Carcinogenic potency is a key factor in the understanding of chemical risk assessment. Measures of carcinogenic potency, for example TD50, are instrumental in the determination of metrics such as the threshold of toxicological concern (TTC), acceptable intake (AI) and permitted daily exposure (PDE), which in turn impact on human exposure. The Carcinogenic Potency Data Base (CPDB) has provided a source of study information, complete with calculated TD50 values. However, this is no longer actively updated. An understanding of carcinogenic potency, which can be derived from dose–response data, can be used as part of human risk assessments to generate safety thresholds under which cancer risk is judged to be minimal. The aim of this paper is to produce a transparent methodology for calculating TD50 values from experimental data in a manner consistent with the CPDB. This was then applied across the same data as used in the CPDB and analysis done on the correlation with the CPDB TD50 values. While the two sets of values showed a high level of correlation overall, there were some significant discrepancies. These were predominantly due to a lack of clarity in the CPDB methodology and inappropriate use of a linear model in TD50 calculation where the data was not suitable for such an approach.
The use of in silico predictions for the assessment of bacterial mutagenicity under the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 guideline is recommended when two complementary (quantitative) structure-activity relationship (Q)SAR models are used. Using two systems may increase the sensitivity and accuracy of predictions but also increases the need to review predictions, particularly in situations where results disagree. During the 4th ICH M7/QSAR Workshop held during the Joint Meeting of the 6th Asian Congress on Environmental Mutagens (ACEM) and the 48th Annual Meeting of the Japanese Environmental Mutagen Society (JEMS) 2019, speakers demonstrated their approaches to expert review using 20 compounds provided ahead of the workshop that were expected to yield ambiguous (Q)SAR results. Dr. Chris Barber presented a selection of the reviews carried out using Derek Nexus and Sarah Nexus provided by Lhasa Limited. On review of these compounds, common situations were recognised and are discussed in this paper along with standardised arguments that may be used for such scenarios in future.
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