116 Information section-- Fd Chem. Toxic. Vol. 21. no. 1

Pharmacokinetics of ethylene dichloride

Reitz, R. H., Fox, T. R., Ramsey, J. C., Quast, J. 17. Langvardt, P. W. & Watanabe, P. G. (1982). Pharma- cokinetics and macromolecular interactions of ethyl- ene dichloride in rats after inhalation or gavage. Toxic. appl. Pharmac. 62, 190.

1,2-Dichloroethane (EDC: ethylene dichloride) was carcinogenic in an NCI bioassay involving the admin- istration of EDC by garage in corn oil to Osborne Mendel rats and B6C3F1 mice (Federal Register 1978, 43, 435641. The time-weighted average doses given to the rats were 47 and 95 mg/kg body weight whereas the actual doses were 50 or 75mg/kg and 100 or 150mg/kg, respectively, given 5 days/wk for various periods during the 78-wk treatment period, which was followed by an observation period of up to 32wk. There were dose-related increases in the incidences of squamous-cell carcinomas of the forestomach and of haemangiosarcomas (mainly in the spleen) in males, and mammary adenocarcinomas developed in high- dose females. However an inhalation study in Spragu~Dawley rats and Swiss mice exposed to 5, 10, 50 or 15ff250ppm EDC, 7 hr/day, 5 days/wk for 78 wk provided no evidence of carcinogen)city (Mal- toni et al. in Banbury Report 5. Ethylene Dichloride, A Potential Health Risk7 p. 3. Edited by B. Ames et al. Cold Spring Harbor Laboratory, New York, 1980). Hooper et al. (in Banbury Report 5. Ethylene Dichlor- ide: A Potential Health Risk? p. 651 compared the two studies and concluded that the most likely explana- tions for the conflicting results were that the strains of test animals used differed in their responsiveness to EDC, that an artefact had been introduced by mor- tality occurring early in the studies that had not been dealt with adequately in the statistical analyses of the results, and/or that the route of exposure makes a difference to the carcinogenic action of EDC. Reitz et al. (cited above) now propose a pharmacokinetic basis for the latter explanation.

Groups of four male Osborne Mendel rats were either given a single dose of 150mg EDC in corn oil/kg body weight by gavage, or exposed to 150 ppm EDC for 6 hr (a dose calculated as c. 113 mg/kg body weight). During inhalation exposure blood levels of EDC reached a peak of 8 101~g/ml after 2 3hr and maintained this level for the remainder of the ex- posure period. Absorption of EDC was very rapid after treatment by gavage. Peak blood EDC levels were reached after less than 15 rain and were con- siderably higher (3(~44 pg/ml) than after inhalation exposure. Modelling of pharmacokinetic data indi- cated that the elimination of EDC may become satu- rated when high blood levels are produced. When 14C-labelled EDC was administered at the same dose levels to groups of four rats the primary route of elim- ination was found to be the urinary excretion of non- volatile metabolites. The distribution of nonvolatile radioactivity was similar following oral or inhalation exposure: about 857,, of the total metabolites were detected in the urine and 7 8, 4 and 21~i, were found in expired C02, the carcass (48 hr after exposure) and faeces, respectively.

The major urinary metabolites were identified as thiodiacetic acid and thiodiacetic acid sulphoxide,

suggesting a role for glutathione in the biotransforma- tion of EDC. This was supported by further studies which indicated glutathione depletion in the livers of rats following exposure to EDC by either route. There were no differences in tissue distribution of radioac- tivity 48 hr after oral or inhalation exposure and no evidence of accumulation of radioactivity in those organs (spleen and forestomach) in which turnouts were induced in the NCI gavage study. Similarly no significant differences were observed between the two routes of dosing or between 'target' and 'non-target' tissue in macromolecular binding of laC. Administra- tion of [a4C]EDC to groups of three rats indicated very low levels of DNA alkylation following adminis- tration by either route, and no differences between 'target' and 'non-target' organs: levels were 3 5 times higher after gavage than after inhalation exposure.

No treatment-related changes detectable by gross or microscopic examination of tissues or clinical chemistry were evident after single inhalation or single or multiple (ten) gavage exposures, and there was no evidence of an increase in cellular regener- ation, as indicated by increased DNA synthesis dur- ing replication, in the spleen or kidney 48 hr after exposure by either route.

The authors consider that since total dose, GSH depletion and macromolecular binding were similar after both dosing routes in this study, and the level of DNA alkylation is low, the carcinogen)city observed in the NCI study may be the result of toxicity that is caused by the saturation of a detoxification pathway. The prolonged toxic insult may lead to tumorigenicity by a nongenetic mechanism.

[However, EDC has been found to be a strong mutagen in a Drosophila test (Cited in F.C.T. 1979, 17, 419), and is also mutagenic in Sahnonella typhi- murium in the presence or absence of metabolizing enzymes (Rannug, in Banbury Report 5. Ethylene Dichloride: A Potential Health Risk? p. 83). The other explanations suggested by Hooper et al. (lot. cir.) for the differences in the results of the NCI and Maltoni studies should not be dismissed, and the results of the repeat NCI study (Food Chemical News 1978, 20 (20), 21 must be awaited with interest.]

Trichlorobenzene metabolism in the rat and monkey

Lingg, R. D., Kaylor, W. H., Pyle, S. M., Kopfler, F, C., Smith, C. C., Wolfe, G. F. & Cragg, S. (1982). Comparative metabolism of 1,2,4-trichlorobenzene in the rat and rhesus monkey. Dru 9 Metab. Dispos. 10, 134.

1,2,4-Trichlorobenzene (TCB) is used as an inter- mediate in industrial syntheses and as a solvent, pesti- cide, dielectric fluid and heat-transfer medium. The metabolism of TCB has previously been studied in rabbits (Kohli et al. Can. J. Biochem. 1976. 54, 203) in which the major urinary metabolites were 2,4,5- and 2,3,5-trichlorophenols (TCPs) which accounted for 5 and 6',?J; of the administered dose, respectively. A metabolic study of TCB in rhesus monkeys and rats has now been reported.

Groups of 16 young male rats were given 10 mg 14C-labelled TCB/kg body weight either orally or by