Research Global Burden of Aflatoxin-Induced Hepatocellular Carcinoma: A Risk Assessment Yan Liu and Felicia Wu Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA c onclusi k ey words Background : Hepatocellular carcinoma (HCC), or liver cancer, is the third leading cause of cancer deaths worldwide, with prevalence 16–32 times higher in developing countries than in developed countries. Aflatoxin, a contaminant produced by the fungi Aspergillus flavus and Aspergillus parasiticus in maize and nuts, is a known human liver carcinogen. o Bjectivs Methods : We sought to determine the global burden of HCC attributable to aflatoxin exposure. : We conducted a quantitative cancer risk assessment, for which we collected global data on food-borne aflatoxin levels, consumption of aflatoxin-contaminated foods, and hepatitis B virus (HBV) prevalence. We calculated the cancer potency of aflatoxin for HBV-postive and HBV- negative individuals, as well as the uncertainty in all variables, to estimate the global burden of aflatoxin-related HCC. r esult : Of the 550,000–600,000 new HCC cases worldwide each year, about 25,200–155,000 may be attributable to aflatoxin exposure. Most cases occur in sub-Saharan Africa, Southeast Asia, and China where populations suffer from both high HBV prevalence and largely uncontrolled afla- toxin exposure in food. : Aflatoxin may play a causative role in 4.6–28.2% of all global HCC cases. : aflatoxin, global disease burden, hepatitis, hepatocellular carcinoma, risk assessment. Environ Health Perspect 118:818–824 (2010). doi:10.1289/ehp.0901388 [Online 19 February 2010] Hepatocellular carcinoma (HCC), or liver cancer, is the third leading cause of cancer deaths worldwide [World Health Organization (WHO) 2008], with roughly 550,000– 600,000 new HCC cases globally each year (Ferlay et al. 2004). Aflatoxin exposure in food is a significant risk factor for HCC (Wild and Gong 2010). Aflatoxins are primarily produced by the food-borne fungi Aspergillus flavus and Aspergillus parasiticus, which colonize a variety of food commodities, including maize, oilseeds, spices, groundnuts, and tree nuts in tropical and subtropical regions of the world. Additionally, when animals that are intended for dairy pro- duction consume aflatoxin-contaminated feed, a metabolite, aflatoxin M1, is excreted in the milk (Strosnider et al. 2006). Aflatoxins are a group of approximately 20 related fungal metabolites. The four major aflatoxins are known as B1, B2, G1, and G2. Aflatoxins B2 and G2 are the dihydro- derivatives of the parent compounds B1 and G1 (Pitt and Tomaska 2001). Aflatoxin B1 (AFB1) is the most potent (in some species) naturally occurring chemical liver carcinogen known. Naturally occurring mixes of aflatoxins have been classified as a Group 1 human carcinogen by the International Agency for Research on Cancer (IARC) and has demonstrated carci- nogenicity in many animal species, including some rodents, nonhuman primates, and fish [International Programme on Chemical Safety (IPCS)/WHO 1998)]. Specific P450 enzymes in the liver metabolize aflatoxin into a reactive oxygen species (aflatoxin-8,9-epoxide), which may then bind to proteins and cause acute toxicity (aflatoxicosis) or to DNA to cause 818 lesions that over time increase the risk of HCC (Groopman et al. 2008). HCC as a result of chronic aflatoxin expo- sure has been well documented, presenting most often in persons with chronic hepatitis B virus (HBV) infection (Wild and Gong 2010). The risk of liver cancer in individuals exposed to chronic HBV infection and aflatoxin is up to 30 times greater than the risk in individu- als exposed to aflatoxin only (Groopman et al. 2008). These two HCC risk factors—aflatoxin and HBV—are prevalent in poor nations worldwide. Within these nations, there is often a significant urban–rural difference in aflatoxin exposure and HBV prevalence, with both these risk factors typically affecting rural populations more strongly (Plymoth et al. 2009). Aflatoxin also appears to have a synergistic effect on hepatitis C virus (HCV)-induced liver cancer (Kirk et al. 2006; Kuang et al. 2005; Wild and Montesano 2009), although the quantitative relationship is not as well estab- lished as that for aflatoxin and HBV in induc- ing HCC. Other important causative factors in the development of HCC, in addition to HBV or HCV infection and aflatoxin exposure, are the genetic characteristics of the virus, alco- hol consumption, and the age and sex of the infected person (Kirk et al. 2006). The IPCS/WHO undertook an aflatox- in–HCC risk assessment in 1998 to estimate the impact on population cancer incidence by moving from a hypothetical total aflatoxin standard of 20 ng/g to 10 ng/g (Henry et al. 1999; IPCS/WHO 1998). Assuming that all food containing higher levels of aflatoxin than the standard was discarded and that enough maize and nuts remained to preserve consump- tion patterns, IPCS/WHO determined that HCC incidence would decrease by about 300 cases per year per billion people, if the stricter aflatoxin standard were followed in nations with HBV prevalence of 25%. However, in nations where HBV prevalence was 1%, the stricter aflatoxin standard would save only two HCC cases per year per billion people. This assessment associated HCC risk with particu- lar doses of aflatoxin; however, these doses do not correspond with actual exposure in differ- ent parts of the world, and the two hypotheti- cal values for HBV prevalence, 1% and 25%, were not intended to represent actual HBV prevalence worldwide. Currently, > 55 billion people worldwide suffer from uncontrolled exposure to afla- toxin (Strosnider et al. 2006). What remains unknown is how many cases of liver cancer can be attributed to this aflatoxin exposure worldwide. Indeed, the Aflatoxin Workgroup (Strosnider et al. 2006), convened by the Centers for Disease Control and Prevention and WHO, identified four issues that war- rant immediate attention: quantifying human health impacts and burden of disease due to aflatoxin exposure, compiling an inventory of ongoing intervention strategies, evaluating their efficacy, and disseminating the results. Addressing this first issue is the aim of our study. We compiled available information on aflatoxin exposure and HBV prevalence from multiple nations in a quantitative cancer risk assessment, to estimate the number of HCC cases attributable to aflatoxin world- wide per year. Shephard (2008) estimated population risk for aflatoxin-induced HCC in select African nations; we expand this to include the rest of the world. We briefly describe interventions that can either reduce Address correspondence to F. Wu, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, 100 Technology Dr., Rm 560, Pittsburgh, PA 15219 USA. Telephone: (412) 624-1306. Fax: (412) 624-3040. E-mail: few8@pitt.edu We thank T. Kensler (University of Pittsburgh), J. Groopman (Johns Hopkins University), and C. Wild (International Agency for Research on Cancer) for their helpful comments. This work was funded by the Bill and Melinda Gates Foundation and the National Institutes of Health (KL2 RR024153). The authors’ salaries are supported in part by the Bill & Melinda Gates Foundation. Received 26 August 2009; accepted 19 February 2010. ovlume 118 | number 6 | June 2010 • Environmental Health Perspectives