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46 DRINKING WATER AND HEALTH These limited data indicate that dichloromethane is not teratogenic to rats. CONCLUSIONS AND RECOMMENDATIONS Because dichloromethane was carcinogenic in both rats and mice, no chronic SNARL has been calculated. Some of the uncertainties involving the cancer bioassay must be resolved before a final assessment is made concerning the potential risk to humans. Dichloromethane is mutagenic in two bacterial test systems, but is not considered to be teratogenic to rats. Its metabolism is mediated by mixed- function oxidases with saturation kinetics exhibited by doses up to 50 ma/ kg. This dose-dependent metabolism may necessitate a closer look at the pharmacokinetics, especially with respect to the doses used in the carcino- genicity bioassays. DINOSEB phenol, 2-sec-butyl4,6~initr~ CAS No. 88-85-7 OH NO/< CH-C2 Hs lo CH3 NO2 Dinoseb has been in use since 1945 as a herbicide and insecticide. Its pri- mary application is in the control of annual weeds in many cereal and vege- table crops. This compound is slightly soluble in water (52 mg/liter at 25C), but it can form salts with inorganic and organic bases, some of which are more soluble in water. METAB OLI SM Dinoseb is believed to enhance metabolic activity by uncoupling oxidative phosphorylation and disrupting adenosine triphosphate synthesis (Brody, 1955), culminating, in extreme cases, in hyperthe~n~ia. In ruminants, dinoseb, an organonitro compound, is reduced to an amine, which may then cause the oxidation of hemoglobin to me/hemoglobin. There have been several reports that dinoseb causes methemoglobinemia and hemoly-

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Toxicity of Selected Contaminants 47 sis in such animals (Froslie 1971a,b, 1973; Karlog et al., 1978~. Elevated temperature (32C) enhanced the acute toxicity of dinoseb in mice, as re- flected by an approximate 30% reduction in the LDso (Preache and Gib- son, 1975~. Dinoseb is metabolized via oxidation of either of the two methyl groups on the sec-butyl side chain, conjugation of the phenolic products, and the formation of many uncharacterized metabolites. In rats, but not in mice, there is a reduction of either of the two phenolic groups and acetylation of the metabolically formed p-amino group (Bandal and Casida, 1972~. HEALTH ASPECTS Observations ir' Humans Dinoseb intoxication of humans accompanied by clinical symptoms of fa- tigue, sweating, and psychological alterations was described by Smith (1981~. Hayes (1982) reported that a tractor driver required hospitalization because of localized pain and swelling that occurred after one eye was acci- dentally contaminated with diluted dinoseb spray. Visual impairment, which persisted for 3 days, was followed by a complete recovery. Observations in Other Species Acute Effects The estimated oral LDSo 24 hours after a single exposure have been determined by Bough et al. (1965) for the male mouse (20-40 mg/kg), male rat (25-40 mg/kg), female guinea pig (20-40 mg/kg), and male chick (40-80 mg/kg). Signs of poisoning revere prostration, rapid respiration, and convulsions, which preceded death. These investigators also observed that dinoseb was rapidly absorbed through the shaved skin of mice, as measured by blood determinations. Doses of 100 mg/kg and 500 mg/kg produced 205to and 90~o lethality, respectively, within 24 hours after exposure. Dinoseb added to the diet of rats resulted in food refusal at approxi- mately 56.7 mg/kg. A level of about 22.7 mg/kg diet caused a small but significant decrease in growth rate and a slight elevation in blood urea ni- trogen (BUN). At about 11.3 mg/kg, only a slight increase in BUN was noted (Spencer et al., 1948~. Chronic Effects Spencer et al. (1948)fed dinoseb at dosages from 5.6 to 22.7 mg/kg low/day to rats for 6 months. There was no effect on growth, BUN, organ weights, or histological findings at the lowest dose tested. Hall et al. (1978, abstract) exposed Sherman rats to dinoseb in their diet at levels of 0, 50, 100, 150, 200, 300, 400, and 500 mg/kg for as long as

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48 DRINKING WATER AND HEALTH 153 days. There was excessive mortality after 21 days in the 300 to 500 ma/ kg dose groups. Dose-dependent decreases in growth were observed in the other exposed groups along with decreases in the organ weights of the liver, spleen, heart, lungs, and brain. Blood alkaline phosphatase, alanine aminotransferase, potassium, and BUN were increased, whereas lactic de- hydrogenase and cholinesterase were depressed. Diffuse tubular atrophy of the testes was noted at 200 mg/kg. Mutagenicity Mutagenicity was not observed when tested in eight Sal- monella histidine-requiring tester strains and in a bacteriophage T4 muta- tion assay (Andersen et al., 1972~. No metabolic activation system was in- cluded in the assay procedures. Mitotic gene conversion was observed in a yeast Saccharomyces cerevisiae assay at concentrations ranging from 185 to 1,665 ppm (Parry, 1973~. No exogenous metabolic activation system was required to elicit the response. Myhr (1973) found that dinoseb strongly inhibited RNA and protein synthesis in HeLa cells exposed to 350 ~g/ml for 30 minutes. A possible mechanism leading to such inhibition is the uncoupling of oxidative phosphorylation. In summary, dinoseb elicited a mutagenic response in one microbial mutagenicity assay, but negative results were obtained in two other micro- bial assays. Carcir~ogenicity Dinoseb did not produce a significant increase in tu- mars in two strains of mice when administered at the highest tolerated dose for 18 months (Innes et al., 19691. Teratogenicity Dinoseb was administered orally, subcutaneously, or intraperitoneally to pregnant Swiss-Webster mice in doses up to 20 ma/ kg/day (Gibson, 1973~. Several schedules were used to administer the doses at different times during organogenesis. At subcutaneous and intra- peritoneal doses of 17.7 mg/kg, maternal and embryo toxicity occurred. The following malformations were observed in the surviving embryos: skel- etal defects, cleft palate, hydrocephalus, and adrenal agenesis. Oral ad- ministration of 20 or 32 mg/kg/day produced no gross or soft tissue de- fects, but some maternal toxicity was reported. Gibson and Rao (1973) demonstrated that dinoseb does not readily cross the placenta, since levels in the fetuses never exceeded 2.5370 of maternal plasma levels. Elimination was also dependent on route of exposure; fol- lowing oral doses, it was approximately 4 times faster. In the fetuses, peak levels were reached much earlier after intraperitoneal exposure. The au- thors concluded that these differences may be responsible for the terato- genicity and fetotoxicity observed following intraperitoneal doses but not after oral exposures.

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Toxicity ot Selected Contaminants 49 McCormack et al. (1980) studied postnatal renal function in rats exposed on days 10 to 12 of gestation by intraperitoneal injection of 16 mg/kg. The dilated renal tubules and peJvics seen in the neonatal period were ei- ther not found or were reduced by the forty-second postnatal day and renal function was normal. Beaudoin and Fisher (1981) administered 10 mg/kg intraperitoneally to rats on day 9 of pregnancy and studied the embryos in vitro after day 10. Little or no effect was observed on growth and develop- ment of the embryos. These data indicate that dinoseb is teratogenic to mice after parenteral doses, but teratogenicity was not observed after oral exposures. CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level (SNARLJ Chronic Exposure Based on the data of Spencer et al. ( 1948), a chronic SNARL can be calculated using the lowest no-observed-effect level in rats of 5.6 mg/kg/day. An uncertainty factor of 1,000 is used because this study was only of 6 months duration. Assuming that a 70-kg human con- sumes 2 liters of water daily and that 20~o of the intake is derived from water, one may calculate the SNARL as: 5.6 mg/kg X 2 X 70 kg = 0.039 mg/liter, or 39 /liter Limited human data indicate that high exposure to dinoseb can result in a variety of physical and psychological symptoms. Since there are no data on chronic lifetime exposures, this information should be generated before limits for dinoseb exposure in drinking water are established. HEXACHLOROBENZENE benzene, hexachIor~ CAS No. 118-74-1 Cl Cl Cl Cl Hexachlorobenzene was evaluated in the first and third volumes of Drink- ing Water and Health (National Research Council, 1977, pp. 667-673;