The development of novel quantitaive methods in toxicology for human risk assessment

The current approach to human health risk assessment is an integrated approach requiring a significant number of studies conducted in experimental animals. The results from these animal studies are usually used to determine the potential for adverse effects in humans resulting from chemical exposure. Because of the number of experimental animal studies needed to conduct an adequate hazard assessment for a compound, there are pressures to decrease the number of studies that are conducted in whole animals. The vision for the future is to shift from the use of whole animals to the use of in vitro testing to evaluate the potential for adverse effects in humans. This desired change in toxicity testing has resulted in an increase in new testing approaches in vitro that capitalize on recent advances in genomics and systems-biology research. The ultimate goal of ongoing research is to find high throughput screening methods that will replace animal testing in the determination of the potential toxicity of compounds in humans. This new vision of toxicity testing, with a focus on the development of computational models combined with in vitro screens, has the potential to decrease animal testing. However, before this new vision can be applied, novel computational approaches must be developed or current approaches extended to address many of the critical issues involved in the process of quantitative human health risk assessment. One approach that presents multiple applications in this new vision of risk assessment is physiologically based biokinetic (PBBK) modeling. The use of these models, in combination with the appropriate data, provides the risk assessor the ability to extrapolate from concentrations in the in vitro setting to concentrations at the target tissue of concern in the human. The goal of the research presented in this thesis is three fold. One goal is to demonstrate an approach to integrate all of the currently available toxicological information on a compound quantitatively to adequately address the potential for adverse effects from chemical exposure. In making use of all of the available information in a quantitative manner, the result will be estimates of potential risk or acceptable concentration that will be biologically sound. The second goal is to address critical issues that could significantly impact dose-response estimates (i.e., children, polymorphisms). Dealing quantitatively with these issues will decrease the potential for adverse effects in the general population resulting from chemical exposure. The third goal is to further extend the development of novel quantitative methods towards the ultimate aim of decreasing the need for animal research.