Modeling the number and size of hepatic focal lesions following exposure to 2,3,7,8-TCDD.
Data on the size and number of placental glutathione S-transferase-positive (PGST+) foci were collected from a two-stage hepatocarcinogenesis model in female Sprague-Dawley rats. the study consisted of multiple 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-exposed dose groups including both diethylnitrosomine (DEN)-initiated and uninitiated animals. Groups were observed after 15 or 31 weeks of TCDD exposure. The parameters in the first half of a two-stage mathematical model of carcinogenesis were estimated from these data. If the model is valid, the results suggest that TCDD stimulates the production of PGST+ foci and promotes the growth of PGST+ foci. This finding suggests a complicated mechanism for TCDD-induced production of Hepatic foci that we refer to as activation, labeling TCDD as an activator. The analysis also indicates that there is an interaction between DEN and TCDD which results in dose-related formation of initiated cells throughout the study period. Best-fitting curves (using maximum likelihood methods) for TCDD-induced activation and promotion reached saturation levels at low doses of TCDD. In summary, the model fit the data well, but leads to an interpretation of the data which either questions the validity of the model or implies that our understanding of the effects of TCDD and DEN is incomplete.
Portier
C J
CJ
Statistics and Biomathematics Branch, National Institute of Environment Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Sherman
C D
CD
Kohn
M
M
Edler
L
L
Kopp-Schneider
A
A
Maronpot
R M
RM
Lucier
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008433:Mathematics; D009154:Mutation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; D004052:Diethylnitrosamine; D000255:Adenosine Triphosphate; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D005952:Glucose-6-Phosphatase