Document Ev9QMyxk7zYYjOeNE6rbeGKy0

American Journal of Industrial Medicine 2 5 -14 (1981) Arsenic-state of the Art Philip J. Landrigan, MD, MSC Approximately 1.5 million workers in the United States are exposed to arsenic. Occupational exposure is primarily by inhalation. NIOSH recommends that time-integrated exposure to arsenic in air not exceed 2 pg/m3. Recent exposure is accurately measured by urine assay; urine arsenic concentrations above 50 Fg/liter indicate increased absorption. Hair assay is a semiquantitative index of past exposure. Toxicity is associated primarily with the trivalent (3+) form of arsenic. Acute poisoning is caused most commonly by contaminated food or drink; it is rarely occupational. Chronic intoxication is characterized by dermatitis, hyperpigmentation, keratoses, peripheral neuropathy (primarily sensory), irritation of the upper and lower respiratory tract, and occasionally by hepatic toxicity and peripheral vasculopathy (blackfoot disease). Arsenic is not carcinogenic in animal species, but is mutagenic in Syrian hamster cells. In man. arsenic is known definitely to cause cancer of skin, lung, and liver (angiosarcoma) and possibly to cause lymphoma. Key words: arsenic. mutagenesis, lung cancer, angiasarcoma of liver, skin cancer, neuropathy INTRODUCTION Arsenic is a metalloid element. a member of group V of the periodic table [National .Academy of Sciences, Committee on Medical and Biological Effects of Environmental Pollutants, 19771. Consumption of arsenic in the United States is estimated to range from 25,000 to 35,OOO tons per year [National Institute for Occupational Safety and Health, 19751. Of this amount, 6000-14,OOO tons are produced domestically. The principal sources are the ores of copper, as well as of lead and zinc, from which arsenic is removed as an impurity during smelting. The National Institute for Occupational Safety and Health (NIOSH) estimates that 1.5 million workers in the United States have the potential for occupational exposure to inorganic arsenic, including arsine and lead arsenate; 660,000 of these workers National Institute for Occupational Safety and Health.Division of Surveillance,Hazard Evaluations, and Field Studies. Cincinnati, Ohio. Address reprint requests to Philip Landrigan. National Institute for Occupational Safety and Health, Division of Surveillance. Hazard Evaluations, and Field Studies. 1676 Columbia Parkway. Cincinnati, OH 45226. .Accepted for publication March 28, 1981. 0271-3586/81/0201-0005%03.00 0 1981 Alan R. L i s , Inc. 6 Landrigan are directly involved in the commercial cycle of arsenic. Approximately 80% of the arsenic consumed each year in the United States is used in the manufacture of pesticides, herbicides, and other agricultural products. HUMAN EXPOSURE Human exposure to arsenic and its compounds occurs mainly either through ingestion, particularly of seafood [Jelinek et al, 19771, or through inhalation of arsenic-containing airborne particulates. Major occupational exposure occurs in smelting [Milham, Jr et al, 19741, but has been reported also in the chemical [Hill et al, 19481, pesticide [Mabuchi et al. 19791, and pharmaceutical industries [Watrous et al, 1945). NIOSH has recently observed an increased exposure to airborne arsenic and elevated urinary arsenic excretion in workers using lead-arsenic alloys ("hard lead") in the manufacture of leadacid batteries [Costello et al, 19801. In populations without occupational or other unusual exposure to arsenic, the daily absorbed dose is calculated to be less than 40-50 Fg. [Nordberg et al. 19791. Excretion of arsenic is mainly via the urine. In primates, excretion after a single injected dose is essentially complete in six days [Charbonneau et al, 19781. In man, the biological half-life of arsenic in blood was measured by Mealey et ai after intravenous injection of radioactive arsenic ('"As) to patients with terminal cancer [ 19591. Excretion proceeded in three phases: plasma was cleared in 10 hours, the main portion of the dose was excreted in 30 hours, and a small residual fraction had a half-life of eight days. The overall half-life of ingested inorganic arsenic in man has been calculated to be 10 hours. Those observations are corroborated by the data of Milham and Strong [ 19741, who found that arsenic levels in the urine of children living downwind of an arsenic-emitting copper smelter in Tacoma, Washington, decreased sharply within 2-3 days following a change in the prevailing wind direction. Human absorption or the "body burden" of arsenic has been assessed through the measurement of the total arsenic concentrations in blood, hair, and urine [Harrington et al, 19781. Because of the short half-life of arsenic in blood [Mealey et al, 1959; Charbonneau et al, 19781, the blood arsenic determination has been found to be of little practical value [Nordberg et aI, 19791. The determination of arsenic in the hair has been found to be a useful, semiquantitative indicator of past exposure to arsenic. In a nationwide survey in the United States of children living near primary smelters, the Center for Disease Control (CDC)found that the mean hair arsenic concentration in 972 children from 11 towns with copper smelters was 2.60 pg/gram; the highest concentration (19.88 @gram) being found in Anaconda, Montana, the most heavily polluted town in the study [Baker et aI, 19771. By contrast, the mean hair arsenic content in 160 children from three comparison towns without smelters was 0.09 pg/gram ( t = 9.72, p < 0.01). The major drawback to the determination of arsenic in hair is that it does not distinguish systemically absorbed from externally deposited arsenic. Thus the intrinsic arsenic content of hair can be modified by such external sources as bathing in arsenic-contaminated water, by contamination with arsenic excreted in sweat. or by exposure to airborne arsenic. The urine arsenic concentration appears to be the best indicator of current or of recent (1-3 days) past exposure to arsenic [Harrington et al, 19781. However, it is very important, as noted previously [Milham. Jr et al, 19741, to consider the timing of the collection of samp in urine. A study (r = 0.58) betwet inated well water smelters, the CDC children from I 1 comparison town> found that the me distance of 0.0-0. ton, and decrease( Although t t arsenic concentrar urine arsenic con. KgAiter [Webster 1978; Morse et Schreibeis [ 1958 reported mean ur and 130 Fg/iiter groups either wc occupational expc ARSENIC TOX: For the mo: than that of the F Acute Poisonir Acute arsei from the ingestic profound gastroir shock [National Environmental P difficulty in swa, hydration, a we: development of to be dilation an< h c t and elsewht of the mucosa t progresses to pel been observed. Subacute and Chronic ar feted-the skin and respiratory I 10-50 pg. `ter a single In man, the intravenous 1. Excretion of the dose It days. The x 10 hours. .who found tting copper ng a change through the farrington et 1959; Char1 be of little I, semiquanUnited States CDC) found wlth copper m g found in et al, 1977). 3anson towns iwback to the bsorbed from 3 be modified Arsenic-State of the Art 7 collection of samples in assessing the biological significance of the arsenic concentration in urine. A study conducted in Fairbanks, Alaska, found a high correlation coefficient ( r = 0.58) between arsenic concentrations in the water and urine of drinkers of contaminated well water [Harrington et al, 1978). Also, in studies of children who lived near smelters, the CDC group found a mean urine arsenic content of 18.7 pg/liter in 712 children from 11 towns with smelters and of 5.8 pg/liter in 193 children from three comparison towns (t = 10.75; p < 0.01) [Baker et al, 19771. Milham and Strong [I9741 found that the mean urine arsenic concentration was 300 pg/liter in children living at a distance of 0.0-0.4 miles from an arsenic-emitting copper smelter in Tacoma, Washington, and decreased to 20 @liter at a distance of 2.0-2.4 miles. Although the range of values considered "normal" in previous studies of urine arsenic concentration has varied, due primarily to differences in laboratory methods, most urine arsenic concentrations in unexposed populations have been found to be below 50 Cgiliter [Webster, 1941; Milham, Jr et al, 1974; Baker et al, 1977; Harrington et al, 1978; Morse et al, 1979: Rosenberg et al, 19801. Three studies, one by Schrenk and Schreibeis [19581, one by Perry et a1 [19481, and a third by Pinto and McGill [I9531 reported mean urinary arsenic concentrations in allegedly unexposed persons of 80, 85, and 130 pg/liter respectively; however, in each of those studies, persons in the control groups either worked in proximity to arsenic-contaminated areas or had had previous occupational exposure to arsenic. ARSENIC TOXICITY For the most part, the toxicity of trivalent ( + 3) arsenic has been found to be greater than that of the pentavalent ( + 5 ) form. Acute Poisoning Acute arsenic poisoning is rare in the occupational setting and results principally from the ingestion of contaminated food or drink. The major symptoms are those of profound gastrointestinal inflammation, sometimes with hemorrhage, and of cardiogenic shock [National Academy of Sciences, Committee on Medical and Biological Effects of Environmental Pollutants. 19771. Symptoms resemble those of cholera and may include difficulty in swallowing, abdominal pain, projectile vomiting, "rice-water" diarrhea, dehydration, a weak irregular pulse. and a loss of blood pressure that is followed by the development of stupor, coma, convulsions, and death. The fundamental lesion appears to be dilation and increased permeability of the small blood vessels in the gastrointestinal tract and elsewhere. Pathological examination shows extensive inflammation and necrosis of the mucosa and submucosa of the stomach and intestine. The necrosis sometimes progresses to perforation of the gut wall. Fatty degeneration of the liver and kidneys has been observed. Subacute and Chronic Toxicity Chronic arsenic intoxication is best discussed in terms of the organ systems affected-the skin, nervous system, liver, cardiovascular system, hematopoietic system, and respiratory tract. 8 Landrigan Skin Toxicity Chronic arsenic exposure has been found in many studies to be associated with dermatitis [Holmquist, 1951;Birmingham et al, 1965). The dermatitides caused by arsenic have been classified as eczematous and follicular [Holmquist, 19511. Conjunctivitis and rhinitis frequently may accompany arsenical dermatitis. Chronic exposure to arsenic has been shown to produce hyperpigmentation, warts (arsenical keratoses) [Perry et al, 19481, and hyperkeratosis of the palms and soles [Tseng, 1977; Nordberg et al, 19791. Arsenic exposure has been associated with three types of skin cancer-Bowen's disease, basal cell carcinoma, and squamous cell carcinoma [Nordberg et al, 19791; these cancers are frequently multiple in origin and develop primarily from arsenical keratoses. The prevalence of arsenic-related skin cancer appears to be related to the total absorbed dose of arsenic [Tseng, 1977; Nordberg et al. 19791. Excess mortality due to arsenicinduced skin cancer has been observed in the chemical [Perry et al, 19481 and wineproducing industries [Roth, 19581, as well as from the consumption of contaminated water [Tseng, 19771. Numerous cases of skin cancer have been attributed to the use of medications containing arsenic [Nordberg et al, 19791. Neurologic Toxicity Peripheral neuropathy affecting primarily sensory function has been encountered in several studies of persons with chronic exposure to arsenic [Heyman et al, 1956; Hindmarsh et al, 19771. A very large outbreak occurred in England in 1900 as the result of widespread consumption of arsenic-contaminatedbeer (RoyalCommission on Arsenical Poisoning, 1901). In a study conducted in Nova Scotia of 92 persons chronically exposed to arsenic in well water, Hindmarsh et a1 [ 19771 found that the prevalence of sensory and motor symptoms correlated positively with the concentration of arsenic in well water as well as with the arsenic content in hair. Also, a positive association was found between well water and hair arsenic concentrations and the prevalence of electromyographic (EMG) abnormalities. Clinical experience suggests that the neuropathy which follows exposure to arsenic is at least partially reversible [Nordberg et al, 19791. Hearing loss, possibly reflecting arsenic toxicity to the eighth cranial nerve, was reported in a study conducted in Czechoslovakia among 56 children who lived near a power plant that burned coal with a high arsenic content and released arsenic-contaminated fly ash [Bencko et al, 19771. However, no hearing impairment was observed by Milham in children living near the arsenic-emitting copper smelter in Tacoma, Washington [Milham. Jr, 19771. Liver Toxicity The chronic absorption of arsenic occasionally produces hepatocellular toxicity which may be the result of an inhibition by arsenic of the enzymes involved in cellular respiration [Fowler, 19771. Trivalent arsenic binds readily to sulfhydryl groups of enzymes and has been shown to inhibit pyruvate dehydrogenase function [Schiller et al, 19771; that alteration has been correlated with the swelling and distortion of the hepatic mitochondria [Fowler et al, 19791. Chronic exposure to arsenic has been reported to produce reversible liver enlargement and has been associated with cirrhosis of the liver [Lee et al, 1969; Nordberg et al, 19791. Anp those case use of Fo recently in water near Cardiova Peril et al, 197 drinking I Those chi gressed in 19771, as? pronouncc in childre appeared HematoC ChV megalobi: the inhibii of delta a animals ds Incr tissues ha Axelson e small and Respirati In th including airborne 3 itant expo it is difficl agents . Lun ofsmelter found a th of 8047 \ mortality : and in thc excess mc the Lee a: arsenic an dted with ly arsenic ,vitls and ,enic has 1, 19481, Bowen's 91; these xatoses. ibsorbed arsenicid wineminated e use of untered , 1956; le result rsenical :xposed ory and vater as >etween (EMG) tposure e, was near a 1 mated .I11ham 2 [Mil- oxlclty ellular izymes 19771; mitopoduce Lee et -Arsenic State of the Art 9 Angiosarcoma of the liver has been associated with arsenic exposure. Exposure in [ h w cases has been through the drinking of contaminated wine [Roth, 19581 or through use of Fowler's solution [Falk et al, 19801. Angiosarcoma of the liver was observed recently in a two-year-old girl who had been exposed to arsenic in the air, dust, soil, and safer near an arsenic-emitting-copper smelter in Ajo, Arizona [Fa& et al, 19801. Cardiovascular Toxicity Peripheral vascular disease has been observed among persons in Chile [Borgono St a], 19711 and in Taiwan [Tseng, 19771 who had had chronic exposure to arsenic in dinking water. Early symptoms included acrocyanosis and Raynaud's phenomenon. Those changes were associated with hyperpigmentation and hyperkeratosis. They progressed in severe cases to frank gangrene of the extremities ("blackfoot disease") [Tseng, I 9771, associated with endarteritis obliterans. In Chile, infants and children showed more pronounced vascular symptoms than adults, and myocardial infarction was reported even in children [Borgono et al, 19711. The prevalence and severity of blackfoot disease appeared to be related to the dose of ingested arsenic [Tseng, 19771. Hematopoietic Toxicity Chronic exposure to arsenic has been associated with disturbed erythropoiesis, and megaloblastic formation has been noted [Nordberg et al, 19791. These changes may reflect the inhibitory effects of arsenic on cellular respiration [Schiller et al, 19771. Depression of delta arninolevulinic acid synthetase and of ferrochelatase activity in experimental animals dosed with arsenic has been reported [Woods et al, 19771. Increased mortality due to malignant neoplasms of lymphatic and hematopoietic tissues has been noted in two studies of workers exposed to arsenic [Ott et al, 1974; .axelson et al. 19781. The number of cases cited in each of those reports was, however, small and further evaluation will be required. Respiratory Toxicity In the smelting industry. inflammatory and erosive lesions of the respiratory mucosa, inc!uding perforation of the nasal septum, have been observed in workers exposed to airborne arsenic [Pinto et al, 1953). Frequently in smelting there are, however, concomitant exposures to sulfur dioxide and to other metallic and unspecified particulates. Thus it is difficult in that environment to distinguish among the imtative effects of the various agents. Lung cancer has been found to account for excess mortality in several populations of smelter workers exposed to arsenic trioxide. In Anaconda, Montana, Lee and Fraumeni found a threefold excess mortality from respiratory cancer over statewide rates in a group of 8047 white male workers [1969]. There was a systematic gradient in lung cancer mortality according to the duration and intensity of arsenic exposure within that population, and in the subgroup of workers with the heaviest and longest (>15 years) exposure, excess mortality from lung cancer was found to be increased eightfold over expected. In the Lee and Fraumeni study. because of the nature of smelter operations, exposures to arsenic and to sulfur dioxide were inextricably linked. 10 Landrigan Previous studies of workers at the Tacoma, Washington, smelter produced conflicting results in regard to lung cancer mortality [Pinto et al, 1963; Milham, Jr et al, 19741. However, a more recent analysis of mortality patterns at the plant showed a threefold excess mortality from lung cancer (standardized mortality ratio, SMR = 300.3) in all workers aged 65 and over [Pinto et al, 19771. When workers were subdivided according to the extent of their exposure, SMRs for respiratory cancer were found to increase from 165.6 in the least heavily exposed group to 810.5 in the most heavily exposed (Fig. 1). At the smelter in Garlield, Utah, Rencher and Carter [1971] found a threefold excess mortality from lung cancer in smelter workers as compared to statewide Utah rates and a fivefold excess as compared to miners employed by the same company (Table I). Among the smelter workers, cumulative exposure indices for persons who died of lung cancer were high not only for arsenic but also for sulfur dioxide, sulfuric acid mist, lead, and copper. Rencher and Carter found evidence for interactive effects on lung cancer mortality between occupational exposures and smoking (Table 11). A subsequent analysis of mortality at the Utah smelter by Milby and Hine found no increase in lung cancer rates when compared to United States or Utah rates [ 19741. However, the study by Milby and Hine excluded from analysis certain categories of exposed workers and included many workers who did not have a significant exposure to arsenic. Excess mortality from lung cancer has been reported in smelter workers exposed to arsenic trioxide in Japan [Kuratsune et al, 19741 and in Sweden [Pershagen et al, 1977; Axelson et al, 19781. In the Swedish studies, the overall SMR for lung cancer mortality in smelter workers was 504. A criticism of the studies of lung cancer in smelter workers exposed to arsenic is that they do not resolve the question of whether arsenic alone is a lung carcinogen or whether concomitant exposure to sulfur dioxide or to other dusts is necessary for the developmenr of lung cancer [National Academy of Sciences, Committee on Medical and Biological Effects of Environmental Pollutants, 19771. Evidence from studies in other industries helps, however, to resolve that issue. Pesticide manufacturing workers in the United Kingdom [Hill et al. 19481 and in the United States [On et al, 19741 who were exposed to arsenic but who had no occupational exposure to sulfur dioxide were found in separate studies to have a three to fourfold excess mortality from respiratory cancer. Likewise, a study of 1393 pesticide workers in Baltimore found a significant excess mortality (SMR = 168) over Baltimore city rates in all workers exposed to arsenic [Mabuchi et al, 19791. A positive dose-response relationship was noted in that study between lung cancer mortality and the duration of arsenic exposure; SMRs ranged less than 100 in workers exposed for under one year to 2750 (2 observed vs. 0.1 expected) in workers heavily exposed for 25 or more years. Excess lung cancer mortality has also been observed in arsenic-exposed workers employed as vineyard-sprayers in Germany [Roth, 19581 and as underground gold miners in Rhodesia [Osburn, 19691. In toto, the results from these studies indicate that neither sulfur dioxide nor other smelter dusts nor cigarette smoking are essential co-factors for the respiratory carcinogenicity of arsenic. Although each of these factors may interact with arsenic in the production of respiratory cancer, the data from these studies provide sufficient evidence that arsenic is itself a lung carcinogen in man. Further epidemiologic studies of possible interactions between arsenic and other materials might be of considerable academic interest. There is, however, no reason to delay reduction of occupational or environmental exposure to arsenic while awaiting the results of such studies. Fig. I Wash1 TAB Utak All c -Lung From TAB (Ken - Sinel Mine Conc From Anirr inabil Acadt Pollur whick intratr given Arsenic-State of the Art 11 0 0 0 0 0 I II I 5000 10000 15000 Exposure Index ~ i g .1 .-Standardized mortality ratios (SMRs) related to total arsenic exposure in smelter workers-Tacoma, Washington. Source: Pinto et a1 [ 19771. TABLE 1. Age-Adjusted Death Rates per 10,OOO at Risk (Kennecott Mine and Smelter, Garfield, Utab, and State of Utah) Smelter Mine State All causes Lung cancer 149.8 10.1 121.8 2.1 121.2 3.3 From Rencher. Caner. and McKee [ 19771. TABLE U. Lung Cancer Deaths as a Percentage of Total Deaths in Smokers and Nonsmokers (Kennecott Mine and Smelter, Garfield, Utah) Smokers Nonsmokers Smelter Mine Concentrator 9.2 3.3 3.3 3.3 0.7 0.8 From Rencher. Caner. and McKee I19771 Animal Studies of Arsenic Carcinogenicity A continuing paradox in the study of the carcinogenicity of arsenic has been an inability to establish a model of arsenic carcinogenicity in any animal species [National Academy of Sciences, Committee on Medical and Biological Effects of Environmental Pollutants, 19771. The basis for this failure is not known. A recent Japanese study in which either arsenic trioxide or smelter dust was administered to groups of rats by intratracheal instillation showed an increased Occurrence of lung cancer in the animals given smelter dust, but not in those administered the pure arsenic compound (although 12 Landrigan one benign pulmonary adenoma was observed in the arsenic-trioxide treated group) [Ishinishi et al, 19771. Good inhalation toxicity studies of animals exposed to arsenic have, however, not been reported. Mutagenic Effects of Arsenic Studies of mutagenesis due to arsenic have not been uniformly positive in bacterial cell systems (eg, Ames test)[Sunderman, Jr, 19791, possibly because of the toxicity of arsenical compounds to such systems. However, in Syrian hamster embryo cells, arsenic was found to cause cell transformation [DiPaolo et al, 19791 and also to enhance the frequency of transformation induced by the SA7 virus [Casto et al, 19791. In addition, arsenic has been found to induce aberrant DNA synthesis and to produce chromosomal aberrations in tissue culture cells [Sunderman, Jr, 19791. Smelter workers exposed to arsenic were found in a Swedish study to have an increased frequency of chromosomal aberrations as compared to controls [Nordenson et al, 19781. Although the mechanism which may have accounted for that observation is not known, the authors speculated that arsenic may have acted by inhibiting DNA repair. In conclusion, the available epidemiologic and toxicologic data, despite the absence of an animal model for arsenic carcinogenesis, indicate that arsenic is a toxin and carcinogen in man. Arsenic has been found to cause cancer of the skin, liver, and lung, and possibly of the hematopoietic and lymphatic tissues. It should be treated accordingly. REFERENCES Axelson 0. Dahlgren E. Jansson CD. Rehnlund SO ( 1978): Arsenic exposure and mortality: a case-referent study from a Swedish copper smelter. Br J Ind Med 35:8-15. Baker EL Jr. Hayes CG. Landrigan PJ. Handke JL. Leger RT. Housworth WJ. Hanington JM (1977): A nationwide survey of heavy metal absorption in children living near primary copper, lead, and zinc smelters. Am J Epidemiol 106:261-273. Bencko V. Symon K ( 1977): Test of environmental exposure to arsenic and hearing changes in exposed children. Environ Health Perspect 19:95-101. Birmingham DJ, Key MM. Holaday DA, Perone VB (1965): An outbreak of arsenical dermatoses in a mining community. Arch Dermatol 91 : 4 5 7 4 6 4 . Borgono JM. Greiber R (1971): Epidemiological study of arsenicism in the city of Antofagasta. In Hemphill DD (ed): 'Trace Substances in Environmental Health-V." Proceedings of the University of Missouri's 5th Annual Conference on Trace Substances in Environmental Health. June 29-July I , 1971, Columbia, Missouri. Publisher: Cniversity of Missouri. Casto BC. Meyers J. DiPaolo JA ( 1979): Enhancement of viral transformation for evaluation of the carcinogenic or mutagenic potential or inorganic metal salts. Cancer Res 39:193-198. Charbonneau SM. Spencer K. Bryce F, Sandi E (1978): Arsenic excretion by monkeys dosed with arseniccontaining fish or with inorganic arsenic. Bull Environ Contam Toxicol 20:470-477. Costello RJ. Landrigan PJ, Vogt R. Donohue MT, Donaldson H (1980): Health Hazard Evaluation Project No. HE 78-98, Globe Union Banery Plant, Bennington. Vermont. Cincinnati: National Institute for Oc- cupational Safety and Health. DiPaolo JA. Casto BC (1979): Quantltative studies of in vitro morphological uansformation of Syrian hamster cells by inorganic metal salts. Cancer Res ?9:1008-1013. Falk H. Herbert IT. Edmonds L. Heath CW Jr. Thomas LB. Popper H (1981): Review of four cases of childhood hepatic angiosarcom-levated environmental arsenic exposure in one case. Cancer 47:382-391. Fowler BA (1977): Toxicology of environmental arsenic. 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Acta Derm Venereol 31: (SUPP26):1-214. lshlnlshi N, Kodama Y, Nobutomo K, Hisanaga A (1977): Preliminary experimental study of carcinogenicity of arsenic trioxide in rat lung. Environ Health Perspect 19:191-196. Jellnek CF. Corneliussen PE 11977):Levels of arsenic in the United States food supply. Environ Health Perspect 19:83-87. Kuraisune M. Tokudome S , Shirakusa M. Yoshida Y. Tokumitsu T,Hayano T, Seita M (1974): Occupational lung cancer among copper smelters. Int J Cancer 13352-558. L ~ SAM, Fraumeni JF Jr (1969): Arsenic and respiratory cancer in man: an occupational study. JNCI 43:1045-1052. .labuchi K . Lilienfeld AM. Snell LM (1979): Lung cancer among pesticide workers exposed to inorganic arsenicals. Arch Environ Health 34:312-320. %lealeyJ Jr. Brownell GL.Sweet WH (1959): Radioanenic in plasma, urine, normal tissues, and intracranial neoplasms. Arch Neurol Psychiatry 81:310-320. 5Iilhy TH. Hine CH (1974):A survey of mortality due to respiratory diseases among employees of the Kennecoa Corporation. Unpublished report submitted to the Kennecott Copper Corporation, New York, NY. lhlham S Jr (1977): Studies of morbidity near a copper smelter. Environ Health Penpect 19:131-132. Milham S Jr. Strong T (1974):Human arsenic exposure in relation to a copper smelter. Environ Res 7:176-1 82. \lone DL, Harrington JM. Housworth J , Landrigan PJ (1979): Arsenic exposure in multiple environmental media in children near a smelter. Clin Toxicol 14:389-399. Nartonal Academy of Sciences. Committee on Medical and Biological Effects of Environmental Pollutants (1977):"Arsenic." Washington, D.C. Nmonal Institute for Occupational Safety and Health (1975~: "Criteria for a Recommended Standard . . . Occupational Exposure to Arsenic, New Criteria." U.S. Government Pnnting Office, Washington. D.C, Sordberg GF. Pershagen G. Lauwerys R ( 1979): "Inorganic Arsenic-Toxicological and Environmental Aspects." Odense. Denmark: Department of Community Health and Environmental Medicine, Odense University. Yordenson 1. Beckman G . Beckman L. Nordsuom S (1978): Occupational and environmental risks in and around a smelter in northern Sweden. 11. Chromosomal aberrations in workers exposed to arsenic. Hereditas 88:47-50. O h m HS (1969):Lung cancer in a mining distnct in Rhodesia. S Afr Med J 43:1307-1312. 011 VG. Hodler BB. Gordon HL ( 1974): Respiratory cancer and occupational health. Arch Environ Health 29:250-255. P e m K . Bowler RG, Buckel HM. Dmett HA, Schilling RSF (1948): Studies in the incidence of cancer in a factory handling inorganic compounds of arsenic. 11. Clinical and environmental investigations. Br J Ind Med 5:7-15. Pershagen G. Elinder CG. Bolander AM ( 1977): Mortality in a region surrounding as arsenic emitting plant. Environ Health Perspect 19:133-137. Pinlo SS. Bennett MB (1963):Effect of arsenic trioxide exposure on mortality. Arch Environ Health 7583-591. Pinto SS. McGill CM (1953):Arsenic trioxide exposure in industry. Ind Med Surg 22:281-287. Pinto SS. Enterline PE, Henderson V. Vamer MO (1977): Mortality experience in relation to a measured arsenic trioxide exposure. Environ Health Penpect 19:127-130. 14 Landrigan Rencher AC. Carter MW (1971): A retrospective epidemiological study at Kennecott's Utah smelter--phase n mortality. Unpublished report submitted to the Kennecott Copper Corporation, New Yo&, NY. Rencher AC. Carter MW. McKee DW (1977): A retrospective epidemiological study of mortality at large western copper smelter. J Occup Med 19:754-758. Rosenberg MI. Landrigan PJ, Crowley S (1980): Low-level arsenic exposure in wood processing plants. Am J Ind Med 199-107. Roth F (1958):iiber den bronchialkrebs in arsengeschadigter Winzer. Virchows Arch Pathol Anat 331:119-137. Royal Commission on Arsenical Poisoning (1901): Lancet 1:672-673, 753, 904-905. Schiller CM, Fowler BA, Woods JS (1977): Effects of arsenic on pyruvate dehydrogenase activation. Environ Health Perspect 19:205-207. Schrenk HH. Schreibeis L Jr (1958): Urinary arsenic levels as an index of industrial exposure. Am Ind Hyg ASSOCJ 191225-228. Sunderman FW Jr (1979): Mechanisms of metal carcinogenesis. Biol Trace Element Res 1:63-86. Tseng W (1977): Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic. Environ Health Perspect 19:109-119. Watrous RM. McCaughey MB (1945): Occupational exposure to arsenic in the manufacture of arsphenamine and related compounds. Ind Med 14:639446. Webster SH (1941): 'The lead and arsenic content of urines from 46 persons with no known exposure to lead or arsenic. US Public Health Service Rep 56:1953-1961. Woods IS. Fowler BA ( 1977):Effects of chronic arsenic exposure on hematopoietic function in adult mammalian liver. Environ Health Perspect 19:209-213. Relation. Resident William W. ' MD, MPH, GlC MS Because and incrc from non cancers r cornparec smelters or death diagnosis each sme from the Key words: arsel INTRODUCT The assc documented [1 Milham and Si et al, 1977; P Administration smelter workel Rocky Mountain C Medicine. Salt La1 Address reprint re, Health. Bldg 512. Accepted for publi. 0271-3586/81/0: