DOSE-RESPONSE RELATIONSHIPS OF TISSUE DISTRIBUTION AND INDUCTION OF CYP1A1 AND CYP1A2 ENZYMATIC-ACTIVITIES FOLLOWING ACUTE EXPOSURE TO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN MICE

Tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has b een shown to be dose-dependent in rats. However, no reported studies i n mice have demonstrated dose- and time-dependent distribution of TCDD and the potential sensitivities of target tissues to enzyme induction . The objectives of this study were to determine in mice the effects o f dose (0, 0.1, 1, or 10 mu g [H-3]TCDD/kg) and time (7, 14, 21, and 3 5 days posttreatment) on tissue distribution (18 tissues) and enzyme i nduction (CYP1A1 in liver, skin, and lung and CYP1A2 in liver). Distri bution of TCDD-derived radioactivity in all tissues was dose- and time -dependent with nonlinear distribution. Liver-to-adipose tissue concen tration ratios range from 0.6 to 3.1 (low to high dose at Day 7) demon strating a dose-dependent shift in the disposition of TCDD. In contras t to liver, relative concentrations of percentage dose/g and percentag e dose/total tissue decreased with increasing doses in all other tissu es. At Day 7 and lowest dose, all tissues contained <3% dose/g except for thyroid, adrenals, skin, liver, and adipose tissue which had 3, 6, 6, 15, and 24% dose/g, respectively. Induction of EROD activity, a ma rker for CYP1A1, was dose-dependent in liver, lung, and skin but did n ot parallel tissue concentrations of TCDD. At the highest dose, fold i nduction of EROD activity was two times greater in lung than liver, wh ile the concentration in liver was 100 times greater than that in lung . Fold inductions of EROD activity in liver and skin were similar but the concentration was 20 times greater in liver than that in skin. Ind uction of hepatic acetanilide-4-hydroxylase (ACOH) activity, a CYP1A2 marker, was dose-dependent. Results of the present study demonstrated dose and time dependency in tissue distribution and induction of CYP1A 1 and CYP1A2 as well as tissue sensitivities for enzyme induction in t he female B6C3F1 mouse. These results provide important considerations for high- to low-dose extrapolations in risk assessments and use of s ensitive markers of enzyme induction as surrogates for estimating expo sure and in predicting risk. (C) 1995 Academic Press, Inc.