The role of contaminants in hexachlorobenzene toxicity.
Hexachlorobenzene (HCB) is hepatotoxic, causing a porphyria with an acquired deficiency of uroporphyrinogen decarboxylase. Conflicts have arisen regarding the toxicological significance of impurities in samples of HCB. In female rats, unpurified practical-grade HCB from Eastman Kodak Company was more porphyrogenic than a sample from Aldrich Chemical Company that had been recrystallized from benzene. To determine whether specific inducers of hepatic microsomal cytochrome P1-450, such as 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), contributed to the difference in toxicity of these samples, induction of porphyria and activities of the cytochrome P1-450-dependent mono-oxygenase, ethoxyresorufin-O-deethylase (ERR), were compared in rats receiving HCB (0.2% w/w) or TCDD (10 micrograms/kg initial dose, then 2.5 micrograms/kg weekly). Porphyria occurred in the former but ERR activity was induced about four times more in the latter. The relative potency of crude and purified HCB samples in inducing ERR activity was further evaluated in C57Bl/6 and DBA/2 mice; ERR activity was three times higher in C57Bl/6 than in DBA/2 mice treated with 0.01% w/w HCB. ERR activity was also higher in C57Bl/6 mice treated with impure than in those treated with purified HCB. These results show that undefined impurities can be important determinants of the biological effects of HCB samples and suggest that these effects are partly mediated via the Ah receptor. However, porphyria induced by HCB appears to be independent of HCB impurities and not solely dependent on induction of the cytochrome-P1-450 mono-oxygenases.
D000818:Animals; D002722:Chlorobenzenes / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1; D004340:Drug Contamination; D005260:Female; D006581:Hexachlorobenzene / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D010088:Oxidoreductases / Q000096:biosynthesis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011164:Porphyrias / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects
D002722:Chlorobenzenes; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D006581:Hexachlorobenzene; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1