Development of a quantitative model incorporating key events in a hepatotoxic mode of action to predict tumor incidence

Toxicological Sciences : an Official Journal of the Society of Toxicology
Nicholas S LukeHisham A El-Masri

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 sim...Continue Reading

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Citations

Nov 13, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Alan F SassoJohn C Lipscomb
Oct 23, 2012·Environmental Health Perspectives·Lauren ZeiseKathryn Z Guyton
May 2, 2015·Regulatory Toxicology and Pharmacology : RTP·Christopher J BorgertRichard A Becker
Nov 6, 2012·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Alan BoobisBernhard Watzl
Sep 8, 2012·Inhalation Toxicology·Minerva Nájera-MartínezArmando Vega-López

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