The human response to environmental carcinogens is highly variable, depending upon environmental, lifestyle, and genetic factors. Genetic factors include polymorphic P450 and DNA repair genes; however, epidemiological studies may lack significance due to inadequate patient numbers. We used budding yeast (Saccahromyces cerevisiae) as a model organism to determine genetic susceptibility to food-associated carcinogens, including benzo[a]pyrene dihydrodiol (BaP-DHD), aflatoxin (AFB1) and heterocyclic aromatic amines (HAAs). Budding yeast does not contain P450s that convert these compounds into genotoxic metabolites, so we introduced expression vectors that contain specific human P450 and NAT2 genes into yeast deletion library collection.. In yeast, either CYP1A2 or CYP1A1 activates AFB1, while both CYP1A2 and NAT2 are required for activation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). To measure genotoxic effects, we measured recombination and mutation frequencies, Rad51 foci, growth inhibition and DNA adducts. To determine resistance genes, we used a high throughput approach for screening the yeast deletion library expressing specific P450 genes. Screens for aflatoxin resistance identified checkpoint, RNA metabolism, and mitochondrial maintenance genes, several of which are risk factors in cancers. We are now performing screens to identify genes involved in resistance to IQ. Preliminary data identified both recombinational repair and DNA damage tolerance genes. Further high throughput analysis will be performed using other food carcinogens, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). These studies thus represent a novel approach for phenotyping P450 polymorphisms and open new avenues for exploring resistance to P450-activatable compounds. Grant Support: National Institutes of Health, 1R15ES023685-01.