Journal of Nucleic Acids support the hypothesis that the formation of DNA adducts is signiﬁcantly inﬂuenced by chronic carcinogen exposure. Furthermore, when study population was subgrouped for the number of risk alleles, a signiﬁcant association with smoking was observed in the subjects carrying three or more risk alleles who reported to smoke for more than 40 years. Conversely, no eﬀect of smoking was observed in smokers bearing one or less risk allele. The contribution of duration of exposure to cigarette smoke has important implications for both research studies and prevention strategies. It has been shown that the age at ﬁrst exposure and duration are associated inﬂuences to the levels of DNA adducts [23]. Smoking during adolescence has been shown to produce physiological changes leading to increased persistence of DNA adducts less, and subjects who begin smoking very early in life tend to be heavy smokers [23]. Two large epidemiological studies demonstrated that duration is more important than intensity of cigarette smok- ing in predicting lung cancer risk [24, 25]. Herein reported results support in part this hypothesis, thus shedding light on the mechanisms involved in the aetiology of smoking related cancers. It is likely that a plateau of the formation of DNA adducts is reached at these time points [5]. In fact, the persistence of DNA adducts in PBLs is less than one decade, which is the maximum lifespan for long-living lymphocytes. Our next results show that DNA adduct levels were com- parable in individuals with benign lung disease or with lung cancer and in controls. However, when speciﬁc combinations of variant alleles were investigated, a not signiﬁcant increased lung cancer risk was observed in individuals bearing the same number of risk alleles. In a meta-analysis of cancer and bulky DNA adducts [26], DNA damage has been reported to be predictive of lung cancer, particularly in smokers. In Veglia’s meta- analysis, smokers presented a signiﬁcant diﬀerence between lung cancer cases and controls, with patients having 83% higher amount of DNA adducts than controls. We know that the interpretation of the meta-analysis is limited by the fact that in case-control studies, the level of biomarker may reﬂect the presence of cancer disease rather than its aetiology. However, an exception is represented by three cohort studies, in which DNA adducts have been found to be prospectively predictive of lung cancer outcome [6– 8]. The importance of these studies is based on the fact that biomarker measurement in PBLs collected several years before cancer onset ruled out the possibility that the higher levels of DNA damage were reﬂecting metabolic changes associated with cancer. No increment of DNA adducts has been found in subjects with diﬀerent benign bronchial pathologies, such as COPD, asthma, and pneumoconiosis, characterized by important inﬂammatory processes in respect to controls. However, such inﬂammatory phenomena can inﬂuence DNA adduct levels in lung target cells by increasing the biologically eﬀective dose of PAH [27]. This hypothesis is consistent with a previous case-control study where the levels of DNA adducts in individuals with inﬂammatory diseases were signiﬁcantly higher than those of controls [28]. 5 DNA damage primarily reﬂects exposures to carcinogens but is modulated by inherited and acquired susceptibilities. Age, gender, and life-style and dietary habits have been reported to inﬂuence levels of DNA adducts [5, 29, 30]. DNA adducts may be also inﬂuenced by the individual’s ability to remove DNA adducts undergoing from interindividual variability [31]. Although the main pathway for removal of bulky DNA adducts is nucleotide excision repair, it has been shown that BER and DSB repair mechanisms may participate in bulky DNA adduct repair, supporting the association of XRCC1 and XRCC3 polymorphisms with such kind of DNA damage [32, 33]. In this study we observed an eﬀect of XRCC3 Thr241Met polymorphism on DNA adducts. Positive nonstatistically signiﬁcant asso- ciations with XRCC1 Arg194Trp and Gln399Gln geno- types were found whereas an inverse signiﬁcant association was detected in XRCC3 Met241Met carriers. Our ﬁndings are in keeping with previous studies showing that the variant alleles of the XRCC1 Arg399Gln polymorphism is associated with DNA adducts [10, 12, 13]. A recent pooled analysis has shown a protective eﬀect conferred by XRRC3 241Met allele carriers against lung cancer [16]. However, other studies have reported higher levels of DNA damage in individuals with XRCC1 Arg194Arg and XRCC3 Met241Met genotypes [12, 33]. Our results suggest that case-control studies are more indicative for the determination of genetic susceptibility than cross-sectional studies. To study the eﬀect of diﬀerent combinations of DNA repair single nucleotide polymorphisms on DNA adducts, we have investigated the combination of the variant allele/s of XRCC1 Arg194Trp and Arg399Gln polymorphisms with the wild type allele of XRCC3 Thr241Met. This was based on the diﬀerent association of XRCC1 and XRCC3 poly- morphisms with lung cancer risk, for example, positive for XRCC1 Arg194Trp and Arg399Gln and negative for XRCC3 Thr241Met [9, 16, 17, 34]. Our ﬁndings show that the combination of diﬀerent polymorphisms can have additive eﬀects on the levels of DNA adducts. In fact, when the number of risk alleles was analyzed, DNA adducts were higher in individuals carrying three-four risk alleles. Furthermore, when our population was categorized in base to the number of risk alleles, the association between smoking and lung cancer risk tended to be present in the same individuals bearing three-four risk alleles. Although statistical signiﬁcances were seen in our analyses, our study is underpowered, and larger studies are needed to conﬁrm the associations between DNA polymorphisms, cancer, and DNA adducts. Furthermore, a previous report has shown that smoking is strong harmful factor that can eliminate the eﬀect of DNA polymorphisms of DNA repair genes on lung cancer susceptibility [34]. Smoking could lead to cancer due to its toxic eﬀect regardless of whether individuals have polymor- phisms with low repair proﬁciency. Thus, the examination of the eﬀect of diﬀerent combinations of DNA polymorphisms for the prediction of lung cancer susceptibility could be more useful in nonsmokers exposed to relatively minor environmental factors.