Present and future directions of translational research on aflatoxin and hepatocellular carcinoma. A review

• Published in: Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment Chemistry, analysis, control, exposure & risk assessment, 2012-02, Vol.29 (2), p.249-257
• Main Authors: Wogan, Gerald N, Kensler, Thomas W, Groopman, John D
• Format: Article
• Language: English
• Subjects: Aflatoxins; Aflatoxins - toxicity; albumins; Animals; Arachis hypogaea; Aspergillus flavus; at-risk population; Bioindicators; Biological and medical sciences; Biomarkers; Cancer; carcinogenicity; Carcinogens; Carcinoma, Hepatocellular - chemically induced; chicks; chlorophyll; chromatography, LC/MS; chronic diseases; cohort studies; DNA adducts; ducklings; Epidemiology; etiology; Excretion; farms; Feasibility studies; fish; food availability; Food Contamination; Food industries; Food science; Food supply; Food toxicology; Fundamental and applied biological sciences. Psychology; genes; genotoxicity; Hepatitis B virus; hepatoma; Humans; laboratory animals; Liver; Liver cancer; Liver Neoplasms - chemically induced; men; Metabolites; molecular epidemiology; peanut meal; poults; Primates; quantitative risk assessment; risk; Risk assessment; risk factors; rodents; Toxicity; turkeys
• ISSN: 1944-0057; 1944-0049; 1944-0057
• DOI: 10.1080/19440049.2011.563370

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 B₁ and G₁ (AFB₁ and AFG₁) were isolated from Aspergillus flavus cultures. Structure elucidation of aflatoxin B₁ was accomplished and confirmed by total synthesis in 1963. AFB₁ 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 AFB₁ 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 AFB₁–N⁷-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 B₁, G₁ and M₁. 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 pre