Bacterial mutagenicity screening in the pharmaceutical industry

Escobar, Patricia; Kemper, Raymond A.; Tarca, James P.; Nicolette, John; Kenyon, Michelle; Glowienke, Susanne; Sawant, Satin G.; Christensen, Joseph; Johnson, Timothy E.; McKnight, Crystal; Ward, Graham W.; Galloway, Sheila M.; Custer, Laura; Gocke, Elmar; O’Donovan, Mike; Braun, K.; Snyder, Ronald D.; Mahadevan, B

doi:10.1016/j.mrrev.2012.12.002

Cited by 58 publications

(35 citation statements)

References 67 publications

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“…In particular: The relative sensitivity of the two versions of the pre‐incubation method was only evaluated with a limited number of direct mutagens and no comparison was made using mutagens which require S9 for activation. Very limited evaluation of the reproducibility of the method at low doses of mutagens has been performed. The robustness of the method has not been evaluated, e.g., in terms of inter‐laboratory reproducibility of results. Although similar systems are in wide use in many laboratories throughout the world, including most large contract research toxicology testing laboratories, very little has been published on their performance or utility with one or two notable exceptions [Escobar et al, , Pant et al, ]. …”

Section: Discussionmentioning

confidence: 99%

“…The robustness of the method has not been evaluated, e.g., in terms of inter-laboratory reproducibility of results. Although similar systems are in wide use in many laboratories throughout the world, including most large contract research toxicology testing laboratories, very little has been published on their performance or utility with one or two notable exceptions [Escobar et al, 2013, Pant et al, 2016.…”

Section: Use In Routine Research Especially When Test Articlementioning

confidence: 99%

“…The 6‐well “Miniscreen” involves an 80% reduction in volume and consequently utilizes 80% less test compound compared with the standard method [Diehl et al, , Flamand et al, ]. The 24‐well test described in this paper is a minor adaptation of a 25‐well version originally described by Brooks [] and Burke et al [] and is referred to as the micro‐Ames or µAmes test here and elsewhere [Escobar et al, ] and uses 95% less material than the conventional Ames test. A slight modification of the 24‐well system involves bioluminescent derivatives of test strains TA98 and TA100 [Côté et al, , Aubrecht et al, , Ackerman et al, ] which facilitates enumeration of revertant colonies.…”

Section: Introductionmentioning

confidence: 99%

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The micro‐Ames test: A direct comparison of the performance and sensitivities of the standard and 24‐well plate versions of the bacterial mutation test

Proudlock¹,

Evans²

2016

Environ and Mol Mutagen

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"Ames" bacterial mutation tests are widely performed for evaluation and registration of new materials including industrial chemicals, agrochemicals, medical devices, pharmaceuticals, pharmaceutical impurities and other materials. Tests are used to predict their potential long-term adverse health effects (including carcinogenicity). Given their importance, pre-screening 'miniaturized' versions have been developed which allow higher throughput and use less test material, including the widely-employed 24-well micro-Ames (µAmes) test which uses 20 times less material. However, little quantitative information has been published on the methodology or sensitivity of this system. We describe methods and results used in direct comparisons of the sensitivity of micro and standard systems using the same cultures, formulations, etc. Initial testing utilized the plate incorporation method and, later, the pre-incubation method. In a subsequent phase of testing, a four-way direct comparison was made between the pre-incubation and plate incorporation methods in both systems using some direct-acting mutagens. Tests used only those strain/S9/chemical combinations where a response was expected. Historical control results accumulated during testing are also presented. Spontaneous and induced revertant colony counts for the µAmes system were consistently proportionate and approximately 1/20th those for the standard Ames test. Sensitivities of the two systems were found to be nearly identical in almost all cases for a wide variety of weak and strong inorganic and organic mutagens. Standardized procedures and increased reliability of the estimate of the background revertant frequency in the µAmes system means that the two systems give equivalent results and are expected to be highly predictive of one another. Environ. Mol. Mutagen. 57:687-705, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Use In Routine Research Especially When Test Articlementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The micro‐Ames test: A direct comparison of the performance and sensitivities of the standard and 24‐well plate versions of the bacterial mutation test

Proudlock¹,

Evans²

2016

Environ and Mol Mutagen

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“…The authors, representing a total of 14 pharmaceutical companies, compared the predictive value of the different methodologies analyzed in two surveys conveyed in the US and European The evaluation was carried out using a large validation set of Ames mutagenicity data comprising over 10,000 compounds, 30 % of which are Roche proprietary data ( Table 3 ). The Roche datasets include the vast majority of compounds (not only impurities) tested in the Ames Standard [ 54 ] and Microsuspension [ 55 ] protocols.…”

Section: Key Aspects Of the Ich M7 Guidelinementioning

confidence: 99%

The Use of In Silico Models Within a Large Pharmaceutical Company

Brigo¹,

Muster²

2016

Methods in Molecular Biology

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The present contribution describes how in silico models are applied at different stages of the drug discovery process in the pharmaceutical industry. A thorough description of the most relevant computational methods and tools is given along with an in-depth evaluation of their performance in the context of potential genotoxic impurities assessment.The challenges of predicting the outcome of highly complex studies are discussed followed by considerations on how novel ways to manage, store, share and analyze data may advance knowledge and facilitate modeling efforts.

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“…This test is designed to detect a point mutationinducing activity of investigated compounds, evidenced by the alternation of growth requirements of tester organisms. 12 Unfortunately, the analysis of the possible in vivo NOC production from nitrosable drugs and the assessment of their mutagenicity still remains outside the regulatory recommendations for standard carcinogenicity tests prior to drug registration. 4 Another important aspect that needs consideration with respect to carcinogenic risk associated with the use of N-nitrosable drugs is their constant chemical degradation that leads to the formation of degradation impurities present in final dosage forms.…”

Section: Introductionmentioning

confidence: 99%