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v The Contribution of Drinking Water to Mineral Nutrition in Humans GENERAL CONSIDERATIONS OF MINERAL INTAKE FROM WATER The initial undertaking of the first Safe Drinking Water Committee (SDWC) was the identification of substances and their concentrations in the national water supply that might pose risks to the public health and, therefore, require the setting of limits. The committee's report, Drinking Water and Health (National Academy of Sciences, 1977) contained gaps for which data were not available or were just emerging at the time the report was written. In other cases. the data were not reviewed in depth because the specific substances were not considered pertinent to the initial charge of the committee, i.e., identification of adverse conse- quences of various substances in water. One such area was that of nutrients, known to be essential or strongly suspected as being necessary for optimal health of humans and animals. While a few of the nutrients, notably the trace elements, were reviewed in the first report, the coverage was generally toxicological. The committee examined them as sources of potential risk to human populations. In view of these considerations, the second Safe Drinking Water Committee established a Subcommittee on Nutrition arid charged it with the responsibility of reviewing this area by selecting elements of interest and evaluating the effects of their presence in water. In this report, the subcommittee has examined the concentrations of nutrients in dr eking water and the contribution of these concentrations to the observed 265

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266 DRINKING WATER AND H"LTH intake and optimal nutrient requirements of human populations. It studied the benefits of the presence of an element in water and, in cases in which symptoms of both deficiency and toxicity are known to occur, adverse effects. This is a departure from most of the studies of the SDWC conducted previously or in progress, which were or are limited to adverse effects. The subcommittee chose to title this review The Contribution of Drinking Water to Mineral Nutrition in Humans, focusing on the positive effects of suites of elements that are known or assumed to interact in the environment or in biological systems. In Drinking Water and Health (National Academy of Sciences, 1977), the committee reviewed eight metals (chromium, cobalt, copper, magne- si-am~ manganese, molybdenum, tin, and zinc) that are essential to human nutrition. The nutritional aspects of others, such as nickel, selenium, arsenic, and vanadium, were not considered. Rather, their toxicity was reviewed. In this study the subcommittee has reviewed potassium, chlorides iron' calcium, phosphorus, and silicon, and has extended the original review only where there was a need for updating or for examining ~ particular element as a nutrient as opposed to a potentially toxic substance. In the section on fluoride, the subcommittee decided against including an in-depth review because of its uncertainty concerning fluoride's essentiality to nutrition. However, in view of the contribution of fluoride to overall dental health and, through this, its eject on total health, some discussion of fluoride has been included. Chromium has not been dealt with at great length because it is not certain that the nutritionally useful form of the element occurs in water. It is generally thought that cobalt has nutritional value only as a component of vitamin By. Although some preliminary studies suggest that inorganic cobalt may have a physiological role independent of its functon in vitamin BE (Roginski and Mertz, 1977), cobalt has not been discussed in this chapter. The subcommittee also examined the difference in water intake between young and adult humans. Infants (7 kg) consume approximately one-third as much water on the average as an adult, but their body weight is only approximately one-tenth of adult weight and their food intake is also obviously lower. For this reason, the water intake of an infant may contribute a significant quantity of a given element (National Academy of Sciences 19744. When people consume unusual diets, e.g., the diets of vegans. who consume no animal foods or dairy products, the intake of certain elements may be significantly different from the average. Athletes or people engaged in heavy labor and those living in a hot climate consume larger than normal amounts of water. In these instances, the contribution

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Contribution of Drinking Water to Mineral Nutrition 267 of water to the overall nutrient intake may be significantly different from the average. The contributions from air have been considered only when amounts of possible significance were suspected. Where such contributions were negligible, no comment has been made. Only in rare instances. such as unusually high airborne levels, might air contribute to the nutrient needs of individuals. It is not always known whether elements taken in from such exposures are used for nutritional (metabolic) purposes. Requirements for nutrients are generally discussed in terms of the recommended dietary allowances (RDA's) (National Academy of Sciences, 1974) or those intakes that have been judged adequate and safe (National Academy of Sciences 1980) not minimal intakes necessary for survival. The subcommittee examined the new literature on water hardness because it involves nutritionally essential elements. However, it found no significant conclusive data concerning the relationship of water hardness and the incidence of cardiovascular disease since Drinking Water and Health (National Academy of Sciences, 1977) was published. An extensive evaluation of the literature in this area has recently been published (National Academy of Sciences, 19791. Therefore, this topic is not covered in this report. Clearly, some elements that have been reviewed are subject to changes in concentration in water because of the activities of humans. Elements in this category are zinc, copper, molybdenum, tin, manganese, nickel, and vanadium. These may require somewhat closer surveillance than elements such as magnesium whose concentrations in water appear to be little affected by human activity. The subcommittee believes that a study of the contribution of drinking water to mineral nutrition in humans is essential in a balanced appraisal of drinking water. It also believes that the data in this review are up-to- date and accurate and that they should help those charged with evaluating the nutritional value of drinking water in the United States. Most information on the mineral composition of water has been gathered from large v~ater-supply systems. In 1975, approximately 35.7 million water consumers ( 16.7% of the population) were served by systems supplying less than 25 persons. The minerals in water from smaller systems and individual supplies, e.g., wells, may exceed the concentrations in large water supplies which form the basis for most levels cited in this report. Therefore, the potential contributions of water to nutrient intake that are given below must not be taken as the absolute . . . llamas. The interplay between mineral elements and nutrition is exceedingly

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268 DRINKING WATER AND H"LTH complex. In this report, it has been considered in light of the best available knowledge, but it should be remembered that this knowledge is still incomplete. CALCIUM Presence in Food and Water Dairy products provide the largest source of calcium in the American diet. Table V-1 lists calcium concentrations for some of these products and other foods (Davidson et al., 19751. In a survey of U.S. surface waters from 1957 to 1969, calcium levels ranged from 11.0 to 173.0 mg/liter (mean, 57.1 mg/liter) for 510 determinations (National Academy of Sciences, 1977~. Finished water that was sampled ire public water supplies for the 100 largest cities in the United States contained almost as much calcium (range, 1-145 mg/liter). The calcium concentrations in 9337O of the city supplies were less than 50 mg/liter (Durfor and Becker, 1964~. Similar results were reported in a Canadian study (Nerd et al., 1977~. Zoeteman and Brinkmann (1977) reported that the public water supplies for 21 large European cities contained between 7 and 140 mg/liter (mean, 85 mg/liter). The daily intake of calcium for most western adult populations averages between 500 and 1,000 mg (Walker, 19721. The U.S. Health and Nutrition Examination Survey estimated calcium intakes for 20,749 people from 1 to 74 years old, and concluded that the only population segment with an intake appreciably (Woo 4057O3 below the recommended daily allowance was the adult black female. The allowance values used in this survey were 450 mg for children aged 1 to 9 years, 650 mg for ages 10 to 16 years, 550 mg for ages 17 to 19 years, 400 mg for men 20 years and older? 600 mg for women 20 years or older, 800 mg for pregnant women, and 1,100 mg for lactating women (Abraham et al., 19771. Requirements The amount of calcium required by the body daily and the level of dietary calcium needed to meet this requirement are controversial issues. Healthy individuals accustomed to low-calcium diets appear to do as well as similar individuals accustomed to high calcium intakes. To some extent, the daily calcium allowances recommended by various interna- tional agencies reflect the calcium levels of normal local diets. In the United States, the Food and Nutrition Board of the National Research

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Contribution of Drinking Water to Mineral Nutrition 269 TABLE V- 1 Calcium Concentrations in Foods and Foodstuffs a Food Item Calcium Concentration, mg/100 g or rngllOO rot Cheese, hard Cheese, soft Milk, cow Milk, human Nutmeats Legumes, dried Vegetables, leafy Vegetables, roots Grains, whole Eggs Fish Sardines, whole Meats Fruits SOO- 1 ,200 80-725 20 20-40 13-250 40-200 25-2s0 20-100 4-60 50-60 17-100 400 3-24 3-60 a Data from Da~dsone~al., 1975. Council (National Academy of Sciences, 1974) has recommended daily calcium intakes of 80{) mg/day for adults on the basis that the daily excretion of calcium is 320 mg and that only 4037c of dietary calcium is absorbed by the average American. However, the excretion rate and absorption percentage can vary with age and physiological state. The recommended dietary allowances (RDA) of calcium for Americans, then, are 360 mg for infants less than 6 months old, 540 mg for 6- to 12- month-old infants, 800 mg for children aged 1 to 10 years, 1,200 mg for 11- to 18-year-old children, and 800 mg for individuals 19 years and older. During pregnancy and lactation the RDA is increased to 1,200 mg/day. Toxicity Versus Essential Levels DEFICIENCY There is no clearly defined calcium deficiency, syndrome in humans. This may be due, in part. to an adaptation in calcium absorption and utilization which varies with calcium intake. In a study of 26 male prisoners ranging in age from 20 to 69 years, Maim (1958) observed that 23 of them achieved calcium balance immediately or within several

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270 DRINKING WATER AND H"LTH months after restricting their calcium intakes from 650 or 930 mg/day to approximately 450 mg/day. The etiology of osteoporosis, a degenerative disease involving loss of bone calcium, is not clear, but prolonged inadequate intakes of calcium may play an integral role. Diets that were deficient in both calcium and vitamin D caused rickets and osteoporosis to develop in rats 6 weeks after they had been started on the diet at weaning. Osteoporosis was reversed when the rats were given a high-calcium diet that still lacked vitamin D (Gershon-Cohen and Jowsey, 1964~. When the animals were 2 months old before receiving the low calcium, vitamin-D-deficient diet, osteoporosis resulted without rickets. Osteoporosis affects a large portion of older people and is most prevalent in older women. Calcium supplements that were given to osteoporosis patients for 2 years did not appear to reverse the calcium loss from bone (Shapiro et al., 1975~. Hypocalcemia due to impaired alimentary adsorption of calcium in newborn children can result in tetany, consisting of twitches and spasms (Davidson et al., 1975, p. 645~. TOXICITY Calcium is relatively nontoxic when administered orally. There have been no reports of acute toxicity from the consumption of calcium contained in various foods. Peach (1975a) indicated that calcium intakes in excess of 1,000 mg/day when coupled with high vitamin D intakes can raise blood levels of calcium. An excess of 1,000 mg/day (2.5 times the RDA) for long periods can depress serum magnesium levels. Diets that are high in calcium have also produced symptoms of zinc deficiency in rats, chickens, and pigs after prolonged feeding. Kidney stones in humans have been associated with high calcium intakes (Hegsted, 1957~. Interactions Low calcium intakes increase the rat's susceptibility to lead poisoning (Snowdon and Sanderson 1974), while high intakes of calcium decrease lead absorption from the intestine (Kostial et al., 1971~. Recent studies in young children have associated high blood levels of lead with low dietary intakes of calcium. MahaFey and coworkers (1976) observed that 12- to 47-month-old children with normal concentrations of lead (~0.03 mg/100 ml) in their blood had higher levels of dietary calcium (and

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Contribution of Drinking Water to Mineral Nutrition 271 phosphorus) than did matched children with elevated (>0.04 mg/100 ml) lead levels in their blood. Dietary calcium intake was not reported. Sorrel and coworkers (1977) found concentrations of lead and calcium in blood inversely correlated in control and lead-burdened children aged 1 to 6 years. For children with high concentrations of lead ~ 20.06 mg/100 ml blood). average daily calcium intakes were 610 + 20 ma, while children with blood lead concentrations <0.03 mg/100 ml had average daily calcium intakes of 770 + 20 ma. Itokawa et al. (1974) suggested that the bone pain in itai-itai disease in Japan was causally related to diets low in calcium and protein coupled with cadmium poisoning. Low calcium intakes increase the intestinal absorption of cadmium and the deposition of cadmium in bone and soft tissue (Pond and Walter, 1975~. Furthermore, cadmium inhibits the synthesis of 1,25-dihydroxycholecal- ciferol by reread tubules (Suda et al., 19731. This hormone facilitates intestinal absorption of calcium (Suda et al., 1974), an especially important function when calcium intake is low. The same or highly similar mechanisms may control the absorption of calcium and ma~e- sium into the bloodstream and their deposition into tissues. Contribution of Drinking Water to Calcium Nutrition Using an average calcium concentration in public water supplies of 26 mg/liter and a maximum of 145 mg/liter (Durfor and Becker, 1964) and assuming that the average adult drinks 2 liters of this water daily, then the drinking water could contribute an average of 52 mg/day and a maximum of 290 mg/day. On an average basis this would represent 5% to 10% of the usual daily intake or approximately 6.5% of the adult RDA. For hard waters with high calcium levels, the water would contribute approximately 29% to 58% of the usual daily intake or approximately 36% of the adult RDA. Thus. public drinking water generally contributes a small amount to total calcium intake, but in some instances it can be a major contributor. Conclusions Current levels of calcium in U.S. drinking water are well below levels that pose known risks to human health. No upper limit for calcium need be set to protect public health. In cases of dietary calcium deficiencies the presence of this element in drinking water may provide nutritional benefit.

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272 DRINKING WATER AND HEALTH MAGNESIUM Presence in Food and Water Schroeder and coworkers (1969) measured the magnesium contents of a variety of foods and foodstuffs using atomic absorption spectrophotome- try. On a wet weight basis, spices, nuts, and whole grains had the highest magnesium contents, and refined sugars, human milk, oils, and fats had the lowest. The food data are summarized in Table V-2. Magnesium and calcium are responsible for most of the hardness of drinking water. In a nationwide study in Canada, the mean concentra- tion of magnesium in finished water before it entered the distribution systems was 10.99 mg/liter. This concentration changed little during distribution (Nerd et al., 19771. In the United States, the mean concentration of magnesium in public water supplies in 100 cities was 6.25 mg/liter (range, ~120 mg/liter). The concentration of magnesium in 96% of the water supplies was <20 mg/liter (Durfor and Becker, 19644. From 1957 to 1969, the average magnesium concentration in U.S. surface waters was 14.3 mg/liter (range, 8.5-137 mg/liter) for 1,143 determinations (National Academy of Sciences, 1977~. In the United States, the average adult ingests between 240 and 480 mg of magnesium daily (Wacker et al., 19774. Approximately 60% to 7090 of this is excreted in the feces. The British diet is reported to provide 200 to 400 mg of magnesium daily (Davidson et al., 19751. Requirements The daily need for dietary magnesium is a function of the amounts of calcium, potassium, phosphate, lactose, and protein consumed. For the average healthy American on an average diet, the daily magnesium intake recommended by the Food and Nutrition Board of the National Research Council (National Academy of Sciences, 1974) is 60 mg for infants less that 6 months old, 70 mg for 6- to 12-month-old infants, 150 mg for 1- to 3-year-old children, 200 mg for 4- to 6-year-old children, 250 mg for 7- to 10-year-old children, and 300 mg for females 11 years and older. For adolescent and adult males the recommended dietary allowances (RDA's) are 350 mg for ages 11 to 14, 400 mg for ages 15 to 18 years, and 350 mg for those 19 years of age and older. The RDA for pregnant and lactating women is 450 ma.

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Contribution of Drinking Water to Mineral Nutrition 273 TABLE V-2 Magnesium Concentrations in Foods and Foodstuffsa Magnesium Concentration, Bag Single Values Food Item or Range Mean Condiments, spices 230-4,225 2,598 Nuts 1,078-3,175 1,970 Grains and cereal products 18-2,526 805 Fish and seafood 154-532 348 Meats 195-402 267 Vegetables, fresh legumes 185-297 241 Fresh roots 75-478 226 Fresh fleshy 66-487 174 Fresh leafy 85-321 170 Dory products, eggs 102-270 183 Fruits and juices 102-270 78 Sugars and syrups 0.1-108 59 Milk, human 28-29 29 Oils and fats 1-27 7 Beverages Coffee 48 barb Tea 3- 11 NR Whisky, gin 0.3-4.5 NR Wine,white 98 FIR Beer 100 NR Vermouth, Italian 135 NR a Data from Schroeder et al., 1969. b NR, not reported. Toxicity Versus Essential Levels DEFICIENCY Despite several studies. magnesium deficiency in humans is still not well defined, primarily because it has been studied in individuals also suffering from other metabolic and physiological disorders. Electrolyte imbalance, especially for calcium and potassium. is characteristic of magnesium deficiency. Magnesium deficiency is most often observed in patients with gastrointestinal diseases that lead to malabsorption and in those with hyperparathyroidism, bone cancer, aldosteronism, diabetes mellitus, and

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274 DRINKING WATER AND H"LTH thyrotoxicosis (Wacker and Parisi, 1968~. Alcohol can deplete magne- sium levels in heavy drinkers by apparently increasing renal loss. These heavy drinkers show extensive neuromuscular dysfunction such as tetany, generalized tonic-colonic and focal seizures, ataxia, vertigo, muscular weakness, tremors, depression, irritability, and psychotic behavior. By giving them magnesium, these dysfunctions can be reversed (Wacker and Parisi, 1968~. In the rat, prolonged magnesium deficiency retards growth and results in loss of hair? skin lesions, edema, and degeneration of the kidney (Kruse et al., 1932~. TOXICITY Because magnesium is rapidly excreted by the kidney, it is unlikely that magnesium in food and water is absorbed and accumulated in tissues in sufficient quantities to induce toxicity. Magnesium salts are used therapeutically as cathartics, e.g., magnesium sulfate (MgSO4), hydrox- ide [Mg(OH)2], and citrate iMg33tOOCCH2COH(COO)CH2COO]; as antacids, e.g., magnesium hydroxide, carbonate iMg(CO3~], and trisili- cate (Mg20~3Si3~; and as anticonvulsants to control seizures associated with acute nephritis and with eclampsia of pregnancy (magnesium sulfate). In patients with renal disease and impaired magnesium excretion, large excesses of magnesium can lead to severe toxicity resulting in muscle weakness, hypotension' sedation, confusion, de- creased deep tendon reflexes, respiratory paralysis, coma, and death. At plasma concentrations exceeding 9.6 mg/100 ml (8 mEq/liter) central nervous system depression is evident. Arlesthesia is reached near 12 ma/ 100 ml ( 10 mEq/liter), and paralysis of skeletal muscle can be produced at plasma concentrations of approximately 18 mg/100 ml (15 mEq/liter) (Peach 1975a). Normal values are 1 to 3 mg/100 ml (0.8 to 2.5 mEq/liter). Calcium ameliorates magnesium toxicity. Interactions The interactions of trace elements in nutrition were reviewed in Drinking Water and Health (National Academy of Sciences, 1977~. The metabo- lism of magnesium is tied closely to that of calcium and potassium. Magnesium deficiency results in potassium loss, probably due to the interaction of magnesium and phosphate in the active transport of potassium and sodium across cell membranes. The release of parathy- roid hormones calcitonin? and 1,25-dihydroxycholecalciferol, which are hormones that govern calcium and phosphorus metabolism, is reduced

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Contribution of Drinking Water to Mineral Nutrition 275 by lowered magnesium intakes. The mechanism for this reduction is not understood. Contribution of Drinking Water to Magnesium Nutrition Using the magnesium concentrations reported by Durfor and Becker (1964) for U.S. drinking waters (median, 6.25 mg/liter; maximum, 120 mg/liter), a daily intake of 2 liters of drinking water would supply an average of approximately 12 mg of magnesium and a maximum of up to 240 ma. For Canadian (Nerd et al. 1977) and Western European (Zoeteman and Brinkmann, 1977) drinking waters the daily contribution would be approximately 20 and 24 mg of magnesium, respectively. Therefore, typical drinking water in the United States, Canada, or Europe provides approximately 3% to 7?'o of the RDA for magnesium intake by a healthy human. In areas where the magnesium concentration is high, over 50% of the RDA could come from 2 liters of water (see Table V-321. Thus, drinking water could provide a nutritionally significant amount of magnesium for individuals consuming a diet that is marginally deficient in magnesium, especially in areas where the magnesium concentration in water is high. Conclusions Current levels of magnesium in U.S. drinking water supplies appear to offer no threat to human health, and no upper limit for magnesium concentrations needs to be set to protect public health. For individuals consuming a magnesium-deficient diet, the presence of this element in drinking water may provide nutritional benefit. PHOSPHORUS Presence in Food and Water Phosphorus, in the form of phosphate, is common to most foods and foodstuffs. In foods of plant origin, phosphorus concentrates in seeds. Nuts, beans, and whole grains contain high levels of phosphorus, whereas leafy vegetables contain low levels. Fruits contain little phosphorus, but meat and fish are relatively rich in the mineral. Table V-3 summarizes the phosphorus contents of some of the foods listed by Sherman (19524. Data collected on the average daily consumption of soft drinks in the

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394 DRlNKlNG WATER AND H"LTH McCabe, L.J., J.M. Symons, R.D. Lee, and G.G. Robeck. 1970. Survey of community water supply systems. J. Am. Water Works Assoe. 62:67~687. National Aeademy of Seienees. 1977a. Arsenic. Report of the Subcommittee on Arsenic, Committee on Medical and Biologic Effects of Environmental Pollutants, National Aeademy of Sxcienees, Washington, D.C. 332 pp. National Aeademy of Seienees. 1977b. Dnnking Water and Health. Safe Drinking Water Committee, National Aeademy of Seienees, Washington, D.C. 939 pp. Nielsen, F.H., and T.R. Shuler. 1978a. Arsenie deprivation studies in chicks. Abstr. No. 3577. Fed. Proe. 37:893. Nielsen, F.H.' and T.R. Shuler. 1978b. Studies on the essentiality of arsenic for the growing chick. Abstr. No. P. 50, p. 599 in Abstracts of the XI International Congress of Nutrition, Rio de Janeiro, Brazil, Aug. 27-Sept. 1, 1978. Nielsen, F.H., S.H. Givand, and D.R. Myron. 1975. Evidence of a possible requirement for arsenic by the rat. Abstr. No. 3987. Fed. Proe. 34:923. Schroeder, H.A., and J.J. Balassa. 1966 Abnormal trace elements in man: arsenic. J. Chronic Dis. 19: 85-106. Sehwarz, K. 1977. Essentiality versus toxicity of metals. Pp. 3-22 in S.S Brown, ea., Clinical Chemistry and Chemical Toxicology of Metals. Elsevier/North-Holland, New York. Silver, A.S., and P. L. Wainman. 1952. Chronic arsenic poisoning following use of an asthma remedy. J. Am. Med. Assoc. 150:58~585. Tseng, W.P. 1977. Effects and dose-response relationships of skin cancer and blaekfoot disease with arsenic. Environ. Health Perspect. 19: 109-119. U.S. Environmental Protection Agency. 1975. Region V. Joint Federal/State Survey of Organies and Inorganics in Selected Drinking Water Supplies. U.S. Environmental Protection Agency, Chicago. 88 pp. U.S. Public Health Service. 1962. Drinking Water Standards. Public Health Service, U.S. Department of Health, Education, and Welfare, Washington, D.C. 61 pp. Vallee, B.L., D.D. Ulmer, and W.E.C. Wacker. 1960. Arsenie toxicology and biochemistry. A.M.A. Arch. Ind. Health 21: 132- 151. Whanger, P.D., P.H. Weswig, and J.C. Stoner. 1977. Arsenic levels in Oregon waters. Environ. Health Perspect. 19: 139-143. World Health Organization. 1973. Trace Elements in Human Nutrition. WHO Teehnieal Report Series No. 532.65 pp. Zaldivar, R. 1974. Arsenic contamination of drinking water and foodstuffs causing endemic chronic poisoning. Beitr. Pathol. Bd. 151 :384~00. Zoeteman, B.C.J., and F.J.J. Brinkmann. 1977. Human intake of minerals from drinking water in the European communities. Pp. 173-211 in R. Amavis, W.J. Hunter, and J.G.P.M. Smeets, eds., Hardness of Drinking Water and Public Health. Pergamon Press, New York. Nickel Babedzhanov, S.N. 1973. Balance of iron, vanadium, manganese, nickel and copper in experimental cholesterol atherosclerosis. Med. Zh. Uzb. 10: 18-21 (in Russian). Catalanatto, F.A., F.W. Sunderman, Jr., and T.R. Macintosh. 1977. Nickel eoneeDtrations in human parotid saliva. Ann. Clin. Lab. Sci. 7: 146 151. Christensen, O.B., and H. Moller. 1975. External and internal exposure to the antigen in the hand eczema of nickel allergy. Contact Dermatitis 1: 13~141.

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Contribution of Drinking Water to Miroeral Nutrition 395 Delves, H.T., G. Shephard, and P. Vinter. 1971. Determination of eleven metals in small samples of blood by sequential solvent extraction and atomic-absorption spectropho- tometry. Analyst (London) 96:260 273. Durfor, C.N., and E. Becker. 1964. Public water supplies of the 100 largest cities in the United States. 1962. U.S. Geological Survey Water Supply Paper 1812. U.S. Govern- ment Printing Office, Washington, D.C. 364 pp. Elakhovskaya, N.P. 1972. Metabolism of nickel entering the body with drinking water. Gig. Sanit. 37:2~22. Greathouse, D.G., and G.F. Craun. 1979. Cardiovascular disease study-occurrence of inorganics in household tap water and relationships to cardiovascular mortality rates. Pp. 31-39 in Deb. Hemphill, ea., Trace Substances in Environmental Health-XII. Proceedings of the 12th Annual Conference, University of Missouri-Columbia, 1978, Columbia, Mo. Katz, S.A., H.J.M. Bowen, J.S. Comaish, and M.H. Samitz. 1975. Tissue nickel levels and nickel dermatitis. I. Nickel in hair. Br. J. Dermatol. 93:187-190. Louria, D.B., M.M. Joselow, and A.A. Browder. 1972. The human toxicity of certain trace elements. Ann. Intent. Med. 76:307-319. Murthy, G.K., U.S. Rhea, and J.T. Peeler. 1973. Levels of copper, nickel, rubidium, and strontium in institutional total diets. Environ. Sci. Technol. 7:1042-1045. Myron, D.R., T.J. Zimmerman, T.R. Shuler, L.M. Klevay, D.E. Lee, and F.H. Nielsen. 1978. Intake of nickel and vanadium by humans. A survey of selected diets. Am. J. Clin. Nutr. 31:527-531. McMullen, T.B., R.B. Faoro, and G.B. Morgan. 1970. Profile of pollutant fractions in nonurban suspended particulate matter. J. Air Pollut. Control Assoc. 20:36~372. National Academy of Sciences. 1975. Nickel. Report of the Subcommittee on Nickel, Committee on Medical and Biologic Effects of Environmental Pollutants, National Academy of Sciences, Washington, D.C. 277 pp. Nechay, M.W., and F.W. Sunderman, Jr. 1973. Measurements of nickel in hair by atomic absorption spectrometry Ann. Clin. Lab. Sci. 3:3~35. Nielsen, F.H. 1977. Nickel toxicity. Pp. 129-146 in R.A. Goyer, and M.A. Mehlman, eds. Advances in Modern Toxicology. Vol. 2. Toxicology of Trace Elements. Hemisphere Publishing Corp., Washington, D.C. Nielsen. F.H. (in press a). Evidence for the essentiality of arsenic, nickel and vanadium and their possible nutritional significance. In H.H. Draper, ea., Advances in Nutritional Research. Vol. III. Plenum Press, New York. Nielsen, F.H. (in press b). Interactions of nickel Title essential minerals. In Biogeochemis- try of Nickel. John Wiley & Sons, Inc., New York. Nielsen, F.H., D.R. Myron, S.H. Givand, and D.A. Ollench. 1975. Nickel deficiency and nickel-rhodium interaction in chicks. J. Nutr. 105:1607-1619. Nielsen, F.H., H.T. Reno, L.O. Titan, and R.M. Welch. 1977. Nickel. Pp. 40 53 in Geochemistry and the Environment. Vol. II. National Academy of Sciences, Washing- ton, D.C. Nielsen, F.H., T.J. Zimmerman, M.E. Collings, and D.R. Myron. 1978. Nickel deprivation in rats: nickel-iron interactions. Abstr. No. 175, p. 140 in Abstracts of the XI International Congress of Nutrition, Rio de Janeiro, Aug.-Sept., 1978. Nodiya, P.I 1972. Study of the body cobalt and nickel balance in students of technical trade schools. Gig. Sanit. 37:10~109. Nomoto, S. 1974. Determination and pathophysiological study of nickel in humans and an mars. II. Measurement of nickel in human tissues by atomic absorption spectrometry. Shinshu Igaku Zasshi 22:39~4 (in Japanese). -

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