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, 34 (4), 281-290

Thresholds of Genotoxic and Non-Genotoxic Carcinogens


Thresholds of Genotoxic and Non-Genotoxic Carcinogens

Takehiko Nohmi. Toxicol Res.


Exposure to chemical agents is an inevitable consequence of modern society; some of these agents are hazardous to human health. The effects of chemical carcinogens are of great concern in many countries, and international organizations, such as the World Health Organization, have established guidelines for the regulation of these chemicals. Carcinogens are currently categorized into two classes, genotoxic and non-genotoxic carcinogens, which are subject to different regulatory policies. Genotoxic carcinogens are chemicals that exert carcinogenicity via the induction of mutations. Owing to their DNA interaction properties, there is thought to be no safe exposure threshold or dose. Genotoxic carcinogens are regulated under the assumption that they pose a cancer risk for humans, even at very low doses. In contrast, non-genotoxic carcinogens, which induce cancer through mechanisms other than mutations, such as hormonal effects, cytotoxicity, cell proliferation, or epigenetic changes, are thought to have a safe exposure threshold or dose; thus, their use in society is permitted unless the exposure or intake level would exceed the threshold. Genotoxicity assays are an important method to distinguish the two classes of carcinogens. However, some carcinogens have negative results in in vitro bacterial mutation assays, but yield positive results in the in vivo transgenic rodent gene mutation assay. Non-DNA damage, such as spindle poison or topoisomerase inhibition, often leads to positive results in cytogenetic genotoxicity assays such as the chromosome aberration assay or the micronucleus assay. Therefore, mechanistic considerations of tumor induction, based on the results of the genotoxicity assays, are necessary to distinguish genotoxic and non-genotoxic carcinogens. In this review, the concept of threshold of toxicological concern is introduced and the potential risk from multiple exposures to low doses of genotoxic carcinogens is also discussed.

Keywords: Genotoxic carcinogens; Non-genotoxic carcinogens; TTC; Threshold; Threshold of toxicological concern.

Conflict of interest statement

CONFLICT OF INTEREST There is no conflict of interest.


Fig. 1
Fig. 1
Models for dose-response curves of non-genotoxic and genotoxic carcinogens. Non-genotoxic carcinogens like as other toxic chemicals have threshold while genotoxic carcinogens have no threshold. Non-genotoxic carcinogens can be used in the society if the intake level is below the threshold. Genotoxic carcinogens are supposed to have carcinogenic risk even at very low doses. Therefore, genotoxic carcinogens are generally not be considered acceptable for use as food additives, pesticides or veterinary drugs.
Fig. 2
Fig. 2
Self-defense mechanisms against genotoxic chemicals. Genotoxic chemicals may be inactivated by metabolic inactivation. When DNA adducts are formed, the adducts may be removed by DNA repair mechanisms. If the adducts remain in DNA, error-free translesion DNA synthesis (TLS) will incorporate correct dNTPs against the lesions, thereby suppressing induction of mutations.
Fig. 3
Fig. 3
Dose response curves of potassium bromate, benzo[a]pyrene plus visible light and 4-nitroquinoline-1-oxide (4-NQO). Closed black circles, Salmonella typhimurium TA1535; closed red circles, YG3001 (same as TA1535 but ΔmutM); closed black squares, TA1975 (same as TA1535 but uvrB+); closed red squares YG3003 (same as TA1975 but ΔmutM). When the mutagenicity of benzo[a]pyrene in the presence of visible light, plates were exposed to fluorescent light 15 W lamps at a distance of 30 cm during incubation at 37°C for two to three days. The data are from references (63,64).

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