A feasibility study: Can information collected to classify for mutagenicity be informative in predicting carcinogenicity?

Petkov, P.; Patlewicz, Grace; Schultz, T.W.; Honma, Masamitsu; Todorov, Milen; Котов, С. В.; Dimitrov, S.; Donner, Erica; Mekenyan, Ovanes G.

doi:10.1016/j.yrtph.2015.03.003

Cited by 16 publications

(15 citation statements)

References 29 publications

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“…In fact, the Panel's WoE assessment provides strong support for a lack of genotoxicity, particularly in the relevant mechanism categories (mutation, chromosomal effects) associated with carcinogen prediction. As additional support for the Panel's WoE conclusion, Table 10 provides a comparison between a set of characteristics associated with confirmed genotoxic carcinogens (Bolt et al 2004;Petkov et al 2015) and the genotoxic activity profiles for glyphosate, AMPA, and GBFs. There is virtually no concordance between the two sets of characteristics.…”

Section: Genetic Toxicity and Oxidative Stress Datamentioning

confidence: 99%

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment

Williams

Aardema²,

Acquavella

et al. 2016

Critical Reviews in Toxicology

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The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is "probably carcinogenic to humans" (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC's assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies. Two of the Panels (animal bioassay and genetic toxicology) also provided a critique of the IARC position with respect to conclusions made in these areas. The incidences of neoplasms in the animal bioassays were found not to be associated with glyphosate exposure on the basis that they lacked statistical strength, were inconsistent across studies, lacked dose-response relationships, were not associated with preneoplasia, and/or were not plausible from a mechanistic perspective. The overall weight of evidence from the genetic toxicology data supports a conclusion that glyphosate (including GBFs and AMPA) does not pose a genotoxic hazard and therefore, should not be considered support for the classification of glyphosate as a genotoxic carcinogen. The assessment of the epidemiological data found that the data do not support a causal relationship between glyphosate exposure and nonHodgkin's lymphoma while the data were judged to be too sparse to assess a potential relationship between glyphosate exposure and multiple myeloma. As a result, following the review of the totality of the evidence, the Panels concluded that the data do not support IARC's conclusion that glyphosate is a "probable human carcinogen" and, consistent with previous regulatory assessments, further concluded that glyphosate is unlikely to pose a carcinogenic risk to humans. ARTICLE HISTORY

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Section: Genetic Toxicity and Oxidative Stress Datamentioning

confidence: 99%

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment

Williams

Aardema²,

Acquavella

et al. 2016

Critical Reviews in Toxicology

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“…Table 1 summarizes the Expert Panel's endpoint weighting assumptions. Weights represent strength, relevance and reliability of evidence and are based on a compilation of information regarding the endpoint's reversibility and susceptibility to false or misleading positive responses with respect to carcinogenicity prediction or relevance to mechanisms involved in initiation of malignancy (Solomon et al 1991;Pierotti et al 2003;Petkov et al 2015).…”

Section: Evidence Weightingmentioning

confidence: 99%

“…To provide greater emphasis to the Expert Panel's WoE conclusion, Table 4 provides a comparison between a set of characteristics found in confirmed genotoxic carcinogens (Bolt et al 2004;Petkov et al 2015) and the genotoxic activity profiles for glyphosate, AMPA, and GBFs. There is virtually no concordance between the two sets of characteristics.…”

Section: Genotoxicity Classification and Moamentioning

confidence: 99%

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Brusick¹,

Aardema²,

Kier

et al. 2016

Critical Reviews in Toxicology

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published a monograph concluding there was strong evidence for genotoxicity of glyphosate and glyphosate formulations and moderate evidence for genotoxicity of the metabolite aminomethylphosphonic acid (AMPA). These conclusions contradicted earlier extensive reviews supporting the lack of genotoxicity of glyphosate and glyphosate formulations. The IARC Monograph concluded there was strong evidence of induction of oxidative stress by glyphosate, glyphosate formulations, and AMPA. The Expert Panel reviewed the genotoxicity and oxidative stress data considered in the IARC Monograph, together with other available data not considered by IARC. The Expert Panel defined and used a weight of evidence (WoE) approach that included ranking of studies and endpoints by the strength of their linkage to events associated with carcinogenic mechanisms. Importantly, the Expert Panel concluded that there was sufficient information available from a very large number of regulatory genotoxicity studies that should have been considered by IARC. The WoE approach, the inclusion of all relevant regulatory studies, and some differences in interpretation of individual studies led to significantly different conclusions by the Expert Panel compared with the IARC Monograph. The Expert Panel concluded that glyphosate, glyphosate formulations, and AMPA do not pose a genotoxic hazard and the data do not support the IARC Monograph genotoxicity evaluation. With respect to carcinogenicity classification and mechanism, the Expert Panel concluded that evidence relating to an oxidative stress mechanism of carcinogenicity was largely unconvincing and that the data profiles were not consistent with the characteristics of genotoxic carcinogens. ARTICLE HISTORY

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“…There are also various reasons why a non‐carcinogen is predicted to be a false positive. The main source of false positive carcinogen predictions is “cytotoxicity.” The degree of cytotoxicity in an in vitro assay is often dependent on the method used for measuring it and the time at which the evaluation is performed (Petkov et al ., ). This is a significant weakness, as the actual cytotoxicity may not be manifested for several hours after the time point at which the assessment is made, and yet the process of cytotoxicity could be well under way.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous work, combinations of measured data from in vitro and in vivo mutagenicity tests (i.e,, mutagenicity category approach) were examined for their performance towards a limited set of chemicals having rodent carcinogenicity data (Petkov et al, 2015). The logical combination of mutagenicity tests resulted principally in decreasing the rate of false positives.…”

Section: Introductionmentioning

confidence: 99%

Integrated approach to testing and assessment for predicting rodent genotoxic carcinogenicity

Petkov

Schultz

Donner

et al. 2016

J of Applied Toxicology

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We investigated the performance of an integrated approach to testing and assessment (IATA), designed to cover different genotoxic mechanisms causing cancer and to replicate measured carcinogenicity data included in a new consolidated database. Genotoxic carcinogenicity was predicted based on positive results from at least two genotoxicity tests: one in vitro and one in vivo (which were associated with mutagenicity categories according to the Globally Harmonized System classification). Substances belonging to double positives mutagenicity categories were assigned to be genotoxic carcinogens. In turn, substances that were positive only in a single mutagenicity test were assigned to be mutagens. Chemicals not classified by the selected genotoxicity endpoints were assigned to be negative genotoxic carcinogens and subsequently evaluated for their capability to elicit non-genotoxic carcinogenicity. However, non-genotoxic carcinogenicity mechanisms were not currently included in the developed IATA. The IATA is docked to the OECD Toolbox and uses measured data for different genotoxicity endpoints when available. Alternatively, the system automatically provides predictions by SAR genotoxicity models using the OASIS Tissue Metabolism Simulator platform. When the developed IATA was tested against the consolidated database, its performance was found to be high, with sensitivity of 74% and specificity of 83%, when measured carcinogenicity data were used along with predictions falling within the models' applicability domains. Performance of the IATA would be slightly changed to a sensitivity of 80% and specificity of 72% when the evaluation by non-genotoxic carcinogenicity mechanisms was taken into account. Copyright © 2016 John Wiley & Sons, Ltd.

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A feasibility study: Can information collected to classify for mutagenicity be informative in predicting carcinogenicity?

Cited by 16 publications

References 29 publications

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Integrated approach to testing and assessment for predicting rodent genotoxic carcinogenicity

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