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Arsenic: Medical and Biological Effects of Environmental Pollutants (1977)

Chapter: 6 Biological Effects of Arsenic on Man

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Suggested Citation:"6 Biological Effects of Arsenic on Man." National Research Council. 1977. Arsenic: Medical and Biological Effects of Environmental Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/9003.
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Suggested Citation:"6 Biological Effects of Arsenic on Man." National Research Council. 1977. Arsenic: Medical and Biological Effects of Environmental Pollutants. Washington, DC: The National Academies Press. doi: 10.17226/9003.
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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

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,

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.

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

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

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

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

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

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

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.

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

184 ARSENIC to arsenic trioxide dust and related compounds.648 The urinary arsenic in this group was about 8 times the normal value, but they were said not to have the pigmentary and keratotic changes seen in the group of Perry et al. 633 Neither paper described the average length of employ- ment or the ethnic backgrounds of the workers, which might help to explain this discrepancy. Chronic Arsenic Exposure Neubauer has provided an exhaustive review of the literature up to 1947, covering all forms of arsenic exposure with analysis for many factors.585 Fierz actually examined 262 patients who had received long courses of medicinal arsenic 6-26 years previously and found keratoses in 40~o and typical skin cancer in 8%.253 There was evidence of a dose relationship for both keratoses and skin cancer. Patients who had received more than 400 ml of Fowler's solution (4 g of arsenic trioxide) had an incidence of hyperkeratoses of greater than So-so, but as little as 60 rnl (600 mg of arsenic trioxide) had resulted in keratotic changes in one patient. As little as 75 ml (750 mg of arsenic trioxide) had been consumed by one patient with skin cancer. The shortest time to cancerous change was 6 years, with an average of 14 years, compared with Neubauer's estimate of 18 years from review of the literature.585 Fierz noted that 1,450 invitations for a free examination had been sent to patients who had been given the therapeutic arsenic.253 Besides the 262 who came for examination, 100 patients provided written reports, and information was obtained about the deaths of 11. Five of the 11 deaths were due to systemic cancer, and three to lung cancer. Sixteen of Fierz's 21 patients with cancer had typical keratoses,253 and Arguello et al.24 reported on a large group of patients seen for arsenical skin cancers in the Cordoba region in Argentina, which had a high arsenic content in the drinking watery and found keratoderma in Blood of our patients." Most patients also had associated hyperhi- drosis and abnormalities of pigmentation, whereas those reported by Fierz did not.253 Arguello et al. noted that the pigmentation appeared early and was variable among the patients.24 It was described as small dark spots 1-10 mm in diameter, with a tendency to coalesce, and appearing predominantly on the trunk, that is, in the areas not exposed to the sun; These and other authors have noted that atrophy may be associated with telangiectasia and loss of color, or leukoderma, be- tween the hyperpigmented areas (the ''raindrop" appearance cited by Reynolds665~.

Biologic Effects of Arsenic on Man 185 The characteristics of the skin malignancies found in chronic arsen- ism have been reviewed by Yeh and Yeh et al. in their reports on the Taiwan cases.~86887 A prominent, even necessary, clinical feature of arsenical skin cancer is its association with the characteristic keratoses or pigment irregularities on the trunk. Several authors have cited a similar association in exposed workers as evidence that arsenic may cause internal cancers, especially of the lung.~0~9~372 605 67~677 679 In addition, the skin lesions are characteristically multiple and predomi- nantly on the areas of the body that are protected by clothing. Both these features are notable, inasmuch as "ordinary" skin cancers tend to be single and have been shown to have a body distribution directly correlated with the amount of sun exposure.78542 Arsenical lesions (both keratoses and cancers) also appear at an earlier average age than do solar (senile) keratoses and related carcinomas. The histopathology of the multiple and varied lesions seen in arsen- ism has been the subject of considerable interest among der- matOpathOlOgists ~6 40 542 554 646 ss6 ss7 Lesions that clinically are kera toses may show proliferation of keratin of a verrucous nature, may exhibit precancerous derangement of the squamous portions of the epithelium equivalent to those seen in Bowen's disease and solar keratosis, or may even be frank squamous cell carcinomas. Lesions that are less keratotic and more erythematous may contain either squamous cell or basal cell carcinoma or a mixture of cell types. Most authors seem to agree that keratotic lesions appear to be able to progress to frank carcinoma, but observation of such an event is rare, and most cancers appear to arise independently of the keratoses. The question of the association of Bowen's disease with arsenism has stimulated considerable controversy. Graham and Helwig analyzed 36 autopsies of patients with Bowen's disease in whom arsenic intake had been ruled out as much as possible.303 It is striking that this group of patients differed from patients with arsenism in several respects: They lacked the typical keratoses and pigmentation; they had a ten- dency for the "typical Bowenoid" squamous cell carcinoma in situ to precede the other cutaneous malignancies by an average of 6 years; there was an incidence of approximately 80~o of associated internal malignancies (some diagnosed only at autopsy); and they had sugges- tive evidence of a familial predisposition to the condition. Of more than 100 living patients with the diagnosis of Bowen's disease surveyed by the same authors, internal malignancy had been diagnosed in 23. These features seem sufficient to distinguish Bowen's disease from chronic arsenism, despite the confusion later introduced by Graham et al. 304 If

186 ARSENIC Graham and Helwig's cases are representative, the association of systemic cancers is much higher in Bowen's disease than has ever been suggested for chronic arsenism. Late Effects of Exposure to Arsenic One of the many unexplained puzzles about arsenic is that the charac- teristic skin cancers may appear years after exposure to the agent has ceased. Despite claims that arsenic could be demonstrated in the lesions,304 there is a possibility that these findings are a result of artifacts,209 and alternative explanations should be sought, especially because it is now known that the half-life of an epidermal cell is only a few weeks and any incorporated material can be presumed to be diluted in new cell generations. Interestingly, arsenic-induced pigment changes-which are irregular and associated with intermingled areas of atrophy, depigmentation, and telangiectasia are reminiscent of those seen after chronic exposure to two well-known carcinogens: ultraviolet radiation and X rays. Cancers that are secondary to these agents also appear long after the relevant exposure. Conceivably, arsenic acts analogously in susceptible people, although it is clear that the car- cinogenic ''efficiency" of arsenic is far lower than that of X irradiation . . . . . in causing skin cancers. Braun reported on 16 patients who had been exposed to arsenic in their occupation as vintners many years before. A No known exposure to arsenic had occurred since. All had keratoses, nine had leukomelanoderma of the trunk, and seven had skin cancer or in- traepidermal carcinoma in situ. Eight had lung cancer. Roth also studied 27 vintners whose arsenic exposure had occurred 10-14 years earlier.679 His population was selected by having come to autopsy. He found that 16 of the 27 had a total of 28 cancers, including five with skin cancer. There was hyperkeratosis of the palms and soles, "particularly in the patients with tumors." Melanosis was also present, but hard to evaluate in the postmortem state. For a few months in 1955, a large number of babies in Japan received a formula made from powdered milk contaminated with arse- nic.525 596 597 702 The report by Hamimoto provides a fascinating view into the medical puzzle that the initial patients presented to their pediatricians.325 The conscientious attention to both the solution of the mystery and the care of the patients is impressive. In the (translated) words of Hamimoto, the episode deserved "the reflection of all those concerned. This is necessary for the sake of the 62 young lives who disappeared."325 The subacute symptoms of poisoning in these infants

Biologic Effects of Arsenic on Man 187 included the usual coughing, rhinorrhea, conjunctivitis, vomiting, diarrhea, and melanosis, but the striking presenting features were fever and abdominal swelling secondary to hepatomegaly. Abnormal labora- tory findings included anemia, granulocytopenia, abnormal electrocar- diograms, and increased density at epiphyseal ends of long bones similar to the familiar "lead line." Nagai et al. reported on a group of these children who were followed for more than 6 months.574 Except for a measurable retardation in ulnar growth, they found that all other features of the syndrome had disappeared, including melanosis. Fol- lowup is continuing, and a report by the Japanese Pediatric Society in 197339~ indicated that growth was still reduced and that there was a probable incidence of leukomelanoderma in the children (aged 17-20 at the time) of 15-30~o. The children had a 15% incidence of keratosis.~85 Of greater concern, however, was the observation of increased inci- dences of mental retardation, epilepsy, and other findings that suggested brain damage in the arsenic-exposed children. Presumably, future studies in this population (more than 10,000 exposed infants) will help to resolve some of the standing questions regarding the latent effects of arsenic exposure. Occupational Episodes of Toxicity Sheep-Dip Factory Workers The cancer experience between 1910 and 1943 in an English factory that manufactured a sodium arsenite sheep dip is described in the section on carcinogenesis. Clinical and environmental studies were done in 1945 and 1946,633 including general air measurements, analysis of urine and hair for arsenic, and clinical examinations. High-exposure areas of the plant had arsenic concentrations ranging from about 250 to 700 ,ug/m3. The relationship of urine and hair arsenic to the prevalence of pigmentation and warts is shown in Table 6-3. Smelters Holmqvist reported eczematous and follicular dermatitis in smelter workers, primarily on exposed skin.365 Patch tests showed sensitivity to both trivalent and pentavalent arsenic. Birmingham et al. reported similar lesions that developed within a few months of the startup of a gold smelter that handled ores containing large amounts of arsenic sulf~de.79 Dermatitis developed in half the mill workers and in 32 of 40 students in a nearby elementary school.

188 ARSENIC TABLE 6-3 Arsenic Concentration and Prevalence of Pigmentation and Wartsa Arsenic Concentration, ppm Prevalence, To No. Workers Persons Urine Hair Pigmentation Warts Chemical workers 33 0.24 108 90 29 Maintenance workers 32 0.10 78 38 3 and packers Controlb 56 0.09 13 18 Derived from Perry et al.633 bIncluding two former chemical workers. Vintners Butzengeiger reported that, of 180 vinedressers and cellarmen with symptoms of chronic arsenic poisoning, about 23~o had evidence of vascular disorders of the extremities. Arsenical insecticides were used in the vineyards, and exposure occurred not only with spraying, but during work in the vineyards by inhalation of contaminated dusts and plant debris. Most of the workers consumed 1-2 liters of wine per day, and it was also believed to be contaminated with arsenic. All 15 workers with vascular disorders had hyperpigmentation, and all but two had palmer and planter keratosis; six of the 15 had gangrene of the fingers and toes. The same association of vascular disorders, hyper- pigmentation, and keratosis was observed in Taiwan. Urinary arsenic content averaged 0.324 mg/liter, and hair arsenic, 0.039 mg/100 g. Thus, the urine and hair had comparable concentra- tions, 0.3 and 0.4 ppm. Butzengeiger reported that the electrocardio- grams of 36 of 192 vinegrowers with chronic arsenic intoxication were definitely abnormal, with no other evident cause. i2) The abnormalities included prolongation of the Q-T interval and a flattened T wave. In treated cases, these abnormalities diminished with the other evidence of toxicity. Similar findings were reported by Barry and Herndon53 and Glazener et al.293 Arsenic-induced myocarditis in these cases was similar to the evidence reported in the Japanese poisoning episodes described earlier.

Biologic Effects of Arsenic on Man Miscellaneous Considerations 189 Organic Arsenicals Organic arsenicals occupy an exciting place in the history of scientific medicine, because they are the result of deliberate attempts to develop chemicals with increased therapeutic efficacy and reduced toxicity and are thus the first of a long line of synthetic chemotherapeutic agents.333 Specifically, these agents were developed to exploit the antibacterial effects of inorganic arsenic while reducing its toxicity by attachment to an organic moiety. The goal was a cure for syphilis. The major cutaneous side effects of the administration of organic arsenicals were rashes of various types, many of which were thought to be allergic. Although the actual incidence of such eruptions may have been quite small, considering the total number of doses given,38i their nature was such as to cause considerable concern over and research into the problem.77~ Harvey stated that the ultimate basis of the action of the organic arsenicals is the inorganic arsenic moiety that results from degradation in the body.333 It is interesting, however, that few, if any, patients receiving large doses of organic arsenic over long periods are reported to have developed the characteristic hyperkeratoses and irregular pigmentation associated with the use of Fowler's solu- tion 266,585 Arsenic in Hair and Nails The keratin of hair and nails is rich in disulfides, and it has been postulated that arsenic is incorporated into the growing portion of the hair root and the nail base.72~ The possibility raised by Lander and Hodge449 that arsenic is excreted in the sweat in cases of acute poisoning must also be considered, although their methodology did not distinguish between eccrine and sebaceous gland secretions. It has been shown that arsenic in the environment reacts avidly with keratin and cannot be removed with repeated washings.46i Thus, attempts to utilize growing hair or nails to determine exposure to ingested arsenic must be performed under circumstances that will guarantee an absence of external contamination.2~9 72~ Hair should be collected from control subjects simultaneously and analyzed in parallel. Even then, con- sideration must be given to the possibility of unsuspected contamination e.g., from hair dyes and shampoos if high arsenic concentrations are found. To avoid spuriously low concentrations, the timing of the hair collection must be such that the root portion has

190 ARSENIC grown out from the hair canal (or the hair may be plucked out, roots and all). If the patient has been acutely ill, the exposure may have been sufficient to arrest hair growth temporarily and thus delay the contami- nated hairs' arrival at the scalp surface still further. Arsenic and the Immune Response Several aspects of the medical side of the arsenic story suggest that arsenic has the capacity to function selectively as a suppressant of the immune response: the medical conditions for which arsenic was most popular were those for which steroid drugs are now the treatment of choice; the high incidence of herpes zoster and herpes simplex in cases of subacute arsenic poisoning is reminiscent of the same phenomenon in patients deliberately immunosuppressed to receive kidney trans- plants; the presentation of children in the Antofagasta episode with recurrent pulmonary infections is reminiscent of the story of children with congenital immunodeficiency syndromes; and the reputed capac- ity of arsenic to reduce the lymphocyte count in leukemia may reflect a selective sensitivity of this cell type to arsenic, which is again analo- gous to the effects of steroids. Although the possible role of the immune response in protecting the body against cancer is not completely understood, that arsenicals may affect such a mechanism clearly warrants further study. Many of the techniques of modern immunology have become available only in the last 10 years and remain to be applied to the study of arsenic. Arsenic as Therapy Except for one brief positive report,330 there is little published evidence that modern analysis has been applied to the question of whether arsenic may have a useful therapeutic role. As the limitations of some of our modern ''miracle drugs" have become evident (e.g., growth retardation, osteoporosis, Cushingoid changes, and hypertension with steroids), serious consideration of reevaluation of this ancient remedy has become more important. Uniqueness of Human Skin Human epidermis has a number of distinguishing characteristics. Its relative hairlessness is associated with a squamous cell layer that is considerably thicker than the two or three cells of furred laboratory animals. In addition, there is a widespread proliferation of eccrine

Biologic Effects of Arsenic on Man 191 sweat glands not seen in any other animal, except a few primates.553 In view of the propensity for arsenical keratoses to appear early and most prominently on the palms and soles, where these glands are heavily concentrated, it is conceivable that these structures are the mechanism through which arsenic exerts its effect; because they are uniquely prominent in human skin, a suitable laboratory model for arsenical changes could be unavailable.553 Other Dermatologic Conditions Palmar keratoses may occur independently of exposure to arsenic, and several syndromes appear to be congenital. In the basal cell nevus syndrome, the palmer lesions are pitted (rather than protruding), tend to appear early in life, and are associated with such congenital abnor- malities as jaw cysts and bind ribs, as well as with multiple basal cell carcinomas that appear in adult life.~57 A single report indicated that patients with internal malignancy may have an increased incidence of palmer keratoses. Dobson et al. examined 671 patients with diagnosed malignancies and 685 patients with other diseases.208 Of the cancer patients, 32% had palmer keratoses, compared with 7~o of the others. Patients with breast cancer were the most striking group, with a 39~o incidence of keratoses. A standardized set of questions was used to ascertain a history of exposure to arsenic, and this revealed no difference between the tumor group and the control group (13% and logo, respectively). TERATOGENESIS The teratogenic effects of arsenic compounds have been recognized only recently. However, potassium arsenate was one of the com- pounds used in the early studies in the 1950's that led to the chick embryo test for teratogenic agents.668 Thus, Ridgway and Karnofsky found that injection of sodium arsenate into embryonate chicken eggs at 4 days in doses of 0.20 mg/egg caused no specific gross abnormalities in the resulting embryos 14 days later. Growth retardation (particularly of the legs), impaired feather growth, and abdominal swelling were noted.668 This sort of response is commonly encountered in the chick embryo system and is generally regarded as nonspecific. Even earlier, Franke et al. performed what might be called the first teratogenic study of an arsenic compound, when they tested the effect of sodium arsenite on the development of chick embryos.264 Injection

192 ARSENIC of sublethal concentrations of arsenic into the eggs produced ectopic conditions, but no monstrosities, such as produced by selenium. More recent studies have shown that teratogenic effects result from the administration of sodium arsenate to hamsters, mice, and rats. In the hamster study,250 sodium arsenate was administered intravenously as a single dose on specified days of gestation, and results were observed on the fifteenth day. It was found that the eighth day was critical; there was a high incidence of embryos with anencephaly and other defects, which occurred much less frequently if the arsenate was administered earlier or later than the eighth day of gestation. A more thorough study of the spectrum of treatment effects caused by the intravenous injection of sodium arsenate at 15, 17.5, or 20 mg/kg as a single dose on the eighth day of gestation has been reported.25 Deionized water was administered to comparable hamsters as a con- trol, and the data were collected on the fifteenth day of gestation. The incidences of dead, resorbed, and malformed embryos depended on dose. Thus, the fraction of the litter resorbed ranged from about S to 80~o, and the incidence of malformations ranged from 20 to 90~o. Up to 80~o of the embryos had anencephaly; up to 65%, rib malformations; up to Who, exencephaly; and approximately 20%, genitourinary malfor- mations. Incidence of renal agenesis and cleft lip and palate were lower. Further analysis of the teratogenic consequences of sodium arsenate by Holmberg and Fern showed that sodium selenite injected at 2 mg/kg simultaneously with a teratogenic dose of sodium arsenate decreased the number of fetal resorptions and congenital malforma- tions caused by the arsenical.363 This observation is of interest, in light of the known metabolic antagonism between selenium and arsenic. The authors of the latter report stressed that the doses of arsenic and selenium used in their experiments exceeded the usual environmental contamination. However, they also pointed out that remarkable species variation can exist in the teratogenic response to any given teratogen (for example, thalidomide caused severe malformations in human embryos in relatively low therapeutic doses, whereas it took extremely high doses of the same compound to produce malformations in experimental animals). The paper concluded on a cautionary note, suggesting that all potential teratogens be carefully evaluated until individual species sensitivity to various teratogens is determined. In mouse studies, Hood and Bishop administered a single dose (25 or 45 mg/kg) of sodium arsenate by intraperitoneal injection on a specified day from the sixth to the twelfth day of gestation and observed the results on the eigthteenth day.367 The injections given on the ninth day were most teratogenic; 60~o of 96 implantations were resorbed or dead,

Biologic Effects of Arsenic on Man 193 and 635to were grossly malformed. The defects included exencephaly, microagnathia, protruding tongue, agnathia, open eye, cleft lip, fused vertebrae, and forked ribs. Mice that received injections of distilled water served as controls. Although teratologic effects were seen at 45 mg/kg, 25 mg/kg was without effect. Sodium arsenite was more effec- tive; preliminary data show that the extent of fetal anomalies caused by sodium arsenite at 10 mg/kg was comparable with that caused by sodium arsenate at 45 mg/kg. Hood and Pike reported that British antilewisite, when administered to mice at 50 mg/kg by intraperitoneal injection within 4 h of sodium arsenate at 40 mg/kg, prevented the arsenic-induced teratogenesis.368 Results similar to those reported for hamsters and mice were re- ported by Beaudoin for rats.57 Each of a group of pregnant Wistar rats received an intraperitoneal injection of sodium arsenate during days 7-12 of gestation. The dosage of sodium arsenate varied; it was either 20, 30, 40, or 50 mg/kg of maternal body weight. The teratogenicity and lethality to embryos of arsenate depended on dosage and time; maxi- mal effects were seen when the dosage was 30 mg/kg and the injection was given on day 8, 9, or 10. The most common malformations were eye defects, exencephaly, and renal and gonadal agenesis. Ribs and vertebrae were the skeletal elements most commonly affected. It is of interest that potassium arsenate was fed to four pregnant ewes at 0.5 mg/kg during most of pregnancy without effect.390 MUTAGENESIS As in the case of teratogenic effects of arsenic compounds, there have been only a few valuable mutagenesis studies. Most of the research has centered on chromosomal reactions to sodium arsenate. There are no data based on the host-mediated assay or the dominant-lethal tech- n~que. One of the earliest observations that has meaning today was made by Levan in 1945.462 Root meristem cultures of Allium cepa were treated for 4 h with an unspecified arsenic salt at 10 concentrations, from lethal to a no-effect. Chromosomal changes were observed, including spindle disturbances and metaphase arrests. Similar effects, with minor varia- tions, were observed after treatment with salts of 24 other metals (mostly nitrates). The changes resembled those caused by colchicine, but they cannot be considered serious damage. Petres and co-workers have reported chromosomal breakage in human leukocyte cultures after short-term in vitro exposure to sodium

194 ARSENIC arsenate637 638 and in cultures obtained after long-term exposure to arsenical compounds in ViVO.639 The cytotoxic and mutagenic effects of sodium arsenate were tested in vitro' on phytohemagglutinin-stimulated lymphocyte cultures in concentrations of 0.05-30 ,ug/ml of culture medium.637 638 It was re- ported that 33% of metaphase plates were pulverized at 0.1 ,ug/ml and 80-lOO~o at concentrations of 2 ,ug/ml or greater. The ''mitosis index" and the ''t3H]thymidine labeling index" were decreased. Arsenate has also been found to increase the total frequency of exchange chromo- somes in Drosophila melanogaster treated with selenocystine,835 and several organic arsenicals have a harmful synergistic effect on the number of abnormalities in barley chromosomes caused by ethyl- methane sulfonate.563 The overall significance of these chromosomal studies is difficult to assess, inasmuch as many unrelated compounds may cause similar effects. The fact that arsenic compounds have caused chromosomal damage in a number of biologic systems, how- ever, should alert toxicologists to a possible role of arsenic in chemi- cally induced mutagenesis. The in vivo studies were made on 34 patients at the University of Freiburg skin clinic.639 Thirteen of these patients had had intensive arsenic therapy, some more than 20 years before the experiment; most of these were psoriasis patients. The control group (21 patients) con- sisted of 14 psoriasis patients and 7 with eczema, none of whom had had arsenic treatment. Phytohemagglutinin-stimulated lymphocyte cul- tures were prepared from each patient for evaluation of chromosomal aberrations. The incidence of aberrations was remarkably greater in the cultures of patients who had been treated with arsenic. Expressed as the frequency per 1,000 mitoses, secondary constrictions were 49 in the arsenic group and 12 in the control, gaps were found in 51 in the arsenic group and 7 in the control, "other" lesions were 26 in the arsenic group and 1 in the control, and broken chromosomes were 65 per 1,000 mitoses in the arsenic group and 2 in the control. Aneuploidy was found at the expected frequency in the arsenic group. The extent of abnormalities attributed to treatment with arsenicals is impressive; it is important that this study be repeated. Paton and Allison investigated the effect of sodium arsenate, sodium arsenite, and acetylarsan on chromosomes in cultures of human leuko- cytes and diploid f~broblasts.620 Subtoxic doses of the arsenicals were added to leukocyte and f~broblast cultures at various times between 2 and 48 h before fixation. In leukocyte cultures treated with sodium arsenite at 0.29-1.8 x 10-8M for the last 48 h of the culture period, 60~o of 148 metaphases examined were found to have chromatic breaks. No

Biologic Effects of Arsenic on Man 195 significant number of breaks were found in cultures treated with sodium arsenate at 0.58 x 10-8 M, the highest nontoxic concentration. However, treatment with acetylarsan at 6.0 x 10-8 M resulted in 20~o chromatic breaks in 50 metaphases examined. Sodium arsenite caused chromosomal damage in diploid fibroblasts to which sodium arsenite (Q.29-5.8 x 10-8M) was added to the medium for the last 24 h of cul- ture; chromatic breaks were found in 2~o of 459 metaphases examined. These results supported the in vitro observations of Petres et al. 6379638 CARCINOGENESIS The purpose of this section is to review and evaluate the evidence of carcinogenic activity of arsenic compounds; the evidence is in four categories: · Clinical reports of skin cancers associated with the medical use of arsenicals. · Occupational studies of workers engaged in the manufacture of arsenic compounds, in smelting, or in the use of arsenicals. · Population studies in areas of great exposure to environmental arsenic, primarily in water supplies. . . . .. ~ mars. · experimental studies or arsenic carcinogenesis in laboratory ani Recent reviews of the literature on carcinogenicity studies in animals and man have been published by the International Agency for Research on Cancer379 and by the National Institute for Occupational Safety and Health.807 Clinical Reports The clinical association of skin cancer with the oral administration of arsenic compounds began with a report by Hutchinson in 1888.377 He described six patients in whom skin cancer occurred and who had suffered for very long periods from diseases of the skin (five with psoriasis, one with pemphigus). In five of the cases, arsenic was known to have been used for a long time. Neubauer in 1947 summarized 143 published cases of medicinal arsenical epitheliomas in a review for the British Medical Research Council.585 A small, but undetermined, proportion of people treated with arseni- cals developed cancers. Of the 143 patients, about 70~o received

196 ARSENIC arsenicals for skin disease; of these, half had psoriasis. Nearly all the 143 patients received arsenic in the inorganic trivalent form, the most common drug being potassium arsenite as Fowler's solution. A typical formula consists of 10 g of arsenic trioxide, 7.6 g of potassium bicarbo- nate, 30 ml of alcohol (or tincture of lavender), and distilled water to 1 liter.642 Approximately 90~o of the patients received Fowler's solution for more than 1 year, and 50% for more than 5 years. The total quantity of arsenic ingested was variable, averaging about 28 g. Multiple horny keratoses, especially the punctate or warty form on the palms and soles, were commonly reported in patients who had received Fowler's solution. Keratoses occurred in about 90~o of the cases of cancer ascribed to treatment with Fowler's solution; only in a few cases did the keratoses spare the hands and feet. Melanosis is a common sign of arsenic ingestion, and the hyperpigmentation is most marked at sites of normal pigmentation and at sites of pressure from clothing. About half the skin cancers were squamous carcinomas arising in keratotic areas, with predilection for the hands (especially the palmer and lateral surfaces of the fingers and the borders of the palms), the heels, and the toes. About half were multiple superficial epitheliomas of the basal cell variety localized to the trunk and proximal parts of the extremities. Only a few of the 143 cases arose in psoriatic patches. There was a substantial frequency of mixed types of epitheliomas. Of the 143 patients, 70~o had multiple lesions. Multiple lesions occurred even when squamous cancers arose in keratoses; there was an average of two lesions per case. The elapsed time from the beginning of administration of the arseni- cal drug to the beginning of the epitheliomatous growth was variable, but averaged 18 years, regardless of the type of lesion. In cases with keratosis, the latent period to the onset of keratosis was about half the latent period to the onset of the epithelioma i.e., about 9 years. In spite of the long induction period, arsenic-related skin cancers started when the patients were relatively young, one-third when they were 40 or younger, and 70% when they were 50 or younger. Of the 143 patients, 13 had or developed miscellaneous cancers at other sites, but such cases were not reported systematically; the reports commonly presented one or a few case histories. For example, Regelson et al. reported a case of hemangioendothelial sarcoma of the liver in a 49-year-old man who had taken Fowler's solution intermit- tently for 17 years to control psoriasis.663

Biologic Effects of Arsenic on Man Occupational Exposure 197 There have been numerous reports of arsenic-induced occupational cancer, such as those of the excess lung-cancer mortality among Southern Rhodesian miners of gold-bearing ores containing large amounts of arsenic605 and of the occurrence of lung and liver cancer and clinical arsenism among German vineyard workers exposed to arsenic-containing insecticides.~0~678679 The association of cancer with a high degree of arsenic exposure has often been based on the existence of palmer or planter keratoses.753 However, because of the increased concentration of arsenic in the lesions of Bowen's disease, arsenic has been considered as a possible cause of the disease and accompanying visceral tumors,304 without overt prior exposure to arsenicals (see also discussion under ''Chronic Arsenic Exposures. A number of relatively quantitative studies of cancer attributable to occupational exposure to arsenicals will be discussed in some detail. A death-record examination was made of a British plant that manu- factured sodium arsenite sheep dip.352 633 The factory was in a small country town within a specific birth and death registration subdistrict. In this and adjacent subdistricts, death certificates of 75 factory work- ers and 1,216 men (not factory workers) in three other occupational groups were obtained for the period 1910-1943. Of the 75 deaths among factory workers, 22 (29%) were due to cancer; of the other 1,216 deaths, 157 (13%) were due to cancer. The proportion of deaths due to cancer was even higher among men who actually worked with the manufacture and packaging of the arsenic-containing material: 16 of the 31 deaths of men so classified were due to cancer. The number of deaths due to cancer according to site for the two groups is shown in Table 6-4, in which those deaths are expressed as a fraction of cancer deaths and as a fraction of total deaths. The absolute numbers of deaths and the fractions of cancer deaths are from the author's paper; the fractions of total deaths were calculated for this report. The data suggest a relative excess in the factory workers of cancers of the respiratory system and skin, whether calculated on the basis of cancer deaths or of total deaths; the corresponding deficits in cancers of the digestive organs and peritoneum disappear when calculated on the basis of total deaths. Although Hill and Faning stated that the numbers of cancer deaths are small, they concluded that ''there is a suggestion in the figures that the factory workers have been especially affected in the lung and skin."352 Hence, there was an investigation of the environmental conditions at the factory and the clinical condition of the workers in

198 TABLE 6-4 Deaths Due to Cancer, by Site a ARSENIC No. Cancer Deaths Fraction of Cancer deaths,b No Fraction of Total Deaths,b Do Other 3 Other 3 Other 3 Occupa- Occupa- Occupa Factory tional Factory tional Factory tional Site Workers Groups Workers Groups Workers Groups Buccal cavity and pharynx 2 10 9.1 6.4 2.7 0.8 Digestive organs and peritoneum 5 91 22.7 58.0 6.7 7.5 Respiratory organs 7 25 31.8 15.9 9.3 2.1 Genitour~nary organs 2 13 9.1 8.3 2.7 1.1 Skin 3 2 13.6 1.3 4.0 0.2 Other or unspecified 3 16 13.6 10.2 4.0 1.3 Total 22 157 99.9 100.1 29.4 13.0 Derived from Hill and Fan~ng.352 bThere were 75 deaths among the factory workers and 1,216 deaths in the other three occupational groups (see text). question, compared with employees in other branches of the factory who were not exposed to arsenic.633 The median air arsenic content for the chemical workers at the various operations ranged from 254 to 696 ,ug/m3. As an upper limit, this was stated to represent the inhalation of about 1 g of arsenic per year. This amount of arsenic is roughly equivalent to the amount received by patients getting arsenic medi- cation for skin diseases. The excretion of arsenic in the urine of 127 current employees was determined; the scatter of these values was very wide. Some exposed workers excreted from I to nearly 2 mg/day, whereas many excreted less than 100 ,ug/day. A few of the persons in the control group had very high excretion rates, for which the authors found no explanation. It is important to note that 20 of 31 factory workers had been exposed to airborne sodium arsenite for more than 20 years, and five of them for 40-50 years. Furthermore, the median age of the 31 exposed workers was 52 years, and the average age was 50. None of these men's lungs had pathologic signs attributable to their exposure to sodium arsenite (radiographs were made, and vital capacity and exercise capacity were measured). The mortality experience of 8,047 white male smelter workers ex- posed to arsenic trioxide during 1938-1963 was compared by Lee and

Biologic Effects of Arsenic on Man 199 Fraumeni with that of the white male population in the same state.460 There was a threefold excess total mortality from respiratory cancer in smelter workers, and this reached an eightfold excess for employees working more than 15 years and heavily exposed to arsenic. When respiratory cancer deaths were grouped according to degree of arsenic exposure, the observed mortality was significantly higher than ex- pected in all three groups: approximately 6.7, 4.8, and 2.4 times the expected mortality in the heavy-, medium-, and light-exposure groups, respectively. In addition to arsenic trioxide dust, smelter workers were concurrently exposed to sulfur dioxide. Exposure to silica and fer- romanganese and lead dusts occurred in parts of the refineries where arsenic concentrations were low. Therefore, a similar classification was made for relative sulfur dioxide exposure. Respiratory-cancer mortality was directly related to sulfur dioxide exposure, with ob- served deaths ranging from 6.0 down to 2.6 times the expected in heavy-, medium-, and light-exposure groups. Most work areas having heavy arsenic exposure were also medium-sulfur dioxide areas, and all jobs with heavy sulfur dioxide exposure were medium-arsenic areas. It was observed that workers with the heaviest exposure to arsenic and moderate or heaviest exposure to sulfur dioxide were most likely to die of respiratory cancer. A study by Pinto and Bennett647 involved a smelting plant in the state of Washington that produced arsenic trioxide as a by-product. The plant had an average employment of 904 during the years 1946-1960. During that period, a total of 229 deaths were reported among active plant employees and pensioners. Thirty-eight of the dead were classi- f~ed as exposed to arsenic. Of the 38, six died of cancer, including three cases of cancer of the respiratory tract. The total cancer experience of the arsenic-exposed workers was not higher than that of the unexposed, although there was twice as much respiratory cancer in both exposed and unexposed smelter workers as expected from male mortality experience in Washington. Mortality among workers at the same plant was restudied by Milham and Strong, who published their survey in 1974.543 They criticized the methods of the Pinto and Bennett study. The records of workers from the same plant revealed 40 deaths from lung cancer, which was significantly higher than the 18 expected on the basis of rates in the general U.S. population. Snegireff and Lombard747 made a statistical study of cancer mortality in a metallurgic plant (A) in which arsenic was handled and in a control plant (Z) in which "working conditions approximate those of Plant A except that no arsenic is handled." From 1922 to 1949, there were 146 deaths among the employees of Plant A who handled large quan

200 ARSENIC titles of arsenic trioxide. Of these deaths, 18 were due to cancer, including seven cases of cancer of the respiratory system. In the control plant, 12 of 109 deaths between 1941 and 1949 were due to cancer, including six due to lung cancer. The authors stated that total cancer mortality in the two plants was not significantly different from the figures for the state as a whole, and they concluded that handling of arsenic trioxide in the industry studied does not produce a significant change in cancer mortality of the plant employees. However, as pointed out in the National Institute for Occupational Safety and Health (NIOSH) publication, Occupational Exposure to Inorganic Arse- nic, New Criteria 1975, 807 there are a number of deficiencies in the report. Specifically, reanalyses of the data have revealed that actually there was a large excess (approximately fivefold) of lung-cancer deaths relative to mortality from all causes among workers in both plants. Thus, the data demonstrated evidence of a carcinogen for the respira- tory system among the workers of both the plant in which arsenic trioxide was handled and the control plant. Findings of increased risk of lung cancer among copper-smelter workers are not limited to the United States. A retrospective study by Kuratsune et al. in Japan revealed that, of 19 males who died of lung cancer in a particular town, 11 had been employed as smelter workers in a local copper refinery, and in all cases the disease had become manifest after the men had stopped working at the refinery.443 The authors' conclusion was that prolonged exposure to arsenic, and possibly also other compounds, seemed to be associated with cancer of the lungs. Additional groups exposed to inorganic arsenic such as gold miners in Rhodesia, 606 hard-rock miners in the United States, 833 and nickel refin- ery workers672-have shown an increased mortality from lung cancer, but evaluation of the role of arsenic is difficult, because of the presence of other suspected carcinogens in the working atmosphere. A study at the Dow Chemical Company examined the incidence of respiratory cancer among 173 decedents who were exposed primarily to lead arsenate and calcium arsenate and 1,809 decedents who worked in the same plant and were not exposed to those compounds.609 Data were presented on the relationship between cumulative arsenic expo- sure and the ratio of observed to expected deaths from lung cancer. The average exposure of each worker was calculated on the basis of records of job assignments and data on the arsenic content of the air in various parts of the plant. Deaths from respiratory malignancy were 7 times greater than expected for total inhaled quantities of 29.8 g and 2 - times greater for 0.13-6.56 g. There was no association between the extent of exposure and the time from beginning of expo

Biologic Effects of Arsenic on Man 201 sure to death; most of the respiratory cancers occurred 20~0 years after initial exposure, regardless of total exposure. The ratio of observed to expected deaths was even higher (3.85: 1) in another category malignant neoplasms of the lymphatic and hematopoietic tissues except leukemia than it was in malignant neo- plasms of the respiratory system (3.45: 11. Six lymphomas were re- ported, with the following diagnoses on the death certificates: four cases of Hodgkin's disease, one of lymphoblastoma, and one of re- ticulum cell sarcoma. By contrast with the Dow Chemical Company workers, orchard workers who sprayed lead arsenate showed no evidence of increased cancer.584 A mortality study involving a cohort of 1,231 workers in Wenatchee, Washington, who had participated in a 1938 morbidity survey of the effects of exposure to lead arsenate insecticide spray was conducted in 1968-1969. Air concentrations of arsenic during spraying averaged 0.14 mg/m3. The population was grouped according to expo- sure in three categories and compared in terms of standardized mortal- ity ratios with the mortality experience of the state of Washington. There was no evidence of increased mortality from cancer, heart disease, or vascular lesions. In 1974, the mortality experience of retired employees of an Allied Chemical Company pesticide plant in Baltimore was analyzed (Baetjer et al.;43 A. M. Baetjer, personal communication). The employees had been exposed to a number of industrial chemicals, including arsenicals; there were no data on the extent of exposure to the various chemicals. Incidence of death among the retirees was 3.5 times that among the general Baltimore population. The excess mortality was concentrated in cancer-caused deaths (14 times the expected), particularly respira- tory cancer and lymphatic cancer. The noncancer deaths were at the expected rates. These calculations were based on a total of 22 deaths in men from all causes during the period 1960-1972. Several human studies not generally available were reviewed in the NIOSH document on occupational exposure to inorganic arsenic,807 including unpublished reports to Kennecott Copper Corporation in 1971 and 1974; unpublished papers presented at the conference on occupational carcinogenesis in New York City on March 24-27, 1975; and an evaluation by NIOSH of the study by Nelson et al. 584 In the last examples, independent sources of information investigated by NIOSH contradicted, rather than confirmed, the report by Nelson et al. The conclusion drawn was that the report apparently did not accurately depict the cancer experience of persons exposed to lead arsenate spray in the Wenatchee Valley.807

202 Population Studies ARSENIC High incidences of skin cancer have been reported in several popula- tion groups exposed to high concentrations of arsenic in drinking water, including people in the district of Reichenstein in Silesia,288 Cordoba Province in Argentina, 73 and Taiwan.798 A study by Tseng et al.798 was done on the southwest coast of Taiwan, where there were artesian wells with high concentrations of arsenic that were used for more than 45 years. The arsenic concentra- tions in the well water of the surveyed villages ranged from 0.05 ppm to over 1.0 ppm, with a median of approximately 0.5 ppm. 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). The total population of the area was approx- imately 100,000, and the survey encompassed the 40,421 inhabitants of 37 villages. The overall prevalence rates for skin cancer, hyperpigmen- tation, and keratosis were 10.6/1,000, 183.5/1,000, and 71.0/1,000, respectively. The male: female ratios were 2.9: 1 for skin cancer and 1.1: 1 for hyperpigmentation and keratosis. Generally speaking, the prevalence of each of the three conditions increased steadily with age, although there was a decline for cancer and hyperpigmentation in women above 69. The prevalence rate for each condition varied directly with the arsenic content of the well water. The systematic effects of age and arsenic content of well water on the prevalence of skin cancer are shown in Figure 6-1. "Blackfoot disease" (a local term for a vascular disorder of the extremities), particularly of the feet, had an overall prevalence rate of 8.9/1,000. A dose-response relationship between this disease and the amount of arsenic in the well water was similar to that observed for skin cancer. The existence of arsenical waters in an eastern area of the province of Cordoba, Argentina, has been known for many decades and is associated with the occurrence of hyperpigmentation, keratosis, and skin cancer. A study made in 1949-1959 indicated a higher proportion of deaths from cancer in the arsenical region than in the rest of the province 23.8% versus 15.3%.73 The excess was due mainly to cancer of the respiratory and digestive tracts in both men and women. The excess cancer was unrelated to socioeconomic differences. Experimental Animal Studies This section presents examples of tests of oral, topical, and parenteral administration of arsenicals to rats, mice, and fish. A number of

Biologic Effects of Arsenic on Man - UJ 12 cr UJ is 20 _ 16 _ 8 A (A 4 o 10 203 / > 0.6 ppm / ~ _ , ~ ~ , / 0.3~.6 ppm - / ~i' / '/ ~_' 0~.3 ppm 1 1 30 40 50 60 70 AGE (yrs) FIGURE 6-1 Prevalence of skin cancer with respect to age and arsenic concentra- tion in well water for both sexes. 798 laboratory animal studies designed to test arsenic compounds for carcinogenicity are not included here, for such reasons as inadequate numbers of test animals, too short a test period, too low an exposure, and poor survival. To our knowledge, no adequate animal studies have been omitted that would add substantially to the examples that follow. In general, animal studies have not shown carcinogenicity for arsenic compounds, even when administered at near the maximally tolerated dosage for long periods. Two notable exceptions are described first, and then several of the negative studies. In 1962, Halver reported the occurrence of hepatomas in trout fed a synthetic diet containing carbarsone at 480 mg/100 g of diet (the data were reviewed by Kraybill and Shimkin;439 the original report is not readily available). Of 50 trout exposed to carbarsone, five developed hepatomas. There were no hepatomas in a large control group fed the synthetic diet without carbarsone. However, aflatoxin contamination of the diet may have been a confounding variable. More recently, Osswald and Goerttler607 reported that subcutaneous injections of sodium arsenate in pregnant Swiss mice caused a con- siderable increase in the incidence of leukemia in both the mothers and

204 ARSENIC their offspring. A 0.005% aqueous sodium arsenate solution was in- jected daily during pregnancy for a total of 20 injections, each contain- ing arsenic at 0.5 mg/kg. Some groups of offspring from the arsenic- treated females were given an additional 20 subcutaneous injections of arsenic (0.5 mg/kg) at weekly intervals. Leukemia occurred in 11 of 24 mothers (46%), 7 of 34 male offspring (21%), 6 of 37 female offspring (16%), and, in the offspring given the additional 20 injections, 17 of 41 males (41%) and 24 of 50 females (48%~. Leukemia developed in only 3 of 35 male (my) and in none of 20 female offspring of untreated control mice. Furthermore, 11 of 19 mice (58%) developed lymphoma after 20 weekly intravenous injections of 0.5 mg each of arsenic as sodium arsenate. Long-term studies of effects of arsanilic acid on chickens, pigs, and rats were reported by Frost et al. 273 No adverse effects were seen in the chickens and pigs after 4 years of feeding, nor in pigs fed 0.01% arsanilic acid for three generations. Male and female weanling rats from the F2 generation of a six-generation breeding study in which 0.01% and 0.05% arsanilic acid was fed were held on the 0.01% arsanilic acid diet or on the control diet for 116 weeks. The overall tumor incidence was the same in all groups and resembled the histori- cal incidence of tumors in the colony, 35-45%. The significance of these data lies in the fact that transplacental exposure to a carcinogen followed by lifetime exposure to the same carcinogen is often the most sensitive technique for detecting carcinogenicity of a substance,793 but this test was negative. Boutwell9~ used female mice (Roekland and a specially bred strain highly susceptible to skin tumors) in a test for cocarcinogenicity of potassium arsenite. It was tested as an initiator, both orally by stomach tube (a total of 2.4 mg in 5 days) and locally (a total of 1.2 mg in eight applications during 5 days). This initiating treatment was followed by topical application of croton oil twice a week for 18 weeks. He also tested potassium arsenite as a promoter by daily applications (a total of 2.3 mg/week) after a single 75-,ug dose of dimethylbenzanthracene (DMBA). The prolonged skin applications of potassium arsenite were hyperkeratotic and ulcerogenic. Other experiments were done to de- termine whether arsenic would increase the yield of skin cancers caused by a suboptimal regimen of DMBA plus croton oil given either at the time of DMBA initiation or during the 24-week period of croton oil promotion. Under the latter condition, the mice were fed potassium arsenite at 169 mg/kg of food. This dietary concentration of 169 ppm (as potassium arsenite) is very high, compared with the 0.5 ppm usually found in the human diet. In no case was there an effect of arsenite on

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

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

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

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

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

of ~ o ~ - o ~ 'e v ~ - ~ - ~ Id o ^ an 50 > o ~ 'e ct ~ ~ o In on 'e ~ pa o of of - ~ o := · - 4 - - - ~ 'e o ~ hi to c: ~ ^ 'e ~ 50 ·4 - c: 'e i X a, ~ ~ ct ~ a' a,, so ~ o ~ ells 'I son ~ =.o o ~ c ~ oN - ^ ~ 'e ~ Ct~= ¢ ~ ~O x c> o c> .s §~ -- ~o oN ~ - §- ~o x ~ c~ l . ~o ~ ~o x o- ~ c7 ' ~D ~ o u' E-o, o e o cD c~ o ~ o o ~ ~ ~ oo ~ . . . . . . . .. . o o o o ~ ~ ~ oo ~ c~ ) } . .. . . . . . . .. . ~ oo ~ oo o o oo ~ - ~o - - - ~ ~ ~ ~ ~ - ~ c~ ~ ~ ~ ~ ~ ~ o o ~ '} ~ - ~ ~t ~ ~ ~ csx o ~ ~) ~ - ~t ~t - . . . . . . . . . . · . (~, - ~ ~p o o ~ ~ ~ x ~ ~ c~ ~ ~ o ~ o ~ ~ ~ o - - ~- - - - - - ~ o ~ ~ - x o ~ ~ ~oN oo o ~ o c~ ~ ~ o ~ ~ ~o ~ - '} d ~ ~ O X - - - ~ - - - - - ~ Oo oN--~ ~ ~ c~- ~ oo 4~ ~ _ _ ~ '} __ _ _ ~, ~ ~ _ - ) - , ~ ~ ~ X ~ _ ~ ~ ~ 0 - ~ - ax 0 ~ ~ ~ ~ ~ x ~ - ~_ oo . ~ _ X ~ ~ `~ ~) _ ~ X ~ ~ ~ X - _ ~ ~_ - \0 r~ ~ ~ X ~ t- 0N \0~ ~ . . . . . . . . . .· - _ ~D O ~ ~ ~ ~ ~ ~ ~- - - ~ ~ 0 o~ oo _ 0 0 _~ o~ _ _ _ -) _ _ _ _ O ~ ~ ~ ~ ~ X ~O ~o ~ ~ _ ~ ~ _ ~_ _ _ U~ ~2 ~ ~ O - -: ~ S ~ ~ ~ ~ D ~ ~ C 210 ~C CO _ D _ C . _ C~ Ct C) ~ ~:5 3= _ ~ c c ~ 3 ·L. U) C D C `:L ~ ~ _ _ CO . -. ~ O ·~: ca ~ ~ ~ ~ C O ~ _ O _ .O ^ ~ ~ ~ C ':) a, a:, ~ C .e X C-;~. ~ O ~ ~ -.C · ~ ~ ~ O O ~ ~ ·_ ~ 3 ~ ~ ~.- ,L, Cq C ~ ~ ~ tV D m C ~ <~~ o ~ ~ C ~ ~ cq ° ~U ~ ~ ~ ~ O ~ C ~-Z

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.

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

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.

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.

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.

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