In silico approaches to predicting cancer potency for risk assessment of genotoxic impurities in drug substances

Bercu, Joel P.; Morton, Stuart; Deahl, J. Thom; Gombar, Vijay K.; Callis, Courtney M.; Lier, R. B. L. Van

doi:10.1016/j.yrtph.2010.03.010

Cited by 33 publications

(8 citation statements)

References 35 publications

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“…is the alkyl halides chemical class, which often occurs in data sets with industrial chemicals but to a lesser extent in drug‐like molecules (Naven et al ., ). The QSAR models that are built using in‐house proprietary data might be advantageous at least for the user, as these are customized models based upon the chemical structures frequently seen during development, and algorithms and software specialized for their own organizational use (Boyer, ; Bercu et al ., ; Naven et al ., ). The disadvantage of such systems is that, because of their proprietary nature, there is little interpretability or verification available for regulatory authorities upon submission of computational toxicology data to support the safety of a substance under review.…”

Section: In Silico (Q)sarmentioning

confidence: 98%

Chemoinformatics and chemical genomics: potential utility of in silico methods

Valerio

Choudhuri

2012

J of Applied Toxicology

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Computational life sciences and informatics are inseparably intertwined and they lie at the heart of modern biology, predictive quantitative modeling and high-performance computing. Two of the applied biological disciplines that are poised to benefit from such progress are pharmacology and toxicology. This review will describe in silico chemoinformatics methods such as (quantitative) structure-activity relationship modeling and will overview how chemoinformatic technologies are considered in applied regulatory research. Given the post-genomics era and large-scale repositories of omics data that are available, this review will also address potential applications of in silico techniques in chemical genomics. Chemical genomics utilizes small molecules to explore the complex biological phenomena that may not be not amenable to straightforward genetic approach. The reader will gain the understanding that chemoinformatics stands at the interface of chemistry and biology with enabling systems for mapping, statistical modeling, pattern recognition, imaging and database tools. The great potential of these technologies to help address complex issues in the toxicological sciences is appreciated with the applied goal of the protection of public health.

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Section: In Silico (Q)sarmentioning

confidence: 98%

Chemoinformatics and chemical genomics: potential utility of in silico methods

Valerio

Choudhuri

2012

J of Applied Toxicology

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“…Furthermore, regulatory criteria have been defined for the use of in silico predictions in drug safety for the genotoxicity evaluation of drug impurities where the presence or absence of specific structural alerts triggers the subsequent management of potential risk posed by the presence of this impurity [39,40]. In this context, new models have been recently proposed to estimate genotoxic or carcinogenic potency in order to estimate safety [40,41] Very good results have been obtained in the evaluation of genotoxic impurities in the industrial sector when in silico data were coupled with expert evaluation [40] achieving a negative predictive value of 99%.…”

Section: Regulatory Context For In Silico Modelsmentioning

confidence: 99%

Molecular descriptors as proxies for the modeling of the materials and their environmental impact

Juranic¹

2016

Zas Mat

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“…(1) can be transformed as follows: (2) is a converted value from the genotoxicity of tap water to 4NQO. The VSD 4NQO was estimated as 0.86 ng/kg/d based on previous reports (Ando, 1981;Urano et al, 1995) and according to assumption i) (Bercu et al, 2010). The GA values, corresponding to the 10 -5 level of carcinogenic risk, could then be roughly estimated using Eq.…”

Section: Significance Level Of Ga Valuesmentioning

confidence: 99%

Quantitative Evaluation of the Genotoxic Activity of Japanese Tap Water Using the Umu Test

Kubo

Wang

Kameya

et al. 2015

J. of Wat. & Envir. Tech.

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The genotoxicity of Japanese tap water was investigated using the umu test in order to clarify the relative and absolute genotoxic levels. Samples were collected at 25 sites in Japan and the umu test was carried out with concentrated solutions. The values of genotoxic activity (GA) varied significantly from less than 72 to 670 ng 4NQO/L depending on the site location and/or sampling period. Typical GA value among the tested tap water samples was around 200 ng 4NQO/L. According to a roughly estimated safety level, it was shown that the genotoxicity level of the tested tap water was not negligible. A comparison of the results of the present study with those of a previous investigation using Ames mutagenicity test indicates that the genotoxic level of Japanese tap water did not decrease significantly between the two investigations. In addition, it was shown that there was a weak positive correlation between the genotoxicity of the tap water and the value of the total organic carbon content.

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In silico approaches to predicting cancer potency for risk assessment of genotoxic impurities in drug substances

Cited by 33 publications

References 35 publications

Chemoinformatics and chemical genomics: potential utility of in silico methods

Chemoinformatics and chemical genomics: potential utility of in silico methods

Molecular descriptors as proxies for the modeling of the materials and their environmental impact

Quantitative Evaluation of the Genotoxic Activity of Japanese Tap Water Using the Umu Test

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