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Drinking Water and Health,: Volume 4 (1982)

Chapter: VI Toxicity of Selected Inorganic Contaminants in Drinking Water

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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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Suggested Citation:"VI Toxicity of Selected Inorganic Contaminants in Drinking Water." National Research Council. 1982. Drinking Water and Health,: Volume 4. Washington, DC: The National Academies Press. doi: 10.17226/325.
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vl Toxicity of Selected Inorganic Contaminants in Drinking Water SELECTION OF CONTAMINANTS In 1977, the Safe Drinking Water Committee examined health effects associated with microbiological, radioactive, particulate, inorganic, and organic chemical contaminants found in drinking water (National Acad- emy of Sciences, 1977~. Additional selected chemical contaminants were considered in a subsequent study (National Academy of Sciences, 1980b). The health effects of the organic and inorganic contaminants evaluated in Chapters VI and VII of this volume were selected for one or more of the following reasons: · They are contaminants that have been identified in drinking water since the previous studies were conducted by the Safe Drinking Water Committee. · Sufficient new data have become available to justify further attention to contaminants evaluated in the earlier studies. · Several compounds were judged to be of concern because of potential spill situations. · They are contamintants associated with the drinking water distribu- tion system. · They are structurally related to known toxic chemicals. 152

Toxicity of Selected Inorganic Contaminants in Drinking Water 153 ACUTE AND CHRON IC EXPOSURE The committee has evaluated the data concerning both acute and chronic exposures to selected chemicals. Information derived from studies of acute exposure provides a basis for judging health effects resulting from accidental spills of chemicals into drinking water supplies. A suggested no-adverse-response level (SNARL) for acute exposures of 24 hours or 7 days has been calculated for these compounds for which suf- ficient data were available. These values were based on the assumption that 100% of the exposure to the chemical was supplied by drinking water during either the 24-hour or 7-day period. When the chemical was a known or suspected carcinogen, the potential for carcinogenicity after acute exposure was not considered. Acute SNARL's were calculated only when there were data on human exposures or data from oral tests in animals. LD50's were not used as a basis for calculation. If no-effect levels were not known, the lowest level producing an observed effect was used with an appropriate safety factor. Some 7-day values were derived by dividing the 24-hour SNARL by 7. The converse was not done, nor were data obtained from studies of lifetime exposures used to establish acute SNARL's. The calculated acute SNARL's should not be used to estimate hazards from exposures exceeding 7 days. They are not a guarantee of absolute safety. Furthermore, SNARL's are based on exposure to a single agent and do not take into account possible interactions with other con- taminants. In all cases, the safety or uncertainty factor used in the calculations of the SNARL's reflect the degree of confidence in the data as well as the combined judgment of the committee members. As in the previous reports, the following assumptions were used when assigning an uncertainty factor to calculate either the acute or chronic SNARL's: · An uncertainty (safety) factor of 10 was used when data on both human exposure and extensive chronic exposures of animals were avail- able. · A factor of 100 was used when chronic and acute toxicity data were available for one or more species. · A factor of 1,000 was used when the acute or chronic toxicity data were limited or incomplete. SNARL's for chronic exposure were calculated for chemicals that were not known or suspected to be carcinogens on the basis of data obtained

154 DRINKING WATER AND HEALTH TABLE VI-1 Summation of Acute and Chronic Exposure Levels for Inorganic Chemicals Reviewed in this Chapter Suggested No-Adverse-Response Level (SNARL), mg/liter, by Exposure Perioda Chemical 24-Hour 7-Day Chronic Aluminum 35.0 5.0 Barium 6.0 4. 7 Cadmium 0.15 0.021 0.005 Chlorate 0.125 0.125 Chlorite 0.125 0.125 Chlorine dioxide 1.2 0.125 Chloramine 1.2 0.125 Strontium 8.4 aSee text for details on individual compounds. during a major portion of the lifetime of the laboratory animals. An ar- bitrary assumption was made that 20% of the intake of the chemical of concern was derived from drinking water. Therefore, it would be inap- propriate to use these values as though they were maximum contaminant intakes. Table VI-1 summarizes the acute and chronic SNARL's for the inorganic chemicals reviewed in this chapter. The 1977 Amendments to the Safe Drinking Water Act of 1974 (PL 93- 523) authorized the committee to revise the earlier studies to reflect "new information which has become available since the most recent previous report [and which shall be reported to Congress each two years thereafter)." Thus, the descriptions of some contaminants in Chapters VI and VII are limited to data generated since the last three volumes of Drinking Water and Health were published. Other contaminants and their health effects are evaluated for the first time in this series of reports. This is one reason why no significance should be attached to the length of the discus- sion devoted to each contaminant. Included in this chapter is information on the toxicity of several metallic ions associated generally with drinking water distribution systems. Other contaminants, such as barium, lead, and strontium, pose problems only in certain local areas. The chlorine derivatives were evaluated because of their possible use as alternatives to chlorine in the disinfection of drinking water.

Toxicity of Selected Inorganic Contaminants in Drinking Water 155 Recently, the EPA Criteria and Standards Division of the Office of Water Planning and Standards released a series of documents on Ambient Water Quality Criteria. Although the committee does not endorse all of the conclusions (e.g., numerical criterion formulations) reached in those documents it does believe that they are a valuable source of general tox- icological information. Several of the contamintants that are examined in Chapters VI and VII of this report were previously evaluated in one of these criteria documents. This committee agrees with the following statement from Drinking Water and Health, Volume 3 (National Academy of Sciences, 1980, p. 68~: It was the belief of this subcommittee that it could perform a more valuable service to the Environmental Protection Agency (EPA) in the future if it evaluated criteria documents that were prepared by the EPA or other groups contracted to conduct these tasks. It will be necessary for the EPA to develop a mechanism for a com- prehensive search and review of the literature in order to make in-depth hazard assessments for these chemicals. It is the consensus of this subcommittee that this cannot be done appropriately by the National Academy of Sciences because time and staff requirements far exceed those available. Neither can it be expected that the scientists who donate their services on these subcommittees will have the resources or time to carry out the routine aspects of this task. In keeping with this philosophy, the committee drew heavily from criteria documents when one had already been prepared for the contami- nant being studied. In such cases, the document was reviewed for ac- curacy and updated when additional information was available. For some of the contaminants reviewed here, appropriate parts of the criteria documents were condensed and included in the final report. The committee commends the EPA for making this valuable material available for study and evaluation. It hopes that future committees with a similar mission will have the opportunity to review documents of this type prior to their general release. Because of the tremendous volume of data to evaluate for the hundreds of potential drinking water contaminants, this type of collaboration is beneficial to all concerned. Aluminum (Al) Aluminum, a silver-white, malleable, and ductile metal, is the third most abundant element in the earth's crust, comprising 8.3% of its volume. In nature, it is generally found in a combined state with various silicates, the most important of which are bauxite and cryolite (Norseth, 1979~. The world production of aluminum in 1974 was estimated to be approx- imately 14 million tons (Norseth, 1979~. There are more than 4,000 ter

156 DRINKING WATER AND HEALTH minal uses of this element in such fields as electrical engineering and the transport and air traffic industries and in such products as building materials, home furnishings, kitchen appliances, farm implements, con- tainers for packaging material, and building structures. In powder form, aluminum is a component of paints, pigments, missile fuel, and chemical explosives. Medicinally, aluminum and its salts are used in antacids, an- tidiarrheals, and protective dermatological pastes. It is also found in cosmetics and deodorants. Aluminum compounds are applied in the pro- cessing, packaging, and preservation of foods. It is also used to line water storage vessels and in the purification of drinking water (Gilman et al., 1980; Norseth, 1979; Sorenson et al., 1974~. Concentrations of aluminum in soils vats widely, and its solubility is determined by pH. Concentrations of aluminum in water also vary. Since large amounts (> 100 ,ug/ml) occur only when the pH is less than 5, the concentration of aluminum in most natural waters is negligible (Sorenson et al., 1974~. In analyses of 1,577 U.S. water samples, Kopp and Korner (1970) found 456 samples positive for aluminum. Concentrations of soluble aluminum were as high as 2.76 ,ug/ml (mean, 0.074~. Aluminum compounds such as aluminum sulfate and potash aluminum and certain aluminum-bearing minerals are commonly used as major coagulants in the treatment of drinking water supplies. The principal coagulants are aluminum sulfate and potash aluminum. Aluminum sulfate is the principal coagulant and bentonite is a coagulating aid. Aluminum ammonium sulfate is used as a dechlorinating agent (Sorenson et al., 1974~. Sodium aluminate is added sometimes to remove fine turbidity. In modern purification practice, aluminum-based coagulants usually result in the presence of lower concentrations of aluminum in the drinking water than in the raw water (Sorenson et al.' 19741. The major sources of aluminum in the normal human diet include plants and processed foods (Crapper and DeBoni, 1980~. The concentrations in foods and beverages vary widely, depending upon the product, the type of processing, and the geographical areas in which the plants are raised (Sorenson et al., 19741. The daily intake of aluminum has been estimated in several studies. In general, the data pertaining to natural dietary intake indicate that concen- trations range from approximately 10 to 50 mg/day (Sorenson et al., 1974~. The use of aluminum in the processing and storing of food increases the aluminum content, but not enough to contribute significantly either to total body burden or the toxic effects (Norseth, 1979; Underwood, 1971~. In general, aluminum has largely been regarded as nontoxic. Neither the international nor the European standards for drinking water (World Health Organization 1970, 1973) lists aluminum among those substances for which

Toxicity of Selected Inorganic Contaminants in Drinking Water 157 limits are specified. The National Academy of Sciences' Committee on Water Quality Criteria recommended the following maximum concentra- tions of aluminum in agricultural and irrigation waters: 5.0 ,ug/ml for waters used continuously on all soil and 20 ,ug/ml for waters used not more than 20 years on fine textured neutral to alkaline soils (National Academy of Sciences, 1973~. Although the question of the essentiality of aluminum for biological func- tion was raised as early as 1915, its function remains unknown (Sorenson et al., 1974~. Failure to demonstrate this essentiality probably results from the difficulty of finding a diet that is deficient in the metal (Norseth, 1979; Underwood, 1971~. METAB OLISM The dynamics of absorption, distribution, and excretion of aluminum are poorly understood. Furthermore, little is known about its metabolism or the factors that determine burdens of aluminum in specific tissues. This is par- tially due to a lack of detection methodology and the universal contamina- tion of laboratory reagents and chemicals with the metal (Crapper and DeBoni, 1980; Norseth, 1979; Sorenson et al., 1974~. The human body burden of aluminum is estimated to range from 50 to 150 ma, most soft tissues containing approximately 0.2 to 0.6 Agog (Underwood, 1971~. Contrary to former opinion, studies by Kaehuy et al. (1977a) have shown that aluminum is readily absorbed from the gastrointestinal tract by normal persons who consume one of several aluminum salts (e.g., hydroxide or car- bonate) or dihydroxy aluminum aminoacetate, but not aluminum phosphate. In earlier studies, Clarkson et al. (1972) found a net gastrointestinal absorption of aluminum ranging from 100 to 568 mg/day in dialysis patients taking antacids containing 2 to 3.4 mg of aluminum daily for 20 to 32 days. In another study, Cam et al. (1976) studied the absorption of aluminum in both normal patients and patients suffering from chronic renal failure. Both groups of patients received approximately 2.5 g of aluminum daily for 23 to 27 days. In the normal group, the maximum ab- sorption of aluminum was approximately 97 mg/day, while in the renal failure patients it was 256 mg/day. In balance studies conducted by Gorsky et al. (1979), the aluminum balance was usually negative in those patients receiving less than 5 mg of aluminum per day. However, when the diet was supplemented with antacids that contributed from 1 to 3 g of aluminum daily, an average positive balance of 23 to 313 mg of aluminum per day was observed over an 18- to 30-day period. Studies by Mayor et al. (1977a,b) strongly suggest that aluminum in the gastrointestinal tract and its subsequent distribution in tissue can be in

158 DRINKING WATER AND HEALTH fluenced by increasing the concentration of parathyroid hormone (PTH). They fed male rats aluminum as 0.1 To of their diet for 2S days. The ready absorption of aluminum from the gastrointestinal tract of these normal rats was enhanced by injections of PTH (17 U twice weekly). There was also increased deposition of the metal in the kidney, muscle, bone, and the gray matter of the brain, but not in the liver or in the white matter of the brain. Thus, the PTH exerted a specific effect on the absorption and distribution of aluminum. In 1977, these same investigators had found a positive correlation between increased serum PTH and serum aluminum levels in dialysis patients. The increase in serum PTH in these patients had been reported earlier by Kleeman and Better (1973~. In patients on dialysis, there are apparently two sources of extraneous aluminum: via the gastrointestinal tract from aluminum antacids, which are used to bind phosphate, and via the dialysate solution. Kaehny et al. (1977b) have shown that aluminum can also be transferred across the dialysis membranes. This transfer can occur even if the levels of aluminum in plasma are much higher than the levels of aluminum in the dialysate solution. Thus, aluminum has been shown to accumulate in the serum and in the tissues of chronic renal failure patients either after ab- sorption from the gastrointestinal tract or from parenteral administration during dialysis with a solution that contains aluminum. Following absorption or parenteral administration, aluminum dis- tributes to nearly all of the organs including the brain (Crapper and DeBoni, 1980; Norseth, 1979; Sorenson et al., 19741. Lundin et al. (1978) have found that approximately 50% of the aluminum in the plasma of normal humans is bound to protein with a molecular weight greater than 8,000. The major route of excretion of aluminum in humans appears to be the bile. Only a small amount is excreted via the urine (Gorsky et al.' 1979~. Parenteral administration of aluminum to laboratory animals increases urinary excretion (Norseth, 19791. HEALTH ASPECTS Since aluminum constitutes a substantial portion of the earth's crust and atmosphere and is a common contaminant in food and drinking water, environmental exposure is virtually universal (Bland. 1979; Goetz and Klawans, 1979; Sorenson et al., 1974~. Its extensive uses in cosmetics. such as aluminum hexahydrate (aluminum chloride) in deodorants, and in medicines also provide opportunities for exposure of humans. In its predominant medical application it serves as an antacid to control gastric hyperacidity. Aluminum hydroxide is generally used for this purpose. In

Toxicity of Selected Inorganic Contaminants in Drinking Water 159 addition, aluminum is frequently combined with a magnesium-containing compound to prevent constipation (Sorenson et al., 1974~. Aluminum hydroxide antacids are administered orally in large doses (5-10 g/day) in renal-failure patients to limit the accumulation of phos- phate (hyperphosphatemia) and the consequent development of meta- static calcifications. The treatment induces phosphate loss by stopping the adsorbability of phosphate in the gastrointestinal tract (Mallick and Berlyne, 1968~. In general, aluminum has been considered to be nontoxic (Sorenson et al., 1974~. However, toxic syndromes have been observed in animals in- jected with the element (Sorenson et al., 1974~. There is also a good deal of interest in the role of aluminum in various syndromes of the central ner- vous system in humans. Recent studies indicate that it may be selectively toxic to certain neurons in the central nervous system (Crapper and DeBoni, 1980; Goetz and Klawans, 1980; Norseth, 19791. Observations in Humans Recently reported adverse effects of aluminum in humans have resulted from inhalation or ingestion of aluminum in concentrations many times greater than the amounts present in normal circumstances. Following large oral doses of aluminum, toxic syndromes involve gastrointestinal tract irritation and, eventually, interference with phosphate absorption, which results in rickets (Casarett and Doull, 19771. Industrial exposure to high concentrations of aluminum-containing airborne dusts has resulted in a number of cases of occupational pneumoconiosis (Norseth, 1979; Sorenson et al., 19741. Most of these exposures were chronic, and other substances were involved in nearly all instances. For example, an asthma- like disease has been reported in workers engaged in the production of aluminum from its oxide. This condition may result from the hydrogen fluoride that evolves from the use of fluorine-bearing materials in the pro- duction of metallic aluminum (Sorenson et al., 1974~. Silicosis, alumi- nosis, aluminum lung, and bauxite pneumoconiosis are the result of pul- monary fibrotic reactions to silica and aluminum-containing compounds' which have been observed in the lung tissue in humans (Sorenson et al.' 1974~. Paradoxically, aluminum powder has been used in the prevention and therapy of silicosis. The rationale is that small amounts of metallic aluminum inhibit the solubility of siliceous materials in the lungs or diminish their fibrogenic properties (Casarett and Doull, 1977; Denny et al., 1939~. There is no unequivocable evidence that the procedure is clini- cally effective (Sorenson et al., 1974~. In one of the earliest cases reported by McLaughlin et al. (1962), an

160 DRINKING WATER kND HEALTH aluminum-ball-mill worker died with encephalopathy and pulmonary fibrosis. After having been exposed to aluminum-containing compounds more than 13 years, the concentration of aluminum in his brain was 20 times greater than that in the brains of controls. In more recent studies, aluminum deposition in the brain has been implicated as an etiologic factor in two necrologic disorders: Alzheimer's disease and chronic renal failure accompanied by senile dementia (Alfrey et al., 1976; Crapper et al., 1973~. Nonetheless, the importance of aluminum as a pathogenic factor in human disease has not yet been established (Crapper and DeBoni, 1980~. Alzheimer's disease usually occurs in humans after the age of 40. It is a slowly progressive, fatal encephalopathy associated with behavioral altera- tions, memoir disturbances, special disorientation, agnosia, dysphasia, and seizures (Crapper and Dalton, 1973a,b; Crapper and DeBoni, 1980~. The role of aluminum as an etiologic agent in Alzheimer's disease rests on circumstantial evidence such as the resemblance between aluminum- induced neurofilamentous aggregates and human neurofibrillar tangles that characterize Alzheimer's disease and senile dementia (Goetz and Klawans, 1980; Klatzo et al., 1965; Terry, 1963~. However, there are im- portant differences between the morphological changes induced in ani- mals by aluminum and those observed in humans with Alzheimer's dis- ease (Crapper and DeBoni, 1980~. Additional circumstantial evidence has been provided by studies of Crapper et al. (1976), who reported elevated aluminum levels in some regions of the brains of patients who had died from Alzheimer's disease. For example, in 28% of the 585 brain regions sampled, aluminum levels exceeded 4 ,ug/g the minimum concentration of metal associated with neurofibrillar degeneration in cats observed in the same laboratory (Crapper et al., 1973~. Trapp et al. (1978) also reported increased aluminum levels in patients who had died from Alz- heimer's disease. However, McDermott et al. (1978) did not find any sig- nificant differences in aluminum levels in brain samples taken from patients suffering from Alzheimer's disease and healthy, age-matched controls. Before aluminum is assigned a role in Alzheimer's disease, further investi- gations must be undertaken (Crapper and DeBoni, 198l)~. Another encephalopathic syndrome in which aluminum has been sug- gested as an etiologic agent has been described as "dialysis enceph- alopathy" or "dialysis dementia," which is a relentlessly progressive form of dementia observed in chronic dialysis patients (AIfrey et al., 1976; Anonymous, 1976; Elliott et al., 1978; Goetz and Klawans, 1979~. This disorder is characterized by an insidious onset of altered behavior, speech disturbances, dyspraxia, tremor, myoclonus, convulsions, personality changes, and psychoses. This syndrome, which results in death within ap- proximately 6 to 7 months (Alfrey et al., 1976; Bland, 1979; Crapper and

Toxicity of Selected Inorganic Contaminants in Drinking Water 161 DeBoni, 1980), has been reported to be the leading cause of death in long- term dialysis patients (Crapper and DeBoni, 1980; Goetz and Klawans, 1979~. The majority of the patients in whom this syndrome developed had been on intermittent hemodialysis for 3 to 7 years before the onset of symptoms. All had routinely received aluminum-containing antacids for the purpose of binding gastrointestinal phosphates for at least 2 years. The possible hazard of aluminum intoxication in dialysis patients was first described by Berlyne et al. (1970~. Subsequent studies by Alfrey et al. ~ 1976) showed that patients dying of the syndrome had significantly higher tissue concentrations of aluminum in their bones, skeletal muscles, and gray matter of the brain. These authors reported that the aluminum concentrations in the gray matter of the brain were approximately 4 times higher in these patients than in any other group. The source of aluminum was not limited to the antacids given to these patients, but was contained in the water used to prepare the dialysate solution as well (Alfrey et al., 1976; Crapper and DeBoni, 1980; Elliott et al., 1978~. Because only a few of the dialysis patients taking large doses of aluminum-containing antacids develop the syndrome. it has been sug- gested that the syndrome may be related to aluminum contamination of the water used for dialysis. One outbreak occurring in Chicago between September 1972 and January 1976 affected 20 patients who had been maintained on long-term hemodialysis (Dunea et al., 1978~. It was later established that the city's adoption of a water purification method using pure aluminum sulfate resulted in higher concentrations of aluminum in the water. The relation- ships of the onset of the dementia to documentations of aluminum in the water and changes in water treatment are shown in Figure VI-1. The first cases of dementia appeared in September 1972, 3 months after the change in water treatment. They coincided with a peak water concentration of aluminum in the water (360 ,ug/liter). Thirteen patients became demented between September 1973 and August 1974, the later cases ap- pearing during the winters of 1974- 1975 and 1975- 1976, shortly after addi- tional peaks in aluminum concentrations in the water. Before the method of water treatment was changed, aluminum concentrations varied from 0 to 150 ~Ag/liter. After the change, concentrations of aluminum were higher, peaking between 300 and 400 ,ug/liter. The other constituents of the water were not significantly altered. Studies by Elliot et al. (1978~. Flendrig et al. (1976), and Ward et al. (1978) also suggest that high concentrations of aluminum in dialysate are important etiologic factors in outbreaks of the dialysis dementia syndrome. Dialysis patients often exhibit multiple osteomalacic fractures and myopathic changes, mostly in the proximal muscles (Flendrig et al., 1976;

400 300 - At ~ 200 a: G 1 00 o L 6 1971 12 6 1 972 1 ~ 12 6 1973 162 DRINKING WATER AND HEALTH ~ Alarm Purif icat~o;;~ A ~ ~ I iA~ 1 12 6 12 6 12 G 12 1974 1975 1976 YEAR _ 2 11 6 O FIGURE VI-1 Relationship between changes in water treatment and dialysis dementia: ~ = period of aluminum sulfate purification; = cater aluminum levels; * * = installation of deionizers at the too hospitals; dementia. Pierides, 1978; Platts et al., 1977~. The clinical features of this syndrome in- clude progressive skeletal pain. proximal muscle weakness, and spon- taneous fractures affecting primarily the ribs, pelvic rami, femoral necks, metatarsals, and other parts of the peripheral skeleton (Pierides, 1978~. The skeletal demineralization may result from the binding of gastrointestinal phosphate by aluminum, leading to a decrease in phosphate absorption, decreased urinary phosphate levels, and an increase in urinary calcium (Spencer and Lender, 19791. In a second interaction, aluminum in the gut also binds with fluoride, thereby decreasing fluoride absorption (Spencer et al., 1979~. This may further contribute to the skeletal demineralization, since fluoride might play a role in the maintenance of normal bone structure. = new cases of dialysis The major etiologic factor associated with this syndrome is untreated aluminum-rich tap water that is used to prepare the dialysis fluid. Aluminum is known to accumulate in the serum and tissues of chronic renal failure patients either after it is absorbed from the gastrointestinal tract (Alfrey et al., 1976) or after parenteral administration of a dialysis fluid containing a high concentration of aluminum (Elliott et al., 1978; Kaehny et al., 1977b). Interestingly, although many chronic renal failure patients consume large amounts of aluminum-containing antacids, this

Toxicity of Selected Inorganic Contaminants in Drinking Water 163 syndrome is distinctly absent in nondialyzed uremic patients, while ex- posure to repetitive hemodialysis for only 6 to 12 months may provoke this syndrome. The close relationship of this syndrome to dialysis is strengthened significantly by the repeated observation that in hemo- dialysis centers troubled by dialysis dementia or osteomalacic syndrome, a change to deionized water has helped to eliminate these complications (Dunea et al., 1978; Flendrig et al., 1976; Ward et al., 1978~. In another study' Pierides (1978) reported no new cases of the syndrome and a strik- ing improvement in 12 patients after the introduction of a water- processing plant involving the use of a water softener, reverse osmosis, and deionization' in that order (Pierides, 19781. Mayor et al. (1977a,b, 1978) indicated that PTH may also play an im- portant role in this syndrome because of its ability to increase the absorp- tion of aluminum in the gastrointestinal tract and because elevated levels of serum PTH have been found in most dialysis patients (Kleeman and Better, 1973~. Observations in Other Species Severe aluminum intoxication following parenteral or oral administration of aluminum hydroxide, chloride, or sulfate to rats is characterized by lethargy, anorexia, or death (Berlyne et al., 1972~. Other authors have found that intratracheal instillation of aluminum salts or metallic aluminum powder has produced pulmonary fibroses (Stacey et al., 1959~. Injected intraperitoneally, aluminum compounds produce fibrotic peri- tonitis (Norseth, 1979; Sorenson et al., 1974~. The LDso's for several aluminum salts administered by the various routes to several animal species are given in Table VI-2. The central nervous system is the major target organ for toxicity in mammals following administration of aluminum (Bland, 1978; Crapper and DeBoni, 1980; Norseth, 1979; Sorenson et al., 1974~. The neurotox- icity of aluminum has been demonstrated in the cat, rat, rabbit, and monkey following systemic administration subcutaneously or per os or after it was introduced directly into the central nervous system either in- tracisternally or intracerebrally (Crapper and Dalton, 1973a,b; Crapper et al., 1976; DeBoni et al., 1976; Klatzo et al., 19651. The major pathologic lesion is neurofibrillar degeneration, which is similar but not identical to that observed in Alzheimer's disease (Crapper and DeBoni, 1980; Crapper et al., 1976~. It has been suggested that this could serve as a model for Alzheimer's disease (Crapper and DeBoni, 19801. Administration of aluminum by oral or parenteral routes to uremic rats (5/6 nephrectomy) produced a clinical syndrome of lethargy, periorbital

164 DRINKING WATER AND HEALTH TABLE VI-2 Acute Toxicity of Aluminum Compounds Route of LDso, Compound Species Administration mg/kg References Aluminum Rat Oral 380 Krasovskii et al., 1979 chloride Guinea pig Oral 400 Krasovskii et al., 1979 Rabbit Oral 400 Krasovskii et al., 1979 Rat Oral 757 Spector, 1956 Mouse Oral 780 Ondreicka et al., 1966 Aluminum Rat Oral 542.5 Spector, 1956 nitrate Mouse (male) Intraper~toneal 37 Hart et al., 1971 Rat (female) Intraper~toneal 37 Hart and Adamson, 1971 Aluminum Mouse Intraperitoneal 6.3 Bienvenu et al 1963 sulfate Mouse Oral 970 Christensen, 1971 bleeding, anorexia, and death (Berlyne et al., 1972~. Other neurological syndromes produced by aluminum include that of epilepsy. High- frequency repetitive firing patterns comprising interictal bursts are consis- tent with findings in aluminum-treated animals (Goetz and Klawans, 1979~. Moseley et al. (1972) originally described such seizure activity in relation to focal hypothermia in a focus induced by aluminum oxide or alumina in experimental animals. Abnormal electrical activity has also been observed in animals given aluminum to induce neurofibrillar degenerative changes. Alterations in electroencephalograms did not occur until late in the encephalopathy. and sequential comparisons of photically evoked responses served as a more sensitive measure of progressive cor- tical pathology (Crapper, 19731. In the opinion of Ward (1972), the aluminum hydroxide model provides one of the most promising ap- proaches for studying processes underlying the epileptic focus. There have been few subacute or chronic studies of animals exposed to aluminum. Sorenson et al. (1974) reported long-term experiments in which laboratory mice were fed aluminum chloride in concentrations ranging from 100 to 200 mg/kg, which resulted in retarded growth and disturbances of phosphate and carbohydrate metabolism in the exposed animals. The same authors described studies of aluminum compounds as food additives. In small amounts (l<7o-2~o)' they stimulated growth, but higher amounts retarded growth and caused grave disturbances of phos- phate and calcium metabolism (Sorenson et al., 19741. The results of other studies in which aluminum was administered either subchronically or chronically are presented in Table VI-3. Schroeder and Mitchener (1975) exposed weanling male and female Long-Evans rats to aluminum potassium sulfate salt in concentrations of 5

Toxicity of Selected Inorganic Contaminants in Drinking Water 165 mg/liter in drinking water over the lifetime of the animals. Males fed aluminum grew significantly heavier, but the weight of the females were similar to those of the controls. Aluminum did not alter life span or the amount of glucose or protein in the urine. However, male rats at autopsy did have an increased incidence of gross tumors, but no increase in malig- nant tumors. Mutagenicity DiPaolo and Casto (1979) studied the effect of various metals on the in-vitro morphological transformation of Syrian hamster embryo cells. The results for aluminum chloride administered in concen- trations up to 20 ~g/ml were negative. In shorter experiments (20 to 30 days), aluminum chloride was given orally to rats, guinea pigs, and rab- bits in doses ranging from 3 to 50 mg/kg/day, and in chronic experiments (6 to 12 months) it was given to rats in oral doses ranging from 0.025 to 2.5 mg/kg. No chromosomal aberrations were found in bone marrow cells as a result of these exposures (Krasovskii et al., 1979~. Carcinogenicity Studies of animals have failed to demonstrate car- cinogenicity that is attributable to aluminum powder or aluminum salts as the hydroxide, phosphate, or oxide administered by various routes to rab- bits, mice, or guinea pigs (Furst, 1971; Furst and Harro, 1969; Shubick and Hartwell, 1969~. Teratogenicity In one study, concentrations of aluminum ranging from 500 to 1,000 ,`4g/g body weight were added to the diets of pregnant rats from day 6 to day 19 of gestation, when the fetuses were removed by Caesarean section. Aluminum in the diet did not affect embryo or fetal mortality rate, litter size, fetal body weight, or length (McCormack et al., TABLE VI-3 Subchronic or Chronic Toxicity of Aluminum Chloride Species Route Dose Duration Effects References Mice Oral 100 mg/kg Rat Oral 150 mg/kg Rat Oral 1 g/kg/day Ondreicka et al., 1966 Ondreicka et al., 1966 6-12 mot No change in growth or reproduction Negative phosphorus balance; decreased incorporation of 32p into phospholipids; decrease in ATP 18 days Decrease in liver Kortus, 1967 glycogen and coenzyme A

166 DRINKING WATER AND HEALTH 1979~. However, in a similarly designed experiment in which the pregnant mothers received subcutaneous injections of PTH (68 U/kg) on days 6, 9, 12, 15, or 18 of gestation, there was an increase only in the resorption rate in those animals receiving aluminum at 1,000 Agog body weight (McCor- mack et al., 19791. CONCLUSIONS AND RECOMMENDATIONS Suggested No-Ad verse-Response Level (SNARL) 24-Hour Exposure Kortus (1967) reported a minimum-effect dose for rats at 1 g/kg/day administered over an 18-day period (see Table VI-2. Using this value, applying a safety factor of 1,000, and assuming that a 70-kg human consumes 2 liters of drinking water daily and that 100% of exposure is from water during this period, one may calculate the 24-hour SNARL as: l.OOOmg/kg X 70 kg = 3s.0m /liter 1,000 x 2 liters g This value exceeds the solubility of aluminum in nonacidic solutions. Thus, it has only limited usefulness. 7-Day Exposure Based on the 24-hour SNARL, the 7-day SNARL is calculated: 35.0 mg/liter 7 = 5.0 mg/liter. This value also exceeds the solubility of aluminum in nonacidic solu- tions and, thus, has only limited usefulness. Chronic Exposure There are no adequate data from which to calculate a chronic SNARL. In view of the wide exposure of humans to aluminum in food, cos- metics, medicines, and water sources, it would appear that aluminum is relatively nontoxic to the majority of the population (Sorenson et al., 1974~. However, epidemiological studies indicate that chronic hemo- dialysis patients comprise a special population at risk. No studies have been conducted to determine what level of aluminum might be tolerated by this patient population. Pierides ( 1978) reported that some nephrologists believe that tap water containing aluminum concentrations of 50 ~g/liter is safe. However, studies by Alfrey et al. (1976) have shown

Toxicity of Selected Inorganic Contaminants in Drinking Water 167 that a positive aluminum balance will occur even at this level. Therefore, it is best if the dialysis fluid is prepared with softened water treated by reverse osmosis and deionization, in that order (Pierides, 19781. Further studies are needed to assess the molecular interaction of aluminum and the components of the central nervous system, which pro- duce the pathological changes observed in patients with Alzheimer's disease. Arsenic (As) Arsenic compounds were evaluated in the first volume of Drinking Water arid Health (National Academy of Sciences, 1977~. The EPA standard for arsenic is 50 ,ug/liter for drinking water (U.S. Environmental Protection Agency, 1977~. Although there is no reliable evidence that arsenic com- pounds produce tumors in laboratory animals, epidemiological studies show that the incidence of epidermoid carcinomas of the skin and lungs and precancerous dermal keratoses may be increased in humans who have been chronically exposed to arsenic compounds by oral or respiratory routes (Leonard and Lauwerys, 19801. Because of the continuing uncertainty surrounding what role, if any. arsenic has in the etiology of epidermoid carcinomas of the skin and lungs and precancerous dermal keratoses this subject needs further evaluation. The followup study to this volume will include a thorough review of the epidemiologic association between arsenic in drinking water and these conditions. Barium (Ba) Barium was reviewed in the first volume of Drinking Water and Health (National Academy of Sciences. 19771. At that time the committee con- curred with the reasoning of Stokinger and Woodward (1958), who con- cluded that a barium concentration of 2 mg/liter of water was safe for adults, but suggested a reduction to 1 mg/liter to provide an added margin of safety for children. This level was calculated from the threshold limit value (TLV) in industrial air, which remains at 0.5 mg/m3 (American Conference of Governmental Industrial Hygienists, 1980~. In the 1977 report, the committee pointed out that there had been no long- range feeding studies to confirm the safety of barium intake. This lack of data persists. Since the 1977 report was published. information has come to light in- dicating that the basis on which the original, and current, drinking water standard (1 mg/liter) was established may have been in error. Stokinger

168 DRINKING WATER AND HEALTH and Woodward (1958) assumed that 90~o of ingested barium was ab- sorped via the gastrointestinal tract. The rationale or documentation for using the 90% figure was not given in their report. Subsequently, Cuddihy and Ozog (1973) reported that the gastric absorption of barium- chloride-133 in Syrian hamsters was 11% + 13%. Another report in- dicated that the intestinal absorption of barium was 5'7o (Committee II on Permissible Dose for Internal Radiation, 1960~. Still another value of 20~o can be interpolated from data on the absorption of strontium and radium, which have physical properties quite similar to those of barium (Interna- tional Commission on Radiological Protection, 1972~. Thus, it seems quite clear that the original figure of 90% for the gastrointestinal absorp- tion of barium cannot be justified. Based on the conservative value of 20~o gastrointestinal absorption, the oral intake limit (maximum allowable con- centration) would increase from 1 mg/liter to 4.7 mg/liter. Calculations for the former oral intake limit were based on the original acceptable daily intake value of 3.75 mg derived from the 0.5 mg/m3 TLV by Stokinger and Woodward (1958), 90~o gastrointestinal absorption, the consumption of 2 liters of water daily, and an additional safety factor of 2: 3 75mg = 4 17mg; 2 mg/liter 2 = 1 mg/liter 4.17mg 2 lit = 2 mg/liter; Substituting the gastrointestinal absorption value of 20~o, one may calculate the oral intake limit as follows: 0 2 g = 18.75 ma; 9.375 mg/liter = 4 7 mg/liter. :Z Hi g = 9.375 mg/liter; Therefore, the committee recommends that the current drinking water standard of 1 mg/liter be reevaluated. One study in animals not reported in the first volume of Drinking Water and Health was conducted by Schroeder and Mitchener (1975~. In this study, male and female weanling Long-Evans rats were given a 5- mg/liter concentration of barium as barium acetate in drinking water over a lifetime. In general, there was no toxicity, in terms of survival time or ef- fect on growth rate. Minor changes were noted in fasting serum glucose and cholesterol values. There was an increase in proteinuria in males. The above results were extended and confirmed when Tardiff et al.

Toxicity of Selected Inorganic Contaminants in Drinking Water 169 (1980) studied the subchronic oral toxicity of barium chloride in adult rats. Groups of rats of both sexes were given barium chloride in their drinking water at levels of 0, 10, 50, or 250 mg/liter for 4, 8. or 13 weeks. The investigators observed no adverse effects on food consumption, body weight, hematologic indices, serum enzymes, serum ions, gross pathology. or histopathology. They noted a slight decrease in the relative weights of the adrenal glands at the highest doses (p = > 0.05~. This study provides further evidence of the low degree of toxicity resulting from the subchronic ingestion of barium. Brenniman et al. (1979) studied death rates from cardiovascular disease in communities with elevated levels of barium in drinking water. They compared the rates in communities with barium levels ranging from 2.0 to 10.0 mg/liter with those from communities with 0.0 to 0.2 mg/liter. When age- and sex-adjusted death rates for cardiovascular disease in high- and low-barium communities were compared, there was a higher (p > 0.05) death rate for both males and females in the high-barium communities for "all cardiovascular deaths," "health disease" (atheroscelerosis), and "all causes." When male and female death rates were analyzed separately' only male deaths from "all cardiovascular disease" and female deaths from "all causes" were significant. The authors mentioned several con- founding factors that make it difficult to interpret the results of this study. For example, the high-barium communities had a considerable popula- tion increase between 1960 and 1970, while the low-barium communities were more stable. This could influence the duration of exposure that would most likely play a role in any possible effect of barium. Moreover, it was not possible to control for the use of home water-softeners. Since there may be a relationship between softened water and cardivascular disease (National Academy of Sciences, 1977), this confounding variable could be important. Brenniman et al. (1981) also studied the effects of barium in public water supplies on blood pressure. They compared two populations in III- inois whose drinking water supplies contained mean barium drinking water levels of 7.3 mg/liter and 0.1 mg/liter. All other drinking water con- stituents were approximately equal in the supplies of the two com- munities. They found no significant differences (p > 0.05) in either systolic or diastolic blood pressures between the high- and low-barium com- munities. Adjustments for duration of exposure, use of home waters softeners, and treatment for hypertension did not alter the findings. This study is of interest because of the current general lack of information on health effects resulting from chronic exposure to barium. It also partially addresses several problems that were encountered in their original (1979) study. Further intensive study of these two populations is strongly recom- mended in light of the conflicting results obtained to date.

170 DRINKING WATER AND HEALTH CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level (SNARL) 24-Hour Exposure The reported lethal dose of barium chloride in humans is 800 to 900 mg (550 to 600 mg of barium) (Sollmannq 1957a). Threshold toxic doses range from 120 to 500 mg/day (Reeves. 19791. Based on a safety factor of 10 and the assumption that 100870 of the exposure during this period comes from a 2-liter daily intake of drinking water, the SNARL would be: 120 mg = 6 0 mg/liter. 10 X 2 liters 7-Day Exposure If the 24-hour SNARL is divided by 7, the value derived (0.86 mg/liter) is less than the current drinking water standard. Therefore, there are no adequate data from which to calculate a reason- able 7-day SNARL. Chronic Exposure The average concentration of barium in U.S. drink- ing water is 28.6 ,ug/liter (range, 1 to 172 ,ug/liter (National Academy of Sciences, 1977~. The drinking water of many communities in Illinois, Kentucky, Pennsylvania, and New Mexico contains concentrations of barium that may be 10 times higher than the drinking water standard. The source of these supplies is usually well water. Because many people are exposed to those concentrations, it would be prudent to extend the observations of Brenniman et al. (1981) to potential effects other than those on cardiovascular disease and blood pressure. The data of Schroe- der and Mitchener (1975) are the only chronic data available. Unfortu- nately, these investigators used only a single dose of barium (5 mg/liter). Although that dose produced no effects, it may be a low estimate of the no-effect level. Therefore, there are no adequate direct data from which to calculate a chronic SNARL for barium. However, the committee believes that the recalculated value of 4.7 mg/liter provides an adequate margin of safety for chronic exposure to barium. Cadmium (Cd) Cadmium was reviewed in the first and third volumes of Drinking Water and Health (National Academy of Sciences, 1977, 1980b) as well as in a recent EPA document (U.S. Environmental Protection Agency, 1979b). Since then, a plethora of research reports concerned with the toxicity of this element have been published. However, few of them deal directly with

Toxicity of Selected Inorganic Contaminants in Drinking Water 171 health effects that are relevant to establishing safe levels of cadmium in drinking water. The current drinking water standard is 10 ~g/liter. The following material is based only on reports not covered in the ear- lier volumes of this series. There is additional information on the possible relationship between cadmium and hypertension (Calabrese et al., 1980), but it is not considered here since it goes beyond a general toxicological review. HEALTH ASPECTS Observations in Humans In humans, acute oral doses of cadmium usually result from the ingestion of food or beverages that have been contaminated during storage in cadmium-plated containers. The initial symptoms include severe nausea, vomiting, diarrhea, muscle cramps, and salivation (Arena, 1963~. When fatal intoxication occurs, these symptoms are followed either by shock due to the loss of liquid and death within 24 hours or by acute renal failure and cardiopulmonary depression and death within 7 to 14 days (Gosselin et al., 1976). According to McKee and Wolf (1963), punch containing cadmium con- centrations of 67 mg/liter has caused sickness. If 200 to 500 ml of punch had been consumed, the cadmium intake would have been 13 to 35 ma. Swedish schoolchildren were acutely poisoned after consuming a fruit drink from a distributing machine that had a cadmium-plated reservoir containing water in which cadmium concentrations ranged from 0.5 to 16 mg/liter (Friberg et al., 1974~. Various estimates of acute oral toxicity to cadmium are as follows: · 3 to 90 mg emetic threshold (Arena, 1963; McKee and Wolf, 19631; · 15 mg experimentally induced vomiting (Browning, 1969; McKee and Wolf, 1963~; · 10 to 326 mg severe toxic symptoms. but not fatal (Gosselin et al., 19761; and · 350 to 3,500 mg estimated lethal doses (Gosselin et al., 1976~. Observations in Other Species The no-effect level for cadmium administered orally to animals in food or drinking water is approximately 10 mg/kg and 10 mg/liter, respectively. Kotsonis and Klaassen (1978) exposed male rats to cadmium at concen- trations of 10, 30, and 100 mg/liter for 24 weeks. Testicular function, blood pressure, heart rate, electrocardiogram, hematocrit, blood

172 DRINKING WATER AND HEALTH hemoglobin, plasma glucose, aniline hydroxylase, hexobarbital oxidase, cytochrome P-450, organ weights, bone calcifications, and histopathology were examined at 3, 6, 12, and 24 weeks. The major toxicity noted was renal injury, which was indicated by an increase in urinary protein for the rats receiving cadmium in concentrations of 30 and 100 mg/liter but not at 10 mg/liter. The chronic exposure SNARL given in Volume 3 of Drink- ing Water and Health (National Academy of Sciences, 1980b) was based on a no-effect level of 10 mg/liter, which was reported by Decker et al. (1958~. After administering drinking water containing cadmium concentrations of 250 mg/liter to male rats for periods of 2 or 8 weeks, Hietanen (1978) reported alterations in hepatic and renal cytochrome P-450 levels. No other concentrations of cadmium were used in this study. Mutagenicity Several reports suggest that cadmium is mutagenic. Deknudt and Gerber (1979) found chromosomal aberrations in bone mar- row cells of male C57BL mice maintained on a low-calcium (0.03~o) diet supplemented with cadmium (0.06~o). DiPaolo and Casto (1979) found morphological transformations of Syrian hamster embryo cells induced by direct exposure to cadmium (0.1, 0.5, and 1.0 ~g/ml). Watanabe et al. (1979) administered cadmium (1.0, 2.0, or 4.0 mg/kg) subcutaneously 5 hours prior to ovulation to study its mutagenic effects on the metaphase II oocyte chromosomes of virgin female golden hamsters. No structural anomalies were observed, but the frequencies of hyperhaploidy and diploidy increased in the cadmium-treated hamsters, especially in those given higher doses. After injecting hybrid (CBA X C57BL)F~ mice with a cadmium dose of 4 ,ug/kg, Vilkina et al. (1978) observed no difference between the number of chromosomal abe'Tations in the bone marrow of the treated mice and in the controls. Carcinogenicity Loser (1980) fed a diet containing cadmium chloride to male and female rats for 2 years. Concentrations of cadmium were 1, 3, 10, and 50 mg/kg. The results of the study showed no association between the oral administration of cadmium and an increased incidence of tumors or of any specific type of neoplasia. CONCLUSIONS AND RECOM~NDATIONS Suggested No-Adverse-Response Level (SNAR1J 24-Hour Exposure From the studies cited by Arena (1963), the threshold emetic dose of cadmium in humans is approximately 3 ma.

Toxicity of Selected Inorganic Contaminants in Drinking Water 173 Therefore, assuming a safety factor of 10, one may calculate the 24-hour SNARL as: 10 X 2 liters = 0.150 mg/liter. 7-Day Exposure Using the data for the 24-hour exposure and dividing by 7, one may calculate the 7-day SNARL as: 0 15mg/liter = 0.021 mg/liter. Benes (1978) has cited a "provisional tolerable weekly intake" of cad- mium for humans as 6.7 to 8.3 ,ug/kg based on a report of the World Health Organization (1973~. Using these data, applying a safety factor of 10, and assuming 100% intake from 2 liters of drinking water daily by a 70-kg human, one may calculate the 7-day SNARL's as: and 6.7pg/kg X 70 kg = 0.o23smg/liter 8.3 ,ug/kg X 70 kg _ 0 0291 /lit Thus, the 7-day SNARL's calculated on the basis of either human or animal data are in rather good agreement. Chronic Exposure These calculations are based on the data of Decker et al. (1958), who gave rats cadmium in water in a concentration of 10 mg/liter for 1 year without effect. Weight loss and anemia were observed when cadmium was administered in concentrations of 50 mg/liter for 3 months. The data of Kotsonis and Klaassen (1978) support the 10 mg/liter con- centration of cadmium as the no-effect level. Assuming that the rats con- sumed an average of 30 ml of water daily and that their average weight was 400 g, one may calculate the daily exposure as: 10 mg/liter X 0.03 liter/day 0.4 kg = 0.75mg/kg.

174 DRINKING WATER AND HEALTH Using a safety factor of 1,000 for a 70-kg human consuming 2 liters of water daily and assuming a 20'%o exposure from drinking water, one may calculate the SNARL as: 0.75 mg/kg X 70 kg X 0.2 1,000 X 2 liters = 0.005 mg/liter. Chlorinated Disinfectants: Chlorine Dioxide (CI02), Chlorate (CIO3-), Chlorite (CIO2-), and Chloramines (NH2CI or NHCI2) Chlorine dioxide, chlorate, chlorite, and chloramines were reviewed in Drinking Water and Health, Volume 3 (National Academy of Sciences, 1980b, pp. 193-202~. The chemistry of these agents was examined in detail in that volume. The following material, some of which became available after that volume was published, updates and, in some instances, reevaluates the information in the earlier report. METAB OLISM Studies in rats suggest that chlorine dioxide is converted to chloride, chlorite, and chlorate. Chlorine dioxide is rapidly absorbed after oral ad- ministration, and plasma levels peak within 1 hour after dosing. Forty- three percent of the administered dose was excreted in urine and feces within 72 hours. None was detected in expired air. The plasma half-life was determined to be 44 hours in rats (Abdel-Rahman et al., 1980a,b). HEALTH ASPECTS Observations in Humans In recently completed experiments (Bianchine et al., 1980), adult male volunteers were given water containing chlorine dioxide, chloramine, chlorite, or chlorate. The study was carefully controlled, and subjects were monitored by physical examination, measurement of vital signs, assess- ment of side-effects, and an extensive battery of clinical laboratory tests. Control subjects were given distilled water, and a positive control group was given water containing chlorine. A brief description of these studies follows. Acute Effects Two adults ingested 250 ml of chlorine dioxide in water containing concentrations of 40 mg/liter. Within 5 minutes of ingestion,

Toxicity of Selected Inorganic Contaminants in Drinking Water 175 sudden headache, nausea, abdominal discomfort, and light-headedness were observed. These effects disappeared within 5 minutes. Subchronic and Chronic Effects In a "rising-dose tolerance study," chlorine dioxide was administered in two separate 500-ml doses of water consumed over lS-minute intervals' 4 hours apart. The concentrations of chlorine dioxide were 0.1, 1.0, 5.0, 10.0, 18.0, and 24.0 mg/liter on days 1, 4, 7, 10, 13, and 16 of the study, respectively. In a similar manner, both chlorite and chlorate were each administered in concentrations of 0.01, 0.1, 0.5, 1.0, 1.8, and 2.4 mg/liter, on the days indicated above, to two additional groups of 10 subjects. Chloramine was given to a sixth group at 0.01, 1.0, 8.0, 18.0, and 24.0 mg/liter on days 1, 4, 7, 10, and 13 of the study, respectively. Accumulated data, averaged for all dose ranges in the study, revealed no striking, clinically relevant changes among these groups. In a subsequent study, groups of healthy adult males were given a 500-ml solution containing chlorine dioxide, chlorite, chlorate, chlorine, or chloramine in concentrations of 5 mg/liter. The solutions were consumed daily for 12 weeks and subjects were monitored for an additional 8 weeks after treatment. No clinically significant alterations were observed in any of the parameters studied. Nor were there serious objections to the taste of the disinfectants at these concentrations. Additional studies were conducted in three subjects deficient in glucose- 6-phosphate dehydrogenase activity who were given sodium chlorite at 5 mg/liter in the same manner as described above. Again, no adverse effect was noted. Other investigators have suggested that persons with this defi- ciency may be at a greater risk of oxidant damage (Moore et al., 19781. Observations ire Other Species Acute Effects In one male cat given sodium chlorite at 64 mg/kg orally, methemoglobin reached 45% of total hemoglobin within 1 to 2 hours and was still at 20~o of the total 6 hours later. In three other cats, given sodium chlorite at 20 mg/kg, methemoglobinemia reached loo to 30~o of total hemoglobin within 2 to 3 hours. In male rats, 20 mg/kg, but not 10 mg/kg, given intraperitonally caused slight but significant methemoglo- binemia, which was shot-lived (30 to 60 minutes). Higher doses produced much greater levels of methemoglobinemia, but these were also short- lived (Heffernan et al. 1979a). Acute oral dosing of rats with chlorine dioxide concentrations of 0.18 to 0.72 mg/kg produced no methemoglobinemia but caused a slight de

176 DRINKING WATER AND HEALTH crease in blood glutathione concentration within 15 minutes. This pro- gressed to an approximately 20~o decrease within 2 hours (Abdel-Rahman et al., 1980b). Subchronic and Chronic Effects Sodium chlorite was administered to male cats in their drinking water for up to 90 days. No change in ratios of kidney, liver, or spleen to body weight were observed after 60 days of ex- posure to 25 mg/liter (Heffernan et al., 1979a). In the same study, dose- dependent decreases in e~throcyte count, hemoglobin, and packed cell volume were observed after 30 days. Yet, these parameters returned to near-normal levels during 60 additional days of exposure. None of these effects were observed in animals consuming 50 mg/liter or less in their drinking water. In contrast, dose-related decreases in glutathione and in- creases in 2,3-diphosphoglyceric acid in the blood were observed in rats drinking 50 to 100 mg/liter (but not 10 mg/liter) sodium chlorite for up to 90 days. These effects rendered the cells more susceptible to oxidative damage and confirmed similar in-vitro observations (Heffernan et al., 1979b). Couri and Abdel-Rahman (1979) conducted similar studies over a 12- month period in male rats given chlorine dioxide, chlorate, and chlorite, and in male mice given chlorine dioxide. Their data suggest oxidative stress to erythrocytes. However, the effects were not clearly dependent on dose. Only four control rats were included, and in some cases both eleva- tion and depression of a parameter were produced by different doses of the same disinfectant. Therefore, it is difficult to assess the biological im- portance of these l~OSUitS. They reported that chlorine dioxide, chlorite, and chlorate, adminstered for 3 months in water, decreased the incor- poration of 3H-thymidine into the nuclei of rat testes and kidneys and in- creased its incorporation into the intestine. No-effect levels and dose dependency of effects were not reported. Cats given sodium chlorite in water concentrations of 500 mg/liter for 5 weeks experienced a signficiant decrease in hemoglobin and packed cell volume. When the concentration was increased to 1,000 mg/liter, hemoglobin decreased sharply. Removal of chlorite from the water was followed by a return toward control values within 3 weeks. Red cell half- life in viva was shortened significantly by concentrations of chlorite at 100 mg/liter or more, but not by concentrations of 10 mg/liter. These latter concentrations were adjusted to account for water consumption variabil- ity, and dosages were estimated to be 0.6 mg/kg/day for 10 mg/liter and 3.0 mg/kg/day for 100 mg/liter (Heffernan et al., 1979a). Mutagenicity No available data.

Toxicity of Selected Inorganic Contaminants in Drinking Water 177 Carcinogenicity No available data. Teratogenicity No available data. CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level (SNARL) Extensive studies of the effects of chlorinated disinfectants in humans per- mit estimation of SNARL's for chlorate, chlorite, chlorine dioxide, and chloramine. The calculations are based on a safety factor of 10 and an assumption that 100% of exposure is through the drinking water and that a 70-kg human consumes 2 liters daily. In order to make comparable cal- culations for chlorine, additional toxicity data are needed. A concentra- tion of 5 mg/liter of each of the disinfectants was not considered to have a seriously objectional taste by the test subjects. 24-Hour Exposure In the "rising-dose tolerance study," subjects con- sumed two 500-ml bolus doses, each containing chlorate in concentrations of 2.4 mg/liter, with no ill effects. In the chronic study, subjects consumed one 500-ml bolus dose daily containing ~ mg/liter without acute effects. Assuming a safety factor of 10 and that 100% of exposure is from drink- ing water during this period, one may calculate the 24-hour SNARL as: 5 mg/liter X 0.5 liter 10 X 2 liters = 0.125 mg/liter. Concentrations of chlorite identical to those for chlorate were also well tolerated in the two studies: 5 mg/liter X 0.5 liter 10 X 2 liters = 0.125 mg/liter. In the rising-dose tolerance study, subjects consumed two 500-ml bolus doses, each containing chlorine dioxide in concentrations up to 24 mg/liter without ill effect. Assuming a safety factor of 10, one may calculate the 24-hour SNARL as: 24 mg/liter X 1 liter 10 X 2 liters = 1.2 mg/liter.

178 DRINKING WATER AND HEALTH Four of the 10 subjects considered concentrations of 10 mg/liter to be unpleasant in taste. Concentrations of chlorami''e up to 24 mg/liter were also well tolerated in the same dosage regime as that for chlorine dioxide. Assuming a safety factor of 10, one may calculate the 24-hour SNARL as: 24 mg/liter X 1 liter to X 2 liters = 1.2 mg/liter. Five of the 12 subjects considered concentrations of 8 mg/liter to be unpleasant in taste. 7-Day Exposure Since concentrations of chlorate, chlorite chlorine dioxide, and chloramine were administered to humans at 5 mg/liter (500 ml daily) for 12 weeks with no apparent adverse effect, this concentration has been selected for projection of a 7-day SNARL. Assuming a safety fac- tor of 10, one may calculate the SNARL as: 5 mg/liter X 0.5 liter 10 X 2 liters = 0.125 mg/liter. Chronic Exposure No additional lifetime studies in animals have been reported since these disinfectants were reviewed in Drinking Water and Health, Volume 3 (National Academy of Sciences. 1980b). A 12-week study conducted by Bianchine et al. (1980) suggests that humans can tolerate daily doses of 500 ml of each of the disinfectants alone in water at 5 mg/liter. However' it would be premature to project this value for chronic exposure. CONCLUSIONS AND RECOMMENDATIONS In light of the evidence that both chlorate and chlorite appear in animals given chlorine dioxide in their drinking water, additional studies are needed to evaluate the effects of lifetime exposure to these agents and to deter- mine no-effect levels. Additional studies are needed to determine if the studies in male laboratory animals and in humans are valid for females of both species. At present, there is not enough information to determine if persons with genetic disorders, such as hereditary methemoglobinemia and glucose-6-phosphate dehydrogenase deficiency, and other persons unusually susceptible to oxidants may be at greater risk than the general population. Additional studies are needed to resolve this.

Toxicity of Selected Inorganic Contaminants in Drinking Water 179 Lead (Pb) Lead was evaluated in the first volume of Drinking Water and Health (Na- tional Academy of Sciences, 1977, pp. 254-261) and more recently by the EPA (U.S. Environmental Protection Agency, 1979a). The following material, some of which became available after the 1977 publication, up- dates and, in some instances, reevaluates the information in the earlier report. Also included are some references that were not assessed in the original report. Since that first volume was published, the EPA standard for lead in water has continued at 50 ,ug/liter (U.S. Environmental Pro- tection Agency, 1977, 1979a). HEALTH ASPECTS Observations in Humans There are a number of recent reviews of the effects of exposure to lead on human health (Goyer, 1974; Goyer and Mushak, 1977; Hammond, 1977; Mahaffey, 1977; National Academy of Sciences, 1980a; Nordberg, 1976; Waldron and Stofen, 1974~. Acute lead poisoning in humans is almost nonexistent today, but subchronic and chronic lead poisoning is common, especially among urban children. In general, the concentration of lead in the blood has been measured to determine if there has been excessive absorption of lead. Specific, lead- induced biochemical or functional disorders are commonly associated with specific ranges of lead concentrations in blood. The concentrations of free erythrocyte porphyrin is becoming widely accepted as a vety sensitive indicator of lead exposure and is currently used in many urban screening programs to detect excessive lead intake (Hammond and Beliles, 1980~. Studies of humans have demonstrated that infants and young children are more susceptible than adult females, who are more susceptible than adult males to biochemical effects of lead. Excessive lead intake results primarily in adverse effects on three target systems: the heme- hemoprotein system, the kidneys, and the nervous system. Effects in the first have been studied most, while effects on the nervous system, especially the developing nervous system, constitute a very active research area. In most cases, recommended maximum daily intakes of lead are based on studies of the heme synthetic pathway or the monitoring of lead concen- trations in blood. Concern about the contribution of drinking water to daily lead intake is not new. It has been well established that soft, acid water will extract lead

180 DRINKING WATER AND HEALTH from lead-containing supply pipes or water storage vessels. This may result in lead concentrations in drinking water that exceed the recom- mended EPA standard of 50 ,ug/liter (Won" and Berrang, 1976~. Morse et al. (1979) suggested that lead leached from pipe may only pose a prob- lem in urban areas where lead intake from sources other than water is significant. In a rural setting (Bennington, Vermont), they found no cor- relation between blood lead and lead concentrations in the water. On the other hand, there have been several recent studies of the relationship be- tween concentrations of lead in water and those in blood. Greathouse et al. (1976) studied 774 persons from 323 greater Boston area households. Their results suggested that lead concentrations in water exceeding 50 ,ug/liter contributed to elevations of lead in blood in excess of 30 ,ug/dl. Moore et al. (1977) also found that blood lead concentrations increased as a function of the level of lead in drinking water but that the relationship was curvilinear. Thus, increasing concentrations of lead in water from 50 to 100 ,ug/liter would elevate lead by only 11% above the value at 50 mg/liter. Calcium, phosphate, and iron in the water may af- fect lead absorption (Ziegler et al., 1978), thereby contributing to disagreement among such studies. In these studies, the water samples included both first-draw morning samples and daytime running water samples. This point is raised because Pocock (1980) recently reported that the lead content of water samples drawn in Great Britain from 1,071 households with lead plumbing varied greatly with the time of sampling. For example! the ratio of lead concen- tration in daytime samples to that in first-draw samples ranged from 0.25 to 2.0. This study emphasizes the need for standardized sampling tech- niques if predictions of lead ingestion from drinking water are based on tap water analyses. Many common problems that can affect the accuracy of measurements of lead in water and elsewhere are discussed in a recent review of lead (National Academy of Sciences' 1980a). It is clear that both analytical and water sampling methodology must be refined. Infants and young children absorb ingested lead more readily than do older children and adults (Ziegler et al., 19781. Mahaffey (1977) recom- mended that the lead intake for children less than 6 months of age should be no more than 100 ,ug/day, and for children between 6 months and 2 years of age, it should be no more than 150 ~g/day. These estimates were based on a critical review of the health effects of lead ingestion in infants and young children, taking into consideration factors such as body weight, body surface area, and food and water consumption. Thus, the current standard of 50 ,ug/liter would permit a child to ingest one-half to one-third of the recommended maximum daily lead intake by consuming

Toxicity of Selected Inorganic Contaminants in Drinking Water 181 1 liter of water daily. This would present no danger if exposure to lead from other sources were minimized (Mahaffey, 19771. Of major concern today are the reported subtle effects of lead on be- havior, especially in infants and young children. Bornschein et al. (1980) have recently prepared a critical review of the major studies of the effects of low-level chronic lead exposure on behavior in children. Adverse effects on behavior and intelligence have been reported to occur at exposure levels below those causing encephalopathy (Hammond and Beliles, 1980; Krigman et al., 1980), but not at blood lead concentrations below 50 g/100 ml (National Academy of Sciences, 1980a, p. 771. Thus, it would seem that alterations in heme synthesis are the most sensitive responses to lead exposure, since such disturbances have been reported in children with blood lead levels of 15 to 30 ,ug/100 ml (National Academy of Sciences, 1980a, p. 77~. Environmental and occupational exposure to lead has been associated with adverse effects on reproduction, e.g., premature births, miscar- riages, sperm abnormalities, etc. However, there are no conclusive data indicating that lead is teratogenic in humans (Krigman et al., 1980; Na- tional Academy of Sciences, 1980a, p. 1271. This is a very serious potential problem and extensive effort should be directed toward a definitive solu- tion. Observations in Other Species Acute Effects The acute LDso of lead acetate administered to rats in- traperitonially is reported to be 150 mg/kg. Oral doses of 300 mg/kg have been reported to be lethal to dogs (Spector, 1956~. Absorption of lead was enhanced in rats made anemic by bleeding (Angle et al., 1977~. Iron deficiency anemia also results in enhanced lead absorption (Six and Goyer, 1972~. Subchronic and Chronic Effects Free erythrocyte porphyrin was measured in adult male and female and suckling rats after oral dosing with lead in drinking water. Young rats were more susceptible than adult females, which were more susceptible than adult males to elevated free erythrocyte porphyrin (Buchet et al., 1978~. Krasovski et al. (1979) ad- ministered lead acetate to rats orally for up to 6 months. They found no adverse effects on biochemical behavior or gonadal function at 1.5 ,ug/kg/day. Yet, at dosages of 5 and 50 ,ug/kg/day, they observed domi- nant lethal, adverse behavioral, and gonadotoxic effects. They suggest that 1.5 ,ug/kg/day is equivalent to 30 ~g/liter in the drinking water. No

182 DRINKING WATER AND HEALTH measurements of blood lead concentrations or free etythrocyte porphyrin were reported. The effects of lead on the nervous system and behavior are being studied in many animal models. Evidence from such studies clearly in- dicates that pre- and perinatal exposure to lead may alter neurological development, behavior, and learning ability in laboratory animals. At present, however, there is insufficient evidence to characterize the dose- effect relationship between lead intake or lead concentrations in tissue with nervous system impairment (Bornschein et al.. 1980; Krigman et al., 1980; National Academy of Sciences, 1980a, pp. 70-75~. Mutagenicity In mice, lead acetate was reported to be mutagenic in the sperm abnormality assay but not in the micronucleus or Salmonella tests (Heddle and Bruce, 19771. Carcinogenicity Several studies have demonstrated that lead can cause renal tumors in rats. There is also some evidence of lead-induced brain tumors in rats, renal tumors in mice, and lung tumors in hamsters. Very high doses of lead were used in all of the tests. The data produced by these studies are inadequate to permit estimates of risk to humans. There is no evidence of lead-induced carcinogenicity in humans (International Agency for Research on Cancer' 1972; National Academy of Sciences, 1980a, p. 128; U. S. Environmental Protection Agency, 1979a). Teratogenicity Teratogenic effects of lead have been observed primarily in the nervous system only after high doses of lead were given to rats on day 9 of gestation. When administered at other times, lead was fetotoxic (Michaelson and Sauerhoff, 19741. CONCLUSIONS AND RECOMMENDATIONS The current Safe Drinking Water Committee agrees with the conclusion reached in the first edition of Drinking Water and Health (National Academy of Sciences, 1977, pp. 260-261~: ... the present limit of 50 ,ug/liter may not, in view of other sources of en- vironmental exposure, provide a sufficient margin of safety, particularly for fetuses and young growing children. Although further studies will be necessary to arrive at a reasonable limit, it is suggested that the limit be lowered. This recommendation is made with the assumption that analytical methodology will be sufficient to detect this value above background.

Toxicity of Selected Inorganic Contaminants in Drinking Water 183 There is no evidence that lead is carcinogenic or teratogenic in humans, and evidence of mutagenicity is scant. But special consideration must be given to the greater susceptibility of infants and young children to lead ac- cumulation and test results suggesting that absorption of 1~1 in In ~ O ~ ~ i_ . . . . In anemic animals. Although it appears that 50 /liter mav not nrovir1~ adequate protection of certain high risk groups, in light of the report by Pocock (1980) and the problems of lead analysis and data interpretation (National Academy of Sciences, 1 980a). this committee can not now c' gest a lower lead standard. The ~x ~, ~. .· r c~ ~ ~ ~- ~^ If ~ v ~ low ~ , ~ ne committee recommends that the following actions be taken: · Studies relating lead concentrations in drinking water to those In blood must be conducted in a way that permits accurate determination of lead ingested in the water consumed. Tap water analyses are too unre- liable for this purpose. · Action is required to minimize extraction of lead from supply system pipes into drinking water. · Additional research is needed to determine whether or not lead is truly a carcinogen in laboratory animals. If it is, then appropriate dose- response data are needed to permit projection of such risks to the human population. · Additional research is needed to determine no-effect levels for lead- induced alterations in behavior and other nervous system effects and to clarify the question of the suggested adverse effects of lead exposure on human intelligence. · Additional research is needed to determine if humans are at increased risk of teratogenic or reproductive effects from lead exposure. Suggested No-Adverse-Respo'~se Level (SNARL) 24-Hour and 7-Day Exposures There are no adequate data from which to calculate a 24-hour or a 7-day SNARL. Chronic Exposure Since the carcinogenicity of lead has not yet been resolved, no chronic SNARL can be calculated. Silver (Ag) Silver was reviewed in the first volume of Drinking Water arid Health (Na- tional Academy of Sciences, 1977) and more recently by the EPA (U.S. Environmental Protection Agency, 1979c).

184 DRINKING WATER AND HEALTH This white, ductile metal occurs naturally in pure form and in ores, most commonly in argentite (Ag2S). It is used principally as an electrocon- ductor and in photographic materials, electroplating, dental alloys, solder and braying alloys, paints, jewelry, silverware, coinage, and mirrors (Goodman and Gilman, 1975~. Silver nitrate (1~o-2~o) is used medicinally in the prophylaxis of ophthalmia neonatorum. Silver protein (Argyrol@) and silver sulfadiazine (Silvadene@) are used as topical antiinfectives (Martin, 1965; Pariser, 1978~. In some instances, silver has been used to purify water since silver con- centrations from 0.001 to 500 ,ug/liter have been reported to be sufficient to sterilize water (McKee and Wolf, 1963~. Concentrations exceeding 150 ,ug/liter have been used to purify swim- ming pools, but because of the cost and the opalescence caused by col- loidal silver chloride, the method is not practical nor is it recommended for public water supplies (National Academy of Sciences, 1977~. Natural freshwaters contain an average silver concentration of 0.2 ,ug/liter, and seawater contains an average of 0.24 ,ug/liter (Boyle, 1968~. Kopp and Kroner (1970) found silver in 6.6~o (130) of 1,577 surface water samples collected in the United States. Concentrations in samples containing silver varied from 0.1 to 38 ,ug/liter, averaging 2.6 ,ug/liter. Examination of finished water in public supplies of the 100 largest cities in the United States revealed trace quantities of silver as high as 7 ,ug/liter (median, 2.3 ,ug/liter) (Durfor and Becker, 1962~. In another survey of finished water, silver was found in 6.1 % of 380 samples in concentrations ranging from 0.3 to 5 ,ug/liter (mean, 2.2 ,ug/liter) (Kopp, 19691. In yet another study, a maximum silver concentration of 26 ,ug/liter was found in 2,595 samples from household taps within 959 public water supply systems (McCabe, 1970~. After reviewing the literature, Snyder et al. (1975) estimated that the average daily intake of silver by Reference Man was 70 ,ug/day, 30 ,ug of which was ingested in food. In earlier balance studies, Kehoe et al. (1940) determined that the daily dietary intake of silver by humans in the United States was 88 ,ug. A source of dietary silver in addition to food and drinking water is possibly dental amalgams, which are dissolved in the mouth by saliva (Wyckoff and Hunter, 1956~. Until 1962, there were no restrictions on silver in drinking water. The current standard for silver in drinking water is 50 ,ug/liter (National Academy of Sciences, 1977~. METABOLISM Silver may enter the body via the respiratory tract, the gastrointestinal tract, mucous membranes, or broken skin. Estimates of the amount of

Toxicity of Selected Inorganic Contaminants in Drinking Water 185 silver absorbed from the gastrointestinal vary widely. A value of 10% is reported by Hill and Pillsbury (1939) but they did not provide documen- tation. A more adequately supported value is given by Scott and Hamilton (1950), who showed that 4 days after administration of silver by stomach tube, 99~o had been eliminated in the feces and 0.18% in the urine of rats. A similar value was reported by Jones and Bailey (1974), who fed some rabbits food containing 4.2 mg/kg of silver iodide and others a diet containing 10 mg/kg of silver nitrate. They found that 99% of the silver was eliminated in 3 days and essentially all of it in 6.3 days. They also noted that after 30 days, when rabbits maintained on a diet containing silver were compared with rabbits on a silver-free diet, the concentration of silver in the livers of both groups was the same. Some silver is retained by virtually all body tissues. In persons not tak- ing silver therapeutically, the primary sites of deposition are the liver, skin, adrenals, lungs, muscles, pancreas, kidney, heart, and spleen. Some silver is also deposited in blood vessel walls, testes, pituitary gland, nasal membrane, trachea, and bronchi (Furchner et al. 1968; Sax, 19631. It tends to accumulate in the body as one ages (Hill and Pillsbury, 1939~. Silver is transported primarily by the globulin fraction of the blood. Most of the absorbed silver is removed from the body via the reticuloen- dothelial system, especially the liver (Scott and Hamilton, 19501. Excre- tion in the urine is very low; only trace amounts ~ < 1.0%) being present. The biological half-life of silver in rats is described by two exponential functions, giving half-life values of 8 days and 20 days (Phalen and Mor- row, 1973~. After inhalation, the half-life in the human lung is approx- imately 1 day (Newton and Holmes, 1966), and the half-life for the other tissues is 15 days (Phalen and Morrow, 1973~. HEALTH ASPECTS While metallic silver is not regarded as toxic, most of its salts are toxic to many organisms. These salts can combine with certain biological molecules, subsequently altering their properties (Goodman and Gilman, 1975~. Large oral doses of silver nitrate cause severe gastrointestinal irrita- tion due to its caustic action. Ingestion of 10 g of silver nitrate is usually fatal. Observations in Humans The most common noticeable effects of chronic and subacute human ex- posure to silver or silver compounds are generalized argyria or localized argyria, involving primarily the eye. The most important causes of argyria

186 DRINKING WATER AND HEALTH are the medicinal application of silver compounds and industrial exposure (Goodman and Gilman, 1975; Hill and Pillsbury, 19391. Symptoms of generalized argyria include a slate-gray pigmentation of the skin, hair, and internal organs resulting from the deposition of silver in the tissues. The degree of pigmentation is highest in portions of skin exposed to light, even though the concentration of silver in the skin of other parts of the body is the same. Additional manifestations include silver coloration of fingernails and conjunctive and a blue halo around the cornea. In localized argyria, pigmentation is limited. Generalized argyria as an occupational disease was never common, occurring mainly among silver nitrate workers. Other toxic effects only indirectly attributable to the use of silver compounds in the treatment of burn patients include: electrolyte imbalance, from hypotonicity of silver nitrate dressings (Wood, 1965), and methemo~lobinemia. from reduction of nitrate to nitrite (Strauch et al., 1969~. ~7 Observations in Other Species Acute toxic effects of silver in animals are usually associated with in- travenous administration of silver nitrate (at approximately 32 mg/kg), which will produce pulmonary edema in dogs (Hill and Pillsbury, 1939~. Other effects involve the central nervous system, producing symptoms such as weakness, rigidity, contractures in the legs, loss of voluntary movements, and interference with cardiac blood supply. The LDso for silver nitrate administered intraperitoneally to male Swiss albino mice was 13.9 mg/kg (Bienvenu et al., 1963~. For silver sulfadiazine given to CF-1 mice, the LD90 ~00 was > 1,050 mg (Wysor, 1975~. in a sunchron~c study lasting i~ weeks, Cane et a`. Ale gave silver to rats via the drinking water in a concentration of 1,000 mg/kg. They observed no effects on body weight, fluid intake, food consumption, or measures of forelimb or hindlimb strength, but water consumption was reduced by approximately 25~o. Mutagenicity Silver has not been found to be mutagenic in the Salmonella Ames test (McCoy and Rosenkrantz, 1978~; in the "rec-assay," in which differential sensitivities to killing by chemicals are observed in wild-type and recombination-deficient strains of Bacillus subtilis (Nishioka, 1975~; or in mutation tests in Micrococcus aureus (Clark, 1953) or Escherichia cold (Demerec et al., 19511. Carcinogenicity Some studies involving implanted foils, disks, or in- jected colloidal suspensions or metallic silver have been found to produce

Toxicity of Selected Inorganic Contaminants in Drinking Water 187 tumors or hyperplasia, but the interpretations of such findings have been questioned (Becker et al., 1967; Northdurft, 1955; Saffiotti and Shubik, 1963~. Furst and Schlauder (1977) did not find any tumor formation from silver powder administered subcutaneously. In summary, although the literature is replete with clinical reports of cases of argyria, the relation- ships between human cancer and silver as the causative agent are very tenuous. Teratogenicity No available data. CONCLUSIONS AND RECOMMENDATIONS Unless some new data become available, this committee remains in agree- ment with the authors of Drinking Water and Health, Volume 1 (National Academy of Sciences, 1977), who stated on page 292: There seem to be no pressing research needs with regard to silver in drinking water. There seems to be little possibility that the addition of oligodynamic silver will have any place in public water supplies, and natural concentrations are so low that consideration should be given to taking silver off the list of substances included in primary drinking-water standards. There are no adequate data from which to calculate 24-hour, 7-day, or chronic SNARL's. Strontium (Sr) Strontium is a silvery-white alkaline earth metal (Periodic Group IIA) that has a valence of two and exists in several isotopic states, some of which are radioactive. Strontium occurs naturally in two ores strontium sulfate (celestite) and strontium carbonate (strontianite) (Browning, 1969~. Strontium and its salts have many industrial uses such as providing the red color in pyrotechnic devices as tracer bullets, distress signal rockets, flares, and fireworks. They are also used as rubber fillers, as corrosion in- hibitors, in plastics, in ceramics, in luminous paints, in sugar refining, and in alloys of tin and lead (Browning, 1969; Venugopal and Luckey, 1978~. In medicine, strontium bromide has been used as a sedative, an an- tiepileptic, and in the therapy of urticaria and skin rashes (Schroeder et al., 1972; Venugopal and Luckey, 1978~. Strontium is the fifteenth most abundant element in nature (400-500 mg/kg in the earth's crust), and it is the most abundant trace element in seawater (8-10 mg/liter) (Schroeder et al., 1972; Venugopal and Luckey, 1978~. Thus, it has become incorporated into all plants and animal tissues

188 DRINKING WATER AND HEALTH since they have evolved in the presence of strontium. The amounts of strontium in natural freshwaters in the United States may vary from ap- proximately 0.007 to 15 mg/liter. averaging about 0.5 mg/liter. The average concentrations of strontium in finished or municipal water sup- plies in the United States is approximately 10 mg/liter (range, 2.2 to 1,200 mg/liter) (Schroeder et al., 19721. The daily intake of strontium varies from about 1.8 to 2.0 mg/day. Of this. a negligible quantity is supplied by air, approximately 60% to 90% by food. and the remaining 10870 to 40% by water (Schroeder et al., 1972; Tipton et al., 19661. Strontium is present in many foods, e.g., spices. seafood, cereals. grains, and leafy vegetables (Beliles, 1979~. Since strontium and its salts are relatively nontoxic or of very low toxic- ity, they are not regarded as industrial health hazards (Beliles, 1979; Browning, 1969; Schroeder et al., 1972; Venugopal and Luckey, 19781. There is some evidence that strontium is essential for the growth of animals, especially for the calcification of bone and teeth (Browning, 1969), but its role as a trace element has not been proven (Schroeder et al., 19721. A maximum ambient environmental level for strontium in potable water was set at 10 mg/liter (Dawson, 19741. This value was extrapolated from minimal lethal dose data obtained in animals and has a very low level of reliability. METAB 0~! SM There is a paucity of recent information on the metabolism of strontium. From previous studies, it would appear that the metabolism of strontium closely resembles that of calcium, especially with regard to bone (Brown- ing, 1969; Schroeder et al.' 19721. However, in most biological processes there is a distinct preference for calcium assimilation and utilization as compared to strontium (Browning, 1969; Chen et al.. 1961~. The gastrointestinal absorption of strontium is described as poor, vary- ing from approximately 5% to 25% of the ingested dose (Browning, 1969; Schroeder et al., 1972~. However, absorption is affected by species, age, and other dietary constituents such as calcium (Browning 1969; Schroeder et al., 1972; Venugopal and Luckey, 1978~. The 70-kg standard human described by Schroeder et al. (1972) con- tains approximately 320 mg of strontium, but this amount may vary with the geographical location. The skeleton contains more than 99% of the strontium. The rest is distributed among soft tissues, the largest concen- trations residing in the aorta, larnyx, trachea, and lower gastrointestinal tract (Beliles, 1979; Schroeder et al., 19721.

Toxicity of Selected Inorganic Contaminants in Drinking Water 189 The pattern of excretion of strontium varies with the species and the route of exposure. Strontium administered parenterally or absorbed from the gastrointestinal tract is excreted primarily via the urine (Browning, 1969; Schroeder et al., 19721. When administered orally, it is excreted primarily in the feces (Browning, 1969~. Strontium is also excreted in the sweat and in the milk of lactating females (Browning, 1969; Schroeder et al., 1972; Sollman, 19571. HEALTH ASPECTS Strontium poisoning is rare and in most instances is accidental (Venugopal and Luckey, 1978~. Current interest in the toxicity of stron- tium is concerned primarily with the radioactive isotope, 90Sr, which is present in radioactive fallout as a fission product from nuclear explosions. This isotope is a potential radiation hazard and has been implicated as a causative agent in bone cancers and leukemia (Chen et al., 1961; Schroeder et al., 1972~. This report is concerned with the chemical toxicity of the stable isotopes of strontium. Observations in Humans There is little evidence that strontium causes chronic disease in humans (Schroeder et al., 19721. As mentioned above, strontium compounds have been used medicinally for various purposes. In an early study, McCance and Widdowson (1939) administered 47 mg of strontium lactate daily for 5 days by intravenous injection. They re- ported no symptoms of toxicity. Although it has been proposed by some that strontium may be essential for the development of mammalian bone structure, nothing is known about its biochemical functions, if any, in bone or soft tissue (Schroeder et al., 19721. In balance studies conducted by Tipton et al. (1966), the average daily intake by adult subjects was approximately 1.8 mg daily, which seemed to be in balance with the amount that was excreted. Observations in Other Species Table VI-4 lists the acute toxicities of some strontium compounds in various species. As can be seen, the toxicity of these compounds van with the anion. Acute poisoning in laboratory animals leads to excess saliva- tion, vomiting, colic, and diarrhea. In rats, death is due to respiratory failure; in cats, it is due to cardiac arrest (Browning, 1969; Venugopal and

190 TABLE VI-4 Acute Toxicity of Strontium Saltsa Dosage/kg Body Weight Metal Compound, Compound Animal Routeh Toxicity' mgmg mM Strontium fluoride Rat iv LDloo625 436 4.98 Guinea pig oral MLD5,000 3,490 39.8 Guinea pig sc MLDS,OOO 3,490 39.8 Strontium chloride Mouse iv LD50148 82 0.94 Mouse ip LDso908 502 5.73 Rat ip LDso405 224 2.56 Rat iv MLD123 68 0.78 Rabbit iv LDso1,060 590 6.73 Strontium chloride Rat iv MLD400 221 2.52 Strontium bromide Rat ip LD501,000 246 2.81 Rat iv MLD500 177 2.02 Strontium iodide Rat ip LDso800 156 1.78 Strontium nitrate Rat ip LDso540 224 2.56 Strontium fluoroborate Rat oral MLD500 155 1.77 Strontium acetate Mouse iv MLD123 52.3 0.60 Mouse iv LD'oo383 163 1.86 Rat iv MLD239 101 1.15 Rat iv LDloo238 101 1.15 Rat iv LDso105 44.5 0.51 Strontium lactate Rat ip LDso900 247 2.82 Strontium salicylate Rat ip LDso363 88 1.0C a From Venugopal and Luckey, 1978. biv, intravenous; sc, subcutaneous; ip. intraperitoneal. CLD, lethal dose; MLD, minimum lethal dose. Luckey, 1978~. Major signs of chronic toxicity, which involve the skeleton, have been labeled as "strontium rickets." Follis (1955) produced rickets in laboratory rats by feeding them strontium carbonate at 2~o strontium in the diet. Johnson (1973) has found that the bones of weanling male and female rats fed a diet high in strontium content (0.2~o) for 8 weeks will generally exhibit severe aberrations. Gross examination revealed that bones were deformed and shorter than normal. Histologically, strontium-laden bone had widened epiphyseal cartilage plates of irregular outline and trabeculae with prominent osteoid seams. These changes were accom ;

Toxicity of Selected Inorganic Contaminants in Drinking Water 191 panted by a marked reduction in bone ash, elevated magnesium and potassium levels, and a depressed calcium content in bone. Mechanism studies by Omdahl and DeLuca (1971, 1972) indicate that the bone aberrations result from an inhibition of calcium absorption by dietary strontium as a result of a block in the renal synthesis of 1,25-dihydroxycholecalciferol from 25-hydroxycholecalciferol (Omdahl and DeLuca. 1971, 1972~. In 90-day studies, Kroes et al. (1977) fed male and female Wistar rats strontium in strontium chloride at 75, 300, 1,200, and 4,800 mg,'kg diet. They did not find any changes in behavior, growth, food intake, or food efficiency, but observed minor changes in hematology and blood chemistry at the highest dose. In the female rats given the highest dose, the glycogen content of the liver was decreased at 12 weeks. Thyroid weights were increased in males in the 1,200 and 4,800 mg/kg groups. Forbes and Mitchell ( 1957) fed adult male and weanling male and female rats strontium in the diet at levels of 10, 30, 100, and 1,000 mg/kg for 8 weeks. They found no differences in food intake, weight gain, total bone ash, calcium and phosphorus composition of the bone ash, or other signs of toxicity in the strontium-fed rats. Mutagenicity Loeb et al. (1977) using an i''-vitro assay to measure the fidelity of DNA synthesis, observed no effects from strontium added in vitro. Carcinogenicity No data available for evaluation. Teratogenicity No data available for evaluation. CONCLUSIONS AND RECOMMENDATIONS The chemical toxicity of the stable isotopes of strontium is considered to be quite low. Although Dawson (1974) suggested that strontium in potable water should not exceed 10 mg/liter based on LDSo data, he evaluated this calculation as having the "lowest level of reliability." Suggested No-Adverse-Response Level {SNARLJ 24-Hour Exposure There are no data from which to calculate the 24-hour SNARL for strontium. However, based on the 90-day study of Kroes et al. (1977), the 24-hour exposure level would be at least 8.4 mg/liter.

192 DRINKING WATER AND HEALTH 7-Day Exposure Using the data of Kroes et al. (1977), who found the no-effect level of strontium to be 3~)0 mg/kg after 90 days of exposure in the diet, and assuming that the rats consumed 20 g of food daily and that their average weight was 250 g, one may calculate the daily exposure level as: 300 mg/kg/day X 0.02 kg/day = 24 mucky 0 25 k -~ ~~~-~ ~~-~ O O Using a safety factor of 100 and assuming that a 70-kg human con- sumes 2 liters of water per day, and that 100% of exposure is from water during this period, one may calculate the 7-day SNARL as: 24mg/kg X70 kg 84 /li tion. Chronic Exposure There are no data from which to make this calcula Sulfate (S04) Sulfate was reviewed in the first volume of Drinking Water and Health (National Academy of Sciences, 1977~. The no-adverse-health-effect level recommended at that time was 500 mg/liter, whereas the taste threshold may be as low as 200 mg/liter. No additional data pertaining to the effects of inorganic sulfates have been reported since that report was published. REFERENCES Abdel-Rahman, M.S, and D. Couri. 1980. Toxicity of chlorine dioxide in drinking water. P. A-29, No. 86 in Abstracts of Papers, Society of Toxicology. Nineteenth Annual Meeting, March 9-13. Washington, D.C. Abdel-Rahman, M.S., D. Couri, and J.D. Jones. 1980a. Chlorine dioxide metabolism in rat. J. Environ. Pathol. Toxicol. 3:421-430. Abdel-Rahman, M.S., D. Couri, and R.J. Bull. 1980b. Kinetics of CIO2, and effects of CIO2, ClO2-, and C103- in drinking water and blood glutathione and hemolysis in rat and chicken. J. Environ. Pathol. Toxicol. 3:431-449. Alfrey, A.C., G. R. LeGendre, and W.D. Kaehny. 1976. The dialysis encephalopathy syn- drome. Possible aluminum intoxication. N. Engl. J. Med. 294:184-188. Angle, C.R., M.S. Mclntire, and G. Brunk. 1977. Effect of anemia on blood and tissue lead in rats. J. Toxicol. Environ. Health 3:557-563. American Conference of Governmental industrial Hygienists. 1980. Threshold limit values for chemical substances and physical agents in the workroom environment with intended

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