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6 Biological Effects of Arsenic on Man
Pages 173-215

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From page 173...
... , 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.
From page 174...
... 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 contained 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 simultaneously using arsenic therapeutically and treating the consequences of excessive exposure from environmental sources.
From page 175...
... Evidence of systemic absorption of arsenic secondary to external 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.
From page 176...
... 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)
From page 177...
... even the minimum dose will produce unpleasant effects," such as one case of erythroderma after 10 mg of arsenic trioxide (7.6 mg of arsenic) taken over a 2-day period.
From page 178...
... 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
From page 179...
... in its development."665 Reynolds also described the nail changes of subacute arsenic poisoning, 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.
From page 180...
... 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.
From page 181...
... 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
From page 182...
... 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.
From page 183...
... 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.
From page 184...
... 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)
From page 185...
... The histopathology of the multiple and varied lesions seen in arsenism has been the subject of considerable interest among dermatOpathOlOgists ~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.
From page 186...
... All had keratoses, nine had leukomelanoderma of the trunk, and seven had skin cancer or intraepidermal carcinoma in situ. Eight had lung cancer.
From page 187...
... 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.
From page 188...
... 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.
From page 189...
... 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 solution 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.
From page 190...
... 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 transplants; 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 capacity of arsenic to reduce the lymphocyte count in leukemia may reflect a selective sensitivity of this cell type to arsenic, which is again analogous 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.
From page 191...
... However, potassium arsenate was one of the compounds 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)
From page 192...
... 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,
From page 193...
... Sodium arsenite was more effective; 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 reported 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.
From page 194...
... 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 leukocytes 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.
From page 195...
... 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.
From page 196...
... A typical formula consists of 10 g of arsenic trioxide, 7.6 g of potassium bicarbonate, 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.
From page 197...
... A death-record examination was made of a British plant that manufactured 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 workers and 1,216 men (not factory workers)
From page 198...
... . The mortality experience of 8,047 white male smelter workers exposed to arsenic trioxide during 1938-1963 was compared by Lee and
From page 199...
... In addition to arsenic trioxide dust, smelter workers were concurrently exposed to sulfur dioxide. Exposure to silica and ferromanganese and lead dusts occurred in parts of the refineries where arsenic concentrations were low.
From page 200...
... Additional groups exposed to inorganic arsenic such as gold miners in Rhodesia, 606 hard-rock miners in the United States, 833 and nickel refinery 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 exposure and the ratio of observed to expected deaths from lung cancer.
From page 201...
... , particularly respiratory cancer and lymphatic cancer. The noncancer deaths were at the expected rates.
From page 202...
... 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.
From page 203...
... More recently, Osswald and Goerttler607 reported that subcutaneous injections of sodium arsenate in pregnant Swiss mice caused a considerable increase in the incidence of leukemia in both the mothers and
From page 204...
... Other experiments were done to determine 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.
From page 205...
... 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.
From page 206...
... , and finally skin cancer.~87 This sequence has been observed under a variety of circumstances involving chronic exposure: potassium arsenite (Fowler~s solution) was used medicinally,585 vineyard 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 populations always involve variables that cannot be controlled as in laboratory experiments; hence, the credibility of information derived from human studies depends on the demonstration of comparable effects under different conditions.
From page 207...
... 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.
From page 208...
... . 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)
From page 209...
... 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)
From page 210...
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From page 211...
... 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.
From page 212...
... 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.
From page 213...
... 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.
From page 214...
... 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 compounds of arsenic appear to have an unusual propensity to alter epithelial morphology (at least in humans)
From page 215...
... 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.


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