*2.2. Risk Assessment of DNA-Reactive Rodent Carcinogens*

In order to evaluate possible safety concerns arising from presence of carcinogens with DNA-reactive MoA in the diet, many regulatory and advisory agencies, including the European Food Safety Authority Panel on Contaminants in the Food Chain (EFSA CONTAM) and the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) the Expert Committee on Food Additives (JECFA) use a margin of exposure (MoE) approach [69,70]. MoE is calculated as a ratio between an appropriate Point of Departure for a tumor response, such as NOAELs obtained from animal studies, and a predicted or estimated human exposure level. A number of considerations should be taken into account when a MoE is derived, including the biological relevance of carcinogenic MoAs to humans [65].

Among DNA-reactive rodent carcinogens, only aflatoxins, aristolochic acid I, benzene, benzo[a]pyrene and ethylene oxide, have been found to be associated with cancer causation in humans (Table 2). Nevertheless, all materials in this class are genotoxic, indicating an MoA that represents human risk [22].

#### *2.3. Risk Assessment of Epigenetic Carcinogens*

The contribution and relevance of epigenetic mechanisms produced by dietary factors leading to the development of cancer in humans is uncertain [71], and the best approach to risk assessment of such carcinogens remains a topic of a debate [72]. Nevertheless, at low intermittent exposures (less than 1 mg/day) epigenetic carcinogens are not considered to pose cancer risks to humans [21]. This may reflect the absence in humans of the processes involved in the MoAs in rodents, e.g., d-limonene alpha 2μ(α2μ)-globulin nephropathy in male rats leading to kidney tumors [73], or the much lower exposures of humans, e.g., forestomach irritation in rats caused by butylated hydroxyanisole leading to squamous cell carcinoma [74]. Additionally, the fact that epigenetic changes can be reversible could contribute to lack of human risk. Hence, for epigenetic carcinogens NOAELs are used to derive safety values, such as tolerable daily intake (TDI) [21].

#### **3. DNA-Reactive Carcinogens and Related Chemicals Present in Food**

This section provides an overview of food-derived carcinogens that typically produce genotoxic and mutagenic effects in vitro and/or in vivo, in particular with appropriate bioactivation. Chemical structures of DNA-reactive carcinogens and related chemicals discussed in this section are provided in Figures 1–5.
