Application of Mode of Action to Biologically Based Models of Dose-Response. R. B. Conolly, CIIT
Computer simulation models in toxicology and risk assessment have focused largely on pharmacokinetics (PK); e.g., PBPK models, while the pharmacodynamic (PD) mechanism(s) linking tissue dose with toxic effect have usually not been described. This reflects the state of knowledge, with mechanisms of PK being better understood than those of pharmacodynamics. Among the few examples of comprehensive models that combine PK with PD are models for chloroform cytotoxicity and formaldehyde carcinogenicity. For each of these comprehensive models, a dosimetry submodel serves as a front end to the pharmacodynamic submodel, since pharmacodynamics cannot be modeled quantitatively without a preceding quantitative description of pharmacokinetics. Even for relatively well-studied chemicals like chloroform and formaldehyde, the PD mechanisms are not understood in detail. The respective PD submodels are therefore more accurately described as mode of action submodels. By this, we mean that the PD submodels capture sufficient biological information to qualitatively constrain the shape of the dose-response curve (e.g., threshold for the cytotoxicity of chloroform and formaldehyde, low dose linear for the direct mutagenicity of formaldehyde). However, many details of the molecular mechanisms by which chloroform and formaldehyde exert their cytotoxic effects, and formaldehyde its directly mutagenic effects, are not understood and cannot be modeled explicitly. The mode of action concept is thus useful for guiding development of comprehensive simulation models of dose-response. While development of a mode of action-based model implies a minimum understanding of the PD mechanism of action, this understanding and its implications for the shape of the dose-response curve can always be refined. Quantitative, though usually not qualitative changes, in the shape of the dose-response curve generated by the PK-PD model would be expected to result of this refinement. The dose-response models for chloroform and formaldehyde will be described in sufficient detail to illustrate their dependence on the mode rather than the mechanism of action.
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