Article | Howsam et al. interaction was not signiﬁcant. This stratiﬁca- tion of cases by genetic alterations also showed some signiﬁcant interactions with other OCs. High levels of p,p´-DDE were associated with increased risk of cancer with wild-type K-ras. Also, p,p´-DDE and α-HCH had signiﬁcant effects on p53-mutated tumors. A similar pat- tern was evident when tumors were stratiﬁed according to p53 overexpression: p,p´-DDE and PCB-118 increased the risk only for tumors overexpressing p53 protein. Tumors with microsatellite instability were rare (n = 11, 8%), and these patients had similar OC levels to other cases. Overall, 81% of the tumors harbored K-ras and/or p53 gene mutations, and a com- bined analysis was performed. Exposure to high levels of the mono-ortho PCB-118 was associated with more mutations (OR = 2.89; 95% CI, 0.66–12.7), with transversions three times more likely than transitions (Table 6). Other OCs analyzed in this way were not related to the type of mutation. Discussion OCs have previously been associated with increased risk of colorectal cancers in studies of occupationally exposed individuals (Acquavella et al. 1996; Soliman et al. 1997; Wilkinson et al. 1997). Other studies have failed to show this association (Hardell 1981; Hoar et al. 1985; Settimi et al. 2001) or even have shown inverse associations with colon cancer (Cantor and Silberman 1999; Wang et al. 2002). These mixed results are not surprising because most occupational studies lack individual exposure Table 5. Colorectal cancer risk for selected organochlorines in relation to K-ras and p53 mutations. Wild-type OR (95% CI) Mutated OR (95% CI) p-Valuea 1.00 3.51 (1.49–8.24) 2.78 (1.21–6.35) 1.00 1.22 (0.57–2.61) 2.16 (0.94–4.97) 1.00 2.78 (1.24–6.25) 1.00 1.78 (0.81–3.90) 2.27 (1.04–4.96) 1.00 2.24 (0.81–6.16) 1.09 (0.39–3.05) 1.00 0.76 (0.29–2.01) 1.22 (0.44–3.34) 1.00 2.16 (0.79–5.91) 1.00 1.72 (0.65–4.53) 1.40 (0.52–3.75) No. (%) 22 (44) 15 (30) 13 (26) 20 (40) 10 (20) 20 (40) 35 (70) 15 (30) 17 (34) 14 (28) 19 (38) 11 (19) 20 (34) 28 (47) 16 (27) 17 (29) 26 (44) 44 (75) 15 (25) 18 (31) 13 (22) 28 (47) K-ras p,p´-DDE Low Medium High α-HCH Low Medium High PCB-28 < LOD > LOD PCB-118 < LOD Medium High p53 p,p´-DDE Low Medium High α-HCH Low Medium High PCB-28 < LOD > LOD PCB-118 < LOD Medium High PCB-118 < LOD Medium High Trend test p-valuec 1464 No. (%) 16 (20) 34 (41) 32 (39) 28 (34) 27 (33) 27 (33) 56 (68) 26 (32) 26 (32) 25 (30) 31 (38) 12 (31) 16 (41) 11 (28) 18 (46) 10 (26) 11 (28) 29 (74) 10 (26) 14 (36) 13 (33) 12 (31) ap-Value for interaction between OC and the genetic alteration adjusted for age, sex, energy intake, and BMI; tests for dif- ferences in the OR between wild-type and mutated cases. Table 6. Colorectal cancer risk for PCB-118 in relation to K-ras and p53 mutation type. No. (%) 20 (37) 17 (32) 17 (32) Transitionsa OR (95% CI) 0.42 1.00 1.09 (0.28–4.28) 1.93 (0.41–9.09) No. (%) 6 (18) 12 (35) 16 (47) Transversionsa OR (95% CI) 0.038 1.00 3.29 (0.66–16.4) 6.52 (1.16–36.6) aMutations in K-ras and p53 classified as transitions (G:C→A:T) or transversions (G:C→T:A). bp-Value for interaction between PCB-118 and the mutation type; tests for differences in the OR between transitions and transversions. cTrend test p-value for the speciﬁc mutation type adjusted for age, sex, energy intake, and BMI. 0.012 0.55 0.88 0.42 0.047 0.045 0.98 0.19 p-Valueb 0.071 indicators and are prone to confounding. To overcome these limitations, we studied a popu- lation not occupationally exposed using serum OC levels as exposure markers. We found an elevated risk of colorectal cancer associated with high levels of mono-ortho PCBs 28 and 118. Other abundant OCs such as p,p´-DDE and α-HCH also showed an increased risk of relevant magnitude; although the associations for these OCs were not significant for the entire population of cases, they were signiﬁcant for the subset of tumors harboring mutations of the p53 gene. We have taken serum concentrations of OCs as indicative of the body burden. Serum concentrations are strongly correlated with those in adipose tissue and feces and reﬂect the historical legacy of uptake and depuration, and as such, they may be taken as markers for long- term, low-level exposure (Alcock et al. 2000; Juan et al. 2002; Moser and McLachlan 2001). Many studies that also used plasma OC con- centrations as exposure markers have reported mixed results for breast cancer (Calle et al. 2002) and non-Hodgkin lymphoma (Cantor et al. 2003; De Roos et al. 2003; Rothman et al. 1997) but increased risk of pancreatic cancer (Hoppin et al. 2000; Porta et al. 1999; Slebos et al. 2000). Altogether, these results suggest that a role for OCs in the etiology of several tumors is likely. Nevertheless, the mechanisms underlying carcinogenicity will differ among both OCs and target organs because chemical properties and toxicity mechanisms of these compounds are diverse. In addition, target organs differing in lipid content might determine distinct degree of local exposure. In our population, high body burdens of mono-ortho PCBs 28 and 118 were associated with an elevated risk of colorectal cancer. These OCs are among the most toxic of the PCBs, together with non-ortho PCBs. The relatively ﬂat (or “planar”) orientation of their biphenyl rings allows them to bind to the aryl hydrocarbon (Ah) receptor in a similar way to polychlorinated dibenzodioxins and dibenzo- furans and may be responsible for our ﬁnding (Safe 1990). This binding induces phase I and phase II metabolic enzymes; mono-ortho PCBs may therefore induce CYP1A and CYP2B enzymes that, in the absence of substrate, can produce reactive oxygen species. Although PCB-118 has a toxic equivalency factor (TEF) of 0.0001, based on its toxicity relative to 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (Van den Berg et al. 1998), PCB-28 has not been assigned a TEF under this scheme and may not, therefore, bind strongly to the Ah receptor and/or significantly induce CYP enzymes. Nevertheless, higher serum levels of PCB-28 were associated with increased risk of colon cancer in this study. Some studies on breast cancer have also reported increased risk being 1.00 1.07 (0.42–2.72) 0.72 (0.29–1.81) 1.00 0.64 (0.25–1.66) 1.75 (0.70–4.37) 1.00 2.83 (1.13–7.06) 1.00 1.35 (0.53–3.43) 1.64 (0.67–4.01) 1.00 2.94 (1.11–7.76) 3.44 (1.39–8.47) 1.00 1.39 (0.58–3.35) 3.44 (1.40–8.45) 1.00 2.06 (0.85–5.01) 1.00 1.31 (0.53–3.26) 2.79 (1.22–6.37) VOLUME 112 | NUMBER 15 | November 2004 • Environmental Health Perspectives