National Academies Press: OpenBook
« Previous: Summary
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

1
Introduction

The purpose of toxicity testing is to generate information about a substance’s toxic properties so that the health and environmental risks it poses can be adequately evaluated. Federal agencies use information from toxicity testing to establish acceptable concentrations of environmental agents in drinking water, to set permissible exposure limits for workers, to establish tolerances for pesticide residues on food, to register and re-register pesticides, and ultimately to protect public health and the environment. As reflected in new directives and initiatives for toxicity testing in the United States and Europe, the demand for toxicity information to provide a rational basis for regulating environmental agents has increased. At the same time, testing technologies and methods have continued to emerge. Thus, the U.S. Environmental Protection Agency (EPA) recognized the need for a comprehensive review of established and emerging toxicity-testing methods and strategies and asked the National Research Council (NRC) to conduct such a review and to develop a long-range vision and strategy for toxicity testing. In response to EPA’s request, the NRC convened the Committee on Toxicity Testing and Assessment of Environmental Agents, which prepared this report.

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

REGULATORY REQUIREMENTS

The U.S. Congress has enacted laws calling for limits on chemical exposures that “provide an ample margin of safety to protect public health” (Clean Air Act; 42 USC §7412(f) [2003]), “assure protection of public health” (Clean Water Act; 33 USC §1312(a) [2003]), provide “a reasonable certainty that no harm will result” (Food Quality Protection Act; 21 USC §346a(b) [2003]), and “adequately assures, to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or functional capacity” (Occupational Safety and Health Act; 29 USC §655(b) [2003]) (see Table 1-1). Federal agencies implement those statutes by promulgating standards or adopting guidance levels—such as air-quality criteria, maximum contaminant levels for drinking water, pesticide-residue tolerances, and permissible exposure limits for workplaces—that limit people’s exposure to chemicals. The standards and guidance levels are often developed through human health risk assessment, although other factors—such as treatment technology, feasibility, benefits, and costs—may also be considered. Toxicity testing in laboratory animals provides much of the information needed to characterize the nature and extent of the risk so that appropriate risk-management action can be taken.

TOXICITY TESTING

Many factors are determinants of health, including socioeconomic status, birth weight, sex, genetics, diet, pathogens, smoking habits, cultural activities, and the environment. Exposures to environmental agents contribute to the aggregate effects of the other factors, but the nature and magnitude of the contribution are often debated. The results of toxicity testing can help to clarify risks to health posed by environmental exposures and provide support for effective risk-management decisions.

Toxicity-testing requirements to evaluate effects on human health often involve studies of whole animals, typically rats, mice, dogs, and rabbits, although other species, including humans, can be used. Exposures can range from short-term (for example, an hour) to long-term (for example, 2 years) and be continuous or episodic or consist of a single event. Tests may focus on a particular life stage, sex, or condition of exposure. The effects evaluated can be numerous and can include such diverse outcomes as subtle behavioral changes, impairment of reproduc-

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

TABLE 1-1 Some Major U.S. Regulatory Agency Authority, Public-Health Goals, and Risk-Management Approaches

Agency and Program

Enabling Statute and Citation

Statutory Mandate: Qualitative Health and Safety Goal

Implementation: Regulatory Risk-Management Requirement or Advisory

EPA, water

Safe Drinking Water Act/42 USC § 300g-1 (2003)

  • Establish contaminant concentrations at which “no known or anticipated adverse effects on the health of persons occur and which allows an adequate margin of safety”; may consider feasibility

  • Maximum contaminant levels

  • Maximum contaminant level goals

Federal Water Pollution Control Act (Clean Water Act)/33 USC §§ 1312-1333 (2003)

  • Control pollutant discharges to “assure protection of public health”; may consider feasibility

  • Establish criteria that “protect public health and welfare”

  • Technology-based effluent limitations

  • Water-quality standards

EPA, pesticides

Food Quality Protection Acta/21 USC § 346a(b) (2003)

  • Ensure that there is “a reasonable certainty that no harm will result from aggregate exposure to pesticide chemical residues”; considers benefits

  • Pesticide-residue tolerances

  • Additional margin of safety to protect infants and children

Federal Insecticide, Fungicide, and Rodenticide Act/7 USC §§ 136a, 136w (2003)

  • Prevent “unreasonable adverse effects on the environment” (includes humans); considers benefits

  • Protect children and adults from serious injury or illness

  • Registration and use limits

  • Safe-packaging requirements

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

Agency and Program

Enabling Statute and Citation

Statutory Mandate: Qualitative Health and Safety Goal

Implementation: Regulatory Risk-Management Requirement or Advisory

EPA, air

Clean Air Act/42 USC §§ 7408(a), 7412(f) (2003)

  • Avoid emissions that “may reasonably be anticipated to endanger public health or welfare”

  • Promulgate standards that “provide an ample margin of safety to protect public health”

  • Air-quality criteria for pollutants

  • Technology-based standards to limit emissions of hazardous air pollutants (“maximum achievable control technology”)

  • Further regulation needed if residual risk exceeds 10−4 or is of public-health significance

EPA, toxic substances

Toxic Substances Control Act/15 USC § 2603 (2003)

  • Determine that a substance “does not or will not present unreasonable risk of injury to health”

  • Toxicity testing when information available is insufficient to determine or predict health effects

EPA, Superfund

Superfund Amendments and Reauthorization Actb/42 USC § 9621 (2003)

  • Establish site-cleanup standards that are “protective of human health”; may consider feasibility

  • Remedial action

OSHA

Occupational Safety and Health Act/29 USC § 655(b) (2003)

  • “Set the standard which most adequately assures, to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or functional capacity”

  • Occupational safety or health standards

  • Permissible exposure limits

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

FDA, food safety

Federal Food, Drug, & Cosmetic Actc/21 USC §§ 348(a) (2003), 379e (2001)

  • Determine that the intended use of a food additive, food-contact substance, or color additive is “safe”

  • No human or animal carcinogens

  • Regulation providing conditions of safe use

  • Requirement of notification for food-contact substances and petition for food additive

  • Listing for use as a color additive

  • Classification as generally recognized as safe

FDA, drug evaluation

21 USC § 355(d) (2001)

  • Show whether a drug is “safe for use,” as well as efficacious

  • Approval of new drug applications, considering risks and benefits

CPSC

Consumer Product Safety Act/15 USC §§ 2057, 2058 (2003)

  • “Eliminate or reduce an unreasonable risk of injury associated with” consumer products; considers costs and benefits

  • Mandatory safety standards

  • Bans

  • Recalls

aAmends the Federal Food, Drug, and Cosmetic Act.

bReauthorizes the Comprehensive Environmental Response, Compensation, and Liability Act (Superfund).

cAs amended by the Food and Drug Modernization Act.

Abbreviations: CPSC, Consumer Product Safety Commission; EPA, U.S. Environmental ProtectionAgency; FDA, Food and Drug Administration; OSHA, Occupational Safety and Health Administration.

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

tion, abnormal development, alterations in gene function, organ toxicity, cancer, and death. New methods that rely on molecular biology, information technology, and alternatives to whole-animal testing are emerging and may provide information that allows better extrapolation of results in test species to the genetically diverse human population. Some new methods may eventually replace various traditional toxicity tests.

Federal agencies and international organizations—including EPA, the National Toxicology Program (NTP) (Chhabra et al. 1990), the Food and Drug Administration (FDA 1997, 2004), and the Organisation for Economic Co-operation and Development (OECD 2004, 2005)—have developed documents that provide guidance on testing protocols. Testing guidelines are intended to convey to members of the regulated community what is expected of them and provide a uniform and sometimes flexible approach to toxicity testing that produces comparable results. The OECD protocols serve not only as standards but as means to harmonize requirements among regulatory authorities and thus reduce repetition of studies. The harmonization efforts should increase efficiency and reduce animal use.

CHALLENGES TO TOXICITY TESTING AND ASSESSMENT

The continuing challenge is to determine the best methods for extrapolating from the exposure conditions and effects observed in the laboratory to those relevant to the human environment. Toxicity-testing data can be used in various ways to aid in that extrapolation. Pharmacokinetic data can provide a better understanding of the qualitative and quantitative comparability of the relationship between exposure and dose in test species and in humans. Population-based studies that examine effects on exposed humans can provide information that improves extrapolation from laboratory-animal data to humans or in some cases eliminates the need to rely on laboratory-animal data altogether. Studies that provide a quantitative understanding of the difference in susceptibility to a chemical between humans and test species can be used to develop an interspecies adjustment factor based on scientific data rather than science policy. Finally, studies that provide an understanding of variations in susceptibility to the effects of a substance in different populations or life stages can help to identify substances that require special regulatory attention to protect sensitive groups and may also identify exposures that will have no deleterious effects even in sensitive people.

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

Studies like those discussed have resulted in much-improved human risk estimation, but substantial challenges remain. Most toxicity tests use exposures that exceed environmental exposures by several orders of magnitude to improve test sensitivity, but high exposures can distort the specificity of a test and its qualitative and quantitative applicability to actual human exposure. Scientific developments and new test methods are needed to address people’s multiple simultaneous chemical exposures, their potential interactions, and the many factors that affect people’s susceptibility to chemical exposures. Thus, even extensive testing and an accurate understanding of biologic modes of action cannot predict exactly what will happen in a diverse human population under environmental conditions of exposure. Precise descriptions of risk are desirable to protect public health, but they remain elusive. Nevertheless, even with these challenges and uncertainties, toxicity-testing data provide critical information for assessing hazard and risk potential and will continue to play a critical role in rational decision-making.

As noted above, EPA and other federal agencies have statutory responsibilities for obtaining and evaluating animal and human toxicity data for regulatory decision-making purposes. The numbers of health outcomes and questions that must be considered have also grown over the years. EPA and others have responded to the increased need to address various outcomes by developing risk-assessment guidelines and testing requirements, such as the risk-assessment guidelines for neurotoxicity (IPCS 2001; OECD 2004; EPA 1998), guidelines on children’s cancer risk (EPA 2005), testing guidelines for developmental neurotoxicity (OECD 2004; EPA 1998) and guidelines for the use of genomics data (EPA 2004). Still, there is a growing recognition that because traditional toxicity testing approaches are time consuming and resource intensive, a large volume of existing and newly introduced chemicals cannot be adequately assessed using current testing practices. EPA recognized the need to review traditional toxicity testing approaches, new data-generation methods, and testing strategies comprehensively and asked NRC to perform such a review.

COMMITTEE’S TASK AND APPROACH

The committee members were selected for their expertise in developmental toxicology, reproductive toxicology, neurotoxicology, immunology, pediatrics and neonatology, epidemiology, biostatistics, in vitro

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

methods and models, molecular biology, pharmacology, physiologically based pharmacokinetic and pharmacodynamic models, genetics, toxicogenomics, cancer hazard assessment, and risk assessment.

The committee was asked to conduct a two-part study to assess and advance current approaches to toxicity testing and assessment undertaken to meet regulatory data needs. For the first part of the study, the committee was asked to review selected aspects of several relevant reports by EPA and others. Those reports included EPA’s 2002 review of the reference-dose and reference-concentration processes (EPA 2002), the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) work to develop a tiered toxicity-testing approach for agricultural-chemical safety evaluations (ILSI-HESI 2004a,b,c), the work of the Interagency Coordinating Committee on the Validation of Alternative Methods to develop and validate alternatives to animal testing (ICCVAM 1997), pertinent NRC reports, and current work of NRC standing committees. Those reports were to be evaluated for specific elements, including analysis of current and anticipated regulatory needs, discussion of the current and planned inventory of toxicity-testing and assessment schemes and methods, evaluation of potential uses and limitations of new or alternative testing methods and analysis of how they might influence or define future testing strategies, and discussion of scientific advances that could affect the nature of information needed to assess potential human toxicity more completely. The present report was prepared to fulfill the first part of the study.

For the second part of the study, the committee was asked to build on the work presented in this report and develop a long-range vision and strategic plan to advance the practices of toxicity testing and human health assessment of environmental contaminants. The second report is expected to be completed by fall 2006.

To accomplish the task of preparing its first report, the committee held four meetings. The first three, held from June 2004 to November 2004, included public sessions. At the public sessions, the committee heard presentations from staff of several EPA offices, including representatives from the Office of Research and Development, the Office of Pesticide Programs, the Office of Children’s Health, the National Health and Environmental Effects Research Laboratory, and the National Center for Environmental Assessment. The committee also heard presentations from staff of other federal agencies and organizations, including the NTP, the FDA Center for Drug Evaluation and Research and Center for Food Safety and Applied Nutrition, the European Center for the Valida-

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

tion of Alternative Methods, and the ILSI HESI and Risk Sciences Institute. The committee considered numerous documents, including those mentioned in the statement of task but also others, such as FDA guidance on pharmacogenomic-data submissions (FDA 2005) and the NTP Roadmap for the Future (NTP 2004).

ORGANIZATION OF THE REPORT

In Chapter 2, the committee presents an overview of consensus-study protocols focusing primarily on EPA guidelines. The objective of that chapter is not to detail each type of testing protocol but rather to indicate the general types of whole-animal and in vitro toxicity testing now in use. Chapter 3 considers a variety of human-based studies ranging from clinical trials to epidemiologic studies. Challenges that have often prevented the use of epidemiologic studies in regulatory risk assessment and possible advances and improvements in epidemiology are discussed. Chapter 4 examines applications of toxicity tests in testing strategies that are used to rank, screen, or characterize chemical toxicity. Several examples of testing strategies are presented. The strategies identified are not meant to be exhaustive but to illustrate the array of toxicity tests that may be required under different circumstances. Chapter 5 provides an overview of risk-assessment guideline documents that deal with the use of toxicity data in human health risk assessment and concludes with observations regarding strengths and weaknesses of the current system for generating toxicologic data to assess environmental risks. Chapter 6 is the committee’s assessment of the various, and often conflicting, demands on the regulatory toxicity-testing framework and a review of near-term and long-term approaches that hold promise for improving toxicity testing. The chapter includes comments on the portion of the EPA review of its reference-dose and reference-concentration process that is relevant to toxicity testing and comments on the proposed ILSI-HESI approaches for pesticides, the NTP Roadmap for the Future, and the European Union’s program. Chapter 7 discusses alternatives to animal testing and a few emerging technologies, such as -omics approaches and computational toxicology. It concludes with a discussion of validation to emphasize the importance of evaluating new toxicity-testing methods to ensure that the information obtained from them is at least as good as, if not better than, conventional mammalian models.

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

REFERENCES

Chhabra, R.S., J.E. Huff, B.S. Schwetz, and J. Selkirk. 1990. An overview of prechronic and chronic toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology Program. Environ. Health Perspect. 86:313-321.


EPA (U.S. Environmental Protection Agency). 1998. Guidelines for Neurotoxicity Risk Assessment. EPA/630/R-95/001F. U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/ncea/raf/pdfs/neurotox.pdf [accessed July 13, 2005].

EPA (U.S. Environmental Protection Agency). 2002. A Review of the Reference Dose and Reference Concentration Processes. Final Report. EPA/630/P-02/002F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/iris/RFD_FINAL%5B1%5D.pdf [accessed March 11, 2005].

EPA (U.S. Environmental Protection Agency). 2004. Guidance on Use of Genomics Data. Computational Toxicology Program, Office of Research and Development, Washington, DC [online]. Available: http://www.epa.gov/comptox/comptoxfactsheet.html#guidance [accessed April 21, 2005].

EPA (U.S. Environmental Protection Agency). 2005. Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. EPA 630/R-03/003F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/iris/children032505.pdf [accessed April 22, 2005].


FDA (Food and Drug Administration). 1997. Guidance for Industry: S1B Testing for Carcinogenicity of Pharmaceuticals. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Washington, DC [online]. Available: http://www.fda.gov/cder/guidance/1854fnl.pdf [accessed March 9, 1005].

FDA (Food and Drug Administration). 2004. Guidance for Industry: Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food: Carcinogenicity Testing VICH GL28. Final Guidance. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Veterinary Medicine, May 24, 2004 [online]. Available: http://www.fda.gov/cvm/guidance/guide141.pdf [accessed March 9, 2005].

FDA (Food and Drug Administration). 2005. Guidance for Industry. Pharmacogenomic data submissions. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Washington, DC [online]. Available: http://www.fda.gov/OHRMS/DOCKETS/98fr/2003d-0497-gdl0002.pdf.

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×

ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods). 1997. Validation and Regulatory Acceptance of Toxicological Test Methods, A Report of the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods. NIH Publication No. 97-3981. National Institute of Environmental Health Sciences, Research Triangle Park, NC. March 1997 [online]. Available: http://iccvam.niehs.nih.gov/docs/guidelines/validate.pdf [accessed March 11, 2005].

ILSI HESI (International Life Sciences Institute Health and Environmental Sciences Institute). 2004a. Systemic Toxicity White Paper. Systemic Toxicity Task Force, Technical Committee on Agricultural Chemical Safety Assessment, ILSI Health Sciences Institute, Washington, DC. November 2, 2004 .

ILSI HESI (International Life Sciences Institute Health and Environmental Sciences Institute). 2004b. Life Stages White Paper. Life Stages Task Force, Technical Committee on Agricultural Chemical Safety Assessment, ILSI Health Sciences Institute, Washington, DC. November 2, 2004.

ILSI HESI (International Life Sciences Institute Health and Environmental Sciences Institute). 2004c. The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments. ADME Task Force, Technical Committee on Agricultural Chemical Safety Assessment, ILSI Health Sciences Institute, Washington, DC. November 2, 2004.

IPCS (International Programme on Chemical Safety). 2001. Neurotoxicity Risk Assessment for Human Health: Principles and Approaches. Environmental Health Criteria 223. Geneva: World Health Organization [online]. Available: http://www.inchem.org/documents/ehc/ehc/ehc223.htm [accessed March 2, 2005].


NTP (National Toxicology Program). 2004. The NTP Vision for the 21st Century. National Toxicology Program, National Institute for Environmental Health, Research Triangle Park, NC [online]. Available: http://ntpserver.niehs.nih.gov/ntp/main_pages/NTPVision.pdf [accessed March 11, 2005].


OECD (Organisation for Economic Cooperation and Development). 2004. Guideline Document for Neurotoxicity Testing. ENV/JM/MONO(2004) 25. OECD Series on Testing and Assessment No. 20. Organisation for Economic Cooperation and Development, Paris [online]. Available: http://appli1.oecd.org/olis/2004doc.nsf/linkto/env-jm-mono(2004)25 [accessed April 1, 2005].

OECD (Organisation for Economic Cooperation and Development). 2005. Chemicals Testing: OECD Guidelines for the Testing of Chemicals - Sections 4: Health Effects [online]. Available: http://www.oecd.org/document/55/0,2340,en_2649_34377_2349687_1_1_1_1,00.html [accessed March 14, 2005].

Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 15
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 16
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 17
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 18
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 19
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 20
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 21
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 22
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 23
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 24
Suggested Citation:"1 Introduction." National Research Council. 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC: The National Academies Press. doi: 10.17226/11523.
×
Page 25
Next: 2 Animal and In Vitro Toxicity Testing »
Toxicity Testing for Assessment of Environmental Agents: Interim Report Get This Book
×
Buy Paperback | $54.00 Buy Ebook | $43.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF
  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!