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18 DRINKING WATER AND HEALTH (1,890 to 6,300 mg/m3) for 7 hours/day on days 6 through 15 of gestation. Fetal size was reduced, but neither resorptions nor malformations oc- curred more frequently than in the controls. Transplacental passage has been shown in pregnant mice (Roschlau and Rodenkirchen, 1969), rats (Tsirel'nikov and Dobrovol'skaya, 1973), and humans (Dowty et al., 1976~. The amounts were not quantified. The car- bon tetrachloride was identified by the use of gas chromatography and mass spectrometry. The data indicate that carbon tetrachloride is not teratogenic to rats. CONCLUSIONS AND RECOMMENDATIONS Carbon tetrachloride is apparently metabolized by mixed-function oxi- dases, which generate a reactive trichloromethyl radical. It is believed that the reactive intermediate induces lipid peroxidation, which leads to hepa- totoxicity. The compound is mutagenic in yeast without metabolic activa- tion, since yeast has an active mixed-function oxidase system. Carbon tetrachloride is not teratogenic to rats exposed orally, subcuta- neously, or via inhalation, but it has been shown to reduce fetal weight after maternally toxic inhalation exposures. The carcinogenicity of carbon tetrachloride was discussed in previous reviews. CHLOROBENZENE monochlorobenzene; benzene' chlorine CAS No. 108-90 7 Cl Chlorobenzene was reviewed in the first volume of Drinking Water and Health (National Research Council, 1977, pp. 709-7101. The following ma- terial, which became available after the 1977 report was prepared, updates and, in some instances, reevaluates the information contained in the pre- vious review. Also included are some references that were not assessed in the earlier report. METAB OLI SM No significant data on the metabolism of chlorobenzene have been re- ported since the initial review. However, there have been reports providing -
Toxicity of Selected Contaminants 19 new information about chlorobenzene's effects on enzyme systems and on metabolism of other chemicals. As noted in the 1977 review, the liver is the primary site of organ toxicity. The observed hepatotoxicity is probably caused by metabolic conversions of chlorobenzene to an epoxide and subsequent reaction with cellular mac- romolecules. Recent literature confirms these effects and also demon- strates additional effects on the hepatic metabolism of other chemicals with resulting hepatotoxicity. Yang et al. (1979) reported that chlorobenzene produced a 10-fold in- crease in bile duct-pancreatic fluid (BDPF) flow along with a 70% de- crease in protein content of the fluid; however' they observed no changes in the chloride concentration in the BDPF, in the bile flow, or in the levels of serum glutamic pyruvic transaminase (SGPT) (now known as plasma alanine aminotransferase, ALT). In this study, male rats (Holtzman Sprague-Dawley stock) received intraperitoneal injections of chloroben- zene (5 mmol/kg in sesame oil) 24 hours before measurements of hepatic function. Since serum SOFT levels were not increased, the authors con- cluded that stimulation of BDPF flow probably occurred independently of hepatotoxicity. In male mice, however, intraperitoneal injection of chloro- benzene produced dose- and time-dependent hepatotoxicity, as shown by increases in serum SGPT levels (Shelton and Weber, 1981~. Results of these two studies suggest species differences in response to chlorobenzene since mice, but not rats, developed liver lesions. This observation may be important when results from any toxicity studies are evaluated. Shelton and Weber (1981) also studied the combined metabolic effects of intraperitoneally administered chlorobenzene plus carbon tetrachlo- ride. They reported additive effects with increased concentrations. The theoretical model used to analyze their results might provide a means to study the combined effects of organohalide chemicals found in drinking water. Before it can be used for this purpose, however, the model should first be verified in tests with oral exposures. HEALTH ASPECTS Observations in Humans No new data were found by the committee. Observations in Other Species Acute Effects The committee found no additional information on acute oral toxicity. In a study of inhalation exposures, Bonnet et al. (1979) observed an LCso value of 1,886 ppm (range, 1,781-1,980 ppm, or 8,195-
20 DRINKING WATER AND HEALTH 9,110 mg/m3) when female mice were exposed for 6 hours. The authors noted that this value is approximately 25 times higher than the time- weighted threshold limit value (TLV) of 75 ppm (350 mg/m3), which is recommended in the United States by the American Conference of Gov- ernmental Industrial Hygienists (1981~. Feeding chlorobenzene to male albino rats at dietary levels that were acutely lethal to some of the animals produced a 6-fold increase in urinary excretion of coproporphyrin, followed by increased excretion of porphobi- linogen and b-aminolevulinic acid (Rimington and Ziegler, 1963~; unfortu- nately, the number of animals in the study was small. Chlorobenzene injected intraperitoneally into male Wistar rats pro- duced dose-dependent increases in hepatic b-aminolevulinic acid synthe- tase at doses of 100 and 200 mg/kg and in heme oxygenase at doses of 50 to 200 mg/kg and a significant decrease in cytochrome P450 at doses of 200 mg/kg (Ariyoshi et al., 1981~. Maximum enzyme activities were noted 24 hours following injection, whereas the cytochrome P450 content was de- creased 24 and 48 hours following injection. These authors suggested that chlorobenzene could induce a rapid degradation of heme or cytochrome P450 and that it also seemed to inhibit, in part, the heme biosynthesis pathway. In adult male albino rats, chlorobenzene at oral doses of 200, 400, or 800 mg/kg/day for 14 days significantly decreased cytochrome P450 and glucose-6-phosphatase at the high dose and increased glucuronyl trans- ferase at all doses but had no effect on isocitrate dehydrogenase, cyto- chrome-c reductase, benzofa~pyrene hydroxylase, or detoxification of EPN (ethyl p-nitrophenyl phenylphosphonothionate) (Carlson and Tardiff, 1976~. The lack of effect on isocitrate dehydrogenase led the authors to conclude that chlorobenzene did not produce frank liver damage, as mea- sured by this test. Chror~ic Effects No new data were found by the committee. Mutagenicity No data were found by the committee. Carcinogenicity Chlorobenzene was tested for carcinogenicity in both sexes of the B6C3~ mouse and the Fischer 344 rat (National Toxicology Program, 1982a). Doses of 60 or 120 mg/kg bw were administered by gavage to female mice and to male and female rats; lower doses of 30 or 60 mg/kg were administered to male mice because of their greater suscepti- bility to the toxicity of this compound. The doses were administered in corn oil to groups of 50 rats and 50 mice of each sex 5 days per week for
Toxicity of Selected Contaminants 21 2 years. There were also corresponding untreated control groups of 50 rats and mice of each sex. There was weak evidence of carcinogenicity in the male rats. The site and incidence rate are discussed in the following section. Carcinogenic Risk Estimate In the above-cited study by the National Toxicology Program (1982a), there was a weak dose-related incidence of hepatic neoplastic nodules in the male rats. The NTP concluded that this provided "some, but not clear evidence of carcinogenic activity in male rats" (Table II-2~. The tumor incidence rates in Table II-2 were used to make statistical estimates of both the lifetime risk and an upper 95~O confidence bound in the lifetime risk. The risk estimates are expressed as a probability of can- cer after a lifetime daily consumption of 1 liter of water containing the compound in a concentration of 1 ~g/liter. The estimates of risk are based on the multistage model for carcinogenesis, i.e., P(tumor/dose"d") = 1espy(qO + qid + q' + ... + qidi)l, where the q's, which are unknown nonnegative parameters, are estimated by maximum likelihood methods and k represents the number of transi- tional events in the carcinogenic process that are related to the carcinogen under test. The conversion of animal doses to human doses is based on body surface area, assuming the following weights: humans, 70 kg; rats, 400 g; and mice, 33 g. The conversion formula is: human consumption = animal consumption X (animal weight/human weight)~'3. The human dose estimates were also reduced by a factor of 5/, to take into account the fact that the test animals were only Savaged 5 days per week. Using the data from the National Toxicology Program (1982a) study, the committee estimated the lifetime risk and upper 95~o confidence estimate of lifetime risk in humans after a daily consumption of 1 liter of water containing the compound in a concentration of 1 ~g/liter (Table II-3~. TABLE II-2 Tumor Incidence in Rats Gavaged win Chlorobenzenea Animal Tumor Sex Site Dose, mg/kg/day Tumor Rates Fischer 344 rat Male Liver o, 60, 120 2/So, 4/49, 8/49 From National Toxicology Program, 1982a.
22 DRINKING WATER AND HEALTH TABLE II-3 Carcinogenic Risk Estimates for Chlorobenzenea l Animal Sex Estimated Human Life- time Risk at a Daily Dose of 1 ~g/liter Upper 95% Confidence Estimate of Lifetime Cancer Risk per ~g/liter Fischer344 rat Male 3.71 X 10-8 2.13 X 10-7 . a Based on data from the National Toxicology Program, 1982a. Using the criteria for interpreting animal carcinogenicity data as out- lined in Chapter I, the committee based the above calculation on limited evidence. Teratogenicity No data were found by the committee. Conclusions and Recommendations A recent report indicates that chlorobenzene was weakly carcinogenic at a dose of 120 mg/kg in male rats. Therefore, a chronic SNARL will not be calculated because chlorobenzene is considered to be potentially carcino- · ~ genie ln humans. The basic conclusions and recommendations contained in the 1977 Dnnking Water and Health report remain valid, and mutagenicity and teratogenicity data are still needed. Bioassays for carcinogenesis fulfill the need for some data; however, well-designed studies of subchronic expo- sures should be conducted to identify species differences in potential hepa- totoxicity and to learn which effects should be used as a basis for establish- ing limits in drinking water. DICHLOROBENZENE I,2~ichiorobenzene, benzene I,2~ichIor~ CAS No. 95-501 ll o-Dichlorobenzene is used primarily as an intermediate in the synthesis of dyestuffs, herbicides, and degreasers. It is also used as a process solvent in the manufacture of toluene diisocyanate (Ware and West, 1977~. It has a