Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology

Abstract

Since their discovery 50 years ago, the aflatoxins have become recognized as ubiquitous contaminants of the human food supply throughout the economically developing world. The adverse toxicological consequences of these compounds in populations are quite varied because of a wide range of exposures leading to acute effects, including rapid death, and chronic outcomes such as hepatocellular carcinoma. Furthermore, emerging studies describe a variety of general adverse health effects associated with aflatoxin, such as impaired growth in children. Aflatoxin exposures have also been demonstrated to multiplicatively increase the risk of liver cancer in people chronically infected with hepatitis B virus (HBV) illustrating the deleterious impact that even low toxin levels in the diet can pose for human health. The public health impact of aflatoxin exposure is pervasive. Aflatoxin biomarkers of internal and biologically effective doses have been integral to the establishment of the etiologic role of this toxin in human disease through better estimates of exposure, expanded knowledge of the mechanisms of disease pathogenesis, and as tools for implementing and evaluating preventive interventions.

FIG. 1.

Time line for key events in the discovery, toxicological evaluation, molecular epidemiology, and regulation of aflatoxins. FDA, Food and Drug Administration; IARC, International Agency for Research on Cancer; IAC, immunoaffinity chromatography; CHL, chlorophyllin.

FIG. 2.

Biotransformation pathways for aflatoxin B₁. Products measured in biofluids for use as biomarkers in epidemiological and intervention studies are highlighted in green (urine) and red (serum).

FIG. 3.

Key steps in the development of HCC by viral (HBV and HCV) and chemical (aflatoxin) factors. Blood- and urine-based biomarkers used in etiological studies are indicated.

FIG. 4.

Mortality from HCC in Qidong, People's Republic of China. (A) Survival curve following diagnosis of HCC in Qidong. Median survival is < 3 months. Adapted from Chen et al. (2003). (B) Age-specific incidence of HCC in Qidong and Beijing, China. The rate of infection with HBV is the same in both Qidong and Beijing, China. Additional environmental factors, such as exposure to aflatoxin (which is more prevalent in Qidong), could underlie the elevated risk of HCC in this region. This regional dichotomy highlights the opportunity to reduce the incidence of HCC simply by reducing the effects of aflatoxin. Adapted from Kensler et al. (2003). (C) Mortality rates of HCC by year in Qidong. Data provided by Dr Jian-Guo Chen, Qidong Liver Cancer Institute. (D) Projected mortality rates from HCC over the next 50 years on the basis of existing vaccination programs against HBV infection (red line) and coupled with possible reductions in aflatoxin exposures (blue line). The impact of vaccination is modeled on the basis of the current experience in Taiwan, where near universal vaccination was implemented in 1984 (Chang et al., 2009). The effect of attenuated aflatoxin exposure is modeled from the results of animal intervention studies, where reduction and delay of incidence of HCC have been observed (Kensler et al., 1997). See text for further discussion.