Effects of glutathione transferase theta polymorphism on the risk estimates of dichloromethane to humans

The carcinogenic potential of dichloromethane (DCM) has been linked to its metabolism to formaldehyde by glutathione-S-transferase theta 1 (GSTT1), GS TT1 is polymorphic in humans. The frequency of the GSTT1 homozygous null ge notype ranges from 10 to 60% in different ethnic and racial populations aro und the world, We investigated how varying GSTT1 genotype frequencies would impact cancer risk estimates for DCM by the application of Monte Carlo sim ulation methods in combination with physiologically based pharmacokinetic ( PBPK) models. The PBPK model was used to estimate the DNA-protein cross lin ks (DPX) caused by metabolism of DCM based on an earlier model. Cancer pote ncy of DCM was obtained by the application of the estimated DPX amounts to the results of a carcinogenicity study by National Toxicology Program in B6 C3F(1) mice. Human risks were estimated based on the carcinogenic potency o f DCM to mice and PBPK-predicted amounts of DPX formed in humans. The Monte Carlo simulations were used to provide distributions of risk estimates for a sample of 1000 PBPK runs, each run representing a collection of biochemi cal and physiological parameters for a single person (with and without poly morphism included in the model). Our results show that average and median r isk estimates were 23-30% higher when GSTT1 polymorphism was not included a t inhalation DCM doses of 1000, 100, 10, and 1 ppm. This increase in risk w as significantly reduced when it was based on the 95th percentile measure f or all the doses, The specific effect of this polymorphism on population ri sk was further investigated by varying the probability that an individual m ay have a nonfunctional form of the enzyme at a constant dose level of 10 p pm of DCM, Higher values of this probability resulted in a corresponding de crease in risk. Again, this drop in population risk was not as significant when the 95th percentile measure was used.