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Ill Epidemiology of the Adverse Health Effects of Arsenic and Asbestos in Drinking Water Both arsenic and asbestos were reviewed in earlier volumes of the Drinking Water arid Health series. The discussions in this chapter are limited primarily to important new epidemiological data that became available after Volumes 1 and 3 had been completed and to reassessments of some older studies of effects of arsenic and asbestos in human populations. ARSENIC Arsenic was evaluated in the first and third volumes of Drinking Water and Health (National Research Council, 1977a, pp. 316-344; 1980, pp. 337-345~. It was also comprehensively evaluated in 1977 by another com- mittee (National Research Council, 1977b). Epidemiological studies re- viewed in those volumes have provided conflicting associations between the presence of arsenic in drinking water and the development of skin cancer. Some studies discussed below were reviewed in previous volumes, while several were published after the previous volumes were prepared. One of the new reports evaluated by the committee is a review of the carcinogenic- ity data on arsenic, which was prepared by the International Agency for Research on Cancer (1980~. That agency concluded that, although there is inadequate evidence for the carcinogenicity of arsenic compounds in ani- mals, there is "sufficient evidence that inorganic arsenic compounds are skin and lung carcinogens in humans." This statement presumably applies to all sources of arsenic, including drinking water. It is based on the conflict-

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Adverse Health Effects of Arsenic and Asbestos 119 ing results from only two epidemiological studies (Morton et al., 1976; Tseng, 1977; Tseng et al., 1968~. The adverse health effects of exposure to arsenic compounds have been examined in epidemiological investigations for nearly a century. Investiga- tors have gathered and examined data from a variety of sources, including patients given prescribed medicinal arsenic compounds, several occupa- tionally exposed groups, and populations exposed to high levels of arsenic in drinking water supplies (Arguello et al., 1939~. Although arsenic expo- sure has been associated primarily with skin cancer, associations with other cancers, cardiovascular dysfunctions, and a peripheral vascular dis- order known as "blackfoot" disease have also been found. Epidemiological investigations in Europe (Geyer, 1898), in several South American countries, e.g., Argentina (Arguello et al., 1939) and Chile (Borgono et al., 1977; Zaldivar, 1974), and in Taiwan (Tseng, 1977; Tseng et al., 1968) have suggested an association between the effects of chronic exposure to high levels of arsenic in drinking water and the occur- rence of a variety of skin disorders, including skin cancer. The most signif- icant of these reports was published by Tseng and colleagues, who not only correlated a high prevalence of skin cancer and blackfoot disease with the arsenic contents of drinking water supplies in Taiwan but also reported a dose-response relationship between both skin cancer and blackfoot disease and the duration of water intake based on a detailed house-to-house medi- cal survey of approximately 40,000 people out of a total exposed popula- tion of about 100,000 individuals (Tseng, 1977; Tseng et al., 1968~. The inhabitants of the area with endemic arsenic exposure began using arte- sian wells with high arsenic levels approximately 45 years before the study by Tseng et al. (1968~. Most of these people were engaged in farming, fish- ing, or salt production, and their socioeconomic status was considered to be poor. Their diet was low in animal protein and fat, but high in carbohy- drates. Their habits and customs were not considered different from those of persons living in other parts of Taiwan. The overall prevalence rates for skin cancer, hyperpigmentation, and keratosis were 10.6, 183.5, and 71.0 per 1,000, respectively. The skin cancers observed were atypical, in that approximately three-quarters of them were located on parts of the body not usually exposed to sunlight and more than 99~o of the patients had more than one lesion. The control population consisted of 7,500 persons living in a low arsenic exposure area, where drinking water concentrations of the element ranged from less than 1 ppb (~g/liter) up to 17 ppb. Approximately two-thirds ~5,000) of the controls lived on the nearby island of Matsu. Most of them were fisherman. The remainder of the controls, who lived in villages near the endemic exposure area, were farmers and salt workers. The sex and

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120 DRINKING WATER AND HEALTH age distribution in the control group was similar to that in the exposed group. Not a single case of melanosis, keratosis, or skin cancer was ob- served in the control population. More than 45~0 of the wells seeing as drinking water supplies for the "exposed inhabitants" had arsenic levels in excess of 400 ppb, compared with the U.S. Environmental Protection Agency (EPA) national drinking water standard of 0.05 mg/liter (50 ppb) (U.S. Environmental Protection Agency, 1976~. In attempts to establish a dose-response relationship, in- vestigators compared three groups, based on drinking water levels of arse- nic: ~ 300 ppb, 300 to 600 ppb, and ~ 600 ppb. There was a definite as- cending gradient or prevalence of effects from the low to high arsenic groups for both sexes in three different age groups, but no calculations of statistical significance across exposed groups were presented. In three epidemiological studies conducted in the United States, investi- gators found no positive relationship between high levels of arsenic in drinking water and adverse health effects. More than 200 residents of Fair- banks, Alaska, exposed to drinking water containing mean arsenic levels of 224 ppb displayed no increases in skin disorders, although the longest exposure in the study population was only 10 years (Harrington et al., 1978~. Similarly, Morton et al. (1976) did not note any increase in the inci- dence of skin cancer between 1958 and 1971 in Lane County, Oregon, where the arsenic content of the drinking water supplies was relatively high; however, only 537O of the arsenic levels of those supplies exceeded 100 ppb. In a recent study in Utah, Southwick et al. (1981) compared the health status of 145 people consuming drinking water containing arsenic levels of approximately 200 ppb and a matched control group of 105 par- ticipants from a neighboring community, where drinking water levels of arsenic averaged 20 ppb. The investigators did not find any cutaneous manifestations of arsenic toxicity. In addition, there was no excess of can- cer incidence and death rates in the exposed community. There are several possible explanations for the apparently conflicting results discussed above. One is the striking difference in the arsenic levels of the drinking water supplies surveyed; the average arsenic content of the supplies in Taiwan greatly exceeds those of the U.S. communities studied. Moreover, the duration of exposure was probably shorter and the amount of arsenic ingested much less in the U.S. studies than in the Taiwan stud- ies, where personal mobility is greatly limited. Furthermore, lack of ade- quate nutrition and exposure to other environmental pollutants may have exacerbated the effects of arsenic exposure in Taiwan. The differences in exposure to sunlight between Taiwan and Alaska may have been a factor in the observed absence of skin disorders in the Fairbanks study (Harrington

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Adverse Health Effects of Arsenic are Asbestos 121 e! al., 1978) and the Utah study (Southwick et al., 1981~. None of the in- vestigators attempted to determine which arsenic compounds were present in the drinking water supplies surveyed. Since arsenic toxicity varies from compound to compound, this may have been a factor in the conflicting results of the different studies. Unfortunately, the Taiwan studies did not include analyses of drinking water constituents other than arsenic in the water sources of the exposed and control groups. This lack of assessment reduces the extent to which confidence can be placed in the postulated association between arsenic lev- els and observed skin cancer. This is particularly relevant since Lu (1978) recently reported the presence of ergot alkaloids in the Taiwan well water associated with blackfoot disease. These alkaloids may cause symptoms similar to those of blackfoot disease. Other aspects of the Taiwan study might also be questioned. For example, there is a possibility that the ob- servers might have been biased by knowledge of the high- or low-exposure areas. Moreover, only about 30% of the skin cancers were verified by bi- opsy. The extent to which these factors may affect the interpretation of the findings is uncertain. The assessment of arsenic for adverse health effects is confounded by several issues. First, it is always of great value when epidemiological associ- ations are supported with animal studies; however, animal studies have generally not indicated that arsenic is carcinogenic (International Agency for Research on Cancer, 1980; U.S. Environmental Protection Agency, 1979~. Second, arsenic is now recognized as an essential nutrient in several mammalian species (e.g., the rat, chick, guinea pig, and goat) and possi- bly in humans as well Extrapolation from data on animals suggests that 25 to 50 fig of arsenic per person may be the daily requirement for humans (U.S. Environmental Protection Agency, 1979~. When deriving the current maximum contaminant level (MCL) for arse- nic, the EPA took into account the consumption of arsenic in food as well as its association with skin cancer in the Taiwan study (U.S. Environmen- tal Protection Agency, 1976~. Using data from Schroeder and Balassa (1966), the agency estimated that humans consumed approximately 900 fig of arsenic daily from food. The SO ~g/liter MCL (0.05 mg/liter) for arsenic in drinking water was based on the assumption that not more than loo of the total ingested arsenic would be prodded by that source. After the in- terim arsenic standard was established, the estimate of dietary arsenic con- sumption was greatly reduced from 900 to approximately 70 Heyday (U.S. Environmental Protection Agency, 1976, 1977, 1979~. Because the ration- ale behind the drinking water standard (U.S. Environmental Protection Agency, 1976) is to keep the arsenic exposure from drinking water at 105ro

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122 DRINKING WATER AND HEALTH of total ingested arsenic, the more recently recognized lower dietary expo- sure may necessitate a reevaluation of the current drinking water stan- dard. An important related issue is that the EPA has decided that there is no threshold dose for chemical carcinogens. Consequently, there is no safe exposure level to a carcinogen. Various biostatistical models have been used to predict the risk of cancer occurrence when human exposures are much lower than those in the observable range for which dose-response relationships are known. The EPA Carcinogen Assessment Group used a modified "one-hit" model to apply this type of downward extrapolation to the Taiwan data (U.S. Environmental Protection Agency, 1981~. The results indicated that the lifetime risk of skin cancer from drinking water containing 20 ppb (or approximately one-half of the federal standard) would be 1 per 100. This prediction is at variance with the negative find- ings in the U.S. epidemiological studies cited above. Although the negative epidemiological studies on U.S. populations raise questions about the can- cer risk estimations based on the Taiwan data, it is not possible to deter- mine whether such discrepancies are caused by inadequacies of the Taiwan studies, the specific risk assessment model used, or a combination of both. CONCLUSIONS AND RECOMMENDATIONS The epidemiological studies on U.S. populations have failed to confirm the association between arsenic in drinking water and the incidence of cancer observed in Taiwan. Furthermore, only 0.4~o of the drinking water sam- ples taken from public water supplies in the United States have exceeded a total arsenic concentration of 0.01 mg/liter (National Research Council, 1980~. This finding is in sharp contrast to the average concentration of 0.4 mg/liter (400 ppb) reported in the Taiwan studies. It is therefore the opin- ion of this committee that 0.05 mg/liter provides a sufficient margin of safety, but that further experimental research and epidemiological evalua- tions of the association of elevated levels of arsenic in drinking water and skin cancer be undertaken. Continued study of those U.S. populations exposed to high levels of ar- senic in their drinking water appear warranted. Efforts should also be di- rected toward discovering the differences that exist between the chemical species of arsenic in Taiwan and those in the United States or the presence of any other potentially confounding factors. Moreover, the development of an appropriate animal model for carcinogenicity studies would help to resolve the equivocal epidemiological studies. In addition, there should be investigations about interactions of arsenic and other environmental fac-

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Adverse Health Effects of Arsenic and Asbestos 123 tors that may account for the observed differences in clinical studies as well as the effects of diet, race, and climate. Research should also be designed to evaluate the possible essentiality of arsenic for humans a requirement that has been demonstrated in four mammalian species. In the absence of new data, the conclusion reached in the third volume of Drinking Water and Health remains valid, i.e., "If 0.05 mg/kg of dietary [total] arsenic is also a nutritionally desirable levee for people, then the adequate human diet should provide a daily intake of approximately 25 to 50 fig. The current American diet does not meet this presumed requirement" (National Research Council, 1980~. The unre- solved status of this issue is further reason for maintaining the current MCL for arsenic. ASBESTOS Asbestos fibers in drinking water and their putative health effects were reviewed in the first volume of Drinking Water arid Health (National Re- search Council, 1977, pp. 144-168~. At that time, there were only limited data from which to evaluate the potential adverse health effects of orally ingested asbestos. A number of research recommendations suggested in that volume have been, to some extent, fulfilled. Advances have been made in the detection, identification, and quantification of asbestos fibers in drinking water. Several chronic feeding studies completed since that time have failed to show an effect between the ingestion of various fiber types and the development of cancer at any site. There have also been a number of epidemiological studies in which the exposure to asbestos in drinking water and the incidence of cancer at se- lected sites have been investigated. This renew is limited to a discussion and evaluation of those studies and the development of a model to predict the risks, if any, from such exposure. BACKGROUND A marked increase in the incidence rates of lung cancer and both pleural and peritoneal mesothelioma has been absented in workers exposed to as- bestos through inhalation (International Agency for Research on Cancer, 1977~. An excess of gastrointestinal tract cancers has also been.found in these occupationally exposed groups. The general population may be exposed to asbestos fibers in "air, be`,er- ages, drinking water, food and pha~..aceutical and dental preparations and by consumer use of asbestos containing products" (International