Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism: use in risk assessment.
Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), or 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) on thyroid hormone metabolism were studied in 13-week feeding studies in female Sprague-Dawley rats. The diets were supplemented with the compounds tested at concentrations ranging from 0.2 to 20 micrograms/kg diet for TCDD, 7 to 180 micrograms/kg diet for PCB 126, or 1.2 to 12 mg/kg diet for PCB 156, respectively. Significant correlations were found for all three compounds between reductions in plasma total thyroxine (TT4) levels and inductions of the microsomal phase II enzyme UDP-glucuronosyltransferase by using T4 as a substrate (T4UGT). Furthermore, the coinduction of certain phase I and II isozymes, i.c., cytochrome P450 1A1 (CYP1A1) and UGT1A1, by these compounds, clearly suggests the involvement of an Ah receptor-mediated mechanism in the disturbance of thyroid hormone metabolism by these polyhalogenated aromatic compounds. These results provide a mechanistic base for the use of certain effects on thyroid hormone metabolism by polyhalogenated aromatic compounds in risk assessment. By using these effects, potencies of PCB 126 and PCB 156 relative to TCDD ranged from 0.008 to 0.1 for PCB 126, and from 0.00007 to 0.004 for PCB 156, respectively. These values correspond very well with relative potencies of PCB 126 and PCB 156 by using some other well-known Ah receptor-mediated toxic and biochemical parameters.
Van Birgelen
A P
AP
Research Institute of Toxicology, University of Utrecht, The Netherlands.
Smit
E A
EA
Kampen
I M
IM
Groeneveld
C N
CN
Fase
K M
KM
Van der Kolk
J
J
Poiger
H
H
Van den Berg
M
M
Koeman
J H
JH
Brouwer
A
A
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004032:Diet; D004435:Eating / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D010088:Oxidoreductases / Q000096:biosynthesis; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018570:Risk Assessment; D013963:Thyroid Hormones / Q000378:metabolism*
D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D013963:Thyroid Hormones; C087667:2,3,3',4,4',5-hexachlorobiphenyl; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D014453:Glucuronosyltransferase; C023035:3,4,5,3',4'-pentachlorobiphenyl