Trihalomethanes and Other Environmental Factors That Contribute to Colorectal Cancer.

Colorectal cancer is a major cause of morbidity and mortality in the United States; it is the third most common site of cancer in men after prostate and lung cancer, and the second most common site of cancer in women after breast cancer (1). Furthermore, the incidence of colorectal cancer is increasing in industrial countries (2). Because familial forms of colon cancer are thought to account for only about 15% of all cases (2), there is a strong likelihood that both environmental factors and inheritance play important roles in the pathogenesis of this disease. The National Toxicology Program reported that trihalomethanes, which are by-products of water chlorination, induce colorectal cancers in rats (3). Epidemiological studies also suggest an association between consumption of chlorination by-products in drinking water and an increased risk for colorectal cancer in humans (4). Although disinfection of drinking water by chlorination has been a major disease prevention treatment, these findings raise an important public health concern because of the large number of people who consume chlorinated water. In recent years there has been extensive study of the molecular events involved in the development ofhuman colorectal cancer. Consequently, the molecular genetics of colorectal carcinoma are among the best understood of any common human cancer. To foster an exchange of information and ideas on potential interactions of environmental factors and molecular genetic events that may occur in the development of colorectal cancer, a workshop, "Trihalomethanes and Other Environmental Factors That Contribute to Colorectal Cancer," was held at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, 14 September 1993. The objectives of the workshop were 1) to review the current status of research on the biology, epidemiology, and genetics of colorectal cancer, and 2) to identify areas in which further research would advance our understanding of the influence of genetic susceptibility and environmental factors (e.g., trihalomethanes) on the occurrence and development of this disease in humans. Colorectal Carcinogenesis An overview on the etiology of colon cancer, focusing on mechanistic relationships between factors identified through studies of the epidemiology, physiology, and molecular biology of this disease was presented. Increased colon cancer risk has consistently been associated with increased consumption of fat, meat, or protein, and the risk rises markedly with consumption of heavily browned meats. Decreased risk has been consistently associated with high consumption of vegetables (and perhaps fruit) and with physical activity. Cause-and-effect relationships are difficult to establish because of the multifaceted and incremental etiology of this disease. Arylamines produced in cooked meats may provide a link between diet and genetic susceptibility because the metabolism of these compounds to DNA-reactive intermediates is genetically variable. Colon cancer risk is increased in individuals with high N-oxidation (hepatic P4501A2) and high Nacetylation (colon NAT2) activities. A K-ras mutation at codon 12 is consistent with the formation of an arylamine adduct as an early event in the multistep carcinogenic process. Other than family history, where two genes have been identified (APC and hMSH4, there is much uncertainty on how to relate population risk factors and physiology to molecular genetic events in colon cancer. The molecular biology of colorectal neoplasia has been studied intensely because this is a relatively common tumor with well-recognized environmental and familial aspects and because precursor lesions are easily identifiable and accessible. The model generally accepted for this disease involves changes in the normal epithelium to an abnormal state of proliferation and differentiation; this is followed by the development of benign neoplasms (adenomas), of which a small subset increases in size and degree of dysplasia. Eventually, some of these lesions progress to infiltrating adenocarcinomas. Genetic changes along this sequence involve a combination of alterations in oncogenes which drive cellular proliferation and in tumor-suppressor genes which lead to dysregulation of normal growth control. Germline mutations in the APC (adenomatous polyposis coli) gene are responsible for familial adenomatous polyposis, a syndrome characterized phenotypically.by the development of hundreds to thousands of colorectal adenomas, with 100% occurrence of colorectal neoplasia if colectomy is not performed. Somatic mutations in the APC gene are frequent in sporadic colorectal tumors. The sporadic disease refers to those cases (about 85%) in which a well-recognized inherited basis has not been established. Currently there is no information on how environmental factors influence sporadic mutations in the APC gene. APC mutations are probably an early event in the development of sporadic neoplasia because they have been detected in aberrant crypt foci and in a high percentage of adenomas. Most mutations in the APC gene lead to truncation of the gene product. Mutations in K-ras and N-ras genes also occur at high rates in colorectal neoplasms. Because ras mutations do not increase in frequency as the adenoma to carcinoma sequence occurs, it is believed that they are typically early events. High rates of deletion of the DCC (deleted in colorectal cancer) gene and high rates of mutations and deletions in the p53 gene have also been observed in human colorectal neoplasms. These are late events because they are uncommon in early adenomas and are increased in frequency in later phase adenomas and in carcinomas. Some carcinomas do not show any identifiable abnormalities in the DCC gene or in p53. One of the functions of the normal p53 gene product is to arrest cells with damaged DNA in the GI phase of the cell cycle and thereby allow DNA repair before the cells progress to S-phase. Comparisons of genetic abnormalities in hereditary and sporadic colorectal cancer cases reveal nearly equal frequencies of APC and p53 mutations, whereas ras mutations may be slightly higher in cancers of patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC). The replication error phenotype (RERT), characterized by instability in microsatellite repeat sequences throughout the genome, is present in the tumors of about 75% of patients with HNPCC and in only 10% of seemingly sporadic tumors. This instability has been attributed to a