<i>In vivo pig‐a</i> and micronucleus study of the prototypical aneugen vinblastine sulfate

Avlasevich, Svetlana L.; Labash, Carson; Torous, Dorothea K.; Bemis, Jeffrey C.; MacGregor, James T.; Dertinger, Stephen D.

doi:10.1002/em.22122

Cited by 6 publications

(2 citation statements)

References 49 publications

(64 reference statements)

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“…Since then, further studies have been performed on specific aspects of these methods addressing the issues identified at the 6th IWGTP (e.g. Itoh et al, 2015;Shimada et al, 2015;Shigano et al, 2016;Avlasevich et al, 2018;Hori et al, 2019;Itoh and Hattori, 2019).…”

Section: A3 Micronucleus Assay Techniques In Tissues Other Than Bone ...mentioning

confidence: 99%

Guidance on aneugenicity assessment

More¹,

Bampidis²,

Bragard³

et al. 2021

EFS2

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The EFSA Scientific Committee was asked to provide guidance on the most appropriate in vivo tests to follow up on positive in vitro results for aneugenicity, and on the approach to risk assessment for substances that are aneugenic but not clastogenic nor causing gene mutations. The Scientific Committee confirmed that the preferred approach is to perform an in vivo mammalian erythrocyte micronucleus test with a relevant route of administration. If this is positive, it demonstrates that the substance is aneugenic in vivo . A negative result with evidence that the bone marrow is exposed to the test substance supports a conclusion that aneugenic activity is not expressed in vivo . If there is no evidence of exposure to the bone marrow, a negative result is viewed as inconclusive and further studies are required. The liver micronucleus assay, even though not yet fully validated, can provide supporting information for substances that are aneugenic following metabolic activation. The gastrointestinal micronucleus test, conversely, to be further developed, may help to assess aneugenic potential at the initial site of contact for substances that are aneugenic in vitro without metabolic activation. Based on the evidence in relation to mechanisms of aneugenicity, the Scientific Committee concluded that, in principle, health‐based guidance values can be established for substances that are aneugenic but not clastogenic nor causing gene mutations, provided that a comprehensive toxicological database is available. For situations in which the toxicological database is not sufficient to establish health‐based guidance values, some approaches to risk assessment are proposed. The Scientific Committee recommends further development of the gastrointestinal micronucleus test, and research to improve the understanding of aneugenicity to support risk assessment.

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Section: A3 Micronucleus Assay Techniques In Tissues Other Than Bone ...mentioning

confidence: 99%

Guidance on aneugenicity assessment

More¹,

Bampidis²,

Bragard³

et al. 2021

EFS2

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“…For the Pig‐a assay, statistical analyses were performed on the mutant cell frequencies CD59‐negative RBC and CD59‐negative RET per 10 6 and RET percent (%RET) as described in Avlasevich et al (Avlasevich et al ., 2018). Accordingly, CD59‐negative RBC and CD59‐negative RET per 10 6 frequencies were log(10) transformed with a 0.1 offset added to each frequency prior to log transformation.…”

Section: Methodsmentioning

confidence: 99%

Testing of acetaminophen in support of the international multilaboratory in vivo rat Pig‐a assay validation trial

Leede

Weiner

Doninck

et al. 2020

Environ and Mol Mutagen

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Acetaminophen, a nonmutagenic compound as previously concluded from bacteria, in vitro mammalian cell, and in vivo transgenic rat assays, presented a good profile as a nonmutagenic reference compound for use in the international multilaboratory Pig‐a assay validation. Acetaminophen was administered at 250, 500, 1,000, and 2,000 mg·kg−1·day−1 to male Sprague Dawley rats once daily in 3 studies (3 days, 2 weeks, and 1 month with a 1‐month recovery group). The 3‐Day and 1‐Month Studies included assessments of the micronucleus endpoint in peripheral blood erythrocytes and the comet endpoint in liver cells and peripheral blood cells in addition to the Pig‐a assay; appropriate positive controls were included for each assay. Within these studies, potential toxicity of acetaminophen was evaluated and confirmed by inclusion of liver damage biomarkers and histopathology. Blood was sampled pre‐treatment and at multiple time points up to Day 57. Pig‐a mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as CD59‐negative RBC and CD59‐negative RET frequencies, respectively. No increases in DNA damage as indicated through Pig‐a, micronucleus, or comet endpoints were seen in treated rats. All positive controls responded as appropriate. Data from this series of studies demonstrate that acetaminophen is not mutagenic in the rat Pig‐a model. These data are consistent with multiple studies in other nonclinical models, which have shown that acetaminophen is not mutagenic. At 1,000 mg·kg−1·day−1, Cmax values of acetaminophen on Day 28 were 153,600 ng/ml and 131,500 ng/ml after single and repeat dosing, respectively, which were multiples over that of clinical therapeutic exposures (2.6–6.1 fold for single doses of 4,000 mg and 1,000 mg, respectively, and 11.5 fold for multiple dose of 4,000 mg) (FDA 2002). Data generated were of high quality and valid for contribution to the international multilaboratory validation of the in vivo Rat Pig‐a Mutation Assay.

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