There are areas of significance to human health in which it is necessary or desirable to examine biological effects that involve the interaction of multiple agents. For example, improved cancer treatment may be achieved through the combination of multiple chemotherapeutic agents or the use of several conventional treatment modalities. Similarly, proper assessment of the potential risks posed by the increasing accumulation of hazardous materials in the environment should include the ability to examine the effects of exposure to multiple toxic agents since this is often the situation in nature. Conventional experimental designs and methods of analysis have several disadvantages in these types of studies. The experiments are necessarily large and therefore technically unwieldly and expensive. In addition, the analysis of data rapidly becomes extremely complex as the number of agents increases. The objective of this proposal is to develop and apply mathematical and statistical techniques which comprise response surface modelling to the study of biological effects resulting from exposure to various combinations of chemical and/or physical agents. Response surface analysis has proven to be a useful tool in combination chemotherapy studies using animal models; this will be the first attempt to apply these techniques to in vitro biological systems. Cell lethality, mutation and sister chromatid exchange will be the biological responses examined. These effects will be quantitated in V79 Chinese hamster fibroblasts using standard procedures following exposure of the cells to ionizing radiation, heat and chemicals in various combinations. Aspects of response surface methodology will include selecting the appropriate experimental designs, fitting multi-dimensional response surfaces to experimental data and exploring the response surfaces in regions of particular interest. A major aim is to use this approach to detect statistically significant interactions that occur between the agents used to produce the various responses. These techniques may result in new ways to improve the technical feasibility and cost effectiveness of in vitro experiments designed to optimize the use of therapeutic agents or to test mixtures of potentially harmful environmental agents utilizing presently available screening systems.