Subchronic exposure of [H-3]-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) infemale B6C3F1 mice: Relationship of steady-state levels to disposition andmetabolism

The present study of subchronic low exposure to 2,3,7,8-tetra-chlorodibenzo -p-dioxin (TCDD) at or near steady-state levels tries to emulate the most p robable mode for human exposure, dietary consumption. This study is the fir st and most intensive pharmacokinetic study to be reported with repeated do sing, multiple times, and multiple doses examining disposition of TCDD-deri ved radioactivity and CYP1A activities in mice. For time-course relationshi ps, animals were dosed (daily, Monday-Friday) with 0, 1.5, or 150 ng [H-3]T CDD/kg for 4, 8, 13, or 17 weeks and also for 13 weeks followed by 4 weeks with no dosing. For dose-response relationships, animals were dosed for 13 weeks (daily, Monday-Friday) with 0, 0.15, 0.45, 1.5, 4.5, 15, 45, 150, or 450 ng [H-3]TCDD/kg. Additional animals dosed for 13 weeks (daily, Monday-F riday) with 1.5 or 150 ng [H-3]TCDD/kg were housed in metabolism cages. Tim e- and dose-dependencies of TCDD were confirmed in all measured tissues. Li ver/fat (LIF) concentration ratios ranged from 0.2-3.4 (low to high dose). Hepatic CYP1A1 enzymatic activity increased (p < 0.05) starting at 0.15 ng/ kg/day with L/F of 0.2 and body burden of 2.8 ng TCDD/kg body weight. By ex amining TCDD exposures at or near steady state, this study reports for the first time and provides direct evidence of low-dose effects on a measured r eversible response at body burdens that are within background levels of the general human population. In addition, this study emphasizes cumulative ef fects of daily dosing and suggests the importance of tissue dosimetry or bo dy burden for a persistent chemical such as TCDD.