ARSENIC
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Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
9-
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3
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ATSDR/TP-88/02
TOXICOLOGICAL PROnLE FOR
ARSENIC
Date Published — March 1989
Prepared by:
Life Systems, Inc.
under Contract No. 68-02-4228
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute. and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
.significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
ill
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Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
James 0. Mason, M.D., Dr. P.H.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD ill
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS ARSENIC? 1
1.2 HOW MIGHT I BE EXPOSED TO ARSENIC? 1
1.3 HOW DOES ARSENIC GET INTO MY BODY? 2
1.4 HOW CAN ARSENIC AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO ARSENIC? 3
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 7
2. HEALTH EFFECTS SUMMARY 9
2.1 INTRODUCTION 9
2.2 LEVELS OF SIGNIFICANT HUMAN EXPOSURE 10
2.2.1 Key Studies 10
2.2.1.1 Oral 11
2.2.1.2 Inhalation 17
2.2.1.3 Dermal 25
2.2.2 Biological Monitoring as a Measure of
Exposure and Effects 25
2.2.2.1 Blood arsenic 25
2.2.2.2 Urinary arsenic 26
2.2.2.3 Hair and nails 26
2.2.2.4 Electromyography 26
2.2.3 Environmental Levels as Indicators of
Exposure and Effects 27
2.2.3.1 Levels found in the environment 27
2.2.3.2 Human exposure potential 27
2.3 ADEQUACY OF DATABASE 27
2.3.1 Introduction 27
2.3.2 Health Effect End Points 28
2.3.2.1 Introduction and graphic summary 28
2.3.2.2 Description of highlights of graphs ... 31
2.3.2.3 Summary of relevant ongoing research 31
2.3.3 Other Information Needed for Human
Health Assessment 31
2.3.3.1 Pharmacokinetics and mechanism of
action 31
2.3.3.2 Monitoring of human biological samples 33
2.3.3.3 Environmental considerations 33
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Concents
CHEMICAL AND PHYSICAL INFORMATION
3.1
3.2 PHYSICAL AND CHEMICAL PROPERTIES
35
CHEMICAL IDENTITY 35
TOXICOLOGICAL DATA
4.1 OVERVIEW
4.2 INORGANIC ARSENIC
4.2.1 Overview
4.2.2 Toxicoklnecics
4.2.2.1 Overview ...
4.2.2.2 Absorption .
4.2.2.3 Distribution
4.2.2.4
4.2.2.5
4.3
Metabolism
Excretion
4.2.3 Toxicity
4.2.3.1 Lethality
4.2.3.2 Systemic/targe: organ toxicity
4.2.3.3 Developmental coxicity
4.2.3.4 Reproductive toxicity
4.2.3.5 Genotoxicity
4.2.3.6 Carcinogenicity
4.2.4 Interactions with Other Chemicals
ORGANIC ARSENIC
4.3.1 Overview
4.3.2 Toxicokinetics
4.3.2.1 Methanearsonates
Phenylarsonates
Fish arsenic
Arsine and methylarsines
4.3.3
4.3.2.2
4.3.2.3
4.3.2.4
Toxicity
4.3.3.1
4,
4.
4.
4.
3.2
3.3
3.4
3.3.5
Methanearsonates
Phenylarsonates
Fish arsenic
Arsine and methylarsines
Summary
MANUFACTURE, IMPORT, USE, AND DISPOSAL
5.1 OVERVIEW
5.2 PRODUCTION
IMPORT
USES
DISPOSAL
5.3
5.4
5.5
ENVIRONMENTAL FATE
6.1 OVERVIEW
6.2 RELEASES TO THE ENVIRONMENT
6.2.1 Anthropogenic
6.2.2 Natural
6 . 3 ENVIRONMENTAL FATE
6.3.1 Atmosphere
6.3.2 Surface Water
6.3.3 Groundwater
6.3.4 Soil
6.3.5 Biota
35
41
41
41
41
42
42
42
44
47
49
50
50
50
54
54
55
56
60
61
61
62
62
62
63
63
63
63
65
66
66
67
69
69
69
69
69
70
71
71
71
71
71
74
74
74
74
75
75
vi
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Cone en cs
7 . POTENTIAL FOR HUMAN EXPOSURE ......................... 77
7 . 1 OVERVIEW ........................................... 77
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ..... 77
7.2.1 Water ....................................... 77
7.2.2 Air ............................................. 78
7.2.3 Soil ........................................... 78
7.2.4 Biota and Food ............................... 78
7.2.5 Resulting Background Exposure Levels .......... 78
7 . 3 OCCUPATIONAL EXPOSURES ............................. 81
7.4 POPULATIONS AT HIGH RISK ............................. 81
7.4.1 Above -Average Exposure ........................ 81
7.4.2 Above-Average Sensitivity ....................... 82
8 . ANALYTICAL METHODS ................................ ' ........... 83
8 . 1 ENVIRONMENTAL MEDIA ................................... 83
8.1.1 Air .............................................. 83
8.1.2 Water ........................................... 83
8.1.3 Soil ............................................ 85
8.1.4 Food ............................................. 85
8 . 2 BIOMEDICAL SAMPLES .................................... 85
8.2.1 Fluids and Exudates ............................ 85
8.2.2 Tissues .......................................... 85
9 . REGULATORY AND ADVISORY STATUS ............................... 87
9 . 1 INTERNATIONAL ........................................... 87
9 . 2 NATIONAL ................................................ 87
9.2.1 Regulations ...................................... 87
9.2.1.1 Air .................................... 87
9.2.1.2 Water ................................. 90
9.2.1.3 Reportable quantities .............. 90
9.2.1.4 Waste disposal ...................... 90
9.2.1.5 Pesticide ............................ 91
9.2.2 Advisory Guidance ............................ 91
9.2.2.1 Air levels ........................ 91
9.2.2.2 Water levels ........................ 91
9.2.3 Data Analysis ................................... 92
9.2.3.1 Reference dose ...................... 92
9.2.3.2 Carcinogenic potency .................. 92
9.3 STATE ................................................. 93
9.3.1 Regulations .................................... 93
9.3.2 Advisory Guidance ............................. 93
10 . REFERENCES ................................................ 95
11. GLOSSARY ..................................................
APPENDIX: PEER REVIEW ........................................ 125
VLl
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LIST OF FIGURES
1.1 Health effects from breathing inorganic arsenic 4
1.2 Health effects from ingesting inorganic arsenic 5
2.1 Effects of inorganic arsenic — oral exposure 13
2.2 Levels of significant exposure for inorganic arsenic — oral ... 14
2.3 Dose-response relationship for arsenic-induced skin cancer
in humans 16
2.4 Effects of inorganic arsenic--inhalation exposure 19
2.5 Levels of significant exposure for inorganic arsenic--
inhalation 20
2.6 Dose-response relationship for lung cancer in
occupationally exposed workers 23
2.7 Availability of information on health effects of arsenic
(human data) 29
2.8 Availability of information on health effects of arsenic
(animal data) 3°
ix
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LIST OF TABLES
2.1 Summary of key studies on oral toxicity of arsenic
in humans 12
2.2 Summary of key human studies on exposure to
airborne arsenic 18
2.3 Summary of lung cancer risk estimates 24
2.4 Summary of ongoing research 32
3.1 Chemical identity of arsenic and selected inorganic
arsenic compounds 36
3.2 Chemical identity of arsine and selected organic
arsenic compounds 37
3.3 Physical and chemical properties of arsenic and selected
inorganic arsenic compounds 38
3.4 Physical and chemical properties of arsine and selected
organic arsenic compounds 39
6.1 Arsenic releases to the environment in 1979 72
6.2 Estimates of arsenic emissions from natural sources 73
7.1 Arsenic levels in foods 79
7.2 Summary of estimated levels of human exposure
to arsenic 80
8.1 Analytical methods for arsenic in environmental samples 84
8.2 Analytical methods for arsenic in biological samples 86
9.1 Regulations and guidelines applicable to arsenic 88
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS ARSENIC?
Arsenic is a naturally occurring element in the earth's crust. Pure
arsenic is a gray-colored metal, but this form is not common in the
environment. Rather, arsenic is usually found combined with one or more
other elements such as oxygen, chlorine, and sulfur. Arsenic combined
with these elements is referred to as inorganic arsenic, whereas arsenic
combined with carbon and hydrogen is referred to as organic arsenic.
Many arsenic-containing substances, both inorganic and organic, are
naturally occurring, while others are man-made. It is important to
maintain a distinction between inorganic and organic arsenic, since the
organic forms are usually less toxic than the inorganic forms.
1.2 HOW MIGHT I BE EXPOSED TO ARSENIC?
Arsenic is very widely distributed in the environment, and all
humans are exposed to low levels of this element. For most people, food
constitutes the largest source of arsenic intake (about 25 to 50
micrograms per day - a microgram is one millionth of a gram), with lower
amounts coming from drinking water and air. Some edible fish and
shellfish contain elevated levels of arsenic, but this is predominantly
in an organic form ("fish arsenic") that has low toxicity. Above-average
levels of exposure are usually associated with one or more of the
following situations:
• Natural mineral deposits in some geographic areas contain large
quantities of arsenic, and this may result in elevated levels of
inorganic arsenic in water. If this water is used for drinking,
high exposures may result.
• Some waste-chemical disposal sites contain large quantities of
arsenic, although the chemical form (inorganic or organic) is often
unknown. If the material is not properly stored or contained at the
site, arsenic may escape into the water, increasing the chances
that nearby residents might be exposed.
• Elevated levels of arsenic in soil (due either to natural mineral
deposits or to contamination from human activities) may lead to
exposure from ingesting soil. This is of particular concern for
small children who swallow small amounts of soil while playing
• Manufacturing (smelting) of copper and other metals often releases
inorganic arsenic into the air. Thus, workers in metal smelters and
nearby residents are exposed to elevated arsenic levels.
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2 Section 1
• Low levels of arsenic are found in most fossil fuels (oil. coal,
gasoline, and wood), so burning of these materials (in power
stations, furnaces, stoves, automobiles, etc.) results in low
levels of inorganic arsenic emissions into the air. There are also
low levels of arsenic in cigarette smoke.
• The main use of arsenic in this country is for pesticides. Some
products, mostly weed killers, use organic arsenic as the active
ingredient. Other pesticides use inorganic forms of arsenic to kill
plants, insects, or rodents, or to preserve wood. Persons who
manufacture or use these pesticides or who handle treated wood may
be exposed to arsenic if adequate safety procedures are not
followed. Widespread application of pesticides (e.g., in orchards
and fields and along roadways) may lead to water or soil
contamination, creating the possibility for more widespread
exposure of residents in the area.
• In the past, inorganic arsenic was contained in household products
such as paints, dyes, and rat poisons, and in medicines for
diseases such as asthma and psoriasis. However, these products are
no longer in general use; therefore, exposure from these sources is
now unlikely.
1.3 HOW DOES ARSENIC GET INTO NT BODYT
Arsenic enters the body principally through the mouth, either in
food or in water. Most ingested arsenic is quickly absorbed through the
stomach and intestines and enters the blood stream, although this varies
somewhat for different chemical forms of arsenic. Arsenic which is
inhaled is also well-absorbed through the lungs Into the blood stream.
Small amounts of arsenic may enter-the body through the skin, but this
is not usually an important consideration.
Most arsenic that is absorbed into the body is converted by the
liver to a less-toxic form that is efficiently excreted in the urine.
Consequently, arsenic does not have a strong tendency to accumulate in
the body, except at high exposure levels.
1.4 HOW CAN ARSENIC AFFECT NT HEALTH?
Inorganic arsenic has been recognized as a human poison since
ancient times, and large doses can produce death. Lower levels of
exposure may produce injury in a number of different body tissues or
system: these are called "systemic" effects. When taken by mouth, a
common effect is irritation of the digestive tract, leading to pain.
nausea, vomiting, and diarrhea. Other effects typical of exposure by
mouth include decreased production of red and white blood cells,
abnormal heart function, blood vessel damage, liver and/or kidney
injury, and impaired nerve function causing a "pins and needles" feeling
in the feet and hands. There is evidence from animal studies that high
oral doses during pregnancy may be damaging to the fetus, but this has
not been well studied in humans.
Perhaps the single most characteristic systemic effect of oral
exposure to inorganic arsenic is a pattern of skin abnormalities
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Public Health Statement 3
Including the appearance of dark and light specs on the skin, and small
"corns" on the pains, soles, and trunk. While these skin changes are not
considered to be a health concern in their own right, some of the corns
may ultimately progress to skin cancer. In addition, arsenic ingestion
has been reported to increase the risk of cancer inside the body,
especially in the liver, bladder, kidney, and lung.
Inhalation exposure to inorganic arsenic dusts or fumes sometimes
produces the same types of systemic health effects produced by oral
exposure. However, this is not c6mmon, and the effects are usually mild.
Of much greater concern is the ability of inhaled arsenic to increase
the risk of lung cancer. This has been observed mostly in humans exposed
to high levels of airborne arsenic in or around smelters, but lower
levels may increase lung cancer risk as well.
Direct dermal contact with arsenic compounds, frequently from
inorganic arsenic dusts in air. may result in mild to severe irritation
of the skin, eyes or and throat.
Despite all the adverse health effects associated with arsenic
exposure, there is some evidence that low levels of exposure may be
beneficial to good health. Animals maintained on a diet with unusually
low concentrations of arsenic did not gain weight normally, and they
became pregnant less frequently than animals maintained on a diet
containing a more normal (but low) concentration of arsenic. Also, the
offspring from these animals tended to be smaller than normal, and some
died at an early age. The estimated daily dose of arsenic that is
beneficial is quite small (about the same as normally supplied in the
diet), and no cases of arsenic deficiency in humans have been found.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO ARSENICT
Several different ways exist for testing people for arsenic
exposure. Measuring the levels of arsenic in urine is the best way to
determine exposures that occurred within the last one to two days.
However, some common tests do not distinguish nontoxic forms such as
fish arsenic from other forms, so a high concentration of arsenic in
urine may not necessarily indicate that a health problem exists.
Measurement of arsenic in hair or fingernails is sometimes used to
detect chronic exposures, but this method is not very reliable for
detecting low levels of arsenic exposure.
1.6. WHAT LEVELS OP EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
The amount of arsenic intake that is required to cause a harmful
effect depends on the chemical and physical form of the arsenic. In
general, inorganic forms of arsenic are more toxic than organic forms.
and forms that dissolve easily in water (soluble forms of arsenic) tend
to be more toxic than those that dissolve poorly in water. Also,
toxicity depends somewhat on the electric charge (the oxidation state or
valence) of the arsenic.
The graphs on the following pages (Figs. 1.1 and 1.2) show the
relationship between exposure to soluble forms of inorganic arsenic and
known health effects. In the first set of graphs labeled "Health effects
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Sacelon 1
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
CONG IN
AIR
(ng/m3)
EFFECTS
IN
HUMANS
EFFECTS
IN
ANIMALS
CONC IN
AIR
(ng/m3)
EFFECTS
IN
HUMANS
ESTIMATED
DEATH LEVEL
INJURY TO
FETUS
IMMUNE
SYSTEM
EFFECTS"
100.000
100.000
10.000
10.000
1000
1000
IMMUNE
SYSTEM
EFFECTS
100
100
SKIN
DISORDERS
10
10
1.0
1 0
Flf. 1.1. Hetftfc effect! froa brcattaf taorfuk
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Public Wealth Scacemenc
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DOSE
(ng/kg/day)
EFFECTS
IN
HUMANS
EFFECTS
IN
ANIMALS
DOSE
(iig/kg/day)
EFFECTS
IN
HUMANS
DEATH •<
r 100.000
^ 10.000
1000
100
DEATH
> SYSTEMIC
EFFECTS
10
1.0
NO OBVIOUS
EFFECTS IN
DOGS OR —
MONKEYS
100.000
10.000
BENEFICIAL
1000
100
SYSTEMIC
EFFECTS/
SKIN LESIONS
10
1.0
Fig. 1.2. Health effects from ingesting inorganic arsenic.
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Section 1
from breathing inorganic arsenic," exposure is measured in raicrograras of
arsenic per cubic meter of air Oig/m3). In all graphs, effects in
animals are shown on the left side, effects in humans on the right.
In the second set of graphs, the same relationship is represented
for the known "Health effects from ingesting inorganic arsenic."
Exposures are measured in micrograms of arsenic per kilogram of body
weight per day (^g/kg/day) .
As shown in the figures, most studies indicate that humans are more
sensitive to arsenic than animals, which means that studies in animals
are of limited utility in predicting exposure levels affecting humans.
Studies in humans indicate that there is considerable variation
among different individuals, and it is difficult to identify with
certainty the exposure ranges of concern. For example, some humans can
ingest over 150 ^gAg/day without any apparent ill-effects, while more
sensitive individuals in exposed populations often begin to display one
or more of the characteristic signs of arsenic toxicity at oral doses of
around 20 ^gAg/day (about 1000 to 1500 jig/day for an adult). Effects
are usually mild at this exposure level, becoming more severe as doses
become higher. Doses of 600 to 700 /igAg/day (around 50,000 ng/day in an
adult or 3,000 A»g/day in an infant) have caused death in some cases.
When exposure is from contaminated water, concentrations of around 100
to 200 micrograms per liter (/*g/L) do not seem to produce significant
noncancer health risks, while typical signs of arsenic toxicity have
been reported in several populations drinking water with 400 /jg/L of
arsenic or more. The levels of arsenic that most people ingest in food
or water (around 50 j»g/day) are not usually considered to be of health
concern.
For inhalation exposure, air concentrations of around 200 Mg/m3 are
associated with irritation to nose, throat and exposed skin, and higher
levels may occasionally lead to mild signs of systemic toxicity similar
to that seen with oral exposure.
Direct skin contact with arsenic compounds can cause mild to severe
skin irritation, but no reliable dose estimates are available on the
exposure .levels at which these effects begin to appear.
Because it is believed that cancer -causing agents can increase risk
even at very low exposures, Figs. 1.1 and 1.2 do not identify dose
ranges for skin cancer or lung cancer. From available data in humans.
the EPA has calculated that lifelong ingestion of 1 ng/kg/day (around 50
to 100 Mg/day in an adult) is associated with a risk of skin cancer of
about 0.1% (1/1000). This dose level is comparable to drinking water
containing 25 to 50 ^g/L for a lifetime. Lifelong inhalation of air
containing 1 /*g/m3 is estimated by EPA to cause a lung cancer risk of
about 0.4% (4/1,000). Since there is considerable uncertainty in the
cancer risk assessment process, quantitative estimates of cancer risk
such as these are intentionally conservative. That is, the actual risks
of cancer could be lower, but are unlikely to be higher.
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Public Health Seacement 7
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH?
The federal government has taken a number of steps to protect
humans from arsenic. The Environmental Protection Agency (EPA) has
established limits on the amount of arsenic that can be released into
the environment from factories which manufacture or use arsenic. EPA has
also restricted or cancelled many of the uses of arsenic in pesticides
and is considering further restrictions. The EPA has established a
Maximum Contaminated Level (MCL) of 50 ng/L for arsenic in drinking
water; this value is presently undergoing review by the Agency as part
of a rulemaking to establish a new MCL for arsenic. The Occupational
Safety and Health Administration (OSHA) has established a maximum
permissible airborne exposure limit of 10 A«g/m3 for inorganic arsenic
and 500 ^g/m3 for organic arsenic in various workplaces where arsenic is
used.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on Che health effects
concerning exposure to arsenic. The purpose of this section is to
present levels of significant exposure for arsenic based on key
toxicological studies, epidemiological investigations, and environmental
exposure data. The information presented in this section is critically
evaluated and discussed in Sect. 4, Toxicological Data, and Sect. 7,
Potential for Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of arsenic and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of arsenic that have been monitored in human fluids and
tissues and information about levels of arsenic found in environmental
media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse-Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to arsenic in the scientific literature and displays
these data in three-dimensional graphs consistent with the format in
Sect. 2.2. The purpose of this section is to suggest where there might
be insufficient information to establish levels of significant human
exposure. These areas will be considered by the Agency for Toxic
Substances and Disease Registry (ATSDR), EPA, and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order co
develop a research agenda for arsenic.
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10 Section 2
2.2 LEVELS OF SIGNIFICANT HUMAN EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas — lethality, systemic/target
organ toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and careinogenieity. The data are discussed in terms of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. Where appropriate, adjustments for exposure duration or
intermittent exposure protocol were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental vs
actual human exposure conditions were considered when estimates of
levels posing minimal risks to human health were made for noncancer end
points. These minimal risk levels were derived for the most sensitive
noncancer end point for each exposure duration by applying uncertainty
factors. These levels are shown on the graphs as a broken line starting
from the actual dose (level of exposure) and ending with a concave -
curved line at its terminus. Although methods have been established to
derive these minimal risk levels (Barnes et al. 1987), shortcomings
exist in the techniques that reduce the confidence in the projected
estimates. Also shown on the graphs under the cancer end point are low-
level risks (10'4 to 10-7) reported by EPA. In addition, the actual dose
(level of exposure) associated with the tumor incidence is plotted.
2.2.1 Key Studies
Investigation and analysis of the toxicity of arsenic are
complicated by the finding that different chemical forms of arsenic are
not equally toxic. In particular, methylated derivatives and more
complex organic derivatives such as "fish arsenic" (arsenobetaine) are
considerably less toxic than inorganic arsenic. For example, oral LDso
values in animals range from 10 to 300 mg/kg for inorganic arsenic
compounds, while LDso values for the monomethyl and dimethyl derivatives
of arsenic acid range from 600 to 2600 mgAg. Arsenobetaine is even less
toxic, producing no clear symptoms at doses of 10,000 mg/kg. For this
reason, this section will focus on studies that address the toxicity of
inorganic arsenic. A summary of available toxicity data on the most
important organic arsenic compounds is presented in Sect. 4.3.
Among inorganic arsenic compounds, those that are easily soluble in
water tend to have more acute toxicity than the poorly soluble ones, and
arsenic(III) compounds are generally observed to be somewhat more toxic
than arsenic(V) compounds. While it is possible to investigate the
-------
Health Effaces Summary 11
toxicity of individual arsenic compounds in animals, information on
arsenic valence and chemical form is often not available for human
studies, and exposure must be expressed in terms of total inorganic
arsenic.
An additional difficulty is raised by the observation that most
studies indicate that animals are less sensitive to the toxic effects of
arsenic than are humans. For example, reported lethal doses in animals
(10 to 300 mg/kg) are significantly higher than lethal doses reported in
humans (0.6 to 2 mg/kg). Similarly, chronic oral exposure of humans to
inorganic arsenic at doses of 50 to 100 /ig/kg/day is frequently
associated with neurological or hematological signs of arsenic toxicity,
but no characteristic neurological or hematological signs of arsenism
were detected in young monkeys exposed to 3700 MgAg/day of arsenate for
one year (Heywood and Sortwell 1979), in dogs exposed to 3700 jig/kg/day
of arsenite or arsenate for two years (Byron et al. 1967), or in rats
given intraperitoneal injections of As203 at an average dose of 700
^g/kg/day for 18 months (Schaumberg 1980). Moreover, while there is good
evidence that arsenic is carcinogenic in humans by both the oral and
inhalation routes, evidence of arsenic -induced carcinogenicity in
animals is mostly negative. For these reasons, dose-response data from
animals are not judged to be reliable for determining levels of
significant human exposure and will not be considered except in the
absence of any human data.
2.2.1.1 Oral
Many reports describe the symptoms and course of inorganic arsenic
poisoning in humans, but only a few of these studies provide sufficient
information on exposure levels to permit accurate estimates of the
ingested dose. These studies are summarized in Table 2.1, and the data
from this table are displayed graphically in Figs. 2.1 and 2.2. While no
one study by itself provides a full description of the dose -response
relationships, taken together, these studies do provide an adequate
basis for estimating NOAEL values for the principal end points of
arsenic toxicity in humans.
Lethality. Reports by Armstrong et al. (1984) and Hamamoto (1955)
indicate that acute or subacute lethality may occur at doses of around
600 MgAg/day or higher. Lethality has not been associated with doses of
100 MAg/day or less.
Systemic/target organ toxic Lty. Although some humans can ingest up
to 150 pgAg/day without apparent ill-effects (Bencko 1987). a number of
studies indicate that, in more sensitive individuals, doses as low as 20
to 60 pgAg/day (roughly 1 to 4 mg/day in an adult) may produce one or
more of the characteristic signs of arsenic toxicity, including gastro-
intestinal irritation, anemia, neuropathy, skin lesions, vascular
lesions, and hepatic or renal injury (Tay and Seah 1975, Mizuta et al
1956. Silver and Wainman 1952. Huang et al. 1985, Borgono et al. 1980,
Tseng et al. 1968). The severity of symptoms in affected individuals
generally tends to increase as a function of exposure duration (Tseng
1977), although in some individuals, effects may occur after relatively
brief exposure periods (e.g., see Mizuta et al. 1956). In most cases of
subchronic or chronic exposure, many or all of the signs of arsenic
-------
ToMrll fMiry ol k«y nttjlka «n Mil loikfc. «l
Chcmicil
lorn.
"
A.O.
"*
AMIII)
*
AncnK
Sulfide
*
AMIII)
*
*
V
*
'
*
E.p«,,.
DDK
Source («|/k|/dr DimunB
Wtui 400-1000 1 2 rat*
(lOOnf/D
Milk po»dei 700 11 dan
IIS liO|/k|)
Wiicr 60 140 Chronic
(06a|/L)
Fo»kf-| JO- 100 Svbchronic
Saluiun
W.ier 6010 2-llyun
(06-Olmt/L)
Madicia.li )) Snbchfouc
Soy Suet M 2 20 dayi
»»_i>i t JO 1 1 21 rnonlhe
Wiiei 40 II ycnn
(0601/L)
W.ier 10-40 Chronic
(OI-04UI/L)
Wiicr 20-10 Chronic
(04-06 OH/L)
W.ur 20 Ckronic
(01-1 IBI/L)
Wiier 20 Ckronic
(OJ Of/LI
Wnla 20 Chrome
(04n|/L)
Wua 10 Chronic
(0001-0 4 a|/L)
Wua 6 Chronic
(02B|/U
Witti 6 Chronic
(02ai|/U
Witer 0 7 Cnranic
(0-002 ni/U
Wild 0 2 Chronic
(000) of /I)
Noacuanofcnic u|ni of loucily obtcmd C.ruaofcnic effect.
Gl Hcaulalaiic NCWIIU/ Skin HCD.IK/ CVS Skin Oihcr
UlhiUl, diurtu .boonnilun oc.rop.lhy la.,., leM, t^,, CMlccf lumorl Slu(1, |l
* * + * Rciidcnu of
Aniul.|iUi thik
+ »•»%) +(21/262) 262Adulu
*'12*' 2 7.000 children
+ (21%) +(2J%) +01%) +(97%) +(19%) +(6/74) +(4/74) 74 .dull,
+ (70%) +(!)%) +(]%) +(20%) +(60%) +(10%) 220»dy|ii
+ + + A
* 1 piiicnl (uihnu)
+ (12%) +(16%) +(4S%) 116«Kkcr.ui
pUni
+ 129%) looo
icnool children
+ «!•%) +(09%) +(428/40.421) 40000 Tii.inac
+(SMR-)M-6)2C +(SMR- 170 2009) 140.000 Tii.uac
+ (AOR-27-19)« 279cuc,indl6»
oonuob
+ <"«») +(4/296) WOrcudcouof
Mcucu 'UUfc
Nff NS "S Groupi of l)io)2
in 6 U S cilia
NS "S NS NS »0 Mormon.
NS NS NS 211 Alukini
NS NS NS 7)00 Tniouac
NS 300 raidcnu of
Hciiun »ill>|c
Reference*
Arnuironi
ci .1 1914
ll.ouaialo 19))
/.Idivir 1974
ricn 196)
Bor|.no tnd
Greiber 1972
l.tiodSuh
197)
Milul. cl .1
19)6
Silver .nd
Wnnm.n 19)2
Hu.nf
ci •! 191)
Bm|.no cl .1
1910
1961
Chen ci .1
191)
Chen cl •!
1916
Ccbrun cl il
191)
Vikniinc ci nl
191)
Souihxick a ml
1911
Huiinflaa
cl .4 1971
Ticnf ci .1
1961
Ccbrun cl .1
191)
N
to
n
n
•U ma reported Mbcrvw by .ylhar or by U>A IM7b cikvliled by uioninf 2 L/day ol »«lei lor . 70-k| odull or I I /diy lor i lO-kf child
1 hen**! lam unknown twi prawmod la be inar|inn .nenic
SMN - tund.rdind non.liiy i.liu
|nifit«ally diflcrcol Iron coalrol or cipctlcd
-------
Health Effects Summary 13
ANIMALS
100.000 i- O MOUSE. DEVELOPMENTAL (As V)
• MOUSE. HAMSTER DEVELOPMENTAL (A* 111)
O MOUSE. HAMSTER. DEVELOPMENTAL (A* III)
10.000 -
1000
100
O DOG. MONKEY. ANEMM. NEUROPATHY. CHRONIC
O MOUSE. REPRODUCTION. 3 GENERATIONS
1 I—
HUMANS
1 00.000 1-
10.000
1000
100
10
LETHALITY (ADULTS)
A LETHALITY (INFANTS)
A ANEMM. SUBCHRONIC
A Gl DISTRESS. NEUROPATHY CHRONIC
A SKIN. VASCULAR LESIONS CHRONIC
- A SKIN. BLOOD. NERVE
• LOAEL FOR ANIMALS A LOAEL FOR HUMANS
ONOAEL FOR ANIMALS A NOAEL FOR HUMANS
Fig. 2.1. Effects of inorganic arsenic—oral exposure.
-------
14 Section 2
ACUTE
(SI 4 DAYS)
DEVELOP- TARGET
LETHALITY MENTAL ORGAN
(ng/Vg/day)
100.000
10.000
[I
INTERMEDIATE
(15-364 DAYS)
TARGET REPRO-
ORGAN DUCTION
CHRONIC
(2365 DAYS)
TARGET
ORGAN CANCER
r. m. h
O m(As V)
• h. m (As III)
O h. m (As III)
1000
O m (3 GENERATIONS)
100
10
10
I
(Gl. NERVE) A (Gl. NERVE
I BLOOD)
t
I
I
vis
I
I
vlx
(Gl. NERVE
BLOOD, SKIN)
A (SKIN
CANCER)
01
001
0001
00001 l-
r RAT
m MOUSE
h HAMSTER
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
A LOAEL FOR HUMANS
A NOAEL FOR HUMANS
I MINIMAL RISK
' LEVEL FOR
J EFFECTS OTHER
Ox THAN CANCER
10~4 —
10~5 —
10-6 —
io-7—I
ESTIMATED
UPPER-BOUND
HUMAN
CANCER
RISK LEVELS
Fig. 2.2. Levcb of significant exposure for ioorguk arsenic—oraL
-------
Wealth Effects Summary 15
coxiclty are detected together, indicating that the dose-response
relationships for the various systemic end points are fairly similar. If
any one effect is most sensitive, it is probably the appearance of the
characteristic pigmentation pattern and hyperkeratotic lesions. Although
it is difficult to identify a no-effect level with certainty, doses of
around 10 jjgAg/day (about 0.7 mg/day in an adult) are not generally
expected to cause measurable signs of arsenic intoxication (e~.g.,
Valentine et al. 1985, Southwick et al. 1981).
Developmental toxicIty. Studies in animals have revealed that very
high oral doses of sodium arsenate (in excess of 100 mg/kg) may be
teratogenic and fetotoxic, while oral doses of 60 to 100 mg/kg/day have
no significant effect (Hood et al. 1977, 1978). Sodium arsenite appears
to be somewhat more toxic, causing increased malformations and prenatal
mortality in mice and hamsters dosed by gavage at levels of 25 to 40
mg/kg/day (Baxley et al. 1981. Hood and Harrison 1982. Willhite and Ferm
1984). These researchers observed no effect at 20 mgAg/day. It should
be noted that these dose levels may cause maternal lethality in exposed
animals and are considerably higher than levels which may cause
lethality in humans (0.6 mg/kg/day). On this basis, it seems likely that
developmental end points are not of primary concern at exposure levels
lower than those which cause maternal toxicity.
Reproductive toxicity. The effects of arsenic exposure on
reproductive parameters have not been well studied. Limited data in mice
suggest that ingestion of water containing 5 mg/L of arsenite (about 0 7
mg/kg/day) for three generations does not significantly impair
reproductive success (Schroeder and Mitenner 1971).
Genotoxicity. The genotoxicity of various inorganic arsenic
compounds has been investigated in a number of prokaryotic and
eukaryotic test systems. Although data are not entirely consistent, che
weight of evidence indicates that arsenic is clastogenic (i.e., causes
chromosomal breaks and aberrations) and induces sister chromatid
exchange (SCE) in cultured mammalian cells (Jacobson-Kram and Montalbano
1985). Trlvalent arsenic compounds (NaAs02. As203, AsCl3, and NaAs02)
tend to be more potent in causing chromosomal aberrations than
pentavalent compounds (Na2HAs04, H3As04, and As205) (Nakamuro and Sayaco
1981). Several studies have reported increased frequencies of SCEs and
chromosome aberrations in lymphocytes from exposed humans, but these
studies have limitations and must be interpreted with caution (EPA
1984a). Despite these cytogenetic effects, arsenic appears to be either
inactive or extremely weak for the induction of specific gene mutations
in vivo.
CarcinogenicIty. The study of Tseng et al. (1968) generally
provides the best available description of the dose-response
relationship for skin cancer. In this study, individuals were classified
into one of three exposure groups on the basis of the concentration of
arsenic in their drinking water: low - 0 to 0.29 mg/L; medium - 0 3 co
0.59 mg/L; high - 0.6 mg/L or more. EPA (1987a) estimated that the
average daily intake of arsenic by these groups was 10.8, 29.9. and 50 9
MgAg/day for males and 6, 8, 18.8, and 32.0 pgAg/day for females.
respectively. As shown in Fig. 2.3. skin cancer prevalence rates in
these groups were proportional to arsenic exposure level. This study Is
-------
16 Section 2
240
~ 210
o
o
UJ
(0
<
o
UJ
oc
UJ
o
z
UJ
Ul
tr
0.
150
120
90
60
30
0 TO 0.29 0.30 TO 0.59 0.60 OR MORE
DRINKING WATER CONCENTRATION (mg/L)
Fig. 2.3. Dwe-respoue relationship for weak-induced skin cancer in
from Tseng et al. 1968.
Source: Adapted
-------
Health Effects Summary 17
consistent: with a number of other studies (see Table 2 1) that detected
increased frequency of skin cancer and/or internal cancer in individuals
exposed to water containing 0.3 mg/L or more. Failure to detect
significant increases at lower doses (e.g., Harrington et al. 1978,
Southwick et al. 1981) may be due to a lack of statistical power in che
studies (Andelman and Barnett 1983), or it could suggest that arsenic-
induced cancers have a threshold dose. Although toxicokinetic data
regarding arsenic methylation (see Sect. 4.2.2 on toxicokinetics)
provide some support for this concept, the EPA has judged that the
evidence is not adequate at present to conclude that arsenic-induced
cancer has a nonzero threshold (EPA 1987b).
Based on the data of Tseng, EPA (1984a) originally calculated that
a dose of 1 ^ig/kg/day corresponded to a skin cancer risk of 1.58 x 10"2
More recently, EPA (1987b) has refined these calculations, having
estimated that a dose of 1 /ig/kg/day corresponds to a risk of 1.5 x 10 "^
As with any cancer risk calculation, there is considerable
uncertainty in this value, especially when extrapolated to very low
exposure levels. In addition, there are a number of limitations to che
Tseng study that may introduce uncertainty concerning the applicability
of this risk estimate to the U.S. population. These uncertainties
include (1) possible exposure of the Taiwanese subjects to arsenic from
sources other than drinking water, (2) an above-average death rate in
the exposed population from Blackfoot disease, (3) differences in diet
between the Taiwanese and U.S. populations, (4) exposure to other
chemicals besides arsenic, (5) lack of blinding in the researchers who
collected data on exposure levels and symptoms in the study populations.
and (6) use of prevalence rates to estimate cumulative cancer incidence
rates (EPA 1987b). Although these uncertainties may cast some doubt on
the precise quantitative value calculated for the oral cancer potency
factor for arsenic, they do not challenge the conclusion that arsenic
ingestion does increase the risk of skin cancer.
None of the available studies provide adequate dose-response daca
to calculate the risk of internal cancers following exposure to arsenic
(EPA 1987b).
2.2.1.2 Inhalation
Host information on human exposure to arsenic dusts and fumes is
derived from occupational settings such as smelters and chemical planes
It should be noted that significant oral and dermal exposures are likely
under these conditions, and that exposure to other metals and chemicals
is also common. Table 2.2 summarizes available reports on health effects
in humans exposed to airborne arsenic. Studies with quantitative
estimates of exposure are shown graphically in Figs. 2.4 and 2 5
Lethality. Inhalation exposure is not usually associated normally
with acute lethality in animals or humans. Webb et al. (1986) reported
that the maximally tolerated nonlethal dose of As203 given by
intratracheal instillation to rats was 17 mg/kg. If a rat inhales about
1 mVkg/day (Guyton 1947) . and approximately 40% of the airborne arsenic
is deposited in the lung (Holland et al. 1959), this would correspond co
an air concentration of over 40 rag/m^.
-------
18 Section 2
TaMe 2.2. Summary of key human undies on exposure to airborne aneaic
Study group
Copper smelter
workers
1 276 smelter
workers
348 smelter
workers
Sodium anenite
factory
Chem workers
Mamt./packers
Controls
Children near
gold smelter
1 1 smelter
workers
Women working
in or living
near smelter
8000 white male
smelter workers
1800 male
smelter workers
2800 male
smelter workers
1900 pesticide
plant workers
2802 male
smelter worken
Airborne
exposure data
High variable;
very high
(over 50 mg/mj)
in some locations
Up to 7 mg/m1
02'
04- 1.0 mg/m3
0.06-0. 16 mg/m1
Not reported
None
None
None
3000-36.000
Mg/m'-years
250-16.000
wg/m'-yean
90-4000
pg/m'-yean*
40-19.500
Mg/m'-years
<750-45,000
Mg/m'-years
Results
Dermatitis, mostly on exposed areas of skin; more
common in work areas of high exposure
Rhinopharyngolaryngitis. tracheobronchitis
One possible case of systemic effects: no
hyperpigmentation; primary observation was
dermatitis, conjunctivitis, pharyngitis
HyperkeraUMCs riiiiniillini
9/31 (29%) 28/31 (90%)
1/32(3%) 12/32(37%)
2/56(4%) 10/56(18%)
Dermatosea. mostly on face and neck
Preclinical neurological effects detected by
EMC; correlation with arsenic levels in hair and
urine
Increased spontaneous abortion rate, decreased
birth weight
Exposure-dependent increase in lung cancer
mortality (overall SMR - 285)
Exposure-dependent increase in lung cancer
mortality (high dose SMR - 548)
Exposure-dependent increase in lung cancer
mortality (overall SMR - 189)
— . . .
cxposuremepenoent increase in lung cancer
mortality (high dose SMR - 694)
Exposure-dependent increase (nonlinear) in lung
cancer mortality (high dote SMR - 477)
References
Holmqvist 19SI
Lundgren >54
Pinto and
McGdl 1953
Perry et al
1948
Birmingham
et al 1965
Landau et al
1977
Nordstrom et al
I978a.b.c,d
Lee-Feldstein
1983
Higgins et al
1982
Enterlme and
Marsh (1982)
On et al (1974)
Enterlme
etal 1987
'ACGIH (1986); bated on urinary arsenic levels.
'Estimated from urinary arsenic levels.
-------
ANIMALS
100 000
10000
1000
100
10
101-
I RAT (MAXIMUM TOLERATED DOSE ACUTE
I MOUSE. FETOTOXICITY GESTATION DAYS 9-19
O MOUSE. FETOTOXICITY GESTATION DAYS 9-12
• MOUSE IMMUNOTOXICITY 1-20 DAYS
O MOUSE IMMUNOTOXICITY 1-20 DAYS
• LOAEL FOR ANIMALS O NOAEL FOR ANIMALS
A LOAEL FOR HUMANS
Health Effects Summary 19
HUMANS
100 000 1—
10000 -
1000 -
100
10
10
MILD SKIN DISORDERS
(HYPERPIGMENTATION
A HYPERKERATOSE5)
A DIRECT DERMAL IRRITATION
Fig. 2.4. Effects of inorganic arsenic—inhalation exposure.
-------
20 Section 2
ACUTE
(SI 4 DAYS)
(WJrtn3)
100.000
10.000
DEVELOP- TARGET
LETHALITY MENTAL ORGAN
• r
INTERMEDIATE
(15-364 DAYS)
TARGET
ORGAN
CHRONIC
(2365 DAYS)
TARGET
ORGAN CANCER
1000
100
10
10
I m (FETOTOXICITY)
m (IMMUNOTOXICITY) m (IMMUNOTOXICITY)
I I
I
&
(LUNG CANCER.
A 5 YEARS)
A (LUNG CANCER.
20 YEARS)
01
001
0001
00001
0 00001
r RAT • LOAEL FOR ANIMALS
m MOUSE O NOAEL FOR ANIMALS
MINIMAL RISK
LEVEL FOR
I EFFECTS OTHER
A LOAEL FOR HUMANS six THAN CANCER
A NOAEL FOR HUMANS
io-7j
ESTIMATED
UPPER-BOUND
HUMAN
CANCER
RISK LEVELS
F1f.2J. Letcb of rignifkaat expoon for horfufc
-------
Health Effects Summary 21
Systemic/target organ effecta. There is a general agreement among
studies of occupationally exposed workers that signs of systemic
toxicity (nausea, neuropathy, and hyperkeratoses) are infrequent and
generally mild. Rather, the primary noncarcinogenic health risk
associated with exposure to airborne arsenic is irritation of the skin
and mucous membranes (dermatitis, conjunctivitis, pharyngitis, and
rhinitis) (Pinto and McGill 1953, Vallee et al. 1960, Stokinger 1981.
ACGIH 1986).
Very few studies provide quantitative information on the
concentrations of arsenic in air that may cause dermatitis or systemic
effects. The data of Holmqvist (1951) and Lundgren (1954) reveal dermal
and mucosal irritation in workers who have been exposed to high levels
of arsenic Ln air, but they do not identify a threshold for these
effects. Perry et al. (1948) reported that chemical workers exposed to
about 0.4 to 1.0 mg/m3 inorganic arsenic in air manifested gross
pigmentation and an elevated frequency of hyperkeratinization, whereas
maintenance workers and packagers with a lower level of exposure
(estimated to be about 0.06 to 0.16 mg/m3 of air) displayed only a
slight tendency toward mild hyperpigmentation. Pinto and McGill (1953)
reported that dermatitis was common in smelter workers whose urinary
arsenic levels exceeded 0.4 mg/L, a value which probably corresponds to
an airborne exposure level of about 0.1 to 0.2 mg/m3 (Pinto et al. 1976,
ACGIH 1986). No cases of hyperpigmentation or hyperkeratoses were
observed in these workers. Based on these limited observations, it
appears that chronic exposure to concentrations of 0.4 mg/m3 or higher
in workplace air may result in characteristic systemic effects in skin,
and that exposure to levels of 0.1 to 0.2 mg/m3 may cause direct dermal
irritation. Levels below 0.1 mg/m3 do not appear likely to cause
significant noncarcinogenic effects. Because these data are derived from
the workplace where exposure is for 8 h/day 240 days/year, these values
must be divided by a factor of 4.56 to yield values appropriate for
continuous exposure (EPA 1984a).
Aranyi et al. (1985) have investigated the effect of inhalation
exposure on pulmonary antibacterial defenses in mice. Animals were
exposed to aerosols containing As203, 3 h/day for 1 to 20 days.
Concentrations of 270 Mg/»3 arsenic or higher resulted in significantly
increased mortality following Infection with active pneumonia-causing
bacteria, while concentrations of 125 Mg/m3 or lower had no significant
effect. This action of arsenic did not appear to be cumulative, since
the sane response was seen following 20 days of exposure as after 1 day
of exposure.
Developmental toxicity. There are very few reports dealing with
developmental effects of arsenic by the inhalation route. Limited data
suggest that women who work in or live nearby smelters may have higher
than normal abortion rates and lower than normal birth weights.
Nordstrom et al. (1978c) reported that the prevalence rate of congenital.
birth defects was about the same (3.0%) in Swedish women working in a
smelter as in women living in the same area but not working in the
smelter. However, there was a decrease in the average birth weight and
an increase In the incidence of spontaneous abortions in the female
workers, with the highest rate (17%) in women who had been employed
during their pregnancy (Nordstrom et al. 1978a,b). The incidence of
-------
22 Section 2
spontaneous abortion in women living near the plant was also higher than
average, although many of the women who lived nearby also worked in the
smelter (Nordstrom et al. 1978d). These observations should be
interpreted with caution, because these studies were designed to
evaluate the effects of smelter pollutants in general. This prevents
making conclusive statements about the specific effects of arsenic from
these findings. NagymaJtenyi et al. (1985) reported that inhalation
exposure of pregnant mice to 28.5 mg/m3 of As2<>3 (4 h/day on days 9 Co
12 of gestation) caused fetotoxic effects, while concentrations of 2.9
or 0.26 mg/m3 caused no changes except for a slight decrease in fetal
weight (9.9% and 3.1%, respectively).
Reproductive toxicity. No information was located on the
reproductive effects of inhalation exposure to arsenic in animals or
humans.
Genotoxicity. As described above for oral exposure, the weight of
evidence indicates that arsenic induces SCEs and chromosome aberrations,
but does not induce detectable gene mutations.
Carcinogenicity. Many studies report above-average lung cancer
rates in groups of people with above-average exposure to airborne
arsenic, but only a few contain adequate quantitative data on exposure
levels and durations to permit derivation of dose-response
relationships. EPA (1981, 1984a) has reviewed the available data and
calculated dose-response curves for cohorts exposed at the Anaconda
smelter in Montana (Lee and Fraumeni 1969; Lee-Feldstein 1983; Higgins
et al. 1982; Brown and Chu 1983a,b), the ASARCO smelter in Tacoma,
Washington (Enterline and Harsh 1982. Pinto et al. 1977), and a
pesticide plant (Ott et al. 1974). In most cases, cumulative exposure
(the time-weighted average of air concentration times years of exposure
expressed as Mg/m3-years) was taken to be the most appropriate index of
exposure, although in some cases (e.g., Enterline and Marsh 1982, Welch
et al. 1982), exposure duration did not appear to be as important as
exposure level. The calculations of exposure are quite complex in some
cases, and the interested reader is referred to the EPA documents (1981,
1984a) for a detailed description. Figure 2.6 shows one typical data set
(Lee-Fel'dstein 1983), which illustrates the approximately linear
increase in relative risk (the frequency of lung cancer in the exposed
group divided by the frequency of lung cancer in the control group) as a
function of increasing exposure. Relative risk was significantly
increased even at the lowest cumulative doses (290 jig/m3 for an average
of 20 years or 580 Mg/m3 for an average of 5.3 years) (EPA 1987a).
Adjusted for intermittent worker exposure (8 h/day, 240 days/year),
these concentrations correspond to continuous exposure levels of 64 and
127 pg/n3. respectively. Based on these analyses, EPA (1984a) concluded
that the most reliable estimates of the dose-response curve were
provided by the reports of Lee-Feldstein (1983), Higgins et al. (1982).
Brown and Chu (1983a,b), and Enterline and Marsh (1982). Table 2.3
presents the estimates of unit risk (the increased risk of lung cancer
associated with lifetime exposure to 1 pg/m3) derived from these
studies. By calculating the geometric mean of these estimates. EPA
(1984a) derived an overall unit risk of 4.3 x 10*3.
-------
Wealth Effects Summary 23
CO
oc
UJ
UJ
cc
CUMULATIVE DOSE (mQ/m -YEARS)
Fig. 2.6. Dose-response relationship for lung cancer in occupationally exposed workers. Source
Adapted from Lee-Feldstein 1983.
-------
24 Section 2
Table 2.3. Summary of lung cancer risk estimates
Study Unit risk"
Lee-Feldstem 1983 2.8 X 10~3
Higgmsetal. 1982 49 X I0~]
Brown and Chu 1983a,b 1.2 X 10~3
Enterline and Marsh 1982 72 X 10~3
"Unit risk is the increased risk of cancer
associated with lifetime exposure to 1 Mg/mJ.
Adapted from EPA 1984a.
-------
Health Effects Summary 25
The Occupational Safety and Health Administration (OSHA) also
conducted a detailed risk assessment for lung cancer from inhalation of
arsenic (OSHA 1983). After review of the epidemiological data of Lee and
Frauoeni (1969). Pinto et al. (1977), Ott et al. (1974), Hill and
Fanning (1948), Lee-Feldstein (1983), Enterline and Marsh (1982),
Hlggins et al. (1982), Mabuchi et al. (1979) and Lubin et al (1981),
OSHA concluded that the risk of lung cancer from a working lifetime of
exposure to inorganic arsenic at an exposure level of 10 Aig/m-* ranged
from 2.2 to 29 excess deaths per 1000 exposed employees, with the
preferred estimate being 8 deaths/1000 employees.
More recently, Enterline et al. (1987) reexamlned the dose-response
relationship between inhalation exposure to arsenic and risk of lung
cancer, using historical records of airborne arsenic levels in the
smelters, along with records of urinary arsenic levels in exposed
workers. The researchers concluded that arsenic Is a more potent lung
carcinogen then previously believed, with a dose-response relationship
concaved downward at exposure levels below 10,000 Mg/nVyear. In
contrast, the relationship between lung cancer and urinary arsenic
levels was linear, suggesting that bloavailability and lung absorption
of arsenic tend to be proportionately greater at low exposure levels
than at high exposure levels.
2.2.1.3 Dermal
As discussed above (see Table 2.2), many reports Indicate that
dermal exposure to inorganic arsenic compounds leads to dermatitis.
However, none of these reports provide quantitative information on
dose-duration relationships. No reports indicating that dermal exposure
is associated with increased risk of cancer were located.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
Arsenic levels In blood, urine, hair, and nails have all been
Investigated and used as biological indicators of exposure to arsenic A
discussion of the utility and the limitations of each of the indicators
for human biomonitoring is provided below.
2.2.2.1 Blood arsenic
Most arsenic is cleared from blood within a few hours (Tarn et al
1979, Vahter 1983), so measurements of blood arsenic reflect exposures
only within the very recent past. Typical values in nonexposed
individuals range from 1 to 5 /*g/L (Heydorn 1970, Valentine et al 1979.
Hindmarsh and McCurdy 1986). Consumption of medicines containing
arsenic is associated with blood values of 100 to 250 jig/L. while levels
in acutely toxic and fatal cases may be 1000 jig/L or higher (Driesback
1980). However, blood levels do not appear to be reliable indicators of
chronic exposure to low levels of arsenic. For example, Valentine et al
(1979, 1981) measured the concentration of arsenic in whole blood of
residents in several U.S communities where arsenic levels in water
ranged from 0.6 to 393 ^g/L They found that In groups with water levels
ranging from 6 to 123 ng/L, average blood levels did not increase in
proportion to Increased exposure. Consequently, measurement of blood
arsenic is not generally considered to be a reliable means of monicqring
human populations for arsenic exposure.
-------
26 Section 2
2.2.2.2 Urinary arsenic
Because absorbed arsenic is rapidly and efficiently excreted in
urine [mostly as monomethylarsonic acid (MMA) and dimethylarsinic acid
(DMA)], analysis of urinary arsenic levels is useful as an indicator of
recent exposure. Normal urinary levels generally range from 2 to 100
Mg/L, with values of 20 to 50 ;*g/L being typical (Pinto et al 1977
Wagner et al. 1979, Foa et al. 1984). Values of 150 /ig/L or higher are
common in industrially exposed populations (Pinto et al. 1976, 1977-
Enterline and Marsh 1982; Beckett et al. 1986) and in populations
exposed to elevated arsenic levels in drinking water (Southwick et al
1981, Valentine et al. 1981, Harrington et al. 1978). Some workers have
found that urinary arsenic levels are linearly related to airborne
concentrations (Pinto et al. 1977, Vahter et al. 1986). but Borgono et
al. (1980) did not find urinary levels to be well correlated with
clinical signs of arsenic toxicity. Elevated levels of arsenic in urine
may occur following ingestion of the nontoxic forms of arsenic present
in fish or seafood (Hindmarsh and McCurdy 1986), illustrating that
increased total urinary arsenic levels may not necessarily reflect
exposures of toxicological significance. Chemical analyses which dis-
tinguish between inorganic arsenic, MMA, DMA, and arsenobetaine in the
urine help to solve this difficulty (Foa et al. 1984, Lovell and Farmer
1985).
2.2.2.3 Hair and nails
Arsenic tends to accumulate in hair and nails, and measurement of
levels in these tissues may be a useful indicator of chronic arsenic
exposure. Normal levels in nails are 0.5 ppm or less, whereas typical
levels in hair range from 0.02 to 1.0 ppm (Gordon 1985, Takagi et al.
1986). These values may increase from several-fold to over 100-fold
following chronic arsenic exposure (Landau et al. 1977, Valentine et al
1979, Southwick et al. 1981, Valentine et al. 1985, Bencko et al. 1986)
The greatest problem with the use of these tissues is that both hair and
nails appear to adsorb and strongly retain arsenic from external sources
as well as from internal deposition. Thus, elevated levels in hair or
nails may not be definite evidence that a significant dose of arsenic
has been absorbed, and could lead to an overestimation of potential
health risks.
2.2.2.4 ELectromyography
Since peripheral neuropathy is one of the characteristic results of
chronic arsenic intoxication, electromyographic measurement of nerve
conduction velocity and amplitude has been evaluated as a means of
detecting preclinical signs of neuropathy in exposed individuals. While
electromyographic abnormalities have been detected in some exposed
populations (Hindmarsh et al. 1977, Landau et al. 1977, Valentine et al
1981), no significant effects were detected in other populations with
moderately elevated exposure in drinking water (Southwick et al. 1981.
Kreiss et al. 1983). Thus, this approach does not appear to be
sufficiently sensitive to be useful as a biological indicator of
exposure (Hindmarsh and McCurdy 1986).
-------
Health Effects Summary 27
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
Arsenic is very widely distributed in the environment. Levels in
water typically range from 0.2 to 10 jig/L. with more than 99% of all
drinking water systems having values lower than SO pg/L. Most
epidemiological studies indicate that water levels of 400 jjg/L or higher
may lead to signs of arsenic toxicity in the population, whereas water
concentrations of 100 ng/L are not usually observed to produce
significant noncarcinogenic effects.
Typical concentrations of arsenic in ambient air range from 2 to
10 ng/m3, with over 99% falling below 80 ng/m3 (Akland 1983). These
levels are not usually associated with any systemic effects, although
they may represent a small increase in the risk of lung cancer.
For most humans, the diet normally represents the largest source of
arsenic exposure (typically about 25 to 50 pg/day) (EPA 1982b). Levels
in different types of food typically vary between 0.01 and 0.10 ppm,
with higher levels in rice (0.4 ppm), chicken (0.5 ppm), and fish or
shellfish (20 ppm). As previously noted, the organic form of arsenic in
seafood is rapidly excreted in urine and is not of toxicological
concern.
2.2.3.2 Human exposure potential
Because arsenic is nearly ubiquitous in air, food, water, and soil,
all humans are routinely exposed at low levels via these routes. Outside
the occupational setting, the greatest potential for exposure of
significant health concern is through ingestion of contaminated water
This could result from natural mineral deposits, wells contaminated wich
arsenical pesticides, or groundwater contaminated by a nearby waste
site. Typically, groundwater will contain a mixture of arsenate and
arsenite, depending on pH and oxidation potential, usually with arsenace
predominating. Another pathway that may be of concern in some cases is
ingestion of contaminated soil. All persons ingest low levels of soil
(around 10 mg/day); however, small children may ingest 200 mg/day or
more (Calabrese et al. 1987). Significant inhalation exposure is likely
to occur only around industrial sites, such as copper smelters or
pesticide factories.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
-------
28 Section 2
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans.
This section identifies gaps in current knowledge relevant to
developing levels of significant exposure for arsenic. Such gaps are
identified for certain health effect "end points" (lethality.
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity, and carcinogenicity) reviewed in Sect. 2.2 of this profile in
developing levels of significant exposure for arsenic, and for other
areas such as human biological monitoring and mechanisms of toxicity.
The present section briefly summarizes the availability of existing
human and animal data, identifies data gaps, and summarizes research in
progress that may fill such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for arsenic will be developed by ATSDR
NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.7 and 2.8, respectively.
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen" by both EPA
and the International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3. For animal carcinogenicity. a substance causes a statistically
significant number of tumors in at least one species, and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists, but does not meet any of these criteria.
-------
HUMAN DATA
SUFFICIENT
INFORMATION*
J
SOME
INFORMATION
NO
INFORMATION
INHALATION
DERMAL
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENtCITV
^ / TOXICITY TOXICITV
as
n>
to
t—
3-
to
SVSTEMIC TOXICITY
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Fig. 2.7. Availability of information on health effects of arsenic (human data).
-------
ANIMAL DATA
ft
O
r»
SUFFICIENT
INFORMATION*
SOME
INFORMATION
NO
INFORMATION
INHALATION
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENIOTY
/ y TOXICITV TOXICITV
SYSTEMIC TOXICITY
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Kig. 2.8. Availability of information < Ith effects of arsenic (animal data).
-------
Health Effaces Summary 31
The absence of a column indicates chat no information exists for
that end point and route. In some cases, information for one route of
exposure may not be applicable for developing levels of significant
human exposure, even if it is available, and this is indicated by a
fully shaded cell on the graph.
2.3.2.2 Description of highlights of graphs
Because arsenic occurs naturally in groundwater and because arsenic
has been used for many years as a poison, a therapeutic agent, and an
industrial material, there is a broad database available on the human
health effects of arsenic exposure. Most quantitative information
available is for oral exposure, although risk of lung cancer from
inhalation exposure has been well studied. Reproductive and
developmental effects have not been adequately studied in humans,
although limited data from animal studies suggest this is not an effect
of major concern. Little quantitative information exists on risks from
dermal exposure. While dermal irritation may be significant, systemic
effects following dermal exposure are rare.
Arsenic toxicity in animals has been reasonably well studied by the
oral route, but only limited data are available for inhalation toxicity
in animals. As previously noted, animals appear to be considerably less
sensitive to arsenic than humans, and several of the most characteristic
effects of arsenic toxicity in humans (neuropathy, skin lesions, and
anemia) have not been observed in animal models at doses where humans
would be affected. Thus, animal data are of limited utility in
estimating significant levels of human exposure.
2.3.2.3 Summary of relevant ongoing research
Table 2.4 summarizes ongoing research projects related to arsenic
that are presently funded by the National Institutes of Health (NIH).
These projects may be expected to produce valuable new information on
the toxicokinetics, mechanism of action, and dose-response relationships
for arsenic. Significant research on arsenic is also being conducted in
Taiwan and Mexico.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Phannacoklnetlcs and mechanism of action
There is good evidence in animal and human studies that inorganic
arsenic is metabolized by methylation. Additional research is needed co
further clarify the relationship between absorbed dose, methylation
capacity, and levels of inorganic arsenic in blood and tissues. In
addition, a more thorough evaluation of the toxicity of the metabolites
(MMA, DMA) and transitory intermediates (e.g., arsenoxy radicals) is
needed. A detailed understanding of these relationships will help in che
selection of appropriate no-effect values for noncarcinogenic effects.
and may also influence the evaluation of mutagenic and carcinogenic risk
from arsenic. Of special importance is the need for studying differences
in methylating capacity between individuals and for distinguishing
"methylators" from "nonmethylators" (Table 2.4).
-------
32 Section 2
Table 2.4. Summary of ongoing research*
Pnncipal
investigator
Institutional
affiliation
Description
of research
Data gap
Carter. D. E.
University of Arizona
Fowler. B. E.
Landolph, J. R.
NIEHS. NIH
University of
Southern California
Investigate pulmonary
toxicity (lung fibrous)
of gallium arsmide
(GaAs). a semiconductor
with growing industrial
use
Investigate molecular
mechanisms which
regulate mtracellular
availability of metals
Molecular biology of
transformation of mouse
fibroblasts in vitro by
arsenic and other metals
Epidemiological studies
of environmental
toxicants, including
arsenic
Absorbtion and clearance
of metals, including
arsenic, adsorbed to
airborne particulates
such as flyash
Improved statistical
means for controlling
the -healthy worker'
effect in epidemic-
logical studies; applied
to mortality data for
8000 arsenic workers
Mutagenisis of metals;
improved techniques for
detecting mutations in
bacterial, viral, and
eukaryotic systems
Snyder. C. A. New York University Respiratory carcinogenicity
of Ai,O, in rodents
Upton. A. C. New York University Inhalation carcinogenicity
of arsenic in rats
Landngan, P. J Mount Sinai. New York
Menzel. D B. Duke University
Robins, J. M. Harvard University
Rossman. T. G. New York University
Toxicity of this
arsenic compound
has not been
studied
Arsenic
toxicokinetics
Mechanism of
arsenic-induced
carcinogenicity
Dose-response
data for arsenic-
induced effects
in humans
Inhalation
toxicokinetics,
role of
paniculate sue
and composition
Better ability
to detect cause-
effect relations
in exposed
humans
Clarification of
the co-mutagenic
activity of
arsenic, and
solubility
Dose-response curve
for lung cancer
Dose-response curve
for lung cancer
•Adapted from NIH CRISP database.
-------
Healch Effects Summary 33
2.3.3.2 Monitoring of human biological samples
A number of biomonicorlng options are available for estimating
short-term and long-term arsenic exposure levels in humans. Arsenic
levels in blood, urine, hair, and nails all tend to increase with
increasing exposure, but there is a wide range in "normal" levels, and
values in people with moderate levels of exposure are sometimes not
distinguishable from typical "background" levels. In addition, in the
low to moderate exposure range of chief concern, there is not a strong
correlation between arsenic levels in these fluids or tissues and the
onset of arsenic-induced toxicity. Thus, these biomarkers are of limited
utility in judging the health risk to populations with low to
intermediate levels of arsenic exposure.
This difficulty is not primarily related to analytical methodology,
but to intra-human variability in toxicokinetics and sensitivity.
Additional research on other potential biomarkers of exposure (skin or
tissue levels, levels in cells, enzyme activity, adducts with proteins
or other molecules, etc.) might lead to a more sensitive and predictive
indicator.
2.3.3.3 Environmental considerations
The environmental fate of arsenic is very complex, involving
processes such as oxidation, reduction, organification, volatilization.
solubllization, and adsorption. While these processes are understood in
general terms (EPA 1984a), there are presently inadequate data to allow
quantitative modeling of arsenic fate in the environment. Development of
rate constants and identification of the key variables in rate processes
would permit a more sophisticated analysis of arsenic fate than is
presently possible.
-------
35
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Arsenic is a naturally occurring metalloid element (atomic number
33). Tables 3.1 and 3.2 list the common name, the Chemical Abstracts
Service (CAS) number, molecular formula, synonyms, and identification
numbers for arsenic and a number of arsenic salts, oxides, and organic
derivatives. These arsenic compounds were selected because their
toxicity and/or presence in the environment identified them as compounds
of concern.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Pertinent physical and chemical properties of arsenic and the
selected arsenic compounds are listed in Tables 3.3 and 3.4. The
inorganic compounds of arsenic are solids at normal temperatures and are
not likely to volatilize. The solubility of these compounds in water
ranges from quite soluble (sodium arsenite and arsenic acid) to
practically insoluble (arsenic trisulfide). Some organic arsenic
compounds are gases or low-boiling liquids at normal temperatures.
Except for the organic arsonic acid compounds, they are not readily
soluble in water.
-------
i me J.i. «.
IO
Identification numbers o\
Chemical name
Anenic
Arsenic acid
Arsenic penloxide
Arsenic irwxidc
Arsenic trisulfide
Calcium ancnale
Gallium arsenide
Sodium anenaie
Sodium anemic
Synonym(i) Formula
Arsemc-75 As
Metallic arsenic
Ancnic black
Colloidal anenic
Onhoanenic acid H,AsO4
Arsenic (V) oxide A*,O,
Arsenic acid anhydride
Diarscnic penloxide
Arsenic oxide As2O,
Arscnous acid anhydride
White arsenic
Arsenolue
Claudetitc
Orpimcnl ASjSj
Arsenic sulfidc
Anenic yellow
Calcium onboarsenate Ca,(AsO4),
Gallium monoarsemic GaAs
Duodium ancnatc Na,HAsO4
Sodium bianenatc
Sodium mclaarscnitc NaAsO,
Wiswcsser NIOSH
line notation CAS registry RTECS
AS4 7440-38-2 CG0525000
H3 AS-O4 7778-39-4 CG0700000
AS2O5 1303-28-2 CG2275000
AS2O3 1327-53-3 CG332SOOO
.AS2S3 1303-33-9 CG2638000
CA3AS-O4*2 7778-44-1 CG0830000
ND 1303-00-0 LW8800000
NA2 AS-O-Q3 7778-43-0 CG0875000
NA AS-02 7784-46-5 CG3675000
EPA
hazardous
waste
D004
K084
KIOI
KI02
POIO
POI1
POI2
P038
ND
ND
ND
ND
DOT/UN/'
NA/IMCO
OHM-TADS' shipping STCC" HSDB*
ND' UN 1558 4923204 509
NA28II 4923207
IMCO 6 1
UN 2760
UN 2759
7217393 UN 1554 4923106 431
UN 1553 49 231 OS
IMCO 6 1
7217408 IMCO 61 49231 12 429
UN 1559
7800005 UN 1561 4923209 419
IMCO 61
7800007 NA 1557 49 232 22 428
7216623 UN 1573 4923217 1433
UN 1574
IMCO 61
ND ND ND 4376
ND ND ND 1675
7800057 UN 1686 49 232 91 693
UN 2027
IMCO 61
n
h—
0
3
to
'Adapted from HSDB 1987. NLM 1987
'Oil and Hazardous Materials/Technical Assistance Data System
Department of Transportation/International Maritime Dangerous Goods Code
'Standard Irantpurlalion Commodity Code
'Hd » Subjlanixj Data Bank
'Ni nmed. as reported in HSDB 1987
-------
IWHC J.4. V.
Identification numbcri
Chemical aame SynooyrnU)
Arsanilic acid 4-Aminopncnylariooic
acid
Arwnobclainc' Fuh arsenic
A rune Arwnic hydride
Arsenic trihydrtde
Dimelhyliriinic Cacodylic acid
acid Dimclhylaricnic acid
DMA
|)imcih»Uriinc- Catodyl hydride
Uuudium methane- USMA
afwnale
Mcihancariunic 4tid Melh|rlarienic acid
MoDomclbylarsooK acid
MMA
McthyUrunc' Aninomelhane
3-Nnro-4-hydroiy- Roiaraonc (
phcnyi.ffoesc Kti Ns'repfceao! erntatc
acid
Sodium araaoilalc Aloiyl
Sodium dimethyl- Sodium cacodylalc
•rainatc
Sodium methane- MSMA
arionaU
Trimclhylamnc' Aricnic Irimelhyl
Gouoga*
•Adapted from HSDB 1987. NLM 1987
•Oil and Hazardous Materials/Technical Aaaiala
Formula
C.H.AiNO,
(CH^At'CH^OO
AaH,
(CH,).HA>O,
(CH.^Atll
CH.Na.AtO,
CH.H.AsO,
CH.AUI,
C.H.AINO.
C.H,AiNO,Na
(CH.hNaAlO,
CH.NaHAkO,
(CH,),Ai
incc Data Syilcm
hPA
Wuwcucr IMIOSH hazardous
line notation CAS registry RTECS waalc
ZR D-AS-QQO 98 50-0 CF7875000 NlX
{ 64436-13-1 g t
AS H3 7784-42-1 CC6475000 ND
Q-AS-OAIAI 75-60-5 CH7525000 ND
I S93-S7-7 g g
Q-AS-QOAIA-NA-2 144-21-8 PA2275000 ND
Q-AS-QOAI 124-58-3 PA 1575000 K03I
( 593-52-2 g I
WNR BQ E-AS-QQO 121-19-7 CY5250000 ND
ND 127-8)-} CF9625000 ND
Q-AS-OAIAIA-NA- 124-65-2 CH7700000 ND
Q-AS-QOAIA-NA- 2163-80-6 PA2625OOO ND
f 593 88-4 f f
DOT/UN/'
NA/IMCO
OHM-TADS* shipping STCC* HSDB*
ND ND ND 432
* tit
ND UN 2188 49 201 35 510
ND ND ND 360
( lit
ND ND ND 1701
ND ND ND 845
( t t I
ND ND ND 4296
ND NU ND 5189
ND IMCO/UN ND 731
6 1/1688
ND ND ND 754
f ( 1 t
'Department of Traruportalion/lnlcrnalioaal Manltme Coodi Code
'Standard Transportation Commodity Code
•Hazardous Subalancea Data Bank
'Not determined, u icporled in HSDB 1987
'Information not available
•Data from lleilbron Daiabaic 1987
3
n>
B
}-•
r>
to
§
»3
a
•XJ
,*
M
n
to
a1
o1
to
n
K—
o
a
-------
lafttsJJ. Physical and rhimlrsl propertlss of arsenic and i
Molecular Vakno
fhcmical name miatit sletA
Arsenic 74.92 0
Arsenic Mad 141.95 -1-5
Ancoic pcfllfttidf 229 M + 5
Ancnic inoiide 197.82 +3
Arsenic msulfide 246.00 +3
Calcium anenatc 398.08 +5
Gallium arsenide 144.64 +3
Sodium arsenatc 185.91 +5
Sodium anemic 130.92 +3
i Melting
point (°C)
817 (28 aim)
35.5
DOQOQlfKMCS Bl
312.3
300-325
1455
1238
57
ND
Boding
pout (eC)
613
(sublimes)
160
315
465
707
ND
ND
ND
ND
Density
(g/cm1)
5.727
2.2
432
3.738
3.46
3.620
5.31
1.87
1.87
Solubility
Slate
Solid
Solid
Amorphous
solid
Solid
Solid
Amorphous
solid
Solid
Solid
Solid
Color
Silver-gray
While
While
Colorless
Yellow or
orange
While
Dark gray
b
White
Water (g/ 100 cm')
Insoluble
302
Freely soluble
2.1
Practically
insoluble
0.013
ND
Very soluble
Freely soluble
Organic solvents
0
Freely soluble in
alcohol and glyccrol
Freely soluble in
alcohol
Soluble in glycerin;
practically
insoluble in chloro-
form and ether
Soluble in alcohol
6
ND
Slightly soluble in
alcohol, soluble in
glyccrol
Slightly soluble in
alcohol
n
rt
t-
Flammabdity O
Dust flammable
when exposed
to beat or
flame
ND
ND
Not flammable
ND
ND
ND
ND
ND
•Adapted from HSDB 1987. Weast 1985
'Information not available
-------
Takk3.4. Physical aod chesilcal propcrtk* of ante ud selected orguk araeak
Chemical name
Ananihc acid
Ancnobclaine*
Arsine
Dimethylarsmic
acid
Dimcihylarnne*
Duodium melhane-
arsonalc
Meihaneanonic acid
Methylanine'
3-Nitro-4-hydro*y-
phenylanonic acid
Sodium arsamlale
Sodium dimelbyl-
snmate
Sodium melhane-
anonaic
Trimethylarsme*
Molecular
weight
217.04
178.06
77.93
13801
10600
18595
13998
9197
263.03
239.05
159.98
16196
12003
Melting Boiling
pout CC) point CO
232 ND
204-210 c
-117 -62.5
195-196 ND
c 36
>355 ND
161 ND
-143 2
ND ND
ND ND
200 ND
119 ND
c 70
Density
(g/cm1)
1.9571
c
2.695
ND
1 213
ND
ND
ND
ND
ND
1 57
c
Solubility
Stale
Solid
Solid
Gas
Solid
Liquid
Solid
Solid
Gas
Solid
Solid
Solid
Solid
Liquid
Color
White
c
Colorless
Colorless
c
Colorless
White
Pale yellow
White
Colorless
to light
yellow
White
c
Water (g/ 100 cm1)
Slightly
soluble
20mL/IOOg
Soluble in
0 5 part water
Insoluble
100
Freely soluble
Insoluble
Slightly
soluble
Soluble
ND
57
c
Organic solvents
Slightly soluble
in alcohol
Soluble in alcohol
Soluble in chloro-
form and benzene
Soluble in alcohol;
practically
insoluble in ether
c
Slightly soluble
in alcohol
Soluble in alcohol
c
Soluble in alcohol and
acetone
Slightly soluble in
alcohol
ND
Soluble in
methanol
c
Flammability
ND
c
ND
ND
Flammable in
air
ND
ND
Ignites
spontaneously
in air
ND
ND
ND
ND
Spontaneously
flammable in
air
_
if
B
I—
n
0)
§
a
•a
a-
^^
(n
n
fti
i—
a
Q
|M
R
o
n
•Adapted fiom HSDB I9K7. Weail 1985
'Data from Meilbron Database 1987
' Information not available
-------
4. TOXICOLOGICAL DATA
4.1 OVERVIEW
Arsenic is an element that forms a variety of inorganic and organic
compounds, of which the toxicity may vary considerably from compound co
compound. In general, soluble inorganic compounds of arsenic(III) are
considered to be the principal toxic species. These compounds are
relatively well absorbed from both the gastrointestinal tract and the
lungs, and are distributed widely throughout the body. Although the
mechanism of action is not known with certainty, it is generally
considered that arsenic(III) exerts its toxicity by reacting with
sulfhydryl groups of cellular proteins, thereby destroying their
activity (Harvey 1970, Knowles and Benson 1984). Soluble inorganic
compounds of arsenic(V) are also toxic, although usually somewhat less
than arsenic(III). The toxicity of this species may be mediated in pare
by in vivo reduction of arsenic(V) to arsenic(III), or may be due to the
ability of arsenate to function as an analogue of phosphate, thereby
interfering with normal cellular energy metabolism (Harvey 1970).
Section 4.2 summarizes toxicological data on inorganic forms of arsenic
In contrast to the inorganic arsenic species, most organic
derivatives have relatively low toxicity. MMA and DMA are formed in vivo
by enzymic methylation of arsenic(III) in the liver. Because mechylacion
reduces toxicity and increases urinary excretion of arsenic, this
metabolic pathway represents an effective detoxification mechanism,
especially at low doses. Higher doses may exceed the methylating
capacity of the liver, leading to a relative increase in the percent of
the dose present in blood and in tissues as inorganic arsenic. Section
4.3 presents a summary of toxicological data for MMA, DMA, and other
organic derivatives of potential health concern.
4.2 INORGANIC ARSENIC
4.2.1 Overview
Because inorganic arsenic (both the trivalent and pentavalenc
forms) are general cellular poisons, it is not surprising that many
tissues are affected by arsenic exposure. By the oral route, the
principal acute effect is irritation of the gastrointestinal tract
Long-term oral exposure may lead to anemia, peripheral neuropathy,
hepatotoxicity, nephrotoxicity, cardiotoxicity, and a group of skin
disorders characterized by hyperpigmentation and hyperkeratoses. Chronic
oral arsenic exposure is also associated with increased risk of skin
cancer and possibly internal cancer as well.
-------
42 Section 4
Inhalation expc> ire to dusts or aerosols containing inorganic
arsenic may lead to che appearance of some of the same symptoms as seen
following oral exposure, but this is rarely of health consequence in
humans. Rather, the principal health concern following inhalation
exposure is increased risk of lung cancer.
Dermal contact with arsenic compounds may produce moderate to
severe skin irritation but is not generally associated with any systemic
effects. y
Despite the variety of adverse effects associated with arsenic
exposure, there is limited evidence that low levels of oral intake may
be beneficial or essential to animals. If so, arsenic is also likely to
be beneficial to humans. However, the estimated required daily Intake is
quite low (similar to the typical daily intake from the diet), and no
cases of arsenic deficiency have been recognized in humans.
4.2.2 Tozlcokinetics
4.2.2.1 Overview
Most toxicokinetic studies of inorganic arsenicals in humans and
animals have been conducted with readily soluble or moderately soluble
salts or oxides. In general, these compounds are well absorbed, both in
the gastrointestinal tract and the lung, and are widely distributed
throughout the body. Trivalent arsenicals are metabolized in the liver
by methylation to form primarily dimethylarsinic acid. This compound is
less toxic than the parent inorganic compounds and is efficiently
excreted in urine. Pentavalent arsenicals undergo reduction to the
trivalent form before methylation may occur. At low-to-moderate doses of
inorganic arsenic, methylation and urinary excretion prevent marked
accumulation in the body, but high doses may lead to the deposition of
inorganic arsenic in some tissues.
Analysis of the absorption, distribution, metabolism, and excretion
of inorganic arsenic compounds is complicated by important differences
between compounds. Of primary importance in absorption is the solubility
of the-compound, with solutions of arsenic and readily soluble compounds
being absorbed more efficiently than solids and poorly soluble compounds
(Harrison et al. 1958, EPA 1984b). Other variables that may influence
absorption are dosing rate and (for solid materials) particle size.
Another important factor in toxicokinetic studies is species
variation. Although some animals appear to absorb and metabolize
inorganic arsenicals similarly to humans, there are a number of cases
where this does not happen. For example, hamsters have low
gastrointestinal absorption, rats have excessive binding in red blood
cells, and marmoset monkeys have low methylating capacity. For these
reasons, toxicokinetic data from animals must be applied to humans with
caution.
4.2.2.2 Absorption
Oral. Absorption of inorganic arsenic is dependent upon the water
solubility of the arsenic compound. There is general agreement that
soluble trivalent (arsenic(III)] or pentavalent (arsenic(V)] arsenic Is
-------
ToxicoLogLcaL Data U}>
almost completely absorbed (more than 90%) from the gastrointestinal
tract of laboratory animals (Vahter 1983, EPA 1984a). Hamsters appear co
be the exception, since they only excreted 30 to 40% of an oral dose of
sodium arsenite in the urine and about 50% in the feces (Charbonneau et
al. 1980a, Marafante and Vahter 1987). When sodium arsenate was
administered to hamsters, substantial absorption, as indicated by
urinary excretion of 75% of the dose, was found (Marafante and Vahter
1987). Studies on mice indicate that absorption does not depend on dose
in the range of 0.4 to 4.0 mg/kg body weight (Vahter and Norin 1980)
Aqueous suspensions of arsenic trioxide were absorbed only to the extent
of 40 and 30% in rabbits and rats, respectively, because of its limited
water solubility (Ariyoshi and Ikeda 1974).
Humans also appear able to absorb extensively arsenic compounds
from the gastrointestinal tract. Greater than 95% of inorganic arsenic
taken orally by man appeared to be absorbed since <5% appeared in the
feces (EPA 1984a). Buchet and coworkers (1981a) administered an oral
dose of 500 jig and found 46% in the urine after 4 days. When multiple
doses were administered, a steady state of 60% of the dose was excreted
in the urine (Buchet et al. 1981b). Feces were not analyzed in these
studies, but it is assumed that the urinary excretion is representative
of extensive arsenic absorption. When insoluble arsenic selenide was
taken orally, there was no absorption as indicated by no increase in
urinary arsenic excretion (Mappes 1977).
Inhalation. Absorption of arsenic from the lungs depends in large
part on particle size. Large particles (e.g., 10 urn) tend to be
deposited in the upper airway and are cleared by ciliary movement with
only limited absorption across lung tissue. In contrast, small particles
(e.g., 0.1 to 1 ^m) tend to penetrate deep into the lung and are
deposited in alveoli where absorption occurs across the respiratory
epithelium (EPA 1984a). Absorption of arsenic that has been deposited in
the lungs will also depend on the chemical form of the arsenic. Animal
studies indicate that water-soluble compounds such as arsenic trioxide
(arsenic(III) ) , sodium arsenate (arsenic(V)], and dimethylarsinic acid
(Dutkiewicz 1977, Stevens et al. 1977a, Rhoads and Sanders 1985,
Marafante and Vahter 1987) are rapidly absorbed. The clearance half-Life
from the lung of rats given an intratracheal instillation of an aqueous
solution of arsenic trioxide was calculated to be 31 min (Rhoads and
Sanders 1985). Despite this very rapid clearance, small fractions of the
arsenic remained in the lungs for several weeks after exposure, with a
half-life of about 75 days. Less soluble arsenic compounds (e.g., lead
arsenate) are not cleared so rapidly, with 45% of an intratracheal dose
remaining in the lung 3 days after instillation (Marfante and Vahter
1987). Similar evidence of slow lung absorption was reported by
Pershagen et al. (1982) for calcium arsenate and by Webb et al. (1984)
for gallium arsenide.
Limited information about pulmonary deposition and absorption has
been reported for humans. Holland and coworkers (1959) studied the
deposition and absorption of arsenic from arsenite-containing cigarettes
and from arsenic-containing aerosols in lung cancer patients.
Approximately 40% was deposited, and 75 to 85% of the deposited arsenic
was absorbed from the lungs within 4 days. Other human studies have
examined the relationship between airborne arsenic concentrations and
-------
44 Section 4
urinary excretion of arsenic (Pinto et al. 1976, Smith et al 1977
Vahter et al. 1986). All studies showed a good correlation between'
arsenic levels In air and urinary excretion of inorganic arsenic
metabolites. Vahter and coworkers (1986) estimated that 42% of the
inhaled arsenic was excreted daily.
Dermal. Insufficient Information exists to evaluate dermal
absorption of the arsenic compounds. Vahter (1983) has reviewed the
clinical reports of arsenic toxlcity after accidents where the only
exposure was through the skin, but the data are not quantitative.
Transplacental. Transfer of Inorganic arsenic to the placenta and
fetus Is rapid after parenteral or oral administration. Hood et al.
(1987) administered sodium arsenate to pregnant mice by gavage
(40 mg/kg) or intraperitoneal injection (20 mg/kg). Levels in placenta
and fetus followed a similar time course of accumulation and clearance
in both cases, reaching maximum values around 1 to 2 h after exposure,
and then declining to near control levels within 24 h. In both cases,
levels (expressed as ^g arsenic/ng tissue) were about 2 to 3 times
higher in placenta than in the fetus. During the first several hours,
most of the fetal arsenic was inorganic, but DMA became the predominant
form within 4 to 6 h. Similar results have been observed for trlvalent
arsenic, which was transferred across the placenta in pregnant rats and
was detected In newborn rats when the dams were fed arsenic trloxide in
their diets (Perm 1977, Hanlon and Fern 1977). Hanlon and Perm (1987)
exposed pregnant hamsters to arsenate, using a subcutaneous osmotic
minipump and observed that tissue levels in placentas were 1.2 to 2.0
times higher than levels in maternal blood. Most of the placental
arsenic was bound to macromolecules. while that in maternal blood was
free. Lindgren et al. (1984) reported that the marmoset monkey showed a
lower rate of placental transfer of arsenate and arsenite than mice.
They suggested that this was probably related to the lack of methylating
ability in the marmoset which resulted in greater tissue binding in the
mother.
4.2.2.3 Distribution
In most animals, all but a small fraction of systemic arsenic is
rapidly cleared from tissues. The rat is an exception, since arsenic is
avidly bound by rat red blood cells (RBC). The rat Is a poor model for
human toxicokinetic data for this reason.
Blood. In studies reviewed by Vahter (1983), humans, dogs, mice.
and rabbits cleared arsenic from blood in a biexponential, or possibly
triexponential, curve. The major part of the blood arsenic (>90%) was
cleared at a high rate, the half-life being 1 to 2 h. The half-lives of
the second and third phases have been estimated to be about 30 and
200 h, respectively. A more detailed study measured the clearance of
arsenate after intravenous administration of 0.4 mg/kg to rabbits
(Marafante et al. 1985). The plasma concentration of arsenic(V)
decreased with a first-order half-life of about 1 h. Some arsenic(V) was
rapidly reduced to arsenic(III); by 15 min, 10% of the plasma arsenic
was in the form of arsenic(III) About 30% of plasma arsenic was as
arsenic(V). and about 60% was bound to plasma protein. The clearance of
arsenic(III) was biexponential. wich half-lives of about 10 min and 2 h
-------
lexicological Data £o
The kinetics of protein-bound arsenic were also biphasic with half-lives
of 15 min and 2.5 h. In RBC, there was more arsenic(III) than
arsenic(V), and arsenic(III) was approximately equal to its plasma
concentration, while arsenic(V) was only 10% of its concentration The
concentration of protein-bound arsenic increased up to 1 h and then
began a slow decline. This suggests an irreversible binding to RBC
protein that was not present with plasma protein.
Vahter and Marafante (1985) examined the blood distribution of
0.4 rag/kg arsenic from sodium arsenate following intravenous injection
in marmoset monkeys, a species which cannot methylate arsenic. Arsenic
was rapidly cleared from the plasma, and the relative amount of
arsenic(III) in the plasma increased from only a few percent 30 min
after injection to about 50% at 6 h. In RBC, arsenic(III), arsenic(V),
and a protein-bound arsenic were found. Arsenic(V) was cleared from RBC
more rapidly than arsenic(III), but both were completely cleared by 72
h. The protein-bound arsenic remained in RBC.
Arsenic in blood is also rapidly cleared in humans (Ducoff et al
1948, Mealey et al. 1959, Tarn et al. 1979). Hunter et al. (1942)
reported nearly complete removal of blood arsenic in humans 24 h after a
subcutaneous injection of potassium arsenite, and Mealey et al. (1959)
reported that more than 90% of an intravenous dose of arsenic is removed
within several hours. Tarn et al. (1979) reported that clearance of
arsenic from blood in humans fit a 3-exponential model with half-lives
of 1, 5, and 35 h.
Heydorn (1969) reported concentrations of arsenic in whole blood,
RBC, and plasma for normal healthy individuals from Denmark and for a
number of population groups in Taiwan with high arsenic exposure levels
In general, the concentration of arsenic (expressed as Mg/D was
somewhat higher (1.1- to 3.3-fold) in RBC than in plasma, with whole
blood having an intermediate value. This may reflect a binding of
arsenic to red-cell proteins.
Other tissues. There is general agreement that exposure of various
animal species to either trivalent or pentavalent arsenic leads to che
initial accumulation of arsenic in liver, kidney, lung, spleen, aorta.
skin, hair, and upper gastrointestinal tract (EPA 1984a). These tissues
are cleared rapidly except for skin and hair where the sulfhydryl groups
of keratin may promote tight arsenic(III) binding. Arsenic is apparently
retained in the brain of experimental animals with slow clearance
reported (Crema 1955).
More detailed studies have been published recently which have
focused on the tissue and subcellular distribution of different arsenic
species. Vahter and Norin (1980) found that levels of arsenic in kidney,
liver, bile, brain, skeleton, skin, and blood were always greater
(twofold to tenfold) in mice given oral doses of arsenic(III) as
compared to arsenic(V), and this difference was greater at the higher
dose. Similar results were reported in Syrian golden hamsters by Cikrc
et al. (1980). An autoradiographic study comparing trivalent and
pentavalent arsenic in pregnant mice and monkeys indicated that
arsenate, but not arsenite. showed affinity for calcified areas of che
skeleton (Lindgren et al. 1984) This is in apparent disagreement wich
earlier studies by Vahter and Norin (1980) but is logical since arsenace
-------
46 Seccion 4
is an analog of phosphate, a normal component of bone. After oral
administration of 4.5 mg/kg arsenic trloxlde to hamsters, Yamauchi and
Yamamura (1985) reported that MMA concentrations were higher than DMA In
organs and tissues and that DMA tended to be detected after the
appearance of MMA. Inorganic arsenic disappeared rapidly from the brain.
liver, lung, and spleen, although concentrations In the hair, skin,
muscle, and kidney remained slightly elevated at 120 h after
administration.
The cellular distribution of the arsenlcals has also been examined.
Fischer et al. (1985) reported that mouse flbroblasts did not take up
arsenic(V) as well as arsenic(lll). Similar findings were reported by
Lerman and Clarkson (1983) in rat liver hepatocytes. Vahter and
Marafante (1983) incubated arsenlte, arsenate, and DMA with homogenates
of mouse and rabbit liver, lung, and kidney and showed that arsenite was
the main form of arsenic bound to tissues.
There are very few studies which have examined the tissue
distribution of arsenic after prolonged exposure. Vahter (1983) gave
arsenic(III) and arsenic(V) orally 3 times per week for 12 weeks to mice
and followed the increase of arsenic concentration with time. Skin and
hair showed the greatest increase while concentrations In liver, kidney,
lung, and intestinal mucosa increased much less. Accumulation was
significantly higher after administration of arsenic(III) than after
arsenic(V).
Tissue distribution of arsenic in humans has been studied using
autopsy and dosing data. Kadowaki (1960) determined that nails contained
0.89 ppm; hair, 0.18 ppm; bone, 0.07 ppm to 0.12 ppm; teeth, 0.08 ppm;
and skin, 0.06 ppm. The researcher found these tissues had the highest
concentrations of arsenic in the body of a Japanese population. Heart.
kidney, liver, and lung contained somewhat lower concentrations in the
range of 0.04 to 0.05 ppm, brain tissue only slightly less (0.03 ppm).
Liebscher and Smith (1968) analyzed soft tissues from nonexposed persons
from Scotland and found that their lungs had the highest concentration
(0.09 ppm), compared with levels of 0.03 ppm in liver and kidney.
Absolute levels were highest In hair (0.46 ppm), nails (0.28 ppm). and
skin (0.08 ppm). Other tissues, including bone and teeth, contained 0.06
ppm or less.
Brune et al. (1980) analyzed samples of liver, kidney, and lung
taken at autopsy from workers who had retired from a nonferrous metal
refinery and smelter. Levels of arsenic in kidney and liver were not
significantly higher than in controls, but levels in lung tissue tended
to be about six times greater than in controls. This was true both for
workers who had been exposed recently (within 1.5 years of their death)
and those who had not been exposed for 2 to 19 years prior to death.
This suggested to Brune et al. that arsenic had a long half-life in the
lung, but this interpretation is complicated by the fact that exposure
levels may have been significantly higher In workers exposed some years
ago, and this group may originally have had higher tissue burdens of
arsenic in the lung.
-------
Tox Leo logical Data 47
4.2.2.4 Metabolism
Substantial information has appeared in the recent literature on
arsenic metabolism. This has been triggered by the recent development of
analytical methods which can separate the metabolites of inorganic
arsenic [arsenic(III), arsenic(V), MMA, and DMA] and distinguish them
from the arsenic compounds found in shellfish (arsenobetaine and
arsenocholine).
Animals. There is general agreement on the products of arsenic
metabolism in mice, rats, rabbits, hamsters, and humans (Klaassen 1974,
Vahter 1983; EPA 1984a; Hanlon and Perm 1986a,b; Marafante and Vahcer
1984, 1986, 1987; Marafante et al. 1985; Yamauchi and Yamamura 1984)
The following general statements can be concluded from in vivo and in
vitro studies:
• The major site of methylation is the liver.
• DMA is the major metabolite in most animals and humans, and it
appears mainly in the urine.
• MMA is most often a secondary metabolite and its appearance in
urine varies with the anima-l species.
• MMA can be partially methylated to DMA, but neither species is
significantly demethylated to inorganic arsenic.
• Methylation results in a detoxification of inorganic arsenic (about
1 order of magnitude per methyl group) and increases the rate of
arsenic excretion.
• Trivalent arsenic is the substrate for methylation, and arsenic(V)
must be reduced to arsenic(III) before methylation can occur.
• Methylation is dependent on dose level. The percentage of DMA in
the urine decreases with increasing inorganic arsenic dose level,
while the amount of retained arsenic increases.
• Earlier data on arsenic metabolism, toxicokinetics, and toxic icy
must be reassessed in light of current knowledge about methylation
in different species.
Several studies have focused on understanding the methylation
process in vivo and in vitro. Rat liver in vitro only accepts trivalenc
arsenic as a substrate for methylation and requires reduced glutathione
for activity (Buchet and Lauwerys 1985). Similar results were obtained
by Lerman et al. (1983), who studied methylation of arsenic(III) and
arsenic(V) in cultured hepatocytes. They observed that arsenite was
converted to DMA, but arsenate was not taken up by the cells and no
metabolism could be detected. The authors postulated that this may be
due to the fact that at physiological pH, arsenite is not ionized.
whereas arsenate is ionized.
Hanlon and Perm (1986a.b) examined the chemical species of arsenic
present in the blood after constant infusion or intraperitoneal
-------
48 Section 4
injection of hamsters with 64.2 /*molAg of sodium arsenace. The major
species in plasma was arsenic(V), with much smaller amounts of
arsenic(III) and DMA. No protein binding was found in plasma. Similar
values were observed in RBC, except that a fraction of the arsenic (13%
of the total at 1 h) was bound to cellular proteins (probably
hemoglobin).
In vivo methylation in mice and rabbits can be blocked by treatment
with 100 ^molAg periodate-oxidized adenosine, and that treatment causes
an increase in the amount of arsenic retained in tissue (Marafante and
Vahter 1984, Marafante et al. 1985). A choline-deficient diet in rabbits
decreases the methylation of arsenic and increases the retention in
liver, lung, and skin (Marafante and Vahter 1986). These maneuvers to
decrease the methylating capacity in animals with concomitant increased
retention of arsenic in tissues may be considered to be a model for
humans who have low methylating capacity, due either to genetic or
dietary factors. Arsenic pretreatment of mouse fibroblast cells made che
cells more resistant to arsenic toxicity and increased the methylation
of inorganic arsenic to MMA and DMA, suggesting the enzymic methylating
system may be inducible (Fischer et al. 1985).
Humans. Several studies indicated that inorganic arsenic is
methylated to MMA and DMA in humans, much as it is in animals. For
example, Buchet et al. (1980) reported that urinary excretion was about
60% DMA, 20% MMA, and 20% inorganic arsenic, both in smelter workers
exposed to As203 and in individuals with typical dietary exposure to
arsenic. Similar proportions of inorganic and organic urinary
metabolites in humans have been reported by Vahter (1983) and Buchet et
al. (1981a,b). Ingestion of MMA is accompanied by limited methylation
(about 13%) to DMA. while no metabolism of ingested DMA occurs (Buchet
et al. 1981a).
In animals, high doses of arsenic appear to saturate the
methylation system. For humans, Love11 and Farmer (1985) studied urinary
excretion of arsenic in patients who ingested very high doses of As203
for the purpose of suicide. Shortly after the exposure, most arsenic in
urine (about 90%) was inorganic, and this fell to about 30% after 100 h,
accompanied by a concomitant increase in the level of organic arsenic
(MMA and DMA), from about 10 to 70%. Buchet et al. (1981b) found that
doses of 125 to 500 /ig/day of sodium arsenite were methylated
approximately equally (about 80%) in human volunteers, but that the
percentage of the dose methylated began to decrease at 1000 Mg/day,
accompanied by a slowed clearance of arsenic. This suggests that the
enzyaic systems of the liver may begin to become saturated at doses
between 500 to 1000 pg/day (EPA 1987b).
Foa et al. (1984) observed a broad variation between individuals in
the percentage of methylated arsenic in urine, both in workers in a
glass factory where exposure to As203 was elevated, and in a group of
people with normal exposures through food. This indicates that some
individuals may have lower methylating capacity than others. The
researchers selected a group of five glass workers with high urinary
arsenic concentrations and suspended their exposure for one month.
Urinary concentrations of inorganic arsenic and its methylated
metabolites decreased with time nearly to that of the control
-------
Toxicologies! Data 49
populacion. When occupational exposure was resumed, only a moderace
increase was seen for urinary inorganic.arsenic and its methylated
metabolites. Two months after exposure resumed, urinary concentrations
of total arsenic were still diminished relative to previous levels. This
suggests that methylating capacity may adapt in proportion to exposure,
but that full methylation capacity for high exposures takes several
months to build up and that any accommodation the body had made to very
high arsenic levels is lost rapidly.
4.2.2.5 Excretion
The major route of arsenic excretion is in the urine for all
chemical species of arsenic that are absorbed. Biliary excretion may be
significant, but enteric reabsorption is such that little arsenic is
excreted in feces.
Urinary. Mice, rabbits, swine, dogs, and monkeys usually excrete
>70% of injected trivalent and pentavalent arsenic in the urine within
24 h (Ducoff et al. 1948, Crema 19SS. Ginsberg and Lotspeich 1963,
Peoples 1964, Munro et al. 1974, Lakso and Peoples 1975, Tarn et al.
1978, Charbonneau et al. 1978a). Urinary excretion of arsenic in the rat
is much slower, with about 10% of a parenteral dose excreted in 4 days
(Gregus and Klaassen 1986). Excretion of DMA administered to rabbits or
mice by injection or by the oral route was essentially complete within
24 h (Vahter and Marafante 1983, Vahter et al. 1984).
Several studies have compared the rates of excretion of trivalent
arsenic and pentavalent arsenic (Vahter and Norin 1980, Vahter 1981,
Marafante et al. 1985). Differences in urinary excretion rates appeared
to relate to the relative degree of methylation of the inorganic
arsenic, with rapid formation of DMA enhancing the urinary excretion
Further, differences in excretion rates were dose-dependent. Marafante
et al. (1985) examined the urinary excretion within the first 6 h after
intravenous sodium arsenate administration to rabbits. It was found that
arsenic(V) was excreted immediately and that DMA excretion required 2 to
3 h before appreciable urinary excretion occurred.
Mappes (1977) administered a single oral dose of sodium arsenite to
a human and found maximal renal excretion at 3 h and about 25% of the
dose in the urine by 1 day after exposure. Crecelius (1977) studied the
urinary excretion of arsenic from a person who had ingested wine
containing 50 /jg arsenic(III) and 13 pg arsenic(V) or water containing
200 pg of mainly arsenic(V). About 80% of the arsenic ingested with wine
was recovered in urine in 61 h, and 50% of the arsenic ingested with
water was found within 70 h. Mealey and coworkers (1959) measured
urinary arsenic in a patient administered trivalent arsenic
intravenously and found -60% of the dose in the urine within 24 h.
Buchet et al. (1981b) administered oral sodium arsenite doses of
125 to 1000 Mg for 5 days and found that a steady state was reached and
that 60% of the administered dose of arsenic appeared in the urine each
day. Vahter et al. (1986) studied urinary excretion of arsenic in
smelter workers exposed to airborne levels of 1 to 194 pg/m^. The amount
of arsenic (inorganic, MMA, and DMA) in urine increased in proportion to
exposure level, and the relationship was well described by a straight -
line equation.
-------
50 Section 4
Fecal. Little arsenic can be recovered in human feces after either
oral doses or parenteral administration of inorganic arsenic (Vahter
1983). Fecal arsenic levels for rabbits administered arsenite
intraperitoneally were -10% of the dose in 4 days (Bertolero et al.
1981). Hamsters administered arsenite by intraperitoneal injection
excreted about 5% of the dose in the bile within 24 h (Cikrt et al.
1980). About 25% of arsenic trichloride given intravenously to rats was
excreted in bile within 2 h, but <10% appeared in feces over a 7-day
period (Klaassen 1974. Gregus and Klaassen 1986). Rats excreted arsenic
in the bile 40 times faster than rabbits and 800 times faster than dogs.
No biliary excretion data exist for humans. Although biliary excretion
may be significant and highly variable between species, it will not
contribute extensively to elimination because of reabsorption from the
intestines (Klaassen 1974, Cikrt et al. 1980).
Other routes. There is no evidence that expired air is a route of
excretion for arsenic. Profuse sweating may eliminate 2 Mg/h. and
desquamation may account for small quantities of arsenic (Vahter 1983).
Hair and nails have been considered as an excretory route for arsenic,
but their contribution would be minor compared to other routes of
excretion.
4.2.3 Toxicity
4.2.3.1 Lethality
Several workers have reported that oral doses of about SO to 300 mg
of inorganic arsenic may be fatal to adults (Vallee et al. 1960,
Hindmarsh and McCurdy 1986, Armstrong et al. 1984, Zaloga et al. 1985).
Subchronic oral exposure to only about 3 mg/day was fatal in a number of
infants exposed to arsenic via contaminated milk (Hamamoto 1955). On
this basis, the acute and subacute lethal dose in humans may be
estimated to be about 0.6 mg/kg/day or higher.
In animal studies, oral LDso values for various inorganic arsenic
compounds have been reported to range from 10 to 300 mg/kg. with soluble
compounds being more toxic than poorly soluble forms (NAS 1977, EPA
1984a). For example, Harrison et al. (1958) reported that the acute oral
LDSO for As203 given to several different strains of mice by gavage
ranged from 26 to 47 mg/kg- A value of 15 mg/kg was reported for rats
dosed by gavage, but the value was much higher (145 mg/kg) when given in
food. Intraperitoneal LDso and LD75 values range from 4 to 20 mg/kg.
These results suggest that animals are not as sensitive to arsenic as
humans, and that this difference is not due entirely to differences in
gastrointestinal absorption.
Inhalation and dermal exposure are not normally associated with
acute lethality in humans or animals.
4.2.3.2 Systemic/target organ toxicity
Gastrointestinal disturbances. Oral exposure of humans to arsenic
often produces a range of gastrointestinal signs, with nausea, vomiting,
diarrhea, and thirst being most common (NAS 1977, EPA 1980c, 1984a).
Armstrong et al. (1984) described an incident in which a family of
8 suffered severe arsenic toxic icy from ingestion of water containing
-------
ToxicologicaL Oaca 5L
108 mg/L of arsenic. All of che exposed Individuals suffered marked
symptoms of gastroenteritis. Vomiting and diarrhea were noted in 7/8 and
6/8 of the individuals, respectively, with swollen throat and abdominal
pain in 3/8. Similar gastrointestinal signs may also occur at much lower
doses. Tay and Seah (1975) noted gastrointestinal involvement in 17 of
74 people ingesting an arsenic-containing herbal preparation at an
estimated dose of 3 to 10 mg/day. Zaldivar (1974) noted diarrhea and
anorexia in residents of Antofagasta, Chile, where drinking water
contained about 0.4 mg/L (corresponding to a dose of about 0.5 to
1 mg/day).
Gastrointestinal signs are chiefly associated with oral exposure
and are rarely noted following inhalation or dermal contact. The most
likely mechanism of these disturbances is direct toxicity to the
epithelial cells of the gastrointestinal tract, with resulting
irritation, injury, and abnormal function.
Hematological effects. The hematopoietic system is affected by
both short- and long-term arsenic exposure. Effects include anemia,
leukopenia, and eosinophilia (EPA 1984a). Hamamoto (1955) reported these
effects in infants exposed to about 3.5 mg/day in contaminated milk for
33 days, and Mizuta et al. (1956) reported anemia and leukopenia in
adults ingesting about 3 mg/day in contaminated soy sauce. Similar signs
of impaired hematopoiesis are also commonly observed in humans
chronically exposed to arsenic in water, medicine, or the workplace (EPA
1984a). Woods and Fowler (1977, 1978) reported that arsenate exposure of
rats (20 to 85 mg/L in water for 6 weeks or more) resulted in decreased
hemoglobin production accompanied by decreased activity of several
enzymes (hepatic w-aminolevulinic acid synthetase and ferrochelatase)
required for heme biosynthesis.
Cardiological and vascular effects. Large oral exposures to
arsenic have been reported to cause injury and abnormal function in
cardiac tissue. Rosenberg (1974) reported that autopsy of 5 children
exposed to high levels of arsenic (up to 0.8 mg/L) in drinking water
supplies in Antofagasta, Chile, revealed evidence of myocardial
Infarction in 2 cases and arterial thickening in all cases, and Zaldivar
(1974) reported several cases of myocardial infarction and arterial
thickening in children consuming water containing about 0.6 mg/L.
Altered electrocardiograms (prolonged Q-T intervals and abnormal T-
waves) have been described in several studies of humans exposed to
arsenic (NIOSH 1975. HAS 1977, EPA 1984a, Zaloga et al. 1985, Hindmarsh
and McCurdy 1986).
Peripheral vascular disease leading to gangrene of the toes and
feec ("Blackfoot disease") has been reported to occur in association
with chronic arsenic exposure from contaminated drinking water in Taiwan
(Tseng et al. 1968, Tseng 1977). The overall incidence of the disease
was 0.9% in a population of 40,000 persons consuming water containing an
average of about 0.4 to 0.6 mg/L of arsenic, while no cases were
observed in a population of 7500 people consuming water containing <0 02
mg/L. Prevalence rates tended to increase as a function of age (i.e ,
duration of exposure) and with the arsenic content of the water. For
example, when exposure was stratified into three levels (low - 0 - 0 29
mg/L, medium. - 0.30 - 0.59 mg/L. high - 0.60 mg/L and above), the
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52 Section 4
prevalence rates (cases/1000) were 4.5, 13.2, and 14.2 for 20- to 39-
year-olds, 10.5, 32.0, and 46.9 for 40- to 59 -year-olds, and 20.3. 32 2,
and 61.4 for those 60 years old and older, respectively. Severity of the
disease was also related directly to duration of exposure. Blackfooc
disease was often fatal, with an overall mortality rate close to 50%.
Similar peripheral vascular lesions have been reported in vintners
exposed to arsenical pesticides (NAS 1977), in persons in Chile
consuming water containing about 0.8 mg/L of arsenic (Borgano and
Greiber 1972), and in patients from a region in Mexico where arsenic
toxicity is endemic (Salcedo et al. 1984). Peripheral vascular disease
is not normally associated with inhalation exposure to arsenic, although
Lager kvist et al. (1986) reported evidence of altered blood vessel
function in copper smelter workers exposed to about 50 ^g/m3 in air.
Some researchers have questioned the role of arsenic in Blackfoot
disease. For example, Kuo and Chen (1969) reported that the prevalence
rate for Blackfoot disease varied widely (from 1.8 to 26.1 cases per
1000) in Taiwanese villages where drinking water levels of arsenic were
quite similar (380 to 850 /ig/L) . Yu (1984) and Yu et al. (1984) noted
that vascular disease was not observed in a number of studies where oral
arsenic exposure was elevated, and- proposed that the occurrence of
vascular lesions in Taiwan may be related to the presence of a
fluorescent arsenic -containing compound of unknown structure which is
present in water where Blackfoot disease is endemic. Ko (1986) noted
that the incidence of Blackfoot disease increased in Taiwan after steps
were taken to reduce arsenic exposure through groundwater and,
therefore, concluded that arsenic may not be the factor causing this
disease.
Neurological effects. Both peripheral and central neuropathy have
been observed in humans following arsenic exposure. Very high oral doses
may produce acute encephalopathy (Armstrong et al. 1984, Danan et al.
1984, Beckett et al. 1986). Other indicators of central damage include
mental retardation in arsenic -exposed children (Hamamoto 1955), hearing
loss, and abnormal electroencephalograms (EPA 1984a) .
Arsenic -induced peripheral neuropathy is typically characterized by
paresthesia, hyperesthesia. and neuralgia, with muscle pain and
weakness. Such effects have been noted in patients exposed to doses of
3 to 10 mg/day for periods ranging from several weeks (Mizuta et al .
1956) up to several years (Silver and Wainman 1952).
Arsenic -induced peripheral neuropathy can sometimes be detected by
electromyographic (EMC) techniques. Characteristic changes include
decreased nerve conduction amplitude with little change in nerve
conduction velocity (NCV) (Donofrlo and Wilbourn 1985). Hindmarsh et al
(1977), studying a group of patients exposed to elevated levels of
inorganic arsenic in drinking water (above 100 Mg/L) , observed EMC
abnormalities in about half of the cases. Valentine et al. (1981)
measured NCVs in residents of several western communities where drinking
water levels of arsenic ranged from 50 to 387 ng/L. Although most
findings were in the normal range, a significant decrease in the ulnar
sensory nerve function was noted in both males and females. Landau et
al. (1977) reported level- and duration- dependent decreases in EMG
measurements in smelter workers exposed to arsenic primarily through
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Toxicologies! Data 53
inhalation. Similar results were reported by Blom et al. (1985), who
concluded that workplace exposure to air levels below 50 /*g/m3 did noc
result in any clinically significant neuropathy. In a study by Southwick
et al. (1981), no significant differences in NCV measurements were noced
between a population consuming water with high (0.2 mg/L) or low
(0.02 mg/L) levels of inorganic arsenic.
Arsenic neuropathy is classified as a distal axonopathy with axonal
degeneration, especially of large myelinated fibers (Hindmarsh and
McCurdy 1986). Both sensory and motor neurons are involved, usually bi-
laterally. Recovery of nerve function following cessation of exposure is
often slow and incomplete (EPA 1984a).
Chronic exposure to doses of up to 10 mg/kg/day (given by injection
once a week for 18 months) did not produce any evidence of neuropathy in
rats (Schaumburg 1980). This exposure level (an average of around
1.4 mg/kg/day) would almost certainly be expected to produce neuropathy,
if not lethality, in humans. This study lends further evidence to the
view that animals are not appropriate models for arsenic toxicity in
humans.
Dermatological effects. Chronic oral arsenic exposure produces a
characteristic group of dermatological manifestations, including
hyperkeratoses on the palms and soles and hyperpigmentation around the
eyelids, temple, neck, nipples, and groin. Usually the appearance is
mottled, like raindrops on a dusty road, but in severe cases the
pigmentation may extend broadly over the chest, back, and abdomen
(Hindmarsh and McCurdy 1986, EPA 1984a. EPA 1987b). Skin disorders of
this type have been observed in a number of epidemiological studies.
with effects being readily apparent in populations consuming drinking
water containing arsenic at levels of 0.4 mg/L or higher (Cebrian et al
1983, Zaldivar 1974, Borgono et al. 1977, Tseng et al. 1968, Huang et
al. 1985). Similar findings of hyperkeratoses and hyperpigmentation were
reported in retrospective studies of patients who had been treated with
Fowler's solution (Fierz 1965) and groups of workers exposed to airborne
arsenic in a pharmaceutical plant (Vatrous and McCaughy 1945) or a
sheep-dip factory (Perry et al. 1948). As described in greater detail in
the section on careinogenieity (Sect. 4.2.3.6), chronic oral arsenic
exposure is also strongly associated with increased risk of skin cancer.
The present consensus is that some hyperkeratinized lesions, which
appear as small corn-like elevations, may develop into squamous-cell
carcinomas. Areas of hyperpigmentation are not thought to be
precancerous (EPA 1987b).
Direct effects on skin and mucous membranes. Direct dermal contact
with arsenic compounds may result in local inflammation and vesiculation
(NAS 1977, Zaloga et al. 1985). Chronic inhalation exposure results in
irritation to the mucous membranes of the eyes and nasopharynx (Vallee
et al. 1960). A.hoarse voice is a common sign in arsenic workers, and a
perforated nasal septum may occur following prolonged exposures (ACGIH
1986). No such effects, however, were noted in workers exposed to
0.2 mg/m3 in air (ACGIH 1986).
Holmqvist (1951) reported evidence that arsenic may act as a
contact allergen, causing an increased response in dermal patch tests of
workers who were chronically exposed to arsenic dusts in a copper
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54 Section 4
smelter. However, Wahlberg and Boman (1986) reported that neither
Na2HAs04 nor NaAs02 induced contact allergy in guinea pigs.
Hepatic and renal injury. High oral exposures to arsenic have been
observed to injure both the liver and the kidneys. In the incident
involving infants poisoned with arsenic-contaminated milk, Hamamoto
(1955) observed swollen liver in all of the victims, and necrosis and
fatty infiltration were noted at autopsy of infants who died. Similar
signs of hepatic fatty infiltration, central necrosis, and eventual
cirrhosis have been described in patients employing Fowler's solution
(Franklin et al. 1950). Other studies have reported an association
between chronic oral arsenic exposure and hepatic cirrhos'is and portal
hypertension (Datta 1976, Viallet et al. 1972, Morris et al. 1974).
Signs of renal injury reported by Hamamoto (1955) included hematuria,
leukocyturia, and glycosuria. Cortical necrosis also has been reported
in some cases (Gerhardt et al. 1978).
Beneficial effects. There are several studies in animals which
indicate that low levels of arsenic in the diet are beneficial or
essential. Schwartz (1977) reported that racs fed diets containing
<0.05 ppm arsenite failed to gain weight normally, while animals
receiving 0.5 to 2.0 ppm did gain weight. Anke et al. (1976, 1978) did
not observe differences in growth of goats and minipigs fed a low
arsenic diet (<0.05 ppm), but conception rate was depressed in both
species, and offspring had decreased birth weight and elevated perinatal
mortality. More recently, Anke et al. (1987) reported the appearance of
ultrastruetural changes in the mitochondria of cardiac tissue from goats
fed an arsenic-deficient diet (0.035 ppb). Uthus et al. (1983) noted
low-arsenic diets (<0.03 ppm) led to growth depression and decreased
fertility in rats. These workers proposed that arsenic plays a role in
arginine metabolism.
While these observations suggest that low levels of arsenic (about
0.5 ppm in the diet) may be essential or beneficial to animals, several
researchers consider the weight of evidence inadequate to conclude this
with certainty (Solomons 1984, Hindmarsh and McCurdy 1986). EPA (1987b)
performed a detailed review of the evidence, concluding that
essentiality, although not rigorously established, is plausible.
If arsenic is essential or beneficial to animals, then it could be
important to humans as well. If so, the daily requirement for humans
probably lies somewhere between 10 and 50 pg/day (NAS 1977. EPA 1987b).
This level of arsenic intake is usually provided in a normal diet, and
no cases of arsenic-deficiency in humans have ever been reported.
4.2.3.3 Developmental toxicity
Information on the teratogenic and fetotoxic potential of arsenic
is derived mainly from studies in animals. Parenteral administration of
10 to 45 mg/kg/day of sodium arsenate to rats, mice, or hamsters during
gestation has been reported to increase the frequency of a number of
fetal malformations (Ferm and Carpenter 1968. Perm et al. 1971, Hood and
Bishop 1972, Burk and Beaudoin 1977. Willhite 1981, Ferm an-. Hanlon
1985). By the oral route, arsenate is ouch less toxic. Dose af
120 mg/kg administered by gavage co mice during gestation i,ased
decreased birth weight and increased prenatal mortality, but no
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Toxicologlcal Data 55
fecotoxic or teracogenic effects were seen with oral doses up to 100
BgAg (Hood et al. 1977, 1978).
Similar results have been reported for sodium arsenlte. although
the teratogenlc and fetotoxlc potential of arsenlte appears to be
somewhat greater than for arsenate. Baxley et al. (1981) administered
single oral doses of sodium arsenite to pregnant mice and observed no
discernable teratogenic or maternal toxicity at doses of 20 rag/kg. Doses
of 40 or 45 mg/kg resulted in both maternal lethality and fetotoxicicy
(decreased fetal weight and increased fetal resorptions), with a low
incidence of gross malformations. Similar findings were reported by Hood
and Harrison (1982) who administered single oral doses of sodium
arsenite by gavage to pregnant hamsters. Doses of 20 mg/kg given on days
9, 10, or 11 produced no significant fetotoxicity, while doses of
25 mg/kg given on day 8 or day 12 lead to Increased prenatal mortality
and decreased fetal weight. Animals exposed on day 8 also showed
evidence of increased fetal malformations, although this was not
significant. The authors concluded that acute oral exposure to arsenite
was not likely to be teratogenic or fetotoxic at doses that are
tolerated by the dam.
The effects of continuous maternal arsenic exposure on the
developing fetus have not been well studied. Perm and Hanlon (1985)
implanted osmotic minipumps containing sodium arsenate in pregnant
hamsters and found time- and/or dose-dependent decreases in the size and
number of living fetuses in dams receiving doses of around
5 to 9 mg/kg/day. Teratogenicity was associated with the exposure level
on day 8 (the critical stage of embryogenesis), and a dose-dependent
increase in malformations was seen at all doses tested (5 to 9
mg/kg/day).
Evidence of developmental effects of arsenic in humans is lacking
Epidemiological studies of smelter workers in Sweden (Nordstrom et al.
1978a,b,c,d) provide limited evidence of decreased birth weight and
increased abortion rate in women working in the smelter or living
nearby, but these data are not adequate to implicate arsenic as the
responsible agent.
4.2.3.4 Reproductive toxicity
The effect of arsenic exposure on reproductive parameters has not
been thoroughly investigated. Schroeder and Mitenner (1971) exposed mice
to drinking water containing 5 mg/L of arsenite (about 0.7 mg/kg/day)
There were no effects on survival over three generations, and the only
effects noted were an increase in the ratio of males to females in the
F3 generation and a small decrease in the average litter size.
4.2.3.3 Genotoxic ity
Gene mutation studies. Arsenic(III) and arsenic(V) compounds have
been tested for gene mutations in a number of systems. Nearly all
results have been negative. One positive report in bacteria (Nishioka
1975) could not be confirmed (Rossman et al. 1980), and other studies in
bacteria have been negative (Leonard and Lauwerys 1980, Lofroth and Ames
1978). Arsenite and arsenate were also reported to be inactive in
gene-specific mutation assays in yeast (Singh 1983) and cultured
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56 Section A
mammalian cells (Amacher and Patllet 1980, Rossman et al. 1980, Oberly
ec al. 1982. Lee et al. 1985). After reviewing the data, EPA believes
the weight of evidence supports the conclusion that arsenic is either
inactive or extremely weak for induction of gene mutations (Jacobson-
Krara and Montalbano 1985) .
Cytogenetic studies. In contrast to the negative results in gene
mutation tests, both arsenate and arsenite have been found to result in
chromosome aberrations and sister chromatid exchanges (SCEs) in cultured
animal and human cells tested in vitro (Jacobson-Kram and Montalbano
1985). For example, Larramendy et al. (1981) incubated Syrian hamster
embryo cells and human peripheral lymphocytes with concentrations of
around 10'5 H NaAs02 and Na2HAs04 and observed highly significant
increases in chromosome aberration frequency with both compounds in both
cell types. Arsenite was about tenfold more effective than arsenate
Dose-related increases in SCE were also reported. Similar results have
been reported by a number of other groups for a variety of arsenic(III)
and arsenic(V) compounds (Nakamuro and Sayato 1981, Nordenson et al
1981, Wan et al. 1982, Lee et al. 1985).
Several studies have described a positive association between
arsenic exposure and chromosome aberrations or SCEs in humans. For
example, Burgdorf et al. (1977) reported about a threefold increase in
SCE in lymphocytes from patients who had taken Fowler's solution for
periods of 4 to 27 years, although no difference in the frequency of
chromosomal aberrations was noted. Conversely, Nordenson et al. (1979)
reported increased frequencies of chromosomal aberrations but similar
frequencies of SCE in patients who had been exposed to total doses of
300 to 1200 mg of arsenic taken in Fowler's solution over many years
However, these and other similar studies in humans are limited by
methodological difficulties, small sample numbers, and likely exposure
of subjects to other clastogenic agents (EPA 1984a), so these results
must be interpreted with caution. No increase in chromosomal aberrations
or SCE was observed in a recent study of residents in Fallen. Nevada.
where drinking water contains about 0.1 mg/L of arsenic (Vig et al.
1984). Poma et al. (1981) examined bone marrow cells and spermatogenia
from mice treated with 4 to 12 mg/kg of As203 and observed no
significant increase in chromosomal aberrations in either cell type
4.2.3.6 Carcinogenicity
Skin cancer. There is clear evidence that chronic oral exposure co
elevated levels of arsenic increases the risk of skin cancer. The most
common cancerous lesions are squamous cell carcinomas which appear to
develop from some of the hyperkeratinized corns described earlier.
although most of these corns remain benign for decades. In addition,
multiple basal cell carcinomas may occur, typically arising from cells
not associated with hyperkeratinization. Although dermal lesions of chis
sort can be removed surgically, they may be fatal if left untreated.
The largest study of arsenic-induced skin cancer was described by
Tseng et al. (1968). The study focused on a large population in Taiwan
where arsenic levels in deep wells used for drinking water ranged from
0.001 to 1.82 mg/L, with average levels of around 0.4 to 0.6 mg/L. Based
on examination of over 40.000 people In the area, the skin cancer race
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Toxicological Daca 57
was found to be 10.6/1000. Typical arsenic blood levels In residents of
this area were around 15 ng/L (Heydorn 1970), somewhat higher than
typical values (2 to 5 ^g/L) in Denmark or the United States (Heydorn
1970, Valentine et al. 1979). There was a strong relationship between
the occurrence of skin cancer and other signs of arsenic intoxication
(hyperpigmentation, hyperkeratinization, and Blackfoot disease) . and
skin cancer incidence was correlated with arsenic levels in the water
No cases of skin cancer or other signs of arsenic poisoning were
reported in a control population of 7500 people consuming water with low
arsenic content (<17
The relevance of this study to skin cancer risk in the United
States occasionally has been questioned, based on concerns that there
may have been significant exposure to arsenic from sources other than
the well water (EPA 1987b) , and that the dietary and socloeconomic
characteristics of the exposed population are quite different from those
of average U.S. citizens (EPA 1984a) . Although these considerations may
call the precise dose-response relationship observed in this study into
question, they do not alter the conclusion that chronic arsenic
ingestion is associated with increased risk of skin cancer.
Cebrian et al. (1983) reported a 3. 6 -fold elevation in the
incidence of ulcerative skin lesions (compatible with a diagnosis of
epidermoid or basal cell carcinomas) in the residents of a Mexican town
where drinking water contained 0.4 mg/L of arsenic, compared to a
similar town where water contained 0.005 mg/L. Similarly, elevated
incidences of skin cancer have been reported in studies of humans who
had used Fowler's solution as a medicine (Scanners and McManus 1953,
Fierz 1965, Cuzick et al. 1982).
Several epidemiological studies performed in the United States have
not detected an increased frequency of skin cancer in small populations
consuming water containing arsenic at levels of around 0.1 to 0.2 mg/L
(Goldsmith et al. 1972, Morton et al. 1976, Harrington et al. 1978,
Southwick et al. 1981). These studies suggest that arsenic-associated
skin cancer is not a common problem in this country, but they lacked
sufficient statistical power to conclude that arsenic exposures of this
sort do not increase the risk of skin cancer (Andelman and Barnett
1983).
Internal cancers. A number of studies suggest that the incidence
of some types of internal malignancies may also be increased by chronic
oral exposure to arsenic (EPA 1987b) , but the data are not adequate to
draw a firm conclusion (EPA 198&a, Philipp 1985). For example, Sommers
and McManus (1953) reported that 10 of 27 patients with skin cancer
following arsenic exposure also had an internal cancer. A similar
increase in the incidence of internal cancer in patients with arsenical
keratoses was noted by Reyraann et al. (1978). Additional support for an
association between arsenic exposure and internal tumors was reported by
Dobson et al. (1965), who noted that palmar keratoses (indicative of
arsenic poisoning) were common in patients with internal tumors.
Several types of internal tumor have been observed in association
with oral arsenic exposure. A number of studies have noted that hepatic
angiosarcoma, a rare tumor in the general population, occurs at
increased frequency in persons exposed to Fowler's solution (Regelson
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58 Section 4
et al. 1967; Lander et al. L975; Falk et al. 1981a,b; Roat et al. 1982;
Kasper et al. 1984). and Roth (1958) also noted angiosarcoma in vintner
exposed to arsenical pesticides. Chen et al. (1985) studied the
correlation between mortality from several types of internal cancer and
exposure to arsenic through ingestion of water containing 0.35 to 1.14
mg/L of arsenic. The standardized mortality ratios (SMR) for bladder,
kidney, lung, and liver tumors were 1100, 772, 320, and 170 in males and
2009, 1119, 413, and 229 in females, respectively. A positive dose-
response relationship with arsenic exposure was noted for bladder, lung,
and liver cancer. In a follow-up case-control study, Chen et al. (1986)
found that the odds ratio for bladder, lung, and liver cancers for those
who had used well water containing arsenic for 40 years of more were
3.90, 3.39, and 2.67, respectively, compared to people who had never
used arsenic-contaminated well water.
Limited observations suggest arsenic might be associated with
several other types of cancer as well, including cancer of the mammary
gland (Knoth 1966), cancer of the lymphatic tissues (Ott et al. 1974),
leukemia (Axelson et al. 1978), and renal adenocarcinoma (Sommers and
NcManus 1953).
Lung cancer. A number of epidemiological studies have been
performed to determine if there is an association between inhalation
exposure to arsenic and increased risk of lung cancer. Although some of
these studies have not detected an association (Snegireff and Lombard
1951, Pinto and Bennett 1963, Nelson et al. 1973, Greaves et al. 1981,
Rom et al. 1982), most have observed an above-average incidence of lung
cancer in exposed populations (OSHA 1983, EPA 1984a, EPA 1986a). As is
often the case, these studies are to some degree limited by confounding
factors such as smoking and exposure to other chemicals; however, the
weight of evidence that arsenic is a risk factor for lung cancer is,
nevertheless, convincing.
Lee and Fraumeni (1969) reported an exposure-dependent increase In
frequency of respiratory cancer in workers in a large copper smelter in
Montana. Observed SMR values were 239, 478, and 667 in low, medium, and
high exposure groups, respectively. Based on industrial hygiene reports,
the average levels of air concentration for these three groups were 0.4,
7, and 62 mg/m3 (Lee-Feldstein 1986). Follow-up studies of this cohort
(Lubin et al. 1981, Higgins et al. 1982, Welch et al. 1982, Lee-
Feldstein 1983, Brown and Chu 1983b) obtained additional evidence of a
level- and duration-dependent increase in lung-cancer risk.
Similar results have been observed in workers at another large
copper smelter In Tacoma, Washington. Studies by Pinto et al. (1977.
1978) and Enterline and Marsh (1982) npted that death rates from lung
cancer In this cohort were several times higher than expected. Airborne
concentrations of arsenic ranged from 3 to 295 Mg/m3 (averaging around
53 pg/m3), however, urinary arsenic excretion levels were Judged to be
the best measure of exposure in each individual. A time-weighted index
of cumulative exposure calculated from urinary arsenic excretion levels
was linearly related to lung cancer mortality and ranged from an SMR of
111 at the lowest cumulative exposure to one of 832 at the highest
cumulative exposure. Based on a reanalysis of the exposure data,
Enterline et al. (1987) concluded chat the risk of lung cancer
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Toxicological Daca 59
associated with airborne arsenic is even greater than previously
believed, with SMR values >200 at a cumulative exposure of 10 mg/m-*-
years. The dose-response relationship was concaved downward, suggesting
that risk at low levels of exposure is greater than expected based on
observations at high levels of exposure.
Increased lung cancer rates in workers at other smelters have been
described by Rencher et al. (1977) and Axelson et al. (1978). Similar
elevations in respiratory cancer rates have been noted in other types of
occupational exposure involving arsenic dusts or fumes (Ott et al 197&,
Blejer and Wagner 1976, Mabuchi et al. 1979, Baetjer et al. 1975, Roth
1958).
Several epidemiological studies suggest that there is also an
increased risk of lung cancer for nonoccupationally exposed individuals
living within several kilometers of arsenic-emitting industries.
Matanoski et al. (1981) noted an elevated lung cancer rate in male
residents around a large pesticide plant in Baltimore. Brown et al.
(1984) reported a 60% increase in lung-cancer incidence in the vicinity
of a smelter in Pennsylvania, and Pershagen (1985) reported a relative
risk of 2.0 for lung cancer in men who lived within 20 km of a large
copper smelter in Sweden.
Carcinogenicity studies in animals. Most attempts to induce tumors
in laboratory animals following oral exposure to arsenic have been
inconclusive or negative (EPA 1986a). The reasons for this inability to
observe a clear carcinogenic response in animals are not known, but
these studies are not considered to refute the positive associations
between exposure and cancer observed in humans.
Some animal studies have produced suggestive evidence for arsenic -
induced lung cancer. In most of these studies, animals were exposed to
arsenic by intratracheal instillation and then observed for their
lifetimes. Ivankovik et al. (1979) reported that a single intratracheal
instillation of an arsenate-containing pesticide mixture caused lung
tumors in rats, and Ishinishi et al. (1983) reported that intratracheal
instillation of arsenic trioxide for 15 weeks caused lung tumors in
hamsters. Pershagen et al. (1984a,b) reported that intratracheal
instillation of As203 along with a carrier dust (charcoal carbon) and
sulfuric acid produces pulmonary carcinomas in hamsters. More recently,
Pershagen (1985) and Pershagen and Bjorklund (1985) reported that
intratracheal instillation of calcium arsenate alone causes an increase
in lung tumors in hamsters.
Mechanism of carcinogenicity. Compounds which are carcinogenic but
which do not cause gene damage directly may do so indirectly through a
variety of mechanisms (Barrett and Shelby 1986), including inhibition of
one or more enzymes involved in DNA replication or repair. Several
studies provide evidence that this may be the case with arsenic
(Nordberg and Anderson 1981, Rossman 1981, Jacobson-Kram and Montalbano
1985, Okui and Fujiwara 1986). This mechanism of action is also
consistent with the view that arsenic acts primarily as a promoter of
lung cancer rather than as an initiator (Hindmarsh and HcCurdy 1986) In
addition, Lee et al. (1986) found that although arsenic alone is a very
weak mutagen, it greatly increases the mutagenicity of other direct-
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60 Section 4
acting mutagens (UV radiation, alkylating agents, cross-linking agents
etc.).
Another possible mechanism of arsenic-induced carcinogenicity is
incorporation of arsenate into DNA in place of phosphate. This concept
is consistant with observations that arsenate must be present during DNA
synthesis in order to be effective. It would explain why arsenic is
clastogenic (the arsenate-phosphate bond would be weaker than the normal
phosphodiester) but does not cause gene mutations (Jacobson-Kram and
Montalbano 1985).
4.2.4 Interactions with Other Chemicals
Arsenic is known to interact with selenium, and the relationship
between these two chemicals has been studied both in vivo and in vitro
Most studies indicate that arsenic and selenium are mutually
antagonistic, each chemical reducing the effects caused by the other.
For example, high levels of selenium in the diet are toxic to livestock
and poultry, and addition of arsenic to the diet or to drinking water
reduces the extent of the selenium-induced injury (Levander 1977, Cabe
et al. 1979, Hill 1975, Sky-Peck 1985). Likewise, low doses of selenium
have an anticarcinogenic effect in animals and humans, and concomitant
arsenic exposure reduces this beneficial effect of selenium and
increases tumor rates (Schrauzer 1987, Schrauzer et al. 1978). With
respect to the effect of selenium on arsenic toxicity, selenium has been
shown to protect against arsenic-induced chromosome aberrations and
sister chromatid exchanges in cultured human lymphocytes (Beckman and
Nordenson 1986, Sweins 1983), against arsenic-induced cytotoxicity in
bovine pulmonary macrophages (Fischer et al. 1986), and against
arsenic-induced teratogenesis in hamsters (Holmberg and Perm 1969).
Gerhardsson et al. (1985) noted that selenium had a possible protective
effect against lung cancer in smelter workers exposed to a variety of
airborne carcinogens, including arsenic. The mechanism by which arsenic
and selenium influence each other is not known, but each chemical tends
to increase the biliary excretion of the other, suggesting that they may
react in the liver to form a conjugate (Hill 1975, Levander 1977).
Some interactions between arsenic and other chemicals have been
documented. Pershagen et al. (1981) reported that smoking and arsenic
inhalation had a multiplicative effect on lung cancer mortality in
smelter workers. There are also evidences of a positive interaction
between arsenic and benzo(a)pyrene in induction of lung tumors in
hamsters (Pershagen et al. 1984a). Mahaffey and Fowler (1977) reported
that weight gain In young rats was reduced more by cadmium and arsenic
given together than expected by the sum of the effects of each agent
alone. In a follow-up study. Mahaffey et al. (1981) found that
interactions between several metallic elements affect both toxicity and
tissue concentrations of the metals. Lead and arsenic in the diet
produced an additive effect on coproporphyrln excretion in male rats,
and arsenic produced a significant increase in renal copper
concentration. In addition, cadmium exposure reduced tissue
concentrations of arsenic. The mechanisms of these interactions have noc
been determined.
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ToxicoLogical Data 61
In a study of classroom behavior. Marlowe et al. (1985) reported
that arsenic and other toxic metals increased the neurotoxic effects of
lead in children as measured by aggressive behavior in the classroom and
reading and spelling achievement. Interaction of arsenic and aluminum
also increased aggressive behavior. Arsenic in the diet of rats has been
reported to have a slight goiterogenic effect, causing increases in
thyroid weight accompanied by decreases in iodine concentration in the
thyroid, even with increased iodine intake (Sharpless and Metzger 1941,
NIOSH 1975) .
4.3 ORGANIC ARSENIC
4.3.1 Overview
Arsenic can form stable bonds with carbon, forming a large number
of organic derivatives. The chemical and physical properties of the most
common organic derivatives of arsenic are summarized in Table 3.4. As
with inorganic arsenic, there are significant toxicokinetic and
toxicological differences between various organic arsenicals and animal
species as well. From the perspective of likely exposure and potential
risk to human health, four groups of derivatives merit special
attention:
• Methyl derivatives of arsenic acid. The most important members of
this group are MMA, DMA, and their salts. These compounds have been
widely used as pesticides (primarily as herbicides and defoliants)
In the early part of this century, DMA and its sodium salt were
employed as medicine for a variety of diseases, including syphilis
By the oral route, these compounds produce symptoms of
gastrointestinal irritation and renal and hepatic injury similar to
some of the effects produced by inorganic arsenic, but the potency
of these methyl derivatives is much lower. As described above (see
Sect. 4.2.2 on toxicokinetics), the methyl derivatives are also
formed in the body by metabolism of inorganic arsenic, and this is
generally viewed as a detoxification pathway.
• Phenyl derivatives of arsenic acid. Several phenyl arsenates (e.g.,
arsanilic acid) and their salts have been widely used as feed
additives to improve weight gain and prevent enteric disease in
poultry and swine. The mechanism of these beneficial effects is noc
known but may be due to effects on intestinal microorganisms rather
than a direct effect on the animal. Exposure of animals to high
levels of phenylarsonate compounds results primarily in sensory and
peripheral nerve injury. The toxicity of these compounds in humans
has noc been investigated extensively.
• "Fish arsenic." Fish and shellfish often accumulate rather high
tissue levels of arsenic. Depending on the species, most of this
accumulation exists in the form of arsenobetaine or arsenocholine
Available data indicate that these organic derivatives have low
toxicity, and ingestion of arsenic in this form is not generally
considered to be of health concern.
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62 Seccion 4
• Methyl derivatives of arsine. Arsine (not a true organic arsenical
but considered here for convenience) and its methyl derivatives ar
not widely used in industry but might be encountered at some
hazardous waste sites. In addition, arsine and its methyl
derivatives may be formed in the environment from other arsenic
compounds by the action of microbial organisms or by inadvertent
chemical reactions that generate strong reducing conditions. These
compounds are highly irritating gases or volatile liquids and
possess varying degrees of hemolytic potential.
4.3.2 Toxicokinetics
4.3.2.1 Methanearsonates
Both MMA and DMA are well absorbed in animals and humans. Buchet et
al. (1981a) reported that gastrointestinal absorption was at least 75 to
80% in humans given oral doses of MMA or DMA. Similar values (about 70%)
have been reported for DMA in rats (Stevens et al. 1977b) and hamsters
(Yamauchi and Yamamura 1984). The extent (92%) and rate (half-time of 2
min) of DMA absorption following intratracheal instillation in rats is
somewhat greater than in gastrointestinal absorption (Stevens et al.
1977b).
Stevens et al. (1977b) reported that administration of DMA to rats
initially lead to high concentrations in whole blood, muscle, kidney,
liver, and lung. Soon thereafter, however, levels decreased rapidly in
all tissues except in whole blood. Vahter et al. (1984) administered DMA
orally to rats and mice and observed that the highest initial
concentrations of arsenic were found in the kidney, lung,
gastrointestinal tract, and testes. Tissues showing the longest
retention of arsenic were lung, thyroid, intestinal wall, and lens.
Marafante and coworkers (1985) reported high concentrations of DMA in
the lung after intraperitoneal injections to rabbits, and attributed
that to rapid uptake by the lung followed by rapid clearance.
Both MMA and DMA are excreted primarily in urine. Buchet et al.
(1981a) administered oral doses (500 pg arsenic) of MMA and DMA to human
volunteers. After four days, the excretion of urinary arsenic was 78 and
75% of'the dose of MMA and DMA, respectively. Analysis of the excretion
productions revealed that DMA was excreted unchanged, while 13% of the
MMA was methylated to DMA. In rats, DMA was not excreted in feces after
intravenous administration, and fecal excretion of arsenic after oral
administration of DMA probably resulted from incomplete absorption
(Stevens et al. 1977a).
4.3.2.2 Phenylarsenates
Phenylarsonic compounds are not well absorbed from the intestinal
tract in humans and animals (NAS 1977). Following oral administration of
74As-arsanilic acid to human volunteers, 74% was excreted in the feces
(Calesnick et al. 1966).
Phenylarsonates do not appear to undergo significant metabolism in
the body. Cristau et al. (1975) administered sodium arsanilate to rats
and guinea pigs, detecting no arsenic-containing compounds in the urine
except the parent arsanilate. Similar evidence indicates that chickens
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ToxicologLcal Data 63
do not metabolize arsanilic acid, acetylarsonic acid, or 3-nitro-4-
hydroxy-phenylarsonic acid (roxarsone) (Moody and Williams 1964a,b).
Fhenylarsonates are not retained in the body but are excreted in
urine. Following parenteral administration of phenylarsonic compounds to
animals, most of the dose is excreted in the urine within 24 to 48 h
(NAS 1977). In chickens fed 50 ppm of roxarsone, only slight increases
in arsenic levels could be detected in skin, muscle, liver, and kidney
(Buck et al. 1973).
4.3.2.3 Fish arsenic
In humans, gastrointestinal absorption of organic.arsenic in fish
and seafood is at least 70% (Vestoo and Rydalv 1972, Charbonneau et al.
1980b). Tarn et al. (1982) reported that in humans, only 0.3% of the
arsenic ingested in fish was excreted in the feces, indicating
essentially complete absorption. Similar results have been obtained in
animals. Charbonneau et al. (1978b) reported that monkeys fed a
homogenate of fish absorbed over 90% of the arsenic present. Vahter et
al. (1983) and Marafante et al. (1984) synthesized radiolabeled
arsenobetaine and arsenocholine and reported that 90 to 98% of oral
doses given by gavage to mice or rats was absorbed.
Both arsenobetaine and arsenocholine are rapidly excreted in the
urine. Tarn et al. (1982) reported about 50% of the arsenic in fish was
excreted in urine by humans within 1 day, and Luten et al. (1982)
reported 70 to 85% urinary excretion of fish arsenic by humans within
5 days. Vahter et al. (1983) reported that over 99% of an intravenous
dose of arsencbetaine in mice was cleared within 4 days, with a half-
time of 12 h. A small fraction of the dose (about 0.2%) was retained and
cleared within a half-time of about 60 days. Only unchanged
arsenobetaine could be detected in urine (Vahter et al. 1983, Cannon et
al. 1983, Kaise et al. 1985).
Arsenocholine is cleared somewhat more slowly than arsenobetaine.
with a half-time of about 12 days in mice. The main urinary product is
arsenobetaine, and metabolic conversion of arsenocholine to
arsenobetaine appears to be the rate-limiting step (Marafante et al.
1984)'.
4.3.2.4 Arslna and methylarsines
No quantitative data on the toxicokinetics of arsine or
methylarsines were located. The principal exposure route of concern is
inhalation, and it seems likely that these compounds would be well
absorbed from the lung. Once arsenic is inhaled, it subsequently breaks
down, releasing inorganic arsenic into the blood (NIOSH 1979). Elevated
levels of arsenic have been observed in the tissues and urine of humans
following arsine exposure (ACGIH 1986).
4.3.3 Toxicity
4.3.3.1 Methanearsonates
Lethality. Acute oral exposure of animals to methanearsonates
results mainly in signs of gastrointestinal irritation (diarrhea and
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64 SecCion 4
vomiting), accompanied by listlessness or hematuria (Palmer 1972). In
extreme cases, sequelae may include stupor, convulsions, paralysis, and
death (Weed Society Handbook 1967). In rats, estimates of the acute oral
LD50 for DMA, its monosodium salt (NaDMA), and the monosodium salt of
MMA (NaMMA) range between 600 and 2600 mg/kg. Calves appear to be more
sensitive than rats, with acute oral LD5Q values for these compounds
ranging from 100 to 450 mg/kg (Hood 1985). Available evidence is not
adequate to determine if humans are more sensitive than animals to these
organic arsenic compounds.
Acute inhalation exposure to methanearsonates usually produces only
mild signs of respiratory distress (Stevens et al. 1977b). Exposure of
rats to aerosols of DMA for 2 h caused labored respiration, rhinorrhea,
irritation of the eyes, and diarrhea, with an estimated LC5Q of
4300 mg/m3. The estimated acute inhalation LC50 for DMA in mice was
>6400 mg/m3 (Stevens et al. 1977b).
Dermal exposure of rabbits to NaDMA at a dose of about 500 mg/kg
did not cause lethality (IBT 1976), while application of 2800 mg/kg of
NaMMA caused death within 2 to 4 days (Nees 1969).
Systemic effects. In humans exposed to methanearsonates in
occupation-related incidents, symptoms most often reported were
vomiting, diarrhea, abdominal pain, eye irritation, and dermatitis. No
long-lasting sequelae of these exposures were observed (Peoples et al
1979).
Early in this century, NaDMA was investigated as a medicine for
syphilis, skin disease, tuberculosis, and anemia (Simon 1932). Typical
doses were 25 to 150 mg/day. Clinical experience eventually led to the
conclusion that DMA was ineffective in this role. Adverse symptoms were
rarely observed after oral dosing, although intravenous administration
led to renal injury in a few cases (Cole 1916).
Data on methylarsonate toxicity in animals are mostly derived from
studies in cattle, sheep, and chickens. Palmer (1972) conducted an
extensive investigation of the toxicity of DMA. NaMMA, and the disodium
salt of MMA (Na2MMA) in these species and found that multiple doses of 5
to 10 mg/kg/day were without ill effects in cattle and sheep. Higher
doses often resulted in diarrhea, anorexia, and weight loss. In
chickens, doses of 100 to 250 mg/kg/day did not affect normal weight
gain. In a 90-day feeding trial in rats and dogs, no effects were
observed at dietary levels of 30 ppm (roughly 1 mg/kg/day) of DMA or MMA
(Ansul Co. 1971). Siewicki (1981) fed rats diets containing 42 ppm
(about 2 mg/kg/day) of DMA for 42 days and observed no effects on body
weight, organ weight, hematology, or urinary excretion of ALA or
coproporphyrin, even though significant levels of arsenic were present
in liver, spleen, and erythrocytes.
Developmental and reproductive effects. Oral administration of
high doses (40 to 100 mg/kg) of DMA has been reported to cause
fetotoxicity (reduced fetal weight, delayed ossification, and cleft
palate) in mice, but this was associated with maternal toxicity and
mortality (Chernoff and Rogers 1975). In a later study, Rogers et ai.
(1981) reported maternal toxicity and skeletal and/or palate anomalies
in fetuses following oral administration of DMA to mice (400 mg/kg/day)
-------
Toxicologies! Data 65
or rats (30 mg/kg/day). Developmental defects were observed at doses
below those that appeared to cause maternal toxicity in the rat, but noc
in the mouse (Hood 1985). Harrison et al. (1980) and Hood (1985)
reported maternal deaths and fetal malformations in hamsters after
intraperitoneal administration of NaDMA at 900 to 1000 mg/kg and Na2MMA
at 500 to 1500 mg/kg. These doses are as much as 100 times greater than
the doses of inorganic arsenic required to cause developmental effects
in mice (Hood and Bishop 1972, Hood 1972).
Mutagenicity/carcinogenicity. Results of mutagenicity tests for
DMA have been negative in bacterial systems (Simmon et al. 1977,
Andersen et al. 1972, Felkner 1980). In yeast (S. cerevisiae), DMA
yielded positive results in tests involving gene conversion, reverse
mutation, and mitotic crossing over (Mortelmans et al. 1980, Simmon et
al. 1977).
Innes et al. (1969) administered DMA orally to mice at
46.4 mgAg/day for three weeks and then at 121 ppm in the diet (about
20 mgAg/day) for 18 months. Histopathologic examinations did not reveal
any evidence of increased tumor frequency. In vitro cell transformation
tests with DMA and NaMMA also gave negative results (Moore 1976)
Johansen et al. (1984) exposed partially hepatectomized rats to DMA in
drinking water (80 mg/L, corresponding to about 20 mg/kg/day) for six
months and observed no increase in hepatic tumors or preneoplastic foci
There was a suggestive increase in tumors and foci in animals treated
with diethy1 nitrosoamine (DENA) as an initiator, indicating that DMA
might have promoted activity, but the data were too limited to draw firm
conclusions.
It should be remembered that most carcinogenicity tests of
inorganic arsenic in animals have been negative, even though inorganic
arsenic appears to be a human carcinogen by both the oral and inhalation
routes. Hood (1985) concluded that available data are inadequate to
assess the human carcinogenic potential of the methylarsonates.
4.3.3.2 Phenylarsonates
Lethality. Phenylarsonic compounds appear to be more toxic than
methanearsonates. Reported oral LD50 values range from 44 to 216 mg/kg
for the rat, and subcutaneous LDso values were 75 mg/kg for the rat and
400 mg/kg for the mouse. Intraperitoneal LDso values for the rat range
from 18.8 to 66 mg/kg (RTECS 1983, Kerr et al. 1963). Symptoms of acute
poisoning include loss of coordination, inability to control limb
movements, ataxia, blindness, and paralysis (NAS 1977).
Systemic effects. Arsanilic acid derivatives have been used as
human therapeutic agents to treat syphilis and trypanisomiasis. Adverse
effects that have been noted in association with this use include opcic
neuritis and loss of peripheral vision, similar to that observed with
other organometals such as organotin or methyl mercury. In some cases,
injury may progress to loss of central vision and optic atrophy (Crane
1974, Potts and Gonasun 1980)
Toxic effects of chronic excess phenylarsonate ingestlon in swine.
include blindness, partial paralysis of the extremities, and poor weight
gain (NAS 1977). Histopathologic changes observed include optic nerve.
-------
66 Section 4
optic tract, and peripheral nerve damage (Buck et al. 1973). No toxic
effects were reported in pigs administered 100 ppm arsanilic acid in the
diet (about 4 mg/kg/day) for three generations (Frost et al. 1962).
However, chronic poisoning of swine has been reported after
administration of 100 ppm roxarsone in the diet for two months (Buck
1969). Kennedy et al. (1986) reported that pigs fed a diet containing
187 ppm of roxarsone (about 7 mg/kg/day) developed a nervous disorder in
10 days. The main symptom was clonic convulsive episodes brought on by
exercise. This was accompanied by histological evidence of myelin and
axonal degeneration. Similar doses of arsanilic acid did not produce
this effect (Rice et al. 1985).
The mechanism of this neurotoxicity is not known, but it is evident
that roxarsone affects copper metabolism in exposed animals. Roxarsone
decreases levels of copper in liver and other tissues both in swine
(Edmonds and Baker 1986) and chickens (Czarnecki et al. 1984a). At
high-dose levels, roxarsone and copper Interact synergistically, causing
more weight loss and toxicity than either agent alone (Czarnecki and
Baker 1984, Edmonds and Baker 1986). Concomitant feeding of roxarsone
and cysteine also increases toxicity, perhaps by a reduction of arsenic
from the pentavalent to the more toxic trivalent form (Czarnecki et al.
1984b).
Reproductive/developmental effects. No reports on reproductive or
developmental effects of phenylarsonates were located.
Mutagenicity/carcinogenicity. Only one study was located which
evaluated the carcinogenic potential of arsanilic acid. Frost et al.
(1962) found no increase in the tumor incidence of rats fed 100 ppm
arsanilic acid in the diet for 116 weeks.
4.3.3.3 Fish arsenic
Arsenobetaine is the principal organic arsenic compound contained
in the flesh of fish, shellfish, and crustaceans. Studies on this
compound indicate that it has very low oral toxicity. Cannon et al.
(1983) administered arsenobetaine by intraperitoneal injection to mice
Doses up.to 500 mg/kg produced no symptoms of toxicity. Similarly, Kaise
et al. (1985) administered oral doses of arsenobetaine as high as 10,000
mg/kg to mice and observed no toxic symptoms. No evidence of
mutagenicity was detected with arsenobetaine in the Ames test or the
hypoxanthine guanine phosphoribosyl transferase (HGPRT) forward mutation
assay, and no increase in SCE was observed in Chinese hamster cells
exposed Co concentrations as high as 10,000 mg/L (Cannon et al. 1983,
Jongen et al. 1985).
4.3.3.4 Arsine and methylarsines
Arslne is a colorless gas that is a powerful local and pulmonary
irritant. High concentrations (10 ppm or above) of this gas may be
lethal within hours (ACGIH 1986). The chief health concern is hemolysis
of red blood cells (NIOSH 1979. Sittig 1985). The characteristic
symptoms of arsine poisoning include discolored urine (hemoglobinurea),
jaundice, and anemia, accompanied in some cases by renal damage
secondary to clogging the nephrons with hemolytic debris (NIOSH 1979,
Sittig 1985).
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Toxicological Daca 67
The hemolytic effects appear to be related primarily to a marked
reduction in reduced glutathione levels and oxidation of hemoglobin in
red cells (Foa and Bertolero 1983, Sax 1984). Intermittant exposure co
concentrations of 0.5 to 2.0 ppm have been observed to cause blood
effects in a few weeks (ACGIH 1986). An average concentration of 0 5 ppm
(0.2 mg/m3) is considered acceptable in the workplace (NIOSH 1979. ACGIH
1986).
Like arsine, the methylarsines (monomethylarsine, dimethylarsine,
and crimethylarsine) are strong irritants, but these compounds are less
powerful than arsine as hemolytic agents (NIOSH 1983). No other
quantitative information on dose-response relationships for the
methylarsines was located.
4.3.3.5 Summary
In general, organic derivatives of arsenic are less toxic than
inorganic forms. The apparent order of toxicity is phenylarsonates >
methylarsonates > fish arsenic (arsenobetaine). The most characteristic
effect of the phenylarsonates is neurotoxicity, with effects occurring
at oral exposure levels of about 4 mg/kg/day or higher. Hethylarsonaces
are primarily associated with irritation of the gastrointestinal tract
or the skin, usually at exposure levels in excess of 10 mg/kg/day.
Arsenobetaine has not been found to cause toxicity in animals even at
very high doses (10,000 mg/kg). Arsine is a powerful hemolytic agent
that breaks down to inorganic arsenic in the body. The methylated
derivatives of arsine are less toxic than arsine itself.
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69
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL
5.1 OVERVIEW
Arsenic is produced primarily as a by-product from the operation of
nonferrous smelters. Currently, there are no producers in the United
States, and all raw materials for the production of arsenic-containing
products must be imported. The major uses of arsenic in this country are
as wood preservatives or as agricultural products. Due to recent
regulatory activities by EPA's Office of Toxic Substances and Office of
Pesticide Programs, these uses will probably be restricted or curtailed
in the future.
5.2 PRODUCTION
Arsenic is produced commercially (primarily as a by-product) from
the flue dust of copper and lead smelters. Arsenic trioxide is
concentrated in these dusts, which are roasted with pyrite or galena to
yield an arsenic trioxide that is 90 to 95% pure. The trioxide is
reduced with carbon to produce arsenic metal (EPA 1982b).
In recent years, arsenic trioxide was produced in the United States
only at the ASARCO smelter in Tacoma, Washington. Annual production was
7300 megagrams (Mg) in 1983, but production decreased to 2200 Mg in
1985. In 1985, the ASARCO smelter ceased operation, and arsenic is no
longer produced in this country (Bureau of Mines 1988).
5.3 IMPORT
In 1979, the United States imported 8940 Mg of arsenic in the form
of arsenic metal or inorganic arsenic compounds (EPA 1982). By 1985,
imports had risen to 19,000 Mg and increased to nearly 28,000 Mg in 1986
after domestic production ceased. Thus, the United States is completely
dependent on foreign suppliers for arsenic (Bureau of Mines 1988).
5.4 USES
The United States made use of approximately 23,000 Mg of arsenic in
1987. Most of this (74%) was used in wood preservatives, with 19% used
in agricultural chemicals (principally herbicides and desiccants), 3% in
glass, 2% in nonferrous alloys, and 2% in other uses (Bureau of Mines
1988). The use of arsenic (as gallium arsenide) in semiconductors is
increasing, but total usage for this purpose (about 5 tons) is still
small compared with other uses.
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70 Section 5
5. 5 DISPOSAL
The principal waste product of arsenic production is slag. In 1979,
1200 Mg of arsenic in che form of slag were disposed of on land. Since
arsenic production is a dry operation, only small quantities of the
chemical were discharged in wastewater (0.4 Mg in 1979) (EPA 1982).
There is essentially no recycling of arsenic from its principal uses as
wood preservatives or agricultural chemicals (Bureau of Mines 1988).
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71
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
Arsenic enters the environment both as the result of natural forces
(volcanos and weathering of arsenic-containing rocks) and human activity
(metal smelting, glass manufacturing, pesticide production and
application, and fossil-fuel burning).
Arsenic in the environment may undergo a complex cycle of chemical
interconversions and transfers between media. Atmospheric emissions,
which are usually adsorbed to particulate matter, may undergo oxidation
before being returned to the surface by wet or dry deposition. Arsenic
in water may undergo either reduction or oxidation, depending on pH, the
electrochemical oxidation-reduction potential (Eh), and other ions
present. Soluble forms of arsenic tend to be quite mobile in water,
while less soluble species adsorb to clay or soil particles.
Microorganisms in soils, sediments, and water can reduce and methylate
arsenic to yield methyl arsines, which volatilize and re-enter the
atmosphere. These forms then undergo oxidation to become methyl arsonic
acids and ultimately transform back to inorganic arsenic.
6.2 RELEASES TO THE ENVIRONMENT
6.2.1 Anthropogenic
Table 6.1 summarizes releases of arsenic into the environment in
1979 as a result of human activity (EPA 1982b). The total amount of
arsenic released was 53,400 Mg, most of which (81%) was deposited on
land. The three largest sources of emissions to air and soil are fossil
fuel consumption, pesticide use, and copper smelting. These three
sources accounted for 35, 26, and 19%, respectively, of total air
emissions in 1979, and similar quantities (32, 19, and 19%) of land
emissions. The largest sources of arsenic in surface water are urban
runoff (37%), pesticide application (25%), and zinc production (20%).
6.2.2 Natural
Table 6.2 summarizes the quantities of arsenic estimated to be
released to the environment from natural sources. In the northern
hemisphere, the single largest source is volcanic emissions, accounting
for 88% of the total releases. Other important natural sources include
weathering of arsenic-containing minerals and ores (160 Mg/year), forest
fires (110 Mg/year), and the terrestrial biosphere (170 Mg/year).
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72
SacCion 6
Table 6.1. Arsenic releases to the environment in 1979"
Source
Estimated environmental arsenic releases (Mg/year)
Air
Land
Water
Surface POTW* Total
Production
ASARCO, Tacoma 210 1,200 <1 Neg< 1,410
Use
Pesticides 1,500 8,100 720 NA* 10,000
Wood preservatives Neg Neg Neg NA Neg
Glass manufacture 10 Neg Neg NA 10
Alloys e e e NA NA
Other 2 10 NA <50 62
Other sources of releases
Fossil fuel consumption
Copper production
Lead production
Zinc production
Iron and steel production
Aluminum production
Boron production
Phosphorous production
'Manganese production
Antimony production
Cotton ginning
POTW
Urban runoff
Total
2,000
1,100
230
280
55
NA
NA
NA
10
NA
300
NA
NA
5.700
14,000
8,100
1,100
5,700
NA
2,200
640
1,400
Neg
580
20
NA
43,000
150
38
Neg
560
9
180
4
160
NA
NA
NA
NA
1.050
2,870
NA
NA
NA
1
6
NA
NA
NA
NA
NA
NA
1,800
NA
1,857
17,000
9,300
1,300
830
5,700
180
2,200
800
1,440
Neg
880
1,820
1,050
53,400
"Adapted from EPA 1982b.
*PubUcly owned treatment works.
"Negligible.
*Not available in reference.
'Included in other sources of releases.
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Environmental Face
73
Table 6.2. Estimates of arsenic emissions
from natural sources"
Source
Ocean
Bubble bursting
Gas exchange
Earth's crust
Particle weathering
Direct volatilization
Volcanoes
Forest wildfires
Terrestrial biosphere
Natural source total
Global
arsenic
emission
(Mg/year)
28
84
240
0.7
7000
160
260
7800
Northern
hemisphere
arsenic
emission
(Mg/year)
12
SO
160
0.5
3500
110
170
4000
"Adapted from EPA 1984c, after Walsh et al.
1979.
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74 Section 6
6.3 ENVIRONMENTAL FATE
6.3.1 Atmosphere
Arsenic released Co the atmosphere as a gas vapor or adsorbed Co
particulate matter may be transported to other media via wet or dry
deposition, making the atmosphere an importanC route of arsenic cransfer
co ocher media. Trivalenc arsenic may undergo oxidation in che air, and
arsenic in che atmosphere is usually a mixture of the trivalent and
pentavalent forms (EPA 1984a).
Most arsenic in air is adsorbed Co particulate matcer, especially
small diameter particles (e.g., less than 2 urn in diameter) (Coles et
al. 1979, as cited in EPA 1982b). The residence time of particulate-
bound arsenic in the air depends on particle size, but a typical value
is about 9 days (Walsh et al. 1979, as cited in EPA 1982b). Arsenic may
persist longer under conditions of limited atmospheric mixing or low
precipitation.
Photolysis is not considered an important fate process for arsenic
compounds (Callahan et al. 1979).
6.3.2 Surface Water
Arsenic in surface water can undergo a complex pattern of
transformations, including oxidation-reduction reactions, ligand
exchange, biotransformation, precipitation, and adsorption (Callahan et
al. 1979). This complexity results in extremely mobile behavior in
aquatic systems, with much of che arsenic entering rivers and eventually
transported to oceans (Callahan et al. 1979). Rate constants for these
various reactions are noc readily available, but the factors most
strongly influencing intramedium fate processes in surface water include
Eh, pH, metal sulfide and sulfide ion concentrations, iron
concentration, presence of phosphorus minerals, temperature, salinity,
and distribution and composition of biota (Callahan et al. 1979).
Sorption onto clays, iron oxides, manganese compounds, and organic
material is an important fate of arsenic in surface water (Callahan et
al. 1979, EPA 1982b), and sediment serves as a reservoir for much of the
arsenic entering surface waters. Sediment-bound arsenic
(arsenate/arsenite), which has been methylated by aerobic and anaerobic
microorganisms, may be released back to the water column (EPA 1982b)
6.3.3 Groundvater
Soluble forms of arsenic interact with soil and travel with the
groundwater mass with which they are associated. Shifts in oxidation
state may occur in either direction, depending on the particular
physical and chemical characteristics of the soil and groundwater.
Volatilization of methylated forms from groundwater is possible
Nonporous soil and heavy vegetation cover are expected to impede
volatilization, and oxidation may transform volatile forms into
nonvolatile species or species that will adsorb to clay, organic matter.
and iron and aluminum complexes.
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Environmental Face 75
6.3.4 Soil
Arsenic occurs in soil predominantly in an insoluble adsorbed form
(EPA 1982b). Clay with high anion exchange capacity (e.g., high
kaolinite content) is particularly effective at adsorbing arsenate via
anion exchange. Complexation and chelation by organic material, iron, or
calcium are also important processes fixing arsenic in insoluble form
(Cooper et al. 1932, as cited in EPA 1982b).
Red and yellow podzols, latosols, arid and limestone soils, and
subsoils high in clay and iron oxides have greater holding capacity for
arsenic than other types of soil (Hiltbold et al. 1974,.as cited in EPA
1982b). A rise in pH in high iron soil, a drop in pH in lime soil, or a
change in redox potential may lead to resolubilization of fixed arsenic
Leaching of arsenic is usually important only in the top 30 cm of
soil (EPA 1982b). Leaching carries arsenic deeper in sandy soils than in
clay or loam soils, although EPA (1982b) reports that no leached arsenic
could be detected below 90 cm in any of the studies.
While arsenate dominates in aerobic soils, arsenite is the
predominant form in slightly reduced soils (e.g., temporarily flooded
soil), and arsine, methylated arsenic, and elemental arsenic predominate
in very reduced conditions (e.g., swamps and bogs) (EPA 1982b).
6.3.5 Biota
As noted above, arsenic in water and soil may be reduced and
methylated by fungi, yeasts, algae, and bacteria, and these forms may
volatilize and escape into the air (Wood 1974). The rate of
volatilization may vary considerably, depending on soil conditions
(oxygenated or anaerobic). The pH value of the soil and microbes present
also influence the rate of volatilization. For example, a report by the
PAX company (1973) estimated that 50% of an applied dose might
volatilize in one year, while Woolson (1976) reported only 1 to 2%
volatilization over a period of several months.
Bioconcentration of arsenic occurs in aquatic organisms, primarily
in algae and lower invertebrates. Biomagnification in aquatic food
chains does not appear to be significant (EPA 1982b, Callahan et al.
1979), although some fish and invertebrates contain high levels of
arsenic compounds which are relatively inert toxicologically (EPA
1984a).
Plants may accumulate arsenic via root uptake from soil solution,
and certain species may accumulate substantial levels (EPA 1982b). In
addition to species differences, the amount of arsenic taken up depends
on soil arsenic concentration, soil characteristics, and other factors.
-------
77
7. POTENTIAL FOR HUMAN EXPOSURE
7 . 1 OVERVIEW
Arsenic is widely distributed in the environment, and all humans
are exposed to low levels via air, water, and food. Typical
"background" exposure levels range from 20 to 70 jjg/day, with most of it
coming from food.
Higher levels of exposure that may lead to significant human health
consequences are most often associated with drinking water contaminated
from natural mineral deposits, pesticide use, or improper disposal of
arsenic chemicals. Emissions from metal smelters or arsenical pesticide
plants may result in significant exposure of workers and nearby
residents .
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Water
A number of surveys of arsenic levels in drinking water, surface
water, and groundwater have been performed (Greathouse and Craun 1978,
EPA 1980d, Irgolic 1982, EPA 1980c, EPA 1982b, Whitnack and Martens
1971, McCabe et al. 1970, Francis et al. 1982. Wentworth 1983). The
main findings of these surveys may be summarized as follows:
• Most drinking water supplies in this country provide water
containing arsenic at levels well below the present standard of
50
• Over 90% of all surface water contains 10 Mg/L arsenic or less.
Concentrations above 10 Mg/L are most often encountered in the
following major river basins: Missouri River, Lower Mississippi.
Colorado River, Western Gulf, Pacific Northwest, and Great Basin.
• Average arsenic concentrations in well water are generally
<20 Mg/L. with highest maximum concentrations occurring in the Ohio
River and Lake Erie basins.
• The average concentration of arsenic in U.S. drinking water
supplies is about 2 Mg/L (Greathouse and Craun 1978).
The chemical form of arsenic in drinking water is predominantly
inorganic and typically contains a mixture of arsenate and arsenite
(Irgolic 1982).
-------
78 Section 7
7.2.2 Air
Average 24-h ambient air arsenic levels in Che United States, based
on National Air Sampling Network data, ranged from a low of 2.6 ng/m3 in
1980 to a high of 10.9 ng/m3 in 1978 (Akland 1983). In all years, the
99th percentile values (the concentration below which 99% of all
measurements fall) were less than 78 ng/m3.
Suta (1980) reported that the highest levels of arsenic detected in
air (up to 1000 ng/m3) were found in the vicinity of copper smelters,
cotton gins, lead and zinc smelters, and glass manufacturers. Arsenic
air levels were lowest (0.4 ng/m3) in remote areas.
Studies by Andreae (1980, 1983), Attrep and Anirudhan (1977),
Crecelius (1974), and Johnson and Braman (1975) indicate that trivalent
and pentavalent forms of inorganic arsenic predominate in the air.
7.2.3 Soil
The natural arsenic content of virgin soils varies between 0.1 and
80 ppm, with an average around 5 to 6 ppm (Walsh and Keenly 1975). The
amount of arsenic in soil depends on geologic inputs from mineral
weathering processes (NAS 1977), atmospheric deposition, and residue
from pesticide application. Soil arsenic is usually bound to clay
surfaces, and the extent to which arsenic is mobile in soil depends on
soil type, pH, and content of phosphate, aluminum, and iron (EPA 1984a).
7.2.4 Biota and Food
Arsenic is found in most organisms that have been sampled, both
animal and plant. Table 7.1 displays typical arsenic levels in several
types of food. Arsenic content in plants typically varies from 0.01 to 5
ppm (NAS 1977). This is due mostly to uptake of arsenic from the soil
(see Sect. 7.2.3 above), but some arsenic may also be present on the
surface as a residue from atmospheric deposition or pesticide
application (EPA 1982b). Marine plants, crustaceans, and some fish
often contain naturally high concentrations of arsenic (EPA 1984a), but
this is in an organic form which has very low toxicity.
7.2.5 Resulting Background Exposure Levels
Table 7.2 summarizes typical levels and probable forms involved in
human exposure to arsenic. Typical inhalation exposures from airborne
arsenic (principally As203) are estimated at 0.06 ^g/day, while maximum
exposures may reach 0.6 /*g/day in the general population. Suta (1980)
in EPA (1982b) provides an estimate of 6 pg/day as the upper limit of
nonoccupational subpopulation exposure to airborne arsenic, while
populations may be exposed to as much as 20 /ig/day of arsenic downwind
of copper smelters and cotton gins.
Ingestion of arsenic via drinking water is expected to occur at
levels between 5 and 4000 /ig/day, with 5 pg/day being typical. The
highest exposure levels are expected in isolated wells in areas of
naturally high background arsenic levels. Arsenate is the predominant
form in most drinking water exposure situations.
-------
Potential for Human Exposure 79
Table 7.1. Arsenic levels in foods"
Food group
Arsenic concentration (mg/kg)6
Range of
mean values Maximum
Meats, eggs, and milk 0.01-0.03
Vegetables and fruits 0 01-0.03
Cereal, nuts, and sugar products 0.01-0.04
Fmfish and shellfish 0.07-1.47
0.5 (chicken)
0.3 (potato products)
0.4 (nee)
19.1 (fin fish)
"Adapted from EPA 1982b, after Jelinek and Corneliussen 1977.
*Arsenic levels are reported as concentrations of As2O3, but this
does not imply that arsenic exists in this form in the food samples.
-------
80 Section 7
Table 7.2. Summary of estimated kreb of
expooorc to metis?
Route
Probable
form
Exposure («ig/day)
Typical Maximum
Assumptions
Surface water
sources
Arsenate
Groundwater
sources
Food-total
diet
High fish
consumption
Wine
consumption
Soil mgestion
(children)
General
atmosphere
Arsenite from
25-100%.
MMA. DMAA.
some arsenate
in less
reduced water,
arsine has
been detected
under very
reduced
conditions
All forms;
large part may
be organically
bound arsenic
Arsenobetame,
MMA. possible
arsenite and
others
Arsenite
predominately
and arsenate
Arsenate or
organic
arsemcals
Arsenic
tnoxide
Cigarette smoking Arsenic
tnoxide
200 Typical Most levels (99 6% of D W
survey) in U S. <10 pg/L.
mean-2 5 «ig/L, consumption of
2 L/day
Maximum. Maximum level in drinking
water supply 100 tig/L, consumption
of 2 L/day
4.000 Typical Small sample of average
groundwater levels at 10 «ig/L or
less, consumption of 2 L/day; there
are many incidences of higher
groundwater levels
Maximum: Maximum levels of 2000 pg/L
in naturally contaminated
supplies, consumption of 2 L/day
21 190 Typical- FDA total diet study
estimate
Maximum. Total diet with seafood
1,000 10.000 Typical Fish or shellfish
containing 10 mg/kg, consumption
of 100 g fish/day
Maximum. Fish or shellfish
containing 100 mg/kg As, consumption
of 100 g fish/day
500 Typical. Wine containing 100 pg/L,
consumption of 28 mL/day
Maximum. Wine containing maximum
levels of 500 Mg/L, consumption of
1 L/day
0.02 20 Typical. Soil containing 2.1 mg/kg
consumption of 10 mg soil/day
Maximum: Soil containing 2100 mg/kg,
consumption of 10 mg soil/day
Inkaladoa
0 06 06 Typical- Average ambient
concentration of 0.003 Mg/m1.
respiratory flow of 20 mj/day
Maximum. Typical urban
concentration in cities (containing
smelters) of 0.03 «ig/mj
90 Arsenic concentration of
12 Mg/cigarette, 15% volatilized;
consumption of 50 cigarettes/day
0004
•Sourer Adapted from EPA I982b.
-------
Potential for Human Exposure 81
Estimates of arsenic exposure from soil ingestion depend on Che
assumed concentration of arsenic in soil and on the amount of soil
ingested per day. EPA (1982) estimated intake from soil to range from
0.02 to 20 jig/day, based on a daily intake of 10 mg of soil. More recenc
estimates of soil intake suggest that children ingest about 200 mg of
soil per day (Calabrese et al. 1987). For soil containing an average of
5 ppm of arsenic (Walsh and Keeney 1975), the average arsenic intake per
day would be about 1 Mg-
Arsenic exposure from dietary intake is estimated to range from 21
to 190 Mg/day (EPA 1982), with a typical value of around 45 to 50 jig/day
(Gartrell et al. 1986). Some individuals may experience higher
exposures, based on the intake of foods that are high in arsenic content
(e.g., fish, shellfish, and some wines). Some of the arsenic ingested in
food (especially that in seafood) may be organic derivatives that are
less toxic.
7.3 OCCUPATIONAL EXPOSURES
The two industries associated with significant risk of arsenic
exposure are metal smelting (especially copper) and arsenical pesticide
manufacture and application.
In the past, air levels of arsenic in metal smelters ranged from
0.2 to 1500 /Jg/m3 (EPA 1981), and this was commonly associated with eye,
nose, throat, and skin irritation. More recently, reductions in
emissions and improved industrial hygiene practices have reduced
occupational exposures substantially.
Another occupation that can lead to significant arsenic exposure is
in the manufacture or use of arsenic-treated wood. The most common
arsenic-based wood preservatives are chromated copper arsenate (CCA) and
ammonium copper arsenate (ACA). Rosenberg et al. (1980) reported that
workers in three plants that prepare treated wood have increased arsenic
exposure as determined by urinary excretion levels, although no
prominent signs of arsenic-induced toxicity were noted in these workers.
In contrast, marked signs of arsenic toxicity have been reported in
individuals who saw or burn CCA-treated wood (Peters et al. 1964, 1986).
The principal exposure pathway is probably through the inhalation of
arsenic-contaminated dust (from sawing) or smoke (from burning),
although dermal contact with treated wood may also be a source of
exposure (ECI 1981).
7.4 POPULATIONS AT HIGH RISK
7.4.1 Above-Average Exposure
Populations relying on groundwater or surface water near geologic
or man-made sources of arsenic are likely to receive higher than typical
exposures. These areas include industrialized areas and areas where
large quantities of arsenic are disposed of in landfills (e.g.,
Pennsylvania, southern New York, Ohio, Indiana, and Washington); areas
of high historical pesticide use, with soil low in available ferrous and
aluminum hydroxides; and areas of high natural levels of arsenic-
containing mineral deposits (e.g., Western United States).
-------
82 Section 7
Populations in Che area of copper and other types of metal smelter
may be exposed to above-average levels both through the air and as a
result of atmospheric deposition in soil and water.
7.4.2 Above-Average Sensitivity
Inorganic arsenic is detoxified in humans by enzymic methylacion to
MMA and DMA, a process carried out mostly in the liver. There may be
differences in the level of the activity of these enzymes between
individuals, and, if so, those with low activity ("nonmethylators") may
be more sensitive to arsenic than those with high enzymic activity. In
addition, individuals with protein-poor diets or choline deficiency may
also be more sensitive to arsenic.
-------
83
8. ANALYTICAL METHODS
Atomic absorption spectrometry (AAS) is the most common analytical
procedure for measuring arsenic concentrations in environmental and
biological samples. Samples may be prepared for AAS in a variety of
ways. Most often the gaseous hydride procedure is employed, in which
arsenic in the sample is reduced to arsine (arsenic H3), a gas which is
trapped and introduced into the flame. This approach measures total
inorganic arsenic; however, it may not detect all organic forms unless a
digestion step is included.
If concentrations of specific arsenic species [arsenic(III),
arsenic(V), MMA, DMA, fish arsenic, etc.] are to be determined,
separation procedures must be used prior to introduction of sample
material into a detection system. Various types of chromatography or
electrophoresis-separation systems are commonly used. Alternately, a gas
chromatography-multiple ion detection system following a hydride
generation/heptane cold trap system can be used to measure specific
organic forms of arsenic (Odanaka et al. 1983).
The following sections briefly describe methods that are often
employed for measuring arsenic in environmental and biological samples
8.L ENVIRONMENTAL MEDIA
Representative methods appropriate for measuring arsenic in various
environmental media are listed in Table 8.1.
8.1.1 Air
The American Conference of Government Industrial Hygienists (ACGIH)
Method 803 measures total particulate arsenic in air (APHA 1977). The
method involves filter collection of air samples, arsine generation, and
silver diethyldithiocarbamate (SDDC) colorimetry. This method is similar
to NIOSH Method 7900, except that with Method 7900, flame atomic
absorption is used for the quantification of arsenic (NIOSH 1984). If
As203 fumes are present (as might occur in or near a smelter), then
NIOSH Method 7901 (which uses a sodium carbonate impregnated filter) is
most appropriate. NIOSH Method 5022 is applicable for the quantification
of particulate organoarsenic compounds (NIOSH 1985).
8.1.2 Vater
The atomic absorption graphite furnace technique (EPA 1983, EPA
1986b) is often used for measurement of total arsenic in water. It also
has been standardized by EPA. Techniques to compensate for chemical and
matrix interferences are described in EPA (1983). Irgolic (1982),
Edwards et al. (1975), and Brown and Button (1979) describe methods for
identifying species of arsenic in water samples.
-------
84 Seccion 8
Table 8.1. Analytical methods for arsenic in environmental samples
Sample
matrix
Air
Water
or soil
Soil
Food
Sample
preparation
Filter
collection
and acid
digestion
Acid
digestion
Hydride
generation-
heptane
cold trap
Dry ashing
or acid
digestion
Analytical
method
Arstne generation-
colorimetric
(Method 803)
Atomic absorption
furnace technique
(Method 206.2)
Gas chromatography-
multiple ion
detection mass
spectrometry
Hydride generation-
AAS
Sample
detection
limit
0.4 /ig/m3
total As'
Ug/L
total As
0.2 ppb
total As
5 ppb
total As
Accuracy
85 to 95%
recovery
76 to 102%
recovery
79 to 117%
recovery
References
APHA 1977
EPA 1983,
EPA 1986b
Odanaka et al.
1983
Tarn and LaCroix
1982
"4 to 9% average deviation (precision).
-------
Analytical Methods 85
8.1.3 Soil
Inorganic arsenic and methylarsenic species can be identified and
measured in soil, using gas chromatography and multiple ion-detection
mass spectrometry after hydride generation and application of a heptane
cold trap to collect material for analysis (Odanaka et al. 1983).
Alternately, acid digestion of the sample followed by direct-furnace AAS
(EPA 1986b) or by hydride generation and AAS can be used for total
arsenic determination.
8.1.4 Food
Dry ashing and wet digestion, followed by hydride generation and
AAS, are often employed for measuring total arsenic in foods. Narasaki
(1985) has successfully used oxygen bomb combustion, followed by hydride
generation-AAS, for arsenic in fatty foods.
8.2 BIOMEDICAL SAMPLES
Methods for measuring arsenic in biological samples are listed in
Table 8.2.
8.2.1 Fluids and Exudates
Total arsenic in blood and urine is usually measured using hydride
generation-AAS techniques (Foa et al. 1984). Norin and Vahter (1981)
described a procedure for determining specific forms of arsenic in body
fluids and exudates.
8.2.2 Tissues
Mushak et al. (1977) described a furnace AAS technique for total
arsenic, and also furnace AAS and gas-liquid chromatography (GLC)
techniques for measuring chemical forms of arsenic in soft mammalian
tissues. Instead of hydride generation, these authors used chelation-
extraction via iodide derivatives to measure chemical forms of arsenic
in these matrices.
-------
86 Section 8
Table 8.2. Analytical methods for arsenic in biological samples
Sample
matrix
Blood
Urine
Adipose
Hair
Liver,
kidney.
other
soft
tissues
Liver,
kidney,
other
soft
tissues
Sample
preparation
Dry ashing
Dry ashing and
ion-exchange
chromatography
Oxygen bomb
combustion
Acid digestion
Acid digestion,
chloroform
extraction,
and iodide
chelation
Acid digestion,
chelation, and
benzene
extraction
Analytical
method
Hydride generation-
AAS
Hydride generation-
AAS
Hydride generation-
AAS
Hydride generation-
AAS
Furnace AAS for
total As
Gas-liquid
chromatography,
electron capture
detection
Sample
detection
limit
0.5 Mg/L
total As
0.5 Mg/L
for each
chemical
form
Sppb
total As
0.06 ppm
total As
0.2 ppm
or better
0.9 ppm
or better*
for chemi-
cal forms
Accuracy
95 to 102%
recovery
98 to 105%
recovery
90 to 102%
recovery
93% recovery
79.8%
recovery
98 to 108%
recovery
References
Foa et al.
Foa et al.
Narasaki
Curatola
1978
1984
1984
1985
et al.
Mushak et al.
1977
Mushak
1977
etal.
"Sample detection limits and accuracy estimates for analysis of butter samples.
*Data not available, lowest analytical spike levels listed.
-------
87
9. REGULATORY AND ADVISORY STATUS
Table 9.1 summarizes regulations and guidelines that apply to
arsenic and inorganic arsenic compounds. These regulations and
guidelines have been established by a number of U.S. and international
advisory or regulatory agencies.
9.1 INTERNATIONAL
The World Health Organization (WHO) recommends a drinking water
guideline value of 0.05 mg/L, based on the human health effects of
arsenic.
9.2 NATIONAL
9.2.1 Regulations
Regulations in Table 9.1 are values that address air emissions,
occupational exposure concentrations, drinking-water levels, presence Ln
food, spill quantities, presence ir. hazardous wastes, and pesticide
usage.
9.2.1.1 Air
The EPA Office of Air Quality Planning and Standards (OAQPS), under
authorization from Section 112 of the Clean Air Act, lists inorganic
arsenic as a hazardous air pollutant (HAP). Hazardous air pollutants are
those substances which may cause an increase in mortality or serious
illness in humans following significant exposure.
EPA promulgated National Emissions Standards for Hazardous Air
Pollutants (NESHAPS) for three stationary source categories known to
emit inorganic arsenic: primary copper smelters, glass manufacturing
plants, and arsenic plants. These regulations, promulgated in 1986,
cover equipment and design specifications, work practices, emission
limits, inspection and maintenance plans, and monitoring requirements
for ambient arsenic concentrations near the plant.
The Occupational Safety and Health Administration (OSHA) sets
permissible exposure limits (PELs) for occupational exposures to
chemicals based on the recommendations of the National Institute for
Occupational Safety and Health (NIOSH). The OSHA PEL for arsenic is 10
Mg/m* in workplace air for a time-weighted average (TWA) (8 h/day. 40
h/week). EPA has also established a TWA permissible exposure limit of 10
/*g/m3 which applies to wood preservative application facilities.
-------
88 Section 9
Table 9.1.
Agency
Description
Value
Ref<
Guideline for drinking water
WHO
EPA OAQPS Hazardous air pollutant (ambient air)
0.05 mg/L
NA'
OSHA
EPA OWRS
EPAODW
FDA
EPAOERR
NESHAPt-Ioorganic aneuc from primary NA
copper smelters, glass manufacturing
plants, and arsenic plants
Permissible TWA* workplace exposure limit 10 Mg Ai/mJ
for inorganic arsenic
Permissible TWA workplace
exposure limit for organic arsenic
General permits under the National
Pollutant Discharge Elimination System
(NPDES)
Criteria aad standards for the NPDES
General pretreatmeat regulations for
existing aad aew sources of pollution
Maximum anmamimut level (MCL) in
drinking water
Permissible level* in food
Muscle meats
Edible meat by-products
Eggs
Reparable quantity (RQ)
Arsenic
Arsenic disulflde
Arsenic penioxide
Aneaic trichloride
Anofiic tnoudo
triralftfe
Calcium aneaate
Calcium anentte
Cupric aoetoaneahe
Dietbytafww
Sodium aneaate
Sodium anenite
RQ (proposed)
Aneafe
AiMne djautfids
Arsenic peatoxido
Ancaic UUJUQC
Aneaie trifulflde
Chalet*"*1 aneaate
Calcium arsenite
Cupric acetoaneahe
Diethylaniae
500 «ig Ai/m1
NA
NA
NA
0.050 mg/L
0.5 |
t.Oppm
0.5 I
Sodium arsenite
1 Ib
5.000 Ib
5.000 Ib
5.000 Ib
5.000 Ib
5.000 Ib
1.000 Ib
1.000 Ib
lOOIb
I Ib
5.000 Ib
1.000 Ib
1.000 Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
w
WHO 1984
48 FR 37886
(06/05/80)
40CFR6I
51 FR 27956
(04/04/86)
29CFR 1910.1018
43 FR 19584
(05/05/78)
29 CFR 1910.1000
40 CFR 122.28
40 CFR 125
40 CFR 403
40 CFR 141.11
40 FR 59566
(12/24/75)
HSDB 1987
40 CFR 3014
50 FR 13456
(04/04/85)
52 FR 8140
(03/16/87)
-------
Regulatory and Advisory Status
89
Tasat9.1 (<
Agency
EPAOSW
EPAOPP
NIOSH
ACGIH
EPAODW
EPAOWRS
IARC
EPA
EPA
OSHA
Washington
Sute
Depeiuiieat
of Ecology
Sute
Agenciei
Detcnptioo
Extremely hazardous substances
Threshold planning quantity (TPQ)
Arsenic pentoude
Arsenous oxide
Arseaous trichloride
Anuw
Calcium aneaate
Potassium arseniu
Sodium anenate
Sodium anenite
Listing as a hazardous waste
constituent (Appendix VIII)
Arsenic and compounds (not other-
wise specified)
Arsenic aod
Arsenic pentoude
Arsenic trioxide
Restricted use pesticide— Inorganic
anemcals for wood preservative use*
Notice of preliminary determination to
cancel registration— Inorganic
anenkals for non-wood preservative uses
National GeAMsMi
Recommend exposure limit for
occupational exposure: ceiling
Threshold limit value (TLV-TWA)
Maximum «""«"•'••"« level goal (MCLG)
(proposed)
Ambient Water Quality Criteria to
iMioti?fi hvTTBn htjahh
Ingesting water and organisms
Ingesting organisms only
Group 1 (carcinogenic rank)
Group A (carcinogenic rank)
Unit rifk (Sofc.i.tiMi, ' r
Unh risk (oral. 1 ng/kg/day)
Point estimate for excess lung
cancer risk for working lifetime
exposure at 10 pg/m'
State HijalnflBBi
Interim community exposure standard
24-h Ambient air concentration
Annual average ambient air
concentration
Water quality standards
Value
100/10.000 Ib
100/10.000 Ib
500 Ib
100 Ib
500/10.000 Ib
500/10.000 Ib
1.000/10.000 Ib
500/10.000 Ib
NA
10 Mg/m1
(8-h TWA)
NA
i
2
-------
90 Section 9
9.2.1.2 Water
The discharge of arsenic in industrial wastewater is regulated by
EPA under the Clean Water Act National Pollutant Discharge Elimination
System (NPDES) and General Pretreatment Regulations. Regulatory
limitations (Effluent Guidelines) for arsenic ami arsenic compounds have
been established for 13 different industrial point source categories
under 40 CFR 415-469.
The EPA promulgated an Interim Maximum Contaminant Level (IMCL) for
arsenic of 0.050 mg/L to protect the public health to the extent
feasible using technologies, treatment techniques, and other means chac
are generally available. The EPA is in the process of setting a new MCL
for arsenic and, to that end, has proposed a Maximum Contaminant Level
Goal (MCLG) of 0.050 mg/L. The MCLG is a nonenforeeable goal, based onlv
on the consideration of health effect data. The MCL is set as close to
the MCLG as possible, taking cost and feasibility into consideration.
9.2.1.3 Reportable quantities
The Comprehensive Environmental Response, Compensation and
Liability Act of 1980 (CERCLA) requires that persons in charge of
vessels or facilities from which a hazardous substance has been released
(except where permitted) in quantities equal to or greater than its
reportable quantity (RQ) immediately notify the National Response Center
of the release. The reportable quantities for arsenic and several
arsenic compounds set by the EPA Office of Emergency and Remedial
Response (OERR) are presented in Table 9.1. EPA has proposed decreasing
the RQ to 1 Ib for each arsenic compound.
Under the Superfund Amendments and Reauthorization Act of 1986
(SARA), EPA published a final rule (EPA 1987a) listing extremely
hazardous substances and corresponding threshold planning quantities
(TPQs) for those substances. The TPQs are intended to help communities
focus on the substances and facilities of the moat immediate concern for
emergency planning and response in case of accidental spills or releases
to the environment. Several arsenic compounds are included on the
extremely hazardous substances list and are listed with their TPQs in
Table 9.1. Some of these compounds are solids and, therefore, have two
TPQs; the first, for solids in forms which potentially can result in an
airborne release, the second, for solids in any other form.
9.2.1.4 Waste disposal
Chemicals are included on the Resource Conservation and Recovery
Act (RCRA) Appendix VIII list of hazardous constituents (40 CFR Part
261) If they have toxic, carcinogenic, mutagenic, or teratogenic effects
on humans or other life forms. Arsenic compounds are included on this
list (see Table 9.1). Wastes containing arsenic are subject to the RCRA
regulations promulgated by the EPA Offlea of Solid Waste (OSW). These
regulations address generation, transport, treatment, storage, and
disposal of hazardous wastes.
-------
Regulatory and Advisory Status 91
9.2.1.5 Pesticide
The EPA Office of Pesticide Programs (OPP) is responsible for the
registration of all pesticide products sold in the United States. The
OPP may cancel or modify the terms of registration whenever it is
determined that the pesticide causes unreasonable adverse effects on the
environment. The OPP has restricted the use of inorganic arsenic for
pressure treating wood. It has proposed cancellation of all registered
uses of inorganic arsenic for non-wood preservative use; however, the
use of calcium arsenate as a turf herbicide, lead arsenate as a
grapefruit growth regulator, sodium arsenite as a grape fungicide, and
arsenic acid as a dessicant are still under review. All copper
acetoarsenite and arsenic acid herbicide registrations have been
voluntarily cancelled by the manufacturers.
9.2.2 Advisory Guidance
Advisory guidance levels are environmental concentrations
recommended by regulatory agencies protective of human health or aquatic
life. While not enforceable, these levels may be used as the basis for
judging acceptable and unacceptable levels of arsenic in the environment
or the workplace. Advisory guidance for arsenic is summarized in Table
9.1 and includes a recommended standard for occupational exposure, a
threshold limit value (TLV), the MCLG for drinking water, health
advisories, and ambient water quality criteria.
9.2.2.1 Air levels
NIOSH sets its recommended exposure limit (REL) for occupational
exposure to arsenic in air at 2 jig/m3 for a 15-minute ceiling, based on
classification of arsenic as a potential human carcinogen.
ACGIH recommends a Threshold Limit Value (TLV) TWA of 0.2 mg/m3
arsenic for soluble arsenic compounds, based on epidemiological evidence
of human health effects from inhaled arsenic.
9.2.2.2 Water levels
As mentioned earlier, the EPA ODW has proposed an MCLG for arsenic
of O.OSO mg/L. The ODW assumes that for carcinogens, there is no
threshold below which adverse effects will not occur and, therefore, the
MCLG for carcinogens is normally zero. Although arsenic has been
classified as a human carcinogen by EPA, the MCLG was not proposed as
zero because increased risks of cancer due to drinking water exposure
have not been found in the United States, and there is evidence
suggesting that arsenic may be an essential element for humans (50 FR
46960). This proposal is currently undergoing Agency review.
The ODW prepared Health Advisories (HAs) for numerous drinking
water contaminants. The HAs describe concentrations of contaminants in
drinking water at which adverse effects would not be anticipated to
occur and include a margin of safety to protect sensitive members of the
population. The HAs are calculated for 1-day, 10-day, longer-term, and
lifetime exposures. For arsenic, the EPA proposes that all HAs be
0.05 mg/L, based on specific recommendations of the National Academy of
Sciences.
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92 Section 9
Ambient water quality criteria are guidelines set by the EPA Office
of Water Regulations and Standards (OWRS) to protect human health from
potential adverse effects from the ingestion of water and/or edible
organisms (fish and shellfish) from surface water sources. Since it is
assumed that for carcinogens, there is no level at which risk is
eliminated, the ambient water quality criteria are given for incremental
lifetime cancer risks of 10'5, 10'6, and 10''. The values for arsenic
for an incremental increased lifetime cancer risk of 10*6 are 2.2 x 10'6
mg/L for ingesting both water and organisms and 1.75 x 10'5 mg/L for
ingesting organisms only (EPA 1980a).
9.2.3 Data Analysis
9.2.3.1 Reference dose
An oral reference dose (RfD) for inorganic arsenic of 1.0 x 10'3
mgAg/day has been established by the EPA in 1988. This value was based
on the study of Tseng (1977) that identified a no-effect level of 1
0gAg/day in chronically exposed humans.
9.2.3.2 Carcinogenic potency
Arsenic is classified by the EPA as a Group A carcinogen (a known
human carcinogen), based on evidence of increased lung cancer mortality
in populations exposed primarily through inhalation and on increased
skin cancer incidence in several populations consuming drinking water
with high arsenic concentrations.
Based on the study by Tseng et al. (1968) (see Sect. 4.2.3 6 on
carcinogenicity), EPA (1987b) calculated that the unit risk for skin
cancer (the increased risk of developing skin cancer after lifetime
ingestion of water containing 1 jig/L) was between 3 and 7 x 10'5. These
values were derived using the generalized multistage model with both
linear and quadratic terms and the maximal likelihood method. The EPA
has selected 5 x 10'3 as the most appropriate single estimate of oral
unit risk for skin cancer (EPA 1988).
For lung cancer. EPA (1984a) used a linear absolute-risk model to
calculate maximal likelihood estimates of the slope of the dose-response
relationship in the epidemiological studies of Lee-Feldstein (1983)
^ffj"8 6t al> (1982>- Brown and Ch" (1983b), and Enterline and Marsh
(1982). From these slope estimates, unit risk values (the additional
risk of lung cancer associated with lifetime exposure to 1 Mg/m3 of
arsenic) were calculated for each study. Since the studies by Lee-
Feldstein (1983), Higgins et al. (1982), and Brown and Chu (1983b) were
all on the same worker population, the individual unit risks from these
studies were combined, and the resulting value was then combined with
the estimate from the Enterline and Marsh (1982) study to yield an
overall geometric mean unit risk value of 4.29 x 10'3.
Using similar epidemiological data on lung cancer incidence in
arsenic-exposed workers, OSHA calculated that chronic exposure of a
worker to inorganic arsenic in air at concentrations of 10 /*g/m3
corresponded to an excess cancer risk of 2.2 to 29 deaths per 1000
exposed employees. This corresponds to a unit risk for occupational
exposure of 0.22 to 2.9 x 10'3.
-------
Regulatory and Advisory Status 93
No quantitative risk estimates have been performed for the risk of
internal cancers associated with oral exposure to arsenic.
9.3 STATE
9.3.1 Regulations
The State of Washington Department of Ecology (DOE) adapted interim
community ambient air exposure standards for arsenic in 1984. The
interim standards are 2.0 pg/m3 arsenic for a 24-h period and 0.3 pg/m3
arsenic as an annual average concentration. The DOE plans to adopt
permanent standards after evaluating the sources of high ambient arsenic
concentrations in the Tacoma, Washington, area (51 FR 28012). No other
state ambient air standards for arsenic were located.
State water quality standards are water quality criteria applied to
waters specified for designated uses. Twenty-seven of the 50 states have
established specific water quality standards for arsenic for waters
designated for general and/or domestic use. Host states set the water
quality standard for arsenic at 0.05 mg/L; however, for a few states,
the values range from 0.005 to 1.0 mg/L (Environment Reporter). In
addition, several states cite the Interim MCL and/or the EPA Water
Quality Criteria as being the guidance for the water quality standards
for toxic pollutants.
9.3.2 Advisory Guidance
(Advisory guidelines from the states were still being compiled at
the time of printing.)
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95
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121
11. GLOSSARY
Acute Exposure -- Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentration Factor (BCF)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxlclty--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FED--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory—An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or irreversible
health effects.
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122 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicolbgircal Profiles.
Immunologic Toxicity--The occurrence'of adverse effects on the immune
system that may result from exposure to 'environmental agents such as
chemicals.
In vitro--Isolated from the riving organism and artificially maintained,
as in a test tube.
In vivo—Occurring within the living organism.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(50) (LCSO)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Doso(SO) (LDSO)--The dose of a chemical which has been calculated
to cause death in 50% of'a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical-in~a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lovest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
'significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Halfornations--Permanent structural changes that may adversely affect
survival, development, or'function.
Minia&l Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(nohcancerous)' over a specified duration of exposure.
Mut«gon--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
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Glossary 123
Reurotoxicity--The occurrence of adverse effects on the nervous system
following exposure to a> chemical-.
No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically oc biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.
q*--The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q^* can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually pg/L for water, mgAg/day for
food, and Mg/«3 for air),.
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD la operationally derived from the
NOAEL (from animal and human studies; by a consistent application of
uncertaincy factors that reflect various types of data used to estimate
RfDs and an additional modifying .factor which is based on a
professional judgment of the entire^database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous .substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 Ib
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity--The occurrence of adverse.effects on the
reproductive system that may result from exposure; to.a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations In sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on tne integrity of
this system.
Short-Term Exposure Limit (STEL)--The maximumr.concentration to which
workers can be exposed for up to 15 mln continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not.be exceeded.
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124 Section 11
Target Organ Toxiclty--This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from thos* vising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)-.A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV mav be
expressed as a TWA, as a STEL, or as a CL
Time-weighted Average (WA)-.-An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used "in, operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the
variation in sensitivity among,-the members of the human population
(2) the uncertainty in-extrapolating animal data to the case of humans
(3) the..uncertainty In extrapolating from data obtained in a study that
TJL« I688 lifetime exposure, and-(4) the uncertainty in using
LOAEL data rather than NOAEL data; Usually each of these factors is set
equal to 10.
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125
APPENDIX: PEER REVIEW
A peer review panel was assembled for arsenic. The panel consisted
of the following members: Dr. J.B. Andelman, University of Pittsburg;
Dr. T.W. Clarkson, University of Rochester; and Dr. R.D. Hood,
University of Alabdma. These experts collectively have knowledge of
arsenic's physical and chemical properties, toxicokinetics. key health
end points, mechanisms of"action, human and animal exposure, and
quantification of risk to humans. All reviewers were selected in
conformity with the ponditions for peer review specified.* in the
Superfund Amendments and Reauthorization Act of 1986, Section 110.
A Joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and.determined.which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile with- a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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