Relative potency values derived from hepatic vitamin A reduction in male and female Sprague-Dawley rats following subchronic dietary exposure to individual polychlorinated dibenzo-p-dioxin and dibenzofuran congeners and a mixture thereof

This stud investigated the potency of individual polychlorinated dibenza-p- dioxins (PCDDs) and dibenzofurans (PCDFs) to reduce hepatic vitamin A in th e rat. Dose-response relationships were determined following long-term diet ary exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-penta chlorodibenzofuran, 1,2,3,4,8-pentachlorodibenzofuran, 1,2,3,7,8-pentachlor odibenzofuran, 1,2,3,6,7,8-hexachlorodibenzofuran, 1,2,3,7,8-pentachlorodib enzo-p-dioxin octachlorodibenzo-p-dioxin, octachlorodibenzofuran, or mixtur es of some of these congeners. The aim was to estimate vitamin A-related re lative potency (REP) values for each congener in relation to that of TCDD a nd to investigate if these values were in accordance with REP values estima ted for the subchronic toxicity observed in the same study. An additional a im was to investigate if the effect on hepatic vitamin A levels was additiv e compared to the effect of the individual congeners. The obtained results demonstrate that hepatic vitamin A reduction occurs as a consequence of lon g-term low-level exposure to 2,3,7,8-substituted but not to non-2,3,7,8-sub stituted congeners. Female rats were slightly more responsive to this effec t as judged from the lower EC50 values for all the congeners in this sex. T he vitamin A-related REP values were similar for female and male rats and w ere in good agreement with the estimated REP values for subchronic toxicity in the same animals. The vitamin A effect of the individual congeners in t he mixture tended to be somewhat less than pure additive for male rats and very close to pure additive for female rats. Ln conclusion, the presented d ata show that reduction of hepatic vitamin A is a sensitive marker of an al tered retinoid homeostasis following long-term low-dose exposure to dioxin- like compounds, which essentially conforms to their assumed additive mechan ism of action. (C) 2000 Academic Press.