Interactive effects between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,2',4,4',5,5'-hexachlorobiphenyl in female B6C3F1 mice: tissue distribution and tissue-specific enzyme induction.
The distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) was studied in female B6C3F1 mice. Single doses of TCDD alone (0, 0.1, 1, or 10 micrograms [3H]TCDD/kg), PCB 153 alone (0, 3.58, 35.8, or 358 mg [14C]PCB 153/kg), and all possible combinations of these doses were administered in corn oil, po. At 7 days after dosing, 11 different tissues were analyzed for radioactivity. When TCDD was administered alone, TCDD-derived radioactivity distributed to all tissues in a dose-dependent manner, increasing with dose in the liver, while decreasing (as a percentage of the administered dose) in all other tissues. When PCB 153 was administered alone, the PCB 153 concentration was dose-dependently (percentage of dose) decreased in liver, skin, lung, adrenals, kidney, and blood; no dosimetric effects were observed in the other organs. Coadministration of low doses of both TCDD and PCB 153 resulted in little or no effect on the distribution of either compound. Interactive effects occurred in the pharmacokinetic behavior of both compounds only at higher doses. For example, the amount of TCDD in the liver was increased by 358 mg PCB 153/kg. In most other organs administration of PCB 153 resulted in a dose-dependent decrease in the TCDD content. Coadministration of PCB 153 with 10 micrograms TCDD/kg increased PCB 153 in the liver, but not in other tissues. These results clearly demonstrate that interactive effects on pharmacokinetic behavior occur only at high doses.
van Birgelen
A P
AP
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Ross
D G
DG
DeVito
M J
MJ
Birnbaum
L S
LS
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; C014024:2,4,5,2',4',5'-hexachlorobiphenyl