Mode of Action and the Assessment of Chemical Hazards in the Presence of Limited Data: Use of Structure-Activity Relationships (SAR) under TSCA, Section 5

Abstract

Section 5 of the Toxic Substances Control Act (TSCA) requires that manufacturers and importers of new chemicals must submit a Premanufacture Notification (PMN) to the U.S. Environmental Protection Agency 90 days before they intend to commence manufacture or import. Certain information such as chemical identity, uses, etc., must be included in the notification. The submission of test data on the new substance, however, is not required, although any available health and environmental information must be provided. Nonetheless, over half of all PMNs submitted to the agency do not contain any test data; because PMN chemicals are new, no test data is generally available in the scientific literature. Given this situation, EPA has had to develop techniques for hazard assessment that can be used in the presence of limited test data. EPA's approach has been termed "structure-activity relationships" (SAR) and involves three major components: the first is critical evaluation and interpretation of available toxicity data on the chemical; the second component involves evaluation of test data available on analogous substances and/or potential metabolites; and the third component involves the use of mathematical expressions for biological activity known as "quantitative structure-activity relationships" (QSARs). At present, the use of QSARs is limited to estimating physical chemical properties, environmental toxicity, and bioconcentration factors. An important overarching element in EPA's approach is the experience and judgment of scientific assessors in interpreting and integrating the available data and information. Examples are provided that illustrate EPA's approach to hazard assessment for PMN chemicals.

Background of QSAR and Historical Developments

“…The use of animals in biological and toxicological experimentation of drugs and other industrial chemicals is objectionable because it shows cruelty to the living animals. The use of an animal model also creates ethical obligations while assessing hazardous potential of chemicals and in this regard QSAR analysis is supported and purported as a valid alternative tool by various international organizations, including the European Commission's European Centre for the Validation of Alternative Methods (ECVAM) [24], the Council for International Organizations of Medical Sciences [25], the European Union's Registration, Evaluation and Authorization of Chemicals (REACH) regulations [26], Office of Toxic Substances of the U.S. Environmental Protection Agency (EPA) [27], Agency for Toxic Substances and Disease Registry (ATSDR) [28], and the Organisation for Economic Co-operation and Development (OECD) [29]. In 1959, Russell and Burch [21] introduced the "3R" concept (namely, replacement, reduction, and refinement), with the aim of improving the treatment of animals toward scientific procedures.…”

Overview of data and conceptual approaches for derivation of quantitative structure‐activity relationships for ecotoxicological effects of organic chemicals

“…Evaluating the potential hazard posed by thousands of untested industrial organic chemicals is a challenge confronting national and international regulatory agencies including the U.S. Environmental Protection Agency (U.S. EPA), Canadian Ministry of the Environment, and the European Union [1–3]. Because of time and funding constraints, conducting toxicity tests on the tens of thousands of new and existing chemicals released into the environment is not feasible.…”

“…Because of time and funding constraints, conducting toxicity tests on the tens of thousands of new and existing chemicals released into the environment is not feasible. To maximize efficiency and consistency in evaluating and prioritizing those chemicals that are empirically assessed for adverse effects, quantitative structure‐activity relationships (QSARs) can be employed as scientifically credible tools for predicting acute toxicity, when few or no empirical data are available [1].…”

Modeling mode of action of industrial chemicals: Application using chemicals on Canada's Domestic Substances List (DSL)

“…Evaluating the potential hazard posed by thousands of untested industrial organic chemicals is a challenge confronting national and international regulatory agencies including the U. S. Environmental Protection Agency (EPA) [1], Canadian Ministry of the Environment [2] and the European Union [3]. Due to time and funding constraints, conducting toxicity tests on the tens-of thousands of new and existing chemicals released into the environment is not feasible.…”

“…Due to time and funding constraints, conducting toxicity tests on the tens-of thousands of new and existing chemicals released into the environment is not feasible. To maximize efficiency and consistency in evaluating and prioritizing those chemicals that have not been adequately assessed for adverse effects, quantitative structure activity relationships (QSARs) can be employed as scientifically-credible tools for predicting acute toxicity, when little or no empirical data are available [1,4].…”