title: Development of a quantitative model incorporating key events in a hepatotoxic mode of action to predict tumor incidence.
abstract: Biologically based dose-response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the nongenotoxic MOA may be operative as a function of dose, it is important to note that the label informs but does not define a MOA. One commonly proposed MOA for nongenotoxic carcinogens is characterized by the key events cytotoxicity and regenerative proliferation. The increased division rate associated with such proliferation can cause an increase in the probability of mutations, which may result in tumor formation. We included these steps in a generalized computational pharmacodynamic (PD) model incorporating cytotoxicity as a MOA for three carcinogens (chloroform, CHCl(3); carbon tetrachloride, CCL(4); and N,N-dimethylformamide, DMF). For each compound, the BBDR model is composed of a chemical-specific physiologically based pharmacokinetic model linked to a PD model of cytotoxicity and cellular proliferation. The rate of proliferation is then linked to a clonal growth model to predict tumor incidences. Comparisons of the BBDR simulations and parameterizations across chemicals suggested that significant variation among the models for the three chemicals arises in a few parameters expected to be chemical specific (such as metabolism and cellular injury rate constants). Optimization of model parameters to tumor data for CCL(4) and DMF resulted in similar estimates for all parameters related to cytotoxicity and tumor incidences. However, optimization of the CHCl(3) data resulted in a higher estimate for one parameter (BD) related to death of initiated cells. This implies that additional steps beyond cytotoxicity leading to induced cellular proliferation can be quantitatively different among chemicals that share cytotoxicity as a hypothesized carcinogenic MOA.
authors.affiliation: Department of Mathematics, North Carolina Agricultural and Technical State University, Greensboro, North Carolina 27411, USA.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Luke
authors.forename: Reeder
authors.initials: R
authors.lastname: Sams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: DeVito
authors.forename: Rory B
authors.initials: RB
authors.lastname: Conolly
authors.forename: Hisham A
authors.initials: HA
authors.lastname: El-Masri
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000493:pharmacokinetics / Q000633:toxicity*; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002725:Chloroform / Q000493:pharmacokinetics / Q000633:toxicity*; D019295:Computational Biology; D003201:Computers; D004126:Dimethylformamide / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008954:Models, Biological; D012038:Regeneration / Q000187:drug effects; D018570:Risk Assessment
chemical_list: D002273:Carcinogens; D002725:Chloroform; D004126:Dimethylformamide; D002251:Carbon Tetrachloride