*2.1. Application of Carcinogenicity Data to Human Risk*

Two types of carcinogenicity data are used in the assessment of risk: human epidemiologic data and tumor data obtained in testing in rodent models [58]. The former is considered more relevant for a variety of reasons [59–62], although such data are often limited in human exposure information and can be poorly controlled [63].

Animal data are usually more robust, but frequently involve findings whose relevance to humans is uncertain [18,64,65], because the tumorigenic effect involves MoAs operational only in rodents. In addition, rodent studies do not mimic real life human exposures with respect to both the concentration and frequency of exposure. The human diet is also composed of mixture of components, which can both enhance and inhibit carcinogenicity.

Thus, in assessing human risk, two considerations are critical, i.e., the MoA of carcinogenicity and human exposure dose [21,25].

Once a chemical has been identified in a food product and its structure determined, it is possible to undertake an in silico analysis to determine, based on structure-activity relationships, the potential for DNA reactivity [66]. While this works well for relatively simple compounds, with the complexity of many natural products, the subtleties of metabolic activation become increasingly difficult to predict. If sufficient material is available, direct testing for DNA reactivity is the preferred approach [18].

This review focuses primarily on chemicals present in food that have sufficient evidence of carcinogenicity in either humans or experimental animals and which were classified by the International Agency for Research on Cancer (IARC) as either carcinogenic to humans (Group 1), probably (Group 2A) or possibly (Group 2B) carcinogenic to humans [58,67]. IARC also recognizes a third group of substances (Group 3) which lack sufficient evidence to be classified as carcinogenic to humans but nonetheless can have the potential to cause carcinogenicity in animals. Moreover, a variety of chemicals has not yet been characterized as to their carcinogenic risk to humans. Where available, evaluations by other expert groups are cited. Data on classification of carcinogens by government agencies and their carcinogenic potencies (TD50) calculated based on the tumorigenicity findings in rodents are provided in Table 2.

**Table 2.** Classifications and characteristics of food-borne carcinogens.


#### **Table 2.** *Cont.*



#### **Table 2.** *Cont.*

<sup>a</sup> IARC group 1—carcinogenic to humans; group 2A—probably carcinogenic to humans; group 2B—possibly carcinogenic to humans; group 3—not classifiable as to its carcinogenicity to humans; group 4—probably not carcinogenic to humans. Source—Agents Classified by the IARC Monographs, Volumes 1–131 [67] . <sup>b</sup> 1—known to be a human carcinogen; 2—reasonably anticipated to be a human carcinogen. Source—NTP Report on Carcinogens, 15th Edition [68] . <sup>c</sup> Only rodent data was included for comparison; Source—Lhasa Carcinogenicity Database, https://carcdb.lhasalimited.org/ (accessed on 9 July 2022). <sup>d</sup> Not discussed in this review. EPI, epigenetic modifications; GTX, genotoxicity; N/A, not available N/L, not listed.

In this review, the evidence for human cancer risk from intake of food borne carcinogens of both the DNA-reactive and epigenetic types is discussed. In the assessment of risk from experimental studies, the greatest weight is given to studies with oral administration since that route of intake is most relevant to human consumption. The demonstration of human carcinogenicity is made in epidemiologic studies, although, the absence of an effect can be due to inadequacy of the studies.
