An elevated risk of bladder cancer has been reported in the endemic region of 'black foot disease' on the southwest coast of Taiwan and may be related to high arsenic levels in artesian well water. Thirteen urothelial tumors from this endemic region were examined for mutations in exons 5-8 of the p53 gene to identify the effects of possible exogenous factors at the DNA level. DNA was extracted from archival tissue after microdissection of tumors and analyzed by PCR-SSCP (polymerase chain reaction-based single strand conformation polymorphism), followed by direct sequencing. Eight cases (62%) showed mutations and 9 of the 10 point mutations observed were transitions. The type and position of the mutations were not significantly different when compared with the spectra of p53 mutations previously reported for transitional cell carcinomas (TCCs). However, two of the mutations were CGC-->CAC base changes at codon 175, a mutational hotspot for many tumor types but previously unreported in TCCs except in cases associated with inflammatory agents. Three of the tumors examined were found to contain double mutations, a relatively rare mutagenic event in human cancers. Our results suggest that the agents responsible for the high risk of bladder cancer in the black foot disease region may operate through an inflammation-based mechanism which increases the amount of DNA damage per mutagenic event.