Development, evaluation and use of a pharmacokinetic model for hexachlorobenzene

This study discusses the background, biological basis, development characteristics, application and evaluation of six physiologically based multicompartment models that describe the absorption, distribution and elimination of hexachlorobenzene (HCB) in growing rats and growing humans. The models for rats and for humans have similar structures but differ in specific physiological parameters. The goal of the modelling effort was to obtain toxicological information about HCB based on its pharmacokinetics. Comparisons were made between estimated tissue concentrations based on the rat models and observed tissue distributions based on pharmacokinetic animal studies with HCB, using both chronic and single-dose studies. The estimates from the female model agreed reasonably well with experimental results, and estimated a long half-life of approximately 180 days in all tissues; it did not, however, duplicate the biphasic tissue efflux of HCB that has been reported in the literature. The male model estimated a half-life of approximately 55 days in all tissues, shorter than that observed experimentally. The estimated yield of metabolites agreed well with values reported in the literature. A pregnancy and offspring model predicted minimal transfer of HCB to the fetal compartment during gestation and extensive mobilization of HCB to the offspring during lactation. This agrees with results reported in the literature. Correlations were obtained between experimentally observed liver toxicity and estimated yield of metabolites; between experimentally observed effects on the central nervous system and estimated HCB concentrations in the brain; and between experimentally observed offspring mortality and estimated extent of lactational HCB transfer. This paper also discusses the effects on tissue concentrations and half-lives of trapping HCB in the intestines by sequestering a large portion of it there. Various characteristics of the human models are discussed. The female model has a biphasic elimination pattern, the second elimination phase having a half-life of greater than 200 days. The pregnancy and offspring model projects extensive transfer of HCB via the milk to the nursing offspring, which correlates with the greater mortality of nursing infants whose mothers were exposed to HCB in Turkey.