ReviewArticte Epidemiological Studies onthe Distribution Tract Cancerand Determinants of Bil - . Iary Masaharu YAMAMOTO '

With the help ef my co}leagues, I haye been conducting epidemiolegical studies on biliary tract cancer (BTC), ineluding gallbladder cancer (GBC) and extrahepatic bile duct caflcer (BDC), in Japan and Chile for about 19 years. Clustered areas with high mortality rates, especially for female GBC were found to correspond with places or prefectures in Japan that were famous for rice production. The roles of known risk factors, such as gallstones and cholecystitis, were examined, but no single factor was impticated in the high mortality rates for GBC in these areas. A working hypothesis, cal]ed the "rice production hypothesis" was formulated; this initial hypothesis was replaced by a new multifactorial causation hypothesis; GBC is more likely to occur in individuals with a genetie susceptibility and a past histo ry of gallstones or cholecystitis who are exposed to geographically specific environmental factors, such as agricultura) chemicals. On the basis of various analytical studies, it is concluded that a certain agricultural chemical was responsible for the occurrence of GBC. At the time of writing, no eyidence has been obtained to disprove our hypothesis. We have also conducted international collaboratiye studies in Chile, which has the highest mortality rate for GBC in the world. Bile from Chileans was found to have a higher mutagenic actiyity than that from Japanese subjects; Chileans with a history of constipatien or a habit of consuming red chilli pepper had a high risk of develeping GBC, if they also had gallstone(s). The presence of a regional difference in pS3 mutagenesis was also obseryed.