Environmental and chemical carcinogenesisValidation of a causal relationship between aflatoxin exposure and hepatocellular carcinoma risk in humans: a molecular epidemiology paradigm demonstrating the power of biomarkersEvaluation of tobacco carcinogens: a model for environmental carcinogenesisTobacco products and cancerTobacco carcinogens and cancerEvaluating the role of specific carcinogens in tobacco-related cancerSummaryHeterocyclic amine carcinogens in our diet: etiological agents for human cancer?Extrapolation of animal carcinogenesis studies to humans-which human?Species differences in the metabolism of carcinogens and drugsInterindividual differences in the metabolism of drugs and carcinogensEffect of environmental context on carcinogenesis by chemicalsMultiple mutations in cancers: sources and consequencesCancer is a chronic diseaseAcknowledgementsReferencesSeminars in Cancer Biology 14 (2004) 473–486Environmental and chemical carcinogenesisGerald N. Wogana,∗, Stephen S. Hechtb, James S. Feltonc,Allan H. Conneyd, Lawrence A. LoebeaBiological Engineering Division, Massachusetts Institute of Technology, Room 26-009, Cambridge, MA 02139, USAbUniversity of Minnesota Cancer Center, 420 Delaware Street, SE, MMC 806, Minneapolis, MN 55455, USAcBiology and Biotechnology Research Program, Lawrence Livermore National Laboratory, University of California, Room 1065,Building 361, 7000 East Avenue, Livermore, CA 94551, USAdDepartment of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The StateUniversity of New Jersey, Piscataway, NJ 08854-8020, USAeDepartment of Pathology, University of Washington, K-072 HSB, Box 357705, 1959 NE Pacific Street, Seattle, WA 98195-7705, USAAbstractPeople are continuously exposed exogenously to varying amounts of chemicals that have been shown to have carcinogenic or muta-genic properties in experimental systems. Exposure can occur exogenously when these agents are present in food, air or water, and alsoendogenously when they are products of metabolism or pathophysiologic states such as inflammation. It has been estimated that exposureto environmental chemical carcinogens may contribute significantly to the causation of a sizable fraction, perhaps a majority, of humancancers, when exposures are related to “life-style” factors such as diet, tobacco use, etc. This chapter summarizes several aspects ofenvironmental chemical carcinogenesis that have been extensively studied and illustrates the power of mechanistic investigation combinedwith molecular epidemiologic approaches in establishing causative linkages between environmental exposures and increased cancer risks.A causative relationshipbetween exposure toaflatoxin, astrongly carcinogenic mold-produced contaminant of dietary staples in Asia andAfrica, and elevated risk for primary liver cancer has been demonstrated through the application of well-validated biomarkers in molecularepidemiology. These studies have also identified a striking synergistic interaction between aflatoxin and hepatitis B virus infection inelevating liver cancer risk. Use of tobacco products provides a clear example of cancer causation by a life-style factor involving carcinogenexposure. Tobacco carcinogens and their DNA adducts are central to cancer induction by tobacco products, and the contribution of specifictobacco carcinogens (e.g. PAH and NNK) to tobacco-induced lung cancer, can be evaluated by a weight of evidence approach. Factorsconsidered include presence in tobacco products, carcinogenicity in laboratory animals, human uptake, metabolism and adduct formation,possible role in causing molecular changes in oncogenes or suppressor genes, and other relevant data. This approach can be applied toevaluation of other environmental carcinogens, and the evaluations would be markedly facilitated by prospective epidemiologic studiesincorporating phenotypic carcinogen-specific biomarkers.Heterocyclic amines represent an important class of carcinogens in foods. They are mutagens and carcinogens at numerous organ sitesin experimental animals, are produced when meats are heated above 180◦C for long periods. Four of these compounds can consistently beidentified in well-done meat products from the North American diet, and although a causal linkage has not been established, a majority ofepidemiology studies have linked consumption of well-done meat products to cancer of the colon, breast and stomach. Studies employingmolecular biomarkers suggest that individuals may differ in their susceptibility to these carcinogens, and genetic polymorphisms maycontributetothis variability. Heterocyclic amines, likemost otherchemical carcinogens, are not carcinogenicper sebutmust be metabolizedby a family of cytochrome P450 enzymes to chemically reactive electrophiles prior to reacting with DNA to initiate a carcinogenicresponse. These same cytochrome P450 enzymes—as well as enzymes that act on the metabolic products of the cytochromes P450(e.g. glucuronyl transferase, glutathione S-transferase and others)—also metabolize chemicals by inactivation pathways, and the relativeamounts of activation and detoxification will determine whether a chemical is carcinogenic. Because both genetic and environmentalfactors influence the levels of enzymes that metabolically activate and detoxify chemicals, they can also influence carcinogenic risk.Many of the phenotypes of cancer cells can be the result of mutations, i.e., changes in the nucleotide sequence of DNA that accumulateas tumors progress. These can arise as a result of DNA damage or by the incorporation of non-complementary nucleotides during DNA∗Corresponding author. Tel.: +1 617 253 3188; fax: +1 617 258 0499.E-mailaddresses:[email protected](G.N.Wogan), [email protected](S.S.Hecht),[email protected](J.S.Felton),[email protected] (A.H.Conney),[email protected] (L.A. Loeb).1044-579X/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.semcancer.2004.06.010474 G.N. Wogan et al./Seminars in Cancer Biology 14 (2004) 473–486synthetic processes. Based upon the disparity between the infrequency of spontaneous mutations and the large numbers of mutationsreported in human tumors, it has been postulated that cancers must exhibit a mutator phenotype, which would represent an early event incancer progression. A mutator phenotype could be generated by mutations in genes that normally function to guarantee