Evaluation of fecal mutagenicity and colorectal cancer risk

Colorectal cancer is one of the most common internal malignancies in Wester n society. The cause of this disease appears to be multifactorial and invol ves genetic as well as environmental aspects. The human colon is continuous ly exposed to a complex mixture of compounds, which is either of direct die tary origin or the result of digestive, microbial and excretory processes. In order to establish the mutagenic burden of the colorectal mucosa, analys is of specific compounds in feces is usually preferred. Alternatively, the mutagenic potency of fecal extracts has been determined, but the interpreta tion of these more integrative measurements is hampered by methodological s hortcomings. In this review, we focus on exposure of the large bowel to fiv e different classes of fecal mutagens that have previously been related to colorectal cancer risk. These include heterocyclic aromatic amines (HCA) an d polycyclic aromatic hydrocarbons (PAH), two exogenous factors that are pr edominantly ingested as pyrolysis products present in food and (partially) excreted in the feces. Additionally, we discuss N-nitroso-compounds, fecape ntaenes and bile acids, all fecal constituents (mainly) of endogenous origi n. The mutagenic and carcinogenic potency of the above mentioned compounds as well as their presence in feces, proposed mode of action and potential r ole in the initiation and promotion of human colorectal cancer are discusse d. The combined results from in vitro and in vivo research unequivocally de monstrate that these classes of compounds comprise potent mutagens that ind uce many different forms of genetic damage and that particularly bile acids and fecapentaenes may also affect the carcinogenic process by epigenetic m echanisms. Large inter-individual differences in levels of exposures have b een reported, including those in a range where considerable genetic damage can be expected based on evidence from animal studies. Particularly, howeve r, exposure profiles of PAH and N-nitroso compounds (NOC) have to be more a ccurately established to come to a risk evaluation. Moreover, lack of human studies and inconsistency between epidemiological data make it impossible to describe colorectal cancer risk as a result of specific exposures in qua ntitative terms, or even to indicate the relative importance of the mutagen s discussed. Particularly, the polymorphisms of genes involved in the metab olism of heterocyclic amines are important determinants of carcinogenic ris k. However, the present knowledge of gene-environment interactions with reg ard to colorectal cancer risk is rather limited. We expect that the introdu ction of DNA chip technology in colorectal cancer epidemiology will offer n ew opportunities to identify combinations of exposures and genetic polymorp hisms that relate to increased cancer risk. This knowledge will enable us t o improve epidemiological study design and statistical power in future rese arch. (C) 2000 Elsevier Science B.V. All rights reserved.