Biologically based modeling in toxicology research.
Biologically based modeling can be described as the process by which the specific mechanistic steps governing tissue disposition and toxic action of chemicals are expressed in quantitative terms by a set of equations leading to prediction of the outcome of specific toxicological experiments by computer simulation. These models are useful in risk assessment because their mechanistic biological basis permits the high-to-low dose, route to route and interspecies extrapolation of the tissue disposition and toxic action of chemicals. By far their greatest utility is not as "finished" risk assessment models, but as research tools that convey a quantitative expression of our hypotheses of tissue disposition and toxic action of a chemical. A structured modeling approach to toxicology problems helps identify the data gaps in the areas of chemical disposition and toxic action, thus prioritizing on-going research to obtain critical information required to conduct quantitative risk assessment. This paper examines progress in developing comprehensive biologically based models for cancer induction by non-genotoxic carcinogens that are cytotoxic in target tissues. The strategies for linking the models on dosimetry, cytotoxicity, and carcinogenicity are described in detail. The basic concepts and approaches discussed here can be applied to many other toxic chemicals and to toxicity endpoints other than cancer.
Andersen
M E
ME
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Krishnan
K
K
Conolly
R B
RB
McClellan
R O
RO
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002725:Chloroform / Q000633:toxicity; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000139:chemically induced*; D012308:Risk Management; D014018:Tissue Distribution; D014116:Toxicology / Q000379:methods*
D002273:Carcinogens; D002725:Chloroform; D002251:Carbon Tetrachloride