Drinking Water and Health,: Volume 5 (1983)

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90 DRINKING WATER AND HEALTH mg/m3) during major organogenesis and found no adverse fetal effects. Ungvary et al. (1978) exposed rats to 1,500 ppm (3,840 mg/m3) during pregnancy and observed that there was increased fetal mortality but no malformations. Although Infante et al. (1976a,b) reported increased rates of malforma- tions in one city where a vinyl chloride plant was located, subsequent stud- ies by Edmonds et al. (1978) revealed that the parents of these children had not been workers in the plant nor had they been living closer to the manu- facturing source than had the controls. Infante et al. (1976b) reported a significant increase in fetal loss among the wives whose husbands had been exposed. As a "control" group, they used workers in rubber plants. Sanotskii et al. (1980) did not find an increase in spontaneous abortions among the wives of vinyl chloride workers. In summary, vinyl chloride does not appear to be teratogenic in rats or rabbits. The data on humans are not adequate for judgment to be made. CONCLUSIONS AND RECOMMENDATIONS A SNARL for chronic exposure was not calculated because orally adminis- tered vinyl chloride is an established carcinogen in humans. It is also car- cinogenic in mice, hamsters, and rats, in which angiosarcomas were found, regardless of route. The older animals and females appeared to be more susceptible. The cancer risk estimate for vinyl chloride can be found in Volume 1 of Drinking Water and Health. URANIUM (U) Uranium was evaluated in the third volume of Drinking Water and Health (National Research Council, 1980, pp. 173-178~. That review was devoted exclusively to the element's chemical toxicity. In the following review, the committee also considers its radiological effects and provides updates and, in some instances, reevaluations of the information on chemical toxicity contained in the previous volume. Included are some references that were not assessed in the earlier report. Uranium is ubiquitously distributed throughout the earth's crust. It has a complex radioactive decay scheme resulting in the emission of different radiations and the production of several radioactive daughter products. Because its abundance in the crust varies geographically, uranium is a highly variable source of contamination of drinking waters that may be directly consumed by humans and incorporated into their diet. In this brief review, the committee discusses the potential for radiation and chemical toxicity from the ingestion of natural uranium and clarifies the difference

Toxicity of Selected Contaminants 91 between radiation toxicity and the rather well-studied chemical toxicity of this element. For the purpose of brevity and conciseness, not all of the primary references have been cited; rather, the committee has provided several references that are representative and sufficiently broad to cover the needs of this report. Natural uranium is present in soils and rocks in concentrations generally varying between 0.5 and 5 ppm. The average is approximately 1.8 ppm in most soils. Higher concentrations are present in salic rock, in granite, and in sedimentary shale. More than 99% of uranium is present as the isotope uranium-238. Another 0.72870 occurs as the fissionable isotope uranium- 235, and 0.0054~o by weight of uranium as uranium-234. The half-lives are: uranium-238, 109 years; uranium-235, 108 years; and uranium-234, 105 years. The radioactivity of the three isotopes in natural uranium aver- ages approximately 7.35 x 105 disintegrations per minute per gram, al- most all of which is from uranium-238 (National Council on Radiation Protection and Measurements, 1975~. Uranium-238 is generally found to be in equilibrium with thorium-234, palladium-234, and uranium-234, so that a gram of natural uranium would contain 0.33 psi of each of the four nuclides. Furthermore, ura- nium-238 and uranium-234 are generally in disequilibrium in nature. The fractionation of 234 from 238 is believed to occur by the displacement of the daughter atom uranium-234 from the crystal lattice by recoil, which renders uranium-234 potentially capable of being oxidized to the hexava- lent stage when it is more easily leached into the water phase than the par- ent 238. Because of the disequilibrium, the 234:238 uranium activity con- centration ratio can vary among water samples. Reported values range from 0.7 up to 9 (United Nations, 1977~. The activity concentration of uranium-238 in tap water is usually re- ported to be less than 0.03 psi/liter. Thus, the contribution of drinking water to total dietary intake is generally small. A report by the United Na- tions (1977), however, states that concentrations of uranium found in Rus- sian tap water have been as high as 70 psi/liter and that concentrations of approximately 1,000 psi/liter have been measured in several wells in Fin- land. The highest concentration actually reported was S,OOO psi/liter. The very high concentration of uranium in the water from those wells was at- tributed to small, localized uranium-rich deposits (Asikainen and Kahlos, 1980; Kahlos and Asikainen, 1980~. Although uranium may adhere to inhaled particles, inhalation is only a minor route of entry into humans. The United Nations (1977) estimated that the daily adult intake via inhalation is approximately 1 X 10-3 psi. The major route of entry is ingestion. The National Council on Radiation Protection and Measurements

92 DRINKING WATER AND HEALTH (1975) assumed a 1.8 kg/day food intake level for a "reference man" and, in limited measurements, determined that drinking water provides to of the 1 psi of uranium ingested daily. Approximately 20~o of the daily in- take is provided by grains and cereal products; 20~o by meat, fish, and eggs; 20% by green vegetables, fruits, and pulses; and 20~o by root vegeta- bles. As much as logo may be present in milk and dairy products. METAB O LI S M The data indicate that approximately 1 psi (~ 1 Age of uranium is con- sumed daily and that from 2 % to 3 % of that amount is derived from drink- ing water (National Council on Radiation Protection and Measurements, 1975~. To a large extent, the uptake and fate of ingested uranium are con- trolled by the total quantity ingested and, to a lesser extent, on the particu- lar chemical form. In general, the smaller the amount ingested, the greater the fraction absorbed (Durbin and Wrenn, 197S). For the purposes of this report, it will be assumed that the quantity of uranium ingested by humans is very small and, therefore, the maximum uptake possible occurs. Hursh and Spoor (1973) cite data indicating that between 12~o and 30~0 of the ingested uranium is absorbed from the intestinal tract into the blood- stream. An inte~.~ediate figure of 20~o is assumed in the following discus- s~on. Of the absorbed uranium, approximately 805to is excreted, logo goes to the kidneys, and the remaining logo is deposited in the skeleton. The kid- ney retention is believed to be brief, with a biological half-life of 1 to 2 weeks. The uranium deposited in the skeleton is divided disproportion- ately between the spongy and compact bone compartments. Approxi- mately 80~o of the skeletal mass is assumed to be compact bone in which ~95~o of the deposited uranium has a short effective half-life ranging from 1 month to 1 year, whereas only ~ to of the absorbed uranium in the remaining 20~o of the skeleton may have an average half-life of about 10 years (Roswell and Wrenn, 1980~. Because of efficient renal clearance of circulating uranium, redistribution of uranium deposits is inefficient and the body burden of uranium probably reflects recent dietary intakes. Natural uranium bicarbonate complexed with proteins is filtered by the kidney glomeruli. The plasma equilibrium is shifted from the proteinate to the bicarbonate until all uranium not deposited in the skeleton has passed through the glomeruli. Once in the kidney tubules, the bicarbonate com- plex is partially dissociated to consenre sodium. With the accompanying renal reabsorption of water, the urine becomes more acidic, the uranium more concentrated, and further bicarbonate disassociation occurs. The freed uranium can bind to the luminal surfaces of the cells lining the proxi-

Toxicity of Selected Contaminants 93 mal renal tubules and, with sufficient time and dosage, can cause tubular damage (Durbin and Wrenn, 1975~. Hodge (1951) noted, "The uranium- inhibited reaction is located on the cell surface, is rate limiting in the pres- ence of uranium, is chemical in nature, is an enzymatic not a diffusion process, is specific, and probably involves the reaction of uranium with the phosphates of adenosine triphosphate." Therefore, the mechanism of tox- icity is likely to be suppression of cellular respiration. The site of action is invariably confined to the proximal convoluted tubules of the kidney (Hursh and Spoor, 1973~. HEALTH ASPECTS Observations in Humans The committee found no reports of radiological toxicity in humans ex- posed to natural uranium by ingestion. Furthermore, as Hursh and Spoor (1973) noted, "The implication that the contamination of drinking water by uranium is an uncommon and relatively unimportant hazard is con- finned by the dearth of precise and unambiguous information in the litera- ture." The excellent summarized history of uranium poisoning by Hodge (1973) indicates that renal injury occurred in uranium-treated diabetics in the last century and early in this century. These patients were generally given hundreds of milligrams per day over extended periods. There are no population studies, and only specific clinical assessments have been re- ported. Recent studies in humans are confined to those in which much lower concentrations of uranium were used. The aim of these studies was to determine the absorption and urinary excretion of oral doses to assist in interpreting reports of early therapeutic administrations. Luessenhop et al. (1958) investigated the effects of intravenous adminis- tration of uranyl nitrate [UO2(NO3~2] in humans. Five volunteers with ter- minal brain cancer received doses that ranged from 0.097 to 0.28 mg/kg (average, 0.15 mg/kg). They noted the following distribution-excretion pattern: from to to 14~o to the skeletal system, 165'o to the kidneys, and 49~o to 84~o excreted in the urine. These percentages are comparable to those found in studies of small animals. The most sensitive indicator of renal damage was an increase in urinary catalase. Other chemical signs included albuminuria, urinary casts, and a suggestion that there was inter- ference with the renal capacity for reabsorption of sodium and chloride and the secretion of potassium. These authors concluded that, of the com- mon laboratory animals, rats appear to correspond most closely in sensitiv- ity to humans in regard to intravenous tolerance to uranium.

94 DRINKING WATER AND HEALTH Observations in Other Species Acute Effects The renal injury associated with uranium toxicity usu- ally manifests itself several days after exposure. In rats, cellular necrosis appears in the lower portion of the proximal convoluted tubules as demon- strated by hyaline casts or casts containing shed necrotic cells. Accompa- nying the pathological changes are functional changes in the kidney, char- acterized by proteinuria, impaired Diodrast and p-aminohippuric acid clearance, and increased clearance of amino acids and glucose (Stone et al., 1961~. In studies in dogs, Thompson and Nechay (1981) demonstrated that uranium as uranyl nitrate [UO2(NO3~2] produced a 74~o inhibition of re- nal calcium Ca2+ ATPase and an 84~o inhibition of renal magnesium Mg2+ ATPase at concentrations of 3 X 10-s M and 1 X 10-s M, respec- tively. They postulated that uranium dioxide (uo2+) may compete with ATP for binding sites on the Ca2+ and Mg2+ ATPase and that this may be a factor in its renal toxicity. Nomiyama et al. (1974) demonstrated in rabbits that early renal injury could be detected by increases of specific enzymes in the urine following one intravenous injection of uranyl acetate (0.2 mg of uranium/kg bw). Urinary alkaline phosphatase, glutamic oxaloacetic transaminase, and glutamic-pyruvic transaminase all increased significantly before changes were observed in routine urinalyses or renal function tests. Thus, assays for selected urinary enzymes may be more sensitive indicators of early renal · . nJury. An interesting phenomenon observed after acute exposure to uranium is the development of tolerance (mainly in rats) to the effects of repeated ex- posure. This tolerance may be related to the ability of "uranium-condi- tioned" animals to excrete uranium more efficiently or to a mechanism in which the renal tubular epithelium does not bind and retain uranium as well as "unconditioned" epithelium (Durbin and Wrenn, 1975~. Maynard and Hodge (1949) also studied the acquired uranium tolerance in rats and concluded that "prolonged exposure to uranium may produce conditions under which injection of an ordinary damaging dose of uranium results in no appreciable renal tubular necrosis." Chronic Effects Many studies have been conducted to compare the toxicity of natural uranium and some of its isotopes after continuous inges- tion. Rodents and dogs continuously fed a wide range of natural uranium concentrations developed no radiogenic cancers. At the higher levels, renal

Toxicity of Selected Contaminants 95 damage predominates as the toxic end point. As pointed out by Durbin and Wrenn (1975), "Because uranium has a long residence time in bone, the radiation dose is limiting for all uranium isotopes except 23su and 238U and all mixtures of uranium isotopes containing at least 91.5~o 238U by weight (12-fold enrichment in 23su by the gaseous diffusion process has at least an equal amount of 234U)." For example, in a classic toxicity study by Finkel (1953), injections of natural uranium in concentrations as high as 1 mg/kg induced no malig- nant bone tumors, whereas uranium-233 doses of 1 mg/kg proved to be a maximally effective bone carcinogen, comparable to uranium-232 at 5 X 10-4 mg/kg. More importantly, the uranium-232 activity was approxi- mately 10 psi/kg' as was that of the uranium-233, whereas the natural uranium contained a maximum of 7 X 10-4 ~Ci/kg. Maynard and Hodge (1949) conducted 2-year studies in which rats were continuously fed different uranium compounds ranging from O.l~o to 20~o of the dietary mass. The lowest dietary levels producing retardation of growth were: uranyl fluoride, 0.1%; uranyl nitrate hexahydrate, 0.5~o; and uranium tetrafluoride, 20~o. Uranium dioxide at 20~o, the highest level tested, produced no effect. The only major pathological effect ob- served as a result of chronic oral exposure was necrosis of the renal tubular epithelium, involving predominantly the proximal convoluted tubule. The same effects were frequently observed in dogs and rabbits exposed for only 30 days. Although chemical toxicity was observed, primarily in the kidney, no radiogenic effects were noted. The same authors also fed various uranium compounds at graded doses of 0.0002 to 0.2 g/kg/day to dogs over a 1-year period. With the exception of one dog fed the highest level (0.2 g/kg/day) of uranyl nitrate, all the dogs survived, gained weight, and were healthy and active. Only at dietary doses greater than 0.02 g/kg/day were any effects of uranium toxicity noted. Moderate elevations in blood nonprotein nitrogen and urea nitro- gen were observed as well as transient urinary sugar and proteinuria. Path- ological effects were not described. The investigators observed~interesting differences in response between dogs dosed for 1 year and rats dosed for 2 years. Rats were more resistant to the toxicity of uranyl fluoride (UO2F2) by a factor of approximately 25. For uranyl nitrate [UO2(NO3~2-6H2O], the rats were more resistant by a factor of about 20, and for uranium tetrafluoride (UF4), by a factor of 4. ln summary, studies in laboratory animals have produced radiation-re- lated cancers only when high specific-activity isotopes of uranium were used. There have been no reports of cancers resulting from the ingestion of natural uranium in laboratory animals.

96 DRINKING WATER AND HEALTH Mutagenicity No data were found by the committee. Teratogenicity No data were found by the committee. CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level (SNARL) Chronic Exposure Because there is no evidence that naturally occur- ring uranium-238 is carcinogenic, a chronic exposure SNARL will be cal- culated. Two-year studies in rats and a 1-year study in dogs by Maynard and Hodge (1949) have indicated that the dog is the more sensitive species. In chronic exposures, the highest dietary level tolerated by dogs with no decreases in body weight gain or symptoms of renal involvement was 1 mg/kg/day. Luessenhop et al. (1958) found 0.15 mg/kg to be the mini- mum-observed-effect dose in humans, but this dose was administered in- travenously. This amount is approximately the same as that absorbed (as- suming 20% gastrointestinal absorption) following an oral dose of 1 mg/kg. Using an uncertainty factor of 100, and assuming that a 70-kg adult consumes 2 liters of water daily and that logo of the uranium intake is provided by the water, one may calculate a chronic SNARL as: 1.0 mg/kg X 70 kg X 0 1 = 0.035 mg/liter, or 35 ~g/liter If one assumes that the isotopic ratios in natural uranium are in equi- librium, then there would be 0.33 pCi/pg of uranium-238. A value of 35 ~g/liter would be equivalent to 11.6 psi/liter, which is about twice the 5 psi/liter established as the current maximum contaminant level (MCL) for radium (U.S. Environmental Protection Agency, 1975a). Ingestion of water containing radium at 5 psi/liter is estimated to cany a risk of be- tween 0.7 to 3.0 fatal cancers per year per million persons exposed. There is currently no standard for uranium. Ike total absence of carcinogenic effects from ingested natural uranium in either animals or humans makes it difficult to develop an appropriate model for the radiotoxicity of that element. Furthermore, the fact that drinking water rarely contributes more than 2~o to 5~o of the total ura- nium ingested daily leads to the conclusion that a radiation risk model for natural uranium is inappropriate and unjustified on the basis of present knowledge. When natural uranium is subjected to an enrichment process resulting in specific activity exceeding 106 disintegrations per minute per gram, it is possible that a radiotoxicity model could be developed (U.S.

Toxicity of Selected Contaminants 97 Energy Research and Development Administration, 1976~. This assump- tion is based primarily on the findings of Finkel (1953), who studied ura- nium-233 and natural uranium, and on the radioactivity rather than the mass relationships of the different uranium isotopes tested in laboratory animals. Finkel reported that the radioactivity, in terms of alpha disinte- gration rate, reached levels comparable to those seen in radium-226 toxic- ity. For purposes of this discussion, the effectiveness of uranium-233 and uranium-235 can be regarded as fairly comparable to that of radium-226, based on ingested psi per unit time. Because of its loo specific activity, natural uranium does not pose a problem of radiotoxicity in drinking water. Assessment of uranium toxicity in drinking water should be based on its chemical toxicity and not on radi- ation toxicity. However, when the specific activity of uranium in drinking water has been altered so that it is greater than that of natural uranium, potential radiotoxicity should be given attention equal to that of the chemi- cal toxicity. The committee also recommends that toxicological assessment of uranium in cater be based solely on its renal toxicity in all instances except when industrial processes result in a marked enrichment of shorter- lived uranium isotopes. Additional research should be carried out to determine with greater pre- cision the dynamics of uranium absorption from the gastrointestinal tract for different chemical forms of uranium. CONCLUSIONS Chronic Toxicity Table II-10 lists the compounds reviewed in this volume for which there were sufficient data to calculate either a chronic SNARL or cancer risk estimate. The statistical methodology for the cancer risk estimate is de- scribed for chlorobenzene on page 21. Further details on methodology can be found in Volumes 1 and 3 of Drinking Water and Health (National Research Council, 1977, 1980~. It is important to stress that the reader should refer back to the discussion on individual compounds for specific details. Mutagenicity As described in Chapter 1, a chemical was judged to be a mutagen when it could be shown that it was mutagenic in any one short- term test. The data summary in Table Il-11 is based on this criterion. It is important to stress that the reader should refer back to the discussion on individual compounds for specific details.

98 DRINKING WATER AND HEALTH TABLE II-10 Summation of Chronic Exposure Levels and Carcinogenicity Risk Estimate for Chemicals Reviewed Chemical Suggested No-Adverse-Response Level (SNARL), mg/liter, for Chronic Exposure Upper 95% Confidence Estimate of Lifetime Cancer Risk per ~g/liter Aldicarb Chlorobenzene o-Dichlorobenzene p-Dichlorobenzene 1, 1 -Dichloroethylene Dinoseb Hexach lorobenzene Methomyl Picloram Rotenone Tetrachloroethylene 1,1, 1 -Trichloroethane Trich loroethylene Uranium o. oo7a 0.3` 0.094a- C 0.10 0.039 0.175 1.05 0.014 0.035 2.13 x 10 - 7b I .85 x l o ha d 2.98 x 10 8b 3.3 X 10 7b aThis is the suggested no-adverse~effect level calculated in Volume I of Drinking Water and [health (lsia- tional Research Council, 1977) and continues to be the recommended SNARL. bBased on limited evidence (see Chapter 1) from ongoing studies being conducted by the National Toxicol- ogy Program ( I 982a.d,e). The studies on these compounds have undergone peer review and the results are . . . . In press at t lIS Writing. This SNARL must be reviewed when the cancer bioassay is completed and reviewed (see text for details). dNeither a SNARL nor a cancer risk estimate has been calculated by the committee pending the outcome of an ongoing study being conducted by the National Toxicology Program (1982d). Teratogenicity The only compound reviewed in this volume that showed teratogenic potential following oral exposure was hexachloroben- zene. Dinoseb was teratogenic following intraperitoneal, but not oral expo- sure. The data for rotenone and trichloroethylene are inconclusive. RE SEARCH REC OMMENI)ATION S Although specific research recommendations are given for many of the compounds reviewed, the major areas are summarized here. 1. The most urgent need is for comparative data on various aspects of metabolism in laboratory animals and humans. Only with such data can relevant animal models be used to predict more accurately the potentially adverse health effects in humans. 2. In conjunction with the above recommendation, these kinds of data ultimately need to be included in the mathematical models now used to estimate cancer risk.

Toxicity of Selected Contaminants 99 TABLE II-11 Mutagenicity Studies of Chemicals Reviewed in this Volume Chemical Mutagenicitya Aldicarb Carbofuran Carbon tetrachloride Chlorobenzene o-Dichlorobenzene p-Dichlorobenzene 1 .2-Dichloroethane 1, l-Dichloroethylene cis- 1 ,2-Dichloroethylene trans- 1 ,2-Dichloroethylene Dichloromethane Dinoseb Hexachlorobenzene Methomyl Picloram Rotenone Tetrach loroethylene 1,1, 1 -Trichloroethane Trichloroethylene Vinyl chloride Uranium NDb _ c ND + + _ c + ND aScc text for details. bND = no data. Inconclusive data, see text for details. 3. Data on reproductive effects including teratogenicity should be gen- erated for the majority of the compounds reviewed. REFERENCES Abdel-Aal, Y.A.I., and T.Y. Hclal. 1980. Relative toxicity and a~ticholinesterase activity of phosfolan and carbofuran to four rodent species. Int. Pest Control 22:4Y)~41. Adams, C.E., M.B. Hay, and C. Lutwak-MaDn. 1961. The action of various agents upon the rabbit embryo. J. Embryol. Esp. Morphol. 9:468491. Ahdaya, S.M., R.J. Monroe, and F.E. Guthne. 1981. Absorption and distribution of intuba- ted insecticides in fasted mice. Pestic. Biochem. Physiol. 16:3W6. Ahmed, A.E., V.L. Kubic, J.L. Stevens, and M.W. Anders. 1980. Halogenated methanes: Metabolism and to~cicity. Fed. Proc. 39:3150-3155. Ahmed, B.E., R.W. Hart, and N.J. Lewis. 1977. Pesticide induced DNA damage and its repair in cultured human cells. Mutat. Res. 42:161-174. Ahr, H.J., L.J. King, W. Nastainczyk, and V. Ullrich. 1980. The mechanism of chloroform and carbon monoxide formation from carbon tetrachloride by microsomal cytoebrome P-450. Biochem. Pharmacol. 29:2855-2861.

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