Subchronic Exposure of [3H]- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female B6C3F1 mice: relationship of steady-state levels to disposition and metabolism.
The present study of subchronic low exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at or near steady-state levels tries to emulate the most probable mode for human exposure, dietary consumption. This study is the first and most intensive pharmacokinetic study to be reported with repeated dosing, multiple times, and multiple doses examining disposition of TCDD-derived radioactivity and CYP1A activities in mice. For time-course relationships, animals were dosed (daily, Monday-Friday) with 0, 1.5, or 150 ng [3H]TCDD/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 [3H]TCDD/kg. Additional animals dosed for 13 weeks (daily, Monday-Friday) with 1.5 or 150 ng [(3)H]TCDD/kg were housed in metabolism cages. Time- and dose-dependencies of TCDD were confirmed in all measured tissues. Liver/fat (L/F) 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 examining 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 reversible response at body burdens that are within background levels of the general human population. In addition, this study emphasizes cumulative effects of daily dosing and suggests the importance of tissue dosimetry or body burden for a persistent chemical such as TCDD.
Diliberto
J J
JJ
U.S. Environmental Protection Agency, ORD, NHEERL, ETD, Research Triangle Park, North Carolina 27711, USA. diliberto.janet@epa.gov
DeVito
M J
MJ
Ross
D G
DG
Birnbaum
L S
LS
D000273:Adipose Tissue / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001822:Body Burden; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005243:Feces / Q000737:chemistry; D005260:Female; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D013223:Statistics as Topic; D013997:Time Factors; D014018:Tissue Distribution; D014316:Tritium; D014556:Urine / Q000737:chemistry*
D000072317:Polychlorinated Dibenzodioxins; D014316:Tritium; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2