Diethylnitrosamine-induced hepatocarcinogenesis in rats: a theoretical study.
Multiple data sets on hepatocarcinogenesis in rats resulting from pulse (single) or continuous exposure to diethylnitrosamine (DEN) are analyzed within the framework of a two-mutation carcinogenesis model in order to identify the underlying biological processes that control the pharmacodynamics of DEN-induced liver cancer. Our findings indicate: (1) Predictions of the two-mutation oncogenic model are consistent with empirical data on DEN-induced hepatocarcinogenesis. (2) The probability of the first genetic alteration (initiation) is linearly dependent on applied dose and decays exponentially following a pulse (single) dose or cessation of exposure. (3) The probability of initiation is proportional to the number of O4-ethyldeoxythymidine DNA adducts resulting from DEN exposure, indicating that these adducts are the likely promutagenic lesions in DEN-induced hepatocarcinogenesis. (4) The mitotic rates of initiated and transformed cells are nonlinear with dose. (5) The average growth rate of initiated hepatocytes as a function of DEN dose is related to Druckery's slope. (6) The probability of the second genetic event (transformation) is independent of applied dose, suggesting that it is the result of a spontaneous genetic alteration.
Travis
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Health and Safety Research Division, Oak Ridge National Laboratory, Tennessee 37831-6109.
McClain
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Birkner
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D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced*; D004052:Diethylnitrosamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D015201:Meta-Analysis as Topic; D008954:Models, Biological; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains
D004052:Diethylnitrosamine