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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;

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50 DRINKING WATER AND HEALTH 1980, pp. 210-215~. The following material, which became available after the 1980 report was prepared, updates and, in some instances, reevaluates the information contained in the previous reviews. Also included are some references that were not assessed in the earlier reports. METAB OLISM Hexachlorobenzene is slowly absorbed from the gastrointestinal tract. When hexachlorobenzene dissolved in rat bile was placed in rat intestinal loops, only To to 12~o was found to be absorbed in 30 minutes (Turner and Shanks, 1980~. The lymph as well as the blood are important in ab- sorption. The ratios of concentrations in blood to those in lymph ranged from 115 to 1,019 in six replications, indicating that both pathways are important in absorption but that uptake by blood is greater than uptake by lymph. However, lymph uptake is important for by that route the first-pass effects of the liver are not a factor in the disposition of the compound. The distribution of hexachlorobenzene administered to pregnant mice and rats either as single or multiple doses has been determined by Courtney et al. (1979) and Svendsgaard et al. (1979~. In both species the amount found in fetuses and placentas was dose dependent at levels rang- ing from 10 to 100 mg/kg given orally. The concentrations were generally higher in the placentas than in the fetuses. In mice the concentrations in both maternal and fetal tissues were higher after multiple low doses than after single high doses. At equivalent concentrations, the amounts in the fetuses of the two species were similar. A preliminary report on the pharmacokinetics of hexachlorobenzene in the beagle dog indicates that an intravenous bolus is rapidly distributed to the highly perfused tissues, but that it quickly disappears between 2 and 8 hours later and more slowly thereafter (Sundlof, 1981~. Adipose tissue con- tained the highest concentration. This was also observed following the oral administration of 10 or 100 mg/kg. Most of the compound was eliminated unchanged Ma the bile. In rodents, however, 96870 of the material in the bile was composed of metabolites rather than parent compound. Smaller amounts were excreted in the urine, which contained no parent com- pound. Debets et al. (1980) suggested that hexachlorobenzene must be metabo- lized before it can exert its porphynnogenic action because inducers of drug metabolism increased the accumulation of porphyrins in chick-em- bryo liver cell cultures and inhibitors decreased the formation of porphy- nns. Koss et al. (1979) reported that pentachlorothiophenol was present in Me tissues of rats exposed to hexachlorobenzene. This metabolite is be-

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Toxicity of Selected Contaminants 51 lieved to come from pentachlorophenylmercapturic acid, a urinary metab- olite of mercapturic acid (Renner et al., 1978) that is possibly produced in the gastrointestinal tract by bacterial action, followed by reabsorption of the pentachlorothiophenol. Diethyl maleate, which lowers tissue glu- tathione levels, caused increased hepatotoxicity and porphyria in female rats fed hexachlorobenzene (0.1 To in the diet) (Kerklaan et al., 1979~. The administration of glutathione offered protection against these effects. These findings illustrate the possible importance of mercapturic acid for- mation as a detoxification pathway. Pharmacokinetic studies in three rhesus monkeys given a single intra- venous administration of hexachlorobenzene in doses ranging from 0.22 to 0.38 mg/kg indicated that cumulative fecal and urinary elimination after 1 year accounted for only 28.2~o and 1.6~o of the dose, respectively (Yang et al., 1978~. Fat, bone marrow, adrenal glands, and liver contained high concentrations 100 days after administration, and concentrations in fat and bone marrow were still significant after 1 year. Bailey et al. (1980) gave lactating rhesus monkeys oral doses of hexa- chlorobenzene at 60 mg/kg/day to study the transfer to their offspring. They noted that the concentration of hexachlorobenzene was 17 to 20 times higher in the milk than in maternal blood, whereas levels in the blood of the infants were 2 to 5 times higher than in the mother. The direct excretion of hexachlorobenzene through the intestine, as op- posed to biliary excretion, has been shown to be an important pathway for fecal elimination from the rat (Richter and Schafer, 1981~. Its importance as a route of elimination was demonstrated in a study by Rozman et al. (1981), who absented that n-hexadecane administered at To in the diet caused a 4- to 13-fold increase in the amount of hexachlorobenzene elimi- nated via this pathway in rats and rhesus monkeys. The rats had been given single oral doses of 100 mg/kg bw and the monkeys had received 0.11 mg/kg bw in pellets daily for 750 days or single or triple oral doses of 100 mg/kg each (Rozman et al., 1981~. HEALTH ASPECTS Observations in Humans Hexachlorobenzene-exposed workers in a plant manufacturing chlori- nated solvents were examined for blood levels of the compound and possi- ble effects on their health (Currier et al., 1980~. Mean blood levels mea- sured each year for 4 years ranged from 160 to 312 ppb for groups of 44 to 50 workers. In comparison to another group of workers manufacturing

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52 DRINKING WATER AND HEAl TH polyethylene and not exposed to hexachlorobenzene or similar com- pounds, there were no differences in urinary porphyrin excretion or in other clinical parameters, including serum enzymes and hemoglobin, and there was no evidence of porphyria cutanea tarda. A small change in he- matocrit was observed, but it was not considered to be clinically signifi- cant. Observations in Other Species Acute Effects The committee found no reports extending previous re- views. Chronic Effects The porphyrinogenic effects of hexachlorobenzene continue to be of concern. Determinations of urinary and fecal porphyrins indicated that iron overload potentiated the effect in female rats fed 0.2% hexachlorobenzene in the diet (Blekkenhorst et al., 1980~. Smith et al. (1980) reported that porphyria developed at different rates in different lobes of the livers in female rats fed diets containing 0.01% hexachloro- benzene. In comparison to the other lobes, the caudate lobe initially had lower porphyrin levels, less depression of uroporphyrinogen decarboxyl- ase, and less elevation of b-aminolevulinate synthetase activity; in the ad- vanced stages of porphyria, no differences were found among the lobes. Mechanism studies in rats given 100 mg/kg concentrations of hexachloro- benzene orally every other day suggest that its porphyrinogenic effects are exerted following conversion to an active form that binds covalently to pro- teins, resulting in products that inhibit uroporphyrinogen decarboxylase (Koss et al., 1980~. Information on the effects of hexachlorobenzene on xenobiotic metabo- lism has been extended to include guinea pigs (Lake et al., 1980~. The administration of 30 mg/kg intraperitoneally for 7 days resulted in in- creases in ethylmorphine N-demethylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and cytochrome P450 levels. Increases in acetanilide hydroxylase and acetanilide esterase were observed following the oral ad- ministration of 0.1 mM/kg/day for 14 days to male rats (Carlson et al., 1979~. Such inducing effects may influence honnone metabolism. Hexa- chlorobenzene concentrations of 250 ppm in the diet of mice for 21 days resulted in an increase in the metabolism of testosterone (Elissalde and Clark, 1979~. There were increases in 6,B-hydroxytestosterone and 7~-hy- droxytestosterone, but a decrease in 16~-hydroxytestosterone formation. ln female rats, hexachlorobenzene given at 80 ppm in the diet for 8 weeks resulted in increased excretion of 1 7,B-estradiol in bile, but uterine weights, 1

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Toxicity of Selected Contaminants 53 estradiol metabolism, and bile flow rate were not affected (Mendoza and Watanabe, 19783. Loose et al. (1979) reported that hexachlorobenzene given to mice at 167 ppm diet depressed antibody synthesis and lowered serum IgA concentra- tions. Gram-negative endotoxin sensitivity was increased 32-fold. Mean survival times following inoculation with Plasmodium berghei (NYU-2) was also decreased. In contrast, the administration of doses as high as 2,000 ppm diet for 3 weeks increased serum IgM but not IgG concentra- tions in rats (Vos et al., 1979~. There was also a 3-fold increase in primary and secondary IgM and IgG titers in response to tetanus toxoid and an increase in the number of splenic lymphocytes. Cell-mediated immunity was not affected, as measured by resistance to Listeria monocytogenes in- fection, rejection of skin grafts, or delayed hypersensitivity to tuberculin. The in vitro response of thymus cells to mitogens was also unchanged. In a four-generation reproduction study in rats, hexachlorobenzene was administered in the diet at levels of 0, 10, 20, 40, 80, 120, 320, and 640 ppm (Grant et al., 1977~. The two highest levels were toxic to the females in the Fo generation, causing a substantial number of deaths. The viability index (i.e., the number of pups surviving 5 days/number of pups born alive X 100) for the pups in these groups was zero and only SS~o for the Bob generation group given 160 ppm. The lactation index (i.e., the number of pups weaned/number of pups alive on day S less culls X 100) was also lower in both the 120 and 80 ppm F tb groups. At 80 ppm and higher doses, there were decreases in the pups' weight at birth and at the fifth and twenty-first days of life. In female rats given oral doses of hexachlorobenze at 178 ~mol/kg (50.7 mg/kg bw) every other day for 15 weeks, there was an apparent equi- librium between intake and elimination after 9 weeks of exposure (Koss et al., 1978~. The elimination rate decreased over time. The biological half- life 38 weeks after the exposure ceased was estimated to be 4 to 5 months. Body weights of the animals did not differ from those of the controls, and although the relative weight of the liver, spleen, kidneys, and adrenal glands increased during the treatment period, they returned to normal by the end of the 38-week recovery period. Porphyrin, b-aminolevulinic acid, and porphobilinogen levels in the urine were elevated during the exposure, but decreased to normal or near normal levels by the end of the recovery period; however, the porphyrin level in the liver was elevated during both periods. Boger et al. (1979) treated female rats orally twice per week with doses ranging from 0.5 to 32 mg/kg bw for 203 days. Dose-dependent de- position of hexachlorobenzene in the liver and an increase in hepatocyte size were observed. Porphyrin deposits, siderosomes, and changes in the size and shape of mitochondria were found in the hepatocytes.

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54 DRINKING WATER AND HEALTH .. Mutagenicity In a dominant lethal test, adult male rats received 0.70 and 221 mg/kg doses of hexachlorobenzene daily for 5 consecutive days (Simon et al., 1979~. There was a dose-dependent reduction in the repro- ductive performance (mating index) in males, but no difference in the per- centage of inseminated females who become pregnant (fertility index). No dominant lethal effects were observed. Guerzoni et al. (1976, abstract) re- ported mutagenic activity in a yeast Saccharomyces cerevisiae assay at 100 ppm. Hexachlorobenzene was also found to be positive in a DNA-cell- binding (DCB) assay in the presence of Iysozyme and rat liver extract (Ku- binski et al., 19811. This assay was based on the observation that nucleic acids, including DNA, form complexes with proteins and with other nu- cleic acid molecules in the presence of active carcinogens. Pretreatment of male and female Wistar rats and pregnant Wistar rats with intraperitoneal 10 mg/kg doses of hexachlorobenzene resulted in in- creased mutagenicity of 2,4-diaminoanisole when tested in the Ames Sal- monella assay in the presence of the liver S9 fraction derived from the pretreated animals. An increase was also observed with the kidney S9 frac- tion, but not with the lung or the fetal liver S9 fraction (Dybing and Aune, 1977~. Hexachlorobenzene-induced liver S9 fraction from male rats dimin- ished the mutagenic activity of tris(2,3-dibromopropyl) phosphate in the Salmonella plate incorporation assay with strain TA100 (Soderlund et al., 1979~. In summary, hexachlorobenzene was negative in a dominant lethal study, but mutagenic activity was observed in one microbial assay. The compound was also found to bind to DNA in a DNA-cell-binding assay. Carcinogenicity The third volume of Drinking Water and Health (Na- tional Research Council, 1980, pp. 210-215) cited a study by Cabral et al. (1977) indicating that hexachlorobenzene was carcinogenic in the Syrian golden hamster, causing a significantly high dose-related incidence of hep- atomas, liver hemangioendotheliomas, and thyroid adenomas. In a follow-up carcinogenicity study, Cabral et al. (1979) fed groups of 30 to 50 Swiss mice of each sex diets containing 0, 50, 100, or 200 ppm (6, 12, or 24 mg/kg) concentrations of hexachlorobenzene for 101 to 120 weeks. Another group of 30 male and 30 female mice was fed 300 ppm of the test material for 15 weeks and was then maintained on hexachloroben- zene-free diets for the duration of the study. A dose- and time-related de- crease in sunrival was observed after 30 weeks on test. The males were more sensitive to the toxicity of hexachlorobenzene. The reduced survival in both sexes was associated with tremors and convulsions. A decreased weight gain, more pronounced in males, was noted in both sexes of the dosed animals. The incidence of liver-cell tumors for the groups receiving

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Toxicity of Selected Contaminants 55 either SO, 100, or 200 ppm hexachlorobenzene in the diet is given in the section below. No liver cell tumors were present in the control animals or in the SO ppm treated group. No other compound-related tumors were detected. This carcinogenicity study confirmed the earlier findings and estab- lished that hexachlorobenzene is carcinogenic in both sexes of two experi- mental models, i.e., the Syrian golden hamster and the Swiss mouse. Fur- therrnore, the study suggests a difference in species sensitivity as indicated by the multitumor type response of the hamster and the single-tumor type response of the mouse. Carcinogenic Risk Estimate In the study by Cabral et al. (1979), there was a dose-related incidence of liver cell tumors in both sexes of the ex- posed outbred Swiss mice. These tumor incidences are summarized in Ta- ble II-4. . . Bach set ot data showing a statistically significant increase was used to estimate a risk and 95% confidence of lifetime risk to humans after a daily consumption of 1 liter of water containing the compound in a concentra- tion of 1 ~g/liter. The risk estimates are based on the multistage model for carcinogenesis described earlier in this chapter for chlorobenzene. The conversion of animal doses to human doses is again based on body surface area, assuming the following weights: humans, 70 kg; rats, 400 g; and mice, 33 g. The conversion formula is: animal consumption = human con- sumption X (human weight/animal weighty. Using the data from Cabral et al. (1979), the committee estimated the lifetime risk and upper 95~o confidence estimate of lifetime risk after daily consumption of 1 liter of water containing the compound in a concentra- tion of 1 ~g/liter (Table II-S). In a previous volume of Drinking Water and Health, the risk estimates from male and female hamsters were averaged to yield one composite num- ber. If one averages the data in Table II-S, the estimated upper 95~o confi- dence estimate of lifetime risk per ~g/liter is 1.85 X 10-6. This is some- what different from the 2.9 X 10-s upper 955to confidence estimate of TABLE II-4 Tumor incidence in Mice Exposed to Hexachlorobenzene Animal Sex Tumor Site Dose Levels, mg/kg/day Tumor Rates Swiss mouse Male Liver 0, 6, 12, 24 Swiss mouse Female Liver 0, 6, 12, 24 0/47, 0/30, 3/29, 7/44 0/49, 0/30, 3/30, 14/41 From Cabral e' al., 1979.

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56 DRINKING WATER AND HEALTH TABLE II-5 Carcinogenic Risk Estimates for HexachlorobenzenP Upper 95% Confidence Estimated Human Estimate of Lifetime Animals Sex Lifetime Riskb Cancer Risk per ~g/liter Swiss mouse Male 3.75 X 10 ~7 1.92 x 10 -6 Swiss mouse Female 3.18 X 10-9 1.78 X 10-6 a Based on data from Cabral et al., 1979. b assuming daily consumption of 1 liter of water containing the compound in a concentra- tion of 1 ~g/liter. lifetime risk per Igniter, which was calculated in the third volume of Drinking Water and Health (National Research Council, 1980, p. 214~. Using the criteria for interpreting animal carcinogenicity data as out- lined in Chapter 1, the committee based the above calculations on limited evidence. Teratogenicity Khera (1974) gave rats single oral doses of hexachloro- benzene ranging from 10 to 120 mg/kg/day during several periods of or- ganogenesis until day 21 of gestation. At the higher doses, extra fourteenth ribs were found, but this was associated with maternal toxicity. The fetal weights and survival rates did not differ from those of controls, and no other defects were found. Dominant lethal studies were negative. Courtney et al. (1976) found cleft palates, clubfoot, reduced kidney weight, and re- nal agenesis in the fetuses of mice given 100 mg/kg. The transplacental passage of hexachlorobenzene has been found in the rat and mouse (Svendsgeardet al., 1979), swine (Hansen et al., 1979), rat (Villeneuve and Hierliby, 1975), rabbit (Villeneuve et al., 1974), and human (Astolfi et al., 1974~. The data indicate that hexachlorobenzene is not teratogenic in the rat, but teratogenic effects in mice have been observed. Its potential for such effects in humans cannot be estimated. CONCLUSIONS AND RECOMMENDATIONS This committee agrees with the findings in earlier reports that the acute toxicity of hexachlorobenzene appears to be low. Because hexachloroben- zene tends to be stored in adipose tissue for prolonged periods, additional perinatal studies are needed. Of major concern is its porphyrinogenic ef- fect in humans, as indicated by studies in animals and some data on hu- mans. There is a great need for epidemiological data, especially in view of its reported carcinogenic effects in two species of test animals.