MOLECULAR EPIDEMIOLOGY OF AFLATOXIN EXPOSURES - VALIDATION OF AFLATOXIN-N7-GUANINE LEVELS IN URINE AS A BIOMARKER IN EXPERIMENTAL RAT MODELS AND HUMANS

Human epidemiology and experimental animal data have provided the stat istical association and biological information necessary to propose th at aflatoxins are risk factors for human liver cancer. As liver cancer causes at least 200,000 deaths per year, prevention measures must be developed to ameliorate this nearly always fatal disease. Preventive s trategies will be facilitated by the identification of individuals at high risk. It is the goal of the molecular dosimetry field to provide facile and accurate biomarkers to identify people at high risk for car cinogen exposure and consequent adverse health effects. We have develo ped methods to detect the major aflatoxin DNA adduct, aflatoxin N7-gua nine (AFB-N7-guanine), in urine, examined the dose-response characteri stics in people living in China and The Gambia, and have found an exce llent association of this biomarker with exposure. In addition to expo sure studies in people, our laboratories have monitored AFB-N7-guanine excretion in the urine of rats whose risk for developing cancer has b een modulated with dietary chemoprotective agents such that independen t groups of animals receiving the same dosage of aflatoxin B1 were at either high or low risk for tumorigenesis. The production of DNA damag e by aflatoxins is not the exclusive mechanism for liver cancer. Many other factors, including hepatitis B virus, cell proliferation, and nu tritional status, can exert strong modification effects in human disea se. Thus, molecular epidemiological investigations that examine only o ne biomarker may greatly underestimate or overestimate the risk for an individual. In our experimental studies, we have found the need to me asure specific, biologically relevant metabolites in a urine sample. O ur data show that the levels of the daily urinary excretion of total a natoxin metabolites are unrelated to risk of anatoxin-induced disease. Similar analyses using the human urine samples from China also reveal ed that total aflatoxin metabolites in urine do not reflect appropriat e exposure assessments. In the rat model, AFB-N7-guanine is a minor, b ut biologically relevant, metabolite representing less than 1% of the excreted material in urine, which does reflect exposure in experimenta l models. Thus, the composite human and experimental data generated fr om our research indicates that a cautious interpretation of the relati onship between any biomarker and tumor outcome must be employed. Howev er, both experimental rat data and human studies have also found that the AFB-N7-guanine adduct in urine is a good, noninvasive, short-term biomarker for determining both aflatoxin exposure and risk of genetic damage in target organs.