Promotion of preneoplastic foci in rat liver with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin and a defined mixture of 49 polychlorinated dibenzo-p-dioxins.
In a two-stage initiation-promotion experiment the hypothesis was investigated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents (TE), calculated from data of CYP1A induction in hepatocytes in primary culture, or international TCDD equivalents (ITE) are useful for evaluating the tumor-promoting potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) and of a defined mixture (M2) of 49 polychlorinated dibenzo-p-dioxins (PCDDs) in comparison with TCDD. Therefore, female Wistar rats were treated with an initiating dose of N-nitrosomorpholine, and subsequently received daily doses of 2, 20 and 200 ng TCDD/kg or equivalent doses of HpCDD or M2, based on TE values. After a promotion phase of 13 weeks, hepatic PCDD levels, CYP1A activity and the relative hepatic volume of adenosinetriphosphatase-negative or glutathione S-transferase P-positive preneoplastic foci were determined. After logarithmic transformation, linear PCDD level-response relationships were obtained for induction of CYP1A activity with TCDD, HpCDD or M2. Based on TE values, inducing potencies of both HpCDD and M2 were over-estimated at higher doses, whereas induction was approximately equivalent at the lowest dose. The best fit of PCDD level-response relationships of relative hepatic volumes of preneoplastic lesions was achieved using a four-parameter logistic model. Significantly different functions were calculated for promotion with TCDD or HpCDD. It is concluded that (i) different PCDD level-response relationships exist for the induction of hepatic CYP1A activity and the promotion of preneoplastic liver foci, and (ii) that TE or ITE factors provide only a rough estimate of the tumor-promoting potency of a PCDD mixture but may overestimate the risk from exposure to higher-chlorinated 2,3,7,8-substituted congeners such as HpCDD.
Schrenk
D
D
Institut für Toxikologie, Universität Tübingen, Germany.
Buchmann
A
A
Dietz
K
K
Lipp
H P
HP
Brunner
H
H
Sirma
H
H
Münzel
P
P
Hagenmaier
H
H
Gebhardt
R
R
Bock
K W
KW
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004147:Dioxins / Q000633:toxicity; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
D002273:Carcinogens; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin