SBIR-STTR Award

In many situations, it is critical to rapidly estimate the safety of new or existing chemicals. For example, in the event of a sudden unexpected exposure of a chemical, such as with a chemical spill or a terrorist attack, an emergency response is needed to determine if and how to mitigate any potential risk from the chemicals' toxicity and to monitor this risk over time. To support chemical research and development, toxicity estimates are needed to ensure compounds are prioritized to minimize safety concerns. In these cases, it is not possible to generate traditional in vivo or even in vitro safety studies ue to the time needed to perform the experiments and interpret the data, as well as the cost associated with performing these tests. The only viable approach for generating this safety assessment is to use computational approaches that retrieve any existing historical data and, in the absence of data, calculate a prediction. These computational or in silico tools are becoming increasingly relied upon in product design and for product prioritization, yet they are not routinely used in regulatory decisions or emergency response situations. This situation is now changing through the introduction of a regulatory guideline that permits the use of in silico tools for prediction of bacterial mutagenicity of pharmaceutical impurities (the ICH M7 guidance). The development of an appropriate guideline along with supporting standard operating procedures (SOPs) has been instrumental in the adoption of in silico tools in this area. In this phase I proposal, two SOPs will be generated to support the evaluation of genetic toxicity and acute toxicity. They will outline how to 1) use and interpret available data, 2) generate predictions based on (Q)SAR methodologies and read-across approaches, how to appropriately interpret prediction results, 3) assess a confidence level for the results and 4) define the contents of an accompanying expert opinion. These SOPs will be created and then published in peer-reviewed publications by a working group of interested parties. Using the principles and procedures outlined in these SOPs, a single software application will be developed to rapidly identify data, generate toxicity predictions, assess prediction confidence and make recommendations on exposure thresholds. New in silico methods will be developed including (Q)SAR models to predict GHS (Globally Harmonized System of Classification and Labelling of Chemicals) classifications for acute toxicity as well methods for prediction of mutagenicity and clastogenicity. In phase II, several new SOPs will be generated to cover the use and interpretation of in silico approaches for all common toxic effects necessary for a complete safety assessment. Existing and newly developed models will be incorporated into to platform. This tool will be commercialized and licensed as an application to support the rapid response to safety questions, including emergency response situations and product design.

Public Health Relevance Statement:


Public Health Relevance:
This project is focused on the computational hazard identification of chemicals with the aim to improve environmental public health and prevent disease, by addressing the backlog of thousands of untested chemicals.

NIH Spending Category:
Bioengineering; Endocrine Disruptors

Project Terms:
acute toxicity; Address; Adoption; Animal Experiments; Area; authority; base; Breathing; carcinogenicity; Categories; chemical spill; Chemicals; Classification; Computer Simulation; Computer software; Consultations; cost; Data; data mining; Databases; Dermal; design; Development; developmental toxicity; Disease; Dose; Emergency response; Endocrine disruption; Ensure; Evaluation; Event; Expert Opinion; Eye; Generations; Genetic; genetic approach; Guidelines; hazard; Hazard Identification; improved; In Vitro; in vivo; interest; irritation; Journals; Label; Laboratories; Lethal Dose 50; Licensing; Literature; Methodology; Methods; Modeling; Monitor; new technology; novel; Oral; Peer Review; Pharmacologic Substance; Phase; prevent; Procedures; Productivity; Protocols documentation; Public Health; public health relevance; Publications; Publishing; Reading; Recommendation; reproductive toxicity; research and development; research study; response; Risk; Safety; safety study; screening; Skin; Structure; System; Testing; Time; tool; Toxic effect; Toxicology; working group

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.

Public Health Relevance Statement:
Narrative 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.

Project Terms:
Agrochemicals; Animal Testing; Area; base; bioaccumulation; Canada; carcinogenicity; Categories; chemical spill; Chemicals; Classification; computational toxicology; Computer Simulation; Computer software; Computing Methodologies; Confidential Information; Cosmetics; cost; Data; Databases; design; Development; developmental toxicity; Disease; Dose; Emergency response; Endocrine; Endocrine disruption; Ensure; Environment; Europe; Exercise; Fingerprint; Food; Functional disorder; Government; Grant; Harvest; hazard; Hazard Assessment; Hazard Identification; Health; Hepatotoxicity; Human; improved; Industrialization; Industry; International; Japan; Knowledge; Label; Laboratory Research; Licensing; Materials Testing; member; Methodology; Methods; model development; Modeling; Oral; Pharmacologic Substance; Phase; Price; Procedures; Process; Productivity; Protocols documentation; Publications; Publishing; reproductive; reproductive toxicity; research and development; Research Design; respiratory; response; Running; Safety; Series; Skin; Specific qualifier value; Structure; Structure-Activity Relationship; System; Technology; Test Result; Time; tool; Toxic effect; Toxicology; United States