In silico toxicology is an important alternative approach to animal testing that provides a fast and inexpensive prediction of toxicity. It uses computer models to predict whether a chemical is safe or if there is a potential hazard. In silico methods are particularly valuable when a decision needs to be made quickly, such as for an emergency response to a chemical spill or when there is little or no test material available such as for an assessment of metabolites. Unfortunately, there are a number of obstacles to performing such analyses. Although running the models is fast, the whole process of making predictions, including selecting and acquiring the models, interpreting the results, performing an expert review, and documenting the results, can be time-consuming. It is also difficult to defend the results, primarily due to a lack of published procedures for performing an in silico assessment. To support the development of such protocols, a 44-member international cross-industry consortium has been assembled. This consortium is led by Leadscope and includes representatives from international regulatory agencies and government research laboratories in the United States, Canada, Japan and Europe, as well as large companies from various industrial sectors e.g., pharmaceutical, food, cosmetics, agrochemicals , academic groups and other stakeholders. This consortium will publish in silico protocols for seven major toxicological endpoints: 1 skin/respiratory/oral sensitization, 2 repeated dose toxicity, 3 carcinogenicity, 4 reproductive and developmental toxicity, 5 endocrine activity and disruptors, 6 liver toxicity and 7 persistence, bioaccumulation and environmental toxicity. The protocols will ensure any in silico assessments are performed in a consistent, repeatable, well-documented and defendable manner. This proposal also outlines the development of a first to market software platform Leadscope Rapid Response that will make toxicity assessments based upon these generally accepted and published protocols. For each major endpoint, a five step methodology for incorporating assessments into the rapid response platform is outlined. This process starts with the development and publication of the protocol. An exercise to understand the structure-activity relationships SAR across public and proprietary databases will be initiated, without revealing any confidential information. A specialized database containing the necessary information on specific studies, as defined in the protocols, will be created. This database and SAR knowledge are then used to build and enhance different computational methodologies and these models and decision frameworks, as outlined in the published protocols, will be integrated into the platform. The platform will be commercialized and made available broadly at a low annual cost, with separate subscription licensing of the models, databases and other tools for integration of proprietary data and knowledge. There will also be a pay-as-you-go pricing option to ensure access for smaller organizations. The successful deployment of this technology provides a significant commercial opportunity for Leadscope Inc. and will support increased productivity for those companies involved in chemical research and development e.g. pharmaceutical companies, agrochemical companies, cosmetics, industrial chemicals and a significant reduction in animal tests.
This project is focused on the computational assessment of the safety of chemicals with the aim of reducing the burden of environmentally associated disease and dysfunction, and to promote the public?s right to a healthy, quality environment.
| Norinder, Ulf; Myatt, Glenn; Ahlberg, Ernst (2018) Predicting Aromatic Amine Mutagenicity with Confidence: A Case Study Using Conformal Prediction. Biomolecules 8: |
| Amberg, Alexander; Anger, Lennart T; Bercu, Joel et al. (2018) Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: is aromatic N-oxide a structural alert for predicting DNA-reactive mutagenicity? Mutagenesis : |
