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). GSTT1 is polymorphic in humans. The frequency of the GSTT1 homozygous null genotype ranges from 10 to 60% in different ethnic and racial populations around the world. We investigated how varying GSTT1 genotype frequencies would impact cancer risk estimates for DCM by the application of Monte Carlo simulation methods in combination with physiologically based pharmacokinetic (PBPK) models. The PBPK model was used to estimate the DNA-protein cross links (DPX) caused by metabolism of DCM based on an earlier model. Cancer potency of DCM was obtained by the application of the estimated DPX amounts to the results of a carcinogenicity study by National Toxicology Program in B6C3F(1) mice. Human risks were estimated based on the carcinogenic potency of 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 biochemical and physiological parameters for a single person (with and without polymorphism included in the model). Our results show that average and median risk estimates were 23-30% higher when GSTT1 polymorphism was not included at inhalation DCM doses of 1000, 100, 10, and 1 ppm. This increase in risk was significantly reduced when it was based on the 95th percentile measure for all the doses. The specific effect of this polymorphism on population risk was further investigated by varying the probability that an individual may have a nonfunctional form of the enzyme at a constant dose level of 10 ppm of DCM. Higher values of this probability resulted in a corresponding decrease in risk. Again, this drop in population risk was not as significant when the 95th percentile measure was used.
El-Masri
H A
HA
Novigen Sciences, Inc., Washington, DC, 20036, USA.
Bell
D A
DA
Portier
C J
CJ
D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008752:Methylene Chloride / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009010:Monte Carlo Method; D011110:Polymorphism, Genetic; D018570:Risk Assessment
D002273:Carcinogens; D008752:Methylene Chloride; D004247:DNA; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase