Article | Organochlorine exposure and colorectal cancer risk limited to mono-ortho PCBs (Aronson et al. 2000; Demers et al. 2002; Lucena et al. 2001). PCBs themselves are hydroxylated by cytochrome P450 enzymes, and their metabo- l i t e s h a v e b e e n s h o w n t o i n d u c e D N A adducts in vitro (McLean et al. 1996). We have not observed a clear differential risk for PCB-28 or PCB-118 in relation to K ras or p53 mutations. However, when mutations in both genes were classified according to their molecular nature, an association between transversions (less likely to occur sponta- neously) and exposure to mono-ortho PCBs was observed. This could be interpreted as indirect evidence for a molecular fingerprint associated with exposure to these pollutants. The role of other OCs in colorectal cancer risk may be more complex. Compounds such as p,p´-DDE and α-HCH that had an overall moderate association with colorectal cancer showed a signiﬁcant increase in risk for tumors with mutation of the p53 gene. A similar result was reported in a Danish study, where higher risk of breast cancer with mutated p53 was observed among women exposed to high levels of dieldrin and PCBs (Hoyer et al. 2002). In our population, p,p´-DDE also increased risk for tumors with wild-type K-ras but not when this oncogene was mutated. Previous studies in pancreatic cancer have provided mixed results regarding OC exposure and K-ras mutation status associated with DDE levels (Porta et al. 1999; Slebos et al. 2000). Several factors suggest that these ﬁndings may be causal: the strength and trend of the associations observed; the restriction of the ﬁndings to mono-ortho PCBs that have a rela- tively planar, dioxin-like structure; the exis- tence of similar ﬁndings in tumors from other organs; the plausibility of carcinogenic mecha- nisms; and the association with speciﬁc muta- tion types. We are aware, however, that this study also has several limitations. Owing to the limitations of our analytical method, we did not study non-ortho PCBs that have a greater affinity for the Ah receptor than do mono- ortho PCBs as a result of their “coplanar” mole- cular structure, which may have strengthened our hypothesis. The retrospective assessment of exposure in the case–control design is not ideal, and the use of hospital controls may introduce information and selection bias. We minimized these biases by careful design, the use of validated questionnaires administered by trained interviewers, and robust analytical methods. However, potential sources of non- differential bias would tend to decrease the magnitude of any positive relationship; in par- ticular, if OC exposure increased the risk of hospital admission, this would bias the associa- tions toward the hypothesis. Furthermore, potential confounding factors were explored in detail and rejected. Special effort was devoted to explore whether the weight loss observed among cases could explain the results, because OCs accumulate in lipids, and changes in BMI due to metabolism of adipose tissue in cancer patients could result in higher serum levels of OCs. However, three observations combine to negate this possibility: a) adjusting for BMI had only a minor effect on risk estimates; b) although more advanced cases exhibited severe weight loss, there was no asso- ciation between OC levels and tumor stage; and c) if lipid mobilization was the reason for observing higher OC levels among cases, this would be true for all OCs but especially the more lipophilic compounds, whereas we observed increased risk only for selected OCs, and these were less lipophilic than p,p´-DDT and PCB-138, PCB-153, and PCB-180, for which no increased risk was observed. Nevertheless, we cannot exclude chance as an explanation of some of the results because this study was conceived as exploratory or hypoth- esis generating and we performed many statis- tical comparisons. In conclusion, these results suggest that exposure to mono-ortho PCBs is associated with an increased risk of colorectal cancer. 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