Polychlorinated dibenzodioxins (PCDDs) have become a major risk to human health and the environment due to their extreme toxicity, widespread environmental contamination and persistence. The long-term objectives of this proposal are to establish the mechanisms(s) and site of action for PCDD induced toxicity and to ultimately assess man's relative sensitivity to these compounds. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent and extensively studied isomer of the PCDDs and thus will be used in this study as a prototype for this group of compounds. Profound, naturally occurring interspecies variability in pathology and LD50 have been reported following exposure of guinea pigs, rats, hamsters, and mice to TCDD. This proposal will attempt to explain this marked interspecies variability and thus obtain information about the mechanism of TCDDs acute toxicity. Comparative studies with these species have thus been designed to investigate the significance of TCDD metabolism and the role of the central and peripheral nervous system in the expression of the acute toxicity of TCDD. Isolated hepatocyte incubations will be used to investigate the in vitro metabolism of radiolabeled TCDD by different species, under various conditions. Once perfected, this in vitro model will be adapted to study TCDD metabolism in human liver. Data from in vitro sutdies will be compared with in vivo investigations of TCDD metabolism in experimental animals. Metabolites of TCDD obtained from urine, bile, and hepatocyte incubations of each species will be isolated and characterized. These and other interspecies comparisons should establish the role TCDD biotransformation plays in the expression of TCDD's acute toxicity. In addition, these studies will provide much needed information regarding the metabolism of TCDD. In the second approach to this problem, the distribution and toxicity of TCDD will be examined in the central and peripheral nervous system of several species. In conjunction with distribution measurements, studies will assess the effect to TCDD exposure on the morphology of the central and peripheral nervous system, permeability of the blood-brain barrier and conduction velocity of peripheral nerves. Together, these and additional studies should establish whether the central and/or peripheral nervous system could be a target site for the toxicity of TCDD.
