The ultimate goal of this work is to develop techniques to better evaluate the potential toxicity of chemicals to humans. Currently, toxicological and pharmacological testing of chemicals requires large numbers of animals. Data obtained from whole animal studies are difficult to accurately extrapolate across species lines and to effects at low doses. Basic metabolic interactions are difficult to monitor. On both economic and ethical grounds it is desirable to reduce the number of animals utilized in such testing. Advances in biotechnology and cell culture present an opportunity to develop alternative methods that can yield both better data and reduced use of animals. This work will combine pharmokinetic models and in vitro cell culture techniques to construct a direct physical analog of the whole animal. This concept will be tested by constructing a mouse analog - using two types of lung cells and hepatocytes from the liver. Direct observations can be made of molecular level mechanisms for biotransformations of xenobiotics. Further incorporation of mechanistic information into the pharmokinetic model will allow extrapolation of observations. Controversies on which cytochromes are responsible for bioactivation of napthalene and on which cell types are primarily responsible for its activation will be addressed.
