It is the long range objective of this project to evaluate the relationships between environmental exposure to potential toxic agents and changes in biochemical, molecular or cytogenetic parameters that may be important in identifying individuals at increased risk to having an adverse health outcome. Animal models and defined human populations exposed to environmental substances are used to evaluate: (1) the utility of using lymphocytes as molecular dosimeters of environmental exposure by determining the biologically-effective dose for different classes of chemical carcinogens through measuring DNA adducts in relation to dose; (2) the relationships between pharmacokinetic parameters of activation/deactivation and the generation of biologically-effective doses, and the resulting consequences of biological endpoints such as SCEs, chromosomal aberrations and DNA damage and repair. A cytogenetic procedure has been developed that distinguishes smokers and PCB-exposed persons from appropriate unexposed populations. Elevations in SCE frequencies in lymphocytes are seen only in exposed individuals following in vitro exposure of blood to the synthetic flavanoid, alpha-naphthoflavone (ANF), a potent P-450 inhibitor. The mechanism for this differential sensitivity is being investigated in animal and in vitro (CHO cell) systems. Our findings have shown that metabolic activation of ANF is required for clastogenicity. Studies are also in progress to determine the relationship between heritable differences in metabolic activation/deactivation of chemicals by human lymphocytes and DNA damage as measured by DNA-adduct levels and/or nucleoid sedimentation. DNA adducts are measured by standard techniques as well as 32P-postlabelling.
