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6 Biologic Effects of Arsenic on Man TOXICITY The medicinal use of arsenic, although practiced for hundreds of years, apparently reached a peak in the middle to late 1800's and was a major mainstay in the limited medical armamentarium of the time. 8~5 Fowler's solution, containing arsenic trioxide at 10 mg/ml (arsenic at about 7.6 mg/rnl), was prescribed for symptomatic relief of many conditions, ranging from acute infections (although the germ theory of disease was not widely accepted until the time of Pasteur, 1822-1895, and Koch, 1843-1910) to epilepsy, asthma, and chronic, recurring skin eruptions, such as psoriasis and eczema. Thus, many patients received arsenic for periods of months and years. It was in such patients that the conse- quences of long-term administration of arsenic were first recognized to be palmer and planter hyperkeratoses, characteristic pigmentary changes on the trunk, and a variety of cancerous and precancerous lesions on the hands, feet, and trunk. There was, in fact, some initial confusion: psoriasis was, for a while, mistakenly thought to be a precancerous condition.33~852 Neubauer has provided an extensive review of these matters.585 The therapeutic usefulness of arsenic is apparently such that it has not been easily abandoned by the medical profession. Some justifica 173

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174 ARSENIC tions for its use were cited by Pillsbury et al. in 1956;645 and a 1972 English text860 stated that a possible use of Fowler's solution is "in elderly patients with bullous disease when steroids are contra-indicated." Fierz cited patient satisfaction in a large number of patients inter- viewed, including 55 of 64 with psoriasis.253 Although still used, especially in Europe,253 Fowler's solution has not appeared in the U.S. Pharmacopoeia since 1950; arsenic trioxide is listed as a reagent in the eighteenth revision, published in 1970. However, both inorganic and organic arsenic preparations are still manufactured for medical and veterinary use in this country; and there is evidence that some goes to people who find it useful in ''tonics" and for a wide variety of symptoms (more than 400 gal, or 1.5 m3 of Fowler's solution were produced in 19741. In addition to the use of medicinal arsenic, there was, during the nineteenth and early twentieth centuries, widespread use of rat poisons and insecticides that con- tained arsenic and that left residue on fruits and vegetables. The combination of these two major ''reservoirs" appears to have resulted in a relatively high frequency of both deliberate and accidental arsenic poisonings, some of them grotesque, such as the mistaken use of powdered arsenic trioxide for talcum powder, which resulted in the deaths of 17 children.362 Thus, physicians of the day were simulta- neously using arsenic therapeutically and treating the consequences of excessive exposure from environmental sources. As DOT and organic pesticides fall into disfavor, increasing use of arsenicals as pesticides and herbicides may again increase the concentration of arsenic in the general environment. This, in turn, would require a renewed ''index of suspicion" by modern physicians for the possibility of arsenic toxicity. Somewhat more recent, but overlapping with the earlier period, has been the involvement of physicians in recognition of and treatment for exposures to arsenic associated with the industrial revolution. Reactions to Contact with Arsenic Arsenic was at one time used in disreputable ''cancer pastes" for its caustic properties. Causticity is a property of arsenic trioxide, and a greater or lesser degree of skin irritation, particularly in creases and where clothing binds, is the primary symptom in smelter workers or their families exposed to dusts with a high arsenic content.79382 A striking consequence of direct contact with the mucous membranes of the nose is perforation of the nasal septum, sometimes occurring after only a week or two of exposure.79222648 Better working conditions,

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Biologic Effects of Arsenic on Man 175 including improved opportunities for personal hygiene, have reduced the incidence of this problem.382 842 That topical exposure to arsenic results in local inflammation and vesiculation such as that seen with the war gas lewisite has been of interest to investigators, including those who developed dimercaprol (British antilewisite) at the time of World War II.333 It is thought that the physical integrity of the epidermis depends on intact pyruvate metabolism and that the sulibydryl-combining properties of arsenicals inhibit the sulfhydryl-containing enzymes related to this pathway.334 This hypothesis has not been subjected to analysis by modern der- matologic biochemical techniques. Besides acting as primary irritants, many arsenicals function as contact allergens, so that very low, noncaustic concentrations may result in either vesiculation or folliculitis in previously sensitized people. Holmqvist studied workers in a large copper-ore smelting facility over a 2-year period and concluded that most of their skin eruptions were based on this mechanism.365 He noted that, on patch testing, to of arsenic workers reacted to concentrations of sodium arsenite, sodium arsenate, and arsenic pentoxide that caused reactions in only 35% of "other" and 30~o of new employees. Holmqvist suggested that selection of nonsensitized workers or "hardening" of the skin of those who were allergic functioned to control the incidence of hypersensitivity reactions.365 His extensive literature review and study of 71 patients did not suggest that any of the late cutaneous sequelae of arsenic ingestion are seen after chronic contact with the material, but no evidence (such as urinary arsenic content) was pre- sented to indicate the extent to which these workers were absorbing arsenic through the skin and mucous membranes into the systemic circulation. Evidence of systemic absorption of arsenic secondary to ex- ternal exposure has been repeatedly recorded, usually in the form of increased urinary arsenic content correlated with the work week.543 633 648 842 Little or no information is available to apply to questions of the quantity of arsenic, its physical and chemical form, and the duration of cutaneous or inhalation exposure required to result in significant systemic effects. It should be noted, however, that evidence of significant systemic concentrations of arsenic has been found in several studies of the incidence of lung cancer in populations exposed to arsenic dusts. The possibility that the effect, if any, of arsenic in this condition operates through a general body mechanism, rather than directly on lung tissue, should not be ignored.

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176 Acute Arsenic Poisoning ARSENIC Exposure to arsenic sufficient to cause severe acute systemic symp- toms requiring prompt medical attention usually occurs through ingestion of contaminated food or drink. The signs and symptoms are somewhat variable in degree and timing and depend on the form and amount of arsenic, the age of the patient, and other unknown factors. 862 The major characteristics of acute arsenic poisoning are profound gastrointestinal damage and cardiac abnormalities. According to Holland,362 tP 408) symptoms may appear within 8 min if the poison is in solution, but may be delayed up to 10 h if it is solid and taken with a meal. The signs, which are variable, range from excruciat- ing abdominal pain and forceful vomiting to cramps in the legs, restlessness, and spasms. "A feeble, frequent, and irregular pulse ushers in the other symptoms of collapse, the livid and anxious face, sunken eyes Edehydration?], cold and clammy skin Eshock?~.... A small proportion of the cases are classed as 'nervous' or 'cerebral' because . . . the . . . conspicuous . . . phenomena are . . . prostra- tion, stupor, convulsions, paralysis, collapse, and death in coma." Only a small fraction of patients will develop any kind of skin reaction secondary to acute arsenic poisoning. Presumably, the arsenic must be absorbed from the damaged gut and find its way to the skin. The usual reaction in these circumstances is an acute exfoliative erythroderma, probably reflecting the fact that arsenic is a capillary and epidermal poison 333,362 Subacute Arsenic Poisoning Systemic exposure to amounts of arsenic sufficient to cause symptoms but inadequate to produce systemic collapse is of particular interest. The patient may go for weeks with gradually increasing or variable signs and symptoms related to several organ systems and giving the appearance of a progressive chronic disease state. If death occurs, it may appear to have been the consequence of the inexorable course of an obscure "natural" disease. This appearance has contributed to the popularity of arsenic as an agent of homicide. Skin manifestations of such victims are particularly important, in that they may offer critical clues in the unraveling of a mystery. The method of arriving at a therapeutic dose of Fowler's solution was based on finding the patient's tolerance to increasing but nontoxic doses. As described by Holland,362 the patient was given 5 drops (about 9 mg of arsenic trioxide, or 6.8 mg of arsenic) "well diluted, after meals

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Biologic Effects of Arsenic on Man 177 fi.e., three times a day], increasing the dose one drop daily until the disease is under control or until the eyelids puff and the bowels move too freely.... The dose is then reduced to a safer quantity, and persisted in until the warning returns, when it is again reduced.... Occasionally persons are encountered fin whom] even the minimum dose will produce unpleasant effects," such as one case of eryth- roderma after 10 mg of arsenic trioxide (7.6 mg of arsenic) taken over a 2-day period. Holland's descriptions of arsenic poisoning were based on personal observation and reports of suicides and criminal cases in which rat or fly poison, as well as Fowler's solution, had been used.362 Occasion- ally, enthusiastic patients would overdo their use of medicinal arsenic, but this was uncommon, because of the associated discomfort. Holland described subacute poisoning as producing loss of appetite, fainting, nausea and some vomiting, dry throat, shooting pains, diarrhea, ner- vous weakness, tingling of the hands and feet, jaundice, and erythema. Longer exposure resulted in dry, falling hair; brittle, loose nails; eczema; darker skin; exfoliation; and a horny condition of the palms and soles. In 1901, Reynolds reported on the clinical findings in over 500 patients that he had personally followed.235 These patients had been drinking for many months 2-16 pints a day of beer contaminated with arsenic. The measured amount of arsenic in the beer was such that "a moderate drinker would only take a tithe of the quantity of arsenic which Ewould be prescribed for] an epileptic." Therefore, the possible additive role of alcohol to the observed symptoms merited considera- tion. Reynolds felt that the clinical manifestations were of four distinct "types" based on whether cardiac, skin, or necrologic symptoms predominated or were equally mixed, and he noted that these features and the sequence of their appearance were in accordance with several previously reported episodes of arsenic poisoning.665 First to appear were digestive symptoms, especially vomiting and diarrhea, to the extent that some patients gave up drinking beer, because it did not ''agree with" them. Most, obviously, did not have so definitive a reason to stop their intake of the poison, and a few were said to have had a stimulation of the appetite. Catarrhal symptons conjunctivitis, rhinitis, laryngitis, and bron- chitis appeared in a few weeks, with various skin eruptions. The generalized mucous-membrane symptoms suggested a selective sen- sitivity of these organs. Hoarseness due to thickening of the vocal cords and hemoptysis were mentioned. Insidious development of necrologic signs and symptoms began

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178 ARSENIC before the appearance of the classical skin lesions, but could be so vague as to go undiagnosed for many weeks. Involvement of the nervous system began with sensory changes, including paresthesias, hyperesthesias, and neuralgias. Marked muscle tenderness was found to be of major diagnostic value. Motor weakness of all degrees, including paralysis with muscle atrophy progressing from distal to proximal groups, was a frequent observation. Mental confusion, espe- cially memory for time and place, was observed; but Reynolds felt that it was less frequent than in straightforward chronic alcoholism and so discounted any effect of arsenic on the cerebral cortex. Left-side heart failure with severe peripheral edema was observed in one-fourth of the patients, and the 13 deaths in this series were all due to congestive heart failure. It is not clear whether this feature and the muscle tenderness described above were direct effects of arsenic on muscle fibers or secondary to its action on blood capillaries and nerve tissue supplying the affected tissue. Skin changes were present to some extent in all the patients, and a facial edema with an associated dusky red color was so typical that it provided a major clue to the diagnosis on first sight of the patient. The most outstanding problem was eryth- romelalgia: the patients complained of pain (possibly related to neuritis) combined with redness and swelling of the extremities, par- ticularly the palms and soles. Excessive perspiration was regularly a feature of the painful, hot, red, swollen feet, and patients would not tolerate bedclothes or walking. Various short-lived generalized ery- thematous eruptions ranging from urticarial to measles-like were fol- lowed by slight thickening and darkening of the skin, especially in the folds. Pigmentation was ''generally not present in light-complexioned pa- tients, or merely amounts to a darkening of pre-existing freckles. In darker people it is practically always present in greater or less degree fend] follows . . . the erythematous blush."665 The distribution of the early stages of the pigmentation was noted to be around scars, the neck, the armpits, the nipples, and, generally more markedly, the trunk; and in some patients, it showed '~well-marked lighter spots like 'rain-drops,'" leading to a punctiform or patchy appearance with the patches tending to run together to form a more or less continuous discoloration. A desquamation similar to that seen in scarlet fever might occur, with some lightening of the dark skin. The familiar arsenical keratoses of the palms and soles were a late manifestation and took several forms: ''it may be in a few isolated scaly masses, either thin or very heaped up in marked prominences, fort the whole palm or sole is thickly covered with large white or dirty grey

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Biologic Effects of Arsenic on Man 179 scales." Reynolds, who watched these processes evolve in his pa- tients, noted that "in cases where there is no pigmentation keratosis may be present and forms a most valuable aid in the diagnosis of a case which might otherwise appear to be merely one of alcoholic paralysis. The process is very slow (many weeks) in its development."665 Reynolds also described the nail changes of subacute arsenic poison- ing, observable some weeks after the intake of the poison was stopped, permitting normal nail to grow out and thus revealing the "transverse white ridge across the nail; proximal to this the nail is normal, but distal to it the nail is whiter, cracked, thin, and towards the tip almost papery and much flattened. In some cases there have been a series of parallel transverse ridges on the nails almost suggesting a series of week-end 'drinking bouts,' ~ ~ 665 This feature of arsenic exposure, commonly given the appellation "Mees lines" on the basis of a 1919 description,537 was also reported by Aldrich, 9 before Mees's report. Viruses were not known in Reynolds's day, and his observation that 21 of his patients had herpes zoster led him to speculate that arsenic might play a role in the etiology of this condition. Modern recognition that herpes zoster is frequently seen in patients with depressed immu- nity suggests that the patients in Reynolds's series had had a suppres- si'on of their immune capacity. It is interesting to note that arsenic was used therapeutically for asthma, psoriasis, and eczema-conditions that also respond to therapy with a modern immunosuppressant, prednisone (see Harter and Novitch335. Since Reynolds's time, reports of subacute arsenic intoxication have tended to confirm his observations, although none has provided such carefully detailed material on so large a group of affected people. Even acknowledging Reynolds's own misgivings about the contribution of alcohol to the necrologic manifestations and allegations that selenium, not arsenic, could have been at fault,268 this article still stands as the definitive medical description of subacute poisoning with ingested arsenic. The likelihood that selenium was also present in variable amounts in the contaminated beer deserves special attention, in view of the many interesting and unresolved questions about relationships between this element and arsenic. Tunnicliffe and Rosenheim8 made the analyses on which they based their conclusion "that selenium compounds have played a definite role in the recent beer-poisoning epidemic." These authors went on to state, however, that this role was "subsidiary to that of arsenic." Willcox863 evaluated the available tests for arsenic and concluded that "the poisoning could not have been due to selenium primarily and arsenic secondarily." Tunnicliffe's testimony before the

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180 ARSENIC Royal Commission on Arsenical Poisoning684 reaffirmed the secondary role of selenium in the epidemic, suggesting that cases of atypical wasting and unusually severe necrologic disease may have resulted from excessive selenium. Certainly, repeated testimony before the Commission by various chemists demonstrated repeatedly the pres- ence of toxic amounts of arsenic in beer from several parts of the country 319609428,477,631,683,685,686 Mizuta et al. reported on 220 patients of all ages who had been poisoned by contaminated soy sauce, with an average estimated inges- tion of roughly 3 mg of arsenic (probably as calcium arsenate) daily for 2-3 weeks. In this group, 85% had facial edema and anorexia; fewer than logo were said to have exanthemata, desquamation, and pigmen- tation; and about 20% had peripheral neuropathy.550 Except for headaches and fevers, the findings in these patients appear to be very similar to those reported by Reynolds, allowing for the more acute nature of the episode and the natural differences in emphasis between physicians separated by two generations and half the world. The Japanese report offered additional information based on the availability of modern diagnostic techniques. Thus, although most patients' livers were enlarged, relatively few abnormalities were found in liver function tests; and the description of five liver biopsies was not particularly impressive. (Zachariae et al. found no differences between liver biopsies of 44 psoriatic patients with a history of arsenic therapy and 37 similar patients without such history.888) Conversely, there were no findings on clinical evaluation of the heart and no evidence of the congestive failure seen in Reynolds's somewhat more chronic patients; but electrocardiograms were abnormal in 16 of 20 patients, confirming the reports of Josephson et al.403 and Nagai et al.574 It is of interest that the Japanese patients' symptoms tended to diminish after 5 or 6 days, despite continued intake of arsenic, and that necrologic symptoms became prominent as much as 2 weeks after arsenic ingestion was discontinued, at which time urinary arsenic content remained high. Hair was found to contain arsenic at 3.8-13.0 ,ug/g (ppm) near the root, compared with 0-1.5 ,uglg near the end and 0.4-2.8 ,uglg in control hair samples. In the early 1960's, physicians in Antofagasta, Chile, noted der- matologic manifestations and some deaths, particularly among chil- dren, that were traced to a water supply containing arsenic at 0.8 ppm. This water supply had been in operation only since 1958. In 1971, Borgono and Greiber reported on a series of studies of the inhabitants of this city.86 Of 21 children referred to Santiago for evaluation and treatment after 1962, 16 had recurrent bronchopneumonia during the

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Biologic Effects of Arsenic on Man 181 first years of life, and all had bronchiectasis. All 21 had been referred because of abnormal skin color and hyperkeratosis. Peripheral vascu- lar manifestations in these children included Raynaud's syndrome, ischemia of the tongue, hemiplegia with partial occlusion of the carotid artery, mesenteric arterial thrombosis, and myocardial ischemia. One autopsy showed hyperplasia of the arterial media. In a survey of 27,088 schoolchildren, 12~o were found to have the cutaneous changes of arsenism; one-fourth to one-third of these had suggestive systemic symptoms. Eleven percent had acrocyanosis. One hundred eighty inhabitants of Antofagasta were compared with 98 people who resided in a city (Iquique) having a normal water supply. Most of the people studied were less than 20 years old. Of the Antofagasta residents, 144 had abnormal skin pigmentation, compared with none in the 98 control subjects. In the 18O, 30~o and 22% had Raynaud's syndrome and acrocyanosis, respectively. Other findings are shown in Tables 6-1 and 6-2. The vascular diseases and the repeated episodes of pneumonia with bronchiectasis observed in the children of this population are dramatic and deserve special attention. Clearly, exposure to significant amounts of arsenic from an earlier age may result in a clinical picture in growing children different from that seen in adults. TABLE 6-1 Clinical Manifestations among 180 Antofagasta and 98 Iquique Inhabitants a Manifestation Incidence in Antofagasta, Incidence in Iquique, Bronchopulmonary disease history 14.9 5.3 Abnormal skin pigmentation 80.0 0.0 Hyperkeratosis 36.1 0.0 Chronic coryza 59.7 1.0 Lip herpes 12.7 0.0 Chronic cough 28.3 4.0 Cardiovascular manifestations: Raynaud~s syndrome 30.0 0.0 Acrocyanosis 22.0 0.0 Angina pectoris 0.0 0.0 Hypertension 5.0 10.0 Chronic diarrhea 7.2 0.0 Abdominal pain 39.1 2.0 aDerived from Borgono and Greiber.86

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182 ARSENIC TABLE 6-2 Clinical Manifestations among 180 Antofagasta Inhabitants according to Skin Pigmentation, 1969a Manifestation Incidence in Persons with Incidence in Abnormal Skin Persons with Pigmentation Normal Skin (N = 144), 56 (N = 36), pro Bronchopulmonary disease history Hyperkeratosis Chronic cough Lip herpes Cardiovascular manifestations: Raynaud's syndrome Acrocyanosis Angina pectorals Hypertension Chronic diarrhea Abdominal pain 38.8 24.3 4.1 6.2 40.9 39.1 15.9 6.2 43.7 38.8 14.5 3.1 3.1 3.1 9.3 12.5 0.0 0.0 0.0 28.1 Derived from Borgono and Greiber.86 The Raynaud's phenomenon and acrocyanosis in this population are reminiscent of the report from Taiwan by Tseng et al. and suggest that chronic arsenism has effects on the vasculature (possibly the neural control of arteries) that are correlated with the more acute phe- nomena described by Reynolds and others as erythromelalgia and acrocyanosis. 798 Tseng et al. surveyed a group of 40,421 (from a population ''at risk" of 103,154) and found hyperpigmentation in 18.4%, keratotic lesions in 7.1%, and blackfoot disease apparently secondary to arterial spasm in the legs in 0.9%.798 They also found an apparent tenfold increase in the incidence of skin cancer in patients over 59 years old. The latter figure is difficult to evaluate, because the usual incidence of these cancers in Taiwan was not given. All these phenomena were shown to increase with increasing arsenic concentration in the well water of the 37 villages studied. They also increased with age, but the earliest ages noted for specific findings were 3 years for the characteristic hyper- pigmentation, 4 years for keratoses, and 24 years for skin cancer. The concentration of arsenic in the wells ranged from 0.017 to 1.097 ppm. No cases of melanosis, keratosis, or skin cancer were found in a group of 2,552 people living in an area where the wells contained almost no arsenic.

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Biologic Effects of Arsenic on Man 183 Feinglass reported on 13 persons exposed for 2.5 months to well water contaminated with buried insecticide.244 Most patients were seen only once, and the most prominent feature was intermittent gastroin- testinal symptoms related to water ingestion. Two of the 13 had nail changes, and five (of eight in whom it was measured) had increased arsenic content of the scalp hair. The author did not mention edema, exanthema, hyperpigmentation, or hyperkeratosis. Heyman et al. studied 41 patients retrospectively in an effort to evaluate the response of arsenical neuropathy to sA~.35i In the 21 patients for whom a history of skin lesions was mentioned, there was a prominence of branny desquamation 1-3 weeks after the exposure and a notable incidence of ''herpetic lesions of the mouth." There are many scattered case reports of subacute to chronic arsenic poisoning. Silver and Wainman provided a meticulous description of a patient who ingested approximately 8.8 mg of arsenic trioxide as Fowler's solution daily for a total period of 28 months, as a remedy for asthma.733 Signs of arsenic poisoning, manifest as increased freckling and as darkening of the nipples, first appeared in association with gastrointestinal symptoms after 13 months; redness and puffiness about the eyes and hyperkeratoses developed at approximately 1.5 years. Neurologic symptoms in the form of paresthesias and weakness were the last to be noted, occurring after 2 years. When the arsenic intake was stopped, the pigmentation lightened, the hyperkeratoses remained, and the asthma became more difficult to control. This report is instructive, because the nature of episodes of accidental arsenic poisoning does not usually permit definitive analysis of the amount or duration of exposure necessary to produce reactions. However, many authors have suggested that there is substantial variation in individual susceptibility to any given symptom or sign. The increased likelihood that hyperpigmentation will occur in people whose skin is naturally darker supports this concept, as does the fact that relatively small fractions of the exposed population have any given feature. Perry et al.633 noted, however, that all of a group of chemical workers handling inorganic arsenic compounds had pigmentary changes and that one-third of them had ''warts," although these were not well described. They reported that the cutaneous ''changes were so evident that Ethe examiner] could readily tell whether the man . . . was a chemical worker."633 All these handlers had increased urinary arse- nic compatible in degree with the extent of exposure; this indicates systemic absorption of the arsenic from dust, probably through the lungs and skin. Pinto and McGill studied urinary arsenic content in workers exposed

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Biologic Effects of Arsenic on Man 205 skin carcinogenesis in these experiments. Many tumors developed in the positive control mice, beginning as early as 6 weeks after treatment began. Baroni, van Esch, and Saffiotti52 carried out a similar study with male and female Swiss mice, testing the oral effects of potassium arsenite (100 ppm in drinking water) as an initiator with croton oil promotion and as a promoter with DMBA and urethane initiation. Local skin applications of sodium arsenate were tested as a promoter after initiation with DMBA or urethane. The arsenicals had no effect on tumorigenesis; and only a very slight degree of keratosis was observed. Milner546 used three strains of mice that differed in susceptibility to the induction of skin tumors by the application to the skin of methylcholanthrene-impregnated paraffin disks for 2-3 weeks. The treated site was transplanted syngeneically and observed for 8 weeks for tumor formation. Arsenic trioxide (100 ppm in drinking water) was administered either during methylcholanthrene exposure, to animals with transplanted skin, or both. Arsenic exposure produced a small increase in the yield of papillomas in the low-susceptibility strain, a small decrease in the high-susceptibility strain, and no effect in the intermediate-susceptibility strain. Byron et al.~23 fed either sodium arsenite or sodium arsenate to Osborne-Mendel rats in a 2-year study at dietary concentrations of 15-250 ppm for arsenite and 30~00 ppm for arsenate. No carcinogenic activity of either material was found. These investigators also did a 2-year arsenic feeding experiment on dogs, with negative results; however, this was an inadequate observation period for studying carcinogenic responses in dogs. Hueper and Payne373 incorporated arsenic trioxide in the drinking water (either plain or with 12~o ethanol) of groups of rats and mice. The initial concentration of 4 mg/liter was increased by 2 mg/liter each month to a maximum of 34 mg/liter at 15 months. Thus, the daily intake of arsenic trioxide ranged from 0.1 to 0.8 mg/rat. The administration of arsenic trioxide was continued until 24 months. Neither the rats nor the mice developed any cancers in suspected target organs skin, lung, and liver. Kanisawa and Schroeder406 and Schroeder et al.7~i found no car- cinogenic effects on mice exposed from weaning to senescence to potassium arsenite at 5 ppm in drinking water406 or on rats on the same regimen.7~i Kroes et al.440 studied the carcinogenicity of lead arsenate and sodium arsenate with sPF-Wistar-derived male and female rats. In addition, some groups were intubated with a subcarcinogenic dose of

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206 ARSENIC diethylnitrosamine to investigate a possible synergistic action leading to lung tumors. Food intake and body weights were recorded, and complete gross and microscopic examinations were made on all ani- mals. Lead arsenate that was incorporated in the diet at 1,850 ppm was toxic and caused increased mortality; an adenoma of the renal cortex and a bile duct carcinoma were found in this group, but no significance can be attached to one or two tumors in any group. No cancer was associated with the feeding of lead arsenate at 463 ppm or sodium Arsenate at 416 ppm. No synergism with the nitrosamines was ob- served. There was a high spontaneous-tumor incidence in this experi- ment. The test diets were fed to female rats from the time of parturition until the young were weaned, and these young were the test animals. Surviving rats were killed after 29 months of feeding. As Fraumeni has pointed out, it is largely because laboratory studies have not succeeded in producing tumors in animals that arsenic has not been accepted universally as a carcinogen.267 Evaluation Skin Cancer There is evidence from clinical observations and occupational and population studies that inorganic arsenic is a skin carcinogen in man. There is a characteristic sequence of skin effects of chronic exposure to arsenic that involves hyperpigmentation initially, then hyperkeratosis (keratosis), and finally skin cancer.~87 This sequence has been ob- served under a variety of circumstances involving chronic exposure: potassium arsenite (Fowler~s solution) was used medicinally,585 vine- yard workers used sprays and/or dusting powders containing arsenic compounds and drank arsenic-contaminated wine,~0i 679 chemical workers manufactured sodium arsenite for use as a sheep dip, 633 and residents of a southwest area of Taiwan had as their only source of drinking water for over 45 years artesian wells contaminated by arsenic from geologic deposits.798 The similarity of responses under these diverse circumstances is important, because studies in human popula- tions always involve variables that cannot be controlled as in labora- tory experiments; hence, the credibility of information derived from human studies depends on the demonstration of comparable effects under different conditions. This requirement has been amply met with arsenic as a cause of skin cancer. The earliest skin effect of chronic arsenic exposure, hyperpigmenta- tion (melanosis), occurs in a dappled pattern predominantly in unex

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Biologic Effects of Arsenic on Man 207 posed areas. After the onset of melanosis, the skin begins to atrophy in a patchy way in hyperpigmented areas, with the formation of keratoses that are the pathognomonic lesions of chronic arsenic exposure.~87 Only a small proportion of the keratoses evolve into skin cancer, and this takes place only after very many years. The sequence is illustrated by the Taiwan data the prevalence of melanosis, keratosis, and skin cancer reached logo in the male population roughly at ages of 18, 30, and 60 years, respectively.798 Chronic exposure to inorganic arsenic thus causes a slowly progressive form of patchy skin damage involving the epidermis and adnexal structures, as well as the underlying dermis, with the precancerous keratoses and cancers forming in the areas of chronic atrophy. The chronic damage and tumorigenesis resulting from arsenic are similar to the effects of ionizing and ultraviolet radiation on the skin. Arsenical skin cancer is readily distinguished from skin cancer induced by sunlight, in that it occurs predominantly on surfaces that are shielded from sunlight and multiple lesions are much more com- mon; for example, in 428 of the 429 cases of skin cancer studied in Taiwan, there was more than one cancer.~87 Substantial doses of inorganic arsenic are required to produce an appreciable incidence of skin cancer. The average intake of persons treated with Fowler's solution who developed skin cancer was around 20-30 g. The prevalence of skin cancer in Taiwanese men exposed to drinking water containing arsenic at 0.3-0.6 ppm was about 15% at age 60 and over. The normal incidence is 2-3%. On the basis of a 2-liter/day water intake for the period over which the artesian wells were used (45 years), the total arsenic intake must have been about 15 g, which is roughly in the same domain as that in clinical cases of the use of Fowler's solution. Thus, the Taiwanese data that demonstrated the requirement for large doses of arsenic to obtain even a modest yield of skin cancer are consistent with the relatively low frequency of skin cancer in patients treated with Fowler's solution. The low potency of inorganic arsenic may explain why no skin effects have been reported in people treated for syphilis with organic arsenicals, inasmuch as the total doses amounted to only a few grams. However, it is also possible that the metabolism of the organic arsenicals is sufficiently different to preclude the occurrence of skin cancer and other forms of arsenical damage even at higher doses. The relative frequency of melanosis, keratosis, and skin cancer was roughly similar in the Taiwanese population and the chemical workers who manufactured sheep dip. On direct examination, the latter showed a 90%0 prevalence of melanosis and a 30~o prevalence of keratosis, for a

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208 ARSENIC ratio of melanosis to keratosis of 3: 1. At comparable ages, the Taiwanese showed a ratio of about 4: 1. Two of the nine keratosis patients in the sheep-dip factory had already been treated for skin cancer, and the proportionality between keratosis and skin cancer was about the same in Taiwan. As in the Taiwan experience, the sheep-dip chemical workers had been exposed to large doses of inorganic arsenic (up to I g/year), but much of this was by inhalation. It is possible that the trivalent and pentavalent forms of inorganic arsenic produce the same effects on skin. This is of interest, particu- larly in view of the different metabolic patterns of trivalent and penta- valent inorganic arsenic the former by interaction with sulfhydryl groups and the latter by substituting for phosphate. The clinical use of Fowler's solution and the manufacture of sodium arsenite as a sheep dip both involved exposure to trivalent inorganic arsenic. The two categories of people developed similar skin responses. The Rhodesian gold miners, in whom the incidence of typical arsenical keratoses was very high, were exposed to arsenopyrite, in which the arsenic becomes trivalent on weathering; the reactions of arsenopyrite in the body are unknown (K. J. Irgolic, personal communication). The chemical form of arsenic in the Taiwanese artesian-well water is also unknown; however, the reported occurrence of methane gas in the water could preclude the existence of arsenic in the pentavalent form (K. J. Irgolic, personal communication). Lung Cancer Of the published reports on mortality from respiratory cancer in copper smelters, the most impressive is that of Lee and Fraumeni.4~2 The study involved a population of 8,047 white male smelter workers who were followed for 26 years; for each employee, information was available on time, place, and duration of employment, maximal arsenic and sulfur dioxide exposures (descriptive, rather than numerical), and cause of death. The life-table method was used to evaluate age-specif~c mortality rates for the various causes of death, and the rates were compared with those of the states in which the smelters were. The number of deaths available for analysis was very substantial 1,877. The study demonstrated a systematic gradient for respiratory cancer according to the magnitude and duration of exposure to both arsenic and sulfur dioxide. These agents, however, were inseparably linked, because of the nature of the smelter operations. The amount of excess cancer was impressive, with an eightfold increase in the workers who had the heaviest arsenic exposure for the longest duration, i.e., more

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Biologic Effects of Arsenic on Man 209 than 15 years. The latent period the interval between first employ- ment and death from respiratory cancer was extraordinarily long and was inversely related to the magnitude of exposure: 34, 39, and 41 years for the categories of heavy, medium, and light arsenic exposure. There were deficiencies in the study, some of which were unavoidable. For example, no indication was given of whether the study population was representative of the total worker population; the exposure rank- ings were based on the maximal arsenic concentrations, rather than weighted averages derived from work histories. No quantitative data were available on exposure. No attempt was made to validate the stated causes of death. No smoking histories were obtained. However, none of these deficiencies could be seriously regarded as invalidating the conclusions of the study. The Kuratsune report dealt with a smaller study that compared lung-cancer mortality rates calculated from the 22 deaths that occurred in a 30-year period in a smelter town with the lung-cancer experience in the same period in a neighboring city and in Japan as a whole.443 The standardized mortality rate for males in the smelter towns was 4 times higher than that for the rest of the country, but equal to that for women. This fourfold excess is comparable with the 3.3-fold excess observed in the Lee-Fraumeni study. Although many of the men in the town worked in the refinery, a much higher proportion of the lung-cancer cases, compared with controls, occurred in men who were heavily exposed to arsenic as smelter operators. As in the case of the Lee- Fraumeni study, the latent period from first exposure to the diagnosis of lung cancer was very long, ranging from 26 to 48 years. The duration of employment was also very long, with a median of about 30 years, although two cases occurred in people who worked for only 2-3 years. Two lung-cancer studies of the American Smelting and Refining Company smelter have produced conflicting results. The 1963 Pinto and Bennett report examined the proportional mortality from lung cancer in a total of 229 deaths in the period 1946-1960.647 This study dealt only with pensioners and workers who died during their employ- ment and did not include people who had left the plant. The reported data showed that the 18 lung-cancer deaths in the plant population as a whole indicated a rate that was higher than the rate in the state of Washington. However, the excess lung cancer for the plant as a whole was due to the high occurrence in controls, i.e., in workers who were considered not to have arsenic exposure. Milham and Strong, by contrast, found, in the years 1950-1971, that there were records of 39 deaths due to respiratory cancer in Pierce County (the smelter locale) in people who were stated to have worked at the smelter.543 Applica

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Biologic Effects of Arsenic on Man 211 tion of U.S. mortality rates to the published figures for the smelter population at risk yielded an expected number of 18 respiratory-cancer deaths, compared with the 39 deaths observed. Pinto et al. (S. S. Pinto, V. Henderson, and P. Enterline, "Mortality experience of arsenic exposed workers," unpublished data) recently resolved the discrepancy between the Pinto and Bennett647 and Milham and Strong543 papers in a study of the same smelter that reevaluated the exposure categories used in the Pinto and Bennett paper647 (which were apparently in error) and also included a longer observation period and therefore more deaths. The data, in Table 6-5, include a total of 32 respiratory-cancer cases and show a progressive increase in stan- dardized mortality ratio with increasing arsenic exposure. The arsenic-exposure index was calculated as a weighted average based on urinary arsenic concentration and duration of employment. It is of interest that the eightfold excess in respiratory cancer for workers with the highest exposures and the threefold excess for all the smelter workers reported by Pinto et al. (see Table 6-5) were very close to the figures reported by Lee and Fraumeni460 and Kuratsune.443 The studies described here indicated that excess respiratory cancer occurs in copper-smelter workers as a function of the magnitude and duration of exposure to arsenic, with latent periods of three to four decades from the time of initial exposure. However, the studies do not permit a resolution of the issue of whether concomitant exposure to sulfur dioxide and other smelter dusts is necessary for the carcinogenic response. Evidence from studies involving entirely different circum- stances of exposure including workers in three pesticide manufactur- ing plants,352 609* vintners who applied pesticides,~0~ 679 and Rhodesian gold miners606-suggests that sulfur dioxide and other unspecified smelter dusts are not essential cofactors for the respiratory car- cinogenicity of arsenic. All the nonsmelter studies had obvious limita- tions, but the lung-cancer excess in each study was relatively large and, taken as a group, they provide significant evidence that arsenic is a lung carcinogen. The Hill-Faning study of 75 deaths in a sheep-dip factory used the indirect method of proportional mortality to evaluate the small group of 22 deaths from cancer; seven of them were cancers of the respiratory tract, compared with an expected 2.4 deaths.352 The Dow arsenic workers609 were evaluated in two ways: by an analysis of death records of those who died from lung cancer (28, or 16.2%, of 173 chemical *Also, A. Baetjer, M. Levin, and A. Lilienfeld, "Analysis of mortality experience of Allied Chemical plant," unpublished data.

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212 ARSENIC worker deaths, compared with 104, or 5.7%, of 1,809 control-case deaths), and then, as a retrospective cohort study, a comparison of the mortality from respiratory cancer (obtained from the records used in the first approach) among 603 persons identified as having worked in the arsenic plant from 1940 to 1973 with the mortality among the corresponding U.S. white male population. The two approaches gave essentially the same results a threefold to fourfold excess. However, the puzzling aspect of the data is that almost 60~o of the respiratory- cancer deaths were in people who had worked with arsenic for less than a year, three decades earlier. Most of the arsenic workers were unskilled short-term employees, of whom a large proportion left the company after a brief period of employment. The followup study, however, dealt only with the people who remained in the company. A confirmation of the excess lung cancer in a followup of short-term arsenic workers who left the company would be very useful. Neverthe- less, there were about a dozen cases in people who worked longer than a year and who were in the highest dose categories, where the excess risk was maximal- fourfold to sixfold. It is possible that the apparent twofold excess in lung cancer in the lower exposure categories, includ- ing those who worked with arsenic for less than a year, would not be ascribable to arsenic, because there was no change in cancer risk over a very wide range of total doses (0.04-1.56 g). Furthermore, these low dose categories consisted predominantly of short-term unskilled work- ers who as a group might have had higher exposures to other hazardous chemicals than the controls. The Allied Chemical Company pesticide manufacturing operations produced a range of products, including some arsenical compounds. A preliminary study of the proportional mortality among retired em- ployees showed a sevenfold excess of lung cancer that accounted for about 40~o of all deaths (A. M. Baetjer, personal communication). Both the Dow and Allied studies also showed a few excess deaths from lymphoma and Hodgkin's disease. The results of a more detailed study of the Allied Chemical Company that is now in progress will be very useful. Arsenic sprays and dusts were widely used in Germany between 1925 and 1942, at which time they were banned. ]0~9679 Vineyard workers also drank wine containing arsenic. Hundreds of workers developed acute and chronic arsenic poisoning. In the 1950's, vineyard workers with lung cancer began to appear in hospitals serving the vineyard regions. An association between arsenic and lung cancer is further suggested by the high proportion of vineyard workers with lung cancer

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Biologic Effects of Arsenic on Man 213 who had the characteristic hyperpigmentation and keratoses associated with chronic arsenic exposure. The same high degree of association of skin arsenism and lung cancer occurred in Rhodesian gold miners who were heavily exposed to arsenopyr~te dust.606 In the period 1957-1963, the occurrence of 37 cases of lung cancer in gold miners represented an incidence of 206/100,000, compared with 34/100,000 for adult males in the Gwanda region of Rhodesia. This represents a sixfold difference in lung cancer . . In miners. The probability of death from lung cancer in persons with keratosis shown in Table 6-6 ranges from 32 to 56%, which is roughly 5-10 times higher than might be expected. The data suggest that there is a very high risk of lung cancer when the exposure to inorganic arsenic dust is high enough to cause keratoses. Liver Cancer The only evidence that arsenic is a liver carcinogen comes from German vintners. Thirteen of the 27 persons whose autopsies were reported by Roth679 had cirrhosis, and three had angiosarcoma, a rare form of liver cancer associated with exposure to a vinyl chemical and Thorotrast. Only two cases of angiosarcoma have been reported in people treated with Fowler's solution.663 There is no evidence of either cirrhosis or liver damage in any of the other studies on arsenic. It is possible that the combined effect of a high alcohol intake and arsenic is TABLE 6-6 Frequency of Lung Cancer in Persons with Keratoses Who Had Heavy Exposure to Arsenical Dusts (a) (b) No. Cases of No. Cases of b/a, Subjects Keratosis Lung Cancer ~Reference Rhodesian gold miners 40 13 32 606 Vintners (Braun) 16 9 56 101 Vintners (Roth) 30 10 33 679 Sheep-dip workersa 12 5 42 633 Total 98 37 38 aAssumes that 41 chemical workers who died in 1910-1943 had the same skin changes as chemical workers examined in 1946.

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214 ARSENIC responsible for the unusual forms of cirrhosis and liver cancer ob- served in vintners. It should also be pointed out that the chemical form . . . Of arsenic In wine Is unknown. Experimentally Induc ed Cant er The fact that there is no established method for producing cancer by treatment with any form of arsenic in an animal model system is an enigma. One must conclude either that arsenic is not a carcinogen or that particular circumstances not yet achieved are essential to demon- strate a role for arsenic in experimental carcinogenesis. A conclusion that carcinogenesis by arsenic is restricted to humans (or cows, horses, and deer425 is highly suspect. Therefore, much effort should be spent in attempting to find conditions in which the presence or absence of arsenic determines the appearance or nonappearance of cancer in an animal model. Some questions need to be explored (their answers may account for the variable incidence of human cancer associated with arsenic exposure): Potassium arsenite, arsenic trioxide, and possibly other com- pounds of arsenic appear to have an unusual propensity to alter epithelial morphology (at least in humans), often acting as irritants and causing hyperplasia, as well as hyperkeratosis. Thus, appropriate forms of arsenic should be tested with known lung carcinogens for synergistic action. Possibilities include the ferric oxide-benzopyrene model in the hamster developed by Saffiotti et al.699 and the sulfur dioxide-benzopyrene inhalation model of Kuschner and Laskin.444 Controls designed to test exposure to arsenicals alone should be included; properly controlled long-term inhalation studies have not been done. Although both Barone et al.52 and Boutwell9~ based their tests in mouse skin on a possible cocarcinogenic role for arsenic and found none, additional experiments of this nature are reasonable. Moreover, because morphologic changes in epithelial tissue are ascribed to arsenic, and because vitamin A and some retinoids control normal epithelial morphology,754 it is appropriate to design experiments in which vitamin A deficiency is induced in animals as a test system for arsenical carcinogenicity (and cocarcinogenicity). In experimental animals, vitamin A deficiency increases susceptibility to chemical carcinogenesis, and high dietary concentrations of retinoids have re- markable ability to prevent chemical carcinogenesis in epithelial tis- sues,754 including skin, breast, and lung.

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Biologic Effects of Arsenic on Man 215 Again, because arsenicals alter epithelial morphology, the possibility that the function of mucus-secreting cells or of the ciliated cells of the lung is interfered with by respirable particles bearing arsenic580 should be investigated. Interference with mucus secretion or ciliary action would facilitate the action of a carcinogen, such as tobacco smoke, entering the lungs. Because compounds of arsenic and the heavy metals that may be associated with them are enzyme poisons, it is possible that chronic exposure to abnormal amounts of these substances partially poisons enzymes that inactivate carcinogens. Model systems might be devised to test this possibility. The interaction of arsenic with some essential nutrients, such as sodium selenite and potassium iodide, is known. This should be considered in designing animal models. Peoples626 has shown that potassium arsenite and sodium arsenate are detoxified via methylation pathways. Biologic changes attributable to arsenic might be accentuated in animals fed diets that are low in labile methyl groups. The administration of some carcinogens to pregnant females may result in an unusually high incidence or early development of cancer in the offspring. Because one such test, by Osswald and Goerttler,607 resulted in an unusual incidence of leukemia in mice, it is especially urgent to design appropriate transplacental tests. Repetition of such a test is essential. The credibility of the Osswald and Goerttler study is limited by their failure to give the vehicle solution to the controls. Because of the failure of repeated tests in lower animals to show carcinogenicity due to arsenicals, consideration should be given to the use of nonhuman primates as test animals. These are only a few examples of approaches to the problem of ascertaining whether an animal model may be devised to account for the association of human cancer with exposure to arsenic.