Efforts have focused on the biological and biochemical effects of bioretained polychlorinated hydrocarbons, for which, because of their frequent occurrence in breast milk, human infants are a particular target. In a study of the toxicokinetics of polychlorinated biphenyls (PCBs), in body fat and in target organs for tumor promotion, a single dose of Aroclor 1254 was administered to neonatal mice and the amounts of specific congeners present in carcass, liver, and lung quantified at intervals of 1 day to 16 weeks. A complex pattern was observed in liver, with early retention followed by more rapid loss, while in lung 7 of 8 congeners were strongly retained, a phenomenon of clear potential relevance to the selective biochemical and tumorigenic toxicity of PCBs in this organ. The biochemical toxicity was investigated in a study in which cytochromes P450 1A1 and 2B1 were quantified by enzyme assay and immunoblot in liver and lung for 30 weeks after a single dose of Aroclor 1254. In lung, while 1A1 showed rapid and prolonged induction over 30 weeks, 2B activity was significantly inhibited for 4 weeks. A highly toxic congener, 2,3,3',4',4'-pentachlorobiphenyl (IUPAC #105) was selectively retained in lung vs carcass. In liver, both cytochromes were significantly induced over the 30-week time course at 2 PCB doses, the lower of which yielded body burdens of PCBs similar to that found in some humans. To begin to dissect the effects of this chemical mixture, and to look at other target organs of interest, single-dose exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), a specific, effective inducer of P450 1A1, was studied. 1A1 was induced in all tissues, with liver, lung and kidney exhibiting an early maximum and gradual decrease over 4 weeks, and intestines a rapid loss of activity with time. The greatest effect was seen with oral administration. These findings demonstrate sensitive, organ-specific induction of cytochromes P450 associated with specific congener retention; the mechanistic relationship of these phenomena to tumor promotion is under investigation (see also project ZO1CP05299).
