Biochemical toxicology of unsaturated halogenated monomers.

Abstract

Previous inhalation toxicity studies from our laboratory have shown that 1,1-dichloroethylene (1,1-DCE), 1,1-dibromoethylene (1,1-DBE), and 2-chloro-1,3-butadiene (2-CBD) are more toxic to fasted rats than to fed rats. Vinyl chloride monomer (VCM) and 1,1-difluoroethylene (1,1-DFE) were not acutely hepatotoxic at 46,500 and 82,000 ppm, respectively, in normal male rats, whether fed or fasted. On a molar basis, 1,1-DBE and 1,1-DCE have similar toxicities while 2-CBD is less toxic. All three compounds produce similar elevation of serum transaminase and bloody ascites, although at differing times following differing exposure concentrations.1,1-DCE produces massive midzonal hepatic necrosis with hepatic thrombosis and chromatolysis within 2 hr after a 4 hr exposure of fasted rats to 200 ppm. Subsequent to formation of this midzonal lesion, the central portion of the lobule collapses, accompanied by congestion, ascites, and an increased hematocrit in the rat. Serum transaminase and sorbital dehydrogenase are greatly elevated at 6 hr. This effect in fasted rats is associated with glutathione (GSH) depletion. Diethyl maleate (DEM) which depletes GSH in fed rats potentiates the injury associated with 1,1-DCE exposure as well as that produced by 2-CBD. Rats fed ad libitum and exposed to 1,1-DCE or 2-CBD at night, a time of low hepatic GSH concentration, exhibit enhancement of hepatotoxic response when compared to animals exposed during the day when GSH is high.

Acute Liver Injury by Vinyl Chloride: Involvement of Endoplasmic Reticulum in Phenobarbital-Pretreated Rats

“…Morphologically, the lesion following 1,1-dichloroethylene is totally dissimilar; it seems to involve primarily nuclear chromatin and mitochondria and spare endoplasmic reticulum (14). …”

Differences in Metabolism of Vinylidene Chloride Between Mice and Rats

“…For example, whilst benzene is highly toxic to blood-forming tissue, it is a relatively mild leukaemic agent, whereas 2-naphthylamine is only slightly toxic to man, but is a powerful frank carcinogen. Although an attempt has been made to define the "biochemical lesion" responsible for DCE carcinogenicity in mice (Hathway, 1977;Jones and Hathway, 1977) and to describe the biochemical mechanism for the acute toxicity in rats (Jaeger et al, 1973(Jaeger et al, , 1975 we feel that it would be extremely difficult to separate completely the biochemical changes belonging to the toxic manifestations from those peculiar to the carcinogenic events. Indeed, it is feasible that the toxic and carcinogenic properties of DCE may be attributable to the same reactive metabolites, viz.…”

Computational Toxicology Methods in Public Health Practice

“…They are caused by parent compounds (i.e., by chloroform and trichloroethylene). Jaeger et al (1975) reported that acute, inhalation coexposure to high concentrations of 1,1-dichloroethylene and vinyl chloride in fasted rats, which are depleted in reduced glutathione, results in an elimination of the hepatotoxicity seen with 1,1-dichloroethylene alone. Inhalation studies in rats show that at high doses, trichloroethylene can compete with 1,1-dichloroethylene for CYP2E1 active sites, resulting in a less than additive metabolic interaction (Andersen et al 1987b;El-Masri et al 1996a).…”