A Bayesian analysis of the influence of GSTT1 polymorphism on the cancer risk estimate for dichloromethane

The carcinogenicity of dichloromethane (DCM) is related to metabolic activa tion mediated by glutathione transferase theta I (GSTT1), whereas oxidation serves as a detoxification pathway. The aim of this study was to calculate the excess cancer risk from DCM, using Bayesian statistics. In a first ste p, a previously developed population physiologically based pharmacokinetic (PBPK) model for DCM was simultaneously fitted to extensive human toxicokin etic data from 27 male volunteers exposed to 250-1000 ppm DCM (Astrand et a l. Scand. J. Work Environ. Health 1, 78-94, 1975; Engstrom and Bjurstrom, S cand. J. Work Environ. Health 7, 215-224, 1977) using Markov chain Monte Ca rlo simulation. Improved population estimates were obtained for the PBPK mo del parameters. In a second step, excess cancer risk was calculated for lif elong exposure to 1-1000 ppm DCM by Monte Carlo simulation. Data on GSTT1 g ene frequencies in the Swedish population were used, including all three ge notypes. Estimated mean and median excess risks were in general agreement w ith those previously derived (El-Masri et al. Toxicol. Appl. Pharmacol. 158 , 221-230, 1999). However, we estimate higher excess risks at the upper con fidence limits. Furthermore, our simulations suggest that 1% of the Swedish population is not covered by a factor 4.2-7.1 away from the mean target do se. The majority of the fraction of the population not covered was classifi ed as GSTT1 homozygote. This indicates that a higher uncertainty factor tha n the commonly used 3.16 should be considered in noncancer risk assessment for substances with polymorphic bioactivation. (C) 2001 Academic Press.