The biological effects of a chemical compound can often be predicted by its molecular structure based on the assumption that similar compounds have similar physical and biological properties. This principle, referred to as Structure Activity Relationships (SAR), is a powerful tool for predicting biological effects of a compound without the cost and time associated with testing by traditional whole-animal laboratory toxicology studies and/or in vitro/in vivo assays. The tools, correlations, and models used to evaluate specific chemical structures and their biological effects are being refined continuously, and are applied both to discover and develop new compounds, as well as in the assessment of health risks posed by existing compounds.
SARs depend on the recognition of structural characteristics that define chemical and biological reactivity, so the ability to draw conclusions about an unknown compound depends on both the database against which the unknown is compared, and professional judgment of the implications when similarities are found. In the case of risk assessment of uncharacterized compounds, this judgment relies on an understanding of the most sensitive toxicological endpoints, such as carcinogenicity and mutagenicity, development and reproductive effects, and skin irritation and sensitization. Exponent has professional toxicologists and chemical engineers trained to use the DEREK (Deductive Estimation of Risk from Existing Knowledge) SAR software (offered by Lhasa Limited , a non-profit organization that facilitates collaborative projects in the pharmaceutical and chemistry-related industries). Unique among SAR and QSAR modeling software, DEREK was originally developed by Schering and includes not only data from the published literature, but also extensive proprietary and confidential data generated by industry sources. A compound can be screened quickly by DEREK, and the results can be interpreted by Exponent staff to help clients make decisions pertaining to hazards related to molecular structure, suggest follow-up testing, and prioritize candidate compounds. We are also experienced in the application of relevant EPA models, such as EPISuites 3.2, to evaluate physicochemical properties and relevance to environmental fate; OncoLogic; and ECOSAR, for aquatic toxicology.
SARs and EPA predictive tools can also be applied to organize groups of compounds and to provide cost-effective data development plans. Because structurally similar compounds are likely to have similar physical and toxicological profiles, this methodology, referred to as cluster analysis, can be applied to both small and large sets of compounds. The overall objective of cluster analysis is to generate sufficient and targeted information to identify and address the data gaps within a group of compounds that share similar substructures. This strategy has been applied successfully to clusters in the EPA’s High Production Volume chemical program and will also be important in safety assessments for the Registration, Evaluation and Authorization of Chemicals (REACH) regulatory initiative (EU). Regulators, industry, and NGOs have embraced cluster analysis as a means to minimize the number of tests and to conserve resources—the costs of conducting studies, the use of laboratory animals, and the time needed to conduct toxicological studies.
Cluster analysis provides a basis to determine whether some or all of the existing data in the cluster can be bridged to others within the cluster. Exponent has extensive experience in organizing data sets and documentating that a set of structurally similar compounds can be grouped based on common biological properties, like metabolic profile and common metabolite(s), environmental fate, and physicochemical properties, such as water solubility, log Kow, and vapor pressure. Our cluster analysis services also include the following:
- Compilation and integration of the existing toxicological and environmental data, with consideration of possible exposure pathways for all of the clustered compounds
- Reading across all the available and modeled data, to provide guidance on the completeness of an existing data set and identify data gaps
- Selection of cluster compounds that potentially represent the best- and worst-case scenarios, including biological effects and the range of physicochemical properties
- Application of expert judgment in integrating all the available toxicology, environmental, metabolism, and physicochemical properties to determine whether the existing data are:
- Either sufficient to fully read across—that is, can be bridged—to proceed to an evaluation of human health and/or environmental risk assessment for the group of compounds that compose the cluster, or
- Alternatively, that there are sufficient data gaps to warrant targeted testing of one or more additional structural/physiochemically related compound(s), to complete the read across for the cluster
The United States and the European Union are currently promoting use of SARs and cluster analysis for screening large numbers of chemicals that have already entered commerce (for example, the High Production Volume and REACH programs), as well as for development and registration of novel compounds. In terms of interpreting SAR results, Exponent offers expertise in:
- Organization of large and small databases of compounds. Identification of hazard concerns and data gaps for individual compounds or groups of compounds
- Design and management of toxicological, ecotoxicological, and physiochemical properties studies to address potential hazards and to fill data gaps
- Conduct safety assessment of developmental candidates, within the context of the relevant regulatory paradigm, to avoid costly and time-consuming delays
- Registration of chemicals with regulatory authorities, including creating strategies that address registration of individual compounds and groups of similar compounds (cluster analysis)
Exponent’s scientists are widely recognized as specialists in applying scientifically defensible knowledge and judgment. Our staff comprises more than 90 technical disciplines that include scientists with significant experience and accomplishments in the application of a wide array of SAR, biological, environmental, and physicochemical properties modeling, as well as mammalian toxicology, chemistry, and environmental risk analysis. We have provided technical SAR and cluster analysis guidance and project management for individual clients and consortia in the evaluation of HPV chemicals, tolerance reassessment of pesticide inert formulation ingredients, and for making early decisions during development of proprietary compounds.