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Toxicity of Selected Contaminants 43 concentration (2.9 mM) of cis-1,2-dichloroethylene; a 90~o survival oc- curred at the highest concentration (2.9 mM) of trans-1,2-dichloroethyl- ene used (Greim et al., 1975~. Under the conditions of these studies neither the cis nor bans isomer of 1,2-dichloroethylene was observed to be mutagenic. Teratogenicity No data were found by the committee. Carcirzogenicity No data were found by the committee. CONCLUSIONS AND RECOMMENDATIONS Both cis- and trans-1,2-dichloroethylene demonstrate a potential for liver and kidney damage. Little information is available on the effects resulting from chronic administration of the materials. Long-term studies, espe- cially those involving oral administration, are needed before a chronic SNARL can be determined. In view of its structural similarity to vinyl chlo- ride, a carcinogenesis bioassay is desirable. In addition, studies are needed to determine the teratogenic and reproductive effects of these isomers, and additional investigations should be conducted to examine their mutagenic properties in mammalian cells. DICHLOROMETHANE methylene chloride; methane, dichIor~ CAS No. 75 09-2 CH2 C12 Dichloromethane was evaluated in the first and third volumes of Drinking Water and Health (National Research Council, 1977, pp. 743-745; 1980, pp. 124-128~. 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 ref- erences that were not assessed in the earlier-report. METAB OLI SM DiVincenzo and Kaplan (1981) measured blood carboxyhemoglobin in workers and volunteers exposed as long as 7.5 hours to atmospheric con- centrations of 50, 100, 150, or 200 ppm (174, 347, 522, or 696 mg/m3) for up to 5 consecutive days. As much as 34~o of the absorbed dichlorome- thane was expired as carbon dioxide, and less than 5~o was exhaled as
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44 DRINKING WATER AND HEALTH unchanged dichloromethane. Maximum carboxyhemoglobin levels of 6.8% were induced at exposure levels of 200 ppm, whereas the average peak carboxyhemoglobin level in exposed workers was 3.9~o. The carboxy- hemoglobin levels of workers exposed to carbon monoxide at the threshold limit value (TLV) of 35 ppm (121 mg/m3) is approximately 6.5~o, or To greater than those in workers exposed to dichloromethane. The metabolism of orally administered ~4C-dichloromethane in rats re- sulted in saturation kinetics up to 50 mg/kg, and both TACO and SCOT was found in the expired air (McKenna and Zempel, 1981~. Eighty-eight percent of a 1 mg/kg dose was metabolized. Ahmed et al. (1980) reported that the metabolism of dichloromethane in vivo and in vitro was mediated by the cytochrome P450-dependent mixed-function oxidase system. HEALTH ASPECTS Observations in Humans No new data were found by the committee. Observations in Other Species New data found by the committee are summarized below. Mutagenicity Dichloromethane was found to be mutagenic in the Ames Salmonella' assay when tested in an open container inside a desicca- tor, but not mutagenic when incorporated directly into the agar. Muta- genic activity was detected with strains TA1535 and TA100 when used at 0.5 ml per desiccator, the only dose level used (Nestmann et al., 1980~. The investigators did not specify whether or not the response was obtained in the presence and/or absence of a mammalian metabolic activation system. When 104 mM and 157 mM concentrations were incubated in suspension with logarithmically growing Saccharomyces cerevisiae D7 cells for 1 hour at 37°C, dichloromethane also induced gene mutation, recombination, and mitotic gene conversion. No exogenous mammalian metabolic activa- tion system was required to induce the genetic effects (Caller et al., 19801. Nestmann et al. (1981) identified dichloromethane as the volatile muta- genic component in six paint and Varnish removers assayed for mutagenic- ity in 9-liter desiccators in the Ames Salmonella assay. Mutagenicity was observed in strains TA1535, TA100, and TA98. All experiments were per- fonned with an Aroclor 1254-induced rat liver metabolic activation system only. Nestmann and colleagues found the chemical to be nonmutagenic when assayed in the HGPRT forward mutation assay with Chinese ham-
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Toxicity of Selected Contaminants 45 ster ovary cells, and it did not increase unscheduled DNA synthesis (UDS) in cultured primary human fibroblasts (AH) and hamster (V79) cells. No exogenous metabolic activation system was included in these experiments. A marginal increase in sister chromatic exchange (SCE) was observed in V79 cells with and without a rat liver metabolic activation system when tested at concentrations of 1%, Two, Two, and 4% for 1 hour at 37°C (Jongen et al., 1981~. An aspecific (nongenetic) inhibition of DNA synthe- sis was observed in cultured primary human fibroblasts (AH) and hamster (V79) cells. These experiments were performed with concentrations rang- ing from 0.5% and 5~O. The cells were examined between 30 minutes and 3.5 hours after treatment. The investigators did not state whether the DNA synthesis experiments were performed with and/or without an exogenous metabolic activation system. In summary, dichloromethane is a volatile mutagenic substance in two bacterial test systems. It was nonmutagenic when tested in several mam- malian test systems. Carcinogenicity In a National Toxicology Program (1982c) bioassay, dichloromethane was tested for carcinogenicity in both sexes of the B6C3F ~ mouse and the Fischer 344 rat. Dichloromethane doses of 500 or 1,000 mg/kg in corn oil were administered by gavage to 50 rats of each sex per dose level; doses of 500 or 1,000 mg/kg were similarly administered to mice for 5 days/week for 2 years. There were also corresponding vehicle and untreated control groups of 50 rats and 50 mice of each sex. Dichloromethane was carcinogenic in both male and female rats. He- patic neoplastic nodules and adrenal cortical adenomas were observed in both sexes, and pancreatic acinar-cell adenomas were found in males. The compound caused hepatocellular carcinomas in both sexes of mice. There may have been an association of thyroid C-cell carcinomas in male rats and leukemia and alveolar/bronchiolar adenomas in female mice. The Na- tional Toxicology Program Technical Review Subcommittee, which evalu- ated this bioassay, concluded that there may have been excessive mortality due to gavage errors and also that the maximum tolerated dose may have been exceeded. Teratogenicity Hardin and Manson (1980) exposed rats via inhalation to 4,500 ppm (15,620 mg/m3) for 6 hours/day before and during the first 17 days of gestation. Some fetal weight reduction occurred, but no in- creases in malformations were found. In the same treatment group, be- havorial studies were done by Bornschein et al. (1980~. Postnatal growth, activity, and avoidance learning were not impaired, but behavorial habitu- ation was more rapid in the exposed group.
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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 25°C), 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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