Multivariate modeling of polychlorinated biphenyl–induced CYP1A activity in hepatocytes from three different species: Ranking scales and species differences

Abstract

AbstractCytochrome P4501A–induced activity of 20 selected polychlorinated biphenyls (PCBs) was evaluated by measuring ethoxyresorufin‐O‐deethylase and methoxyresorufin‐O‐demethylase activities induced in the hepatocytes of cynomolgus monkeys, male castrated pigs, and chicken embryos. Quantitative structure‐activity relationships have been established, including 52 physi‐cochemical parameters and different measures of the dose‐response curves. Relative effect potencies are predicted for the 154 tetra‐to hepta‐PCBs and reported for the most potent congeners according to both EC50 and maximal response values. Important physicochemical parameters of the PCBs as related to the modeled activity are parts of their ultraviolet absorption spectra, the Henry's law constant, the ionization potential, and the octanol‐water partition coefficient. Interspecies differences were found in terms of varied sensitivity to different structural subgroups of the compounds. The chicken hepatocyte assay showed the most specific structure‐activity relationship, with high activity for the non‐ortho PCBs, whereas the pig hepatocytes responded even for some di‐ to tetra‐ortho PCBs. An interspecies response, the principal induction potency, is presented for the 41 most potent PCBs. These responses showed strong correlation with the toxic equivalency factors and are likely to be useful in risk assessment of the compounds.