EPA-540/1-86-020
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfynd
&EPA
HEALTH EFFECTS ASSESSMENT
FOR ARSENIC
-------
EPA/540/1-86-020
September 1984
HEALTH EFFECTS ASSESSMENT
FOR ARSENIC
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati. OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
U S Environmental Protection Agency
- Street
Chicago, Illinois 60b04
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DISCLAIMER
This report has been funded wholly or 1n part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and It has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with arsenic.
All estimates of acceptable Intakes and carcinogenic potency presented 1n
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-line literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/OATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The fol-
lowing Office of Health and Environmental Assessment (OflEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Arsenic.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-021. NTIS PB 81-117327.
U.S. EPA. 1983a. Reportable Quantity for Arsenic (and
Compounds). Prepared by the Environmental Criteria and Assessment
Office, Cincinnati, OH., OHEA, for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 19835. Review of Toxlcologlcal Data In Support of
Evaluation for Carcinogenic Potential of Arsenic and Compounds.
Prepared by the Carcinogen Assessment Group, OHEA, Washington DC.
for the Office of Solid Waste and Emergency Response, Washington DC.
U.S. EPA. 1984. Health Assessment Document for Inorganic
Arsenic. Environmental Criteria and Assessment Office. Research
Triangle Park, NC. EPA-600/8-83-021F. NTIS PB 84-190891.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc. Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the llfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure Is
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
111
-------
The AIC, acceptable Intake chronic, Is similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained In U.S. EPA (1983c).
For compounds for which there 1s sufficient evidence of carc1nogen1c1ty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-)*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context, the
reader 1s referred to the preface of this document. The preface outlines
limitations applicable to all documents of this series as well as the appro-
priate Interpretation and use of the quantitative estimates presented. In
addition, the preface defines the terminology used 1n the text and summary
tables.
Arsenic and compounds have been classified as Group A compounds-based on
evidence for excess cancer risk for skin and lung cancers In humans exposed
to Inorganic arsenic compounds. The evidence for the cardnogenlcHy of
arsenic 1n experimental animals 1s equivocal. The U.S. EPA (1984) used data
on skin cancer In people 1n Taiwan exposed to arsenic 1n the drinking water
to estimate a unit risk based on oral exposure of 15.0 (mg/kg/day)"1. A
unit risk of 4.29xlO"3 (ug/m3) for Inhalation was estimated from four
ep1dem1olog1cal studies concerning respiratory cancers 1n workers at two
copper smelters. Applying the assumptions discussed 1n Section 6.3.2., this
value corresponds to a unit risk of 50.1 (mg/kg/day)"1.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was the Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response. Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati. OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati. OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS ....
2.1.
2.2.
ORAL .
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral ,
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS ,
3.3.1. Oral ,
3.3.2. Inhalation ,
TOXICANT INTERACTIONS , . . ,
CARCINOGENICITY .
4.1.
4.2.
4.3.
4.4.
HUMAN DATA ,
»
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS ,
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
P^qe
. . 1
. . 3
. . 3
. . 4
. . 6
. . 6
. . 6
. . 9
. . 9
. . 9
. . 12
. . 12
. . 12
. . 12
. . 12
. . 14
, . 14
. . 14
. . 16
. . 24
, . 24
, . 25
, . 25
. . 26
5. REGULATORY STANDARDS AND CRITERIA 27
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 28
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 28
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 28
6.3. CARCINOGENIC POTENCY (q-|*) 28
6.3.1. Oral 28
6.3.2. Inhalation 29
7. REFERENCES 31
APPENDIX: Summary Table for Arsenic 48
V111
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LIST OF TABLES
No. TUIe Page
3-1 Subchronlc Oral Toxldty of Arsenic 7
3-2 Chronic Oral Toxlclty of Arsenic 10
4-1 Age-Exposure-Specific Prevalence Rates for Skin Cancer. ... 15
4-2 Data from Table 8 of Enterllne and Marsh (1982) with
Person-Years of Observation Added 18
4-3 Observed and Expected Deaths from Respiratory Cancer,
with Person-Years of Follow-up, by Cohort and Degree of
Arsenic Exposure 19
4-4 Observed and Expected Lung Cancer Deaths and Person-Years
by Level of Exposure, Duration of Employment, and Age at
Initial Employment 20
4-5 Respiratory Cancer Mortality 1938-1978 from Cumulative
Exposure to Arsenic for 1800 Men Working at the Anaconda
Copper Smelter 24
6-1 Combined Unit Risk Estimates for Absolute Risk Linear
Models 30
1x
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF Bloconcentratlon factor
CAS Chemical Abstract Service
CS Composite score
ONA Deoxyr1bonucle1c acid
1050 Median lethal dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Arsenic (atomic weight 74.92) Is a nonmetal or metalloid belonging to
Group VA of the periodic table. Elemental arsenic has a CAS Registry number
of 7440-38-2. The major stable valences of arsenic are 3-, 3+ and 5+.
Arsenic can enter aquatic media through atmospheric wet and dry deposi-
tion (Boyle and Jonasson, 1973), through runoff from soils and through
Industrial discharge Into surface waters. The processes that are likely to
dominate the fate of arsenic 1n aquatic media are chemical speclatlon.
volatilization, sorptlon and blotransformatlon (Callahan et a!., 1979).
Generally, arsenate (As* ) 1s the dominant species In aquatic systems.
However, the speclatlon of arsenic 1n natural waters 1s significantly
Influenced by the presence of biota 1n the water bodies. The biological
activities 1n water may reduce arsenate Into arsenlte (As* ) and finally
i
to methylated arsenlcals (As~3) (Callahan et a!., 1979). In the presence
of biological activity or a highly reducing condition, arsenic 1n water
•
bodies may be converted to methyl arsenics (AsH3). These latter compounds
are volatile and may evaporate from water, accounting for some loss of
arsenic. In polluted water bodies, arsenic may form complexes with organic
compounds present 1n the water. Various sorptlon and subsequent precipita-
tion of both arsenate and organic complexes of arsenic may reduce the level
of arsenic 1n water bodies. Clay, Iron oxides, and partlculate matters high
1n organic content are excellent materials for the sorptlon of arsenic from
aquatic media (Callahan et al., 1979). The precipitated arsenic may be
metabolized by a number of organisms to organic arsenlcals, thereby In-
creasing arsenic mobility In the aquatic media (Callahan et al., 1979).
-1-
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The major source of atmospheric arsenic 1s coal combustion (U.S. EPA,
1980b). Other sources Include smelting operations, dust fnom the earth's
crust, and vaporization of volatile compounds (Graedel, 1978). The dominant
atmospheric species appears to be arsenic trloxlde (As-O-) (Graedel,
1978). The principal removal mechanisms for atmospheric arsenic appear to
be wet and dry precipitation (Graedel. 1978).
Arsenic can enter the soil from wet and dry precipitation of atmospheric
arsenic, from runoff of surface waters and from disposal of arsenic-con-
taining waters. The fate of arsenic 1n soil 1s Inadequately studied. How-
ever, the fate may be dependent on the nature of soil. The factors that may
significantly determine the fate of soil arsenic are organic matter content,
* •
clay content and mlcroblal activity capable of metabolizing arsenic. Soil
containing high levels of sorptlve materials, such as clay or organic
matter, are likely to retard the Teachability of arsenic In soils. However,
i
arsenic may leach Into groundwater from soils with low sorptlve capacity.
Indirect evidence suggests that leaching of arsenic from soils Into ground-
water may be quite common (Page, 1981).
The BCFs for arsenic 1n aquatic organisms have been determined by a few
Investigators and have been found to vary from 333-6000 (Callahan et al.,
1979).
-2-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Absorption of arsenic from the GI tract 1s predominantly governed by the
solubility of the specific compound administered and the dosing rate.
Coulson et al. (1935) reported that solutions of either trlvalent or penta-
valent soluble Inorganic arsenic compounds were almost completely absorbed
from the GI tracts of rats. Solutions of arsenic trloxlde have been re-
ported to be 88% absorbed In rats (Urakabo et al., 1975; Dutk1ew1cz, 1977),
90% absorbed 1n pigs (Munro et al., 1974), and 98% absorbed 1n monkeys
(Charbonneau et al., 1978). Absorption 1s reduced when the arsenic trloxlde
Is administered as a suspension, with 40% of the administered dose being
absorbed by rabbits and 30% by rats (Arlyoshl and Ikeda, 1974).
Coulson et al. (1935) and Ray-Bettley and O'Shea (1975) estimated that
>95% of the Inorganic arsenic that man consumes 1s absorbed. Slightly lower
>
estimates may be obtained from the study of Mappes (1977), who observed that
one human subject given a dally dose of -0.8 mg trlvalent arsenic excreted
~70% of the dally dose 1n the urine each day. Mappes (1977) reported that,
1n contrast to the high absorption of soluble Inorganic arsenic, Insoluble
arsenic trlselenlde (As2Se3) passed through the GI tract with negligible
absorption. Buchet et al. (1981) reported that human volunteers treated
with sodium met a arsenlte that provided arsenic at 125-1000 yg/day
excreted 60% of their dally dose 1n the urine. Steady state was achieved
within 5 days.
Arsenic 1s present In crustaceans and fish 1n a highly complexed organic
form known as "shrimp" arsenic. The pharmacoklnetlcs of this form of
arsenic have been Investigated recently In considerable detail (LeBlanc and
Jackson, 1973; Westoo and Rydalv, 1972; Munro, 1976; Edmonds et al., 1977;
-3-
-------
Penrose et al., 1977; Crecellus, 1977; Edmonds and Francesconl, 1977). Col-
lectively, these studies suggest that "shrimp" arsenic appears to be exten-
sively absorbed and rapidly excreted as an Intact organoarsenlcal complex by
man and animals and, therefore, does not appear to be a health threat.
2.2. INHALATION
Absorption of arsenic from the respiratory tract Is governed by the
specific chemical compound and, In the case of aerosols or dusts, the par-
ticle size. Particles smaller than 1-2 ym 1n diameter are deposited 1n
the alveoli and may, thus, be absorbed through the respiratory epithelium.
Larger particles are predominantly deposited 1n the upper respiratory tract,
expelled by retrodHary movement, and swallowed.
The effect of solubility on the pulmonary retention of arsenic compounds
was Investigated by Inamasu et al. (1982), who administered single 1ntra-
tracheal doses of -2 mg of arsenic as arsenic trloxlde (slightly soluble) or
i
calcium arsenate (nearly Insoluble) to rats. Groups of 4-5 rats were killed
at Intervals from 15 minutes to 7 days after treatment and the amount of
*
arsenic retained 1n the lungs was measured. At 15 minutes after treat-
ment, the amounts of arsenic recovered from the lungs were 1146 and
620 yg, respectively, 1n the calcium arsenate and arsenic trloxlde treated
rats. By 24 hours post-treatment, almost all the arsenic trloxlde had been
cleared from the lungs, but -50X of the calcium arsenate was retained. Very
little additional clearance of calcium arsenate was observed by 7 days
post-treatment, while the small amount of arsenic trloxlde remaining at the
end of 24 hours had been cleared. These data suggest that arsenic trloxlde
Is absorbed by the lung to a much greater extent than 1s calcium arsenate.
Similar conclusions were reached by Pershagen et al. (1982), who admin-
istered 4 weekly Intratracheal doses of arsenic trloxlde, arsenic trlsulflde
-4-
-------
and calcium arsenate at doses of 0.3, 0.5 and 0.5 mg arsenic, respectively,
to Syrian golden hamsters. ' In animals sacrificed Immediately after treat-
ment, the lung contents of arsenic were 386, 755 and 866 mg/kg 1n the above
three treatment groups, respectively. At the end of the fourth treatment,
lung contents of arsenic were -0.3, 3.0 and 800 mg/kg, respectively. Mor-
tality and severe lung damage occurred only 1n the calcium arsenate treated
hamsters.
Outk1ew1cz (1977) observed similar tissue distribution dynamics 1n rats
following either Intratracheal or Intravenous administration of pentavalent
arsenic. Indicating extremely rapid absorption across the respiratory epi-
thelium. Rapid absorption has also been observed 1n rats and mice following
exposure to condensation aerosols of arsenic trloxlde (1.0, 3.7 or 46
vg/m3) (Rozenshteln, 1970) or a solid aerosol of fly ash containing 180
yg arsenlc/m3 (Bencko and Symon, 1970). Pinto et al. (1976) found that,
i
1n workers at a copper smelter, urinary excretion of 38-55 yg arsenic/1
occurred 1n men exposed to atmospheric concentrations ranging from 3-295
*
vg/m3. Smith et al. (1977) reported that urinary levels of trlvalent,
pentavalent, methyl- and dimethylarsenic 1n copper smelter workers were
directly correlated with atmospheric concentrations. In a quantitative
study, Holland et al. (1959) found that, within 4 days, 75-85% of the de-
posited arsenHe was absorbed from the lungs of a group of lung cancer
patients who Inhaled arsenlte-contalnlng aerosols or smoke from arsenlte-
contalnlng cigarettes.
-5-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
In general, the rat 1s not a good model for arsenic toxldty. Lanz et
al. (1950) found that, 1n contrast to other mammals, the rat stored 79% of
an Intramuscularly administered arsenic dose bound to hemoglobin 1n red
blood cells. Cats were found to accumulate 5.6% 1n the blood, and dogs,
chicks, guinea pigs and rabbits stored <0.27% 1n the blood. This binding
results 1n an extremely slow excretion of arsenic by rats as compared with
other species, Including man, following Intravenous administration (Ducoff
et al., 1948; Mealey et al., 1959). Blood levels are much higher In rats
(125 ppm) than 1n guinea pigs (4 ppm), rabbits (1.5 ppm) or hamsters (2.5
ppm) following administration of diets containing 50 mg arsenic tMox1de/kg
diet for 21 days (Peoples, 1975). For this reason, toxldty data 1n rats
cannot be reliably extrapolated to man. The subchronlc and chronic toxldty
of arsenic depends principally on the chemical form, physical state, par-
i
tlcle size and solubility of the material tested. Generally, Inorganic
trlvalent arsenic 1s regarded to be more toxic than the pentavalent form.
Methylated forms appear to be less toxic and "shrimp" or "fish" arsenic Is
generally regarded as non-toxic (NAS, 1977; Pershagen and Vahter, 1979; WHO,
1981).
3.1. SUBCHRONIC
3.1.1. Oral. The subchronlc oral toxldty of arsenic Is summarized In
Table 3-1. Byron et al. (1967) administered diets containing 0, 5, 25, 50
or 125 mg arsenic/kg diet, as either sodium arsenHe or sodium arsenate, to
groups of three male and three female beagle dogs for up to 2 years. Sodium
arsenHe was more toxic than sodium arsenate, with 5/6 dogs 1n the high-dose
group dying or becoming moribund following 3-9 months of treatment. The
no-effect level was 50 mg/kg diet for both compounds.
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TABLE 3-1
Subchronlc Oral Toxtclty of Arsenic
Compound
Sodium
arsentte
Sodium
ar senate
Arsenlc(III)
oxide
Species/
Strain
dog/beagle
dog/beagle
rat/Ulstar
Dose
0, 5. 25. 50
or 125 mg
arsenic/kg diet
0, 5. 25. SO
or 125 mg
arsenic/kg diet
0, 0.125. 12.5
or 62.5 mg
arsenlc/ft h^O
Length of
Exposure
up to 2 years
up to 2 years
7 months
Effects Reference
t
Slight to moderate anemia, anorexia, Itstlessness, Byron et al.. 1967
and decreased body weight In high-dose group.
5/6 died between 3 and 9 months, and all were
dead by 19 months. No effects at doses of
<50 mg/kg diet.
At a dose of 125 mg/kg diet, one dog had severe Byron et al.. 1967
weight loss and died by 13.5 months. All had
mild anemia and granular Iron-positive pigment
In liver macrophages. No effects at a dose of
<50 mg arsenic/kg diet.
Slightly decreased water consumption In high-dose Ishlntshl et al.. 1980;
group. Dose-related Increase In absolute and Hlsanaga, 1982
relative liver weight, degenerative changes In
Calcium
arsenate
(probably)
NR
human
human/
Infants
3 mg/day
NR
2-3 weeks
•a few
months*
Arsenlc(III) human
oxide or
arsenic
trtsulftde
2.5 mg arsenic/
day or 10.3 mg
arsenic/day,
respectively
dally for
several
months or
•Intermit-
tently1 for
up to 15 years
liver, and sloughing of the kidney tubular
epithelium.
Facial edema and anorexia In 187/220. Less than
10X with exanthemata, desquamatlon. and
hyperplgmentatton. Approximately 20X with
peripheral neuropathy.
Coughing, rhlnorrhea. conjunctivitis, vomiting.
dtaiVhea, melanosls. fever, abdominal swelling.
hepatomegaly, anemia, granulocytopenla. abnormal
electrocardiograms.' Increased density at
eptphyseal ends of long bones. Symptoms were
reversible, except for a retardation of ulnar
growth. Follow-up Indicated Increased Incidences
of leukomelanoderma. keratosls. mental retardation.
growth retardation and epilepsy.
Polyneuropathles In -SOX of 74 patients. Hyper-
pigmentation and hyperkeratosts.
Nlzuta et al.. 1956
Nasahlkl and Hldeyasu. 1973;
Okamura et al., 1956;
Satake. 1955; Nagal et al..
1956
Tay and Sean. 1975
-------
Ish1n1sh1 et al. (1980) and Hlsanaga (1982) administered 0, 0.125, 12.5,
or 62.5 mg arsenlc/l drinking water, as arsenlc(III) oxide, to Wlstar rats
for 7 months. Most of the arsenic-treated rats had cloudy swelling of the
hepatocytes, spotty coagulatlve necrosis, proliferation of Interlobular bile
ducts, and angltls of adjacent blood vessels. Sloughing of the tubular
epithelium was observed In the kidneys from all three treatment groups.
Two studies In humans present useful dose-response Information (Mlzuta
et al., 1956; Tay and Seah, 1975). Tay and Seah (1975) Investigated 74
patients 1n Singapore who had Ingested arsenic-containing antlasthmatlc
herbal preparations for periods ranging from <6 months to (Intermittently)
15 years. Doses were estimated to be 2.5 mg arsenic/day as arsenlc(III)
oxide or 10.3 mg arsenic/day as arsenic sulfldes. The organ systems In-
volved were cutaneous (91.9%), neurological (51.3%), GI (23%), hematologlcal
(23%) and renal and others (19%); 5.4% of the patients had Internal mallg-
*
nancies. The major effects, occurlng In more than 10% of the subjects, were
generalized hyperplgmentatlon (arsenic melanosls), hyperkeratosls of palms
•
and soles, "raindrop" deplgmentatlons, palmar and plantar hyperhldrosis,
multiple arsenical keratoses, sensorlmotor polyneuropathy, fine finger
tremors, persistent chronic headache, lethargy, weakness and Insomnia, psy-
chosis, gastritis or gastroenteritis, mild Iron deficiency anemia as a
result of toxic marrow suppression, and transient albumlnurla without
azotemla. The Internal malignancies consisted of two squamous-cell carci-
nomas of the lungs, one squamous-cell carcinoma of the gall bladder and one
hemanglosarcoma of the liver. Mlzuta et al. (1956) observed similar neuro-
logical effects 1n people who consumed ~3 mg arsenic/day 1n contaminated soy
sauce for 2-3 weeks.
-8-
-------
3.1.2. Inhalation. A gaseous arsenic compound, arslne. has a high acute
toxlclty and can be formed 1n the environment under conditions of low pH,
high reducing potential and low oxygen pressure, or as a by-product of
Industrial processes (Callahan et al., 1979; ACGIH, 1980). Other Investi-
gators have Indicated that airborne arsenic compounds are associated with
skin lesions, cardiovascular and respiratory effects, and peripheral neuro-
pathy, but no adequate exposure Information Is available for any of these
studies (Stoklnger, 1981; IARC, 1980; ACGIH, 1980; U.S. EPA, 1980b; NIOSH,
1975).
3.2. CHRONIC
3.2.1. Oral. The chronic oral toxlclty of Inorganic arsenic compounds 1s
summarized In Table 3-2. The most common effects observed In humans were
skin lesions, peripheral vascular disease and peripheral neuropathy. In
experimental animals, decreased survival without apparent cause was
frequently observed. The only species, other than human, 1n which dermal
pathologies were observed was the mouse, and these changes were relatively
mild and did not Include skin cancers. Peripheral neuropathies were not
observed 1n any experimental animals tested. Hepatic degenerative changes
and renal damage were frequently observed In rats, but not 1n other species.
Tseng (1977) Investigated the relationship between blackfoot disease, a
peripheral circulatory disease characterized by gangrene of the extremities,
and the arsenic concentration 1n drinking water of residents of the south-
west coast of Taiwan. A total of 40,421 Individuals In 37 villages were
Included In the study. Arsenic concentrations ranged from 0.001 to 1.82
mg/i. The overall prevalence rate for blackfoot disease was 8.9/1000,
with a positive correlation between the prevalence rate and arsenic concen-
tration and duration of Intake. This study established a NOAEL of 0.001-
0.017 mg/a for blackfoot disease.
-9-
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TABLE 3-2
Chronic Oral Toxlclty of Arsenic
o
i
Compound
Arsenlc(III)
oxtde
Sod tin
arsenlte
Sodium
arsenate
Sodlun
arsentte
Sodium
arsentte
Sodium
arsenate
Lead
arsenate
Species/
Strain
•Ice/Swiss
rats/NR
rats/NR
rats/Long-
Evans
mice/CD
rats/Utstar
rats/Utstar
Dose
0.01X In
drinking water
0. 15.63, 31.25.
62.5. 125 or
250 *g arsenic/
mg diet
0. 15.63. 31.25.
62.5. 125. 250
or 400 mg
arsenic/kg diet
5 tig/ml H20
5 vg/M H20
100 mg arsenic/
kg diet
100 or 399 mg
arsenic/kg diet
Length of
Exposure
•lifetime"
2 years
2 years
-2 years
-1 years
29 Months
29 Months
Effects ' Reference
Slight hyper ker at os Is with occasional areas of Baronl et al.. 1963;
epidermal hyperplasla. Shubtk et al.. 1962
Decreased survival and body weight and enlargement Byron et al.. 1967
of common bile duct at high-dose level. Slight
decrease In body weight and enlargeMent of common
bile duct at 125 mg/kg diet.
400 mg arsenic from sodium arsenate produced
approximately the same effects as 250 mg arsenic from
sodium arsentte. Slight decrease In survival and
body weights and enlargement of the conmon bile
ducts In 250 mg/kg diet group.
No effect on growth, longevity or hlstopathology. Schroeder et al., 1968
Increased serum cholesterol and decreased serum
glucose In males.
Decreased survival rates and longevity. No treat- Schroeder and Balassa. 1967
ment-related htstopathologlcal effects.
No effects on survival, body weight gain, food Kroes et al.. 1974
consumption, blood hemoglobin levels, erythrocytes.
gross anatomy or histology.
In the high-dose group, males had decreases In blood
hemoglobin values and packed cell volumes. Food
consumption and body weight were decreased and
mortality was Increased In both sexes. Htstopatho-
loglcal changes fncluded enlarged bile ducts.
bile duct proliferation, pertcholangltls,
cholangloftbrosls. and Intranuclear eoslnophlllc
Inclusions. In the kidneys. No effect at a dose
of 100 mg/kg diet.
-------
TABLE 3-2 (cont.)
1
1
Compound
NR
NR
Species/
Strain
human/NA
human/NA
Arsentc(III) human/NA
oxide
NR - Not
reported
Bose
O.S98 mg
arsenlc/l
H20
0.01-1.82 mg
arsenic/ft HjO
8.8 mg/day
Length of
Exposure
IS years
>4S years
28 Months
Effects
Leukomelanoderma. hyperkeratosls. chronic coryia,
abdominal pain, Raynaud's syndrome
Hyperptgmentatton, keratosls. sktn cancer.
blackfoot disease
Characteristic dermal lesions and peripheral
neuropathy
' Reference
Zaldlvar and Ghat. 1980;
Borgono and Grelber. 1972;
Zaldlvar. 1974; Borgono
el al., 1977
Tseng et al.. 1968;
Tseng. 1977
Silver and Ualmun. 1952
NA . Not applicable
-------
3.2.2. Inhalation. Chronic Inhalation exposure to arsenic compounds
results 1n symptoms similar to those observed following oral exposure. For
example. Landau et al. (1977) reported a direct relationship between the
length and Intensity of exposure of smelter workers to airborne arsenic,
predominantly as arsenic trloxlde, and alterations In peripheral nerve func-
tion. No studies were available 1n which exposure levels are characterized
to an extent sufficient for the determination of dose-response relationships.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Hood et al. (1977) reported that oral administration of 120
mg sodium arsenate/kg bw to mice during pregnancy had less of an effect on
prenatal mortality, reduction 1n fetal weight, or the occurrence of fetal
malformations than did Intraperltoneal administration of 40 mg/kg bw.
Hatsumoto et al. (1973a,b) reported that oral doses of up to 40 mg/kg bw/day
for 3 consecutive days resulted 1n decreased fetal weights; however, admln-
i
1strat1on of diets containing up to 100 mg arsen1te/kg diet (~5 mg/kg
bw/day) throughout pregnancy had no effect on the offspring (Kojlma, 1974).
Baxley et al. (1981) Indicated that a single oral dose of 40-45 mg/kg bw on
any gestation day between days 8-15 will produce adverse effects 1n develop-
ing mice.
3.3.2. Inhalation. No data pertinent to the teratogenldty or other
reproductive effects of Inhaled arsenic were located 1n the available
literature.
3.4. TOXICANT INTERACTIONS
The best-known Interactive effect of arsenic Involves a protective
effect In cases of selenium poisoning. Hoxon (1938) found that 5 mg
arsenlc/i H-0, as sodium arsenlte, prevented liver damage In rats fed
-12-
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diets containing 15 mg selenium/kg diet. In a later study Dubols et al.
(1940) determined that sodium arsenHe and sodium arsenate were equally
effective, but that the arsenic sulfldes were Ineffective.
-13-
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Numerous arsenic compounds, particularly trlvalent
Inorganics, have been associated with lung and skin carcinomas 1n humans.
Tseng et al. (1968) and Tseng (1977) surveyed 40,421 residents of Taiwan who
consumed artesian well water containing 0.01-1.8 mg arsenlc/l for 45-60
years. A dose-response relationship (Table 4-1) was established between the
prevalence of skin cancer and arsenic consumption, based on arsenic concen-
trations 1n different wells and length of exposure (age). The overall Inci-
dence of skin cancer was 10.6/1000, with a maximum Incidence of 209.6/1000
1n males over 70 years of age.
Arsenic sulfldes and arsenic trloxlde have also been associated with the
development of malignancies 1n 74 patients 1n Singapore (Tay and Seah,
1975). These patients had consumed herbal preparations containing arsenic
for up to 15 years. Malignancies of the skin were reported 1n 6/74
patients, and malignancies of the Visceral organs 1n 4/74.
In contrast, Morton et al. (1976) found no Increase 1n skin cancer
Incidences In an area of Oregon where arsenic levels 1n the drinking water
are high. No Increase 1n Internal malignancies was observed 1n patients
treated with arsenlcals for various skin diseases, although an Increased
Incidence of basal-cell carcinoma was observed 1n females (Reymann et al.,
1978).
Cuzlck et al. (1982) reported on a cohort study of patients treated with
Fowler's solution (potassium arsenlte). They found an excess of both fatal
and nonfatal skin cancers, often associated with other signs of chronic
arsenic poisoning. They hypothesized the existence of a susceptible sub-
population that Initially develops dermatologlcal symptoms, followed by the
development of skin cancers.
-14-
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TABLE 4-1
Age-Exposure-Specific Prevalence Rates for Skin Cancer3
Exposure In ppm&
0-0.29
(0.15)
0.30-0.59
(0.450)
>0.6
(1.2)
20-39
(30)
0.0013
0.0043
0.0224
Aqe
40-59
(50)
0.0065
0.0477
0.0983
*
>60
(70)
0.0481
9.1634
0.2553
aSource: Tseng et al., 1968
''Range given by authors. Midpoint Is 1n parentheses.
-15-
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4.1.2. Inhalation. Numerous Investigators have reported an association
between occupational exposure to arsenic and the development of tumors.
This exposure Is presumably largely by the respiratory route. Pinto and
Bennett (1963) failed to find an association between arsenic exposure and
tumor formation 1n copper smelter workers; however, a follow-up study found
an Increase 1n deaths from all cancers, particularly respiratory cancer, at
th1,s smelter (Pinto et al., 1978). Numerous other Investigators have
reported an Increase 1n lung cancer among arsenic-exposed workers, but the
exposure concentrations are Insufficiently characterized for use 1n risk
assessment (Axelson et al., 1978; Lee and Fraumenl, 1969; Rencher et al.,
1977; Tokudome and Kuratsune, 1976; Osburn, 1969; Pershagen et al., 1977;
H111 and Fanlng, 1948; Perry et al., 1948; Ott et al., 1974).
The U.S. EPA (1984) used an absolute-risk linear model applied to the
data from four epldemologlcal studies Involving copper smelters. Those
studies are briefly reported here; however, U.S. EPA (1984) provides a more
exhaustive discussion of these studies and other studies that did not lend
themselves to quantitative risk assessment.
The four studies from which the U.S. EPA (1984) derived unit risks for
respiratory cancer all deal with different cohorts of workers at the
Anaconda copper smelter 1n Montana (Brown and Chu, 1983; Lee-Feldste1n,
1983; H1gg1ns et al., 1982) or the ASARCO smelter 1n Tacoma, WA (Enterllne
and Marsh, 1980, 1982).
In the Tacoma, WA, case, Enterllne and Marsh (1980, 1982) studied the
vital statistics of a cohort of male workers who were employed 1n the period
1940-1964. Since work-related exposure for >1 year was required for Inclu-
sion 1n the cohort, follow-up did not begin until 1941 and extended through
-16-
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1976. The cohort Initially contained 2802 Individuals. The vital statis-
tics of 51 could not be verified, so final studies Involved 2751 persons;
results are presented In Table 4-2. During this period, 1061 deaths
occurred. A significant Increase 1n deaths due to cancers (all respiratory)
was noted. Arsenic exposure for each worker was estimated on the basis of
average urinary arsenic of workers In each department factored by the length
of time each worker remained 1n that department. When estimated this way,
Enterllne and Marsh (1980, 1982) observed a dose-related response between
estimated arsenic exposure and the Incidence of lung cancer.
The other ep1dem1olog1cal studies concern statistics that were gathered
from workers at the Anaconda copper smelter In Montana. Lee-Fe1dste1n
(1983) studied the mortality of workers from this plant from 1938-1977. The
8045 workers were assigned to cohorts on the basis of length of exposure:
cohort 1 worked >25 years, cohort 2, 15-24 years, cohort 3, 10-14 years,
cohort 4, 5-9 years and cohort 5, 1-4 years. SMRs were calculated by com-
paring the Incidences of 13 causes of death among the workers to those of
the combined male populations of three western states. Of the 13 causes of
death considered, only death due to respiratory cancer showed a significant
Increase 1n the ratio of observed to expected deaths coupled with a positive
gradient related to length of employment (Table 4-3).
Brown and Chu (1983) further discussed the data and conclusions of the
Lee-Feldste1n (1983) study, particularly regarding the suitability of
applying the multistage theory of cancer to these data (Table 4-4). They
Indicated that the observation of an Increasing risk of lung cancer mor-
tality at Increasing age of Initial exposure and the observation that mor-
tality appeared to be Independent of time after exposure ceased were
evidence that arsenic acts as a late-stage carcinogen.
-17-
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TABLE 4-2
Data from Table 8 of Enterllne and Harsh (1982)
with Person-Years of Observation Added
Cumulative Exposure3 Person-Years Observed Expected
iig/m'-years of Observation*1 Deaths Deaths
0 Lag
91.8 10,902 8 4.0
263 21,642 18 11.0
661 14,623 21 10.3
1381 13,898 26 14.1
4091 9398 31 12.7
10-Year Lag
91.8 27,802 10 6.4
263 16,453 22 12.5
661 11,213 26 11.5
1381 9571 22" 12.4
4091 5423 24 9.7
Exposures are 1n yg/m3 — years estimated by the formula (I yg/i-years)
(0.304) where I Is mean urinary exposure Index from Enterllne and Marsh
(1982) and 0.304 Is the relation between urinary and airborne arsenic esti-
mated by Pinto et al. 1977.
bFurn1shed by Dr. Enterllne (personal communication to U.S. EPA, 1984)
-18-
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TABLE 4-3
Observed and Expected Deaths from Respiratory Cancer, with
Person-Years of Follow-up, by Cohort and Degree of Arsenic Exposure3
Maximum Exposure to Arsenic (>12
Years of
Exposure
25 years*
15-24
<15 years
Heavy
Obs/Expc
13/2.5
9/1 .3
11/2.4
P-Yd
2400
2629
6520
Medium
Obs/Exp
49/7
13/4.0
31/9.3
P-Y
6837
6509*
24,594
months)13
L1qht
Obs/Exp
51/16.3
16/ 8.6
69/31
P-Y
14,573
12,520
78,245
aSource: Lee-Feldste1n, 1983
bThe 1562 men who worked <12 months 1n their category of maximum arsenic
exposure were not Included 1n this table.
C0bserved/Expected
^Person-years of follow-up furnished by Dr. Lee-Feldste1n (personal com-
munication to U.S. EPA, 1984).
-19-
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TABLE 4-4
Observed and Expected Lung Cancer Deaths and Pers.on-Years by
Level of Exposure, Duration of Employment, and Age at Initial Employment*
Duration of Employment (years)
Age at Initial
Employment
H1qh Exposure Level
<20 Obs
Exp
Pyr
20-29 Obs
Exp
Pyr
30-39 Obs
Exp
Pyr
40-49 Obs
Exp
Pyr
50^. Obs
Exp
Pyr
0-9
Group
0
0.001
206
0
0.008
624
0
0.030
398
0
0.083
210
0
0.066
78.0
10-19
0
0.009
408
0
0.051
637
0
0.077
207
0
0.054
80.0
0
0.027
23.2
20-29
0
0.065
588
2
0.164
495
3
0.106
155
0
0.034
49.1
0
0.0
0.0
30-39
3
0.249
499
0
0.277
308
0
0.053
59.1
0,
0.007
6.88
0
0.0
0.0
40+
0
0.193
172
2
0.082
64.4
0
0.001
0.86
0
0.0
0.0
0
0.0
0.0
Medium Exposure Level Group
<20 Obs
Exp
Pyr
20-29 Obs
Exp
Pyr
30-39 Obs
Exp
Pyr
40-49 Obs
Exp
Pyr
0
0.010
1801
0
0.035
2636
0
0.167
1939
0
0.167
1190
0
0.039
1763
0
0.118
1622
0
0.473
1137
0
0.414
448
1
0.171
1500
2
0.331
1099
1
0.329
438
1
0.098
98.9
4
0.591
1206
4
0.717
951
3
0.161
194
3
0.010
12.1
1
0.597
579
7
0.514
654
0
0.045
68.2
0
0.0
0.0
-20-
-------
TABLE 4-4 (cont.)
Duration of Employment (years)
Age at Initial
Employment
<50+
Low Exposure
<20
20-29
30-39
40-49
50+
Obs
Exp
Pyr
Level
Obs
Exp
Pyr
Obs
Exp
Pyr
Obs
Exp
Pyr
Obs
Exp
Pyr
Obs
Exp
Pyr
0-9
0
0.262
295
Group
0
0.056
8524
0
0.115
9951
0
0.390
5218
2
1.29
3703
3
1.62
1945
10-19
0
0.076
71.2
0
0.117
5249
0
0.334
4724
3
0.802
2218
1
1.18
1319
2
0.385
371
20-29
0
0.011
14.5
1
0.478
4038
2
0.892
2965
1
0.937
1364
1
0.344
386
0 "
0.041
65.4
30-39
0
0.0
0.0
1
1.59
3175
5
1.74
2117
0
0.662
715
l'
0.035
52.7
0
0.0
0.0
40+
0
0.0
0.0
3
1.57
1376
6
0.796
834
1
0.062
74.6
0
0.001
2.00
0
0.0
0.0
*Source: Brown and Chu, 1983
-21-
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In another study of the same smelter, H1gg1ns et al. (1982) reported on
a sample of 1800 workers, 277 from a "heavy exposure category" and a random
sample (20%) of the remaining known workers. Workers with at least 1 year
of work experience were entered Into the study. Smoking histories were
obtained. SMRs were calculated by comparison with the white male population
of Montana and also of the United States. Estimates of workroom atmospheric
concentrations of arsenic for 52 smelter departments were based on Indus-
trial hygiene records for the years 1943-1965 or by analogy with those areas
In which the concentrations were known. The departments were classified
Into four categories based on atmospheric arsenic concentration: low, <100
vg/ma; medium, 100-499 vg/ma; high, 500-4999 »ig/m3; or very
high, >5000 yg/m3
The data were analyzed by five exposure/follow-up methods that differed
primarily In the amount of overlap permitted between exposure period and
i
follow-up period. Data analysis method I was the primary method used by the
authors and Included the worker's arsenic exposure up to the time he was
entered Into the cohort with follow-up from day of entry until 1978. No
overlap between exposure and follow-up occurred. Method IV, exposure from
date hired until 1964 and follow-up from 1964-1978, also had no overlap.
Complete overlap was permitted 1n methods II and V. Method II Involved
exposure from date hired through 1964 and follow-up from 1938-1964 and
\
method V Involved exposure from date hired to termination and follow-up from
1938-1978. Partial overlap occurred with method III; exposure from date of
hire to 1964 and follow-up from 1938-1978.
Analysis of the data obtained (presented In Table 4-5) resulted 1n the
following conclusions: (1) that exposure to arsenic In the workroom was
strongly correlated with excess mortality due to respiratory cancer; (2)
-22-
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TABLE 4-5
Respiratory Cancer Mortality 1938-1978 from Cumulative Exposure
to Arsenic for 1800 Hen Working at the Anaconda Copper Smelter3
Cumulative
Exposure
pg/m3-years
0-500
(250)b
500-2000
(1250)
2000-12,000
(7000)
>12,000
06,000)
Person-Years
of Observation
13,845.9
10,713.0
11,117.8
9015.5
Observed
Deaths
4
9
27C
40C
Expected
Deaths
5.8
t
5.7
6.8
7.3
aSource: H1gg1ns et al., 1982
^Numbers 1n parentheses Indicate assumed average exposures.
C51gn1f1cant at 0.01 level
-23-
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exposure to other occupational contaminants, such as sulfur dioxide and
asbestos did not appear to cause excess deaths due to respiratory cancer;
(3) smoking accounted for only a small fraction of excess respiratory cancer
deaths; (4) the SMRs reflected Increased Incidences of excess lung cancers
positively correlated with exposure category; and (5) that SMRs dropped sub-
sequent to 1923 when additional methods were Instituted that resulted 1n
Increased arsenic fume and dust recovery.
4.2. BIOASSAYS
4.2.1. Oral. Animal bloassays with a variety of arsenic compounds have
generally produced negative results. Hueper and Payne (1962) and Baronl et
al. (1963) administered 0.0034% or 0.01% arsenic tMoxIde In the drinking
water to mice. No Increase 1n tumor Incidence was observed at either dose
level. In a similar study, Kanlsawa and Schroeder (1967, 1969} administered
5 mg sodium arsen1te/l drinking water to mice or 5 mg sodium arsenate/J.
>
to rats over their entire Hfespan without producing any Increase 1n tumor
Incidence. Hueper and Payne (1962) found that drinking water levels of up
to 34 mg arsenic tr1ox1de/l had no effect on tumor Incidences 1n rats.
Both sodium arsenate and sodium arsenlte were found to be Ineffective 1n a
2-year feeding study In dogs fed diets containing arsenic, as at levels
between 5-125 mg/kg diet (Byron et al., 1967). Shlrachl et al. (1983)
reported that sodium arsenlte did not Induce renal tumors (species unspeci-
fied) but did Increase the Incidence of d1methyln1trosam1ne-1n1t1ated kidney
tumors. These authors, therefore, considered arsenlte to be a tumor
promoter.
Other Investigators have reported tumorlgenlc effects of arsenic treat-
ment. Schrauzer et al. (1978) reported that an unspecified arsenic com-
pound, at a concentration of 2 mg/l drinking water, fa-lied to Increase the
-24-
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number of treated female mice bearing mammary adenocardnomas, but the
growth rate and Incidence of multiple tumors In tumor-bearing animals were
Increased. Knoth (1966/1967), In a brief and Incomplete report, found an
Increase In adenocardnomas of the skin, lung, peritoneum and lymph nodes of
mice dosed with arsenic trloxlde or Fowler's solution (1% arsenic trloxlde)
orally once per week for 5 months.
4.2.2. Inhalation. Ish1n1sh1 et al. (1976, 1977) administered 15 weekly
Intratracheal Instillations of arsenic trloxlde (0.26 mg), copper ore (3.95%
arsenic), or refinery flue condensate (10.5% arsenic) to W1star-K1ng rats.
Tumor Incidences were not Increased over those of controls during the
Ufespan of the animals. Berteau et al. (1978) exposed female mice to a 1%
aqueous aerosol of sodium arsenlte, 20-40 minutes/day, 5 days/week, for 55
weeks. No significant Increase 1n tumor Incidence was observed. In con-
trast, a single Intratracheal Instillation of Bordeaux mixture (4% calcium
>
arsenate) resulted 1n the Induction of lung tumors 1n 9/15 rats (Ivankovlc
et al., 1979).
4.3. OTHER RELEVANT DATA
Singh (1983) tested sodium arsenlte for mltotlc gene conversion and
reverse mutation 1n Saccharomyces cerevlslae 07. Under the conditions of
this assay, sodium arsenlte was weakly positive for reverse mutation and
negative for mUotlc gene conversion.
Arsenic compounds have been observed to produce chromosomal damage both
in vitro and in vivo (Petres and Hundelker, 1968; Petres et al., 1970,
1972). Walker and Bradley (1969) reported that arsenate Increased the total
frequency of exchange chromosomes In OrosophHla melanogaster treated with
selenocystlne. Petres et al. (1970) studied lymphocytes from 34 patients at
the University of Freiburg Skin Clinic, 13 of whom had received extensive
-25-
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arsenic therapy up to 20 years before. There was a remarkable Increase 1n
the frequency of aberrations observed 1n the arsenic-treated group. Beckman
et al. (1977) found an Increase 1n gaps, chromatld aberrations, and chromo-
some aberrations 1n short-term cultured leukocytes from mine workers exposed
to arsenic at the Ronnskar smelter 1n northern Sweden.
4.4. WEIGHT OF EVIDENCE
IARC (1980) has found that "there 1s Inadequate evidence for the car-
c1nogen1c1ty of arsenic compounds 1n animals. There 1s sufficient evidence
that Inorganic arsenic compounds are skin and lung carcinogens 1n humans."
Applying the criteria proposed by the Carcinogen Assessment Group of the
U.S. EPA for calculating the overall weight of evidence for cardnogenlcHy
to humans (Federal Register, 1984), arsenic 1s most appropriately classified
1n Group A - Human Carcinogen.
-26-
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5. REGULATORY STANDARDS AND CRITERIA
ACGIH (1980) has established a TWA of 0.2 mg/m3 for arsenic and
soluble arsenic compounds, as measured as arsenic, and the compound arslne.
Arsenic trloxlde 1s classified as an "Industrial Substances Suspect of
Carcinogenic Potential for Man" and no TWA has been established. NIOSH
(1973) recommended a TWA of O.OS mg arsen1c/m3 as a workplace air stan-
dard. This was changed to a 15-mlnute celling of 0.002 mg/m3 (NIOSH,
1975). In 1978, OSHA established a standard of 0.01 mg/m3 for airborne
Inorganic arsenic (U.S. EPA, 1980b).
The U.S. PHS established a maximum allowable level of 50 yg/SL for
arsenic In drinking water supplied by Interstate carrier water supplies In
1942. This standard was continued when the U.S. EPA Drinking Water Stan-
dards became effective 1n June of 1977. The U.S. "EPA (1980b) has subse-
quently recommended a criterion of 22 ng/i, which would result 1n an
t
estimated excess cancer risk of 10~9.
-27-
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Arsenic has been determined to be carcinogenic to humans and data exist
from which carcinogenic potencies have been estimated. It 1s, therefore,
Inappropriate to determine an AIS for arsenic.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Arsenic has been determined to be carcinogenic to humans and data exist
from which carcinogenic potencies have been estimated. It 1s, therefore.
Inappropriate to determine an AIC for arsenic.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. As described 1n Chapter 4, numerous studies have Implicated
arsenic 1n the etiology of human cancer. Since arsenic has not consistently
produced tumors 1n animals. 1t 1s necessary to rely on human data for the
derivation of a unit risk. Tseng et al. (1968) found a positive correlation
i
between the levels of arsenic 1ngest1on and the development of skin cancer
In southwest Taiwan. The U.S. EPA (1984) fH the Incidence of" skin cancer
data to a model generated for estimating the cance'r rate as a function of
drinking water arsenic concentration. A unit risk of 15.0 (mg/kg/day)'1
was estimated, assuming that humans drink 2 I of water/day and that
absorption of arsenic 1s 100%. A detailed discussion of the data and
assumptions employed In the estimation of this carcinogenic potency can be
found 1n U.S. EPA (1984).
The Issue of risk associated with oral arsenic exposure 1s currently
being reevaluated (U.S. EPA,'1985). This assessment should be evaluated for
possible Impact on the present document when H becomes available 1n
reviewed, final form.
-28-
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6.3.2. Inhalation. The U.S. EPA (1984) applied the data from the eplde-
ra1olog1cal studies of copper smelting 1n Montana (Brown and Chu, 1983; Lee-
Feldsteln, 1983; H1gg1ns et al.t 1982) and Washington (Enterllne and Marsh,
1980, 1982) to an absolute risk linear model and estimated unit risks for
these studies as summarized In Table 6-1. The U.S. EPA (1984) provides an
1n-depth discussion of this risk assessment. The geometric mean of the
several unit risks 1s 4.29x10"* (yg/m3)"1. Applying the assumptions
that humans weigh 70 kg, Inhale 20 ma/day and absorb 30% of Inhaled
arsenic, a unit risk of 50.1 {mg/kg/dayr* 1s calculated (U.S. EPA, 1984).
-29-
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TABLE 6-1
Combined Unit Risk Estimates for Absolute Risk Linear Models3
Exposure
Source
Unit R1skb
Geometric Mean
Unit R1skb
Final
Estimated
Unit R1skb
Reference
Anaconda
(Montana)
smelter
ASARCO
(Washington)
smelter
1.25xlO"»
2.80x10"'
4.90x10"'
6.81xlO"»c
7.60xlO"'c
2.56x10"'
7.19x10"'
4.29x10"'
Brown and Chu,
1983
Lee-Feldste1n,
1983
.Hlgglns
et al., 1982
Enterllne and
Marsh, 1980
aSource: U.S. EPA. 1984
bUn1t risk values presented as
cUn1t risk estimated from data gathered using two different follow-up
periods
-30-
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1980.
Documentation of the Threshold Limit Values for Substances 1n Workroom Air,
4th ed. with supplements through 1981. Cincinnati, OH. p. 4-27. (Cited in
U.S. EPA, 1983a)
Ar1yosh1, T. and T. Ikeda. 1974. On the tissue distribution and the excre-
tion of arsenic 1n rats and rabbits of administration with arsenical com-
pounds. 0. Hyg. Chem. 20: 290. (Cited 1n U.S. EPA, 19805)
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