Information Resources in Toxicology, Volume 1: Background, Resources, and Tools

This new fifth edition of Information Resources in Toxicology offers a consolidated entry portal for the study, research, and practice of toxicology. Both volumes represents a unique, wide-ranging, curated, international, annotated bibliography, and directory of major resources in toxicology and allied fields such as environmental and occupational health, chemical safety, and risk assessment. The editors and authors are among the leaders of the profession sharing their cumulative wisdom in toxicology’s subdisciplines. This edition keeps pace with the digital world in directing and linking readers to relevant websites and other online tools.

Due to the increasing size of the hardcopy publication, the current edition has been divided into two volumes to make it easier to handle and consult. Volume 1: Background, Resources, and Tools, arranged in 5 parts, begins with chapters on the science of toxicology, its history, and informatics framework in Part 1. Part 2 continues with chapters organized by more specific subject such as cancer, clinical toxicology, genetic toxicology, etc. The categorization of chapters by resource format, for example, journals and newsletters, technical reports, organizations constitutes Part 3. Part 4 further considers toxicology’s presence via the Internet, databases, and software tools. Among the miscellaneous topics in the concluding Part 5 are laws and regulations, professional education, grants and funding, and patents. Volume 2: The Global Arena offers contributed chapters focusing on the toxicology contributions of over 40 countries, followed by a glossary of toxicological terms and an appendix of popular quotations related to the field.

The book, offered in both print and electronic formats, is carefully structured, indexed, and cross-referenced to enable users to easily find answers to their questions or serendipitously locate useful knowledge they were not originally aware they needed. Among the many timely topics receiving increased emphasis are disaster preparedness, nanotechnology, -omics, risk assessment, societal implications such as ethics and the precautionary principle, climate change, and children’s environmental health.

• Introductory chapters provide a backdrop to the science of toxicology, its history, the origin and status of toxicoinformatics, and starting points for identifying resources
• Offers an extensive array of chapters organized by subject, each highlighting resources such as journals, databases,organizations, and review articles
• Includes chapters with an emphasis on format such as government reports, general interest publications, blogs, and audiovisuals
• Explores recent internet trends, web-based databases, and software tools in a section on the online environment
• Concludes with a miscellany of special topics such as laws and regulations, chemical hazard communication resources, careers and professional education, K-12 resources, funding, poison control centers, and patents
• Paired with Volume Two, which focuses on global resources, this set offers the most comprehensive compendium of print, digital, and organizational resources in the toxicological sciences with over 120 chapters contributions by experts and leaders in  the field

• Language: English
• Publisher: Academic Press
• Release date: May 16, 2020
• ISBN: 9780128137253

Book preview

Information Resources in Toxicology

Volume 1: Background, Resources, and Tools

Fifth Edition

Edited by

Philip Wexler

Table of Contents

Cover image

Title page

Copyright

Dedications, with Love

List of Contributors

Foreword to Fourth (previous) Edition

Foreword to Fifth Edition

Preface

Part I: Introduction

Chapter 1. Toxicology: a primer

Abstract

References and further reading

Chapter 2. History of toxicology

Abstract

Highlights in the history of toxicology

References

Further reading

Key figures and documents

Chapter 3. Development of toxicoinformatics

Abstract

Introduction

The realm of toxicology information

Background in toxicology information systems

The technology wave in toxicology information systems

Applications of toxicology information systems

Challenges ahead for toxicology information systems

Future directions

Summary

Acknowledgment

References

Further reading

Chapter 4. Toxicoinformatics today

Abstract

TOXNET

Resources

Journal articles

Organizations

Databases

Acknowledgments

Chapter 5. Starting points for finding toxicology resources

Abstract

Periodicals

Databases

Online subject guides

Bibliography

Occupational

Registries

Teratogens

Design Considerations

Part II: Subject categorization: books and more

Chapter 6. General texts

Abstract

Resources

Chapter 7. Analytical toxicology

Abstract

Introduction

Resources

Review articles

Chapter 8. Animals in research

Abstract

Introduction

Resources

Review article

Journals

Databases

Organizations

Chapter 9. Biomarkers

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Other resources

ICH regulatory guidelines

FDA regulatory guidance

Joint FDA–EMEA regulatory guidance

Chapter 10. Biotechnology

Abstract

Introduction

Information resources section

Journal articles—reviews and other key papers

Organizations

Online databases, resources, and tools

Other resources

Chapter 11. Biotoxins

Abstract

Introduction

Resources

Journal articles

Organizations

Databases from universities and other institutions

Chapter 12. Cancer

Abstract

Introduction

Resources

Book chapters

Book series

Journals

Journal articles

Organizations

Databases

Guidelines for genotoxicity and carcinogenicity testing

Chapter 13. Chemical compendia

Abstract

Introduction

Resources

Chapter 14. Chemicals: cosmetics and other consumer products

Abstract

Introduction

Resources

General

Risk and safety assessment

Development and efficacy

Methodologies

Journals

General works

Databases

Organizations

Other associations and professional organizations

Chapter 15. Pediatric environmental health: exposures and interactions

Abstract

Introduction

References

Resources

Journal articles

Organizations

Non-US government

Nongovernmental organizations

Databases

Chapter 16. Climate change toxicology resources

Abstract

Introduction

Disclaimer

Related chapters

Journals

Journal articles

Journal articles

Books and reports

Professional societies

Governmental and intergovernmental agencies and projects

Chapter 17. Drugs

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Acknowledgments

Chapter 18. Chemicals: dusts and fibers

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Standards

Chapter 19. Metal toxicology

Abstract

Introduction

Databases

Books and chapters

Journal articles

Organization

Chapter 20. Chemicals: pesticides

Abstract

Introduction

Books/monograph series

Reviews of environmental contamination and toxicology

Journal titles

Journal articles

Pesticides and amphibians

Pesticides and bees

Pesticides and bees—hazard identification and risk assessment studies

Pesticide and bees—field studies

Miscellaneous notable papers addressing environmental hazards and exposure

Organophosphorous insecticides (hazard characterization, exposure assessment, and epidemiology)

Pyrethroid insecticides

Exposure assessment studies (miscellaneous pesticides)

Atrazine and glyphosate—carcinogenicity and other chronic effects

Glyphosate—exposure assessment

Selected agricultural health studies and analyses based on AHS data

Neonicotinoids (human health hazard characterization and exposure assessment)

Transgenerational epigenetic effects

Websites and databases for pesticide information and regulatory decisions

Chapter 21. Chemicals: solvents

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Chapter 22. Chemicals: selected chemicals

Abstract

Introduction

Resources

Journal articles

Alcohols

Arsenic

Caffeine

Dioxin

Fluoride

Formaldehyde

PCBs

Rubber

Tobacco

Chapter 23. Clinical toxicology and clinical analytical toxicology

Abstract

Introduction

Resources

Review articles

Journals

Databases

Organizations

Chapter 24. Developmental and reproductive toxicology

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Chapter 25. Disaster preparedness and management

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Additional publications and websites of interest

Chapter 26. Environmental toxicology: aquatic

Abstract

Introduction

References

Resources

Reviews and other key papers

Organizations

Online databases and tools

Chapter 27. Environmental toxicology: air

Abstract

Introduction

Resources

Journal articles

Funding agencies

Chapter 28. Environmental toxicology: hazardous waste

Abstract

Introduction

Resources

Journal articles

Organizations

Chapter 29. Environmental toxicology: terrestrial

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Chapter 30. Environmental toxicology: wildlife

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Chapter 31. Epidemiology

Abstract

Introduction

References

Resources

Journal articles

Organizations

Databases

Other resources

Chapter 32. Ethical considerations

Abstract

Introduction

Reference

Journal articles

Organizations

Other resources

Chapter 33. Exposure science

Abstract

Introduction

Journals

Books, reports, and technical guidance documents

Professional organizations and societies

Agencies and organizations

Exposure factor databases and handbooks

Exposure data and exposure model inventories

Select human exposure models

Exposome research projects and programs

Chapter 34. Food and nutrient toxicology

Abstract

Introduction

Resources

Journal articles

Organizations

Databases and online resources

Chapter 35. Forensic toxicology

Introduction

Resources

Selected journal articles

Organizations

Chapter 36. Genetic toxicology

Abstract

Introduction

Chapter 37. Chemical mixtures: toxicologic interactions and risk assessment

Abstract

Introduction

Glossary

Books and book chapters

Government documents

Journal articles

Databases

Organizations

Chapter 38. Molecular, cellular, and biochemical toxicology

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Chapter 39. Nanotechnology

Abstract

Introduction

Resources

Reviews and other key papers

Organizations

Databases

Chapter 40. Noise and Noise-Induced Hearing Loss (NIHL)

Abstract

Introduction

Resources

Journal articles

NIHL in the laboratory animals and the mechanisms

Factors potentiating NIHL

Factors protecting against NIHL

Professional organizations and associations

Chapter 41. Occupational health

Abstract

Introduction

Resources

Review articles

Journals

Organizations

Chapter 42. Omics resources

Abstract

Introduction

References

Resources

Journal articles

Organizations

Chapter 43. Pathology

Abstract

Introduction

Resources

Journal articles

Organizations

Websites

Chapter 44. Toxicokinetics, pharmacokinetics, and absorption, distribution, metabolism, and excretion

Abstract

Introduction

Resources

Review articles

Organizations

Recommended courses

Commonly used software for pharmacokinetic analysis and physiologically based pharmacokinetic simulations

Select online resources

Chapter 45. Precautionary principle

Abstract

Introduction

Journal articles

Organizations

Other resources

Chapter 46. Radiation information and resources online

Abstract

Books

Journals

Organizations

US Government

International

Databases

Other resources

List servers

Nuclear weapons, weapon reduction, and accidents

Review articles

Chapter 47. Regulatory toxicology

Abstract

Introduction

References

Resources

Journals

Journal articles

Organizations

Other resources

Chapter 48. Risk assessment

Abstract

Introduction

References

Resources

Chapter 49. Substances of abuse

Abstract

Introduction

Resources

Chapter 50. Target sites: general

Abstract

Introduction

References

Further reading

Resources

Journals

Journal articles

Organizations

Databases

Chapter 51. Target sites: cardiovascular

Abstract

Introduction

Resources

Journal articles

Organizations

Other resources

Chapter 52. Endocrine toxicology

Abstract

Information resources section

Reviews and other key papers

Organizations

Online databases and tools

Other resources

Chapter 53. Gastrointestinal tract

Resources

Journal articles

Online web-based resources

Chapter 54. Target sites: hematopoietic

Abstract

Introduction

Resources

Journal articles

Organizations

Databases

Chapter 55. Target sites: immune

Introduction

Resources

Journal articles

Databases

Chapter 56. Target sites: kidney

Abstract

Introduction

Resources

Review articles

Journals

Organizations

Chapter 57. Target sites: liver

Abstract

Introduction

Resources

Review articles

Journals

Chapter 58. Target sites: nervous system

Abstract

Introduction

Journal articles

Organizations

Other resources

Chapter 59. Target sites: respiratory

Abstract

Introduction

Resources

Journal articles

Organizations

Chapter 60. Target sites: sensory

Abstract

Introduction

Resources

Review articles

Journals

Databases

Organizations

Chapter 61. Target sites: skin

Abstract

Introduction

Resources

Journal articles

Journals

Online resources

Organizations

Chapter 62. Terrorism and warfare (chemical, biological, and radioactive and nuclear)

Abstract

Introduction

Chemical terrorism

Biological terrorism (bioterrorism)

Radiological terrorism

Innovations in delivery

Resources

Chapter 63. Testing methods and toxicity assessment (including alternatives)

Abstract

Introduction

Toxicity testing methods

Scientific information

Resources

Review articles

Databases

Chapter 64. Veterinary toxicology

Abstract

Introduction

Resources

Journal articles

Organizations

Part III: Other resources

Chapter 65. Organizations

Abstract

Introduction

Listing of organizations

Special groups

Chapter 66. Journals and blogs

Abstract

Introduction

Profile of journals from the web of science database

Citation metrics

PubMed Central

Predatory publications preying on the gullible and vain

References

Chapter 67. General interest, popular, and trade works: informing the citizenry

Abstract

New environmental threats and concerns, new vigilance

Role of libraries and librarians as gate keepers

General interest and periodical and serial sources

Popular magazines

Academic search complete tells some stories

Different database (slightly) different results

Trade journals

Popular and general interest books and monographs

References

Chapter 68. Government information and documents and technical reports

Abstract

Introduction

Government policies and actions affecting documents, information, and reports

Government documents’ finding tools and utilities

Additional finding tools and reporting resources for US federal environmental law and government documentation and reports

Online services

Treatises

International sources

Research guides

State government documents and reports

New York state, as an example

Tribal governmental information

Government information

National Institutes of Health

Centers for Disease Control and Prevention (CDC)

Environmental Protection Agency (EPA)

EPA national library network

Special considerations for government resources

General Accountability Office (GAO)

Technical report literature

TRAIL: a new road to search for technical documents

Silencing and denying science

Data rescue

References

Further reading

Chapter 69. Audio visual, nonprint, graphic, and other visualized resources

Abstract

Introduction

Films and motion pictures

Seminal reference works for film studies, films, and movies

Film and motion picture finding databases

TED Talks

Webinars and online training

Podcasts for environmental law

Graphics Interchange Format (GIF)

Photographs and posters

References

Further reading

Part IV: The online environment and data science

Chapter 70. The internet: recent trends

Abstract

Introduction

Journal articles

Search engines

Open access publishing

Wikis

Social networking platforms, big data and data fusion tools, and methodologies

Semantic web

Deep learning

Big data, toxicology, clinical and public health

Future directions

Additional papers

Chapter 71. Web-based databases

Abstract

Introduction

Web sites/portals with integrated databases, data analytics or visualizations for toxicological information

Databases with a focus on toxicology and related subjects

State or local government information

Focus on toxicogenomics

Chapter 72. Software tools for toxicology and risk assessment

Abstract

Introduction

Structure activity relationship (SAR) and (quantitative) SAR

QSAR tools

The broad universe of QSARs

QSAR applications for chemical screening, prioritization, and regulatory and corporate decision-making

QSAR reliability and validity

QSAR applications

Global context of QSARs and application by regulatory agencies

Resources

Journals special issues

Journal articles

Conclusions

Part V: Special topics

Chapter 73. Laws and regulations

Abstract

Introduction

Chemicals versus products and regulatory authorities

Laws, agencies, and regulations

Major international legislations

Compliance

Information resources

Chapter 74. Resources for chemical hazard communication compliance

Abstract

Introduction

Background

What is the core of chemical hazard communication?

What are the steps in communicating chemical hazards?

What is a SDS?

What resources are needed?

Are there other resources for hazard communication?

Chapter 75. Careers and professional education in toxicology

Abstract

Introduction

Careers and education in toxicology

Continuing education for professionals

Chapter 76. K-12 and public education

Abstract

Introduction

K-12 educational resources

Journal articles – education related

General educational resources

Public education resources

Environmental justice resources

Spanish resources

Chapter 77. Grants, scholarships, and funding

Abstract

Introduction

Funding legacy of the environmental protection agency

Funding issues at other federal departments and agencies

Superfund

Grants and funding finding tools and sources

Grantsmanship and grant writing resources

Private grants and funding finding sources

Federal Government Sources

Crowdsourcing and microfinancing

Education grants: scholarships and fellowships

References cited

Further reading

Chapter 78. Poison control centers

Abstract

Introduction

History

Poison centers

Poisons information service

Clinical treatment/intensive care units

The assessment of poisonings

Poison severity score

Single case evaluation

Notifications of poisonings

International associations

Literature

Chapter 79. Patents

Abstract

Introduction

References

Further reading

Resources

Journal articles

Organizations

Databases

Other resources

Acknowledgements

Index

Copyright

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Copyright © 2020 Elsevier Inc. All rights reserved.

Exception to the above (Chapter 5): 2020 Published by Elsevier Inc.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Note about the National Library of Medicine’s (NLM) Toxicology Information Resources

For decades, the U.S. National Library of Medicine has played a prominent role in offering free publicly available information resources in toxicology. These have been built variously by NLM and other organizations and made accessible via its Toxicology and Environmental Health Information Program (TEHIP), a unit within the Division of Specialized Information Services (SIS). In June of 2019, SIS was merged into the Division of Library Operations (LO) and the Office of Computer & Communications Systems (OCCS). NLM has reviewed and evaluated services and offerings formerly offered by SIS, including TEHIP, identifying which products support the NLM Strategic Plan and represent unique offerings from NLM. NLM has been intent on integrating SIS offerings into more current and standard technology and migrated TOXNET information, a large part of which has been retained, to PubChem, PubMed, and Bookshelf, in late 2019 and early 2020.

The authors and editors have tried to assure that individual chapter information related to NLM resources, as well as those originating elsewhere, is current as we were going to press. Inevitably there is a gap in time between seeing proofs and actual hard copy monograph publication. In short, this note is intended as a caveat for readers to dig further if, for example, a particular resource seems to be no longer available or a URL may not work.

For more information on NLM resources - [e-mail] or 1-888-346-3656; also consider consulting https://support.nlm.nih.gov and https://www.nlm.nih.gov/toxnet/index.html.

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Dedications, with Love

Philip Wexler

To my wife, Nancy; mom, Yetty; dad, Will (in memory of); son, Jake; and spaniel mix, Gigi

Steven G. Gilbert

To knowledge, may it lead to truth.

Asish Mohapatra

To my wife Sarah, daughter Maya, my Mom (Kanak), and Dad (Mahendra)

Sol Bobst

I dedicate this edition to Jessica Culley, for her love and support of my projects and business, and for being gracious with me and my idiosyncrasies.

Antoinette Hayes

To my husband and fellow scientist Martin, my son Tauer, and my daughter Gigi

Sara T. Humes

To my husband Richard and my parents Ed and Maria

As Well As

To the many casualties of the 2020 global COVID-19 pandemic and the brave, caring, and generous people helping us get through it and return to normalcy.

and

With appreciation to the scientists and other good people working to reverse the ravages of pollution and global climate change and take us to a habitable, clean, healthy, and sustainable environment.

List of Contributors

Martins O. Ainerua,     Cardiovascular Division, University of Manchester, Manchester, United Kingdom

Iris An,     Milken Institute School of Public Health, The George Washington University, Washington, D.C., United States

Charles C. Barton,     Independent Consultant, Alpharetta, GA, United States

Sol Bobst,     ToxSci Advisors LLC, Houston, TX, United States

Marie Bourgeois,     Center for Environmental/Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, United States

Megan Branson,     Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States

Bruce Busby,     Fred Hutchinson Cancer Research Center, Seattle, WA, United States

Brenda Carito,     Alnylam Pharmaceuticals, Cambridge, MA, United States

Clark Carrington,     Spoiled Hike LLC, Stanardsville, VA, United States

Grace A. Chappell,     ToxStrategies, Inc., Asheville, NC, United States

Guang-Di Chen,     Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, NY, United States

Debra Cherry,     University of Washington, Seattle, WA, United States

Karen Chou,     Michigan State University, East Lansing, MI, United States

Joseph A. Cichocki,     Alnylam Pharmaceuticals, Cambridge, MA, United States

Louis Anthony Cox Jr.

Cox Associates, Denver, CO, United States

University of Colorado, Denver, CO, United States

Yuri Bruinen de Bruin,     European Commission Joint Research Centre, Knowledge for Security & Migration, Ispra, Italy

Aisha S. Dickerson,     Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States

David C. Dorman,     Department of Biomedical and Molecular Sciences, College of Veterinary Medicine North Carolina State University, Raleigh, NC, United States

Ruth A. Etzel,     Milken Institute School of Public Health, The George Washington University, Washington, D.C., United States

Allan S. Felsot,     Washington State University, Richland, WA, United States

Jeremy A. Freeman,     Omeros Corporation, Seattle, WA, United States

Katie Frevert,     Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States

Elizabeth Friedman,     Children's Mercy Hospital, Kansas City, MO, United States

Shayne Gad,     Gad Consulting Services, Raleigh, NC, United States

Victoria Gifford,     Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States

Steven G. Gilbert,     Institute of Neurotoxicology and Neurological Disorders, Seattle, WA, United States

Julie E. Goodman,     Gradient, Boston, MA, United States

Anshul Gupta,     Amgen Research, Department of Pharmacokinetics and Drug Metabolism, Cambridge, MA, United States

Kevin Guth,     Center for Environmental/Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, United States

Axel Hahn,     Federal Institute for Risk Assessment, Max-Dohrn-Straße, Berlin, Germany

Raymond D. Harbison,     Center for Environmental/Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, United States

Esther M. Haugabrooks,     Physicians Committee for Responsible Medicine, Washington, D.C., United States

A. Wallace Hayes

University of South Florida, College of Public Health, Tampa, FL, United States

Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, United States

Antoinette Hayes,     Scientist II Nonclinical Development Toxicology, Sage Therapeutics, Cambridge, MA, United States

Stacey Herriage,     Physiological Sciences, College of Veterinary Medicine, Interdisciplinary Toxicology Program, Oklahoma State University, Stillwater, OK, United States

Richard C. Hertzberg,     Biomathematics Consulting, Atlanta, GA, United States

Stephanie Holmgren,     Office of Data Science, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC, United States

Tamara House-Knight,     Ramboll US Corporation, Little Rock, AR, United States

Sara T. Humes,     Department of Environmental and Global Health, Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, United States

Devin Hunt,     Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States

William Irwin,     Risk Assessment Division, United States Environmental Protection Agency, Washington, D.C., United States

Maryam Zare Jeddi,     Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands

Samantha J. Jones,     Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, D.C., United States

James E. Klaunig,     Laboratory of Investigative Toxicology and Pathology, School of Public Health, Indiana University, Bloomington, IN, United States

Cecile M. Krejsa,     Kartos Therapeutics, Bellevue, WA, United States

Meredith G. Lassiter,     Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, Durham, NC, United States

Abby A. Li,     Senior Managing Scientist, Health Sciences, Exponent, Inc., Oakland, CA, United States

Edward P. Locke,     Homeland Security Studies, School of Security and Global Studies, American Public University System, American Military University, American Public University, Charles Town, WV, United States

Heather N. Lynch,     Cardno ChemRisk, Boston, MA, United States

Andrew Maier,     Cardno ChemRisk, Cincinnati, OH, United States

Stacey Mantooth,     VISTA Technology Services, Inc. Contractor for the NIEHS Library, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC, United States

M. Elizabeth Marder,     Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Sacramento, CA, United States

Asish Mohapatra,     Contaminated Sites, Environmental Health Program, Health Canada, Calgary, AB, Canada

Virginia Moser,     Consultant, Apex, NC, United States

M. Moiz Mumtaz,     ATSDR, Atlanta, GA, United States

Lewis S. Nelson,     Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark, NJ, United States

Kenneth J. Olivier, Jr.,     Olivier KOnsulting, Attleboro, MA, United States

Amanda S. Persad,     Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States

Mark Pershouse,     Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States

Rebekah Petroff,     Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, United States

Carey Pope,     Physiological Sciences, College of Veterinary Medicine, Interdisciplinary Toxicology Program, Oklahoma State University, Stillwater, OK, United States

Elizabeth Putnam,     Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States

Gary O. Rankin,     Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States

Glenn E. Rice,     US EPA, Cincinnati, OH, United States

Tara Sabo-Attwood,     Department of Environmental and Global Health, Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, United States

Cynthia Santos,     Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark, NJ, United States

Barbara B. Saunders-Price,     Retired NBC Consultant, Applied Science and Analysis, Kaneohe, HI, United States

Johanna E. Schaaper,     Independent Consultant, Durham, NC, United States

Dietrich (Dieter) Schwela,     Stockholm Environment Institute, University of York, York, United Kingdom

Jane Ellen Simmons,     US EPA, Research Triangle Park, NC, United States

Gregory J. Smith,     Department of Genetics, University of North Carolina, Durham, NC, United States

Kenneth R. Still,     Executive Director/Toxicology Consultant, Occupational Toxicology Associates, Inc., Lake Oswego, OR, United States

Frederick W. Stoss,     State University of New York University at Buffalo, Buffalo, NY, United States

Dexter W. Sullivan, Jr.,     Gad Consulting Services, Raleigh, NC, United States

Michele R. Sullivan,     MRS & Associates, Arlington, VA, United States

Alicia A. Taylor,     Exponent, Inc., Oakland, CA, United States

Greet B.A. Teuns,     Global Safety Pharmacology, Nonclinical Safety, Janssen Research & Development, Janssen Pharmaceutica N.V., Beerse, Belgium

Karen Tilmant,     Bayer S.A.S., Valbonne, Sophia Antipolis Cedex, France

Monica A. Valentovic,     Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States

Sander Van Der Linden,     Biocides Department, European Chemicals Agency, Helsinki, Finland

Nina Ching Y. Wang,     Environmental Public Health Science, Health Protection Branch, Public Health and Compliance Division, Alberta Health, Edmonton, AB, Canada

Katherine D. Watson,     Reader in History, School of History, Philosophy and Culture, Oxford Brookes University, Oxford, United Kingdom

Eleanor Weston,     VISTA Technology Services, Inc. Contractor for the NIEHS Library, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC, United States

Philip Wexler,     National Library of Medicine, Bethesda, MD, United States (Retired)

Catherine F. Wise,     Department of Biological Sciences, Environmental and Molecular Toxicology Program, North Carolina State University, Raleigh, NC, United States

James T.F. Wise,     Division of Nutritional Sciences, Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, United States

John Pierce Wise Sr.,     Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, United States

John P. Wise Jr.,     Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, United States

Jamie L. Young,     Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, United States

Robert R. Young,     MilliporeSigma, BioReliance® Testing Services, Rockville, MD, United States

Foreword to Fourth (previous) Edition

John Doull, University of Kansas Medical Center, Kansas City, KS, United States

Toxicology, like other sciences, has developed in phases. Toxicologists, however, claim that the initial phase of our discipline preceded that of most other biological sciences since it involved recognition by primitive man of the safe and dangerous agents in his environment. The next phase (antiquity and the Middle Ages) was characterized by the use of this information for good (therapeutics) and evil (poisoning). It was during the Renaissance that Paracelsus recognized the importance of the dose–response paradigm, and this marked the beginning of modern toxicology. Today toxicology is focused on molecular mechanisms, and using the Internet to store and exchange this and other information is becoming a key part in the evolution of toxicology. A major problem with using the Internet in toxicology is that the amount of information is overwhelming and that it varies greatly in quality. Information Resources in Toxicology addresses this problem by providing a roadmap for today’s online enthusiast, and an annotated bibliography for other information sources in toxicology. This book is a gold mine for those of us who make lists of our favorite toxicology and regulatory websites, and will be invaluable to everyone who wants to know where to find general and specific information in all areas of toxicology and risk assessment in the United States and around the world.

The fourth edition of Information Resources in Toxicology reflects the exponential growth of our discipline. Despite the book’s increased size, it is easier to navigate because its many chapters have been logically clustered into relatively few sections. Each chapter in the global arena and subject categorization sections has been written by a well-recognized expert to insure that it is both authoritative and current. Similarly, the chapters on the Internet and Digital Tools and Special Topics (legal, education, funding, etc.) provide a pragmatic hands-on approach that will be of immense value to scientific researchers not well versed in such ancillary concerns. The section on Other Resources offers chapters on print media (journals, newsletters, bibliographies and similar collections, agency and organization documents and reports, etc.), as well as a delightful chapter on General Interest and Popular Works which nicely supplements the chapters on Scientific Principles and History in the introductory section.

Foreword to Fifth Edition

A. Wallace Hayes, University of South Florida, College of Public Health, Tampa, FL, United States; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, United States

Toxicology is a paradoxical science; it has been used to kill and to cure. Like a living system, toxicology has a dynamic that reflects the almost daily changes in our understanding of biology and the interests, capabilities, and needs of toxicologists, regulators, and the public. Toxicologists must be involved in the decision-making processes, recognizing the need for scientific understanding, including translation of scientific findings into understandable terms that are suitable for decision-making and ensuring consistent prediction of hazards and risks before the actual exposure has occurred and to permit benefit–risk assessments of the consequences for such exposure.

Remember the scares about artificial sweeteners, pesticide residues in foods, genetically modified organisms, fluoride in toothpaste and drinking water, plasticizers, and flame-retardant chemicals? The problem generally comes from a narrow focus on an effect in isolation without giving equal weight to the biology of the system or species and the exposure. There often has been a lack of caution in extrapolating toxicity to other species and circumstances. How often do we have to relearn Paracelsus’ fundamental concept about the primacy of the dose?

The 5th edition of Information Resources in Toxicology helps with many of these misconceptions by guiding the toxicologist, the regulator, and the public health official to the numerous resources on the internet as well as providing a bibliography for an array of other information resources. This guidance directs the reader to both general and specific information in toxicology and risk assessment in the broadest global sense.

This new 5th edition somehow manages to contain the explosive growth of toxicology and risk assessment and the ever-increasing big data explosion in a mere two volumes. They are organized in a logical manner with chapters clustered appropriately, making for an easy read and for readily finding information, especially in exploring online sources. Part III (Other Resources) is unique, and may be the most useful, section of Volume I. Arranged by various resource formats, it complements the other specialized topical chapters. Volume II (The Global Arena) highlights resources available across the globe. The book is well indexed for quick and easy referencing. Chapter authors represent an array of experts, well recognized in the areas for which they have been asked to write. This is a tome that should be on your bookshelf.

Preface

The 1st edition of this work, Information Resources in Toxicology (IRT), was published in 1982 almost ancient times by scientific reckoning. Toxicology, back then, although not quite a fledgling science, had yet to achieve maturity. The evolution of its experimental and theoretical underpinnings was gradual and continues to be refined, although its standing as a peer of other scientific disciplines has for some time now been assured.

The societal impact of toxicology lends it a layer of practical relevance that not every science can claim. Given that we cannot avoid interacting with xenobiotics on a daily basis, toxicology is, in a sense, integral to our lives. News reports of toxicological incidents continue to fascinate and alarm. The media regularly reminds us of old and ongoing, or new and emerging, concerns to broad segments of the population, be it the exposure of inner-city residents, particularly children, to lead exposure, the scourge of tobacco and smoking (and now new potential dangers of vaping), human and animal food poisoning, the health effects of pesticides on homeowners, applicators, and their families, or the burgeoning opioid crisis. Individual incidents whether high-profile cases cloaked in intrigue such as the nerve agent poisonings of four people in the United Kingdom, victims of a suspected Russian assassination attempt, or the average (perhaps not quite average) Virginia man who pleaded guilty to attempting to kill his 95-year-old mother-in-law by spiking her coffee with methamphetamine, easily grab world and local headlines.

On the scale of the wider environment, chemicals are ubiquitous and adamant in their refusal to respect geographic boundaries. Developing countries with burgeoning economies are fueling much of this pollution, compromising the health of their citizens and people at a distance. And yet asking the developing world to eschew rapid economic progress in favor of a paced and sustainable approach for the benefit of the Earth and future generations requires discussion, diplomacy, compromise, and patience. While piecemeal efforts are being made around the globe to limit greenhouse gas emissions and otherwise rein in chemical releases, there is no international coordinated approach available, although the United Nations’ Paris Agreement, ratified by 185 Parties as of April, 2019 is a start. Much work remains to be done. Those who ignore the reality of global climate change do so at the peril of the Earth and civilization.

The current 5th edition’s (IRT-5) overall structure and goals adhere closely to those established in the previous four editions. The intent remains to provide an extensive annotated bibliography and sourcebook to information in toxicology, a compilation of references to key documents, organizations, and other resources. The extent to which digital versions of these resources, either complementing or replacing traditional paper formats, has expanded, is considerable. It becomes an ever-greater challenge to encompass the diversity and multiple nodes of toxicology within a single publication such as this one. However, the editors felt that despite the pervasiveness of information on the Internet, its search capabilities and free availability, there were still significant advantages to a structured compendium, avoiding much of the extraneous information widely scattered on the web, and focusing on the relevant, regardless of format. For some, hard copy books remain the reference tool of choice, even today. But IRT-5’s availability on Elsevier’s ScienceDirect gives readers more comfortable with the digital environment the option of also navigating and searching the book’s content in an online environment.

IRT-5 also benefits from being a highly curated work. The resources have been selected by six editors and well over 100 authors, prominent leaders in toxicology with expertise in the various topical and geographical areas represented in the chapters. Readers can feel confident that the resources here have not been indiscriminately thrown together but selected for quality and organized to facilitate efficient retrieval.

The dual stream of advances in the science of toxicology itself and in the information technology to assist in its research and deliver its results has resulted in an array of new tools for generating, capturing, organizing, and disseminating data. These web tools and resources have been extensively covered in this new edition.

Toxicology’s forward scientific advance has resulted in the blossoming of a host of new areas ripe for further investigation. Emerging subjects, such as -omics (including transcriptomics), nanotechnology, high-throughput screening, predictive modeling, alternative test systems, utilizing new biochemical reactivity assays, humans on a chip, etc., are joined with new perspectives on issues rooted in the past (e.g., chemical and biological warfare, animal welfare, effects of mixtures, risk assessment, ethical concerns). The Tox21 initiative (Toxicology in the 21st Century), for example, is a US federal research collaboration aimed at developing methods to rapidly and efficiently evaluate the safety of commercial chemicals, pesticides, food additives and contaminants, and medical products. The US Environmental Protection Agency, the National Toxicology Program, the National Center for Advancing Translational Sciences, and the Food and Drug Administration constitute the consortium which formed Tox21.

And who can tell what the implications will be of other cutting-edge and still to come technologies such as robotics. To what extent, for example, will drones help us monitor and perhaps neutralize carbon emissions and other sources of pollution. Or, for that matter, the recent creation of the world’s first 3D-printed heart using human tissue may offer a new approach to noninvasively testing toxic agents on human organs.

Although the focus of toxicology has always been on chemicals, the scope of each edition of IRT, including this one, has included biological and physical agents, particularly radiation, since their potentially hazardous effects are widespread and part and parcel of the science.

The online web environment is now an inevitable part of the professional and personal lives of most of us in the developed world, and remote and economically deprived regions are catching up quickly. Google, Wikipedia, blogs, online social networking, virtual environments, and 5G networks, have entered our daily vocabulary and lives, and offer ever-more novel approaches to make sense of raw, sprawling information, offering ways to make it find just what we are looking for whenever, wherever. Toxicology has benefited from these technologies.

IRT-5 also continues the tradition of being as globally encompassing as practicable. We have included virtually all the countries from the 4th edition, plus added over a dozen more, highlighting their most significant toxicological information resources. A separate chapter looks at multilateral activities, including international conventions and initiatives relevant to the science.

Thanks are due, foremost, to my five Associate Editors, Sol Bobst, Steve Gilbert, Toni Hayes, Sara Humes, and Asish Mohapatra. Their unparalleled knowledge of the science and significance of toxicology and its information infrastructure proved invaluable. Our overlapping networks of well-informed colleagues from whose ranks we drew chapter contributors, and our ability to work well together, made the creation of this book a smooth and enjoyable process. And, of course, our many contributors, among whom the above editors are also included, form both the backbone of the book and the cement which holds it together.

Additional acknowledgment and praise is due to Kattie Washington, Megan Ashdown, and Punithavathy Govindaradjane, our Acquisitions, Developmental, and Production Editors respectively, and other staff on down the Elsevier line, for recognizing the value of a fifth edition, nudging it through its amorphous beginning and helping it solidify into a well-designed whole.

Editor-in-Chief

Philip Wexler

Part I

Introduction

Outline

Chapter 1 Toxicology: a primer

Chapter 2 History of toxicology

Chapter 3 Development of toxicoinformatics

Chapter 4 Toxicoinformatics today

Chapter 5 Starting points for finding toxicology resources

Chapter 1

Toxicology: a primer

A. Wallace Hayes¹, ²,    ¹University of South Florida, College of Public Health, Tampa, FL, United States,    ²Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, United States

Abstract

Toxicology has advanced from the art of poisoning to a scientific-based discipline striving to understand how chemicals adversely alter homeostatic mechanisms and to developing paradigms to predict the safe use of chemicals in daily life. Newer and better tools are continuously being developed, including in silico, omics, and systems biology, along with exciting new methods to not just understand dose but also to understand the more relevant dose time paradigm. Following centuries of trial and error, three axioms have emerged that are central to toxicology: people differ, dose matters (as does timing), and things change. The real and most difficult question for the toxicologist is Is It Safe? and under what exposure conditions. To answer these questions, sufficient, and appropriate information (data) is needed in two broad areas: the toxicity or hazard profile of the chemical and the exposure details regarding the individual or population under consideration.

Keywords

Tox21; toxicology; dose matters; people differ; things change

Toxicology is the science of poisons or the study of the untoward effects of chemicals or physical agents on biological systems. It has evolved over the centuries from the trial and error skills of the hunter-gatherer in finding safe food, to the applied art of poisoning enemies, to a highly sophisticated science of mechanisms that is built upon numerous biomedical disciplines, including systems biology, molecular genetics, and molecular biology. The study of the deleterious interactions between an agent and a biological system falls within the scope of toxicology. Yet toxicology remains a paradox—All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy. So stated, presciently, Philippus Theophrastus Aureolus Bombastus von Hohenheim (Paracelsus), a 16th century German–Swiss physician and alchemist.

From the beginning of civilization, man, in his quest for food, learned the ironic fact that certain potential foods produced varying degrees of illness or even death, and he soon was able to differentiate between the harmful and beneficial consequences associated with taking such materials into his body. Substances were, perhaps too readily, assigned a tag either of safe or toxic, a dichotomy that in some ways has persisted to the present day. However, it is impossible to describe such a clear line of demarcation between strictly beneficial chemicals and harmful ones. The degree of harm or safety for any chemical is not always clear, though, because as Paracelsus noted, the dose makes the poison. All chemicals, including therapeutic drugs, can cause harmful effects in sufficiently large amounts. For example, both botulinum toxin (a neurotoxin protein produced by the bacterium Clostridium botulinum and one of the most poisonous natural toxicants known) and thalidomide (a synthetic chemical that caused severe birth defects in the offspring of mothers taking the sedative during pregnancy) are now Food and Drug Administration (FDA)-approved for selected treatments in humans.

Many of the earliest practitioners of toxicology were women. For example, Lucrezia Borgia, the daughter of Rodrigo Lenzuoli Borgia or Pope Alexander VI, who specialized in faith-based poisoning, was an early Italian who helped develop poisoning into a simple but fine art. It is said that the Borgias selected and laid down rare poisons in their cellars with as much thought as they gave to their vintage wines. Catherine de Medici of Florence and Queen Consort of France tested and carefully studied the effects of various toxic concoctions on the poor and sick, noting the onset of action, and symptoms that occurred. Marquise de Brinvillers poisoned her father, two brothers, and her sister for their inheritance. Catherine Deshayes or La Voisin, who traded in selling poisons to wives who wished to rid themselves of their husbands, was later burned at the stake. One of the most prolific arsenic-poisoners in history was Goeie Mie (Good Mary) of Leiden, The Netherlands, who lived in the 19th century. She poisoned at least 102 friends and relatives (27 died) between 1867 and 1884, distributing arsenic trioxide in hot milk to her victims after opening life insurance policies in their names. An even earlier practitioner of the art was Locusta of Gaul, the notorious poison mixer in ancient Rome who was hired in CE 54 by Agrippina the Younger, the wife of Emperor Claudius, to poison her husband, and by Nero in CE 55 to poison his half brother, Britannicus. She accomplished her task for Nero but only following her second attempt; it is not clear as to the outcome of her service to Agrippina. Locusta was condemned to death in CE 69 by Emperor Galba.

History is filled with toxic events, such as Cleopatra’s voluntary suicide by an asp (a venomous snake) or Socrates’ mandated suicide by hemlock (the poisonous plant, Conium maculatum, a common European herb that was probably the state poison of Ancient Greece). Adding arsenic or hellebore (an herb that is a cardiac poison) to wine was discreet, nearly undetectable, and considerably less messy than a gun or a knife. Little has changed in the ensuing years. Poisons, as the solution to delicate political problems, became an art form not unlike painting or sculpture during the Renaissance period. Claims have been made that members of the Politburo allegedly gave Stalin warfarin (a synthetic derivative of coumarin, a chemical found naturally in many plants, and used as an anticoagulant medication) and that the Central Intelligence Agency (CIA), using botulinum-laced pills, made attempts on the life of Cuban Dictator Fidel Castro. Evidence strongly suggests that Ukrainian President Viktor Yushchenko was poisoned with dioxin (the common name for the group of compounds classified as polychlorinated dibenzodioxins) in an attempt to remove him from office as recently as 2006. Even more recently, radioactive, and Novichok nerve agents have been used, both successfully and unsuccessfully.

The first biological weapon described in Western literature may be the poison from a many-headed serpent, the Hydra, to poison Hercules’ arrows. This led to the term toxic (from toxikon, Greek for poison arrow). The Romans used a variety of biological weapons as did Hannibal who had his sailors catapult pots full of venomous snakes onto the decks of opposing fleets. Other biological weapons have included (1) the use of bellows in 4th century BCE China to pump smoke from mustard and other noxious vegetable matter into tunnels dug by besieging armies; (2) smallpox-infected blankets that the British sent to the American Indians during the French and Indian Wars; (3) animal carcasses thrown by Confederate forces into wells during the US Civil War; and (4) sharp bamboo stakes smeared with human feces by the Vietcong during the Vietnam War.

More modern toxic weaponry includes chlorine gas (the first lethal chemical used in modern warfare), phosgene, hydrogen cyanide, mustard gas, tear gas, and Zyklon B (crystallized hydrogen cyanide). Chemical agents (mustard, sarin, and tabun) were used in the Iran–Iraq War between 1983 and 1985 during which it was reported that as many as 7000 people were killed by these gases. Sarin gas contained in lunch boxes was released in the Tokyo subway system in 1995 killing 12 people. This attack was followed by the deaths of five people in the United States in 2001 by anthrax-laced letters. And one should not forget the cyanide-laced grape punch that Jim Jones forced his followers to consume killing the entire congregation of 912 people, including 276 children, or the incident in New Sweden, Maine, where one person died from consuming coffee laced with arsenic. Because of its potency and its frequent use among the ruling class, arsenic is often referred to both as The King of Poisons and The Poison of Kings. And we must never forget the unthinkable use of Zyklon B by the Nazis during World War II.

Poisons may be found naturally in our foods. These natural toxicants include fungal toxins such as aflatoxin, shellfish toxins, bacterial toxins, and algal poisons. The world is full of toxins produced by a variety of plants and animals. Man has added to the list of poisons arising from his ability to chemically synthesize a large number of useful but potentially harmful materials. Environmental and workplace pollutants, arising from natural and man-made chemicals, are another cause of concern to the toxicologist.

Ultimately, the purposes of toxicology are (1) to protect individual and public health, and the environment; (2) to provide information about the nature and severity of potentially harmful effects on human and animal health, and the environment; (3) to ensure safe working conditions; (4) to ensure that products including our food, water, and air are safe; and (5) to mitigate damage to natural habitats while at the same time allowing humankind to enjoy the benefits of a modern society. To achieve these goals, toxicology borrows freely from the basic sciences.

The multidisciplinary nature of toxicology is its greatest strength. By incorporating the capabilities and techniques of the biomedical sciences, including epidemiology and statistics, and the physical sciences of chemistry and physics, toxicologists utilize a wide range of expertise to investigate issues of critical concern to society.

Toxicology can be subdivided in a number of ways. One such division is based on the disciplines involved: (1) environmental; (2) economic; and (3) medical. Environmental toxicology includes the roles that engineers, environmental scientists, and chemical specialists play in the identification and quantification of both natural and synthetic pollutants, and the transfer of chemicals between and within air, soil, and water. Economic toxicology involves biologists, chemists, and basic medical scientists who identify and quantify the chemicals responsible for toxicological problems in industry, in foods, in consumer products, and in drugs both for humans and our animal friends. Medical toxicology utilizes the capabilities of physicians and veterinarians for the diagnosis and therapy of chemical intoxications, including the forensic aspects of clinical toxicology.

The consequences of the adverse effects of chemicals can be divided into one of two broad categories: (1) irreversible damage such as mutagenicity, carcinogenicity, teratogenicity, or death; and (2) reversible damage provided the initial insult does not totally overwhelm the exposed organism. Reversible effects may include, for example, organ damage (liver enlargement, gastrointestinal erosion) and functional damage (enzyme induction, respiratory depression).

There are at least four basic principles that are generally applicable to all chemically induced biological effects of toxicological interest:

1. The chemical must reach a receptor site in a biological system before an effect can be produced. The pharmacokinetics (i.e., how the body acts on the chemical) and pharmacodynamics (how the chemical acts on the body) of the chemical in the biological system are essential in understanding how a chemical reaches the receptor.

2. Not all chemically induced effects are harmful (the basis for drug therapy).

3. The occurrence, intensity, and frequency of chemically induced biological effects are dose-related (remember our old friend, Paracelsus).

4. Effects of chemicals on animals, if properly qualified, are generally applicable to humans. The physiology, biochemistry, and anatomy must be evaluated and correlated between the test species and the human; generally, when the pharmacokinetics and pharmacodynamics of two species operate in a similar fashion, these two species will respond similarly to the same chemical.

How do we determine these untoward or adverse effects? There are sufficient data to indicate that every chemical is capable, under some conditions, of producing an effect on a biological system. These conditions vary greatly; from being practically unattainable under ordinary circumstances to being so readily attained that exposure of living tissue to minute doses of certain chemicals destroys cells. Effects vary from insignificance (i.e., the cell is able to carry on its normal function) to deleterious, and even lethal, effects resulting from extremely small amounts of some chemicals.

Most of the toxicological test methods that have been developed are the results of the practical need to obtain as much information as possible about the effects of chemicals on humans and the environment. Human experimentation is generally not part of a toxicology testing protocol because of moral, ethical, and legal restrictions. Exceptions include testing of therapeutic agents and, to a much more limited extent, some consumer products and pesticides where stringent human protocols are employed. Testing methods in toxicology, therefore, most often involve the use of animals based on the hypothesis that results of toxicity studies in suitable animal models may be extrapolated to humans. That is, one may infer, to some extent, the human response based upon the response of an appropriate animal model. Today, more and more toxicity testing procedures include the use of nonmammalian species, cell cultures, individual cells, and in silico approaches (i.e., computer-simulated).

Over the years certain types of toxicity testing procedures have been designed, modified, and improved so that they are generally acceptable by most toxicologists. In fact a number of such protocols have been harmonized and accepted by governmental agencies around the world based upon acceptance of the protocol established by the Organization for Economic Cooperation and Development (OECD). OECD is an international organization helping governments tackle the economic, social, and governance challenges of a globalized economy. Thirty-five countries now comprise the OECD and these countries have agreed to accept toxicology studies undertaken using OECD protocol guidelines. In addition, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration. ICH’s mission is to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed in the most resource-efficient manner. The founding regulatory members are the European Union, the United States, and Japan. There are six additional regulatory members of ICH along with a number of drug companies.

Toxicological tests are designed to define the conditions that must be present when a biological cell is affected by a given chemical entity, and the nature of the effect produced. The result is manifested as an effect on the function, and in many cases the structure, of the biological system. Toxicity tests are conducted not only for the purpose of demonstrating the existence of toxic effects but also to help estimate the limits of safety associated with the use of a chemical. In any attempt to establish a concentration of a chemical in any toxicological test procedure, it is important to define what is meant by effect and the confidence that can be placed on the results of the test. Essentially, certain measurable detrimental changes must take place within the animal, and within a reasonable amount of time after exposure.

In a properly conducted toxicity test, a control is run in parallel to the assay to ensure the viability and validity of the test system. Except for the omission of the test chemical, a negative control is run under exactly the same conditions as the test assay, including any vehicle (or solvent). The test outcome (cell growth, death, tumor incidence) must be statistically different from the negative control for the test to be considered positive. Ideally, there will also be a positive control (i.e., an agent that is known to give a positive result in the test assay). This is important because, in the event that the test results are negative, the positive control will demonstrate that it is at least possible to elicit the toxicity under investigation in the same species and using the same assay system. Otherwise, it is not known if the species or assay system is at all capable of showing the type of toxicity under investigation. The extent to which a chemical is studied in the toxicology laboratory is largely dependent on the intended use of the compound. Those compounds that are intended for introduction into humans, such as drugs or food additives, require extensive toxicological testing. If the chemical (i.e., a drug) is to be used for only short periods, the extent of the toxicological testing is different than that for chemicals that are to be used over long periods of time. Any chemical that is incorporated into hundreds of household or consumer products requires extensive toxicological testing even though the material may not be intended for direct consumption by humans.

Extensive toxicological testing means that the chemical or product is subjected to a series of individual tests that are designed to detect specific types of toxicity. If the chemical or product eventually will become an environmental pollutant, the extent of testing may well involve insects, fish, wildfowl, and/or the species of interest. Thus in modern society, no chemical or product should be made available for human exposure (use or potential misuse) without appropriate toxicological evaluation by accepted methodology.

Toxicology testing protocols include the following types of tests: in situ (to examine the phenomenon exactly in place where it occurs; examining a cell within a whole organ intact and under perfusion); in silico, in vitro, and in vivo procedures. A list of the various types of animal toxicological tests is found in Table 1.1. Details of the tests summarized in Table 1.1 as well as the importance of care and maintenance of experimental animals can be found in Hayes and Kruger (2014).

Table 1.1

Notes on Table 1.1:

Acute testing takes place during relatively short periods of time in relation to an animal’s life span. Chronic testing takes place during relatively long periods of time in relation to an animal’s life span. Subchronic testing falls somewhere in between the two extremes.

The Lethal Dosage 50 (LD50) is the amount of a chemical that is lethal to 50% of the experimental animals exposed to it, when ingested. Lethal Concentration 50 (LC50) is a similar type of lethality expressed as a function of concentration, usually when animals are exposed to the chemical via inhalation.

Toxicological tests are necessary to assess the harm or safety of medicines, consumer products, foods and food additives, pesticides, household products, and industrial chemicals. Traditionally, these methods have used animals; however, in recent years, there has been increasing interest in developing alternative methods that reduce or replace animal use and that refine animal use to lessen or eliminate pain and distress.

Russell and Burch (1959) were the first to describe the concept of alternative methods. Commonly referred to as the 3R, this concept involves reducing the number of animals needed for a test, replacing animals with nonanimal systems and approaches, and refining animal use to lessen or avoid pain and distress. Laws have been passed in the United States and around the globe requiring consideration of alternative methods prior to the use of animals in biomedical research and testing.

Following centuries of trial and error and detailed scientific investigation in more recent times, three axioms have emerged that are central to toxicology. These axioms, as posited originally by Mitchell et al. (2004) and expanded by Hayes and Dixon (2017) are (1) people differ; (2) dose matters; and (3) things change.

People differ: Individual differences are due to a number of factors including individual genetic makeup (polymorphisms), age (fetus, neonate, children, adults, elderly), gender (male, female, pregnant female), inherent drug metabolism, lifestyle factors (smoking, alcohol use, previous exposures), health status including various diseases, and preexisting or simultaneous exposure to environmental agents, household products, or therapeutic agents. Classic examples of the fact that people differ include allergies to food (e.g., peanuts and shellfish) and to drugs (e.g., penicillin).

Even more striking are the differences in the effects of the same chemical on a single individual that may be observed during various stages of life (in utero, neonate, young adult, elderly). Table 1.2 illustrates how much more sensitive newborn rats are than older rats to dichlorodiphenyltrichloroethane (DDT).

Table 1.2

Dose matters: A good starting point for understanding toxicology is the postulate that all substances have the potential to be toxic. Sodium chloride (table salt) used in moderation is fine in the human diet, but consuming half a cup of salt a day causes electrolyte and kidney problems and eventually death. A small amount of another salt, potassium cyanide, can kill a human. Knowledge of the relative toxicity (potency) of a chemical and its potential benefits helps determine whether the material is acceptable for a particular use and, if so, in what dose. Table 1.3 shows examples of typically safe daily doses of some common chemicals and their respective lethal doses.

Table 1.3

We are exposed to a myriad of chemicals, both natural and man-made, at work, home, and play every day—chemicals that we voluntarily consume in the foods we eat, in the drugs we ingest, in the water we drink, and in the air we breathe. We are also exposed to chemicals in the various personal care products that we apply to our skin. Fortunately, when a potentially hazardous material is distributed widely enough over an area, it is usually innocuous. For toxicity problems to arise, relatively high concentrations of the chemical are usually required (Botulinum toxin is one counter example where even a tiny amount results in adverse effects). We also need to remember that natural is not the same as safe. Depending upon a host of conditions, both synthetic and natural products may be safe or hazardous.

As Paracelsus articulated, the relationship between the dose of a chemical and its toxicity is fundamental to toxicology. Although we cannot always measure it, there is a dose at which there is no untoward or adverse effect (threshold) or, indeed, a beneficial effect, as with drugs. Similarly, there is an upper dose yielding a maximal response. Elucidation of this threshold phenomenon depends upon which parameters of toxicity or response are measured because there are different dose concentrations for different types of toxicity, ranging from measures of morbidity (elevated enzymes) to mortality. Consider Fig. 1.1, showing a safe and therapeutic dose of aspirin at about 100 mg/kg and the variety of effects that occur as the dose increases.

Figure 1.1 Individual dose–response relationship.

A threshold, or concentration, below which no adverse effect is observed, depending upon a variety of factors and circumstances, is deemed to be safe following certain adjustments. Hence, such designations as (1) threshold limit values for workplace exposure; (2) No Observable Effect Level for industrial chemicals; and (3) No Observable Adverse Effect Level for pesticides, have been developed and accepted by regulatory agencies around the world.

The concept of a threshold for noncarcinogenic chemicals is for the most part universally accepted; however, controversy exists as to whether a threshold exists for genotoxic carcinogenic chemicals. Establishing a threshold for such chemicals poses serious challenges. However, intuitively, human exposure to low doses of known or suspected cancer-causing agents, without ill effect, suggests that carcinogenic thresholds, at least for some such chemicals, must exist. Sunlight (ultraviolet, or UV, radiation), certain consumer products containing formaldehyde or formaldehyde-releasing chemicals as a preservative, and grilled and fried goods (containing benzo-a-pyrene and/or acrylamide) are examples of genotoxic cancer-causing chemicals that have thresholds.

The overall toxicity profile of a chemical depends on a number of factors, including but not limited to the following: dose, intake route (ingestion, inhalation, dermal), exposure period (single