**1. Introduction**

Foods and beverages are essentially complex mixtures of chemicals consumed for either sustenance or pleasure. The diversity of chemicals found in food is vast, as are their varying properties. It has long been known that chemicals with carcinogenic activity in rodent models can be found in many commonly consumed foods [1–5] from a variety of sources including plants, microorganisms, contaminations, additive uses and reactions which occur during storage, processing and cooking [2] (Table 1). In addition, carcinogens can be formed endogenously, from food materials [6–8]. This review focuses mainly on carcinogens, both rodent and human, present in foods and beverages at low concentrations which are imperceptible, and a few components present at levels associated with adverse effects. It does not address drinking water contaminants, such as arsenic, or the contributions of caloric content and macro components such as fat content, or the excess consumption of alcoholic beverages, all of which, nevertheless, have been implicated in increased cancer risks in humans [9–16].

Chemical carcinogens exert their effects through two distinct types of mechanism of action (MoA), which have been characterized as DNA-reactive (genotoxic) and epigenetic (non-genotoxic) [17–20], as discussed below. Chemical structure determines the carcinogenic MoAs; DNA-reactive carcinogens have structures that form reactive electrophiles, either directly or following bioactivation, whereas epigenetic carcinogens lack such properties, but have structures that exert other molecular and cellular effects leading

**Citation:** Kobets, T.; Smith, B.P.C.; Williams, G.M. Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk. *Foods* **2022**, *11*, 2828. https://doi.org/10.3390/ foods11182828

Academic Editors: Andreas Eisenreich and Bernd Schaefer

Received: 9 August 2022 Accepted: 8 September 2022 Published: 13 September 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

to cancer [17,18]. These differences in MoA underly the nature of human cancer risks from exposures [21,22].

**Table 1.** Sources of detectable carcinogens in food.


<sup>a</sup> Many of the agents listed are detectable only at minute levels by highly sensitive analytical techniques.

#### *1.1. Mechanisms of Carcinogenicity of DNA-Reactive Carcinogens*

DNA-reactive carcinogens have structures that permit formation of electrophilic reactants that covalently bind (adduct) to nucleophilic sites in nuclear DNA, as well as in other macromolecules, including RNA and proteins, in the target tissue(s) of carcinogenicity [23–25]. In target tissue(s), a single DNA reactant can form different DNA adducts on various nucleophilic sites either on a single base or on different bases. Each adduct can undergo different rates of repair depending upon its location in the genome. For example, adducts in transcriptionally active regions are repaired by a transcription-coupled repair system whereas adducts in transcriptionally silent regions are repaired by a global repair system [26]. The levels of DNA adducts resulting from exposures are a function of several metrics including dose levels, the frequency of exposure, and rates of DNA repair for specific adducts. Each adduct has a characteristic efficiency with which it gives rise to mutations, with those at sites of base pairing being more mutagenic.

Pro-mutagenic DNA alterations are converted to mutations during cell replication [27–29]. Mutations in critical growth control genes lead to neoplastic conversion, and subsequent neoplastic development [28,30]. DNA-reactive carcinogens can also exert other cellular effects, such as cytotoxicity, leading to enhanced cell proliferation, which can contribute to their carcinogenic activity [31,32]. DNA-reactive carcinogens can have additive effects with one another in their target organ(s).

Some DNA adducts evidently do not lead to carcinogenicity, since some adducts can be found in tissues where no tumors are induced following administration of a carcinogen [33–36]. For example, acrylamide, which is discussed below, forms adducts in target and non-target tissues [37]. It could also be the case that epigenetic effects are required to enable neoplastic conversion resulting from some adducts [38,39].

As a result of DNA interactions, DNA-reactive carcinogens are typically genotoxic in assay systems in which appropriate bioactivation is represented [17,18,24,40,41]. Moreover, DNA-reactive carcinogens often produce tumors at multiple sites and with a short duration of exposure, even after administration of a single dose for some. This property underlies their activity in limited short-term bioassays [18].

Some DNA-reactive carcinogens have been demonstrated to exhibit no-observedadverse-effect-levels (NOAELs) for carcinogenic effects in animal models [25,31,42–46], although conflicting data have been reported. Based on the steps for tumorigenesis, it is evident that biological thresholds that may influence the likelihood of cancer progression for genotoxic carcinogens exist. Nevertheless, currently, thresholds are not generally accepted for DNA-reactive carcinogens from a risk assessment and management perspective [47]. It is acknowledged that the derivation of NOAELs can be dependent on the study design, and more research is needed in this space. It is outside the scope of this paper to discuss thresholds for carcinogens in detail; however, this topic is reviewed elsewhere [25,31,42–46].

#### *1.2. Mechanisms of Carcinogenicity of Epigenetic Carcinogens*

Epigenetic carcinogens do not chemically react with DNA [17,20,48–52]. In the target tissue(s) of carcinogenicity, MoAs of these types of carcinogens involve molecular or cellular effects, which through secondary mechanisms, can either indirectly result in modification of DNA function or cell behavior [17,48]. For example, epigenetic carcinogens can induce oxidative stress, resulting in oxidative DNA damage [53–55], leading to either neoplastic conversion or stimulation of cell proliferation, thereby facilitating neoplastic development, often from cryptogenic pre-neoplastic cells. Epigenetic carcinogens can also affect gene expression [56,57], leading to neoplastic conversion. Such effects are often specific for rodents (e.g., d-limonene). Epigenetic carcinogens can enhance carcinogenicity of DNAreactive carcinogens through interactive effects such as neoplasm promotion (e.g., butylated hydroxyanisole).

Due to their lack of direct DNA reactivity, epigenetic carcinogens, in contrast to DNA-reactive agents, are typically negative in genotoxicity assays, even in the presence of bioactivation, unless some artifact, such as extreme cytotoxicity, mediates mutagenicity. To exert their carcinogenicity, epigenetic agents often require prolonged high-level exposures. Their MoA underlies the fact that in limited bioassays they are negative for initiating activity, but may be positive for promoting activity [18].

Epigenetic carcinogens are well established to exhibit NOAELs for the cellular effect underlying their carcinogenicity in animal models [17,19], as discussed for several of the food-borne carcinogens reviewed herein. Accordingly, thresholds are generally accepted for DNA-reactive carcinogens from a risk assessment perspective [47].
