Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation

Boobis, Alan R.; Brown, P.J.; Cronin, Mark T.D.; Edwards, John S.; Galli, Corrado L.; Goodman, Jay I.; Jacobs, Abigail; Kirkland, David; Luijten, Mirjam; Marsaux, Cyril F. M.; Martin, Matthew T.; Yang, Chihae; Hollnagel, Heli M.

doi:10.1080/10408444.2017.1318822

Cited by 35 publications

(40 citation statements)

References 67 publications

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“…Indirect DNA-damaging agents are, for example, aneugens that cause effects such as the inhibition of enzymes or proteins involved in the segregation of chromosomes during the cell cycle [26,27]. As aneugenic and clastogenic substances are not direct DNA-reactive mutagens [11], they are regulated with a Cramer Class III threshold [28][29][30].…”

Section: Genetic Toxicologymentioning

confidence: 99%

Evaluation of the Suitability of Mammalian In Vitro Assays to Assess the Genotoxic Potential of Food Contact Materials

Pinter

Rainer

Czerny

et al. 2020

Foods

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Background: Non-targeted screening of food contact materials (FCM) for non-intentionally added substances (NIAS) reveals a great number of unknown and unidentified substances present at low concentrations. In the absence of toxicological data, the application of the threshold of toxicological concern (TTC) or of EU Regulation 10/2011 requires methods able to fulfill safety threshold criteria. In this review, mammalian in vitro genotoxicity assays are analyzed for their ability to detect DNA-damaging substances at limits of biological detection (LOBD) corresponding to the appropriate safety thresholds. Results: The ability of the assays to detect genotoxic effects varies greatly between substance classes. Especially for direct-acting mutagens, the assays lacked the ability to detect most DNA reactive substances below the threshold of 10 ppb, making them unsuitable to pick up potential genotoxicants present in FCM migrates. However, suitability for the detection of chromosomal damage or investigation of other modes of action makes them a complementary tool as part of a standard test battery aimed at giving additional information to ensure safety. Conclusion: improvements are necessary to comply with regulatory thresholds to consider mammalian genotoxicity in vitro assays to assess FCM safety.

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Section: Genetic Toxicologymentioning

confidence: 99%

Evaluation of the Suitability of Mammalian In Vitro Assays to Assess the Genotoxic Potential of Food Contact Materials

Pinter

Rainer

Czerny

et al. 2020

Foods

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“…Another challenge to the regulatory policy is that DNA-reactive genotoxic carcinogens have no threshold is the concept of “threshold of toxicological concern” (TTC) or “threshold of regulation” (TOR) ( 65 ). Essentially, the underlying concept of TTC or TOR is that it is impossible to completely suppress the excess lifetime cancer risk associated with chemical exposure and that there is an increasing number of new chemicals for which there is insufficient toxicological information.…”

Section: Threshold Of Toxicological Concern (Ttc) Of Genotoxic Carcinmentioning

confidence: 99%

“…The COC chemicals are also excluded from the TTC approach. Currently, the use of the TTC approach has been established to regulate chemicals in several areas, such as food contact materials, food flavoring agents, and pharmaceutical impurities ( 65 ). A TTC approach for non-genotoxic carcinogens was also proposed ( 67 , 69 ).…”

Section: Threshold Of Toxicological Concern (Ttc) Of Genotoxic Carcinmentioning

confidence: 99%

Thresholds of Genotoxic and Non-Genotoxic Carcinogens

Nohmi

2018

ToxicolRes

113

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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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“…The TTC for evaluation of genotoxicity risk (TTC genotox ) of 0.15 mg/person/day was proposed by Kroes and colleagues (Kroes et al 2004) as the dose below which cancer risk does not exceed 1 in 10 6 , specifically for compounds that have structural alerts for genotoxicity other than those of highly potent carcinogens, such as aflatoxin, certain azo-and azoxy-compounds or N-nitrosocompounds, for which no threshold can be determined. The TTC genotox is 10-fold lower (more stringent) than the threshold of regulation (TOR) for cancer risk previously established for substances with no indication of DNA reactivity [for details, see (Kroes et al 2004;Boobis et al 2017;Patlewicz et al 2018)]. The application of the TTC genotox is consistent with a risk assessment approach rather than a strict hazard evaluation (EFSA 2016; Nohmi 2018).…”

Section: The Fema Expert Panel Approach To the Genotoxicity Evaluatiomentioning

confidence: 58%

“…Therefore, the FEMA Expert Panel conducts a complete assessment of probable risk rather than merely a hazard assessment limited to the intrinsic genotoxic potential (hazard) of flavoring substances. This can involve the use of an appropriate TTC value for genotoxic potential, currently considered as 0.15 mg/person/day (Kroes et al 2004;Boobis et al 2017).…”

Section: The Fema Expert Panel Approach To the Genotoxicity Evaluatiomentioning

confidence: 99%

The safety evaluation of food flavoring substances: the role of genotoxicity studies

Gooderham

Cohen

Eisenbrand

et al. 2020

Critical Reviews in Toxicology

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The Flavor and Extract Manufacturers Association (FEMA) Expert Panel relies on the weight of evidence from all available data in the safety evaluation of flavoring substances. This process includes data from genotoxicity studies designed to assess the potential of a chemical agent to react with DNA or otherwise cause changes to DNA, either in vitro or in vivo. The Panel has reviewed a large number of in vitro and in vivo genotoxicity studies during the course of its ongoing safety evaluations of flavorings. The adherence of genotoxicity studies to standardized protocols and guidelines, the biological relevance of the results from those studies, and the human relevance of these studies are all important considerations in assessing whether the results raise specific concerns for genotoxic potential. The Panel evaluates genotoxicity studies not only for evidence of genotoxicity hazard, but also for the probability of risk to the consumer in the context of exposure from their use as flavoring substances. The majority of flavoring substances have given no indication of genotoxic potential in studies evaluated by the FEMA Expert Panel. Examples illustrating the assessment of genotoxicity data for flavoring substances and the consideration of the factors noted above are provided. The weight of evidence approach adopted by the FEMA Expert Panel leads to a rational assessment of risk associated with consumer intake of flavoring substances under the conditions of use.

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Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation

Cited by 35 publications

References 67 publications

Evaluation of the Suitability of Mammalian In Vitro Assays to Assess the Genotoxic Potential of Food Contact Materials

Evaluation of the Suitability of Mammalian In Vitro Assays to Assess the Genotoxic Potential of Food Contact Materials

Thresholds of Genotoxic and Non-Genotoxic Carcinogens

The safety evaluation of food flavoring substances: the role of genotoxicity studies

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