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The nephrotoxicity of hexachlorobutadiene has been investigated in germ-free rats and compared to conventional rats that have a normal intestinal microflora. Presynthesized mercapturate intermediates of hexachlorobutadiene, the glutathione and the cysteine S-conjugate, were also administered. Germ-free rats appeared to be slightly more susceptible to hexachlorobutadiene by judging the extent of morphological changes compared to conventional ones. A similar response was also observed after treatment with the glutathione and cysteine S-conjugates. However, no significant difference between germ-free and conventional animals was monitored in the extent of elevation of blood urea nitrogen and plasma creatinine after treatment with hexachlorobutadiene or the glutathione and the cysteine S-conjugates. The urinary excretion of marker enzymes was monitored and showed that γ-glutamyl transferase was significantly more increased in the germ-free rats when treated with the cysteine S-conjugate. In addition, no difference in the rate of glutathione conjugation of hexachlorobutadiene was measured between the two groups. Although a tendency toward a protective effect by the presence of an intestinal microflora was observed, the role of the intestinal microflora in detoxifying hexachlorobutadiene seems to be of limited importance in rats.

New nephrons developed in goldfish, Carassius auratus, several weeks following hexachlorobutadieneinduced (HCBD) nephrotoxicity. Basophilic clusters of presumptive nephrogenic cells incorporated 5-bromo, 2'deoxyuridine (BrdU) one week after HCBD injection, indicating initiation of DNA synthesis. These clusters, like renal vesicles in the developing kidney, elongated, fused with collecting ducts and developed into immature nephrons during the next 2 weeks. Stereologic quantification showed the volume percent of the kidney occupied by the developing nephrons was greater in HCBD-treated fish 2, 3, 4, and 10 weeks after injection than in the control fish. The presence of large numbers of developing nephrons may provide a marker for renal injury in fish from contaminated waterways.

The nephrotoxicity of hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate (HCBD-CYS), and its N-acetyl cysteine conjugate (HCBD-NAC) were compared in male and female Alderley Park rats. Rats, six to eight weeks of age, were given a single intra-peritoneal injection of HCBD or its conjugates and killed 24 hours later. Nephrotoxicity was assessed by histological examination and plasma urea. All three glutathione-derived conjugates produced an elevation of plasma urea and proximal renal tubular necrosis with a similar localization in the pars recta as seen with HCBD. All the conjugates were more nephrotoxic than HCBD itself. HCBD was about four times more toxic to female rats than males. This sex difference was also shown by all the HCBD metabolites.