Guidance for the classification of carcinogens under the Globally Harmonised System of Classification and Labelling of Chemicals (GHS)

McGregor, Douglas; Boobis, Alan R.; Binaglia, Marco; Botham, Phil; Hoffstadt, Laurence; Hubbard, Sue; Petry, Thomas; Riley, Anthony; Schwartz, Dirk; Hennes, Christa

doi:10.3109/10408440903384717

Cited by 19 publications

(11 citation statements)

References 154 publications

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“…Regarding data from experimental animals, the information on nasal carcinogenesis in rats after inhalation (McGregor et al 2010) showed that the tumour incidence was slightly elevated at an exposure level of 6 ppm formaldehyde and clearly elevated at 10 ppm and above, whereas at 0.7 and 2 ppm no additional nasal tumours occurred. Thus, there is a non-linear dose-response relationship.…”

Section: Dose-response Relationship Of the Carcinogenicity Of Formaldmentioning

confidence: 99%

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

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The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as “omics” approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.

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Section: Dose-response Relationship Of the Carcinogenicity Of Formaldmentioning

confidence: 99%

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

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“…The UN-GHS, and therefore, the EU CLP approach are based on UN harmonised criteria for weighing the evidence from rodent studies. Regulatory (European Chemicals Agency 2015) and non-regulatory (McGregor et al 2010) guidance is available for weighing the evidence in line with the UN-GHS criteria. Table 7 summarises the assessment of the different UN-GHS Weight of Evidence elements in the EU assessment, and includes a comparison with the weight provided in the IARC evaluation.…”

Section: Discussionmentioning

confidence: 99%

Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC

et al. 2017

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Glyphosate is the most widely used herbicide worldwide. It is a broad spectrum herbicide and its agricultural uses increased considerably after the development of glyphosate-resistant genetically modified (GM) varieties. Since glyphosate was introduced in 1974, all regulatory assessments have established that glyphosate has low hazard potential to mammals, however, the International Agency for Research on Cancer (IARC) concluded in March 2015 that it is probably carcinogenic. The IARC conclusion was not confirmed by the EU assessment or the recent joint WHO/FAO evaluation, both using additional evidence. Glyphosate is not the first topic of disagreement between IARC and regulatory evaluations, but has received greater attention. This review presents the scientific basis of the glyphosate health assessment conducted within the European Union (EU) renewal process, and explains the differences in the carcinogenicity assessment with IARC. Use of different data sets, particularly on long-term toxicity/carcinogenicity in rodents, could partially explain the divergent views; but methodological differences in the evaluation of the available evidence have been identified. The EU assessment did not identify a carcinogenicity hazard, revised the toxicological profile proposing new toxicological reference values, and conducted a risk assessment for some representatives uses. Two complementary exposure assessments, human-biomonitoring and food-residues-monitoring, suggests that actual exposure levels are below these reference values and do not represent a public concern.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-1962-5) contains supplementary material, which is available to authorized users.

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“…In order to start this effort, it is mandatory to find an agreement on the type and quality of data to be used. Papers by Sonich-Mullin et al [ 72 ] or McGregor et al [ 73 ] made attempts defined a number of such criteria for experimental studies to be suitable for risk assessment of possible chemical carcinogens. In most cases such data are used instead of cancer data from human epidemiology.…”

Section: Risk Assessment: Stepwise Approaching the ‘True Risk’mentioning

confidence: 99%

What is the meaning of ‘A compound is carcinogenic’?

Schrenk

2018

Toxicology Reports

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Chemical Carcinogens are compounds which can cause cancer in humans and experimental animals. This property is attributed to many chemicals in the public discussion, resulting in a widespread perception of danger and threat. In contrast, a scientific analysis of the wide and non-critical use of the term ‚carcinogenic’ is warranted. First, it has to be clarified if the compound acts in a genotoxic or non-genotoxic manner. In the latter case, an ineffective (safe) threshold dose without cancer risk can be assumed. In addition, it needs to be investigated if the mode-of-action causing tumors in laboratory animals is relevant at all for humans.In case the compound is clearly directly genotoxic, an ineffective threshold dose cannot be assumed. However, also in this case it is evident that high doses of the compound are generally associated with a high cancer risk, low doses with a lower one. Based on dose-response data from animal experiments, quantification of the cancer risk is carried out by mathematical modeling. If the safety margin between the lowest carcinogenic dose in animals and the relevant level of exposure in humans exceeds 10,000, the degree of concern is classified as low. Cases, where the compound turns out to be genotoxic in one study or one test only but not in others or only in vitro but not in vivo, are particularly difficult to explain and cause controversial discussions. Also for indirectly genotoxic agents, an ineffective (threshold) dose must be assumed. The situation is aggravated by the use of doubtful epidemiological studies in humans such as in the case of glyphosate, where data from mixed exposure to various chemicals were used. If such considerations are mixed with pure hazard classifications such as ‘probably carcinogenic in humans’ ignoring dose-response behavior and mode-of-action, the misinformation and public confusion are complete. It appears more urgent but also more difficult than ever to return to a scientifically based perception of these issues.

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Guidance for the classification of carcinogens under the Globally Harmonised System of Classification and Labelling of Chemicals (GHS)

Cited by 19 publications

References 154 publications

Mode of action-based risk assessment of genotoxic carcinogens

Mode of action-based risk assessment of genotoxic carcinogens

Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC

What is the meaning of ‘A compound is carcinogenic’?

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