0.0
0.0
4
0.591
1206
4
0.717
951
3
0.161
194
3
0.010
12.1
0
0.0
0.0
0
0.193
172
2
0.082
64.4
0
0.001
0.86
0
0.0
0.0
0
0.0
0.0
1
0.597
579
7
0.514
654
0
0.045
68.2
0
0.0
0.0
0
0.0
0.0
013AS6/A
5-112
June 1983
-------
TABLE 5-27 (Continued)
Age at
Initial
Employment
Low Exposure Level
<20 Obs
Exp
Pyr
20-29 Obs
Exp
Pyr
30-39 Obs
Exp
Pyr
40-49 Obs
Exp
pyr
50+ Obs
Exp
Pyr
0-9
Group
0
0.056
8524
0
0.115
9951
0
0.390
5218
2
1.29
3703
3
1.62
1945
Duration
10-19
0
0.117
5249
0
0.334
4724
3
0.802
2218
1
1.18
1319
2
0.385
371
of Employment (years)
20-29
1
0.478
4038
2
0.892
2965
1
0.937
1364
1
0.344
386
0
0.041
65.4
30-39
1
1.59
3175
5
1.74
2117
0
0.662
715
1
0.035
52.7
0
0.0
0.0
40+
3
1.57
1376
6
0.796
834
1
0.062
74.6
0
0.001
2.00
0
0.0
0.0
Source: Brown and Chu (1983a).
Assuming that age at initial exposure is equivalent to age at initial
employment, and that duration of employment and exposure are equivalent, Brown
and Chu (1983c) fitted equation 13 to the data in Table 5-27. They used the
maximum likelihood method, assuming a binomial distribution where Obs is the
number of positive responses, Pyr is the sample size, and the rate of response
is p = Exp/Pyr + r(d,t ), where d,t are the averages for each cell. Using
this approach, the value for k is estimated to be 6.8, and c = .603, 1.42,
-13
1.74, x 10 for the light, medium, and heavy exposure categories, respec-
tively.
013AS6/A
5-113
June 1983
-------
Brown and Chu (1983c) did not attempt to give an exposure rate estimate
to the heavy, medium, and light exposure groups of Lee and Fraumeni, (1969).
One reason for this was that "heavy" and "medium" were defined as "having
worked at least one year in a heavy or medium exposure area." The "total time
worked" was not necessarily an indication of the total time worked in a heavy
or medium exposure area. As a result, the use of the exposure rate in the
areas defined as medium or heavy would tend to overestimate the true average
exposure over an individual's working history. This bias did not exist for
those in the light exposure group, since almost all of their working time was
spent in light exposure areas. In addition, these low environmental exposures
are of greater utility in estimating risks.
As a result of these factors, only the light exposure group was used to
obtain a dose response model. In this group, Brown and Chu (1983c) estimated
that the respiratory cancer rate for an individual first exposed at age t for
a duration of d years would be
r(d,to) = .603 x 10"13 [(d + to)5'8 - to5'8]. (14)
Only limited information exists concerning the time-weighted exposure of
workers in the light exposure areas. Arsenic concentrations in several light
exposure areas, as given in a NIOSH criteria document (1975), are shown in
Table 5-28.
In the absence of information to the contrary, it is assumed that the
person-hours spent in each area are equal. Thus an estimate of the time-
weighted average for workers in the light exposure category is
1/3 x .7 + 1/3 x .17 + 1/3 x .004 = .291 mg As/m3.
013AS6/A 5-114 June 1983
-------
TABLE 5-28. ARSENIC EXPOSURES: 1965 SMELTER SURVEY ATMOSPHERIC ARSENIC
CONCENTRATIONS (mg/As/m3)
"Heavy exposure area" as classified by Lee and Fraumeni
Arsenic Roaster Area
0.10 0.20
0.10 0.22
0.10 0.25
0.10 0.35
0.10 1.18
0.10 5.00
0.17 12.66
Mean: 1.47
Median: 0.185
"Medium exposure areas" as classified by Lee and Fraumeni
Reverberatory Area
0.03 0.93
0.22 1.00
0.23 1.27
0.36 1.60
0.56 1.66
0.63 1.84
0.66 1.94
0.76 2.06
0.78 2.76
0.78 3.40
0.80 4.14
0.83 8.20
Treater Building and Arsenic Loading
0.10 0.48
0.10 0.62
0.10 3.26
0.11 7.20
"Light exposure areas"
Copper Concentrate Transfer System
0.25
0.65
1.20
Samples from Flue Station
0.10
0.24
Reactor Building
0.001 0.003
0.002 0.009
0.002 0.010
0.002
Mean: 1.56
Median: 0.88
Mean: 1.50
Median: 0.295
as classified by Lee and Fraumeni
Mean: 0.70
Median: 0.65
Mean: 0.17
Median: 0.17
Mean: 0.004
Median: 0.002
Source: Table X-3, NIOSH Criteria Document (1975).
013AS6/A 5-115
June 1983
-------
Under the linear assumption, equation 14 may be expressed in terms of mg
As/m3 working exposure by dividing by .291, which gives the result
r(d,to) = 2.07 x 10"13 [(d+t0)5-8 - to5'8]. (15)
In this case, exposure is expressed in mg As/m3 per 8-hr working day. To
change the relationship so that it expresses the risk due to a lifetime of
continuous exposure to I ug As/m3, we assume 240 days worked per year,
one mg As/m3 on the job gives the same cumulative exposure as 103 x
1/3 x 240 = 219 ug As/m3 continuous exposure.
365"
The age-specific rate due to a continuous 1 ug As/m3 exposure is obtained
by substituting t = 0 and d = t = age into equation (15) and dividing by 219
to arrive at the correct number of exposure units. This gives the result
r(t) = 9.45 x 10"16 t5'8. (16)
The unit risk is approximately equivalent to the risk of induced respira-
tory cancer in the median life span. Based upon 1976 U.S. vital statistics,
the median life span is 76.2 years, so that the unit risk is expressed approxi-
mately as
9 45
P 1 Jo75'2 9.45 x 10"16 t5'8 = -- (76.2)6'8 x 10"16 - 8.71 x 10"4. (17)
An additional approximation consistent with the previous unit calcula-
tions is obtained by assuming that
r(t) = 9.45 x 10"16 rt- + t.-l-,5.8 t. , < t
-------
where t. are the ages at the interval boundaries given in U.S. vital statis-
J
tics records. This assumes that the age-specific death rate due to the
exposure is constant throughout the interval and equal to the true value at
the midpoint of the interval. Under this approximation, using 1976 vital
-3
statistics, the unit risk is estimated to be P ^ 1.25 x 10 .
Evaluation of Goodness-of-Fit. It is desirable to assess whether the data for
the low-exposure group is consistent with the model utilized to estimate the
unit risk. However, two factors tend to create a situation that would de-
crease this goodness-of-fit and bias the results. First, the exact values for
each cell of d, t are presently not available. Second, the value of k was
determined on the basis of all three exposure groups, and does not give as
good a fit as would be obtained using the low-exposure group alone.
Brown states (personal communication, 1983) that the exact values of d,tQ
are very close to the midpoint of the interval, and that the values of k
appear to be statistically consistent between exposure groups. Thus, distor-
tions of the data because of the use of midpoint values and average k, al-
though inevitable, are not appreciable.
The expected number of cases in each cell are calculated using the rela-
tionship
E = Exp + Pyr x .603 x 10"13 [d + tQ)5-8 -tQ5'8], (19)
in which Exp and Pyr are taken from Table 5-27 and d,t are the midpoints of
the intervals. These results are shown in Table 5-29. A standard chi-square
goodness-of-fit test is then run, resulting in a chi-square value of X^ =
13.85 with 23.2 = 21 degrees of freedom and an associated p-value of .88.
Unfortunately, due to the low expected number of cases in many of the cells,
the X2 approximation is of questionable validity for this situation.
013AS6/A ' 5-117 June 1983
-------
TABLE 5-29. OBSERVED AND EXPECTED NUMBER OF RESPIRATORY CANCER
DEATHS FOR EACH CELL IN THE LOW-EXPOSURE GROUP OF TABLE 5-27
d
to 5 15 25 35 45
18
25
35
45
0 0 1
.088 .314 1.;
1 3
>0 3.504 3.836
00 256
.258 .858 2.145 4.358 3.321
03 101
.723 1.641 2.556 2.791 .497
21 110
2.023 2.508 1.428 .371 .026
32 0
55
2.582 1.234 .418
Xli = 13.85, p = .88
To obtain a more stable approximation, cells with low frequency that are
as close as possible to each other are usually combined. It is important to
have some criteria for combining the data that do not depend upon inspection
of the data itself. Two methods of combining the data are used here. The
first is across columns (duration exposed), so that the maximum number of
cells are obtained, with the constraints that combined cells must have at
least three expected cases, and that all cells combined are consecutive within
a row. The second approach uses the same technique within a column (age first
exposed). The results are shown in Tables 5-30 and 5-31 respectively, giving
chi-square values of 7.01 and 7.61, with p-values of .41 and .38. Thus the
assumed model is shown to be consistent with the observed low-exposure data.
013AS6/A
5-118
June 1983
-------
TABLE 5-30. CELLS FROM TABLE 5-29 COMBINED WITHIN ROWS TO
OBTAIN CELLS WITH THREE OR MORE EXPECTED RESPIRATORY CANCER DEATHS
d
to 5 15
18
25
35
45
55
25
2
3.261
4
4.920
5
4.234
35 45
2 3
5.106 3.836
5 6
4.358 3.321
1
3.288
5
6.356
X2 = 7.01, p = .41
TABLE 5-31. CELLS FROM TABLE 5-29 COMBINED WITHIN COLUMNS TO
OBTAIN CELLS WITH 3 OR MORE EXPECTED RESPIRATORY CANCER DEATHS
d
to 5 15
18
25
35
45
5 6
55 5.674 6.555
25 35 45
1 3
3.504 3.836
3 5
3.345 4.358
1 7
3.162 3.844
2
4.402
X2 = 7.61, p = .38
013AS6/A
5-119
June 1983
-------
5.2.1.4.2.6 The Enterline and Marsh (1982) study. This study included all
men (2802 in all) employed at the Tacoma, Washington copper smelter for a year
or more during 1940-1964. Their mortality experience was observed through
1976. The study involved over 70,000 person- years of observation, and 104
deaths from cancer of the respiratory system were recorded (Table 5-32).
Respiratory cancer deaths had an SMR of 189.4, which was significantly in-
creased at the 1% level. Expected deaths for Table 5-32 were based upon U.S.
white male mortality rates. The respiratory cancer SMR increases to 198.1
when Washington State mortality rates are applied.
Enterline and Marsh estimated individual exposures to airborne arsenic
using individual work histories, urine arsenic measurements, and an estimated
correlation between exposure to airborne arsenic and resulting levels of
arsenic in urine. Average urine arsenic levels were available by department
for the years 1948-52, 1973, 1974, and 1975. Linear interpolations were used
to estimate levels between 1952 and 1973. Levels during 1949-1952 were as-
sumed to hold prior to that time. By coupling these data with employee work
histories, Enterline and Marsh estimated individual cumulative exposures for
various times in units of ug-years/A urinary arsenic.
Pinto et al. (1977) compared airborne concentrations of arsenic with
urinary arsenic levels for 24 workers wearing personal air samplers for 5
successive days. A regression analysis of these data showed a highly signifi-
cant linear correlation between airborne and urinary arsenic (p < 0.01).
Average airborne arsenic in units of ug/m3 was estimated to be 0.304 times
average urinary arsenic levels in units of ug/£.
013AS6/A 5-120 June 1983
-------
TABLE 5-32. OBSERVED DEATHS AND SMRs FOR 2802 SMELTER WORKERS
WHO WORKED A YEAR OR MORE 1940-64, FOLLOWED THROUGH 1976, BY CAUSE OF DEATH
Cause of death (7th revision code)
All causes of death
Tuberculosis (001-019)
Malignant neoplasms (140-148)
Buccal cavity and pharynx (140-148)
Digestive organs & peritoneum (150-159)
Esophagus (150)
Stomach (151)
Large intestine (153)
Rectum (154)
Biliary passages and liver (155-156)
Pancreas (157)
All other digestive organs (residual)
Respiratory system (160-164)
Larynx (161)
Bronchus, trachea, and lung (162-163)
All other respiratory system (residual)
Prostate (177)
Testes and other genital (178-179)
Kidney (180)
Bladder and other urinary organs (181)
Malignant melanoma of skin (19)
Eye (192)
Central nervous system (193)
Thyroid gland (194)
Bone (196)
Lymphatic & haematopoietic (200-205)
Lymphosarcoma and reticulosarcoma (200)
Hodgkins' disease (201)
Leukemia and aleukemia (204)
Other lymphopoietic tissue (202, 203, 205)
Other malignant neoplasms (residual)
Benign neoplasms (210-239)
Diabetes mellitus (260)
Stroke (333-334)
Heart disease (400-443)
Hypertension without heart disease (444-447)
Nonmalignant respiratory disease (470-527)
Influenza and pneumonia (480-493)
All other respiratory diseases (residual)
Ulcer of stomach and duodenum (540-541)
Cirrhosis of liver (581)
Chronic nephritis (592)
External causes of death (800-998)
Accidents (899-962)
Suicides (963, 970-979)
Other external causes (residual)
Other causes of death (residual)
Unknown causes
TB ; — frm me • — ;r-= — — — — — — — — — — — ^_— — — ^— — ___
Observed
Deaths
1061
4
231
7
65
3
17
21
9
3
11
1
104
2
100
2
11
1
6
4
0
1
3
0
2
17
4
2
6
5
10
2
12
91
412
1
60
24
36
7
22
6
81
61
17
3
85
47
SMR
103.2
27.6**
123.6**
110.7
108.9
66.2
122.1
120.4
122.4
64.1
106.0
71.6
189.4**
67.7
194.9**
305.0
79.0
92.6
133.3
63.0
—
492.7
59.8
—
175.0
93.8
93.2
83.9
78.7
130.4
82.3
78.6
84.8
111.4
92.5
18.8
108.6
92.9
122.4
75.5
101.9
87.5
94.2
100.6
84.8
56.2
86.1
--
p <.05, ** p <.01
Source: Enter!ine and Marsh (1982).
013AS6/A 5-121 June 1983
-------
To investigate dose-response, Enter!ine and Marsh divided the total
person-years of observation into 5 groups by cumulative arsenic exposure (0
lag), and also by cumulative arsenic exposure up to 10 years prior to the year
of observation (10-year lag). In this type of analysis, as a worker continues
to be exposed to arsenic, he or she will contribute person-years to progres-
sively higher exposure categories. The numbers of respiratory cancer deaths
and corresponding expected numbers for each of these groups are given in Table
5-33. In this table, urinary arsenic levels provided by Enterline and Marsh
have been converted to airborne exposures in ng/m3-years, using the factor
0.304 estimated by Pinto et al. (1977). The observed numbers of cancers are
all significantly increased at the higher exposure levels.
Although the Enterline and Marsh (1982) study is not as large as that of
Lee-Feldstein (1982), it does involve a sizable number of respiratory cancer
deaths (104). Workers were followed for an extended period—an average of 25
years per individual. Several features of the analysis render it more amen-
able to quantitative risk estimation than the analysis used by Lee-Feldstein.
Enterline and Marsh made estimates of individual exposure histories, whereas
Lee-Feldstein did not. The type of dose-response analysis used by Enterline
and Marsh is also more suitable for quantitative risk estimation. The expo-
sure estimates based on a 10-year lag probably yield a more realistic dose-
response than those that do not utilize a lag; because the latency period for
respiratory cancer is generally greater than 10 years (cf. Doll and Peto,
1978), exposure during the last 10 years prior to observation would not be
expected to affect respiratory cancer mortality.
013AS6/A 5-122 June 1983
-------
By applying urinary arsenic measurements made during the years 1948-52 to
earlier years, Enter!ina and Marsh probably underestimated exposures prior to
1948. This would result in an overestimate of the carcinogenic potency of
arsenic. A calculation by Enterline and Marsh of SMRs by both year of hire
and cumulative exposure indicates that workers in a given cumulative exposure
category tend to have at least roughly comparable SMRs irrespective of the
year of hire. This suggests that exposure estimates for earlier years are not
greatly in error. However, further investigation of this problem would be
useful.
Because smoking is also an important risk factor for respiratory cancer,
it would have been helpful if data on smoking habits had been available for
analysis. Pinto and Enterline (undated) report on smoking histories obtained
in 1975 from 550 active employees at the Tacoma smelter. Of these employees,
59.6% were active smokers, compared to 45.4% in 1970 for U.S. males aged
21-64. If this excess of smokers holds in general for the smelter workers,
then a small fraction of the excess in respiratory cancer could have been due
to smoking.
Development of risk estimates: The data from Table 5-33 were used for
quantitative risk assessment. The relative risks (observed/expected) from
this table are graphed in Figures 5-6 and 5-7, and the absolute risks
([observed- expected]/person-years) in Figures 5-8 and 5-9. Although there is
no clear trend of increasing SMRs with increasing exposures, such a trend is
present for absolute risk. Results of applying chi-square goodness-of-fit
tests of the relative- and absolute-risk models with k = 1 and k = 2 are
recorded in Table 5-25. The maximum likelihood estimates of the carcinogenic
013AS6/A 5-123 June 1983
-------
TABLE 5-33. DATA FROM TABLE 8 OF ENTERLINE AND MARSH (1982)
WITH PERSON-YEARS OF OBSERVATION ADDED
Cumulative Exposure3 Person-Years . Observed Expected
ug/m3-years of Observation Deaths Deaths
91.8
263
661
1381
4091
0 Lag
10902
21642
14623
13898
9398
8
18
21
26
31
4.0
11.0
10.3
14.1
12.7
10-Year Lag
91.8
263
661
1381
4091
27802
16453
11213
9571
5423
10
22
26
22
24
6.4
12.5
11.5
12.4
9.7
Exposures are in ug/m3-years estimated by the formula (I |jg/l-years) (0.304)
where I is mean urinary exposure index from Enterline and Marsh (1982) Table 8
and 0.304 is the relation between urinary and airborne arsenic estimated by
Pinto et al. (1977).
Furnished by Dr. Enterline (personal communication).
013AS6/A 5-124 June 1983
-------
3-
w
E
0)
to
0)
DC
Dose-response data
is from Table 5-33.
Fit is by absolute
risk model.
o-
1000 2000 3000
Cumulative Dose (yug/m3- years)
4000
Figure 5-6. Relative risks and 90% confidence limits for zero-lag data of Enterline
and Marsh (1982).
5-125
June 1983
-------
3 ~"
—
rr
Dose response data
is from Table 5 33
Fit is by relative
risk model
0-
1000
2000
3000
4000
Cumulative Dose (/vg/m3-years)
Figure 57. Relative risks and 90% confidence limits for 10 year lag data of Enterline
and Marsh (1982).
5-126
June 1983
-------
o
o
o
If)
E
0)
Dose-response data
is from Table 5-33.
Fit is by absolute
risk model.
0
1000
2000
3000
4000
Cumulative Dose (>L/g/m3- years)
Figure 5-8. Absolute risks and 90% confidence limits for zero-lag data of Enterline
and Marsh (1982).
5-127
June 1983
-------
Q)
O
(fi
Dose-response data
is from Table 5 33
Fit is by relative
risk model
1000 2000 3000
Cumulative Dose (pg/m3- years)
I
4000
Figure 5-9. Absolute risks and 90% confidence limits for 10 year lag data of Enterline
and Marsh (1982).
5-128
June 1983
-------
potency parameter a1 are also listed in Table 5-25. The maximum-likelihood
fits of these models are graphed in Figures 5-6 through 5-9. The quadratic
fit (k = 2) is poor for both the absolute- and relative-risk models with
either 0 lag or 10-year lag data (p less than 0.001 in each case). The linear
fits to the relative risk models are also relatively poor (p = 0.02 for the 0
lag data and 0.006 for the 10-year lag data). On the other hand, the linear
fits of the absolute risk model are all acceptable (p = 0.24 for 0 lag data
and 0.14 for 10-year lag data).
The unit risks (additional risks of respiratory cancer death from life-
3
time exposure to 1 |jg/m airborne arsenic) obtained from each of the fits for
which the chi-square p-value is 0.01 or higher, are also listed in Table 5-25.
These risks were estimated by applying (1) or (2), (8), and (9) with D. based
3
upon a constant exposure of 1 ug/m . Specifically,
D. = 4.56[5(i-l) + 2.5] (17)
was used for the 0 lag data, and
D. = 4.56[5(i-l) - 7.5] (18)
was used for the 10-year lag data. These D. represent the cumulative exposure
3 3
in ug/m resulting from a constant exposure to 1 ug/m from birth to the
mid-point of the ith 5-year age interval. The factor 4.56 converts from
occupational to environmental exposures, and is explained at equation (11).
5.2.1.4.2.7 The Ott et al. (1974) study. Ott et al. (1974) compared the
age-specific death patterns of 174 decedents exposed to arsenic in the produc-
tion of pesticides to those of 1809 decedents who were not exposed to arseni-
cal s. By fitting the death patterns of the unexposed decedents to a mathe-
matical function, an estimate was obtained of the probability that a death at
a particular age and during a particular epoch was due to respiratory cancer.
013AS6/A 5-129 June 1983
-------
This function was used to estimate expected respiratory cancer deaths in
various exposure categories for the exposed decedents. Cumulative exposures
were estimated for exposed decendents, using work histories and estimates of
average exposures in various jobs. The exposure estimates were made by indus-
trial hygienists familiar with the processes. Expected cancer deaths were
compared with observed to obtain observed- to-expected ratios. Table 5-34
shows the results of Ott et al.'s dose-response analysis. The data in this
table are all reproduced directly from Table 4 of Ott et al. (1974), except
for the cumulative exposures. Average total exposures in mg provided by Ott
et al. were converted to cumulative exposures in pg/m3 years by multiplying by
the factor
1000 ijg/mg . (19)
(4 m /day)(21 days/mo)(12 mo/year)
The values included in this factor are not in doubt because use of the factor
simply negates the calculation of total exposure made by Ott et al.
Decedent studies such as this are more subject to bias then prospective
studies such as those of Lee-Feldstein (1982) and Enter!ine and Marsh (1982).
If, for example, in some age category arsenic exposure increased the mortality
from some other disease in addition to respiratory cancer, an analyis of
decedents might show an artificially low effect of arsenic upon respiratory
cancer for this age group (because there might be an artificially large number
of total deaths). It is also of some concern that Ott et al. did not clearly
describe how the study cohort was defined.
013AS6/A 5-130 June 1983
-------
TABLE 5-34. DATA FROM TABLE 4 OF OTT ET AL. (1974)
Cumulative Exposure
ug/m3-years
41.8
125
250
417
790
1544
3505
6451
29497
Observed
Deaths
1
2
4
3
3
2
3
5
5
Expected
Deaths
1.77
1.01
1.38
1.36
1.70
0.97
0.77
0.79
0.72
Exposures are in ng/m3-years estimated by:
d mg x 1000 ug/mg
4 m3/day 21 days/month 12 months/year
where d is average total exposure from Table 4 of Ott et al.
This study involved primarily short-term exposures, as less than 25% of
the decedents had worked with arsenicals for more than one year. Thus, this
study is less appropriate for estimating risks from lifetime environmental
exposure than a comparable study involving longer exposures. The study also
was quite small; only 28 respiratory cancer deaths occurred among exposed
decedents.
Development of risk estimates: The dose-response data in Table 5-34 were
used in an assessment of risk. Because of the nature of the study, only a
relative risk model could be applied to these data. The dose-response for
relative risk is graphed in Figure 5-10. The response in the most highly
exposed group falls far below that predicted by the lower-dose data, and is
omitted from Figure 5-10. This is possibly due to the fact that some of the
013AS6/A 5-131 June 1983
-------
£86L
Relative Risk
3; 31
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n
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more highly exposed workers wore respirators. Because of this shortfall in
response, and also because the exposures to this group were the furthest from
the low-level environmental exposures of interest, the data from the highest
exposure group were omitted from the analysis.
Results of applying chi-square goodness-of-fit tests of the relative-risk
model with k = 1 and k = 2 are listed in Table 5-25. The maximum-likelihood
estimates of the carcinogenic potency parameter a1 are also listed in this
table. The maximum-likelihood fits are graphed in Figure 5-10. Both of these
fits are acceptable (p = 0.66 for k = 1 and p = 0.23 for k = 2), although the
data appear to be more linear than quadratic. It should be kept in mind that
the sample size was quite small in this study, and consequently a wide range
of curve shapes would probably provide an acceptable fit.
The risk estimation method described in the previous section is based
upon the life table method of analysis, and does not seem particularly appro-
priate for a decedent analysis. Because the method employed by Ott et al.
seems to estimate a relative probability of respiratory cancer death, it was
decided to estimate the extra lifetime probability of respiratory cancer death
3
from lifetime exposure to d ug/m airborne arsenic, using the expression
P0(l + a'[(72)(4.56)d]k) - PQ - PQa'[(72)(4.56)]k. (20)
Here PO is the lifetime probability of respiratory cancer mortality given by
(8), and is equal to 0.0451 if 1976 U.S. mortality rates are used. The factor
72 represents life expectancy in the U.S. in years. The factor 4.56 converts
from occupational to environmental exposures, and is explained at equation
(11). Thus, the term in the square brackets in (20) represents the average
3
total exposure over a life span in ug/m years, which is the same as the
measure used in estimating the potency a1.
013AS6/A 5-133 June 1983
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5.2.1.4.2.8 Discussion. Table 5-25 summarizes the fits of both absolute- and
relative-risk models, with either k = 1 or k = 2, to dose-response data from 4
different studies. Table 5-25 also displays the carcinogenic potencies a1.
It should be noted that the potencies estimated from different models are in
different units, and are therefore not comparable.
In every case, a linear model (k = 1) fitted the data better than the
corresponding quadratic model (k = 2). In every case but two, the fits of the
quadratic model could be rejected at the 0.01 level. The two exceptions
involved the two smallest data sets (Higgins et al. absolute risk, and Ott et
al.) and in the former case the fit was very marginal (p = 0.017). On the
other hand, for each data set a linear model provided an adequate fit. Also,
in every case, an absolute-risk linear model fit the data better than the
corresponding relative-risk linear model. The p-values for the fits of the
absolute-risk linear model ranged from 0.025 to 0.75.
The estimated unit risk is presented for each fit for which the chi-
square goodness-of-fit p-value is greater than 0.01. The unit risks derived
from linear models--8 in all—range from 0.0013 to 0.0136. The largest of
these is from the Ott et al. study, which probably is the least reliable for
developing quantitative estimates, and which also involved exposures to penta-
valent arsenic, whereas the other studies involved trivalent arsenic. The
unit risks derived from the linear (k = 1) absolute-risk models are considered
to be the most reliable; although derived from 5 sets of data involving 4 sets
of investigators and 2 distinct exposed populations, these estimates are quite
consistent, ranging from 0.0013 to 0.0076.
To establish a single point estimate, the geometric mean for data sets is
obtained within distinct exposed populations, and the final estimate is taken
to be the geometric mean of those values. This process is illustrated in
Table 5-35.
013AS6/A 5-134 June 1983
-------
_ o
The final estimate is 4.29 x 10 , where exposure is in ug/m3 of continu-
ous exposure. Based upon an assumed 20m tidal volume of air and a 30% ab-
_3
sorption rate, this amounts to a unit risk of 4.29 x 10 ~ (.3 x 20 x .001/70)
= 50.1 in units of mg/kg absorbed dose per day.
TABLE 5-35. COMBINED UNIT RISK ESTIMATES
FOR ABSOLUTE-RISK LINEAR MODELS
Geometric
Mean Unit Final Estimated
Exposure Source Study Unit Risk Risk Unit Risk
-3
Anaconda smelter Brown & Chu 1.25 x 10 , ~
Lee-Feldstein 2.80 x 10"^ 2.56 x 10 ,,
Higgins 4.90 x 10 6 4.29 x 10 5
ASARCO smelter Enter!ine & ,
Marsh 6.81 x 10 , ,
7.60 x 10 J 7.19 x 10 ^
Although the estimates derived from the various studies are quite consis-
tent, there are a number of uncertainties associated with them. The estimates
were made from occupational studies that involved exposures only after employ-
ment age was reached. In estimating risks from environmental exposures through-
out life, it was assumed, through either the relative-risk model (1) or the
absolute- risk model (2), that the increase in the age-specific mortality
rates of lung cancer was a function only of cumulative exposures, irrespective
of how the exposure was accumulated. Although this assumption provides an
adequate description of all of the data, it may be in error when applied to
exposures that begin very early in life. Similarly, the linear models pos-
sibly are inaccurate at low exposures, even though they provide excellent
descriptions of the experimental data.
013AS6/A 5-135 June 1983
-------
The risk assessment methods employed were severely constrained by the
fact that they were based only upon the analyses performed and reported by the
original authors—analyses that had been performed for purposes other than
quantitative risk assessment. For example, although other measures of expo-
sure might be more appropriate, the analyses were necessarily based upon
cumulative dose, since that was the only usable measure reported. Given
greater access to the data from these studies, other dose measures, as well as
models other than the simple relative-risk and absolute-risk models, could be
studied. It is possible that such wide analyses would indicate that other
approaches are more appropriate than the ones applied here.
5.2.1.4.3 Unit risk for water. The best data available for making quantita-
tive cancer risk estimates for ingestion of arsenic in water are the data
collected by Tseng et al. (1968). They surveyed a stable population of 40,421
individuals who lived in a rural area along the southwest coast of Taiwan and
who were known to have consumed drinking water containing arsenic. The
occurrences of skin cancer among this population, and the arsenic concentra-
tions in their drinking water, were measured. Since the population was stable,
the study can be viewed as a lifetime feeding study, and the data may be used
to predict the lifetime probability of skin cancer caused by the ingestion of
arsenic.
A model estimating the cancer rate as a function of drinking water arse-
nic concentration was generated using information from the above study in its
published form, which is a summary of data collected by the investigators. If
the original data had been available, a more exact mathematical analysis would
have been possible.
013AS6/A 5-136 June 1983
-------
Doll (1971) has suggested that the relationship between the incidence of
some site-specific cancers, age, and exposure level of a population may be
expressed as:
I(x,t) = kBx"^'1 (21)
where x is the exposure level (which can be measured by the water concentra-
tion in ppm), t is the age of the population, and B, m, k are unknown para-
meters.
However, the data collected by Tseng et al. (1968) was obtained at one
point in time, and since skin cancer has only a marginal effect on the death
rate, the obtained rates may be viewed more accurately as the probability of
having contracted skin cancer by time t. The relationship between this prob-
ability, often referred to as the cumulative probability density or prevalence
F(x,t), and the incidence or age-specific or hazard rate, may be expressed as:
F(x,t) = 1 - exp [-/oKx,s) ds]. (22)
Utilizing equation (21) as the form of the incidence rate, the prevalence
may be expressed as
F(x,t) = 1 - exp (-Bxmtk), (23)
which is a Weibull distribution.
In Table 5-36, adapted from information in Tseng, et al. (1968), estimates
are given of F(x,t) for different age and water concentration groupings for
males. The prevalence for females is less than for males, and therefore is
not used to estimate risk.
013AS6/A 5-137 June 1983
-------
To use this data, specific values for x and t had to be obtained for the
intervals. Where the intervals were closed, the midpoint was utilized. For
the greater than 0.6 ppm group, the midpoint between 0.6 and the greatest
recorded value, 1.8, was taken, resulting in 1.2 ppm. For age 60 or greater,
a value of 70 was utilized somewhat arbitrarily, being the same increase over
TABLE 5-36. AGE-EXPOSURE-SPECIFIC PREVALENCE RATES FOR SKIN CANCER
Exposure
in ppm3
0 - .29
(0.15)
0.30 - 0.59
(0.450)
>0.6
Tl.2)
Source: Tseng
20-39
(30)
0.0013
0.0043
0.0224
et al. (1968).
AGE
40-59
(50)
0.0065
0.0477
0.0983
>60
T70)
0.0481
0.1634
0.2553
aRange given by authors. Midpoint is in parentheses.
the lower level as that in the other two age intervals. The values for (x,t)
to relate to the prevalence estimates are shown in parentheses in Table 5-36.
From equation (23) it follows that
= ln(B) + m ln(x) + k ln(t), (24)
which is multiple-linear in form. Estimating the parameters by the usual
least-square techniques, the following relationship is obtained:
ln( - ln[l - F(x,t)]) = 17.548 + 1.192 ln(x) + 3.881 ln(t), (25)
013AS6/A 5-138 June 1983
-------
which is an excellent fit, having a multiple correlation coefficient of 0.986,
and a standard error on the exposure regression m of .138.
Equation (25) may be expressed as
F(x,t) = l-exp-[2.429 x 10*8(X1'192)(t3-881)]
i 192
= l-exp-[X H(t)] (26)
If the parameter m = 1.192 were in fact equal to 1, then for a given value of
t, equation (26) would be "one-hit" in form.
To test this hypothesis (i.e., Ho: m = 1) the student "t" test is used,
giving the result:
1.192-1
6 0.138
which is not significant at the 0.1 level. Thus, there is insufficient evi-
dence to reject the hypothesis that the dose-response relationship is "one-hit"
even at the 0.1 level. However, a quadratic model would be rejected at the
p<.001 level.
Fixing m = 1, the following relationship is obtained:
F(x,t) = 1 - exp[-g(t)x]. (27)
013AS6/A 5-139 June 1983
-------
Transforming this equation to its linear form (as in equation 23) and obtain-
ing the least-square linear estimates of B and v, it is found that:
g (t) = exp(-17.5393) t3'853, where B = 2.41423 x 10"8, k = 3.853.
The data used to obtain these estimates are shown in Table 5-37, and the
goodness-of-fit is illustrated in Figure 5-11.
The function
F(x,t) = l-exp[-2.41423 x 10"8 x t3'853], (28)
is the probability of contracting skin cancer by age t, given that an indi-
vidual had a life-time exposure to x ppm in his drinking water (and lived
until age t).
To obtain a unit risk estimate, lifetime risk is assumed to be approxi-
mately equal to the risk to the median life span in the absence of competing
risk. The unit risk is thus obtained by substituting x = 1 and t = 76.2 (the
median U.S. life span based upon 1976 vital statistics data) into equation
(28). This gives the result
P(l) - l-exp[-2.414 x 10"8 x 76.23'853] = .350 (29)
013AS6/A 5-140 June 1983
-------
TABLE 5-37. DATA UiILIZED TO OBTAIN PREDICTOR EQUATION AND FIGURE 5-12
ppm Age at Medical
Arsenic Examination
x
0.15
0.45
1.20
t
30
50
70
30
50
70
30
50
70
Skin Cancer
Prevalence Rate
F(x,
Observed
Rate
0.0013
0.0063
0.0481
0.0043
0.0477
0.1634
0.0224
0.0983
0.2553
t)
Expected
Rate
0.0031
0.0127
0.0455
0.0053
0.0375
0.1304
0.0141
0.0969
0.3110
Transformed Skin
Cancer Prevalence Rate
-ln(-lntl-F(
-17.5393 + 3.
Observed
6.64474
5.03269
3.00993
5.44699
3.01849
1.72368
3.78739
2.26844
1.22155
8531nt+lnx
Expected
6.33160
4.36341
3.06695
5.23299
3.26480
1.96834
4.25216
2.28397
0.98751
The exponent is the slope estimate for cancer risks at low doses, so that:
P(x)-.430 x for small x, where x is in ppm. (30)
To express the unit in mg/kg/day exposures, it is assumed that two liters
of water are consumed per day by an individual weighing 70 kg. Under the
assumption that 100% of the arsenic is absorbed through the gut, the slope in
units of mg/kg/day absorbed dose is .430 -=-(.24- 70) = 15.8.
A number of potential factors exist that could possibly make the Taiwan-
ese data unsuitable as surrogate data for the U.S. population. Among them are
racial, dietary, and nutritional differences. Also, exposure to ergotamine
was confounded with arsenic exposure in the well water—a fact which also
could have modified the results. However, there is no direct evidence demon-
strating the role of these agents in the carcinogenic response to ingested
013AS6/A 5-141 June 1983
-------
0.0009--7.0
0.0025- • 6.0
0.0067-
0.0181- • 4.0
0.0486- -3.0
0.1266- -2.0
0.3078--1.0
0.6321 -+ 0.0
-2.
t=30
-5.0
t=50
-1.6 -1.2 --8
logx
-.4 .0 .4
-I 1 1 1 1 1 1
0.135 0.202 0.301 0.449 0.670 1.000 1.492 x(ppm)
Figure 5-11. Relationship between transformed prevalence and log ppm arsenic in
water, log age.
5-142
June 1983
-------
arsenic. Furthermore, a recent extensive review by Andelman (1983) of the
arsenic dose-response model developed here, demonstrates that presently there
is no quantitative evidence that is inconsistent with the model. The Andelman
study also showed that there does not appear to be any population in the U.S.
that could be studied that would have a reasonable power to contradict the
hypothesis that the Taiwanese dose-response model is consistent with the U.S.
dose-response.
5.2.1.4.4 Relative Potency. One of the uses of the concept of unit risk is to
compare the relative potencies of carcinogens. To estimate relative potency
on a per-mole basis, the unit risk slope factor is multiplied by the molecular
weight, and the resulting number is expressed in terms of (mMol/kg/day)-1.
This is called the relative potency index.
Figure 5-12 is a histogram representing the frequency distribution of
potency indices of 52 chemicals evaluated by the CAG as suspect carcinogens.
The actual data summarized by the histogram are presented in Table 5-38.
Where human data were available for a compound, they were used to calculate
the index. Where no human data were available, animal oral studies and animal
inhalation studies were used, in that order. Animal oral studies were selec-
ted over animal inhalation studies because they have been made on most of the
chemicals, thus allowing potency comparisons by route.
The potency index for arsenic, based on the Tseng et al. study, is 2.25 x
3 ~1
10 (mMol/kg/day) . This is derived by means of the slope estimate from the
Tseng et al. study, which is 15(mg/kg/day) .
Multiplication by the molecular weight of 149.8 gives a potency index of
+3
2.25 x 10 . Rounding off to the nearest order of magnitude gives a value of
013AS6/A 5-143 June 1983
-------
4th
quartile
3rd
quartile
2nd
quartile
+-
2x10
1st
quartile
1x10
4x10
+3
o
I
246
Log of Potency Index
8
Figure 5-12. Histogram representing the frequency distribution of the potency
indices of 52 suspect carcinogens evaluated by the Carcinogen Assessment Group.
5-144
June 1983
-------
TABLE 5-38. RELATIVE CARCINOGENIC POTENCIES AMOUNG 52 CHEMICALS EVALUATED
BY THE CARCINOGEN ASSESSMENT GROUP AS SUSPECT HUMAN CARCINOGENS
Compounds
Acrylonitrile
Aflatoxin B-,
-L
Aldrin
Ally! Chloride
Arsenic
B[a]P
Benzene
Benzidine
Beryllium
Cadmium
Carbon Tetrachl oride
Chlordane
Chlorinated Ethanes
1,2-dichl oroethane
1,1, 2- trichl oroethane
1,1,2, 2- tetrachl oroethane
Hexachl oroethane
Chloroform
Chromium
DDT
Dichlorobenzidine
1,1-dichloroethylene
Dieldrin
Dinitrotoluene
Diphenylhydrazine
Epichlorohydrin
Bis(2-chloroethyl)ether
Bis(chloromethyl)ether
Slope Molecular
(mg/kg/day)-l Weight
0.24(W)
2924
11.4
1.19xlO~2
15(H)
11.5
5.2xlO~2(W)
234(W)
4.86
6.65(W)
l.SOxlO"1
1.61
6.90x!0"2
5.73xlO"2
0.20
1.42x!0"2
7xlO~2
41
8.42
1.69
1.04(1)
30.4
0.31
0.77
9.9xlO~3
1.14
9300(1)
53.1
312.3
369.4
76.5
149.8
252.3
78
184.2
9
112.4
153.8
409.8
98.9
133.4
167.9
236.7
119.4
104
354.5
253.1
97
380.9
182
180
92.5
143
115
Order of
Magnitude
Potency (Iog10^
Index Index
lxlO+1
9xlO+5
4xlO+3
gxio"1
2xlO+3
3xlO+3
4x10°
4xlO+4
4xlO+1
7xlO+2
2xlO+1
7xlO+2
7x10°
8x10°
3xlO+1
3x10°
8x10°
4xlO+3
3xlO+3
4xlO+2
lxlO+2
lxlO+4
6xlO+1
lxlO+2
9X10"1
2xlO+2
lxlO+6
+1
+6
+4
0
+3
+3
+1
+5
+2
+3
+1
+3
+1
+1
+1
0
+1
+4
+3
+3
+2
+4
+2
+2
0
+2
+6
013AS6/A
5-145
June 1983
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TABLE 5-38. (continued)
Compounds
Ethylene Dibromide (EDB)
Ethyl ene Oxide
Formaldehyde
Heptachlor
Hexachl orobenzene
Hexachlorobutadiene
Hexachl orocycl ohexane
technical grade
alpha isomer
beta isomer
gamma isomer
Nickel
Nitrosamines
Di methyl nitrosamine
Di ethyl nitrosamine
Di butyl nitrosamine
N-nitrosopyrrol idine
N-nitroso-N-ethyl urea
N-nitroso-N-methylurea
N-nitroso-di phenyl ami ne
PCBs
Phenols
2,4,6-trichlorophenol
Tetrachl orodi oxi n
Tetrachl oroethyl ene
Toxaphene
Trichl oroethyl ene
Vinyl Chloride
Slope Molecular
(mg/ kg/day )-l Weight
8.51
0.63(1)
2.14X10"2
3.37
1.67
7.75xlO~2
4.75
11.12
1.84
1.33
1.15(W)
25.9(not
43.5(not
5.43
2.13
32.9
302.6
4.92xlO"3
4.34
1.99xlO"2
4.25xl05
5.31xlO"2
1.13
1. 26x10" 2
1.75xlO"2
187.9
44.0
(I) 30
373.3
284.4
261
290.9
290.9
290.9
290.9
58.7
by qi)74.1
by q*)102.1
158.2
100.2
117.1
103.1
198
324
197.4
322
165.8
414
131.4
(I) 62.5
Order of
Magnitude
Potency (Iog10^
Index Index
2xlO+3
3xlO+1
exio"1
lxlO+3
5xlO+2
2xlO+1
lxlO+3
3xlO+3
5xlO+2
4xlO+2
7xlO+1
2xlO+3
4xlO+3
9xlO+2
2xlO+2
4xlO+3
3xlO+4
1x10°
lxlO+3
4x10
lxlO+8
9x10°
5xlO+2
2x10°
1x10°
+3
+1
0
+3
+3
+1
+3
+3
+3
+3
+2
+3
+4
+3
+2
+4
+4
0
+3
+1
+8
+1
+3
0
0
013AS6/A
5-146
June 1983
-------
TABLE 5-38 (continued)
Remarks:
1. Animal slopes are 95% upper!imit slopes based on the linear multi-
stage model. They are calculated based on animal oral studies,
except for those indicated by I (animal inhalation), W (human occu-
pational exposure), and H (human drinking water exposure). Human
slopes are point estimate, based on linear non-threshold model.
2. The potency index is a rounded-off slope in (mMoI/kg/day)-! and is
calculated by multiplying the slopes in (mg/kg/day)-l by the mole-
cular weight of the compound.
3. Not all the carcinogenic potencies presented in this table represent
the same degree of certainty. All are subject to change as new
evidence becomes available.
10 , which is the scale presented on the horizontal axis of Figure 5-12. The
index of 2.25 x 10 lies at the bottom of the first quartile of the 52 suspect
carcinogens.
Ranking of the relative potency indices is subject to the uncertainty
involved in comparing estimates of potency for different chemicals based on
different routes of exposure to different species, and using studies of dif-
ferent quality. Furthermore, all the indices are based on estimates of low-
dose risk using linear extrapolation from the observational range. Thus,
these indices are not valid for the purpose of comparing potencies in the
experimental or observational range if linearity does not exist there.
5.2.1.5 Summary and Conclusions of the Carcinogenicity of Arsenic
5.2.1.5.1 Qualitative summary. Human studies of the effects of arsenic from
smelters, drinking water, pesticide manufacturing plants, and medicinals have
been conducted. These are summarized in Table 5-1. Studies of five indepen-
dent smelter worker populations have all found an association between occupa-
tional arsenic exposure and lung cancer mortality. Several of the smelter
013AS6/A 5-147 June 1983
-------
studies have found a dose response both by intensity and by duration of expo-
sure. The risk of lung cancer mortality in the high dose group of one study
of smelter workers in Japan was found to be 10 times that expected. In addi-
tion, some studies of communities surrounding smelters have found an associa-
tion between geographic proximity to the smelter and lung cancer mortality.
Both proportionate mortality and cohort studies of pesticide manufactur-
ing workers have demonstrated an excess of lung cancer deaths in that occupa-
tion. One study of the population around a pesticide manufacturing plant found
that residents of the area surrounding the plant were also at an excess risk
of lung cancer. Several case reports of arsenical pesticide applicators have
also shown an association between arsenical exposure and lung cancer.
A study of 40,000 persons in Taiwan exposed to arsenic in the drinking
water found a significant excess prevalence of skin cancer over that of 7,500
other Taiwanese and residents of Matsu Island who drank water relatively free
of arsenic. Water supplies in Chile and Argentina were also reported to be
the cause of arsenic-induced skin cancers. Studies of populations in the
United States exposed to relatively high levels of arsenic in the drinking
water by U.S. standards did not find any excess of skin cancer. The studies
were limited, however, by small sample sizes. Furthermore, the level of
arsenic in the water was much lower than that found in Taiwan. In addition,
persons exposed to arsenical medicinals have been shown to be at a risk of
skin cancer. Using the International Agency for Research on Cancer (IARC)
classification scheme for evaluating carcinogens, the evidence for arsenic as
a human carcinogen is considered sufficient. This is evidenced by the high
relative risks, the consistency in findings in different studies, and the
specificity of tumor sites (i.e., skin and lungs).
013AS6/A > 5-148 June 1983
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There is inadequate evidence, either positive or negative, to evaluate
the carcinogenic effect of arsenic compounds in animals. All of the animal
studies are summarized in Table 5-20. One study (Ivankovic et al. 1979), did
report positive tumorigenie response in BDIX rats by intratracheal instilla-
tion of a "Bordeaux" mixture (which contains 4% calcium arsenate). Because
arsenic was only part of the mixture, however, it cannot be concluded that it
was the causative agent. Thus, to date, no animal model of the carcinogeni-
city of arsenic has been found.
5.2.1.5.2 Quantitative summary. Unit risks are estimated for both air and
water exposures to arsenic. The air estimates were based on data obtained in
five separate studies involving three independently exposed worker popula-
tions. Linear and quadratic dose response models in both the absolute and
relative form are fitted to the worker data. It was found that for the models
that fit the data at the P = .01 or better level that the corresponding unit
-4 -2
risk estimates ranged from 1.05 x 10 to 1.36 x 10 . However linear models
fit better than quadratic models and absolute better than relative models.
Also it was felt that exposure to trivalent arsenic was more represent!'ve of
low environmental exposure than pentavalent arsenic. Restricting unit risk
estimates to those obtained from linear absolute models where exposure was to
-3 -3
trivalent arsenic gives a range of 1.25 x 10 to 7.6 x 10 . A weighted
average of the five estimates in this range gave a composite estimate of 4.29
x 10"3.
An extensive drinking water study of the association between arsenic in
well water and an examination for skin cancer of a population who lived in a
rural area of Taiwan was used to estimate the unit risk for ingestion. Using
the male population who appeared to be more susceptible, it was estimated that
the unit risk associated with drinking water contaminated with 1 ug/£ of arsenic
013AS6/A 5-149 June 1983
-------
-4
was 4.3 x 10 . To compare the air and water unit risks, the exposure units in
both cases were converted to mg/kg/day absorbed doses, resulting in unit risk
estimates of 50.1 and 15.0, respectively.
The potency of arsenic compared to other carcinogens is evaluated by
noting that an arsenic potency of 2.25 x 10 (mMol/kg/day)"1 lies in the
first quartile of the 52 suspect carcinogens that have been evaluated by CAG.
5.2.1.5.3 Conclusions. Skin cancer and lung cancer have been shown by numerous
epidemiologic studies to have an association with arsenic exposure. Arsenic
has not been found to be a carcinogen in animal studies, however. In applying
the IARC criteria for evaluating a substance as to the weight of evidence for
human carcinogenicity, arsenic would be placed in group 1, which IARC charac-
terizes as "carcinogenic to humans".
Using the linear absolute risk model, the composite estimate for cancer
3
risk due to a lifetime exposure to 1 |jg/m trivalent arsenic in the air is es-
timated to be 4.29 x 10 . The unit risk due to lifetime exposure to 1 ug/£ of
-4
arsenic in drinking water is estimated to be 4.3 x 10 . On the basis of
mg/kg/day absorbed dose, the unit risk slopes estimates for air and water are
50.1 and 15, respectively. While it is unlikely that the true risks would be
higher than these estimates, they could be substantially lower. Compared to
other compounds on a mole unit basis, the carcinogenic potency for arsenic falls
towards the lower end of the first quartile.
5.2.1.6 Arsenic Mutagenesis—Both i_n vivo and iji vitro mutagenic responses
have been shown for tri- and pentavalent inorganic arsenic (Arsenic, NAS,
1977; Pershagen and Vahter, 1979; WHO, 1981). In vivo and ijn vitro chromo-
somal effects are tabulated in Table 5-39, while Table 5-40 summarizes other
indicators of arsenic effects.
A 1977 report (Beckman et al. , 1977) focused on the possible association
of exposure to arsenic and the occurrence of chromosome aberrations in workers.
013AS6/A 5-150 June 1983
-------
o
I—I
00
co
Study
TABLE 5-39. CHROMOSOMAL EFFECTS OF INORGANIC ARSENIC IN MAN AND ANIMALS
Agent
Cytological System
Effects
Reference
3
fD
<£>
00
Chromosomal
aberrations
in vivo
Chromosomal
aberrations
in vivo
Chromosomal
aberrations
in vivo
Sister chroma-
tid exchange
frequency (SCE)
jri vivo
Chromosomal
aberrations
in vivo
Arsenite and
possibly arsenate
Fowler's
solution
Arsenic triox-
ide and other
toxic agents
Fowler's
solution
Arsenic triox-
ide and other
possible toxi-
cants
Lymphocytes from 14 psoria-
sis patients given Fowler's
solution and vine-growers.
Lymphocytes from 8 psoria-
sis patients
Lymphocytes
workers
from 9 smelter
Lymphocytes from 6 psoria-
sis patients treated with
Fowler's solution
Lymphocytes from 39
smelter workers having
variable air arsenic
exposure
Chromatid breaks,
gaps, acentric
fragments and
secondary construc-
tions far above
controls
Highly significant
increases in fre-
quency of gaps
and breaks. No
difference in SCE
frequency
Frequency of gaps,
chromatid and
chromosome aber-
rations signifi-
cantly above that
of controls
SCE frequency
significantly
elevated vs.
controls
Frequency of
aberrations
significantly
higher than
controls, no
correlation with
exposure levels
Petres et al.,
1977
Nordenson et
al., 1979
Beckman et
al., 1977
Burgdorf et
al., 1977
Nordenson et
al., 1978
-------
TABLE 5-39. (continued)
o
>—>
CO
oo
ro
Study
Agent
Cytological System
Effects
Reference
en
I
en
r>o
Chromosomal
effects
in vivo
Chromosomal
effects i_n
vitro
Chromosomal
effects
in vitro
Chromosomal
effects
iji vitro
Chromosomal
effects
in vitro
Arsenic (III)
Oxide
Potassium
arsenite
Sodium arsenate
or arsenite
Sodium arsenate
Arsenate or
arsenite in
several chemical
forms
Bone marrow cells
and spermatogonia
Human peripheral
lymphocytes
Human diploid fibroblasts
and leukocytes
Human peripheral
lymphocytes
Human leukocytes and
skin fibroblasts
No chromatid or
chromosomal
aberrations, 48 hr.
after single i.p.
injection.
Gaps, breaks, and
diGentries.
Frequency of chromatid
breaks greater than
controls, arsenite
more effective than
arsenate
Chromosome pulveriza-
tion with reduced
number of mitotic
cells.
Chromosome-breaki ng
activity in both
leukocytes and
fibroblasts greater
for trivalent than
pentavalent arsenic.
Poma et al. ,
1981
Oppenheim and
Fishbein, 1965
Paton and
Allison,
1972
Petres and
Hundieker,
1968
Ndkamuro and
Sayato, 1981
c
=3
(V
wo
00
CO
-------
TABLE 5-40. SUMMARY OF STUDIES INVESTIGATING ARSENIC-INDUCED MUTAGENIC EFFECTS
o
t—•
CO
CO
ro
en
to
c
3
rt>
Study
Point
mutation
Point
mutation
Point
mutation
Agent Cytological System
Sodium
arsenate
Sodium arsenate
and arsenite
Sodium arsenite
E. coli
B. subtil is and
E. coli
E. coli
~~V79~~
Effects
No reversions seen
Both salts mutagenic,
arsenite greater
effect than arsenate
No effects
Reference
Fiscor and
Piccolo,
Nishioka,
1975
Rossman et
1980
1972
al.,
Dominant lethal
effects
DNA repair
DNA repair
Sodium arsenite
Sodium arsenate
Sodium arsenite
ICR-SP, mice
Human epidermal
cells, xenon
lamp exposure
UV-irradiated
E. coli
Lymphocyte Sodium arsenate Human peripheral
transformation lymphocytes
Acute dosing (250 mg/kg Sram and
negative; chronic Bencko, 1974
(10 mg/1 water) dosing
positive for dominant
lethality
Decrease in DNA dark
repair and DNA
synthesis
Jung, 1969
Jung and
Trachsel, 1970
Decreased mutation Rossman et al.,
frequency of irra- 1977
diated cells deficient
for excision repair;
no effect for post-
replication repair
Inhibition of
thymidine incorpo-
ration into DNA
Petres et al.,
1977
Baron et al.,
1975
00
CO
-------
These preliminary data were obtained from the city of Umea. Several kinds of
chromosomal aberrations were studied in cultured human lymphocytes from study
subjects. The aberrations studied were gaps, chromatid aberrations, and
chromosome aberrations. In a preliminary analysis of the data, the frequency
of all aberrations constituted 8.7 percent of all cells examined for exposed
subjects and 1.3 percent for controls and was significantly higher in workers
than controls. Also, all three individual types of aberrations were found to
be significantly higher in exposed workers as compared to control subjects.
A later study by Nordenson et al. (1978) looked at this suggestive asso-
ciation in a more detailed manner. The health center at Ronnskar collected
blood samples obtained from a group of workers stratified by degree of arsenic
exposure as well as from other recently employed workers. No specification of
the procedures used to recruit study subjects was provided in the paper. Data
on age, time of employment, smoking habits and other possible exposures were
collected after the cytogenetic analysis. The health center then stratified
the subjects into 3 exposure groups (high, medium, and low) based on information
concerning the kind of work with arsenic, duration of exposure, systemic
perforations and "arsenic burns". Urinary arsenic values were available for
all but the recently employed group. A relatively undefined control group
consisting of apparently healthy males from Umea was also involved in the
study.
The workers only totaled 39 people and were not evenly distributed over
the 4 exposure groups. Further complicating the interpretation of the data is
the fact that the age distribution was not uniform, with the high exposure
group being on the average 20 years older than the other groups. The fre-
quency of all aberrations was higher in all worker-exposure categories than
for the control group (range 0.048 to 0.092 aberrations/cell in exposed to
013AS6/A 5-154 June 1983
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0.016 in control subjects). All three kinds of aberrations were significantly
higher in the exposed workers as opposed to the control group. The observed
correlation between frequency of aberrations and arsenic exposure, however,
was not very good. Recently employed workers had a higher frequency than did
low exposed longer-term workers. A good correlation was demonstrated only
between chromosome aberrations and arsenic exposure. The effect of smoking on
chromosomal aberrations was examined in concert with an assessment of arsenic
exposure. No isolated effect of smoking was observed; however, the authors
suggested the possibility of a synergistic effect occurring.
Chromosome studies were made on 34 patients at the University of Frieburg
skin clinic (Petres et al., 1977). Thirteen of these patients had had inten-
sive arsenic therapy, some more than 20 years before the experiment; most of
these were psoriasis patients. The control group (21 patients) consisted of
14 psoriasis patients and 7 eczema patients, none of whom had had arsenic
treatment. Phytohemagglutinin-stimulated lymphocyte cultures were prepared
from each patient for evaluation of chromosomal aberrations. The incidence of
aberrations was remarkably greater in the cultures of patients who had been
treated with arsenic. Expressed as the frequency per 1,000 mitoses, 49 versus
12 secondary constrictions, 51 versus 7 gaps, 26 versus 1 "other" lesions, and
65 versus 2 broken chromosomes were seen in the arsenic and control groups,
respectively. The study of Nordenson et al. (1979) supports the above obser-
vations. Although SCE frequency was altered in the Burgdorf et al. study,
this was not confirmed in the Nordenson et al. report.
Both arsenate and arsenite appear to impair DNA repair processes in
E. coli (Rossman et al., 1977) and human epidermal cells (Jung et al., 1969)
after UV irradiation, while arsenate inhibits human lymphocyte transformation
via retardation of thymidine incorporation into DNA (Petres et al. , 1977;
Baron et al., 1975).
013AS6/A 5-155 June 1983
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Support for an i_n vivo mutagenic effect of inorganic arsenic on chromo-
somes arises from HI vitro data (Table 5-39). In particular, Petres et al.
(1977) noted that the same chromosome changes were seen when lymphocyte cul-
tures from healthy subjects were exposed to arsenate at 0.1 to 500 ug As/ml
culture.
The ability of arsenic compounds to induce gene mutations in bacteria and
mammalian cells has been investigated (Fiscor and Piccolo, 1972; Nishioka,
1975; Rossman et al., 1980). However, the results are inconclusive at this
time.
Taken collectively, the data on chromosomal effects, DNA repair, and
inhibition of nucleic acid synthesis suggests that arsenic is genotoxic.
5.2.2 Non-Carcinogenic Chronic Effects
5.2.2.1 Neurotoxic Effects—Arsenic neurotoxicity, including both peripheral
and central nervous system injury, has long been recognized as being associ-
ated with acute, sub-acute, and chronic exposures to relatively high levels of
inorganic arsenic. These have been well characterized as to their major
pathophysiological features, clinical course, sequelae and associated histo-
pathology.
Reynolds (1901) provided one of the earliest detailed descriptions of
arsenic-induced neurotoxic effects in his report on the clinical assessment of
more than 500 patients who had consumed arsenic-contaminated beer.
Neurological involvement started with sensory changes, e.g., paresthe-
sias, hyperesthesias, and neuralgias, accompanied by considerable muscle
tenderness. Varying degrees of motor weakness, progressing from distal to
proximal muscle groups, also occurred and culminated at times in paralysis of
affected muscle groups or extremities. Certain indications of central nervous
system (CNS) damage, e.g., loss of memory and general mental confusion, were
013AS6/A 5-156 June 1983
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also observed but were discounted by Reynolds (1901) as being less likely due
to arsenic than chronic alcoholism or concurrent excessive selenium intake.
Peripheral nervous system (PNS) effects similar to those described by
Reynolds (1901) have since been observed in numerous other cases of acute,
subacute, and chronic arsenic exposures (Silver and Wainman, 1952; Mizuta et
al., 1956; Heyman et al. , 1956; Jenkins, 1966; Hara et al., 1968; Chhuttani et
al., 1967; Ishinishi et al., 1973; Nakamura et al., 1973; Nagamatsu and Igata,
1975; O'Shaughnessy and Kraft, 1976; Frank, 1976; Garb and Hine, 1977; LeQuesne
and McLeod, 1977) and are now recognized as classic clinical symptoms of
arsenic poisoning. Such symptoms include peripheral sensory effects charac-
terized by the appearance of numbness, tingling, or "pins and needles" sensa-
tions in the hands and feet, as well as decreases in touch, pain, and tempera-
ture sensations in a symmetrical distribution. These symptoms are often
variously accompanied by burning sensations, sharp or shooting pains, and
marked muscle tenderness in the extremities. Peripheral neuritis symptoms
originate distally and, over the course of a few weeks, often progressively
become more widespread in both lower and upper extremities, usually appearing
first in the feet and later in the hands.
Collectively, the above components of the classical clinical syndrome
associated with excessive arsenic exposure are highly indicative of progres-
sive peripheral polyneuropathy, involving both sensory and motor nerves, and
most intensively affecting long-axon neurons. In addition, biopsy and autopsy
studies have provided histopathological evidence verifying peripheral nerve
damage, especially Wallerian degeneration of long-axon myelinated nerve fibers
in cases of human arsenic exposure where frank neurological signs and symptoms
were manifested (Heyman, et al., 1956; Jenkins, 1966; Chhuttani, et al., 1967;
Ohta, 1970; LeQuesne and McLeod, 1977).
013AS6/A 5-157 June 1983
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The pattern of development of peripheral neuropathic effects is closely
associated with the type of exposure. Acute exposure to a single, high dose
of arsenic can produce a fairly rapid onset of both motor dysfunctions and
paresthesias. In one report the onset was within 10 days (LeQuesne and McLeod,
1977) after exposure. Slow, incomplete recovery is usually seen in these
cases.
Under more chronic occupational exposure conditions to lower levels of
arsenic compounds, the development of neuropathy symptoms can be more gradual
and insidious, and not only bilateral, but unilateral polyneuropathies without
motor paralysis have been reported (Ishinishi et al. 1973; Nakamura et al.,
1973). Again, the time course for recovery from the neuropathies, once in-
duced, tends to be slow and on the order of years. Gradual onsets of peri-
pheral neuropathies and slow recoveries have also been reported with subacute
or chronic exposures to arsenic via ingestion of contaminated soy sauce (Mizuta
et al., 1956) or anti-asthmatic herbal preparations containing arsenic tri-
oxide or arsenic sulfide (Tay and Seah, 1975).
It is difficult to determine the levels of arsenic associated with the
induction of peripheral neuropathies. For subacute or chronic poisoning
situations, information has been provided in only a few studies by which
effective exposure parameters can be estimated. Mizuta et al. (1956), for
example, reported that peripheral neuropathies occurred in 20 percent of 220
patients of all age groups poisoned by ingestion of arsenic-contaminated soy
sauce, with approximately 3 mg arsenic (likely as calcium arsenate) estimated
to be ingested daily for 2-3 weeks resulting in total effective doses up to
approximately 60 mg. Also, Tay and Seah (1975) reported polyneuropathies in
approximately 50 percent of 74 patients poisoned by daily ingestion of 3.3 or
10.3 mg/day of arsenic trioxide or arsenic sulfide in anti-asthmatic medicinal
pills.
013AS6/A 5-158 June 1983
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More subtle peripheral neurotoxic effects arising from chronic exposure
to lower levels of arsenic in occupational or non-occupational groups are more
difficult to establish, particularly as indexed by abnormal electromyographic
or nerve conduction velocity findings. In one such study, Landau et al.
(1977) reported relationships between length and intensity of occupational
arsenic exposure (mainly to arsenic trioxide via inhalation) of smelter workers
and alterations in peripheral nerve functioning. The manner in which the data
were reported, however, precludes precise characterization of dose-effect/
dose-response relationships.
In their study of arsenic in the drinking water of residents from Millard
County, Utah, Southwick et al. (1981) conducted neurological examinations on
all study participants 47 years of age and younger (see Section 5.2.1.2.2 for
discussion of the total study population). Neurological examination revealed
that conduction velocities for nerves studied (ulnar motor, median motor,
ulnar sensory, median sensory, peroneal, sural) did not vary significantly
with respect to age or community. In those individuals that exhibited below
normal conduction velocities, a slightly greater proportion was seen in exposed
participants -- 12 percent of 67 controls versus 16 percent of 83 exposed. The
sural nerve seemed most often to be affected even after adjusting by a correction
factor of 1.8 m/s/degree in individuals who had nerve temperatures below 30°
C. (Velocities below 37 m/s at 30° C or above were considered abnormal).
Slowing of sural nerve conduction was reported equally in exposed and control
participants. Nerve conduction velocities regressed against annual arsenic
dose and the log of the dose showed no significant associations.
Similar difficulties have been encountered in attempts to characterize
dose-effect/dose-response relationships for arsenic-induced peripheral nerve
functional deficits (as demonstrated by electromyographic recording tech-
niques) in studies of two other populations chronically exposed to arsenic:
013AS6/A 5-159 June 1983
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(1) a population of Yellowknife Canadian Indians exposed via occupational
contact with arsenic in a gold mining and smelting facility, or, in the case
of the families of such workers, via arsenic emissions from the facility into
the ambient environment (Canadian Public Health Assoc., 1978); and (2) a Nova
Scotia population exposed, via geological arsenic contamination of wells, to
levels >0.05 ppm arsenic in drinking water (Hindmarsh, et al. 1977).
Several of the clinical reports discussed above not only document peri-
pheral nerve damage but also contain descriptions of arsenic-induced central
nervous system (CMS) disturbances or encephalopathy effects ranging in severity
from memory losses and general mental confusion to convulsions, stupor, coma
and even death (Heyman et al. 1956; Jenkins, 1966: Frank, 1976; Nagamatsu and
Igata, 1975; O'Shaughnessy and Kraft, 1976; Garb and Mine, 1977). The onset
and courses of such CMS effects have not been well defined, but they appear to
closely parallel the development of peripheral neuropathy effects. Cases of
prolonged encephalopathy indexed by electroencephalogram (EEC) recordings of
abnormal brain wave patterns up to a year after cessation of exposure have
been reported (Freeman and Couch, 1978; Bental et al. 1961). Such effects
appear to be a much less constant feature of arsenic-induced neurotoxic effects
in adults than are peripheral neuropathies.
Certain studies suggest, in contrast, that children may be more sus-
ceptable to arsenic-induced CNS damage. For example, severe CNS deficits have
been observed in children exposed for several months as babies to arsenic-
contaminated powdered milk formulas in Morinaga, Japan (Hamamoto, 1955; Okamura,
et al. 1956; Yamashita, et al. 1972; Masahiki and Hideyasau, 1973; Japanese
Pediatric Society, 1973). Follow-up studies on the children exposed to arsenic
as infants have revealed (1) increased incidence of severe hearing loss (>30 dB)
in 18 percent of 415 children examined compared to less than 1 percent inci-
dence of hearing loss in corresponding age group children; (2) increased
013AS6/A 5-160 June 1983
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incidence of abnormal electroencephalographic (EEC) brain wave patterns in 14
percent of the exposed children, more than double the expected rate for com-
parable normal pediatric populations; and (3) observations of increased inci-
dences of persisting mental retardation, epilepsy, and other indications of
severe brain damage.
In another study (Bencko and Syman, 1977), hearing losses in children
were reported to be associated with arsenic exposure derived from emissions
from a nearby coal-fired power plant combusting high-arsenic content coal.
Both air and bone conduction hearing losses were observed, suggesting inner
ear damage. Failure to find analogous hearing losses in children exposed to
atmospheric arsenic emitted from a copper smelter in the United States (Milham,
1977) has raised questions regarding arsenic-induced damage to the inner ear
in children.
Very few animal toxicology studies have focussed on investigation of
neurotoxic effects of arsenic on the CNS. Rozenshtein (1970), for example,
reported evidence of CNS functional deficits, as indexed by altered condi-
tioned reflexes, as well as histopathologic evidence of CNS structural damage,
e.g,. pericellular edema and neuronal cytolysis in the brain, in rats exposed
for three months to an arsenic trioxide aerosol resulting in an arsenic con-
centration of 46 ug/m . Similar but less severe effects were also obtained
with exposure of other rats to a 3.7 pg As/m aerosol. CNS deficits, indexed
by impaired avoidance conditioning in the absence of demonstrable histopatho-
logic changes in brain tissue, were also reported (Osato, 1977) for suckling
rats administered 2 or 10 mg arsenic trioxide via stomach intubation over a 40
day period.
5.2.2.2 Cardiovascular Effects—A specific cardiovascular effect is the
so-called Blackfoot disease, a peripheral vascular disease leading to gangrene
of the toes, feet, legs and fingers. This disease has been reported in the
013AS6/A 5-161 June 1983
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area of Taiwan, where exposure to inorganic arsenic via drinking water is
known to occur. The same population used for studies on skin cancer and
hyperkeratosis (as discussed in the section on skin cancer) was also used for
investigating the occurrence of Blackfoot disease (Tseng et al. 1968, Tseng
1977). The total prevalence of Blackfoot disease was lower than the preva-
lence of skin cancer, but higher in the younger age groups (Table 5-41). The
overall prevalence rate for Blackfoot disease was 0.9-1.2 percent for males
and 0.7 percent for females after age 39.
A group of 1108 patients with Blackfoot disease from the endemic area
were identified during 1958 to 1975 (Tseng, 1977). There were 669 males and
439 females. Patients were included in the series if they had 1) objective
TABLE 5-41. PREVALENCE OF BLACKFOOT DISEASE (per 1000)
BY AGE AND ARSENIC EXPOSURE (ppm)
Arsenic content
of drinking water
(ppm)
<0.3
0.3 - 0.6
>0.6
20-39
4.5
13.2
14.2
Age
40-59
10.5
32.0
46.9
>60
20.3
32.2
61.4
Source: Adapted from Tseng, 1977.
signs of ischemia and 2) subjective symptoms of ischemia. Follow-up was
attempted using a variety of methods to trace the subjects. At the end of
follow-up, 528 patients had died, a fatality rate of 47.7 percent.
A history of typical ischemic symptoms such as numbness was used to
estimate the date of onset of Blackfoot disease. Duration of intake of arsenic
water at the time of onset represents the period of time between first use of
013AS6/A 5-162 June 1983
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such intake and the time of onset of the disease. Duration o_f intake o£
arsenical water represents the duration of time during which the patient
started drinking artesian well water up to the time of survey or up to the
time of change of source of drinking water. For native patients, the duration
is estimated to be equivalent to their ages, but for patients who came from
areas without artesian wells the duration was counted as starting from the
year of arrival.
A classification system of percentage of permanent disability was created
and each patient was assigned to the appropriate category.
It was determined (determination not specified) that all patients with
Blackfoot disease had consumed artesian well water before the onset of disease,
and none of the residents of the endemic area who had consumed surface water
or water from shallow wells developed Blackfoot disease.
In some parts of the arsenic endemic area, a new source of drinking water
was provided in 1956. The incidence of Blackfoot disease was therefore examined
in year of onset periods (1955 and before, 1956-1965, and 1966-1975). There
were no cases of Blackfoot disease among area residents who were born after
the tap water supply was instituted in 1956. Furthermore, as the duration of
intake of arsenical water increased (across all 3 exposure levels) the inci-
dence of Blackfoot disease increased. In addition, the degree of permanent
disability of patients was significantly correlated with duration of intake of
arsenical water at time of onset of the disease.
There are also data indicating that other substances may be involved in
the etiology of Blackfoot disease. Lu et al., (1977, 1978) found fluorescent
compounds in water samples from an area with endemic Blackfoot disease. Of
the compounds discovered, tentative identifications of D-lysergic acid and/or
013AS6/A 5-163 June 1983
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ergometrine, ergotamine and calciferol have been made (Irgolic, 1982). These
substances may have been at least contributing factors to this disease, since
some of them, or similar compounds, are known vasoactive agents.
Vascular changes were also noted among persons living in Antofagasta,
Chile. (The study groups have been mentioned in the section on skin cancer.)
Raynauds syndrome and acrocyanosis were reported to occur in 30 and 27 per-
cent, respectively, in a group of 100 persons studied by Borgono and Greiber
(1972).
Raynauds syndrome has also been reported to occur among German vintners.
Butzengeiger (1940) studied 180 persons and found that 22.8 percent had evidence
of vascular disorders of the extremities. Butzengeiger (1949) studied 192
vinegrowers and found that 28.7 percent had ECG changes. There was, however,
no control group.
In epidemiological studies of smelters, peripheral vascular disease has
generally not been found. However, mortality studies indicate that there
might be some cardiovascular effects, although study results have been con-
flicting. Thus, Axelson et al. (1978) found a higher mortality in cardiovas-
cular disease, but analysis of the data indicate that if such an effect occurred
it probably needed higher exposure levels than those causing lung cancer. The
study by Ott et al. (1974) indicated, on the other hand, that the arsenic
exposed workers had less mortality than expected.
In both the original Lee and Fraumeni (1969) report and in the follow-up
study by Lee-Feldstein (1982), cardiovascular mortality was found to be signi-
ficantly elevated--SMR=118 and SMR=129, respectively (p <0.01)--but not related
to duration of arsenic exposure. In the Higgins et al. (1982) study on the
Anaconda smelter workers, cardiovascular disease mortality increased with
increasing ceiling arsenic exposure among smokers, but not among nonsmokers--at
013AS6/A 5-164 June 1983
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500-4999 ug/m3, SMR=165** for smokers (p <0.01), SMR=100 for nonsmokers; at
>5000 ug/m , SMR=182** for smokers (p <0.01), SMR=166 for nonsmokers. In
contrast, Lubin ot al. (1981) did not find an excess in cardiovascular disease
mortality (SMR=108) in their study cohort of workers from the same smelter.
The cohorts in all four of these studies were slightly different.
The conflicting findings of these reports suggest that the relationship
between arsenic exposure and cardiovascular disease is quite complex and in
need of additional research.
5.2.2.3 Teratogenesis and Developmental Effects
5.2.2.3.1 Animal studies. In a recent review of the toxicological effects of
prenatal exposure to arsenic, Hood (1982) aptly discussed the considerable
number of variables that influence effects on offspring of maternal arsenic
exposure during pregnancy. Included in his list of variables were the forms
of arsenic administered, species and individual differences in susceptibility,
dose level and exposure route, peak level attained in the conceptus, maternal
metabolism and excretion, and timing of exposure during gestation, the length
of the list indicative of the complex nature of arsenic toxicity induced
during prenatal exposure.
As noted by Hood, teratogenic effects of arsenic compounds at least at
relatively high exposure levels, have been demonstrated in a number of animal
species. Studies by Ridgeway and Karnofsky (1952), for example, demonstrated
no gross abnormalities in chick embryos following injection of sodium arsenate
into embryonate eggs at 0.20 mg As/egg on day 4 of gestation. Retardation in
body weight gain and feather growth, as well as certain other abnormalities,
were, however, observed in chickens hatched from arsenic-treated eggs.
013AS6/A 5-165 June 1983
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Other experimental studies on mammalian species have demonstrated tera-
togenic effects of arsenic in hamsters, rats and mice. Perm and Carpenter
(1968) produced malformations in 15 day hamster fetuses via intravenous (I.V.)
injections of sodium arsenate into pregnant dams on day 8 of gestation at dose
levels of 15, 17.5 or 20 mg/kg body weight. The variety of malformations
obtained with prenatal arsenic exposure of hamsters -- including exencephaly,
encephaloceles, skeletal defects and genitourinary system defects and the
effects of other related experimental manipulations, e.g., protective effects
of co-treatment with selenium - are reviewed in a later report by Perm (1977).
WiUnite (1981) injected arsenate (20 mg/kg) or arsenite (2-10 mg/kg)
into pregnant golden hamsters at day 8 of gestation and observed axial skeletal
disorders in offspring—cranioschisis aperta with exencephaly and cranio-
schesis occulta--while 10 hours after dosing, embryos showed a delay in neural -
fold elevation and neural tube closure with arsenate exposure. Methylated
arsenic was not teratogenic, even at a dose of 100 mg/kg.
Teratogenic and embryotoxic effects of prenatal arsenic exposure of mice
have also been reported (Hood and Bishop, 1972; Hood and Pike, 1972; Hood et
al., 1977). Increased fetal resorption, decreased fetal weights and various
malformations (such as exencephaly, micrognathia, agnathia, exophthalmos,
anophthalmia, hydroencephaly, cleft lip, ectrodactyly, micromelia, fused ver-
tebrae and forked ribs) were observed following single I.P. injections of
sodium arsenate (45 mg As/kg body weight) in Swiss-Webster mice (the single
injection occurring on one day between days 6 and 12 of gestation) (Hood and
Bishop, 1972). Co-treatment with BAL reduced arsenic associated malformations
(Hood and Pike, 1972; Hood et al. 1977).
013AS6/A 5-166 June 1983
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Many similar embryotoxic and fetal teratogenic effects, along with other
effects (renal and gonaual agenesis), have also been observed following I.P.
injections of sodium arsenate in pregnant rats (Beaudoin, 1974; Burk and
Beaudoin, 1977), again at relatively high dose levels (e.g., 30 mg/kg body
weight).
The above studies are suggestive of significant effects on reproduction
and development of mammalian species being induced by prenatal arsenic exposure.
However, only very minimal effects, or none at all on fetal development, have
been observed in studies on chronic oral exposure of pregnant rat or mice dams
to relatively low levels of arsenic via the drinking water (Schroeder and
Mitchener, 1971). Nadeyenko, et al., (1978) reported that intubation of rats
with arsenic solution at a dose level of 0.0025 mg/kg for a period of 7 months,
including pregnancy, produced no significant embryotoxic effects and only very
infrequent slight expansion of ventricles of the cerebrum, renal pelvises and
urinary bladder. Also, Hood et al. (1977) reported that very high single oral
doses of arsenate solutions (120 mg/kg) to pregnant rats were necessary to
cause prenatal fetal toxicity, while multiple doses of 60 mg/kg on 3 days had
little effect. This report suggests that the higher doses required with oral
versus parenteral exposure relate to the more rapid methylation to less toxic
forms of oral arsenic owning to its initial passage through the liver, where
methylation may occur.
Animal studies on the effects of early postnatal administration of arsenic
compounds on growth and development have generally failed to yield any signi-
ficant positive results at sublethal arsenic dose levels. Tamura (1978), for
example, reported no effects on the growth and development of postnatal rats
fed arsenic trioxide in their diet from the 7th to 21st day following birth at
013AS6/A 5-167 June 1983
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a dose level of 1.5 mg/kg/day, in comparison to a 50 percent mortality rate at
a 15.0 mg/kg body weight dose. Similarly, Ferslew and Edds (1979) observed no
significant effects on growth or development of young swine fed arsanilic
acids at 0.01% concentration for 31 days commencing at 3 weeks of age, despite
observations of significant alterations by organo-arsenic of white blood cell
counts, serum alkaline phosphatase activity, and other blood chemistry para-
meters and significant increases of arsenic in various soft tissues and urine.
In another study (Heywood and Sortwell, 1979), both 3.75 and 7.5 mg/kg/day
doses of an arsenic compound fed to adolescent or infant rhesus monkeys re-
sulted in mortality in most of the exposed animals, but no notable effects in
growth or development of animals surviving the dosing period. Unfortunately,
the lack of experimental data in the above studies on the effects of exposure
across a range of dose levels, besides the ones employed, greatly limit their
utility in terms of determining possible dose-effect or dose-response rela-
tionships between postnatal arsenic exposure and induced effects on growth and
development.
It should be noted that, whereas some of the above animal studies provide
highly suggestive evidence for arsenic effects on reproduction and develop-
ment, at least at high exposure levels, one cannot confidently extrapolate the
results to estimate the probability of occurrence of similar or analogous
effects in man. Still, some suggestions of possible arsenic effects on human
reproduction and development have been derived from certain epidemiology
studies discussed below.
5.2.2.3.2 Human studies. Available data are mainly from studies in Sweden on
male and female smelter workers. These studies were not designed specifically
to study effects of arsenic but rather to study the effects, in general, of the
smelter work. While data from these studies suggest a low-level effect of
013AS6/A 5-168 June 1983
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smelter pollutants on neighboring (proximate) populations, the diverse agents
involved preclude making conclusive statements about the specific effects of
arsenic.
Congenital malformations were found to occur at about the same rate, 3.0
percent among women employed at the Rbnnskar smelter as among women living in
six areas belonging to the hospital serving the Rb'nnskar area (Nordstrom et
al. 1978c). However, mean birthweights were lower among offspring to female
Ronnskar workers (Nordstrom et al. 1978a, 1978b).
The number of spontaneous abortions were also increased among women
working in this smelter; the highest rate (17 percent) was found among women
employed during pregnancy or who had been employed prior to pregnancy and
lived close to the smelter. Women working in close connection with smelting
processes had a rate of 28 percent of spontaneous abortion compared with other
female employees. When both parents were employed the abortion rate was 19.4
percent compared to 13.5 percent when the father was not employed.
Studies on spontaneous abortion among women living in the vicinity of the
smelter were also conducted (Nordstrom et al. 1978d). In four areas the rate
varied between 7.6 and 11.0 percent. The highest rate occurred in the area
closest to the smelter, but many women employed at the smelter live in that
area.
5.2.2.4 Hematological Effects—The hematopoietic system in man has been shown
to be affected by arsenic exposure in cases of acute, subacute or chronic
intake, taking the form of anemia, leukopenia, granulocytopenia and eosino-
philia. Such effects appear to be reversible, the system recovering in a
matter of weeks after exposure ends.
013AS6/A 5-169 June 1983
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Hamamoto (1955), in his report of infant poisoning by arsenic-contami-
nated milk in Japan, described marked anemia and leukopenia with lymphocytosis
in most of a group of 59 infant patients. Erythropoiesis was disturbed in
bone marrow of 19 children studied. Within a month, the hematology appeared
to show normal values. Similarly, Mizuta et al. (1956) found blood disturb-
ances, including anemia with leukopenia and lymphocytosis, in subjects sur-
veyed for ingestion of soy sauce contaminated with arsenic.
Two recent studies dealing with acute and sub-acute arsenic poisoning
(Feussner et al., 1979; Lerman et al. 1980) have demonstrated arsenic induced
megaloblastic anemia, Feussner et al. (1979) demonstrating arsenic being
present in bone marrow using electron-probe microanalysis.
Chronic exposure to arsenic occasions hematological effects which resemble
those seen with subacute exposure. Terada (1960), in his survey of patients
exposed to arsenic in well water contaminated by industrial activity in Niigata,
Japan, saw anemia as a common feature, with the anemia being either normo-
chromic (50 percent) or hyperchromic (30 percent). In their study on indivi-
duals living in communities in Utah where arsenic was present in drinking water,
Southwick et al. (1981) also reported the presence of anemia in certain indi-
viduals; however, anemia was not significantly more prevalent in exposed popu-
lations. Anemia has been reported in subjects exposed to arsenic occupationally
or in medicinals (Kyle and Pease, 1965; Westhoff et al., 1975).
In animals, decreased hemoglobin production has been seen in rats fed
both arsenate (Mahaffey and Fowler, 1977) and arsenite (Byron et al., 1967)
and in cats given either form orally (Massmann and Opitz, 1954). The study of
Woods and Fowler (1977) in which arsenate was given orally to rats and mice at
20, 40 or 85 ppm in drinking water showed that the sites of disturbance of the
heme biosynthetic pathway by arsenate mainly involved depression of ALA-
013AS6/A 5-170 June 1983
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synthetase and heme synthetase activity, with elevation in the urinary levels
of chiefly uroporphyrin and also coproporphyrin. The increase in uroporphyrin
appears to be specific to arsenic.
5.2.2.5 Hepatic Effects—In the reports of Hamamoto (1955) and Mizuta et al.
(1956), dealing with arsenic contamination in infant milk and soy sauce,
respectively, swollen livers appeared to be a common clinical feature. Of the
children exposed to milk arsenic, all subjects presented with this feature
(61/61). In the autopsies of fatal outcome cases, hemorrhagic necrosis and
fatty degeneration of the livers were seen. In the survivors, liver function
tests were not very revealing, being within normal limits in most cases. In
both of the above episodes, liver size returned to normal after exposure
ceased.
Over the years, chronic intake of arsenic has been reported to be asso-
ciated with hepatic damage in the form of portal hypertension, malignant liver
disease and cirrhosis. In the Manchester beer poisoning episode, Reynolds
(1901) noted widespread liver disease in drinkers of such beer, with the
extent of the disease being related to the amount of arsenic in the beverage.
The incidence of hepatic cirrhosis among German vintners has been re-
viewed by Luchtrath (1972), who noted that the frequency of liver cirrhosis
decreased with the banning of arsenical pesticides. The use of arsenic as an
anti-syphilitic is also known to be associated with hepatic cirrhosis (Baldridge,
1934).
Non-cirrhotic portal hypertension has been infrequently noted in the
literature (Morris et al. , 1974; Szuler et al., 1979). Szuler described one
case report of presinusoidal portal hypertension in a patient taking an arsenic
antiasthmatic for 55 years. Cirrhosis was absent and liver function was not
disturbed.
013AS6/A 5-171 June 1983
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In the smelter study by Axel son et al. (1978) there was a tendency towards
an increased mortality in liver cirrhosis among arsenic-exposed workers.
5-2.2.6 Renal Effects—Functional and/or biochemical impairment of the human
renal system is mainly known in acute poisoning by arsine, AsHL (Uldall et
al., 1970; Fowler, 1977). Oligouria and anuria progressing to renal failure
are common acute responses. Persistent renal sequelae in subjects surviving
the acute stage of arsine poisoning include chronic renal insufficiency and
hypertension. Histologically, the injury is mainly tubular and interstitial.
Acute or chronic renal effects associated with arsenate or arsenite
exposure are less well characterized. Gerhardt et al. (1978) have recently
described a case of acute arsenic poisoning from contaminated illicit liquor.
Acute renal bilateral cortical necrosis was diagnosed in the patient, who
survived the acute stage to eventually develop reduced renal size and cortical
calcification.
In the clinical survey of Hamamoto (1955) of Japanese infants poisoned
with arsenic-contaminated milk, possible renal injury was diagnosed by the
presence of hematuria, leukocyturia and glycosuria (23,7 percent, 42.3 percent
and 13.5 percent, respectively). Reversibility of these indices was apparent,
with only three percent of the patients still showing pathological changes
after one month. Terada (1960) also noted proteinuria in cases of arsenic
poisoning in Niigata, Japan, arising from ground water contamination from an
arsenic plant.
5.2.2.7 Respiratory Effects Other Than Cancer—Nasal septum perforation is a
rapid tissue response in workers encountering high airborne arsenic levels
(NAS, 1977; Hine et al., 1977; Lundgren, 1954).
013AS6/A 5-172 June 1983
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In the detailed smelter worker study of Lundgren (1954), 1,276 subjects
3
in a worksite with levels up to 7 mg As/m showed two types of respiratory
disturbances relating to the nature of the processing and presumably the form
of the arsenic. Refined arsenic handling was associated with septal perfora-
tion and rhino-pharyngo-laryngitis while workers in the roaster, furnace and
connector areas showed tracheobronchitis and signs of pulmonary insufficiency.
In the latter group, exposure was mixed—including both arsenic and sulfur
dioxide. A recent report has suggested, furthermore, that workplace arsenic
may also be present as the sulfide (Smith et al., 1976).
Chilean children exposed to arsenic in drinking water (Borgono et al.,
1977) showed a chronic cough and bronchitis history.
5.2.2.8 Immunosuppressant Effects—The role of inorganic arsenic as an immuno-
suppressant in man is mainly inferred from indirect data accumulated over the
years (Arsenic. NAS, 1977).
First, the therapeutic utility of arsenicals, such as arsenite-based
Fowler's solution in the treatment of steroid-responding disorders and as a
lymphocytostatic agent, suggests action as an immunosuppressant.
Secondly, certain manifestations indicative of likely immune system
disorders have been observed with arsenic exposure, (e.g., the occurrence of
herpes simplex and chronic pulmonary infections) and suggest a role of arsenic
as an immunosuppressant (Arsenic. NAS, 1977). Histories of chronic cough and
bronchitis in Chilean children exposed to arsenic in drinking water (Borgono
et al., 1977) would tend to support such a role.
5.3 FACTORS AFFECTING ARSENIC TOXICITY
The most widely recognized and studied arsenic interactive behavior is
with selenium, and much of the early data has been reviewed by Levander (1977).
013AS6/A 5-173 June 1983
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The known antagonistic relationship of arsenic and selenium in a number
of animal species was first described by Moxon and co-workers (Moxon and
Dubois, 1939; Dubois et al., 1940), who also demonstrated the utility of
dietary arsenic supplementation in protecting livestock from the toxic levels
of selenium in certain fodders. Both penta- and trivalent arsenic are equally
effective in protecting against selenium toxicity, and do so regardless of the
chemical form by which selenium exposure occurs.
An understanding of the i_n vivo mechanisms by which arsenic imparts a
protective effect on selenium toxicity has only recently been gained.
The ability of arsenic to retard the formation of volatile selenium in
the form of dimethyl selenide (Kanstra and Bonhorst, 1953) apparently involves
inhibition of microsomal methyl transferase activity, an enzyme sensitive to
arsenite (Ganther and Hsieh, 1974). An over-all protective effect still
exists, however, since arsenic promotes the biliary excretion of selenium
(Levander and Baumann, 1966; Ganther and Baumann, 1962). According to Levander
(1977), enhanced biliary clearance of selenium in the presence of arsenic
probably involves an excretory conjugate of both, since selenium likewise
enhances the biliary excretion of arsenic.
Rb'ssner et al. (1977) have shown a protective effect for arsenite against
the cytotoxicity of selenite using suspension cultures of mouse fibroblasts
exposed to these agents at 10 to 10 M. Interestingly, selenite in turn
had only a low protective effect against arsenite cytotoxicity.
Little data exists for interactive relationships between arsenic and
other elements. In one of the few pertinent studies bearing on this issue,
the effects of concomitant oral exposure to cadmium, lead and arsenic versus
single agent exposure effects have been reported by Mahaffey and Fowler (1977).
Cadmium and arsenic together retarded weight gain in young adult rats to a
greater extent than either element alone.
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6. ARSENIC AS AN ESSENTIAL ELEMENT
Mertz (1970) has set forth a set of logical criteria which trace elements
should obey in order to be considered physiologically essential for man and/or
animals. One of the most obvious of these, and one which should be readily
demonstrable, is that the element meet a unique requirement physiologically,
and, consequently, that a deficiency in that element be associated with de-
leterious effects.
In the case of arsenic, early reports attempting to show a nutritional
requirement for the element in animals were inconclusive (Arsenic. NAS, 1977;
Underwood, 1977). Part of the problem was undoubtedly technical in nature,
i.e., the difficulty of carrying out such studies in an experimental environ-
ment where rigorous exclusion of a ubiquitous element from the diet is neces-
sary. More recently, however, several carefully controlled studies have been
reported to have demonstrated nutritional essentiality for arsenic in at least
some mammalian species.
Nielsen et al. (1978) have noted that deprivation of pregnant rats of
arsenic-supplemented diets resulted in offspring showing such post-weaning
effects as slow growth, enlarged spleens, and increased red cell osmotic
fragility. Greater perinatal mortality among pups from arsenic-deprived dams
was also noted in a second experimental group.
In a recent review by Uthus et al. (1982), the authors reported on studies
with chicks that suggest that arsenic influences arginine metabolism. It was
reported that arsenic deprivation influenced the effects of dietary arginine,
manganese and zinc, the fluctuations of which variously affected growth,
kidney arginase, plasma alkaline phosphatase, plasma urea, plasma uric acid
013AS1/G 6-1 June 1983
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and hematocrit. The authors suggested that the four components interacted to
affect the conversion of arginine into urea and ornithine.
Anke et al. (1978) studied the nutritional requirements for arsenic using
goats and mini-pigs and a semi-synthetic diet containing less that 50 ppb
arsenic. Effects attributed to arsenic deficiency in both species were seen
not only in the adult animals but in their offspring. Arsenic deficiency
increased the mortality of adult goats as well as altered the mineral profiles
for copper and manganese in the carcass. Significant reproductive effects for
both arsenic-deficient goats and mini-pigs included reduction of the normal
litter size. Furthermore, the mortality of kids and piglets from the As-defi-
cient groups was significantly higher than controls. Manganese levels were
elevated in As-deficient kids and piglets, but no perturbation of hematological
indices (hemoglobin, hematocrit or mean corpuscular concentration) was noted.
This is in contrast to the experimental observations with rats (Nielsen et
al., 1974), where decreased hematocrits, elevated iron content in spleen and
increased osmotic fragility of cells are seen. Given the fact that the rat is
known to be an anomalous animal model for arsenic metabolism (see Chapter 4),
this difference is probably peculiar to this species.
Schwartz (1977) has noted growth effects of arsenite on rats fed an
arsenic-supplemented diet, with an optimal effect seen at 0.25 to 0.5 ppm.
Interestingly, this worker noted that pentavalent arsenic as sodium arsenate
is less effective.
Remaining to be independently demonstrated is a physiological role for
arsenic, the existence of any specific carrier agent in the body, or arsenic
essentiality in man.
A feature of essential element metabolism is homeostatic control of
levels and movement of a particular element i_n vivo. From the information
013AS1/G 6-2 June 1983
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considered earlier, there is no effective absorption barrier for most soluble
inorganic arsenicals, but efficient excretory mechanisms (kidney, hair) and
biotransformation appear to provide some control over any absorption-excretion
balance.
013AS1/G , 6-3 June 1983
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7. HUMAN HEALTH RISK ASSESSMENT FOR ARSENIC
This portion of the report places the information in the earlier Chapters
into a quantitative perspective with regard to non-occupational population
exposure and health effects of arsenic germane to such a population.
Data for levels of arsenic encountered by humans in air, water, food and
other sources, such as cigarette smoking, were set forth in Chapter 3 and are
combined with data on rates of intake and rates of absorption to provide
information on the total assimilation of arsenic on a daily basis. Health
effects of arsenic most germane to non-occupational population exposures are
then summarized. Generally, these are chronic effects associated with long-
term intake of relatively low levels of arsenic. In the case of hazardous
wastes, however, some health effects of concern may be associated with acute
exposures; therefore, acute and sub-acute effects must also be considered.
The section dealing with dose-effect/dose-response data includes conside-
ration of various indices of internal exposure followed by quantitative data
for intake and population response.
Populations at risk, identified at least along qualitative lines, are
included for discussion.
7.1 AGGREGATE EXPOSURE LEVELS TO ARSENIC IN THE U.S. POPULATION
Among individuals of the general population (not occupationally exposed
to arsenic), the main routes of exposure to arsenic are typically via inges-
tion of food and water, with lesser exposures occurring via inhalation.
Representative intake figures are presented in Table 7-1. Intake by inhala-
tion is augmented among smokers in proportion to the level of smoking.
013AS5/E 7-1 June 1983
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TABLE 7-1. ROUTES OF DAILY HUMAN ARSENIC INTAKE
Route/level
Ambient air/0.006 pg/m3(a)
Drinking water/< 10 pg/liter
Food/50 pg daily (elemental As)
Cigarettes/6 pg in main-
stream smoke/pack^
Total: < 60 pg nonsmokers
Rate
20 m3
2 liters
--
1/2 pack
1 pack
2 pack
Total intake
0.12 pg
1 20 pg
50 pg
3 pg
6 pg
12 pg
Absorbed amount
0.036 pg(b)
< 20 pg(c)
40 pg(d)
0.9 pg'f^
1 R ,,n(f)
-i--y M9/-f\
2 "7 \ J
• ' M9
^National average for 1981 (see Section 3.3.1)
^Assumes 30 percent respiratory absorption (see text).
(c)
v ^Assumes total absorption (see text).
*• ^Assumes 80 percent absorption (see text).
(e)
v ^Assumes 20 percent of cigarette content in inhaled smoke (see text).
^Assumes 30 percent absorption of inhaled amount (see text).
3
Assuming a daily ventilation rate of 20 m , and a national population
inhalation average of 0.006 ug/m /As, the total daily inhalation exposure for
arsenic can be projected to be approximately 0.12 ug. Assuming 30 percent
absorption, approximately 0.03 pg of arsenic would be absorbed on a daily
average.
013AS5/E 7-2 June 1983
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Contribution of tobacco-borne arsenic to the respiratory burden would
depend upon the.rate of cigarette smoking. If one assumes a mass of 1 gram/
cigarette and an average tobacco value of 1.5 ppm, this yields 1.5 ug arsenic/
cigarette. With 20 percent of this amount in mainstream smoke, the inhaled
amount for each pack of cigarettes would be approximately 6 ug arsenic, and of
this amount, 40 percent would be deposited in the respiratory tract (see
Chapter 4). Assuming an absorption of 75 percent of the deposited fraction,
one arrives at an absorption of approximately 2 ug/pack of cigarettes or a
factor of 10 to 100 times greater than intake for nonsmokers in given ambient
air settings. One may assume that the rates of absorption for trivalent and
pentavalent arsenic in the respiratory tract are equivalent.
Since drinking water arsenic is mainly in a soluble form (arsenate or
arsenite) virtually all of it is absorbed in the GI tract (see Chapter 4).
Thus, assuming an average daily consumption of two liters of water containing
at most 10 ug As/liter as an outside high figure, one can estimate that the
total arsenic absorbed from drinking water would be approximately 20 ug/day.
Most individuals would, in reality, take in much less than this amount, while
those in the Western U.S. with well water supplies much higher in arsenic
content would assimilate proportionately more.
Food arsenic values taken from the 1974 FDA survey indicate a daily total
dietary intake of approximately 50 ug elemental arsenic. Based on information
presented in Chapter 4, the major portion (80 percent) of food arsenic would
be absorbed resulting in a net daily food arsenic absorption of 40 ug total.
Thus, a non-smoker would have a total daily absorption from all exposure
media of approximately 60 ug arsenic/day or less. Of this, the diet would be
013AS5/E 7-3 June 1983
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the major contributor, assuming levels in water much below 10 |jg/liter. For
cigarette smokers, one would add 2 ug arsenic/pack of cigarettes smoked daily.
If one views aggregate intake not in terms of total arsenic intake but in
terms of toxicologically significant forms of the element, then much of the
dietary fraction, for reasons given earlier, such as complex organoarsenicals
being present, becomes relatively less important than the forms in water and
air as well as in cigarette smoke. Arsenic forms in such media include:
pentavalent arsenic in most water supplies; variable mixtures of tri-and
pentavalent arsenic in ambient air; and probably an arsenic oxide in cigarette
smoke. From this view point, utilizing the examples already given above, non-
smokers would absorb 20 ug or less daily of toxicologically significant arse-
nic. Heavy smokers having otherwise very low air and water exposure, conceiv-
ably could receive their major exposure via cigarettes.
7.2 SIGNIFICANT HUMAN HEALTH EFFECTS ASSOCIATED WITH AMBIENT EXPOSURES
7.2.1 Acute Exposure Effects
Serious acute effects and late sequelae from exposure to arsenic will
appear after single or short-term respiratory or oral exposures to large
amounts of arsenic. Available data indicate that inorganic trivalent com-
pounds of arsenic are generally more acutely toxic than inorganic pentavalent
compounds, which in turn are more toxic than organic arsenic compounds.
Serious effects will also appear after long-term exposure to respiratory or
oral doses of arsenic.
The acute symptoms following oral exposure consist of gastrointestinal
disturbances, which may be so severe that secondary cardiovascular effects and
shock may result and cause death. Also, direct toxic effects on the liver,
bloodforming organs, the central and peripheral nervous systems, and the
013AS5/E 7-4 June 1983
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cardiovascular system may appear. Some symptoms, especially those from the
nervous system, may appear a long time after exposure has ceased and may not
be reversible, whereas the other effects seem to be reversible. Infants and
young children especially are susceptible with regard to effects on the cen-
tral nervous system. The Japanese followup after the so-called Morinaga milk
poisoning showed that persisting damage, especially mental retardation and
epilepsy, is a late sequela in children of short-term oral exposure to large
doses of inorganic arsenic. Among adults, the central nervous system is not
as susceptible, but peripheral neuropathy has been a common finding.
Both in adults and children, acute oral exposure has resulted in dermal
changes, especially hyperpigmentation and keratosis, as a late sequela.
Acute inhalation exposures have also resulted in irritation of the upper
respiratory tract, even leading to nasal perforations.
Direct dermal exposure to arsenic may lead to dermal changes; allergic
reactions may also be involved.
7.2.2 Chronic Exposure Effects
Both carcinogenic and noncarcinogenic effects are associated with long-
term exposures, which do not cause any obvious immediate effects. For the
purpose of this document, such chronic effects will be discussed in sequence
as follows:
1. Respiratory tract cancer
2. Skin cancer
3. Non-cancerous skin lesions
4. Peripheral neuropathological effects
5. Cardiovascular changes
Cancer of the respiratory system is clearly associated with exposure to
arsenic via inhalation. This association has been especially noted among
workers engaged in the production and usage of pesticides and among smelter
013AS5/E 7-5 June 1983
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workers. While it is not known to what extent exposure to other compounds in
industrial atmospheres has contributed to the excess of lung cancer, the In-
ternational Agency for Research on Cancer (IARC) has concluded that there is
sufficient evidence that inorganic arsenic compounds are lung carcinogens in
humans.
Cancer of the skin has been found as a dose-related effect in a popula-
tion in Taiwan, with lifetime exposure to arsenic in well water. It has also
been found among people treated with large doses of arsenite for skin disor-
ders. Skin cancer often has a long latency period in the order of decades,
the latency time decreasing with increasing intensity of exposure. IARC has
concluded that there is sufficient evidence that inorganic arsenic compounds
are skin carcinogens in humans.
Hyperkeratosis and hyperpigmentation, sometimes with precancerous changes,
have been a common finding in persons ingesting arsenic. These skin lesions,
as well as the manifest cancer, develop on skin surfaces usually unexposed to
sunlight. In studies in the United States, an association between skin lesions
or skin cancer has not been demonstrated. These studies have been limited,
however, by sample sizes too small to be able to detect the dose response seen
in studies outside the U.S.
The effects on the peripheral nervous system range from sensory disturb-
ances to motor weakness and even paralysis. The more severe signs have been
noted in subacute poisonings, but more subtle changes after long-term low-level
exposure have been found by using electromyography or measuring nerve conduc-
tion velocity. These subclinical effects are slow in recovery and may persist
for years after cessation of exposure. In a study in Canada, electromyographic
(EMG) changes were noted when water concentrations of arsenic exceeded 0.05
mg/1.
013AS5/E ' 7-6 June 1983
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Cardiovascular effects have been noted especially in Taiwan, where the
so-called Blackfoot Disease (peripheral vasculopathy) occurred after long-term
exposure to arsenic in well water. However, the presence of ergotamine-like
compounds raises the possibility of vascular effects from these agents.
Peripheral vascular changes were also found among German vintners who were
exposed both occupationally, by spraying arsenic containing pesticides, and
orally, by drinking wine with elevated arsenic levels. Studies on occupation-
ally exposed persons have been inconclusive in showing that arsenic causes an
increase in mortality from cardiac disease.
7.3 DOSE-EFFECT/DQSE-RESPONSE RELATIONSHIPS
7.3.1 General Considerations
This section generally attempts to define, as presently feasible, human
dose-effect/dose-response relationships for health effects of likely greatest
concern at ambient environment exposure levels for arsenic in the United
States. As such, the present section highlights mainly the quantitative
carcinogenic risk estimates that were derived in Section 5.2.1.4.
The general question of how to define and employ a dose factor in at-
tempts at quantitative assessments of human health risk for any toxicant is
highly dependent upon 1) the available information on the body's ability to
metabolize the agent, and 2) the assessment of the relative utility of various
internal indices of exposure.
The time period over which a given total intake occurs is highly impor-
tant. For example, intake of one gram of arsenic over a period of years would
be quite different pathophysiologically from assimilating this amount at one
time, the latter probably having a lethal outcome. This time-dependent be-
havior is related in part to the relative ability of the body to detoxify
inorganic arsenic by methylation as a function of both dose and time.
013AS5/E 7-7 June 1983
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In cases of acute and sub-acute exposure, indicators of internal exposure
such as blood or urine arsenic levels are probably appropriate for assessing
the intensity of exposure.
With chronic, low-level exposure, however, the available data would
indicate that the total amount assimilated is probably more important than an
indicator concentration without knowledge of the total exposure period. An
added problem is the background level of arsenic found in these indicators due
to dietary habits. For example, in acute exposures, levels in blood or urine
would be greatly elevated over background values while low-level chronic
exposures would only result in moderate increases over background.
In regard to hair arsenic levels as an indicator of internal arsenic ex-
posure, no reliable methods exist for distinguishing external contamination
levels from those accumulated via absorption and metabolic distribution. Hair
arsenic levels cannot, therefore, be employed as reliable indicators of either
current or cumulative long-term exposures for individual subjects, but rather
may provide only a rough overall indication of group exposure situations.
Given the above considerations and limitations concerning the use of
blood, urinary or hair arsenic concentrations as internal indices of cumula-
tive, long-term low-level arsenic exposures of concern here, the dose-effect/
dose-response relationships summarized below are done so mainly in terms of
external arsenic exposure levels via either inhalation or ingestion.
7.3.2 Effects and Dose-Response Relationships
It is difficult to define a precise acute lethal dose of arsenic for man,
because such exposure situations rarely allow accurate determination of the
effective amounts. However, for trivalent arsenic, the figure is believed to
range from 70- 180 milligrams.
013AS5/E 7-8 June 1983
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For subacute exposure, it appears that for children, about one gram
assimilated over a period of 3-4 weeks will induce death with severe effects
in survivors, while for adults, that dose will occasion significant clinical
effects. In one poisoning episode, intake of approximately 50 milligrams over
a period as short as two weeks resulted in clinically demonstrable effects in
adults.
7.3.2.1 Respiratory Cancer—A considerable number of studies have shown asso-
ciations between occupational exposure to arsenic and cancer of the respira-
tory system. The best information available for making quantitative risk es-
timates for lung cancer are derived from 5 sets of data involving 4 sets of
investigators and 2 distinct exposed populations. The 4 sets of investigators
are Brown and Chu (1983a,b,c), Lee-Feldstein (1982) and Higgins (1982)--who
conducted studies on workers at the Anaconda smelter in Montana—and Enter!ine
and Marsh (1982)—who conducted a study on the workers at the ASARCO smelter
in Tacoma, Washington.
Using an absolute-risk linear model and the data from the four smelter
studies, the lifetime lung cancer risk, due to continuous exposure of 1 ug/
As/m3, was estimated to range from 1.25 x 10 3 to 7.6 x 10 3. A weighted
average of the five estimates* in this range gave a composite estimate of 4.29
x 10 3 (see Section 5.2.1.4.2). This represents a plausible estimate of the
upper limit of risk—that is, the true risk would not likely be more than the
estimated risk, but it could be substantially lower.
7.3.2.2 Skin Cancer—Chronic arsenic exposure, both occupational and non-
occupational, is associated with a distinctive hyperkeratosis, which is usually
followed by a later onset of skin cancer. The best data available for making
*Two risk estimates were derived from the Enterline and Marsh study based
upon exposure periods lagged 0 and 10 years. See Table 5-25.
013AS5/E 7-9 June 1983
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quantitative risk estimates for skin cancer are the data collected by Tseng et
al. (1968). In this study, the authors surveyed a stable population of 40,421
individuals who lived in a rural area along the southwest coast of Taiwan and
who were known to have consumed drinking water containing arsenic. The occur-
rences of skin cancer among this population, and the arsenic concentrations in
their drinking water were measured. Since the population was stable, the data
obtained from the study lends itself to predictions of lifetime probability of
skin cancer caused by the ingestion of arsenic.
Using an absolute-risk linear model and the data from Tseng et al., the
lifetime skin cancer risk from drinking water containing 1 ug/liter of arsenic
was estimated to be 4.3 x 10"4 (see Section 5.2.1.4.3). It is not likely that
the true risk for skin cancer would be more than this estimated risk, but it
could be considerably lower.
7.3.2.3 Non-cancerous Skin Lesions — As noted above, in man, chronic oral
exposure to arsenic induces a sequence of changes in skin epithelium, proceeding
from hyperpigmentation to hyperkeratosis, characterized as keratin proliferation
of a verrucose nature, and leading, in some cases, to late onset skin cancers.
These effects have been noted both in populations which have ingested arsenic
via drinking water and among people treated with large doses of arsenite for
skin disorders. In a recent report by Pershagen and Vahter (1979), the authors,
using the data from a patient population exposed to arsenic via Fowler's
solution (Fierz, 1975), noted an increase in prevalence of hyperkeratosis with
increasing dose of arsenic. The U.S. EPA is presently examining this informa-
tion, along with information from other studies, in order to determine whether
quantitative dose-response relationships, similar to those seen for skin
cancer, can be established for these precancerous skin lesions.
7.3.2.4 Peripheral Neuropathological Effects and Cardiovascular Changes —
While the qualitative evidence for peripheral neurological effects and cardio-
013AS5/E 7-10 June 1983
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vascular changes in arsenic exposed populations is incontrovertible, the data
are insufficient to establish quantitative dose-response relationships at the
present time.
7.4 POPULATIONS AT SPECIAL RISK TO ARSENIC EXPOSURE
In reviewing the literature dealing with the acute, subacute and chronic
effects of arsenic in children and adults, the evidence suggests that children
may be at special risk for the effects of inorganic arsenic under conditions
of acute or subacute exposure.
In earlier sections, reference was made to the outbreak of pediatric
poisoning by arsenic in Japan due to the presence of arsenic in infant milk
formula (Hamamoto et al. , 1955). From the clinical reports published at the
time of the mass poisoning as well as those from follow-up studies, a number
of signs of central nervous system involvement were noted both at the time of
the episode and much later, with the follow-up studies showing behavioral
problems, abnormal brain wave patterns, marked cognitive deficits, and severe
hearing loss in some of those children who survived the acute episode. Some
of these same tardive effects have also been noted in adults but appear to be
a much less constant feature of arsenic-induced neurotoxic effects than are
the peripheral neuropathies.
Because children consume more water per body weight than do adults, the
daily intake of arsenic via drinking water per kilogram body weight would be
greater in children. This may have implications regarding chronic exposure
effects in children. Zaldivar (1977) developed a regression equation describ-
ing this relationship. It should be noted, however, that serious health ef-
fects due to chronic exposure of arsenic in drinking water have not been found
at a greater frequency in children than adults.
013AS5/E 7-11 June 1983
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Individuals residing in the vicinity of certain arsenic emitting sources,
e.g., certain types of smelters, may be at risk for increased arsenic intake
because of both direct exposure to arsenic in air and indirect exposure via
arsenic secondarily deposited from air onto soil or other human exposure media.
The relative contribution of such indirect exposures to increased risk of these
individuals for arsenic health effects is difficult to define due to the lack
of information on this subject. However, it is most likely minimal in relation
to the direct effects arising from inhalation of arsenic, including lung cancer.
As a large class of the general population at risk for increased arsenic
intake, one would have to include cigarette smokers. However, it is not clear
to what extent some increased arsenic intake from tobacco smoke poses a speci-
fic heightened health effect risk although it is clear that internal indicator
levels, e.g. blood arsenic, are somewhat elevated in the case of cigarette
smokers relative to nonsmokers.
013AS5/E 7-12 June 1983
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