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Thresholds of Genotoxic and Non-Genotoxic Carcinogens

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  • Published: 01 October 2018
  • volume 34, pages 281–290 (2018)
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Thresholds of Genotoxic and Non-Genotoxic Carcinogens
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  • Takehiko Nohmi1 

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Abstract

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.

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Abbreviations

WHO:

World Health Organization

ADI:

Acceptable daily intake

NOAEL:

No observable adverse effect level

NTP:

National Toxicology Program

ICH:

International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use

S9 mix:

9,000 × g supernatant of liver homogenates of rats pretreated with inducers of drug metabolizing enzymes plus NADPH-generating system

EFSA:

European Food Safety Authority

IARC:

International Agency for Research on Cancer

TLS:

Translesion DNA synthesis

4-NQO:

4-Nitroquinoline-1-oxide

TTC:

Threshold of toxicological concern

TOR:

Threshold of regulation

bw:

Body weight

COC:

Cohort of concern

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  1. Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-9501, Japan

    Takehiko Nohmi

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Correspondence to Takehiko Nohmi.

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Nohmi, T. Thresholds of Genotoxic and Non-Genotoxic Carcinogens. Toxicol Res. 34, 281–290 (2018). https://doi.org/10.5487/TR.2018.34.4.281

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  • Received: 03 July 2018

  • Revised: 10 August 2018

  • Accepted: 30 August 2018

  • Published: 01 October 2018

  • Issue Date: October 2018

  • DOI: https://doi.org/10.5487/TR.2018.34.4.281

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Key words

  • Genotoxic carcinogens
  • Non-genotoxic carcinogens
  • Threshold
  • Threshold of toxicological concern
  • TTC
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