In Vitro Toxicity Testing Of Environmental Agents

These two volumes contain the papers presented at a North Atlantic Treaty Organization (NATO) Advanced Study Institute held on September 22-28, 1979 in Monte Carlo, Monaco. The conference was entitled "In Vitro Toxicity Testing of Environmental Agents: Current and Future Possibilities." This international conference presented an opportunity for the participants to exchange informa tion and ideas on the current approaches (both scientific and po litical) for toxic assessment of environmental agents. The poten tial health effects of these compounds as well as future needs in the environmental research field were discussed. The scientific content of the conference seminars included an overview of the various cellular, subcellular, organ, animal, and genetic systems which have been used to assess the health effects of environmental agents. The scientific principles behind short term assays and an evaluation of their applicability to health effects monitoring and analysis were investigated. Included among major topics were: (1) the biochemistry and pharmacology of selected environmental agents; (2) molecular mechanisms of car cinogenesis, mutagenesis, and transformation; (3) bacterial muta genesis and toxicity; (4) mammalian cell mutagenesis, toxicity, and transformation; (5) in vitro carcinogens and mutagens; (6) teratogenic and other developmental toxic effects; and (7) the development of short-term neuro-behavioral toxicity assays.

Toxicity testing in laboratory animals provides much of the information used by the Environmental Protection Agency (EPA) to assess the hazards and risks associated with exposure to environmental agents that might harm public health or the environment. The data are used to establish maximum acceptable concentrations of environmental agents in drinking water, set permissible limits of exposure of workers, define labeling requirements, establish tolerances for pesticides residues on food, and set other kinds of limits on the basis of risk assessment. Because the number of regulations that require toxicity testing is growing, EPA called for a comprehensive review of established and emerging toxicity-testing methods and strategies. This interim report reviews current toxicity-testing methods and strategies and near-term improvements in toxicity-testing approaches proposed by EPA and others. It identifies several recurring themes and questions in the various reports reviewed. The final report will present a long-range vision and strategic plan to advance the practices of toxicity testing and human health assessment of environmental contaminants.

These two volumes contain the papers presented at a North Atlantic Treaty Organization (NATO) Advanced Study Institute held on September 22-28, 1979 in Monte Carlo, Monaco. The conference was entitled "In Vitro Toxicity Testing of Environmental Agents: Current and Future Possibilities." This international conference presented an opportunity for the participants to exchange informa tion and ideas on the current approaches (both scientific and po litical) for toxic assessment of environmental agents. The poten tial health effects of these compounds as well as future needs in the environmental research field were discussed. The scientific content of the conference seminars included an overview of the various cellular, subcellular, organ, animal, and genetic systems which have been used to assess the health effects of environmental agents. The scientific principles behind short term assays and an evaluation of their applicability to health effects monitoring and analysis were investigated. Included among major topics were: (1) the biochemistry and pharmacology of selected environmental agents; (2) molecular mechanisms of car cinogenesis, mutagenesis, and transformation; (3) bacterial muta genesis and toxicity; (4) mammalian cell mutagenesis, toxicity, and transformation; (5) in vitro carcinogens and mutagens; (6) teratogenic and other developmental toxic effects; and (7) the development of short-term neuro-behavioral toxicity assays.

Advances in molecular biology and toxicology are paving the way for major improvements in the evaluation of the hazards posed by the large number of chemicals found at low levels in the environment. The National Research Council was asked by the U.S. Environmental Protection Agency to review the state of the science and create a far-reaching vision for the future of toxicity testing. The book finds that developing, improving, and validating new laboratory tools based on recent scientific advances could significantly improve our ability to understand the hazards and risks posed by chemicals. This new knowledge would lead to much more informed environmental regulations and dramatically reduce the need for animal testing because the new tests would be based on human cells and cell components. Substantial scientific efforts and resources will be required to leverage these new technologies to realize the vision, but the result will be a more efficient, informative and less costly system for assessing the hazards posed by industrial chemicals and pesticides.

In the laboratory, testing the toxic effects for a single compound is a straightforward process. However, many common harmful substances occur naturally as mixtures and can interact to exhibit greater toxic effects as a mixture than the individual components exhibit separately. Complex Mixtures addresses the problem of identifying and classifying complex mixtures, investigating the effect of exposure, and the research problems inherent in testing their toxicity to human beings. A complete series of case studies is presented, including one that examines the cofactors of alcohol consumption and cigarette smoke.

In 2007, the National Research Council envisioned a new paradigm in which biologically important perturbations in key toxicity pathways would be evaluated with new methods in molecular biology, bioinformatics, computational toxicology, and a comprehensive array of in vitro tests based primarily on human biology. Although some considered the vision too optimistic with respect to the promise of the new science, no one can deny that a revolution in toxicity testing is under way. New approaches are being developed, and data are being generated. As a result, the U.S. Environmental Protection Agency (EPA) expects a large influx of data that will need to be evaluated. EPA also is faced with tens of thousands of chemicals on which toxicity information is incomplete and emerging chemicals and substances that will need risk assessment and possible regulation. Therefore, the agency asked the National Research Council to convene a symposium to stimulate discussion on the application of the new approaches and data in risk assessment. The symposium was held on May 11-13, 2009, in Washington, DC, and included presentations and discussion sessions on pathway-based approaches for hazard identification, applications of new approaches to mode-of-action analyses, the challenges to and opportunities for risk assessment in the changing paradigm, and future directions.

First Published in 1994, Introduction to In Vitro Cytotoxicology examines in vitro cytotoxicology, which offers new methodologies to toxicity testing. This important new discipline of modern toxicology is gaining increased acceptance as a viable alternative to traditional testing methods. The text discusses the application of in vitro cytotoxicology to toxicity testing and human risk assessment, and it analyzes the advantages and limitations of the tests performed under scientific and regulatory conditions. The book also reviews the optimum utilization of certain tests for specific groups of chemicals relevant to validation programs currently in progress. This book is a useful reference tool for students, researchers, and practitioners interested in academic, industrial, and regulatory toxicology; environmental health; cell biology; pharmacology; dentistry; or human and veterinary medicine.

The United States Navy has been concerned for some time with protecting its military and civilian personnel from reproductive and developmental hazards in the workplace. As part of its efforts to reduce or eliminate exposure of Naval personnel and their families to reproductive and developmental toxicants, the Navy requested that the National Research Council (NRC) recommend an approach that can be used to evaluate chemicals and physical agents for their potential to cause reproductive and developmental toxicity. The NRC assigned this project to the Committee on Toxicology, which convened the Subcommittee on Reproductive and Developmental Toxicology, to prepare this report. In this report, the subcommittee recommends an approach for evaluating agents for potential reproductive and developmental toxicity and demonstrates how that approach can be used by the Navy. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: James Chen (National Center for Toxicological Research), George Daston (Procter and Gamble Company), Jerry Heindel (National Institute of Environmental Health Sciences), Grace Lemasters (University of Cincinnati), and John Young (National Center for Toxicological Research).