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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.

Animals↗

Proposal to boost children's health.

In a bid to provide better protection for children's health, U.S. Senators Barbara Boxer (D-California) and Frank Lautenberg (D-New Jersey) introduced the Children's Environmental Protection Act (CEPA), on 24 May 1999. CEPA is an amendment to the Toxic Substances Control Act of 1976 and seeks to protect children from exposures to hazardous substances such as toxic air pollutants and pesticides sprayed in schools. The act would also provide parents with the information necessary to make decisions about how to protect their children against such health threats.

Child↗

United States governmental efforts to improve the regulation of toxic substances.

The U.S.'s efforts to improve its regulation of toxic substances presently have their focus in the administration of the Toxic Substance Control Act (TSSC), the Cancer Policy of the regulatory agencies, and the Drug Regulation Reform Act. By improving interagency communication and cooperation as well as establishing a coherent federal approach to the control of toxic substances with public and industrial input, the U.S. government should significantly strengthen the functioning of its regulatory agencies while decreasing the financial burden for everyone involved.

Carcinogens↗

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.

Animals↗

Isopropanol: summary of TSCA test rule studies and relevance to hazard identification.

The toxicity of isopropanol (IPA) has been extensively studied as a result of a Test Rule under Section 4 of the Toxic Substances Control Act. In general, the data showed that IPA has a low order of acute and chronic toxicity; does not produce adverse effects on reproduction; is neither a teratogen, a selective developmental toxicant, nor a developmental neurotoxicant; and is not genotoxic or an animal carcinogen. IPA is, however, a potential hazard for transient central nervous system depression at high exposure levels. In addition, IPA produced effects to several rodent toxicity endpoints at high dose levels (i.e., motor activity, male mating index, and exacerbated renal disease) which are of unclear relevance to human health. The data generated by these studies confirmed that IPA acts as a typical short-chain alcohol in mammalian biological systems. It produces a significant narcotic effect upon exposure at high levels for extended periods of time, with no irreversible effects even after repeated exposure, which is consistent with other short-chain alcohols. The metabolism of IPA appears equivalent across species with rapid conversion to acetone and carbon dioxide. Overall, these studies demonstrate IPA exposure is a low potential hazard to human health. This information will allow for an improved assessment of the human health risks from IPA exposure.

1-Propanol↗

Chemical testing strategies for predicting health hazards to children.

The United States Environmental Protection Agency has proposed the development of a Children's Health Test Program under the Toxic Substances Control Act. The Environmental Protection Agency's proposal for the children's health test battery has 12 different assays including general toxicity, genotoxicity, carcinogenicity, neurotoxicity, and developmental and reproductive toxicity. The current Environmental Protection Agency testing proposal is an "all or nothing" test battery. An alternative and preferable approach would be to use a science-based, tiered testing scheme. It is proposed that the Screening Information Dataset program, currently used by the Organization for Economic Co-operation and Development (OECD) for the Screening Information Dataset-High Production Volume test battery, or equivalent, be considered for the first step. Step 1 would include acute and repeat dose toxicity testing, developmental toxicity testing (first species OECD 414 or OECD 422), reproductive toxicity screening (OECD 415 or 422), and genetic toxicity testing. For this step, the rat would be the initial and only species tested unless the mouse was used for in vivo genetic toxicity. Step 2 of the proposed children's health test battery would include developmental testing (second species OECD 414) or special mode of action studies performed for those chemicals that proved to be developmental toxicants in Step 1. Those chemicals that tested positive as reproductive toxicants in Step 1 would be tested in a two-generation reproduction study (OECD 416) or a special mode of action study. Steps 1 and 2 provide information on whether oncogenicity or developmental neurotoxicity testing is useful. Step 3 would include chronic toxicity/oncogenicity testing for those chemicals that tested positive for genetic toxicity in Step 1, and positive for developmental concerns in Step 2. In this step, chemicals would also be tested for developmental neurotoxicity if they showed evidence of neuropathy, behavioral effects, or neurotoxic potential in earlier studies. This stepwise approach would conserve resources and answer scientific questions in a logical, orderly, timely, and cost-effective manner.

Animals↗

U.S. Chemical program: purpose, challenges, and evolution.

This article explores long-term issues and problems that have seriously undermined the U.S. Chemical Testing Program established by the Environmental Protection Agency (EPA) under the Toxic Substances Control Act. This program is meant to gather information needed to protect human health and the environment from damaging exposure to toxic chemicals. Despite seemingly broad and impressive authority under the statute, there are a number of inherent difficulties, as well as substantial political constraints, that impede comprehensive oversight of chemicals in U.S. commerce. The article discusses several approaches that EPA has adopted to overcome statutory and political limitations and increase chemical testing information. The most recent and promising of these efforts has involved international negotiations to harmonize testing approaches with OECD nations and to cooperate on an agenda that will better share the testing burden on an international level.

Journal Article↗

Evolution of attitudes toward occupational health in the U. S. A.

Attitudes toward ill-health associated with workplace are inevitably closely linked to attitudes toward disease occurring generally, and these have evolved remarkably slowly since the Middle Ages. By the nineteenth century in western countries, at least, people considered disease as a retribution for sins against God, or as a result of bad luck. Certainly this attitude was a factor in why the advent of the germ theory was followed only very slowly by measures aimed at preventing infections brought about from water, food, or airborne sources, even when methods for doing so were well understood. Today, attention is directed toward chronic degenerative diseases and cancer, with their long periods of development, and preventive approaches to these diseases are similarly slow to be applied. In part because the U. S. A. is a relatively young country, with a rapid influx of immigrant labor in this century, the contribution of occupations to injury, ill health and disease has been too seldom recognized. Doctors or nurses working in industries have usually focussed their attention on traditional health care techniques. In the U. S. A. there has recently been, however, a change, at least by ordinary citizens, toward recognizing the importance of prevention of disease. In the context of work-related illness, this recognition has been accelerated by recent legislation which makes employers legally responsible for detecting adverse effects on health of workers and the general public arising from their operations. Paradoxically the Occupational Safety and Health Act of 1970 has been less effective in bringing about a change of awareness of occupational disease than has the Toxic Substances Control Act of 1977.(ABSTRACT TRUNCATED AT 250 WORDS)

Accidents, Occupational↗

EPA's requirements for dermal irritation and sensitization testing.

This paper presents an overview of EPA guidelines for dermal irritation and sensitization testing (part of Subdivision F Guidelines) for the registration of pesticide products [Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)]. In addition, these data and others may be needed for chemicals submitted for the Premanufacture Notification or testing under Section 4 of the Toxic Substances Control Act (TSCA). The EPA periodically reviews its recommended test procedures and revises them when indicated scientifically.

Animals↗

Testing toxic substances for protection of the environment.

The Toxic Substances Control Act requires pre-production testing of chemicals for potential hazards to human and environmental health. Effective control of chemicals requires evaluations of chemical hazard that go beyond determinations of toxicity to humans to include the effects, transport, and fat of chemicals in the environemnt. Formulation of meaningful hazard evaluations depends on integrating information from tests of chemical effects, transport, and fate or by developing testing tools that integrate these factors during experimentation. Chemical effects may be acute or chronic and they may be observed individual organisms, populations or organisms, or in total ecosystems. Chemical transport through the environment depends on physico-chemical characteristics of the chemical and the medium (soil, water, or air) as well as environmental factors and biotic processes. The ultimate fate of chemicals (persistence, transformation, or degradation) is determined by numerous physical and biological processes occurring in the environment, and must be acknowledged to effectively determine the hazard. Many techniques are available for the separate and routine evaluation of the effects, transport and fate of environmental contaminants. However, separate identification of the importance and magnitude of each of these factors limits their utility in assessments of chemical hazard. The microcosm (model ecosystem) method integrates many of these tests in replicable experimental units, and may provide substantial information on chemical hazard in ecosystem context.

Chemical Phenomena↗

Aquatic toxicity of acrylates and methacrylates: quantitative structure-activity relationships based on Kow and LC50.

Recent EPA scrutiny of acrylate and methacrylate monomers has resulted in restrictive consent orders and Significant New Use Rules under the Toxic Substances Control Act, based on structure-activity relationships using mouse skin painting studies. The concern is centered on human health issues regarding worker and consumer exposure. Environmental issues, such as aquatic toxicity, are still of concern. Understanding the relationships and environmental risks to aquatic organisms may improve the understanding of the potential risks to human health. This study evaluates the quantitative structure-activity relationships from measured log Kow's and log LC50's for Pimephales promelas (fathead minnow) and Carassius auratus (goldfish). Scientific support of the current regulations is also addressed. Two monomer classes were designated: acrylates and methacrylates. Spearman rank correlation and linear regression were run. Based on this study, an ecotoxicological difference exists between acrylates and methacrylates. Regulatory activities and scientific study should reflect this difference.

Acrylates↗

The U.S. experience in promoting sustainable chemistry.

BACKGROUND, AIM AND SCOPE: Recent developments in European chemicals policy, including the Registration, Evaluation and Authorization of Chemicals (REACH) proposal, provide a unique opportunity to examine the U.S. experience in promoting sustainable chemistry as well as the strengths and weaknesses of existing policies. Indeed, the problems of industrial chemicals and limitations in current regulatory approaches to address chemical risks are strikingly similar on both sides of the Atlantic. We provide an overview of the U.S. regulatory system for chemicals management and its relationship to efforts promoting sustainable chemistry. We examine federal and state initiatives and examine lessons learned from this system that can be applied to developing more integrated, sustainable approaches to chemicals management. MAIN FEATURES: There is truly no one U.S. chemicals policy, but rather a series of different un-integrated policies at the federal, regional, state and local levels. While centerpiece U.S. Chemicals Policy, the Toxic Substances Control Act of 1976, has resulted in the development of a comprehensive, efficient rapid screening process for new chemicals, agency action to manage existing chemicals has been very limited. The agency, however, has engaged in a number of successful, though highly underfunded, voluntary data collection, pollution prevention, and sustainable design programs that have been important motivators for sustainable chemistry. Policy innovation in the establishment of numerous state level initiatives on persistent and bioaccumulative toxics, chemical restrictions and toxics use reduction have resulted in pressure on the federal government to augment its efforts. RESULTS AND CONCLUSIONS: It is clear that data collection on chemical risks and phase-outs of the most egregious chemicals alone will not achieve the goals of sustainable chemistry. These alone will also not internalize the cultural and institutional changes needed to ensure that design and implementation of safer chemicals, processes, and products are the focus of the future. Thus, a more holistic approach of 'carrots and sticks'--that involves not just chemical producers but those who use and purchase chemicals is necessary. Some important lessons of the US experience in chemicals management include: (1) the need for good information on chemicals flows, toxic risks, and safer substances.; (2) the need for comprehensive planning processes for chemical substitution and reduction to avoid risk trade-offs and ensure product quality; (3) the need for technical and research support to firms for innovation in safer chemistry; and (4) the need for rapid screening processes and tools for comparison of alternative chemicals, materials, and products.

Chemical Industry↗

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.

Animals↗

Fish acute toxicity syndromes and their use in the QSAR approach to hazard assessment.

Implementation of the Toxic Substances Control Act of 1977 creates the need to reliably establish testing priorities because laboratory resources are limited and the number of industrial chemicals requiring evaluation is overwhelming. The use of quantitative structure activity relationship (QSAR) models as rapid and predictive screening tools to select more potentially hazardous chemicals for in-depth laboratory evaluation has been proposed. Further implementation and refinement of quantitative structure-toxicity relationships in aquatic toxicology and hazard assessment requires the development of a "mode-of-action" database. With such a database, a qualitative structure-activity relationship can be formulated to assign the proper mode of action, and respective QSAR, to a given chemical structure. In this review, the development of fish acute toxicity syndromes (FATS), which are toxic-response sets based on various behavioral and physiological-biochemical measurements, and their projected use in the mode-of-action database are outlined. Using behavioral parameters monitored in the fathead minnow during acute toxicity testing, FATS associated with acetylcholinesterase (AChE) inhibitors and narcotics could be reliably predicted. However, compounds classified as oxidative phosphorylation uncouplers or stimulants could not be resolved. Refinement of this approach by using respiratory-cardiovascular responses in the rainbow trout, enabled FATS associated with AChE inhibitors, convulsants, narcotics, respiratory blockers, respiratory membrane irritants, and uncouplers to be correctly predicted.

Animals↗

Uncertainties for endocrine disrupters: our view on progress.

The hypothesis that hormonally active compounds in the environment--endocrine disrupters--are having a significant impact on human and ecological health has captured the public's attention like no other toxicity concern since the publication of Rachel Carson's Silent Spring 1962. In the early 1990s, Theo Colborn and others began to synthesize information about the potential impacts of endocrine-mediated toxicity in the scientific literature (Colborn and Clement, 1992) and the popular press (Colborn et al., 1997). Recognizing the possibility of an emerging health threat, the U.S. Environmental Protection Agency (EPA) convened two international workshops in 1995 (Ankley et al., 1997; Kavlock et al., 1996) that identified research needs relative to future risk assessments for endocrine-disrupting chemicals (EDCs). These workshops identified effects on reproductive, neurological, and immunological function, as well as carcinogenesis as the major endpoints of concern and made a number of recommendations for research. Subsequently, the EPA developed a research strategy to begin addressing the recommendations (EPA, 1998a), and the federal government as a whole, working through the White House's Committee on the Environment and Natural Resources, increased funding levels and coordinated research programs to fill the major data gaps (Reiter et al., 1998). In parallel with these research efforts that were attempting to define the scope and nature of the endocrine disruptor hypothesis, the U.S. Congress added provisions to the Food Quality Protection Act (FQPA) and the Safe Drinking Water Act of 1996 to require the testing of food-use pesticides and drinking water contaminants, respectively, for estrogenicity and other hormonal activity. These bills were enacted into law, giving the EPA the mandate to implement them. The EPA, with the help of an external advisory committee, the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), determined that other hormonal activity should include androgens and compounds that affect thyroid function, and expanded the mandate to include all chemicals under EPA's jurisdiction, potentially including the 70,000 chemicals regulated under the Toxic Substances Control Act (Endocrine Disruptor Screening and Testing Advisory Committee [EDSTAC], 1998). EDSTAC recommended an extensive process of prioritization, screening, and testing of chemicals for endocrine-disrupting activity, including a screening battery that involves a combination of at least eight in vitro and in vivo assays spanning a number of taxa (EDSTAC, 1998). What started out as a hypothesis has become one of the biggest testing programs conceived in the history of toxicology and the only one that has ever been based on mechanism of action as its premise. As we pass the 10th anniversary of the emergence of the endocrine disruptor hypothesis, it is useful to look back on the progress that has been made in answering the nine questions posed as data gaps in the EPA's research strategy (EPA, 1998a)--not only to see what we have learned, but also to examine whether the questions are still appropriate for the goal, what gaps remain, and what directions should be emphasized in the future.

Animals↗

Subchronic inhalation neurotoxicity study of amyl acetate in rats.

An inhalation toxicity study was conducted with rats to examine the potential for amyl acetate vapor to produce alterations in nervous system structure and function following repeated exposure. The study was performed as part of a USEPA Toxic Substances Control Act (TSCA) Section 4e Enforceable Consent Agreement for amyl acetate. Rats (CD) were exposed to amyl acetate vapor at concentrations of 0, 300, 600 or 1200 ppm, 6 h per day, 4 or 5 days per week, for at least 65 exposures. Treatment groups consisted of 15 rats per gender for the control and 1200 ppm groups and 10 rats per gender for the 300 and 600 ppm groups. Evaluations included clinical observations before, during and after each exposure, weekly detailed clinical examinations, weekly body weight and food consumption measurements and monthly functional observational battery and motor activity measurements conducted on non-exposure days. Neuropathology examination of the central and peripheral nervous system was performed at the end of the study. Exposure to amyl acetate did not result in overt clinical signs of toxicity or changes in body weight or food consumption. Transient, subtle decreases in general activity level during the 6-h exposure period were noted for animals in the 600 and 1200 ppm groups during the first 2 weeks of the study. Functional observational battery evaluations, automated motor activity measurements and neuroanatomy were unaffected by exposure. The no observed-effect level for subchronic neurotoxicity for this study was at least 1200 ppm, which is greater than an order of magnitude above the occupational threshold limit value (8-h, time-weighted average) for amyl acetate (100 ppm).

Administration, Inhalation↗

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.

Animals↗