The new chemicals process at the Environmental Protection Agency (EPA): structure-activity relationships for hazard identification and risk assessment.

Section 5 of the Toxic Substances Control Act (TSCA) does not require any toxicity testing as a prerequisite for submission of a Premanufacturing Notice (PMN) for a new chemical. In order to compensate for the lack of actual test data, a process involving structure-activity relationships (SAR) for assessing hazard potential was constructed. The hazard assessment is then coupled with an estimation of potential exposure to determine potential risk. This process involves the use of multiple interdisciplinary teams that work within a 90-day time frame to complete approximately 2000 risk assessments per year.

U.S. EPA regulatory perspectives on the use of QSAR for new and existing chemical evaluations.

As testing is not required, ecotoxicity or fate data are available for approximately 5% of the approximately 2,300 new chemicals/year (26,000 + total) submitted to the US-EPA. The EPA's Office of Pollution Prevention and Toxics (OPPT) regulatory program was forced to develop and rely upon QSARs to estimate the ecotoxicity and fate of most of the new chemicals evaluated for hazard and risk assessment. QSAR methods routinely result in ecotoxicity estimations of acute and chronic toxicity to fish, aquatic invertebrates, and algae, and in fate estimations of physical/chemical properties, degradation, and bioconcentration. The EPA's Toxic Substances Control Act (TSCA) Inventory of existing chemicals currently lists over 72,000 chemicals. Most existing chemicals also appear to have little or no ecotoxicity or fate data available and the OPPT new chemical QSAR methods now provide predictions and cross-checks of test data for the regulation of existing chemicals. Examples include the Toxics Release Inventory (TRI), the Design for the Environment (DfE), and the OECD/SIDS/HPV Programs. QSAR screening of the TSCA Inventory has prioritized thousands of existing chemicals for possible regulatory testing of: 1) persistent bioaccumulative chemicals, and 2) the high ecotoxicity of specific discrete organic chemicals.

The application of structure-activity relationships (SARs) in the aquatic toxicity evaluation of discrete organic chemicals.

The Office of Pollution Prevention and Toxics (OPPT), United States Environmental Protection Agency (USEPA) routinely uses structure-activity relationships (SAR) for the aquatic hazard assessment of new chemicals submitted under Section 5 of the Toxic Substances Control Act (TSCA). With 15 years of experience and the general acceptance of toxicity predictions based on SARs, OPPT has expanded the use and application of the methodology to include existing chemicals used in printing, dry cleaning, and paint stripping. SAR analysis has also been used in the hazard evaluation of the U.S. and EU/OECD high production volume (HPV) chemicals. This paper describes the assumptions, limitations, and methodology for the use of SARs to evaluate large sets of discrete organic chemicals.

Environmental hazard and risk assessment under the United States Toxic Substances Control Act.

The Toxic Substances Control Act (TSCA) was enacted in 1976 and provides for the regulation of industrial chemicals. TSCA allows for regulation of a chemical if there is an unreasonable risk towards human health or the environment, and it allows for testing if a chemical may present an unreasonable risk or has significant exposure towards humans or the environment. Risk assessment under TSCA consists of the integration of the hazard assessment for a chemical with the chemical's exposure assessment. The environmental hazard assessment consists of identifying all of the effects of a chemical towards organisms in the environment, and towards the populations, communities, and ecosystems to which those organisms belong. Toxicity data for a chemical consists of effective concentrations (EC) which indicate the type of effect and the seriousness of that effect at a known concentration of chemical. Effective concentrations are either measured or predicted using structure activity relationships (SAR). SAR may consist of nearest analog analysis, member of a toxic chemical class, or quantitative SAR (QSAR). A collection of all of the ECs for a chemical is called a hazard profile or a toxicity profile. The environmental exposure assessment consists of measuring or predicting the environmental concentrations of a chemical from releases due to its production, processing, uses, and disposal. There are two types of exposure assessment most frequently used under TSCA: the Percentile Stream Flow Method and the Probability Dilution Model (PDM) Method. Environmental risk assessment under TSCA is performed by using the quotient method. This method simply compares an EC with the actual or predicted environmental concentrations (PEC). If the PEC is greater than the EC, then you have a potential risk. The risk assessment process usually consists of three steps: (i) worst case risk assessment, (ii) identification of the type or risk (e.g., acute and/or chronic risk), and (iii) quantification of the degree of environmental risk or the potential environmental impact expected for each type of risk. If the risk assessment determines that a chemical presents a potential risk to the environment, then the results of this assessment are integrated with the economic assessment, any relative risk factors, and governmental policy in order to decide whether a chemical may present an unreasonable risk to the environment.

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.

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.