Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture

Groups of male Sprague-Dawley rats were administered orally the following chlorinated dibenzo-p-dioxins (CDDs) in corn oil/acetone (95/5; v/v): 30–60 μg/kg 2,3,7,8-tetrachlorodibenzo-dioxin (tetra-CDD), 160–270 μg/kg 1,2,3,7,8-pentachlorodibenzo-p-dioxins (penta-CDD), 630–1249 μg/kg 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD) and 5000–8000 μg/kg 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD) or a mixture of the four homologues such that each was present in the mixture at one quarter of its dose as a single compound. Animals were killed at 2 and 8 days after dosing. Livers were immediately removed, and aliquots frozen in liquid nitrogen. Storage occurred at ?80°C until further use. About 0.2 g of each lyophilized rat liver was extracted, the extract purified by column chromatography and analyzed by GC/MS for CDD content. Results obtained suggest that the absorption of CDDs after oral administration decreases in the order of tetra-CDD≥penta-CDD>hexa-CDD>hepta-CDD, indicating that the dose was an incomplete surrogate of exposure in parts I–III of this publication series (Stahl et al. 1992; Weber et al. 1992a,b). Moreover, data also support the notion that the pharmacokinetics of CDD mixtures at high doses are somewhat different from those expected based on single compound exposures. Our findings suggest that the intrinsic relative potency in terms of toxic equivalents (TEQ) of the higher chlorinated homologues is slightly greater (about a factor of 2) than suggested by Stahl et al. (1992), because of reduced absorption, whereas the contribution to total potency of the lower chlorinated homologues in mixtures is slightly higher (about a factor of 2) because of increased relative liver concentrations. This later finding appears to be due to altered pharmacokinetics of mixtures of CDDs, probably originating in changes of partial solubility of the lower chlorinated homologues in fat under conditions of near saturation.