2.5.2. Genetically sensitized animals should be tested for low-dose toxicant effects.
Does the heterogeneous response of a population of test animals to toxicants give a detectable effect that reflects genetic heterogeneity? To determine the role of genetic differences, various mouse strains can be produced with limiting levels of activity of particular developmental components, and these strains can be tested for their sensitivity to a standard set of toxicants representing a variety of suspected mechanisms of action. Such tests would be a measure of whether animals that are genetically close to abnormal development due to their genetic constitution are more sensitive than normal animals to toxicants, and if so, whether a general sensitivity or a specific one is related to the particular limiting component.
Because genetically sensitized models can approximate more closely potentially susceptible members of the human population, risk assessors can use the toxicity data more comfortably. Developmental toxicologists might want to explore the relationship between genetic variation of toxicodynamic components and toxicant sensitivity in model animals before human variants of developmental components are identified in the future. (The association of cigarette smoking, TGF variants, and cleft palate is already an example.)
Improved information on human exposures gained from other areas of study (e.g., improved biomarkers) should provide additional information to predict more accurately the human exposure range for any given chemical or mixture. Such information could then be used to set exposure concentrations for model-animal assessments in levels 2 and 3.
2.6. Quantitative risk assessment: modeling extrapolation from test animals to humans.
The informational framework in Chapter 8 should provide a guide for obtaining the kinds of test-animal data that are needed for a comprehensive cross-species toxicokinetic and toxicodynamic model of exposure and development of test animals, such as mice, to humans. As outlined in Table 8-1B, information from improved human biomarkers of exposure, susceptibility (both genetic and nongenetic), and effect would be used in the model as well. Such models, difficult as they are to devise and fill with satisfactory data, are needed if a chemical’s potential for developmental effects are to be extrapolated to humans in a meaningful way. For example, complex computational models and abundant data are needed to estimate in utero and postnatal exposures in mammals and to link this information with toxicological impacts.
Interest in such models is demonstrated by the efforts of the National Institute of Environmental Health Sciences to link exposure information with mechanistic toxicity data. However, only a few such specialized models exist, and none adequately combines toxicokinetic and toxicodynamic information, especially the information on molecular and cellular impacts. The lack of an adequate frame-