**6. Discussion and Conclusions**

A wide variety of carcinogens is present in foods and beverages consumed by humans. Categorization of these as operating through MoAs that are either DNA-reactive or epigenetic reveals important differences. Dietary carcinogens of the DNA-reactive type often produce hazardous effects at much lower doses compared to the epigenetic carcinogens. In addition, they frequently affect multiple target tissues, whereas epigenetic carcinogens often affect no more than two sites, where their MoA is exerted. Most importantly, several DNA-reactive carcinogens found in diet are recognized as causes of human cancer, including aflatoxins, aristolochic acid, benzene, benzo[a]pyrene, ethylene oxide, and preserved food components. Other food-derived DNA-reactive chemicals that are considered likely to contribute to human cancer include nitrosamines from several sources, as well as polycyclic aromatic hydrocarbons and heterocyclic amines formed during processing or cooking of food. In contrast, the only food-borne epigenetic carcinogen considered by some authorities to be associated with increased cancer in humans, although not from low-level food exposure, is dioxin (TCDD). Accordingly, DNA-reactive carcinogens represent a much greater risk than epigenetic carcinogens.

**Author Contributions:** Conceptualization, G.M.W.; writing—original draft preparation, T.K. and G.M.W.; writing—review and editing, T.K., B.P.C.S. and G.M.W.; funding acquisition, T.K., B.P.C.S. and G.M.W. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by the Chemical Risk Assessment Fund (New York Medical College Grant no. 161140) and the National Research Foundation Singapore Whitespace grant (Grant no. W20W3D0002) administered by the Agency for Science, Technology & Research.

**Data Availability Statement:** Data sharing not applicable. No new data were created or analyzed in this study. Data sharing is not applicable to this article.

**Conflicts of Interest:** The authors report no competing interests to declare.

#### **Abbreviations**

2-HEX, *Trans*-2-hexenal; 2-MI, 2-methylimidazole; 4-MI, 4-methylimidazole; AC, Acrylamide; AA, Aristolochic acid; AB, Alkenylbenzenes; ADI, Acceptable daily intake; AF, Aflatoxin; BaP, Benzo[a]pyrene; BHA, Butylated hydroxyanisole; BHQ, tert-Butylhydroquinone; BHT, Butylated hydroxytoluene; bw, body weight; BZ, Benzene; CA, Crotonaldehyde; CAR, Constitutive androstane receptor; CP, 3-chloro-1,2-propanediol; CONTAM, Panel on Contaminants in the Food Chain; CYP, Cytochrome P450; DDD, *p*,*p*- -dichlorodiphenyl-dichloroethane; DDE, *p*,*p*- -dichlorodiphenyldichloroethylene; DDT, *p*,*p*- -dichlorodiphenyl-trichloroethane; diMeIQx, 2-amino-3,4,8-trimethylimid azo[4,5-*f*]quinoline; DEHP, Di(2-ethylhexyl) phthalate; DMBA, 7,12-dimethylbenz[a]anthracene; DLC, Dioxin-like compound; DP, 1,3-dichloro-2-propanol; EC, Ethyl carbamate; EDI, estimated daily intake; EFSA, European Food Safety Authority; EMA, European Medical Agency; EtO, Ethylene oxide; FAO, Food and Agriculture Organization; FB1, Fumonisin B1; FC, Fusarin C; FDA, US Food and Drug Administration; FEMA, Flavor and Extract Manufacturers Association; GA, Glycidamide; GSH, Glutathione; GST, Glutathione S-transferase; HCA, Heterocyclic amine; HNE, 4-hydroxynonenal; HQ, Hydroquinone; IARC, International Agency for Research on Cancer; IQ, 2-amino-3-methylimidazo[4,5-*f*]quinoline; JECFA, WHO/FAO Joint Expert Committee of Food Additives; MAM, Methylazoxymethanol; MDA, Malondialdehyde; ME, Methyl eugenol; MeIQ, 2-amino-3,4-dimethylimidazo[4,5-*f*]quinoline; MelQx, 2-amino-3,8-dimethylimidazo[4,5-*f*]quinoline; MIBK, Methyl isobutyl ketone; MoA, Mechanism of action; MoE, Margins of exposure; NDEA, *N*nitrosodiethylamine; NOAEL, No-observed-adverse-effect-level; NPL, 32P-nucleotide postlabeling; OTA, Ochratoxin A; PA, Pyrrolizidine alkaloid; PAH, Polycyclic aromatic hydrocarbon; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-para-dioxin; PCDF, polychlorinated dibenzofuran; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-*b*]pyridine; PMTDI, Provisional maximum tolerable daily intake; PPARα, peroxisome proliferator-activated receptor alpha; PUFA, Polyunsaturated fatty acids; PUL, Pulegone; ROS, reactive oxygen species; SAF, Safrole; SCE, Sister chromatid exchange; SCF, Scientific Committee on Food; T4, Thyroxine; TCDD, Dioxin; TD50, Carcinogenic potency; TDI, Tolerable daily intake; TEF, Toxic equivalency factor; TSH, Thyroid stimulating hormone; UDS, Unscheduled DNA synthesis; WHO, World Health Organization.
