and breast cancer risk (Gammon et al. 2002b). In our analyses among control women, indi- vidual GSTT1, GSTM1, GSTP1, and GSTA1 genotypes were not associated with detectable PAH–DNA adducts, nor was the number of variant GST alleles. Even after stratifica- tion on smoking, the number of variant GST alleles was not associated with detectable PAH–DNA adducts; however, ever smok- ers with either the GSTM1 or GSTM1 present genotype had a reduced risk of detect- able PAH–DNA adducts (Table 5). We observed a similar finding within the strata of ever smokers and the GSTP1 common genotype compared with never smokers with the common genotype. Our results are the first published findings regarding GSTA1 polymorphisms and PAH–DNA adducts. Our findings related to polymorphisms in GSTM1 and PAH–DNA adduct formation are in contrast with one study (Rundle et al. 2003), while being consistent with others that report no significant difference in detectable PAH–DNA adducts based on GSTM1 status (Grinberg-Funes et al. 1994; Rothman et al. 1995; Weiserbs et al. 2003). However, the LIBCSP results reported here are based upon a much larger sample size than previous anal- yses, which yields more stable effect estimates. Additionally, we used different methods to measure the PAH–DNA adducts in the vari- ous studies, possibly influencing the results. Methodological considerations. In an epi- demiologic study, the use of a biomarker of exposure, such as PAH–DNA adducts, is con- sidered superior because exposure assessment is not based on self-report, eliminating con- cerns for recall bias. Reliability in the meas- urement of genotype and adducts was high. Measurement error was possible, although unlikely with genotyping and analysis of adducts; however, because the laboratory was blinded to status of samples, any measure- ment error in measuring genotype and of PAH–DNA adduct status was independent of case–control status. Therefore, any resulting bias would have been nondifferential. Our study power was limited when we examined interactions within subgroups of women, such as those with PAH–DNA adducts. However, the LIBCSP is the largest study conducted to date with information on PAH–DNA adducts with which to evaluate these associations, and thus our study power was better than that of previously reported studies. We selected the GST polymorphisms because of their role in phase II metabolism, specifically metabolism of PAH-reactive inter- mediates. Because PAH–DNA adducts may be related to inherited differences in the metabo- lism of PAHs, this pathway was hypothesized to be important in individual breast cancer suscep- tibility. GSTP1 and GSTM1 have been shown to have a role in detoxification of PAH carci- nogenic intermediates produced by cytochrome P450 in phase I metabolism (Butkiewicz et al. 2000). GSTT1 and GSTA1 have also been implicated in the metabolism of PAH inter- mediates (Garte et al. 2007; Hayes and Pulford, 1995; Korashy and El-Kadi 2006). Conclusion Our previous analyses have shown that breast cancer risk was modestly elevated in rela- tion to PAH–DNA adducts (Gammon et al. 2002b, 2004b), among certain subgroups of smokers (Gammon et al. 2004a), and among women with multiple variant alleles in GST genes (Steck et al. 2007b). In this analysis, however, we did not find strong evidence for further elevation of breast cancer risk, either on a multiplicative or on an additive scale, when we considered the joint effect of mul- tiple GSTs and PAHs (cigarette smoking or PAH–DNA adducts), despite the biologic plausibility of such an interaction. These find- ings are based upon the largest population- based study of breast cancer conducted to date with a biomarker of PAH exposure. Further study may be warranted incorporating other biologic measures of PAH metabolism. Ref Rencs Ahn J, Gammon MD, Santella RM, Gaudet MM, Britton JA, Teitelbaum SL, et al. 2006. Effects of glutathione S-transferase A1 (GSTA1) genotype and potential modi- fiers on breast cancer risk. Carcinogenesis 9:1876–1882. Ambrosone CB, Freudenheim JL, Graham S, Marshall JR, Vena JE, Brasure JR, et al. 1995. Cytochrome P4501A1 and glutathione S-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk. Cancer Res 55(16):3483–3485. Assmann SF, Hosmer DW, Lemeshow S, Mundt KA. 1996. Confidence intervals for measures of interaction. Epidemiology 7(3):286–290. Bell DA, Thompson CL, Taylor J, Miller CR, Perera F, Hsieh LL, et al. 1992. Genetic monitoring of human polymorphic cancer susceptibility genes by polymerase chain reaction: application to glutathione transferase mu. Environ Health Perspect 98:113–117. Boffetta P, Jourenkova N, Gustavsson P. 1997. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control 8:444–472. Brescia G, Celotti L, Clonfero E, Neumann GH, Forni A, Foa V, et al. 2004. The influence of cytochrome P450 1A1 and glu- tathione S-transferase M1 genotypes on biomarker levels in coke-oven workers. Arch Toxicol 73:431–439. Butkiewicz D, Grzybowska E, Phillips DH, Hemminki K, Chorazy M. 2000. Polymorphisms of the GSTP1 and GSTM1 genes and PAH-DNA adducts in human mononuclear white blood cells. Environ Mol Mutagen 35(2):99–105 Cavalieri EL, Higginbotham S, RamaKrishna KNVS, Devanesan PD, Todorovic R, Rogan EG, et al. 1991. Comparative dose– response tumorigenicity studies of dibenzo[a,l]pyrene ver- sus 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and two dibenzo[a,l]pyrene dihydrodiols in mouse skin and rat mammary gland. Carcinogenesis 10:1939–1944. Coles B, Nowell SA, MacLeod SL, Sweeny C, Lang NP, Kadlubar FF. 2001b. The role of human glutathione S-transferases (hGSTs) in the detoxification of food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymor- phism in hGSTA1 on colorectal cancer risk. Mutat Res 482:3–10. Coles BF, Kadlubar FF. 2003. Detoxification of electrophilic compounds by glutathione S-transferase catalysis: deter- minants of individual response to chemical carcinogens and chemotherapeutic drugs? Biofactors 17:115–130. Environmental Health Perspectives • volume 117 | number 4 | April 2009 PAH–DNA adducts, GSTs, and breast cancer Coles BF, Kadlubar FF, Sies H, Packer L. 2005. Human alpha class glutathione S-transferases: genetic polymorphism, expression, and susceptibility to disease. Methods Enzymol 401:9–42. Coles BF, Morel F, Rauch C, Huber WW, Yang M, Teitel CH, et al. 2001a. Effect of polymorphism in the human gluta- thione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. Pharmacogenetics 11:663–669. el-Bayoumy K, Chae YH, Upadhyaya P, Rivenson A, Kurtzke C, Reddy B, Hecht SS. 1995. Comparative tumorigenicity of benzo[a]pyrene, 1-nitropyrene and 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine administered by gavage to female CD rats. Carcinogenesis 16:431–434. Fannon WR. 2002. Single nucleotide polymorphism (SNP) analysis of a variety of non-ideal DNA sample types by SEQUENOM MassARRAY matrix assisted laser desorp- tion/ionization time of flight (MALDI-TOF). Proc Am Assoc Cancer Res 43:53. Fields WR, Morrow CS, Doss AJ, Sundberg K, Jernström B, Townsend AJ. 1998. Overexpression of stably transfected human glutathione S-transferase P1-1 protects against DNA damage by benzo[a]pyrene diol-epoxide in human T47D cells. Mol Pharmacol 54(2):298–304. Gammon MD, Eng SM, Teitelbaum SL, Britton JA, Kabat GC, Hatch M, et al. 2004a. Environmental tobacco smoke and breast cancer incidence. Environ Res 96(2):176–185. Gammon MD, Neugut AI, Santella RM, Teitelbaum SL, Britton JA, Terry MB, et al. 2002a. The Long Island Breast Cancer Study Project: description of a multi-institutional collaboration to identify environmental risk factors for breast cancer. Breast Cancer Res Treat 74:235–254. Gammon MD, Sagiv SK, Eng SM, Shantakumar S, Gaudet MM, Teitelbaum SL, et al. 2004b. Polycyclic aromatic hydrocarbon- DNA adducts and breast cancer: a pooled analysis. Arch Environ Health 59:640–649. Gammon MD, Santella RM. 2008. PAH, genetic susceptibility, and breast cancer risk: an update from the Long Island Breast Cancer Study Project. Eur J Cancer 44(5):636–640. Gammon MD, Santella RM, Neugut AI, Eng SM, Teitelbaum SL, Paykin A, et al. 2002b. Environmental Toxins and Breast Cancer on Long Island I. Polycyclic aromatic hydro- carbon DNA adducts. Cancer Epidemiol Biomarkers Prev 11:677–685. García-Closas M, Kelsey KT, Hankinson SE, Spiegelman D, Springer K, Willett WC, et al. 1999. Glutathione S-transferase mu and theta polymorphisms and breast cancer susceptibility. J Natl Cancer Inst 91(22):1960–1964. Garte S, Taioli E, Popov T, Kalina I, Sram R, Farmer P. 2007. Role of GSTT1 deletion in DNA oxidative damage by expo- sure to polycyclic aromatic hydrocarbons in humans. Int J Cancer 120(11):2499–2503. Grinberg-Funes RA, Singh VN, Perera FP, Bell DA, Young TL, Dickey C, et al. 1994. Polycyclic aromatic hydrocarbon- DNA adducts in smokers and their relationship to micro- nutrient levels and the glutathione-S-transferase M1 genotype. Carcinogenesis 15(11):2449–2454. Hatsukami DK, Benowitz N, Rennard S, Oncken C, Hecht SS. 2006. Biomarkers to assess the utility of potential reduced exposure tobacco products. Nicotine Tob Res 8:599–622. Hayes JD, Pulford DJ. 1995. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30:445–600. Hecht SS. 1996. Chemoprevention of lung cancer by isothio- cyanates. Adv Exp Med Biol 401:1–11. Hecht SS. 1999. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91(14):1194–1210. Hecht SS. 2000. Inhibition of carcinogenesis by isothio- cyanates. Drug Metab Rev 32(3–4):395–411. Hecht SS. 2003. Tobacco carcinogens, their biomarkers, and tobacco induced cancer. Nature Rev Cancer 3:733–744. Hecht SS, Carmella SG, Yoder A, Chen M, Li Z, Le C, et al. 2006. Comparison of polymorphisms in genes involved in polycyclic aromatic hydrocarbon metabolism with uri- nary phenanthrene metabolite ratios in smokers. Cancer Epidemiol Biomarker Prev 15:1805–1811. Helzlsouer KJ, Selmin O, Huang HY, Strickland PT, Hoffman S, Alberg AJ, et al. 1998. Association between glutathi- one S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer. J Natl Cancer Inst 90(7):512–518. Hosmer DW, Lemeshow S. 1989. Applied Logistic Regression. New York:John Wiley and Sons. Hu Y, Li G, Xue X, Zhou Z, Li X, Fu J, et al. 2007. PAH-DNA 557