Green Processes: Designing Safer Chemicals

By Wiley

The shift towards being as environmentally-friendly as possible has resulted in the need for this important reference on the topic of designing safer chemicals. Edited by the leading international experts in the field, this volume covers such topics as toxicity, reducing hazards and biochemical pesticides.
An essential resource for anyone wishing to gain an understanding of the world of green chemistry, as well as for chemists, environmental agencies and chemical engineers.

• Language: English
• Publisher: Wiley
• Release date: Apr 23, 2014
• ISBN: 9783527688432

Book preview

CONTENTS

Cover

Related Titles

Title Page

Copyright

About the Editors

List of Contributors

Preface

Chapter 1: The Design of Safer Chemicals: Past, Present, and Future Perspectives

1.1 Evolution of the Concept

1.2 Characteristics of a Safer Chemical

1.3 The Future of the Concept

1.4 Disclaimer

References

Chapter 2: Differential Toxicity Characterization of Green Alternative Chemicals

2.1 Introduction

2.2 Chemical Properties Related to Differential Toxicity

2.3 Modeling Chemical Clearance – Metabolism and Excretion

2.4 Predicting Differential Inherent Molecular Toxicity

2.5 Integrating In Vitro Data to Model Toxicity Potential

2.6 Databases Relevant for Toxicity Characterization

2.7 Example of Differential Toxicity Analysis

2.8 Conclusion

2.9 Disclaimer

References

Chapter 3: Understanding Mechanisms of Metabolic Transformations as a Tool for Designing Safer Chemicals

3.1 Introduction

3.2 The Role of Metabolism in Producing Toxic Metabolites

3.3 Mechanisms by Which Chemicals Produce Toxicity

3.4 Conclusion

References

Chapter 4: Structural and Toxic Mechanism-Based Approaches to Designing Safer Chemicals

4.1 Toxicophores

4.2 Designing Safer Electrophilic Substances

4.3 Structure–Activity Relationships

4.4 Quantitative Structure–Activity Relationships (QSARs)

4.5 Isosteric Substitution as a Strategy for the Design of Safer Chemicals

4.6 Conclusion

4.7 Disclaimer

References

Chapter 5: Informing Substitution to Safer Alternatives

5.1 Design for Environment Approaches to Risk Reduction: Identifying and Encouraging the Use of Safer Chemistry

5.2 Assessment of Safer Chemical Alternatives: Enabling Scientific, Technological, and Commercial Development

5.3 Informed Substitution

5.4 Examples that Illustrate Informed Substitution

5.5 Conclusion

5.6 Disclaimer

References

Chapter 6: Design of Safer Chemicals – Ionic Liquids

6.1 Introduction

6.2 Environmental Considerations

6.3 Ionic Liquids – a Historical Perspective

6.4 From Ionic Liquid Stability to Biodegradability

6.5 Conclusion

References

Chapter 7: Designing Safer Organocatalysts – What Lessons Can Be Learned When the Rebirth of an Old Research Area Coincides with the Advent of Green Chemistry?

7.1 Introduction

7.2 A Brief History of Organocatalysis

7.3 Catalysts from the Chiral Pool

7.4 Rules of Thumb for Small Molecule Biodegradability Applied to Organocatalysts

7.5 Cinchona Alkaloids – Natural Products as a Source of Organocatalysts: Appendix 7.A [91,92,94–96,108–120]

7.6 Proline, the Most Extensively Studied Organocatalyst: Appendix 7.B [40, 54, 58d, 97–99, 103–107, 124–174]

7.7 Process of Catalyst Development

7.8 Analogs of Nornicotine – an Aldol Catalyst Exemplifying Natural Toxicity

7.9 Pharmaceutically Derived Organocatalysts and the Role of Cocatalysts

7.10 Conclusion

7.11 Summary

References

Chapter 8: Life-Cycle Concepts for Sustainable Use of Engineered Nanomaterials in Nanoproducts

8.1 Introduction

8.2 Life-Cycle Perspectives in Green Nanotechnologies

8.3 Release of Nanomaterials from Products

8.4 Exposure Modeling of Nanomaterials in the Environment

8.5 Designing Safe Nanomaterials

8.6 Conclusion

References

Chapter 9: Drugs

9.1 Introduction

9.2 Pharmaceuticals – What They Are

9.3 Pharmaceuticals in the Environment – Sources, Fate, and Effects

9.4 Risk Management

9.5 Designing Environmentally Safe Drugs

9.6 Conclusion

References

Chapter 10: Greener Chelating Agents

10.1 Introduction

10.2 Chelants

10.3 Common Chelants

10.4 Issues with Current Chelants

10.5 Green Design Part 1 – Search for Biodegradable Chelants

10.6 Comparing Chelating Agents

10.7 Six Steps to Greener Design

10.8 Case Study – Six Steps to Greener Chelants for Laundry

10.9 Conclusion

10.10 Abbreviations

References

Chapter 11: Improvements to the Environmental Performance of Synthetic-Based Drilling Muds

11.1 Introduction

11.2 Drilling Mud Composition

11.3 Characteristics and Biodegradability of SBFs

11.4 Case Study: Improvements in the Environmental Performance of Synthetic-Based Drilling Muds

11.5 Conclusion

References

Chapter 12: Biochemical Pesticides: Green Chemistry Designs by Nature

12.1 Introduction

12.2 The Historical Path to Safer Pesticides

12.3 Reduced-Risk Conventional Pesticides

12.4 The Biopesticide Alternative: an Overview

12.5 Biochemical Pesticides

12.6 Are Biochemical Pesticides the Wave of the Future?

12.7 Conclusion

12.8 Disclaimer

References

Chapter 13: Property-Based Approaches to Design Rules for Reduced Toxicity

13.1 Possible Approaches to Systematic Design Guidelines for Reduced Toxicity

13.2 Analogy with Medicinal Chemistry

13.3 Do Chemicals with Similar Toxicity Profiles Have Similar Physical/Chemical Properties?

13.4 Proposed Design Guidelines for Reduced Human Toxicity

13.5 Using Property Guidelines to Design for Reducing Acute Aquatic Toxicity

13.6 Predicting the Physicochemical Properties and Attributes Needed for Developing Design Rules

13.7 Conclusion

References

Chapter 14: Reducing Carcinogenicity and Mutagenicity Through Mechanism-Based Molecular Design of Chemicals

14.1 Introduction

14.2 Mechanisms of Chemical Carcinogenesis and Structure–Activity Relationship (SAR)

14.3 General Molecular Parameters Affecting the Carcinogenic and Mutagenic Potential of Chemicals

14.4 Specific Structural Criteria of Different Classes of Chemical Carcinogens and Mutagens

14.5 Molecular Design of Chemicals of Low Carcinogenic and Mutagenic Potential

14.6 Conclusion

14.7 Disclaimer

References

Chapter 15: Reducing Ecotoxicity

15.1 Introduction to Key Aspects of Ecotoxicology

15.2 Environmental Fate and Pathways of Exposure to Chemicals in the Environment

15.3 Mechanisms of Toxic Action

15.4 Examples of Methods That Can Be Used in Designing Chemicals with Reduced Ecological Risks

15.5 Overview, Conclusions, and the Path Forward

References

Chapter 16: Designing for Non-Persistence

16.1 Introduction

16.2 Finding Experimental Data

16.3 Predicting Biodegradation from Chemical Structure

16.4 Predicting Chemical Hydrolysis

16.5 Predicting Atmospheric Degradation by Oxidation and Photolysis

16.6 Designing for Biodegradation I: Musk Fragrances Case Study

16.7 Designing for Biodegradation II: Biocides Case Study

16.8 Designing for Abiotic Degradation: Case Studies for Hydrolysis and Atmospheric Degradation

16.9 Conclusion

16.10 Disclaimer

Abbreviations

References

Chapter 17: Reducing Physical Hazards: Encouraging Inherently Safer Production

17.1 Introduction

17.2 Factors Affecting the Safety of a Production System [1]

17.3 Chemical Safety and Accident Prevention: Inherent Safety and Inherently Safer Production

17.4 Incentives, Barriers, and Opportunities for the Adoption of Inherently Safer Technology

17.5 Elements of an Inherently Safer Production Approach [2, 3]

17.6 A Methodology for Inherently Safer Production

References

Chapter 18: Interaction of Chemicals with the Endocrine System

18.1 Interaction with the Endocrine System

18.2 Estrogens

18.3 Androgens

18.4 Hypothalamic-Pituitary-Thyroid (HPT) Axis

18.5 Endocrine Disruptor Data Development Efforts

18.6 Research Needs and Future

References

Index

End User License Agreement

List of Tables

Table 2.1

Table 2.2

Table 2.3

Table 2.4

Table 2.5

Table 3.1

Table 3.2

Table 3.3

Table 4.1

Table 4.2

Table 5.1

Table 5.2

Table 5.3

Table 5.4

Table 5.5

Table 6.1

Table 6.2

Table 6.3

Table 7.1

Table 7.2

Table 7.3

Table 7.4

Table 7.5

Table 8.1

Table 8.2

Table 8.3

Table 8.4

Table 9.1

Table 9.2

Table 9.3

Table 10.1

Table 10.2

Table 10.3

Table 10.4

Table 10.5

Table 10.6

Table 10.7

Table 11.1

Table 11.2

Table 11.3

Table 12.1

Table 12.2

Table 12.3

Table 13.1

Table 13.2

Table 13.3

Table 13.4

Table 14.1

Table 14.2

Table 14.3

Table 14.4

Table 14.5

Table 14.6

Table 14.7

Table 14.8

Table 14.9

Table 14.10

Table 14.11

Table 14.12

Table 14.13

Table 14.14

Table 14.15

Table 14.16

Table 14.17

Table 15.1

Table 15.2

Table 15.3

Table 15.4

Table 16.1

Table 16.2

Table 16.3

Table 16.4

Table 16.5

Table 18.1

Table 18.2

Table 18.3

List of Illustrations

Figure 1.1

Figure 1.2

Scheme 3.1

Scheme 3.2

Scheme 3.3

Scheme 3.4

Scheme 3.5

Scheme 3.6

Scheme 3.7

Scheme 3.8

Scheme 3.9

Scheme 3.10

Scheme 3.11

Scheme 4.1

Scheme 4.2

Scheme 4.3

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Scheme 4.4

Figure 4.6

Figure 5.1

Figure 5.2

Figure 5.3

Scheme 5.1

Scheme 5.2

Scheme 5.3

Scheme 5.4

Scheme 5.5

Scheme 5.6

Scheme 5.7

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 6.5

Figure 6.6

Figure 6.7

Figure 6.8

Figure 6.9

Figure 6.10

Figure 6.11

Figure 6.12

Figure 6.13

Figure 7.1

Figure 7.2

Figure 7.3

Figure 7.4

Figure 7.5

Figure 7.6

Figure 7.7

Figure 7.8

Figure 7.9

Figure 7.10

Figure 7.11

Figure 7.12

Figure 7.13

Figure 7.14

Figure 7.15

Figure 8.1

Figure 8.2

Figure 8.3

Figure 8.4

Figure 8.5

Figure 8.6

Figure 9.1

Figure 9.2

Figure 9.3

Figure 9.4

Figure 9.5

Figure 9.6

Figure 9.7

Figure 9.8

Figure 9.9

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 10.5

Figure 10.6

Figure 10.7

Figure 10.8

Figure 10.9

Figure 10.10

Figure 10.11

Figure 11.1

Figure 11.2

Figure 11.3

Figure 11.4

Figure 11.5

Figure 12.1

Figure 12.2

Figure 12.3

Figure 12.4

Figure 12.5

Figure 12.6

Figure 12.7

Scheme 13.1

Scheme 13.2

Scheme 13.3

Scheme 13.4

Figure 13.1

Figure 13.2

Figure 13.3

Figure 13.4

Figure 13.5

Figure 13.6

Figure 13.7

Figure 13.8

Figure 13.9

Figure 14.1

Figure 14.2

Figure 14.3

Figure 14.4

Figure 14.5

Figure 14.6

Figure 14.7

Figure 14.8

Figure 14.9

Figure 14.10

Figure 14.11

Figure 14.12

Figure 14.13

Figure 14.14

Figure 14.15

Figure 14.16

Figure 14.17

Figure 14.18

Figure 14.19

Figure 14.20

Figure 14.21

Figure 14.22

Figure 14.23

Figure 14.24

Figure 15.1

Figure 15.2

Figure 15.3

Figure 15.4

Figure 15.5

Figure 15.6

Figure 15.7

Figure 15.8

Figure 15.9

Figure 16.1

Figure 16.2

Figure 16.3

Figure 16.4

Figure 16.5

Figure 16.6

Figure 16.7

Figure 16.8

Figure 17.1

Figure 18.1

Figure 18.2

Figure 18.3

Figure 18.4

Figure 18.5

Figure 18.6

Figure 18.7

Figure 18.8

Figure 18.9

Figure 18.10

Figure 18.11

Figure 18.12

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Handbook of Green Chemistry

Volume 9

Designing Safer Chemicals

Edited by

Robert Boethling and Adelina Voutchkova

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Print ISBN: 978-3-527-32639-6

About the Editors

Series Editor

Paul T. Anastas joined Yale University as Professor and serves as the Director of the Center for Green Chemistry and Green Engineering there. From 2004–2006, Paul was the Director of the Green Chemistry Institute in Washington, D.C. Until June 2004 he served as Assistant Director for Environment at the White House Office of Science and Technology Policy where his responsibilities included a wide range of environmental science issues including furthering international public-private cooperation in areas of Science for Sustainability such as Green Chemistry. In 1991, he established the industry-government-university partnership Green Chemistry Program, which was expanded to include basic research, and the Presidential Green Chemistry Challenge Awards. He has published and edited several books in the field of Green Chemistry and developed the 12 Principles of Green Chemistry.

Volume Editors

Robert S. Boethling has been at the US Environmental Protection Agency headquarters in Washington, DC, Office of Pollution Prevention and Toxics (OPPT) since 1980. After earning his PhD degree in microbiology at UCLA (1976) he spent 2 years in Martin Alexander's soil microbiology lab at Cornell University, and came to EPA as it began its implementation of the Toxic Substances Control Act (TSCA). For many years he led environmental fate review for new chemical (Premanufacture Notice) substances under TSCA, the program from which predictive capabilities, tools and software in environmental chemistry emerged starting in the 1980s. He was a principal contributor in the development of several widely used computer programs, notably EPI Suite, the PBT Profiler, and the BIOWIN biodegradability estimation program. He is the recipient of many EPA medals for distinguished service and several EPA Science and Technology Achievement Awards (STAA), including awards for review of new chemical substances under TSCA and the Handbook of Property Estimation Methods for Chemicals: Environmental Health Sciences (Lewis/CRC, 2000, with Don Mackay).

Adelina Voutchkova is an Assistant Professor at the Department of Chemistry at the George Washington University. She received her Ph.D. from Yale University and subsequently joined the Center for Green Chemistry and Green Engineering at Yale as a research associate. Dr. Voutchkova's current research interests span both facets of green chemistry - the design of tools that chemists can apply to the rational design safer industrial chemicals, and the development of greener metal-catalyzed organic transformations.

List of Contributors

Paul Anastas

Yale University

Department of Chemistry

225 Prospect Street

New Haven, CT 06520

USA

Fred Arnold

U.S. Environmental Protection Agency

Office of Pollution Prevention and Toxics

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Nicholas A. Ashford

Massachusetts Institute of Technology

Technology and Law Program

77 Mass Avenue, Room E40-239

Cambridge, MA 02139

USA

Charles Auer

Charles Auer & Associates, LLC

17116 Campbell Farm Road

Poolesville, MD 20837

USA

Sajida Bakhtyar

Curtin University

Department of Environment and Agriculture

Kent Street

Perth, WA 6845

Australia

Ian Beadham

Dublin City University

School of Chemical Sciences

Collins Avenue

Dublin 9

Ireland

Robert S. Boethling

U.S. Environmental Protection Agency

Office of Pollution Prevention and Toxics

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Mary Cushmac (Retired)

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Clive Davies

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Stephen C. DeVito

U.S. Environmental Protection Agency

Office of Environmental Information

Toxics Release Inventory Program

1200 Pennsylvania Avenue NW

Washington, DC 20004

USA

David DiFiore

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Nicholas J. Dixon

Innospec Ltd.

Oil Sites Road

Ellesmere Port, Cheshire CH65 4EY

UK

Marthe Monique Gagnon

Curtin University

Department of Environment and Agriculture

Kent Street

Perth, WA 6845

Australia

Nicholas Gathergood

Dublin City University

School of Chemical Sciences

Collins Avenue

Dublin 9

Ireland

Fadri Gottschalk

EMPA – Swiss Federal Laboratories for Materials Science and Technology

Technology and Society Laboratory

Lerchenfeldstrasse 5

9014 St. Gallen

Switzerland

Kelly Grant (Former AAAS Science and Technology Policy Fellow)

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Monika Gurbisz

Dublin City University

School of Chemical Sciences

Collins Avenue

Dublin 9

Ireland

Mark Hanson

University of Manitoba

Department of Environment and Geography

Winnipeg, MB R3T 2N2

Canada

Katherine Hart

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Carol Hetfield

U.S. Environmental Protection Agency

Office of Pollution Prevention and Toxics

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Philip H. Howard

SRC, Inc.

7502 Round Pond Road

North Syracuse, NY 13212

USA

Russell S. Jones

U.S. Environmental Protection Agency

Biopesticides and Pollution Prevention Division

Office of Pesticide Programs

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Richard Judson

U.S. Environmental Protection Agency

National Center for Computational Toxicology

109 T.W. Alexander Drive

Research Triangle Park, NC 27711

USA

Jakub Kostal

Yale University

Department of Chemistry

225 Prospect Street

New Haven, CT 06520

USA

Klaus Kümmerer

Leuphana University Lüneburg

Institute of Sustainable and

Environmental Chemistry

Scharnhorststraße 1

21335 Lüneburg

Germany

David Y. Lai

U.S. Environmental Protection Agency

Office of Pollution Prevention and Toxics

Risk Assessment Division

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Emma Lavoie

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Chuantung Lin

U.S. Environmental Protection Agency

Office of Pollution Prevention and Toxics

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Meghan Marshall (Former Student Career Experience Program Intern)

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Michael McDavit

U.S. Environmental Protection Agency

Biopesticides and Pollution Prevention Division

Office of Pesticide Programs

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Laura Morlacci

SRC, Inc.

2451 Crystal Drive, Suite 475

Arlington, VA 22202

USA

Nicole C. Mueller

EMPA – Swiss Federal Laboratories for Materials Science and Technology

Technology and Society Laboratory

Lerchenfeldstrasse 5

9014 St. Gallen

Switzerland

John L. Nelson

Eastern Michigan University

Chemistry Department

Ypsilanti, MI 48197

USA

Bernd Nowack

EMPA – Swiss Federal Laboratories for Materials Science and Technology

Technology and Society Laboratory

Lerchenfeldstrasse 5

9014 St. Gallen

Switzerland

Thomas G. Osimitz

Science Strategies, LLC

Citizens Commonwealth Center

300 Preston Ave

Charlottesville, VA 22902

USA

Keith R Solomon

University of Guelph

Centre for Toxicology and School of Environmental Sciences

2120 Bovey Building

Gordon Street

Guelph, ON N1G 2W1

Canada

Claudia Som

EMPA – Swiss Federal Laboratories for Materials Science and Technology

Technology and Society Laboratory

Lerchenfeldstrasse 5

9014 St. Gallen

Switzerland

Elizabeth Sommer

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Kathleen Vokes

U.S. Environmental Protection Agency

Office of Air and Radiation

Office of Atmospheric Programs

Climate Protection Partnership Division

ENERGY STAR Labeling Branch

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Adelina Voutchkova

Yale University

Department of Chemistry

225 Prospect Street

New Haven, CT 06520

USA

Melanie Vrabel

U.S. Environmental Protection Agency

Design for the Environment Program

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Yin-tak Woo

U.S. Environmental Protection Agency

Office of Pollution Prevention and Toxics

Risk Assessment Division

1200 Pennsylvania Avenue NW

Washington, DC 20460

USA

Preface

Design is a statement of human intention. You can't design by accident. It has to be a conscious decision. To make the design decisions you need considerations; you need criteria. If you want to design molecules for reduced hazard, those criteria need to be based on an understanding of the molecular basis of hazard. Fortunately, there are data from the world of molecular toxicology that provide us with insights for the foundations for our problems and concerns around chemicals. At some level, the only reason to deeply understand a problem is to use that understanding to inform and empower the solution to the problem. That is what this volume of Designing Safer Chemicals is about; solving (and avoiding) problems.

Synthetic chemistry is a highly advanced field, and chemists have developed the expertise in designing chemicals for specific industrial or pharmaceutical functions. Unfortunately, even today relatively little systematic consideration is given to rationally minimizing undesired toxic and environmental effects at the design stage.

Principle 4 of the Twelve Principles of Green Chemistry, "Designing safer chemicals," stresses preserving useful function while reducing toxicity, and is an emerging field. This volume highlights illustrative examples of how chemicals have been designed, or redesigned, to minimize toxicity, and provides some basic guidelines for minimizing some types of unintended biological activity. It also underscores the important need for research and development focusing on design strategies that are based on mechanisms of biological action and relevant physical and chemical properties.

If we consider the design of commercial chemicals that are not only benign to humans but also to the environment, we see that toxicity is not the only consideration. In fact, we can broadly segregate hazards into three types, as shown in Figure 1: toxicological (human and environmental), physical (such as explosivity, material corrosion and flammability) and global (large scale effects on our planet: influencing climate change, causing an increased loading of persistent and bioaccumulative chemicals). The majority of this text focuses on toxicological hazards, but several chapters, such as Chapter 16 (Howard/Boethling) and Chapter 17 (Ashford) introduce the topic of global and physical hazards.

Figure 1. Classification of intrinsic chemical hazard into physical, toxicological and global.

The idea of deriving molecular design strategies for reduced intrinsic hazard may seem idealistic to chemists, who are trained to think of all chemicals as potentially hazardous. However, the achievements of the field of medicinal chemistry has shown us that it is possible to design chemicals with highly specific and desirable biological activity, and those lessons can be extended to inform the design of other commercial chemicals for reducing undesirable biological activity. Although this is unquestionably challenging due to the plethora of possible biological mechanisms of action, this text aims to show that there are strategies that can be applied.

The focus of this text, therefore, is minimization —at the molecular level— of potential health and environmental chemical hazard. This is distinct from risk assessment, which seeks to characterize the probability of harm. Implicit in risk assessment is knowledge of the potential toxicity and associated dose-response relationships, as well as a reasonable estimate of the exposure that an organism will receive under certain circumstances (the external dose). While risk assessment is a useful tool in evaluating comparative risks of existing chemicals and the identification of risk management strategies when needed, we submit that the focus for new chemicals should be on the reduction of intrinsic hazard, as exposure cannot always be predicted or controlled. Benign by design is the ultimate precautionary approach and this volume seeks to empower that approach.

The current understanding of how to design safer chemicals is an emerging field of research and application. Prior to this volume, there have been foundational treatments of the topic that laid the conceptual framework for how this idea can be developed and implemented. It is the hope of the editors and chapter authors that this text is built upon by others with further explorations that demonstrate how commercial chemicals can be rationally designed to minimize biological and environmental activity.

1

The Design of Safer Chemicals: Past, Present, and Future Perspectives

Stephen C. DeVito

1.1 Evolution of the Concept

Recognition of the need for chemists to design chemicals that are not only useful but of minimal hazard can be traced back to at least 1928, when Alice Hamilton, a well-known physician and pioneer in industrial medicine, made the following statements in her chapter Protection against industrial poisoning in the book Chemistry in Medicine [1]:

Chemistry and medicine have thus made possible real progress in the protection of working men and women against industrial poisons. ... Much remains to be done in this field, even in the light of our present knowledge, and greater progress will be made possible in the future through advances in chemistry. For instance, substitutes which are relatively non-toxic may be found to take the place of toxic compounds now in use. ... Toxicology must join with chemistry in testing the new compounds which chemistry introduces into industry. ... Synthetic chemistry must have as one of its great objectives the further safeguarding of health and of life in the industries into which chemistry itself has introduced new poisons.

In the era when these statements were made they were quite bold, if not radical, and likely to have been received with much indifference and perhaps opposition, especially since the statements were made by a woman. In 1928, only 8 years had elapsed since the Nineteenth Amendment to the US Constitution had, after intense debate, become law and allowed women to vote. The US economy was doing well and jobs were plentiful. Although it undoubtedly existed, pollution was not viewed as a problem by the general population or the federal government. As such, very few federal laws or regulatory authorities existed that regulated the development and marketing of commercial industrial chemicals, pesticides, or pharmaceutical substances to protect human health and the environment from risks posed by such substances.

Over time, it became apparent that many chemicals have the potential to pose serious risks to human health and the environment. To address these concerns, federal regulatory agencies such as the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) were established in the USA. These organizations were empowered by many laws to control the risks posed by new and existing drug substances (FDA), pesticides (EPA), and industrial chemicals (EPA). Similar organizations were established and laws enacted in many other countries. Hamilton's views on the importance of chemical safety and the need for synthetic chemists to develop chemicals that are relatively nontoxic were both brilliant and far ahead of her time.

As discussed below, not only have the above organizations helped to protect human health and the environment from the risks posed by chemicals, but also their regulatory requirements and mandates have effectively forced changes in the way in which chemists are trained and their approach to chemical design. This is especially so in drug and pesticide development, but to much lesser extent in the design of industrial chemicals.

1.1.1 In the Development of Drug Substances: Emergence of the Medicinal Chemist

The Federal Food Drug and Cosmetic Act (FFDCA) became effective in 1938, and has since been amended several times to address emerging societal concerns regarding the safety of drug substances. Among other provisions, this law, as amended, authorizes the FDA to require that pharmaceutical firms provide evidence of safety and efficacy of new drug substances before such substances can be marketed. Through the FFDCA, the FDA requires pharmaceutical firms to conduct extensive testing to identify and characterize a candidate drug substance's clinical pharmacological efficacy, bioavailability, bodily distribution, metabolites, excretion, and any adverse or toxic effects the substance may cause in experimental animals and in humans during pre-market clinical trials. Pharmaceutical firms have to develop these data, ostensibly as proof that their new drug is safe and effective.

This information is submitted to the FDA as part of an application for new drug approval, and undergoes extensive review. If the FDA determines that the drug substance is clinically efficacious and has minimal adverse effects, it will approve its marketing and use. Even with the streamlined processes currently used, the development and marketing of a new drug product are time consuming and resource intensive. Typically, for every new drug that reaches the market, more than 8000 potential drug candidates were synthesized, tested to varying extents along the way, and judged to be unsuitable. The identification of a candidate drug substance, its testing, and FDA approval usually take many years and, nowadays, cost upwards of hundreds of millions of dollars. Because of the costs and rigorous approval process outlined above, relatively few new drug substances are approved and registered by the FDA on an annual basis.

Promulgation of the FFDCA in 1938, specifically the pre-market testing that it mandates, led to the publication of many studies that reported the metabolism, pharmacological, and toxicological properties of many classes of chemicals undergoing evaluation as potential pharmaceuticals. This wealth of information allowed the characterization of relations between structure, pharmacological activity, potency, and toxicity of many classes of organic chemicals. Identification of these relationships would provide organic chemists with a rational basis from which molecular modifications expected to maximize the desired pharmacological effect while minimizing toxicity could be inferred and, thereby, used to design new molecules in which therapeutic effectiveness was maximized and toxicity minimized.

The problem was that organic chemists received none of the academic training in the biological sciences that was needed to enable them to analyze and interpret such information, and integrate it with their training in organic synthesis to design new and improved drug substances. There was a need for a new type of organic chemist, a medicinal chemist: a chemist hybrid who received extensive training not only in synthetic organic chemistry but also in biochemistry, pharmacology, and toxicology, and the relationships between chemical structure with physical properties, pharmacological action, and toxicological effects. Such a chemist would be well prepared to design new, clinically efficacious drug substances of low toxicity.

The noted biochemist R. Tecwyn Williams and the noted organic chemist Alfred Burger recognized this need. In 1947, Williams published the first edition of his classic text on mechanisms of drug metabolism, Detoxication Mechanisms: the Metabolism of Drugs and Allied Organic Compounds [2], which is an extensive compilation of the metabolic pathways that many of the drugs and industrial chemicals in use at the time undergo in experimental animals and humans. Burger, in 1951 and 1952, published a two-volume book set entitled Medicinal Chemistry: Chemistry, Biochemistry, Therapeutic and Pharmacological Action of Natural and Synthetic Drugs [3, 4], to provide graduate students majoring in organic chemistry who plan to pursue careers in drug development, and organic chemists working for pharmaceutical firms, a framework from which safe and efficacious drug substances could be designed [5].

Burger's book helped to establish the field of medicinal chemistry. Soon after publication of the two volumes in 1951 and 1952, many drug companies formed departments of medicinal chemistry, and many colleges, particularly colleges of pharmacy, did the same. This eventually led to the availability of professionals who were specifically and formally trained to design and develop therapeutically useful but safe drug substances. Within 10 years, the Journal of Medicinal Chemistry was founded, also by Burger [5], and the American Chemical Society established its section on Medicinal Chemistry. The important lesson to be learned here is that the field of medicinal chemistry evolved, largely by necessity, from the FFDCA.

The environmental fate and environmental impact of a planned drug substance are also considered as part of the design strategy of the substance. In 1969, the National Environmental Policy Act was passed. This Act requires the FDA to consider the environmental impacts of drug substances as an integral part of its process for reviewing and approving new drug applications. Pharmaceutical firms are required, under certain circumstances, to provide the FDA with an assessment that focuses on characterizing the fate of the drug substance in the environment, and the effects that the drug substance or its environmental metabolites may have on the environment following discharges of the drug from patients, or industrial manufacture or processing [6].

More recently, it has become apparent that genetics play a major role in determining how an individual will metabolize a drug substance (or any chemical substance) and respond to the drug. The implications of genetic causes of individual variations in drug response (pharmacogenomics) are beginning to affect drug development issues such as drug safety, productivity, and personalized healthcare [7], and an increasing number of drug labels approved by the FDA contain pharmacogenomic information [8, 9]. Integration and use of genetic biomarkers in drug development, regulation, and clinical practice will undoubtedly continue to increase [9, 10].

1.1.2 In the Development of Pesticide Substances

In June 1947, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was enacted, to provide the US federal government with authority to regulate the distribution, sale, and use of pesticide substances. Similarly to the FFDCA and the rigorous pre-market approval process established by the FDA for registering drug substances in the USA, under FIFRA, all pesticides intended to be distributed or sold in the USA must first be registered by the EPA. Before the EPA registers a pesticide, the applicant must show, among other things, that the use of the pesticide according to specifications will not generally lead to unreasonable risk to humans or the environment, taking into account the economic, social, and environmental costs and benefits of the pesticide's use.

As with the FFDCA, the FIFRA requires pesticide firms to conduct batteries of extensive testing to identify and characterize a candidate pesticide's bioavailability, distribution, metabolites, routes of excretion in experimental animals, and any adverse or toxic effects that the substance may cause, so that the safety of the pesticide can be assessed. In addition, in cases of pesticides intended to have food uses, extensive field trials must be conducted to characterize residues of the pesticide or metabolites thereof remaining on or in raw agricultural commodities.

Pesticide registrants must also submit environmental fate and effects data to the EPA as part of an application for pesticide registration. The EPA uses such environmental data to characterize the persistence and partitioning of a pesticide in the environment and the pesticide's environmental metabolites and degradates. This information is used by the EPA to assess the potential for human exposure via drinking water contamination and environmental exposure of organisms such as fish, wildlife, and plants to the pesticide or its metabolites.

The above information undergoes extensive review by the EPA, and is submitted to the EPA as part of an application for approval and registration of a new pesticide substance, or re-registration of an existing pesticide. Development of a candidate pesticide substance, its testing, and EPA approval usually take many years and are expensive.

The stringent pre-market health-related and environmental testing requirements of the FIFRA effectively caused changes in the way in which organic chemists are trained and approach the design of pesticides – not unlike how similar requirements under the FFDCA caused the evolution of the medicinal chemist and changes in the way in which chemists are trained and approach drug design. Not long after the enactment of the FIFRA, books devoted to the metabolism, excretion, toxicity, structure–activity relationships, modes of action, and environmental fate and effects of pesticide chemicals became available. Classic examples of some of theses publications include the writings of Adrien Albert [11], Anthony Brown [12], Robert L. Metcalf [13], Richard D. O'Brien [14], Wayland J. Hayes [15], and Ronald J. Kuhr and Wyman Durough [16].

As these books emerged, many colleges that had agriculture departments restructured their chemistry curricula to include courses in biology, biochemistry, toxicology, and insect physiology, to better enable their students to design pesticides that are efficacious and of reduced toxicity. Again, the lesson to be learned here is that the field of pesticide chemistry, at least as it exists in the USA, evolved largely from enactment of the FIFRA.

The FIFRA has been amended several times since it was originally passed in 1947. The amendment that made the most changes occurred in 1996, with passage of the Food Quality Protection Act (FQPA). The FQPA stipulates, among other things, that when determining the safety of a pesticide chemical, the EPA shall base its assessment of the risk posed by the chemical on aggregate (i.e., total dietary, residential, and other nonoccupational) exposure to the pesticide, and available information concerning the cumulative adverse effects to human health that may result from dietary, residential, or other nonoccupational exposure to other substances that cause the same primary toxic effect as the pesticide by the same biochemical mechanism. Additionally, the FQPA specifically mandates the EPA to consider the extra susceptibility and sensitivity that infants and children may have to the toxic effects caused by pesticides. The EPA is required by the FQPA to impose more stringent regulations on pesticide chemicals that may be especially harmful to infants and children as a result of prenatal or postnatal exposure. Chapter 12 discusses the latest directions being taken in the design of safer pesticides.

1.1.3 In the Development of Industrial Chemical Substances

Prior to 1976, in total contrast to the extensive testing and other pre-market approval requirements established under the FFDCA for new substances intended to be marketed as drugs, and under the FIFRA for new substances intended to be marketed as pesticides, there were no pre-market statutory requirements for new industrial chemicals to protect human health and the environment from the risks posed by such substances. In the USA, chemical manufacturers could produce and market any new industrial chemical at will and without notifying the EPA.

In 1976, the Toxic Substances Control Act (TSCA) was enacted, in part to (1) require chemical manufacturers to notify the EPA of their intent to introduce a new chemical into commerce, (2) enable the EPA to determine whether the new chemical poses unreasonable risks to human health or the environment, and (3) enable the EPA to implement restrictions to mitigate any identified risks. In addition, the TSCA provides the EPA with the authority to regulate the production, use, and disposal of new and existing chemicals used in commerce within the USA, and to require testing of such chemicals at the discretion of the EPA.

Under the TSCA, a new chemical is a chemical substance that is not already included on the TSCA Inventory, and is intended to be used for a commercial purpose (other than as a drug or pesticide) in the USA. Section 5 of the TSCA requires manufacturers or importers of a new chemical to notify the EPA (i.e., submit a pre-manufacture notification, PMN) before manufacturing or importing the chemical. The EPA has only 90 days (extendable to 180 days under certain circumstances) from the time of receipt of the notification to determine if an unreasonable risk may or will be presented by any aspect of the new industrial chemical, and make risk management decisions and take action to control any unreasonable risks posed by the chemical [17]. If after 90 days the submitter of a new chemical is not notified by the EPA of any regulatory restrictions or test requirements, they can legally market or import the chemical.

The TSCA departs from the FDCA and FIFRA with regard to regulations of new chemicals in two ways. First, under the TSCA, the EPA does not approve or register a new chemical substance. It only imposes regulatory restrictions when deemed necessary before the chemical is marketed or imported to mitigate unreasonable risk. Second, and perhaps most significantly, Section 5 of the TSCA does not require any testing of a new chemical by a manufacturer or importer prior to its submission to the EPA as a PMN. Since no testing is required, most manufacturers or importers do not conduct such tests on new chemicals or measure their physical properties, to supplement their PMN submissions.

Unlike submissions of new drug applications or new pesticide registrations, there is no burden of proof on the part of the submitter of a PMN to show that the new chemical is safe or, for that matter, efficacious. In fact, in reality, in order for the EPA to impose regulatory restrictions on a new chemical submitted under Section 5 of the TSCA, the onus is on the EPA to justify the restrictions. More simply, the submitter of a PMN is not required to prove or provide evidence that the chemical is safe, but the EPA would have to have some basis for concluding that the new chemical substance is not or may not be safe in order to regulate it.

Less than half of the new chemical submissions received by the EPA contain any kind of test data. The EPA can obtain and review whatever toxicity or physical data on the new chemical happen to be available, such as data from literature sources, but usually there are none. For most new chemical submissions, measured values for chemical, toxicological, or environmental fate properties are not available for the EPA to use to make decisions regarding hazards or risks that the chemical may pose to human health or the environment, or its global impact.

The EPA receives and reviews approximately 1500–2000 PMN submissions annually. Given that there are about 245 work days per year, and about 8 h per work day, this means that on average EPA staff characterize the hazards and risks and make regulatory decisions on over six new chemical submissions per work day, or roughly one new chemical per hour, with little experimental data or information!

As the EPA's new chemical review program is not an approval or registration program, the decision to market a new chemical after it has been reviewed by the EPA is largely in the hands of the submitter of the notification. Since the enactment of the TSCA in 1976, the EPA has received and reviewed over 60 000 submissions for new chemicals. Of these, about 24 000 new chemicals have entered commerce.

To fill the data gaps for determining potential hazards to human health and the environment, the EPA often relies on internally developed estimation methods. These include empirical data available for structural analogs and computational methods for the estimation of physicochemical properties, which in turn are used to estimate environmental fate, bioavailability, toxicity in humans and aquatic organisms, and exposure [17].

1.1.3.1 Stagnation of the Concept Because of Section 5 of the TSCA

The FFDCA and FIFRA prescribe stringent pre-market federal approval requirements for new drugs and pesticides, respectively. These strict requirements essentially forced the evolution of the medicinal chemist and pesticide chemist to design drugs and pesticides such that they meet or exceed these requirements. Enactment of the TSCA, however, did not result in any paradigm changes in how organic chemists who plan to have careers in the chemical manufacturing industry are trained or think with regard to designing commercial chemicals that are both efficacious and of minimal impact on human health and the environment.

This is not to say that chemists in the chemical industry had or have no interest in designing safer commercial chemicals, or do not strive to make useful chemicals that are safe – quite the contrary, as this chapter and others in this book illustrate. However, since there are no pre-market test requirements for characterizing the safety of new commercial chemicals, there is a considerably small driving force for chemical manufacturers to devote resources to designing chemicals that are commercially efficacious and safe. More bluntly, because it is relatively inexpensive under the TSCA to get a new commercial chemical on the market, enactment of the TSCA did not lead to the evolution of a new type of chemist analogous to the medicinal chemist in the case of drugs. Thus, despite the enactment of the TSCA over 35 years ago, the status quo in the chemical industry has persisted.

However, the need for chemists to have a tangible construct for the rational design and development of safer commercial chemicals did not go unnoticed. A robust framework developed specifically for industrial chemists to use to design safer commercial chemicals was originally published by the noted medicinal chemist E.J. Ariëns in 1980 and 1982, just a few years after the enactment of the TSCA [18, 19]. In these publications Ariëns discusses and illustrates how many of the well-established approaches and considerations used by medicinal chemists to design safer and efficacious drug substances can be used to design safer and efficacious commercial chemicals.

In September 1983 the EPA co-sponsored a symposium with the Society of Toxicology and the Oak Ridge National Laboratory that was devoted to the design of safer commercial chemicals. Presentations that covered all aspects of safer chemical design were presented by renowned individuals from academia, government, and industry. Most of these presentations were published in 1984 in a series of issues of the journal Drug Metabolism Reviews [20], including one by Ariëns [21].

From 1984 until 1996, virtually nothing was published with regard to a construct for the design of safer chemicals. In 1996, the first book devoted exclusively to the design of safer commercial chemicals appeared in the form of an American Chemical Society Symposium Series volume edited by Stephen DeVito and Roger Garrett entitled Designing Safer Chemicals: Green Chemistry forPollution Prevention [22]. This book served as a framework for the design of safer commercial chemicals, and contains chapters written by scientists in government, academia, and industry that illustrate with many examples how the framework can be used as a rational approach to design safer chemicals.

No other comprehensive publications devoted to the design of safer chemicals appeared for nearly another 14 years, when Voutchkova, Osimitz, and Anastas published a review that builds upon the publications of Ariëns, DeVito, and Garrett, and provides newer information and additional insight that can be used to design chemicals of reduced hazard [23]. Twelve years earlier, in 1998, Anastas and Warner put forth 12 Principles of Green Chemistry in their book Green Chemistry: Theory and Practice, which are intended to guide chemists in the practice of green chemistry. Among these are two principles that encompass elements of safer chemical design, specifically that chemicals should be designed to have minimal toxicity, and to biodegrade to innocuous products [24].

Despite these publications [18–24], and the general widespread acceptance of at least the conceptual basis of the design of safer chemicals as a logical approach to protect human health and the environment, considerably less progress has been made in its development when compared with other areas of green chemistry. This sluggishness is likely due in part to how organic chemists continue to be trained. Given that most of the formal training that organic chemists receive is still based largely (if not entirely) in the physical sciences, chemists probably find the designing safer chemical paradigm esoteric, since it also pulls from the toxicological and environmental sciences.

Although much emphasis is given nowadays to the practice of green chemistry as a means to achieve sustainable development, and despite the fact that within the past decade many colleges and universities have implemented centers for green chemistry research, few, if any, of these colleges or universities have restructured their course curricula at the undergraduate or graduate level to include courses in toxicology, the environment, and the relationships between chemical structure and physical properties with human and ecological hazards, environmental persistence, bioaccumulation, and global impact. The majority of the individuals who graduate with advanced degrees in chemistry and plan to practice green chemistry in their careers still receive little, if any, formal training or teaching on how to design chemicals to be safe.

The ultimate cause, however, of the relative lack of progress regarding application of the design of safer commercial chemicals as a subspeciality in green chemistry can be traced to Section 5 of the TSCA, since it does not require chemical manufacturers to develop commercial chemicals that are safe, as discussed above. If the development of commercial chemicals that are safe were to be required under the TSCA, such a mandate would undoubtedly lead to changes in the formal training of chemists who plan to pursue careers in the chemical industry, similarly to how such requirements under the FFDCA and FIFRA caused changes in the training of chemists who intend to work in the areas of drug and pesticide development, respectively.

Nowadays, few would challenge Alice Hamilton's position that chemists should intentionally design chemicals to be safe in addition to being efficacious with regard to use. However, until statutory changes are made in the TSCA that authorize the EPA to require that chemical manufacturers provide evidence of safety of new industrial chemical substances before such substances can be marketed, the concept of designing safer chemicals will never fully be adopted, regardless of how many more well-written papers or books are published on the topic.

It is possible that such statutory changes not only will occur, but will do so in the foreseeable future. At the time of this writing (January 2012), the TSCA is being considered for reauthorization, making it subject to be amended. The EPA has publicly committed to working with Congress, members of the public, the environmental community, and the chemical industry to reauthorize the TSCA, and has identified six principles that should serve as the basis for any amendments to the TSCA [25]. Among these is principle 2, which states that manufacturers should provide the EPA with the necessary information to conclude that new and existing chemicals are safe and do not endanger public health or the environment.

1.2 Characteristics of a Safer Chemical

Exactly what is a safer chemical? Many people naturally think of chemical safety from the context of human health, and automatically interpret safer chemical to mean a chemical that is or is expected to be of reduced toxicity to humans, usually with regard to some other chemical that fulfills the same commercial purpose. This occurs because we tend to prioritize human health over that of other species in our environment. Thus, many of the publications referenced in this chapter that focus on the design of safer chemicals are devoted primarily to the design of chemicals that are expected to have a minimal effect on human health. The same may be said of this book.

This human safety first way of thinking is only natural and understandable, and not likely to change anytime soon. It is important to stress, however, that a safer chemical should not be thought of only as a chemical that has low toxicity in humans. Safer must encompass minimal hazard to humans, ecological receptors (e.g., birds, fish), and the global environment as a whole, in addition to having less of a propensity for exposure of humans, ecological receptors, and the global environment. Regarding reduced propensity for exposure, this can be achieved if, or to the extent that, a chemical does not persist in the environment or bioaccumulate in food webs.

So, what is a safer chemical? A safer chemical is a chemical that causes minimal adverse impacts on human health, other forms of life, and the Earth. It is a relative term, and should not be interpreted to mean that the safer chemical does not cause any adverse impact at any level of exposure, or is in fact totally safe or without risk. A safer chemical is one in which any adverse effects that it may have on humans, other organisms, or the Earth are tolerable, or at least more tolerable than the adverse effects caused by some other chemical under similar conditions of exposure.

The word tolerable as used in this context is complex. Tolerability of a chemical's unwanted properties is something federal authorities deal with on a day-to-day basis in making decisions as to (1) whether to permit a chemical to be marketed and (2) if marketing is to be permitted, what regulatory restrictions are needed to limit the use and waste management of the chemical in order to minimize exposure to it, without compromising the societal benefits that the chemical may offer. In the end, the extent to which a federal authority will tolerate a chemical's unwanted properties and the risks it poses, and how the authority will regulate the chemical to mitigate the risks, are ultimately based on the importance of the chemical to society and societal values.

Society generally places greater value on protecting human life, especially the health of the unborn, infants, and children, than on other forms of life, such as avian or aquatic life forms, or on protecting the planet. Therefore, regulatory authorities tend to be more concerned with (less tolerant of) the toxic effects that a chemical may cause in humans, particularly fetuses, infants, and children, than with effects on other forms of life. This is blatantly evident in the Food Quality Protection Act (FQPA), mentioned earlier, as it explicitly mandates the EPA to consider the extra susceptibility and sensitivity that infants and children may have to the toxic effects caused by pesticides, and to impose more stringent regulations on pesticide chemicals that may be especially harmful to infants and children as a result of pre- or postnatal exposure.

Within the realm of human toxicity, cancer is probably the illness that is most feared by society, since it is a difficult disease to treat and cure, and often culminates in a slow, painful, emaciating death. Hence chemicals that are known to cause, or are even suspected of causing, cancer are generally less tolerated and are regulated more stringently than chemicals that do not cause cancer but may cause other toxicities that are associated with lower morbidity and mortality, and for which better treatment modalities exist (e.g., nephrotoxicity).

Chemicals that can or are believed to cause developmental toxicity are those that produce adverse effects on a developing fetus, infant, or child from exposure of either parent to the chemical prior to conception, during prenatal development, or postnatally. These chemicals are also of very high concern to society, and tend to be stringently regulated by federal authorities. With developmental toxicity there is also an element of additional societal concern because of the logical view that we should not transmit effects across generations, to progeny that are of course defenseless victims of our inability to make and use safe chemicals.

Toxicity to the central nervous system (CNS) is another highly feared illness. Although often not fatal, it is usually long lasting (if not permanent) and debilitating. Fetuses, infants, and even children tend to be more susceptible and sensitive to chemical-induced injury to the CNS. This is because the brain cells and the membranes of the capillaries that surround and protect the brain cells (the blood–brain barrier) from toxic contaminants in the blood are not fully developed in infants and children.

There is further analogy with yet extra concern for toxic chemicals that may also persist in the environment and be transported great distances from their point of entry into the environment. Here the unifying general notion is that unsuspecting individuals are placed at risk, and are thus less able to defend than are the perpetrators. Mercury is a classic example of such a chemical. Mercury is extremely toxic to the CNS. Fetuses, infants, and toddlers are especially sensitive and susceptible to the neurotoxic properties of mercury. Mercury also persists in the environment, and is known to bioaccumulate in the food web and biomagnify up the food chain.

Mercury metal is found naturally in fossil fuels. A major anthropogenic source of mercury emissions is from the combustion of fossil fuels in the production of electricity. Mercury oxides are thus formed and emitted to the atmosphere, where they can travel long distances and deposit on land or water bodies. Bacteria in soils and sediments transform the inorganic mercury oxides into methylmercury, a form of mercury that can be readily taken up by small animals and tiny aquatic organisms (e.g., algae and phytoplankton). Fish eat these organisms and build up (bioaccumulate) mercury in their bodies. As ever-bigger fish eat smaller ones, the methylmercury is concentrated (biomagnified) further up the food chain to human receptors.

Pregnant or nursing women exposed to methylmercury through their diet or otherwise also expose their developing fetus or breast-fed infant to the chemical, since methylmercury passes through placental membranes and enters the fetal bloodstream, and also enters breast milk. This is particularly problematic since fetuses and infants (and toddlers) are more susceptible and sensitive to the neurotoxic properties of mercury than are adults.

While the severe neurotoxic properties of mercury are independent of its ability to persist in the environment and bioaccumulate and biomagnify within the food web, these additional albeit nontoxic properties increase the likelihood of human exposure to mercury and, as such, augment its toxicity.

Thus, in designing a safer chemical, it is reasonable to focus attention on human safety first. Particular attention should be given to designing chemicals that are unlikely to cause cancer, developmental toxicity, or neurotoxicity to any degree. Chemicals should also be designed such that they do not persist for long periods in the environment, bioaccumulate significantly, or biomagnify in the food web. Although these properties by themselves are not harmful, they inherently enhance exposure to a chemical, and are undesirable. A toxic chemical that also persists in the environment and bioaccumulates in the food web is generally of more concern than a chemical of equal toxicity that does not persist or bioaccumulate.

1.2.1 Types of Safer Chemicals

There are two general types of safer chemicals. The first and perhaps more common type is the considerably safer structural analog or congener of another commercially useful chemical for which toxicity or another unwanted property is a concern. In this case, because of their overall structural similarities, both the safer chemical and the existing chemical(s) have similar commercial utility, and may very well possess the same intrinsic undesirable properties. However, the structural differences in the safer chemical are such that higher levels of exposure or environmental discharges are required in order for it to elicit its undesirable properties. Thus, the chemical is much less potent in causing the unwanted effect (or may not cause it at all). The unwanted effect may even be of less intensity (magnitude).

Ideally, the levels of exposure to the safer chemical that are needed to cause the unwanted effect should be much higher than the exposure levels that are anticipated to occur from the intended use of the chemical, its release into the environment, or from waste management activities involving the chemical. If the level of exposure needed for the safer chemical to cause such an effect is very large, the safer chemical may be said to be safe for all practical purposes.

An example of this type of a safer chemical is methacrylonitrile 1 compared with acrylonitrile 2 (Figure 1.1). Both compounds are α,β-unsaturated aliphatic nitriles, and structurally very similar, but 2 causes cancer whereas 1 does not appear to do so. Among other applications, 2 is used in the production of acrylic and modacrylic fibers, elastomers, acrylonitrile–butadiene–styrene and styrene–acrylonitrile resins, nitrile rubbers, and gas barrier resins. In a study conducted by the US National Toxicology Program (NTP) in which 2 was administered orally to mice for 2 years, there was clear evidence that it caused cancer in the treated mice (in addition to causing other toxic effects), and is classified by the NTP as a probable human carcinogen [26].

Figure 1.1 Structures of methacrylonitrile 1 (noncarcinogenic) and acrylonitrile 2 (probably a human carcinogen).

Methacrylonitrile 1 differs from 2 only in that it has a methyl (CH3) group on the α-carbon atom. It too