Research Article Organochlorine Exposure and Colorectal Cancer Risk Mike Howsam,1 Joan O. Grimalt,2 Elisabet Guinó,3 Matilde Navarro,3 Juan Martí-Ragué,4 Miguel A. Peinado,5 Gabriel Capellá,3 and Victor Moreno3 for the Bellvitge Colorectal Cancer Group* 1Laboratoire Universitaire de Médécine du Travail, Lille, France; 2Consejo Superior de Investigaciones Cientiﬁcas, Department of Environmental Chemistry, Institute of Chemical and Environmental Research, Barcelona, Catalonia, Spain; 3Catalan Institute of Oncology, Barcelona, Catalonia, Spain; 4Ciudad Sanitaria i Universitaria de Bellvitge, University of Barcelona, Barcelona, Catalonia, Spain; 5Oncology Research Institute, Barcelona, Catalonia, Spain Organochlorine compounds have been linked to increased risk of several cancers. Despite reduc- tions in their use and fugitive release, they remain one of the most important groups of persistent pollutants to which humans are exposed, primarily through dietary intake. We designed a case–control study to assess the risk of colorectal cancer with exposure to these chemicals, and their potential interactions with genetic alterations in the tumors. A subsample of cases (n = 132) and hospital controls (n = 76) was selected from a larger case–control study in Barcelona, Catalonia, Spain. We measured concentrations in serum of several organochlorines by gas chro- matography. We assessed point mutations in K-ras and p53 genes in tissue samples by polymerase chain reaction/single-strand conformation polymorphism and assessed expression of p53 protein by immunohistochemical methods. An elevated risk of colorectal cancer was associated with higher serum concentrations of mono-ortho polychlorinated biphenyl (PCB) congeners 28 and 118. The odds ratio for these mono-ortho PCBs for middle and higher tertile were, respectively, 1.82 [95% confidence interval (CI), 0.90–3.70] and 2.94 (95% CI, 1.39–6.20). α-Hexachlorocyclohexane, hexachlorobenzene, and p,p´-DDE (4,4´-dichlorodiphenyltrichloro- ethene) showed nonsignificant increases in risk. Risk associated with mono-ortho PCBs was slightly higher for tumors with mutations in the p53 gene but was not modiﬁed by mutations in K-ras. Mono-ortho PCBs were further associated with transversion-type mutations in both genes. These results generate the hypothesis that exposure to mono-ortho PCBs contributes to human colorectal cancer development. The trend and magnitude of the association, as well as the observa- tion of a molecular fingerprint in tumors, raise the possibility that this finding may be causal. Key words: case–control study, colorectal cancer, K-ras mutations, organochlorines, p53 muta- tions, PCBs. Environ Health Perspect 112:1460–1466 (2004). doi:10.1289/ehp.7143 available via http://dx.doi.org/ [Online 15 July 2004] Colorectal cancer is the third most common human cancer and the second most important cause of cancer-related death in Western countries, affecting men and women about equally. The etiology of sporadic colorectal cancer is relatively poorly understood, although diet is thought to play an important role in modifying risk. Vegetables, fruit, and dietary fiber are protective, whereas red and processed meats, fat, total energy intake, and obesity all increase risk (Potter 1996). Diet is also an important source of expo- sure to many synthetic organic chemicals used in industry, agriculture, or accidentally released to the environment. Among them, the industrial organochlorine compounds (OCs) hexachlorobenzene (HCB) and poly- chlorinated biphenyls (PCBs) and the pesti- cides DDT (dichlorodiphenyltrichloroethane) and lindane [γ-hexachlorocyclohexane (HCH), including α-HCH and β-HCH isomers] have been classified as “probably” or “possi- bly” carcinogenic to humans [International Agency for Research on Cancer (IARC) 1987, 1991]. Most of the data for these classifications come from animal studies, although evidence for carcinogenic effects in humans is accumulating from occupational and nonoccupational exposure studies 1460 [Agency for Toxic Substances and Disease Registry (ATSDR) 2000, 2002]. Despite reductions in their use and fugi- tive release, OCs remain one of the most important groups of persistent pollutants to which humans are exposed, primarily via dietary intake. More lipophilic OCs, and those that are not easily metabolized, accumu- late in adipose tissue, and the half-lives of these compounds in the body can be on the order of years or decades, whereas those com- pounds that are more water soluble or more easily metabolized have half-lives on the order of hours or days. Eventually, OCs recirculate in blood and are excreted in feces (Moser and McLachlan 2001). Serum concentrations are strongly correlated with fecal concentrations, particularly for the more lipophilic com- pounds that accumulate in adipose tissue and are generally more chlorinated (Juan et al. 2002; Moser and McLachlan 2001). Exposure of tissue in the gastrointestinal tract to OCs is the result, therefore, not only of uptake from food but also of depuration from the tissue to the lumen. The long residence time (1–2 days) of feces in the colon offers poten- tially greater opportunity for exchange of OCs between the lumen and the epithelium than elsewhere in the gastrointestinal tract. However, the physicochemical characteristics of the compound (speciﬁcally, its solubility in water) will be more important in determining the relative importance of these exchange processes in the colon than in the small intes- tine, given the predominantly aqueous nature of the colonic milieu (Moser and McLachlan 2001; Schlummer et al. 1998). Therefore, colon epithelium is likely to be a major target for putative carcinogenic effects of OCs via luminal and blood-borne exposure. OCs have been shown to mimic hor- mones, and this has been postulated as a mechanism for carcinogenesis in hormone- dependent cancers (Davis et al. 1993). Although colorectal cancer cannot be consid- ered a hormone-dependent cancer, there is evi- dence that hormones play a role, at least in women: hormone replacement therapy and, possibly, high parity and oral contraceptive use are all protective factors (Potter 1999). Studies of cancers of the pancreas and breast have shown that OCs may interact with genetic alterations in tumors such as K-ras mutations or p53 overexpression (Hoyer et al. 2002; Porta et al. 1999; Slebos et al. 2000). Research on these interactions is relevant because they are frequent in colorectal cancer, and one potential mechanism of OC toxicity may be the induction of mutations in these genes. Address correspondence to V. Moreno, Servei d’Epidemiologia i Registre del Cancer, Institut Catala d’Oncologia, Gran Via km 2.7, L’Hospitalet, 08907 Barcelona, Catalonia, Spain. Telephone: 34-93-260- 7812; Fax: 34-93-260-7787. E-mail: v.moreno@ iconcologia.catsalut.net *Members of the Bellvitge Colorectal Cancer Study Group: Victor Moreno, Matilde Navarro, Joan Martí-Ragué, Javier de Oca, Alfonso Osorio, Carlos del Río, Sebastiano Biondo, Josep Mª Badosa, María Cambray, Felip Vilardell, Belén Lloveras, Valeri Novell, Elisabet Guinó, Laura Pareja, Miguel A. Peinado, and Gabriel Capellá. We thank E. Marco, R. Mas, R. Chaler, and D. Fanjul for their assistance with organochlorine analysis. The study was supported by grants from the Fundació La Marató de TV3 (48/95), the Spanish Fondo de Investigaciones Sanitarias (FIS 96/0797, FIS 00/0027, FIS 01/1264, FIS 03/0114, ISCIII, Red de Centros RCESP C03/09, and Red de Centros de Cancer C03/10) and Comisión Interministerial de Ciencia y Tecnología (SAF 00/81), and a European Union Marie Curie Fellowship for M.H. (HPMF- CT-2000-00888). The authors declare they have no competing ﬁnancial interests. Received 1 April 2004; accepted 14 July 2004. VOLUME 112 | NUMBER 15 | November 2004 • Environmental Health Perspectives