A comparison of transgenic rodent mutation and in vivo comet assay responses for 91 chemicals

Kirkland, David; Levy, Dan D.; LeBaron, Matthew J.; Aardema, Marilyn J.; Beevers, Carol; Bhalli, Javed A.; Douglas, George R.; Escobar, Patricia; Farabaugh, Christopher S.; Guérard, Melanie; Johnson, George E.; Kulkarni, Rohan; Curieux, Frank Le; Long, Alexandra S.; Lott, Jasmin; Lovell, David P.; Luijten, Mirjam; Marchetti, Francesco; Nicolette, John; Pfuhler, Stefan; Roberts, Daniel J.; Stankowski, Leon F.; Thybaud, Véronique; Weiner, Sandy; Williams, Andrew; Witt, Kristine L.; Young, Robert R.

doi:10.1016/j.mrgentox.2019.01.007

Cited by 37 publications

(28 citation statements)

References 24 publications

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“…the liver if hepatic metabolic activation is suspected, the GI tract as a tissue of high local compound concentration in the case of the oral administration of the chemical, or organs in which toxic effects or drug accumulation have been observed. In the case of a positive effect in the Ames test, transgenic animals, the comet assay, or the Pig-A assay are available to investigate gene mutations in vivo (Kirkland et al 2019;OECD 2011). In any case, the conditions need to be appropriate to provide arguments to exclude a human risk with sufficient stringency, for example with respect to doses and treatment schedules used.…”

Section: Strategies For Genotoxicity Assessmentmentioning

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: Strategies For Genotoxicity Assessmentmentioning

confidence: 99%

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

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“…Recently, the database has been also used as a data source to develop an animal-free strategy for the prioritization of substances of genotoxic concern, specifically food contact materials [ 34 ]. Moreover, the Health and Environmental Sciences Institute’s (HESI) Genetic Toxicology Technical Committee used part of the information stored in the database to provide more detailed advice on which in vivo test to choose to follow-up on in vitro positive results [ 35 ], and to inform case studies to illustrate the approach for a next-generation testing strategy for assessment of genomic damage [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

EURL ECVAM Genotoxicity and Carcinogenicity Database of Substances Eliciting Negative Results in the Ames Test: Construction of the Database

Madia

Kirkland²,

Morita

et al. 2020

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Highlights EURL ECVAM Consolidated Genotoxicity and Carcinogenicity Database extended. Negative Ames test results were compiled and reviewed. A database of Ames negative results was constructed. Database chemical space characterization was conducted. OFG representation of carcinogens and non-carcinogens was characterised.

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“…The assays were performed according to the OECD 489 and 474 guidelines, respectively [53,54] with some alterations, as described by Diez-Quijada et al [43]. The combined comet-MN assay [58] reduces the use of animals according to the 3Rs principles (Replace, Reduce, and Refine), and it increases the sensitivity and specificity of the assays, decreasing the number of false negative results [59]. Moreover, in this case, the use of DNA repair enzymes (Endo III and Fpg) was also included, increasing the sensitivity of the in vivo comet assay [60,61].…”

Section: Discussionmentioning

confidence: 99%

“…The application of the alkaline comet assay in stomach, liver, and blood cells is a good complement to the bone-marrow and peripheral blood MN test [58] because this combination allows assessment of the DNA damage in various potential target tissues (site of contact, metabolism and peripheral distribution) and it can detect multi-endpoint genotoxic effects [59]. In the present study, the absence of effects is in consensus with a previous in vivo combined study carried out with CYN alone in male rats under similar experimental conditions [43].…”

Section: Discussionmentioning

confidence: 99%

Cylindrospermopsin-Microcystin-LR Combinations May Induce Genotoxic and Histopathological Damage in Rats

Díez-Quijada

Medrano-Padial

Llana-Ruiz-Cabello

et al. 2020

Toxins

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Cylindrospermopsin (CYN) and microcystins (MC) are cyanotoxins that can occur simultaneously in contaminated water and food. CYN/MC-LR mixtures previously investigated in vitro showed an induction of micronucleus (MN) formation only in the presence of the metabolic fraction S9. When this is the case, the European Food Safety Authority recommends a follow up to in vivo testing. Thus, rats were orally exposed to 7.5 + 75, 23.7 + 237, and 75 + 750 μg CYN/MC-LR/kg body weight (b.w.). The MN test in bone marrow was performed, and the standard and modified comet assays were carried out to measure DNA strand breaks or oxidative DNA damage in stomach, liver, and blood cells. The results revealed an increase in MN formation in bone marrow, at all the assayed doses. However, no DNA strand breaks nor oxidative DNA damage were induced, as shown in the comet assays. The histopathological study indicated alterations only in the highest dose group. Liver was the target organ showing fatty degeneration and necrotic hepatocytes in centrilobular areas, as well as a light mononuclear inflammatory periportal infiltrate. Additionally, the stomach had flaking epithelium and mild necrosis of epithelial cells. Therefore, the combined exposure to cyanotoxins may induce genotoxic and histopathological damage in vivo.

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A comparison of transgenic rodent mutation and in vivo comet assay responses for 91 chemicals

Cited by 37 publications

References 24 publications

Mode of action-based risk assessment of genotoxic carcinogens

Mode of action-based risk assessment of genotoxic carcinogens

EURL ECVAM Genotoxicity and Carcinogenicity Database of Substances Eliciting Negative Results in the Ames Test: Construction of the Database

Cylindrospermopsin-Microcystin-LR Combinations May Induce Genotoxic and Histopathological Damage in Rats

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