**1. Introduction**

The mycotoxin aflatoxin B1 (AFB1) is the most potent known liver carcinogen [1] and is also a lung [2] and esophageal carcinogen [3]. The International Agency for Research and Cancer (IARC) has classified AFB1 as a Group 1 human carcinogen [1]. AFB1 was discovered as the causative chemical agent in Turkey X disease, so named after a 1960 occurrence where 100,000 turkeys in Great Britain died after feeding on contaminated peanut meal imported from Brazil [4]. Its notoriety is underscored by its persistence in grain supplies, ground nuts and animal feed, which must be continually monitored [5]. Produced by aspergillus parasiticus and aspergillus flavis, the mycotoxin is a particular problem in subtropical areas of China, and in tropical areas of Southeast Asia and Africa [6, 7]. In temperate climates, such as in North America, high levels of AFB1 contamination have been found in corn and nuts, such as almonds and pistachios [8]. To minimize health risks in humans, the Food and Drug Administration (FDA) mandates that the

human food supply contain no more than 20 ppb AFB1 [5]. While human food supply is relatively protected in developed countries, outbreaks of acute mycotoxin contamination have been noted in third world countries and among animals, as recently as 2006 [5]. Although the incidence of acute aflatoxicosis is rare, it is estimated that a large fraction of the population in the developing world are chronically exposed to AFB1 and thus at a higher risk for aflatoxin-associated cancer, especially liver cancer [6].

 Liver cancer ranks third in all worldwide cancer mortalities [9–11] and ninth in cancer mortalities in the United States [12, 13]. 4–28% of cancer cases are related to AFB1 exposure [2]. Most liver cancer is characterized as hepatocellular carcinoma (HCC). HCC is highest where there is both a high rate of hepatitis B (HBV) [14, 15] and C virus (HCV) infection [15–17] and high levels of AFB1 contamination in the human food supply, especially in areas of Southeast Asia, China and Africa [6]. Interestingly, the incidence for liver cancer is higher in men than women, regardless of whether the cancer is associated with AFB1 exposure [18]. Because diagnosis is often late and there is no effective treatment for late-stage cancer, the five year survival rate is low in both men and women [12, 13]. The carcinogenic potency of AFB1 is correlated with AFB1 being a strong genotoxin, the signature p53 mutation, p53 249ser [19, 20], is found in 40–60% of all liver cancer derived from patients in heavily contaminated areas [2]. Animal studies have further strengthened the idea that AFB1 carcinogenicity is associated with its genotoxicity; AFB1-associated DNA adduct levels are directly proportional to the number of the animals stricken with liver cancer [21, 22].

Observations that HCC incidence is correlated to AFB1 exposure continues to motivate biomedical researchers to study the repair and toleration of AFB1 associated DNA adducts, the cellular response to these DNA adducts, and associated factors that may enhance or mitigate the high mutagenicity of the DNA adducts in humans. This review will address (1) associated risk factors that enhance or synergize with AFB-associated DNA adducts that increase liver cancer incidence, (2) genetic instability phenotypes associated with AFB1-associated DNA adducts, and (3) repair mechanisms that have been elucidated in model organisms and conserved in humans, (4) cellular responses that enhance repair mechanisms, and (5) future directions in understanding the contributions of genes in AFB1-associated DNA repair. In particular, novel research that addresses epigenetic factors that can alter the repair of AFB1-associated genotoxic damage will be addressed.
