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 ------- 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 ------- 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 ------- 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. ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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- ------- 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- ------- 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- ------- 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. -6- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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- ------- 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) Axelson, 0., E. Dahlgren, C.D. Jansson and S.O. Rehnlund. 1978. Arsenic exposure and mortality: A case-referent study from a Swedish copper smelter. Br. J. Ind. Med. 35: 8-15. (Cited In U.S. EPA, 1983b) t Baronl, C., G.J. Van Esch and U. Safflottl. 1963. Cardnogenesls tests of two Inorganic arsenlcals. Arch. Environ. Health.. 7: 668-674. (Cited In U.S. EPA, 1983a,b) Baxley, M.N., R.D. Hood, G.C. Vedel, W.P. Harrison and G.M. Szczech. 1981. Prenatal toxlclty of orally administered sodium arsenlte 1n mice. Bull. Environ. Contam. Toxlcol. 26: 749-756. (Cited 1n Lederer and Fensterhelm, 1983) Beckman, G., et al. 1977. Chromosome aberrations In workers exposed to arsenic. Environ. Health Perspect. 19: 145. (Cited 1n U.S. EPA, 1980b) -31- ------- Bencko, V. and K. Symon. 1970. The cumulation dynamics 1n some tissue of hairless mice Inhaling arsenic. Atmos. Environ. 4: 157-161. (Cited In U.S. EPA. 1980b) Berteau, P.E., 3.0. Flom, R.L. D1mm1ck and A.R. Boyd. 1978. Long-term study of potential cardnogenldty of Inorganic arsenic aerosols to mice Toxlcol. Appl. Pharmacol. 45: 323. (Abstr.) (CHed 1n U.S. EPA, 1983b) Boyle, R.W. and I.R. Jonasson. 1973. The geochemistry of arsenic and Us use as an Indicator element 1n geochemlcal prospecting. J. Geochem. Expl. 2: 251-296. (Cited 1n U.S. EPA, 1983b) Brown, C.C. and K.C. Chu. 1983. Implications of the multistage theory of carclnogenesls applied to occupational arsenic exposure. J. Natl. Cancer Inst. 70: 455-463. (Cited In U.S. EPA, 1984) Buchet, J.P., R. Lauwerys and H. Roels. 1981." Urinary excretion of Inorganic arsenic and Its metabolites after repeated Ingestlon of sodium meta arsenlte by volunteers. Int. Arch. Occup. Environ. Health. 48: 111-118. (CHed 1n U.S. EPA, 1984} Byron, U.R., G.W. Blerbower, J.B. Brouwer and W.H. Hansen. 1967. Patho- logical changes In rats and dogs from two-year feeding of sodium arsenlte or sodium arsenate. Toxlcol. Appl. Pharmacol. 10: 132-147. (CUed 1n U.S. EPA, 1980b, 1983a,b) -32- ------- Callahan, H.A., H.M. SUmak, N.W. Gabel, et al. 1979. Water-Related Environmental Fate of 129 Priority Pollutants, Vol. I. OWPS, OWWM, U.S. EPA, Washington, DC. EPA-440/4-79-029a. (CUed 1n U.S. EPA, 1983a) Charbonneau, S.M., K. Spencer, F. Bryce and E. Sandl. 1978. Arsenic excretion by monkeys dosed with arsenic-containing fish or with Inorganic arsenic. Bull. Environ. Contain. Toxlcol. 20: 470-477. (Cited 1n U.S. EPA, 1980b) Coulson, E.J., et al. 1935. Metabolism 1n the rat of the naturally occur- ring arsenic of shrimp as compared with arsenic trloxide. J. Nutr. 10: 255-270. (CHed 1n U.S. EPA, 1980b) Crecellus, E.A. 1977. Changes 1n the chemical spedatdn of arsenic following 1ngest1on by man. Environ. Health. Perspect. 19: 147-150. (Cited 1n U.S. EPA, 1984) Cuzlck, J., S. Evans, M. Glllman and O.A. Price Evans. 1982. Medicinal arsenic and Internal malignancies. Br. J. Cancer. 45(6): 904-911. (Cited In U.S. EPA, 1983b) Dubols, K.P., et al. 1940. Further studies on the effectiveness of arsenic 1n preventing selenium poisoning. J. Nutr. 19: 477. (CHed 1n U.S. EPA, 1980b) -33- ------- Ducoff, H.S., W.B. Neal, R.L. Straube, L.O. Jacobson and A.M. Brues. 1948. Biological studies with arsenic. II. Excretion and tissue localization. Proc. Soc. Exp. B1ol. Med. 69: 548-554. (Cited In NAS, 1977; U.S. EPA, 19805) Dutklewlcz, T. 1977. Experimental studies on arsenic absorption routes In rats. Environ. Health Perspect. 19: 173. (Cited 1n U.S. EPA, 1980b) Edmonds, J.S. and K.A. Francesconl. 1977. Methylated arsenic from marine fauna. Nature 265: 436. (Cited In U.S. EPA, 1984) Edmonds, J.S., K.A. Francesconl, J.R. Cannon. C.L. Raston, B.W. Skelton and A.H. White. 1977. Isolation, crystal structure and .synthesis of arseno- betalne, the arsenical constituent of the western rock lobs»ter, Panullrus longlpes cygnus George. Tetrahedron Lett. 18: 1543-1546. (CHed 1n U.S. EPA, 1984} Enterllne, P.E. and G.H. Harsh. 1980. Mortality studies of smelter workers. Am. J. Ind. Med. 1: 251-259. (CHed 1n U.S. EPA, 1984) Enterllne, P.E. and G.M. Marsh. 1982. Mortality among workers exposed to arsenic and other substances 1n a copper smelter. Am. J. Ep1dem1ol. 116: 895-910. (Cited 1n U.S. EPA, 1984) Federal Register. 1984. Environmental Protection Agency. Proposed guide- lines for carcinogenic risk assessment. Federal Register. 49: 46294-46299. -34- ------- Graedel, I.E. 1978. Chemical Compounds 1n the Atmosphere. Academic Press, NY. p. 1-49. Hlgglns, I., K. Welch and C. Burchflel. 1982. Mortality of Anaconda smelter workers In relation to arsenic and other exposures. Ann Arbor, MI., Dept. of Epidemiology, Univ. of Michigan, 1982. (Cited In U.S. EPA, 1984) Hill. R.H. and E.L. Fanlng. 1948. Studies 1n the Incidence of cancer 1n a factory handling Inorganic compounds of arsenic. I. Mortality experience 1n the factory. Br. J. Ind. Med. 5: 1. (Cited 1n U.S. EPA, 1983b) Hlsanaga, A. 1982. Chronic toxldty of arsenous add 1n rats with special reference to dose response. Fukuoka Igaku Zasshl. 73(1): 46-63. (Eng.) (Cited 1n U.S. EPA, 1983a) » Holland, R.H., et al. 1959. A study of Inhaled arsenic - 74 1n man. Cancer Res. 19: 1154. (Cited 1n U.S. EPA, 19805) Hood, R.D., G.T. Thacker and B.L. Patterson. 1977. Effects 1n the mouse and rat of prenatal exposure to arsenic. Environ. Health Perspect. 19: 219-222. (Cited In U.S. EPA, 1980b) Hueper, W.C. and W.W. Payne. 1962. Experimental studies 1n metal cardno- genesls. Chromium, nickel, Iron, arsenic. Arch. Environ. Health. 5: 445. (Cited In U.S. EPA, 1983b) -35- ------- IARC (International Agency for Research on Cancer). 1980. Arsenic and arsenic compounds, in: Some Metals and Metallic Compounds. IARC Mono- graphs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. IARC, WHO, Lyon, France. 23: 39-142. (Cited 1n U.S. EPA, 1983b) Inamasu, T., A. Hlsanaga and N. Ish1n1sh1. 1982. Comparison of arsenic trloxlde and calcium arsenate retention 1n the rat lung after Intratracheal Instillation. Toxlcol. Lett. 12: 1-5. (CHed 1n U.S. EPA, 1984) Ishlnlshl, N., K. Osato, Y. Kodama and E. KunHake. 1976. Skin effects and carclnogenldty of arsenic trloxlde: A preliminary experimental study 1n rats. ITK Effects and Dose-Response Relationships of Toxic Metals, G.F. Nordberg, Ed. Elsevler Scientific, Amsterdam, p. 471-479. (Cited 1n IARC, 1980; U.S. EPA, 1983b) , Ish1n1sh1, N., Y. Kodama, K. Nobutomo, K. and A. Htsanaga. 1977. .Prelimi- nary experimental study on carclnogenldty of arsenic trloxlde 1n rat lung. Environ. Health Perspect. 19: 191-196. (Cited 1n U.S. EPA, 1983b) Ishlnlshl, N., M. Tomlta and A. Hlsanaga. 1980. Chronic toxlclty of arsenic trloxlde In rats with special reference to liver damages. Fukuoka Igaku Zasshl. 71(1): 27-40. (Eng.) (Cited 1n U.S. EPA, 1983a) Ivankovlc, S., G. Elsenbrand and R. Preussmann. 1979. Lung carcinoma Induction 1n BD rats after single Intratracheal Instillation of an arsenic- containing pesticide mixture formerly used 1n vineyards. Int. J. Cancer. 24: 786-788. (CHed 1n U.S. EPA, 1983b) -36- ------- Kanlsawa, H. and H.A. Schroeder. 1967. Life term studies on the effects of arsenic, germanium, tin, and vanadium on spontaneous tumors 1n mice. Cancer Res. 27: 1192. (Cited In U.S. EPA, 1983b) Kanlsawa, M. and H.A. Schroeder. 1969. Life term studies on the effect of trace elements on spontaneous tumors 1n mice and rats. Cancer Res. 29: 892. (Cited 1n U.S. EPA, 1983b) Knoth, W. 1966/67. Arsenic treatment. Arch. KUn. Exp. Derm. 227: 228-234. (Ger.) (Cited In IARC, 1980; U.S. EPA, 1983D) KoJIma, H. 1974. Studies on development pharmacology of arsenlte. II. Effect of arsenlte on pregnancy, nutrition and hard tissue. Pol. Pharmocol. Japon. 70: 149-163. (Cited 1n Lederer and Fensterhelm, 1983) * Kroes. R., M.J. Van Logten, J.M. Berkvlns, I. deVcles and G.J. van Esch. 1974. Study on the carc1nogen1c1ty of lead arsenate and sodium arsenate and on the possible synerglstlc effect of diethylnltrosamlne. Food Cosmet. Toxlcol. 12: 671-679. (Cited 1n U.S. EPA, 1983a,b) Landau, E., et al. 1977. Selected noncarclnogenlc effects of Industrial exposure to Inorganic arsenic. U.S. EPA, Washington, DC. EPA 569/6-77-018. (Cited 1n U.S. EPA, 1980b) Lanz, H., Jr., P.U. Wallace and J.G. Hamilton. 1950. The metabolism of arsenic In laboratory animals using As74 as a trace. Univ. Calif. Pub. Pharmacol. 2: 263-282. (Cited 1n NAS, 1977) -37- ------- LeBlanc, P.J. and A.L. Jackson. 1973. Arsenic 1n marine fish and Inverte- brates. Mar. Pollut. Bull. 4: 88-90. (Cited 1n U.S. EPA, 1984) Lederer, W.H. and R.J. Fensterhelm, Ed. 1983. Arsenic. Proc. Arsenic Symp., 1981, Galthersburg, HD. Van Nostrand Relnhold Company, NY. Lee, A.M. and J.F. Fraumenl, Jr. 1969. Arsenic and respiratory cancer 1n men: An occupational study. J. Natl. Cancer Inst. 42: 1045. (Cited 1n U.S. EPA, 19835) Lee-Fe1dste1n, A. 1983. Arsenic and respiratory cancer In man: Follow-up of an occupational study. In: Arsenic -- Industrial, B1omed1cal and Environmental Perspectives, W. Lederer and R. Fensterhelm, Ed. Van Nostrand Relnhold. New York. (Cited In U.S. EPA, 1984} J Nappes, R. 1977. Versuche zur Auscheldung von Arsen 1n Ur1n. [Experiments on excretion of arsenic In urine.] Int. Arch. Occup. Environ. Health. 40: 267. (Cited 1n U.S. EPA, 1980b) Masah1k1, 0. and A. Hldeyasu. 1973. Ep1dem1olog1cal studies on the Morlnaga powdered milk poisoning Incident: Final report of the Joint pro- ject team from Hiroshima and Okayama Universities for survey of the Senol area. Jap. J. Hyg. 27: 500. (Cited In U.S. EPA. 1980b) Matsumoto, N., T. Oklno, H. Katsunuma and S. I1J1ma. 1973a. Effects of Na-arsenate on the growth and development of the foetal mice. Teratology. 8: 98. (Cited 1n Lederer and Fensterhelm, 1983) -38- ------- Matsumoto, N., T. Oklno, H. Katsumuma and S. I1J1ma. 1973b. Effects of Na-arsenlte on the growth and development of the foetal mice. CongenU. Anom. Curr. LH. 13: 175-176. (Cited 1n Lederer and Fensterhelm, 1983) Mealey, J., Jr., G.L. Browne!! and W.H. Sweet. 1959. Rad1oarsen1c 1n plasma, urine, normal tissues, and 1ntracran1al neoplasms. Arch. Neurol. Psychiatry. 81: 310-320. (Cited 1n NAS, 1977) Hlzuta, N., et al. 1956. An outbreak of acute arsenic poisoning caused by arsenic contaminated soy sauce (shoyu): A clinical report of 220 cases. Bull. Yamaguchl Med. Sch. 4: 131. (Cited 1n U.S. EPA, 1980b, 1983a) Morton, W.t 6. Starr, D. Pohl, J. Stoner, S. Wagner and P. Heswlg. 1976. Skin cancer and water arsenic 1n Lane County, Oregon. ,Cancer. 37: 2523-2532. (Cited In U.S. EPA, 1980b, 1983b) * Moxon, A.L. 1938. The effect of arsenic on the toxldty of selenlferous grains. Science. 88: 81. (Cited In U.S. EPA. 1980b) Munro, I.C. 1976. Naturally occurring toxicants 1n foods and their significance. CUn. Toxlcol. 9: 647-663. (Cited 1n U.S. EPA, 1984) Munro, I.e., S.M. Charbonneau, E. Sandl, K. Spencer, F. Bryce and H.C. Grlce. 1974. Biological availability of arsenic from fish. Toxlcol. Appl. Pharmacol. 29: 111. (Abstr.) (Cited 1n U.S. EPA, 1980b) -39- ------- Nagal, H., R. Okuda, H. Nagaml, A. Yagl, C. Mori and H. Wada. 1956. Subacute-chronU "arsenic" poisoning 1n Infant — Subsequent clinical observations. Ann. Pedlat. 2: 124-132. (Cited 1n U.S. EPA, 1980b) NAS (National Academy of Sciences). 1977. Medical and biologic effects of environmental pollutants: Arsenic. NAS, Washington, DC. NIOSH (National Institute for Occupational Safety and Health}. 1973. Criteria for a Recommended Standard...Occupational Exposure to Inorganic Arsenic. U.S. DREW, PHS, CDC, Cincinnati, OH. (Cited In ACGIH, 1980) NIOSH (National Institute for Occupational Safety and Health). 1975. Criteria for a Recommended Standard...Occupational Exposure to Inorganic Arsenic. DHEW (NIOSH) Publ. No. NIOSH 75-149. U.S. DHEW, PHS, CDC, Cincin- nati, OH. (Cited 1n U.S. EPA, 1983a) « Okamura, K., et al. 1956. Symposium on arsenic poisoning by powdered milk (2). Dlagnos. Ther. 9: 240. (Jap.) (Cited 1n U.S. EPA, 1980b) Osburn, H.C. 1969. Lung cancer In a mining district 1n Rhodesia. S. Afr. Med. J. 43: 1307. (Cited In U.S. EPA, 1983b) Ott, M.G., B.B. Holder and H.L. Gordon. 1974. Respiratory cancer and occupational exposure to arsenlcals. Arch. Environ. Health. 29: 250-255. (Cited 1n U.S. EPA, 1983b) -40- ------- Page, 6.W. 1981. Comparisons of groundwater and surface water for patterns and levels of contamination by toxic substances. Environ. Sd. Technol. 15: 1475-1481. Penrose, W.R., H.B.S. Conacher, R. Black, et al. 1977. Implications of Inorganic/organic Interconverslon on fluxes of arsenic In marine food webs. Environ. Health Perspect. 19: 53-59. (CUed 1n U.S. EPA, 1984) Peoples, S.A. 1975. Review of arsenical pesticides. In: Arsenical Pesti- cides, E.A. Wool son, Ed. ACS Symp. Ser. 7. Am. Chem. Soc., Washington, DC. (Cited 1n NAS, 1977) Perry, K., R.G. Bowler, H.M. Buckell, H.A. Druett and R.S.F. Schilling. 1948. Studies 1n the Incidence of cancer 1n a factory handling Inorganic i compounds of arsenic. II. Clinical and environmental Investigations. Br. J. Ind. Med. 5: 6. (Cited In U.S. EPA, 1983b) « Pershagen, G. and H. Vahter. 1979. Arsenic. A toxlcologlcal and epIdemlologUal appraisal. Llbertryck, Stockholm, Sweden, SNV PM-1128 (CHed In U.S. EPA, 1984) Pershagen, G., C.G. Ellnder and A.M. Bolander. 1977. Mortality 1n a region surrounding an arsenic emitting- plant. Environ. Health Perspect. 19: 133-137. (Cited 1n U.S. EPA, 1983b) -41- ------- Pershagen, G., B. L1nd and N.E. Bjorklund. 1982. Lung retention and toxlclty of some Inorganic arsenic compounds. Environ. Res. 29: 425-434. (CHed 1n U.S. EPA, 1984) Petres, 3. and M. Hundelker. 1968. "ChromosomenpulveMsatlon" nach Arsene1nw1rkung auf Zellkulturen 1n vitro. Arch. Klin. Exp. Dermatol. 231: 366. {CHed 1n U.S. EPA, 1980b) Petres, 3., et al. 1970. Chromosomenaberratlonen an menschllchen Lymphozy- ten be1 chronlschen Arsenschaden. Dtsh. Hed. Wochenschr. 95: 79. (CHed In U.S. EPA, 1980b) Petres. J., et al. 1972. Zum Elnfluss anorganlschen Arsens auf die DNS-Synthese menschllcher Lymphocyten in vltr. Arch. Derm. Forsch. 242: 343-352. (CHed In U.S. EPA, 1980b) * Pinto, S.S. and 8.M. Bennett. 1963. Effect of arsenic trloxlde exposure on mortality. Arch. Environ. Health. 7: 583-591. (CHed 1n U.S. EPA, 1980b, 19835) Pinto, S.S., et al. 1976. Arsenic trloxlde absorption and excretion 1n Industry. J. Occup. Hed. 18: 677. (Cited In U.S. EPA, 1980b) Pinto, S.S., P.E. Enterllne, V. Henderson and M.O. Varner. 1977. Mortality experience 1n relation to a measured arsenic trloxlde exposure. Environ. Health Perspect. 19: 127-130. (CHed 1n U.S. EPA, 1984) -42- ------- Pinto, S.S., V. Henderson and P.E. interline. 1978. Mortality experience of arsenic-exposed workers. Arch. Environ. Health. 33: 325-332. (Cited 1n U.S. EPA, 1983b) Ray-Bettley, F. and J.A. O'Shea. 1975. The absorption of arsenic and Us relation to carcinoma. Br. J. Dermatol. 92: 563. (Cited 1n U.S. EPA, 1980b) Rencher, A.C., M.W. Carter and D.W. McKee. 1977. A retrospective epidemic- logical study of mortality at a large western copper smelter. J. Occup. Med. 19: 754-758. (CUed In U.S. EPA, 1983b) Reymann, F., R. Holier and A. Nielsen. 1978. Relationship between arsenic Intake and Internal malignant neoplasms. Arch. Dermatol. 114: 378-381. (CHed 1n U.S. EPA, 1983b) » Rozenshteln, I.S. 1970. Sanitary toxlcologlcal assessment of low concen- trations of arsenic trloxlde 1n the atmosphere. Hyg. SanH. 34: 16-21. (Cited 1n U.S. EPA, 1980b) Satake, S. 1955. Concerning the cases of arsenic poisoning caused by prepared powdered milk. Jap. J. Pub. Health. 2: 22-24. (CUed 1n U.S. EPA. 1980b) Schrauzer. 6.N., D.A. White, J.E. HcGlnness, C.J. Schneider and L.J. Bell. 1978. Arsenic and cancer: Effects of Joint administration of arsenlte and selenlte on the genesis of mammary adenocarclnoma 1n Inbred female C3H/ST mice. Bloorg. Kh1m. 9(3): 245-253. (CUed 1n U.S. EPA, 1983b) -43- ------- Schroeder, H.A. and J.O. Balassa. 1967. Arsenic, germanium, tin, and vanadium 1n mice: Effects on growth, survival, and tissue levels. J. Nutr. 92: 245-252. (Cited 1n U.S. EPA, 1983a) Schroeder, H.A., M. Xanlsawa, O.V. Frost and M. HHchener. 1968. German- ium, tin, and arsenic 1n rats: Effects on growth, survival, pathological lesions, and Hfespan. J. Nutr. 96: 37-45. (Cited 1n U.S. EPA, 1983a) Sh1rach1, D.Y., M.G. Johansen, J.P. McGowan and S.H. Tu. 1983. Tumor1gen1c effect of sodium arsenlte 1n rat kidney. Proc. West. Pharmacol. Soc. 26: 413-415. (CA 99: 117554u) Shublk, P., U. Safflottl, W. L1J1nsky, et al. 1962. Studies on the tox- 1c1ty of petroleum waxes. Toxlcol. Appl. Pharmacol. 4(suppl.): 1-62. (CHed In U.S. EPA, 1983a) Singh, I. 1983. Induction of reverse mutation and mltotlc gene conversion by some metal compounds 1n Saccharomyces cerevlslae. Hutat. Res. 117(1-2): 149-152. Smith, T.3., E.A. Crecellus, and J.C. Reading. 1977. Airborne arsenic exposure and excretion of methylated arsenic compounds. Environ. Health Persp. 19: 89-93. (CHed 1n U.S. EPA, 1980b) Stoklnger, H.E. 1981. The metals: Arsenic. .In: Patty's Industrial Hygiene and Toxicology, Vol. II, 3rd ed., C.O. Clayton and F.E. Clayton, Ed. John Wiley and Sons, Inc., NY. p. 1517-1531. (CHed 1n U.S. EPA, 1983a) -44- ------- I I Tay, C.H. and C.S. Seah. 1975. Arsenic poisoning from anti-asthmatic herbal preparations. Hed. J. Aust. 2: 424. (Cited 1n U.S. EPA, 1983a,b) Tokudome, S. and M. Kuratsune. 1976. A cohort study on mortality from cancer and other causes among workers at a metal refinery. Int. J. Cancer. 17: 310-317. (Cited 1n U.S. EPA, 1983b) Tseng, W.P. 1977. Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic. Environ. Health Perspect. 19: 109-119. (Cited In U.S. EPA, 1980b, 1983a,b) Tseng, W.P., H.H. Chu, S.W. How, J.M. Fong, C.S. L1n and S. Yeh. 1968. Prevalence of skin cancer In an endemic area of chronic arsenlclsm 1n Taiwan. J. Natl. Cancer Inst. 40: 453-463. (Cited 1n U.S. EPA, 1980b, 1983a,b, 1984) * Urakabo, G., et al. 1975. Studies on the fate "of poisonous metals In experimental animal (V). Body retention and excretion of arsenic. J. Food Hyg. Soc. Jap. 16: 334. (Jap.) (Cited In U.S. EPA, 1980b) U.S. EPA. 1980a. Guidelines and Methodology Used In the Preparation of Health Effects Assessment Chapters of the Consent Decree Water Quality Criteria. Federal Register. 45: 79347-79357. U.S. EPA. 1980b. Ambient Water Quality Criteria for Arsenic. Environ- mental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-021. NTIS PB 81-117327. -45- ------- I I U.S. EPA. 1983a. Reportable Quantity for Arsenic (and Compounds). Pre- pared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1983b. Review of lexicological 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. 1983c. Methodology and Guidelines for Reportable Quantity Deter- minations Based on Chronic Toxldty Data. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Washington, DC. i 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. U.S. EPA. 1985. Acceptable Dally Intakes for Volatile Organic Chemicals, Inorganic Chemicals and Synthetic Organic Chemicals. Criteria and Standards Division, Office of Drinking Water. Draft Federal Register Notice. Walker, G.W.R. and A.M. Bradley. 1969. Interacting effects of sodium monohydrogenarsenate and selenocystlne on crossing over 1n DrosphUa melano- qaster. Can. J. Genet. Cytol. 11: 677. (Cited 1n U.S. EPA, 1980b) U.S. Environments! Protection Agency Rs •'•-- " 230 South Co,. Chicago, lliir.u;s 60C-J4 -46- ------- ' • 1 Westoo, G. and M. Rydalv. 1972. Arsenic levels 1n foods. Var Foda. 24: 21-40. (In Swedish with English summary). (Cited In U.S. EPA, 1984) WHO (World Health Organization). 1981. Environmental Health Criteria 18: Arsenic. International Program on Chemical Safety. Geneva. (Cited In U.S. EPA, 1984) -47- ------- |