The
aflatoxins were discovered in toxic peanut meal causing "turkey X" disease, which killed large numbers of turkey poults, ducklings and chicks in the UK in the early 1960s. Extracts of toxic feed induced the symptoms in experimental animals, and purified metabolites with properties identical to
aflatoxins B(1) and G(1) (AFB(1) and AFG(1)) were isolated from Aspergillus flavus cultures. Structure elucidation of
aflatoxin B(1) was accomplished and confirmed by total synthesis in 1963. AFB(1) is a potent liver
carcinogen in rodents, non-human primates, fish and birds, operating through a genotoxic mechanism involving metabolic activation to an
epoxide, formation of
DNA adducts and, in humans, modification of the p53 gene.
Aflatoxins are unique among
environmental carcinogens, in that elucidation of their mechanisms of action combined with molecular epidemiology provides a foundation for quantitative risk assessment; extensive evidence confirms that contamination of the food supply by AFB(1) puts an exposed population at increased risk of developing
hepatocellular carcinoma (HCC). Molecular
biomarkers to quantify
aflatoxin exposure in individuals were essential to link
aflatoxin exposure with
liver cancer risk.
Biomarkers were validated in populations with high HCC incidence in China and The Gambia, West Africa; urinary AFB(1)-N (7)-Guanine excretion was linearly related to
aflatoxin intake, and levels of
aflatoxin-
serum albumin adducts also reflected
aflatoxin intake. Two major cohort studies employing
aflatoxin biomarkers identified their causative role in HCC etiology. Results of a study in Shanghai men strongly support a causal relationship between HCC risk and the presence of
biomarkers for
aflatoxin and HBV
infection, and also show that the two risk factors act synergistically. Subsequent cohort studies in Taiwan confirm these results. IARC classified
aflatoxin as a Group 1 human
carcinogen in 1993, based on sufficient evidence in humans and experimental animals indicating the carcinogenicity of naturally occurring mixtures of
aflatoxins,
aflatoxin B(1), G(1) and M(1).
Aflatoxin biomarkers have also been used to show that primary prevention to reduce
aflatoxin exposure can be achieved by low-technology approaches at the subsistence farm level in sub-Saharan Africa. Also, in residents of Qidong, China, oral dosing with
chlorophyllin, a chlorophyll derivative, prior to each meal led to significant reduction in
aflatoxin-
DNA biomarker excretion, supporting the feasibility of preventive measures to reduce HCC risk in populations experiencing unavoidable
aflatoxin exposure. The systematic, comprehensive approach used to create the total
aflatoxin database justifies optimism for potential success of preventive interventions to ameliorate
cancer risk attributable to
aflatoxin exposure. This strategy could serve as a template for the development, validation and application of molecular and
biochemical markers for other
carcinogens and
cancers as well as other
chronic diseases resulting from environmental exposures.