In a previous blog entry, Dr. Glenn Myatt discussed the impetus for developing a consortium to define best in silico practices around toxicological endpoints, such as, genetic toxicity, skin sensitization, carcinogenicity, neurotoxicity and acute toxicity, to name a few. The aim of these protocols is to reduce the burden on industry and regulators to justify their use, as well as ensure in silico assessments are performed in a consistent and reproducible manner to support good in silico practices. The consortia’s activities support a number of emerging or existing regulatory guidelines such as the ICH M7: DNA reactive (mutagenic) impurities in pharmaceuticals.
Group activities result in either protocols (which define implementable rules and principles), position papers (which describe the current state of science and the extent to which in silico tool use is feasible), case studies, structure-activity relationships, or fit-for-purpose evaluations. To date, the reliability scoring paradigm1, which serves as a useful extension of the Klimisch scoring of experimental data has been cited by the World Health Organization, EHC240: Principles and Methods for the Risk Assessment of Chemicals in Food, subchapter 4.5. Genotoxicity2. Further, elements of the ‘In silico toxicology protocols’1 and ‘Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses’3 have been cited by the European Medicines Agency (EMA)’s reflection paper on the qualification of non-genotoxic impurities4 and the ICH guideline M7 on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk – questions & answers Step 2b5.
Several working groups are in progress, and new working group activities including an expansion of the carcinogenicity position paper6 to develop case studies in support of the development of new approaches and protocols using information from target safety assessments7, in silico approaches and in vitro/in vivo data are being formed. Additional working groups, including the assessment of biomolecule reactivity and drug/drug interaction are on the horizon. If you are interested in any of these topics, or have a comment, question, or problem that you are facing please contact firstname.lastname@example.org or email@example.com.
- Myatt, G.J., Ahlberg, E., Akahori, Y., et al. (2018), In Silico Toxicology Protocols. Regul. Toxicol. Pharmacol. 98, 1-17. doi:10.1016/j.yrtph.2018.04.014. Open access: https://doi.org/10.1016/j.yrtph.2018.04.014
- World Health Organization & Food and Agriculture Organization of the United Nations (2020), Principles and methods for the risk assessment of chemicals in food. Subchapter 4.5 Genotoxicity. Environmental health criteria 240
- Amberg, A., Andaya, R.V., Anger, L.T., et al. (2019) Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses. Regul. Toxicol. Pharmacol. 102, 53–64. 10.1016/j.yrtph.2018.12.007
- European Medicines Agency (2018) Reflection paper on the qualification of non-genotoxic impurities
- European Medicines Agency (2020) ICH guideline M7 on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk – questions & answers Step 2b
- Tice at al., In Silico Approaches In Carcinogenicity Hazard Assessment: Current Status and Future Needs, submitted to Regulatory Toxicology and Pharmacology