Strategy for genotoxicity testing: Hazard identification and risk assessment in relation to in vitro testing

Thybaud, Véronique; Aardema, Marilyn J.; Clements, Julie; Dearfield, Kerry L.; Galloway, Sheila M.; Hayashi, Makoto; Jacobson‐Kram, David; Kirkland, David; MacGregor, James T.; Marzin, Daniel; Ohyama, Wakako; Schuler, Maik; Suzuki, Hiroshi; Zeiger, Errol

doi:10.1016/j.mrgentox.2006.10.003

Cited by 117 publications

(52 citation statements)

References 23 publications

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“…A weight of evidence approach was applied to these data that considers the same factors used by Williams et al (2000) and which are consistent with recommendations for weight of evidence evaluations for genotoxicity data (EFSA, 2011; ICH S2(R1), 2011; UK COM, 2011; U.S. EPA, 1986; U.S. FDA, 2006). Additional considerations include the robustness of the experimental protocols and more recent elaborated considerations relevant to whether genotoxic effects result from direct interaction with DNA or are secondary to other processes such as cytotoxicity (Kirkland et al, 2007;Thybaud et al, 2007).…”

Section: Genotoxicity Weight Of Evidence Conclusionmentioning

confidence: 99%

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Kier

Kirkland²

2013

Critical Reviews in Toxicology

120

102

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An earlier review of the toxicity of glyphosate and the original Roundupä-branded formulation concluded that neither glyphosate nor the formulation poses a risk for the production of heritable/somatic mutations in humans. The present review of subsequent genotoxicity publications and regulatory studies of glyphosate and glyphosate-based formulations (GBFs) incorporates all of the findings into a weight of evidence for genotoxicity. An overwhelming preponderance of negative results in well-conducted bacterial reversion and in vivo mammalian micronucleus and chromosomal aberration assays indicates that glyphosate and typical GBFs are not genotoxic in these core assays. Negative results for in vitro gene mutation and a majority of negative results for chromosomal effect assays in mammalian cells add to the weight of evidence that glyphosate is not typically genotoxic for these endpoints in mammalian systems. Mixed results were observed for micronucleus assays of GBFs in nonmammalian systems. Reports of positive results for DNA damage endpoints indicate that glyphosate and GBFs tend to elicit DNA damage effects at high or toxic dose levels, but the data suggest that this is due to cytotoxicity rather than DNA interaction with GBF activity perhaps associated with the surfactants present in many GBFs. Glyphosate and typical GBFs do not appear to present significant genotoxic risk under normal conditions of human or environmental exposures.

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Section: Genotoxicity Weight Of Evidence Conclusionmentioning

confidence: 99%

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Kier

Kirkland²

2013

Critical Reviews in Toxicology

120

102

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“…The need to assess in vivo dose-response relationships as a follow-up to hazard screening when evaluating the risks associated with human exposure was recognized at the time regulatory genetic toxicology testing was first introduced [Flamm et al, 1977;Thybaud et al, 2007], but the lack of suitable in vivo methods for evaluating mutations and other genetic damage available at the time, coupled with initial enthusiasm about the apparent excellent correlation between bacterial mutagenicity and rodent carcinogenicity [McCann and Ames, 1976], led to the establishment of a qualitative screening battery designed to categorize agents as either non-mutagens or demonstrated mutagens (e.g., see [Dearfield et al, 1991]). In contrast to other toxicology disciplines, decisions about genotoxic risk continue to be based on qualitative factors that classify an agent as ''positive'' or ''negative'' in the above test battery and supplementary tests.…”

Section: Introductionmentioning

confidence: 99%

Quantitative approaches for assessing dose–response relationships in genetic toxicology studies

Gollapudi

Johnson

Hernández

et al. 2012

Environ and Mol Mutagen

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132

130

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Genetic toxicology studies are required for the safety assessment of chemicals. Data from these studies have historically been interpreted in a qualitative, dichotomous ''yes'' or ''no'' manner without analysis of doseresponse relationships. This article is based upon the work of an international multi-sector group that examined how quantitative dose-response relationships for in vitro and in vivo genetic toxicology data might be used to improve human risk assessment. The group examined three quantitative approaches for analyzing dose-response curves and deriving point-of-departure (POD) metrics (i.e., the no-observed-genotoxic-effectlevel (NOGEL), the threshold effect level (Td), and the benchmark dose (BMD)), using data for the induction of micronuclei and gene mutations by methyl methanesulfonate or ethyl methanesulfonate in vitro and in vivo. These results suggest that the POD descriptors obtained using the different approaches are within the same order of magnitude, with more variability observed for the in vivo assays. The different approaches were found to be complementary as each has advantages and limitations. The results further indicate that the lower confidence limit of a benchmark response rate of 10% (BMDL 10 ) could be considered a satisfactory POD when analyzing genotoxicity data using the BMD approach. The models described permit the identification of POD values that could be combined with mode of action analysis to determine whether exposure(s) below a particular level constitutes a significant human risk. Subsequent analyses will expand the number of substances and endpoints investigated, and continue to evaluate the utility of quantitative approaches for analysis of genetic toxicity dose-response data. Environ. Mol. Mutagen. 54:8-18, 2013. V V C 2012 Wiley Periodicals, Inc.

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“…The analysis of a database of 533 carcinogens revealed that the percentage of them yielding positive results was 58.8% in the Ames test, 73.1% in the mouse lymphoma assay, 78.7% in the micronucleus test and 65.6% in the chromosomal aberrations assay. However, it should be considered that recent data [34,35] have shown that in vitro assays commonly employed in regulatory screening strategies are often positive for chemicals considered not to present a significant genotoxic or carcinogenic risk in vivo, the rate of positive responses for non-carcinogens becoming exceptionally high when test batteries are employed. According to Tweats et al [36], there is a growing body of evidence that compound-related disturbances in the physiology of rodents can result in increases in micro-nucleated cells in bone marrow that are not related to the intrinsic genotoxicity of the compound under test.…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Brambilla

Mattioli

Robbiano

et al. 2013

Basic Clin Pharma Tox

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This survey is a compendium of genotoxicity and carcinogenicity information of bronchodilators and antiasthma drugs. Data from 46 marketed drugs were collected. Of these 46 drugs, 25 (54.3%) did not have retrievable genotoxicity or carcinogenicity data. The remaining 21 (45.7%) had at least one genotoxicity or carcinogenicity test result. Of these 21 drugs, 10 had at least one positive finding: three tested positive in at least one genotoxicity assay, eight in at least one carcinogenicity assay, and one of them gave positive results in both genotoxicity assay and carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the result(s) of long-term carcinogenesis assays, 15 drugs had both genotoxicity and carcinogenicity data: seven of them (46.6%) were neither genotoxic nor carcinogenic, 6 (40.0%) were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, 1 (6.7%) tested positive in genotoxicity assay but was non-carcinogenic, and 1 (6.7%) gave positive responses in both genotoxicity and carcinogenicity assay. Only 11 (23.9%) of the 46 drugs considered had all data required by current guidelines for testing of pharmaceuticals, but a large fraction of them were developed and marketed prior to the present regulatory climate.Bronchodilators and antiasthma drugs are continuously or frequently used in the treatment for chronic airways diseases. Among the various adverse reactions of concern that these pharmaceuticals might cause, genotoxic and carcinogenic effects cannot be excluded. Therefore, we deemed useful to verify to what extent the drugs of this family have been tested for their potential genotoxic and carcinogenic risk to human beings.The regulatory authorities of USA, Europe and Japan recommend th at genotoxicity and carcinogenicity assays are performed before application for marketing approval of pharmaceuticals. Present guidelines for genotoxicity testing of pharmaceuticals [1-3] indicate a standard test battery that consists of (i) a test for gene mutation in bacteria; (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mammalian cells gene mutation assay and (iii) an in vivo test for chromosomal damage performed with rodent hematopoietic cells. Guidelines for carcinogenicity testing of pharmaceuticals [4,5] indicate that long-term carcinogenicity studies in rodents should be performed for all pharmaceuticals whose expected clinical use is continuous for at least 6 months as well as for pharmaceuticals used frequently in an intermittent manner in the treatment for chronic recurrent conditions. In long-term carcinogenicity assays, the highest dose should be at least 25 times higher, on a mg/m 2 basis, than the maximum recommended human daily dose or represent a 25-fold ratio of rodent to human AUC. In the chapter bronchodilators and antiasthma drugs of the 2007 edition of Martindale: The Complete Drug Reference [6] are included 46 drugs still on the market, the majority of wh...

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Strategy for genotoxicity testing: Hazard identification and risk assessment in relation to in vitro testing

Cited by 117 publications

References 23 publications

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Quantitative approaches for assessing dose–response relationships in genetic toxicology studies

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

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