Principles and Practice of Mixtures Toxicology E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1270

Veröffentlichungsjahr: 2011

Beschreibung

This first comprehensive treatment of the subject for more than a decade includes the latest research on nanoparticle toxicology. The practical handbook addresses all areas where toxic mixtures are encountered, from environmental via occupational to medical settings, giving special consideration to air and water, and to the specific requirements for study design in mixture toxicology. While no extensive prior knowledge or toxicological experience is required, the practice-oriented case studies and examples in the second part make this the ideal companion for the professional toxicologist in industry or healthcare institutions with little time for academic study.

Leseprobe

Contents

Cover

Related Titles

Title Page

Dedication

Copyright

Foreword

Preface

List of Contributors

Chapter 1: Introduction to Mixtures Toxicology and Risk Assessment

1.1 Chemical Mixtures Exposure

1.2 Superfund Research Program

1.3 SRP and Mixtures Research

1.4 Drug–drug Interactions and Nanomaterials

1.5 Waste Sites and Mixtures Risk Assessment

1.6 Alternative Testing Methods

1.7 Translational Research

Acknowledgment

References

Chapter 2: Chemical Mixtures in the Environment: Exposure Assessment

2.1 Risk Assessment Paradigm: A Chemical Mixtures Context

2.2 Occurrence of Chemical Mixtures in the Environment

2.3 Drivers for Assessing Exposures to Chemical Mixtures

2.4 Using Conceptual Models to Guide the Development of Mixture Exposure Assessments

2.5 Overview of Environmental Fate for Chemical Mixtures

2.6 Methods and Applications for Assessing Mixture Exposures

2.7 Illustrative Example: Assessing Exposures to DBP Mixtures in Drinking Water

2.8 Summary

2.9 Future Directions

Acknowledgments

References

Chapter 3: Application of a Relative Potency Factor Approach in the Assessment of Health Risks Associated with Exposures to Mixtures of Dioxin-Like Compounds

3.1 Dioxin-Like Chemicals

3.2 Introduction of TEF Methodology

3.3 Evolution of TEF Approach

3.4 Relative Potency Estimates

3.5 Derivation of TEF Values – Past, Present, and Future

3.6 Assumptions, Limitations, and Uncertainties of the TEF Approach

3.7 Closing Remarks

References

Chapter 4: Statistical Methods in Risk Assessment of Chemical Mixtures

4.1 Principles of Statistics

4.2 Statistical Approaches for Evaluating Mixtures

4.3 Alternative Approach: Use of Ray Designs with Focus on Relevant Mixing Ratios

4.4 Testing for Additivity in the Low-Dose Region

4.5 Sufficient Similarity in Dose Responsiveness

4.6 Summary

References

Chapter 5: Kinetic Interactions of Chemical Mixtures

5.1 Pharmacokinetic Modeling

5.2 PBPK Modeling of Individual Chemicals

5.3 PBPK Modeling of Binary Chemical Mixtures

5.4 PBPK Modeling of Complex Chemical Mixtures

5.5 Summary and Future Directions

References

Chapter 6: Toxicodynamic Interactions

6.1 Introduction

6.2 Historical Perspective of Chemical Mixtures

6.3 Current Status

6.4 Tissue Repair

6.5 Interactions Leading to Increased Liver Injury, But Not Death

6.6 Two-Stage Model of Toxicity

6.7 Tissue Repair Follows a Dose Response After Exposure to Chemical Mixtures

6.8 Tissue Repair Determines the Outcome of Toxicity

6.9 Molecular and Cellular Mechanisms of Tissue Repair

6.10 Implications for Risk Assessment

6.11 Conclusions

References

Chapter 7: Toxicological Interaction Thresholds of Chemical Mixtures

7.1 Introduction

7.2 Statistical Analysis for Interaction Thresholds

7.3 Predictive Modeling of the Interaction Threshold

7.4 “No Interaction” Exposure Levels

References

Chapter 8: Characterization of Toxicoproteomics Maps for Chemical Mixtures Using Information Theoretic Approach

8.1 Introduction

8.2 Current Proteomics Technologies

8.3 Mathematical Proteomics Approaches

8.4 Experimental Methods

8.5 Theoretical Calculation of Information Theoretic Biodescriptors

8.6 Results

8.7 Discussion and Conclusion

Acknowledgments

References

Chapter 9: Pharmacokinetic Mechanisms of Interactions in Chemical Mixtures

9.1 Introduction

9.2 Absorption-Level Interactions

9.3 Distribution-Level Interactions

9.4 Metabolism-Level Interactions

9.5 Elimination-Level Interactions

9.6 Pharmacokinetic Interactions and Impact on Internal Dose

9.7 Conclusions

Acknowledgments

References

Chapter 10: Chemical Mixtures and Cumulative Risk Assessment

10.1 Introduction

10.2 Toxicology Basis for Mixtures and Cumulative Risk Assessment

10.3 Mixtures and Cumulative Risk Assessment Methods

10.4 Future Directions

References

Chapter 11: Application of ATSDR's Mixtures Guidance for the Toxicity Assessment of Hazardous Waste Sites

11.1 Introduction

11.2 ATSDR's Process for Evaluating Chemical Mixtures

11.3 Case Studies

11.4 Overall Conclusions from the Case Studies

References

Chapter 12: Application of Mixture Methodology for Workplace Exposures

12.1 Introduction

12.2 Occupational Exposure Limits

12.3 Regulating Mixed Exposures in the United States

12.4 Hazard Communications

12.5 Emerging Approaches

12.6 Summary

References

Chapter 13: Assessing Risk of Drug Combinations

13.1 Safety Considerations for Drug Combination Products

13.2 Evaluating Adverse Drug Interactions and Patient Outcomes

References

Chapter 14: Dermal Chemical Mixtures

14.1 Introduction

14.2 Mechanisms of Interactions

14.3 Mixture Interactions in Skin

14.4 Potential Impact of Multiple Interactions

14.5 Summary

Acknowledgments

References

Chapter 15: Synergy: A Risk Management Perspective

15.1 Introduction

15.2 Synergy

15.3 Risk Management and Synergy

15.4 Models of Mixture Toxicity

15.5 Placing Doses Used in Studies Demonstrating Synergy into a Risk Management Framework

15.6 Extending the Approach to Mixtures of Three or More Chemicals

15.7 Using the Graphic Framework to Place Data on Synergy into a Risk Management Context

15.8 Doses of Mixture Components Permitted Under Current Models of Mixture Risks for Humans

15.9 Relationship between Toxicity and Synergistic Potential

15.10 Discussion

15.11 Summary and Conclusions

Acknowledgment

References

Chapter 16: Chemistry, Toxicity, and Health Risk Assessment of Drinking Water Disinfection By-Products

16.1 Introduction

16.2 Regulation of DBPs in the United States

16.3 DBP Mixture Health Effects Data Collection and Related Risk Assessment Approaches

16.4 Health Effects Data on DBP Mixtures

16.5 Summary and Conclusions

References

Chapter 17: Endocrine Active Chemicals

17.1 Introduction

17.2 Common Characteristics of EAC Mixtures

17.3 Toxicity of EAC Mixtures

17.4 Is the Concept of “Common Mechanism” Relevant for EAC Mixtures?

17.5 Summary and Conclusions

Acknowledgments

References

Chapter 18: Evaluation of Interactions in Chemical Mixtures

18.1 Introduction

18.2 Methodology for Identification of Priority Mixtures

18.3 Methodology for the Joint Toxicity Assessment of Mixtures

18.4 Evaluations of Mixtures Related to Background Exposures

18.5 Evaluation of Mixtures Related To Hazardous Waste Sites

18.6 Future Directions

References

Chapter 19: Thyroid-Active Environmental Pollutants and Their Interactions on the Hypothalamic–Pituitary–Thyroid Axis

19.1 Thyroid-Active Environmental Pollutants

19.2 Interaction of Chemical Mixtures on the HPT Axis

19.3 Case Study with Binary Mixture of PCB126 and Perchlorate

19.4 Experimental Challenges

19.5 Dose-Response Computational Modeling of Chemical Effects on the HPT Axis

References

Chapter 20: Toxic and Genotoxic Effects of Mixtures of Polycyclic Aromatic Hydrocarbons

20.1 Introduction

20.2 Sources

20.3 Source Apportionment

20.4 Hazardous Effects of Polycyclic Aromatic Hydrocarbons

20.5 Pharmacokinetics

20.6 Genetic Sensitivities

20.7 Biomarkers of Exposure

20.8 Conclusions

References

Chapter 21: Development of In Vitro Models to Assess Toxicity of Engineered Nanomaterials

21.1 Introduction

21.2 In Vitro Nanotoxicity Models

21.3 Toxicology of Nanomixtures

21.4 The In Vitro Debate

21.5 Characterization of Nanomaterials

21.6 Conclusions

References

Chapter 22: The Application of Physiologically Based Pharmacokinetics, Bayesian Population PBPK Modeling, and Biochemical Reaction Network Modeling to Chemical Mixture Toxicology

22.1 Why is Computer Simulation Not Only Important But Also Necessary for Chemical Mixture Toxicology?

22.2 What Do We Mean by “Computer Simulation?” What Does it Entail?

22.3 What is Physiologically-Based Pharmacokinetic Modeling? How Does it work?

22.4 What is Bayesian Inference and Population PBPK Modeling? What is Markov Chain Monte Carlo Simulation? Why Do We Need These Technologies?

22.5 What is Biochemical Reaction Network Modeling? Where Did It Come From? How Does It Work? Why Do We Need It for Chemical Mixture Toxicology?

22.6 What is “Multiscale Modeling?” How Do PBPK, Bayesian Population PBPK Modeling, and BRN modeling Fit Into “Multiscale Modeling?” Any Possible Inclusion of Other Types of Computer Modeling?

22.7 Can We Predict Chemical Mixture Toxicities? What is the Potential Real-World Application of Such a “Multiscale Computer Simulation” Approach?

22.8 Concluding Remarks

References

Chapter 23: Food Ingredients are Sometimes Mixtures

23.1 Introduction

23.2 Safety Evaluation

23.3 Description of the Priority-Based Assessment of Food Additives

23.4 Food Additives

23.5 Color Additives

23.6 GRAS Substances

23.7 Flavorings

23.8 Natural Flavor Complexes

23.9 Botanical Ingredients

23.10 Food Contact Substances/Formulations

23.11 Conclusions

Acknowledgments

References

Chapter 24: Biomonitoring

24.1 Introduction

24.2 Considerations for Biomonitoring

24.3 Interpretation

24.4 Summary

References

Chapter 25: Adverse Drug Reactions and Interactions

25.1 Introduction

25.2 Drug Toxicity in Major Body Organs

25.3 Drug Interactions

25.4 Conclusions

Acknowledgments

References

Index

Related Titles

Bernhard, D. (ed.)

Cigarette Smoke Toxicity

Linking Individual Chemicals to Human Diseases

2011

ISBN: 978-3-527-32681-5

O'Brien, Peter J., Bruce, W. Robert (eds.)

Endogenous Toxins

Targets for Disease Treatment and Prevention

2010

ISBN: 978-3-527-32363-0

Salthammer, T., Uhde, E. (eds.)

Organic Indoor Air Pollutants

Occurrence, Measurement, Evaluation

2009

ISBN: 978-3-527-31267-2

Külpmann, W. R. (ed.)

Clinical Toxicological Analysis

Procedures, Results, Interpretation

2009

ISBN: 978-3-527-31890-2

Kumar, C. S. S. R. (ed.)

Nanomaterials - Toxicity, Health and Environmental Issues

2006

ISBN: 978-3-527-31385-3

The Editor

Dr. Moiz Mumtaz

ATSDR, Toxicology and

Environmental Medicine (F-62)

1600 Clifton Road

Atlanta, GA 30333

USA

Cover picture: Anne Christine Kessler

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.

© 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

ISBN: 978-3-527-31992-3

Dedicated to

My father, M.A. Raheem: an educationist and adviser, who instilled in me the significance of the word “read” and my mother, Khairunnisa Begum who personified patience.

My brothers and sisters who encouraged me and had the confidence that I could accomplish my goals. My wife, Farzana, for a lifelong partnership and her everlasting support.

My son, Nabeel, for his motivation and support.

Foreword

As toxicologists, we have two jobs. The first is to identify and characterize the adverse effects that chemicals and other agents can produce in biological systems. The second is to use this information to improve public health. We do this by making safety predictions, and the credibility and public support of our discipline depends on how well we do both jobs. Toxicology is what we do but risk assessment is why we do it. Historically, our ability to make accurate predictions for the adverse effects of mixtures has been limited by the difficulty of acquiring data for all the possible combinations of dose and time that exist even in simple mixtures. Such predictions are also compromised by our use of single-agent toxicity studies since most “real-world” exposures are to mixtures. This has resulted in a variety of approaches (models, protocols, techniques, etc.) to address these issues. These are described in detail in the two dozen chapters of this book along with case studies of mixtures that illustrate their use, advantages, limitations, and regulatory applications. After reviewing the exciting advances taking place in mixture toxicology, it seems to me that the greatest future impact will result from the use of high-throughput testing and the inclusion of emotional stress as a mixtures agent. The use of high-throughput testing as described in the NAS/NRC report “Toxicity Testing in the 21st Century” will enable us to resolve many of the data acquiring limitations of the past [1]. Before discussing emotional stress, I would like to describe how the approach that I use [2] to characterize toxicity can be adapted to the effects of mixtures.

The effects of chemical, biological, and physical agents (and combinations of these) have two things in common. First, all the effects that they produce are the result of an interaction between the agent(s) and a target and we define this interaction as the exposure. We can define each agent by the effects it is capable of producing and the target by its susceptibility to these effects. After doing this, we must then agree that if the exposure is sufficient to produce a specific effect in the target, we have defined a threshold for that effect even if we are not able to measure it. The bottom line here is that we should focus on the measurement problem rather than arguing about whether biological effects have thresholds since they all do.

The second thing that these agents have in common is that all their effects result from an action of the agent on a target (dynamics) or from the action of the target on the agent (kinetics). Thus, the key or rate-limiting events that we use to define the mode of action must occur in the dynamic or kinetic pathways. We focus on the mechanisms of injury and recovery for events in the dynamic pathway and on half-life (intake, distribution, metabolism, and elimination) for those in the kinetic pathway. Therefore, distinguishing the key events that occur in the dynamic pathway from those occurring in the kinetic pathway is a critical first step for defining the mode of action of the agent(s).

These two observations are applications of general biologic principles, but extending them to the “real-world” situation can be complicated. For example, the main factors of exposure are dose and time, but there are other factors such as the route and the presence of other ingredients (vehicles, mixtures). Dose can be a simple variable such as mass or surface area (as in nanotechnology), but time includes not only the duration and frequency but also the persistence of the agent (kinetics) and its effects (dynamics). Agents may be mixtures not only of chemicals but also of pathogens, radiation, and so on. Targets can range from genes to cells to organs and systems and from individuals to populations. Most agents exhibit multiple effects with increasing exposure (hormesis), and some exhibit adaptation or altered susceptibility with repeated exposure (allergens). For most chemical agents, recovery is slower (and therefore rate limiting) than injury in the dynamic pathway and elimination is slower than absorption in the kinetic pathway. In the dynamic pathway, injury can be reduced by adaptation and recovery is modulated by repair, reversibility, and adaptation. Distribution, biotransformation, and excretion are the major factors in the kinetic elimination pathway of chemicals. With pathogens, the rate of multiplication and the host defenses of the target can influence both the dynamic and the kinetic pathways. Exposure to physical agents (radiation, heat, vibration, noise, etc.) introduces new exposure units but the basic principles still apply.

With this approach, it is evident that there is no effect if the agent, target, or exposure is missing and it is equally evident that there are effect thresholds for each combination of agent(s) and target(s) where the exposure exceeds the homeostatic capability of the system. A log probit plot or a log-normal plot plus the Gaussian distribution can be used to identify the individual thresholds and estimate the relative risks in a population or an individual.

Emotional stress or psychosocial factors can certainly produce adverse effects, but including these as mixture agents in the above scheme will be a challenge since they not only have different exposure criteria but their mechanism of action and effects are also different. Furthermore, the proponents of the “exposome” concept are now suggesting that behavior, dietary, aging, lifestyle, and other environmental factors should also be incorporated as mixture components that influence human health and disease. Two things that would help us meet these challenges in mixture toxicology are, first, updating our definition of adversity and, second, developing methods for quantifying benefits to the same level of sophistication as currently exists for risks. This would make risk/benefit analysis a more attractive alternative for conventional (single-agent) and mixture toxicology.

John Doull University of Kansas Medical Center Kansas City, Kansas

References

1. NRC (National Research Council) (2007) Toxicity Testing in the 21st Century: A Vision and a Strategy, National Academy Press, Washington, DC.

2. Rozman, K.K., Doull, J., and Hayes, W.J. (2010) Chapter 1: Dose and time determining and other factors influencing toxicity, in Hayes Handbook of Pesticide Toxicology, 3rd edn, vol. 1 (ed. R. Krieger), Elsevier, Amsterdam.

Preface

On a daily basis we encounter chemicals in our lives. So throughout our lifetime, intentionally or unintentionally, we are exposed to chemicals in combination with one another [mixtures]. Exposures to a variety of mixtures occur through the food we eat, air we breathe, water we drink or through contact with soil. These mixtures, natural or synthetic, have the potential to cause adverse health effects under specific exposure scenarios. In the world of contaminants, it is especially important to identify and study significant mixtures in order to understand their mechanisms of action. From this we can develop methods to evaluate the risk they pose in the real world. Chemical mixtures toxicology is a rapidly developing sub-discipline of toxicology where advances are often based on using concepts and techniques developed through basic biomedical research. To provide a permanent platform for exchange of research and application of scientific advances in diverse fields, the Society of Toxicology has recently established a Mixtures Specialty section.

The risk assessment process involving mixtures uses the same National Academy of Sciences paradigm as for single chemicals, but incorporates mixtures issues in every aspect of exposure assessment, hazard identification, dose response assessment and risk characterization. Through this process new data needs have been recognized and research funded and performed to fill them. Mixtures research founded in molecular biology, statistical and mathematical modeling has led to routine use of models developed. For this field to remain current and continue making significant advances, the latest developments must translate basic research into usable methods and routine practice in the context of public health and protection of the environment. Recently several mixtures issues have become salient, and are deserving of a review that illustrates how new techniques have been applied to real life problems.

The goal of this book is to highlight basic concepts and new methods that may have major impact on general toxicology, as well as the field of safety and risk assessment of chemicals and their mixtures. National and international scholars and prominent toxicologists have provided timely perspectives on how the latest science can be applied to existing problems and provide overviews of areas where significant progress has been made. The target audiences for this book are practicing and future toxicologists in academia, government and industry. We anticipate the book may be especially useful to those individuals interested in the practical aspects of the risk assessment of chemical mixtures. It may also serve as a useful text for “special topics” courses for graduate curricula.

Each author was encouraged to write their chapter(s) in the style and format that suited their contribution, so the chapter formats may vary somewhat. The contents of these chapters do not represent the policy of any agency or organization, unless explicitly stated.

Atlanta, July 2010

Moiz Mumtaz

List of Contributors

S. Satheesh Anand

DuPont Haskell

Global Centers for Health and

Environmental Sciences

Newark, DE 19714

USA

Melvin E. Andersen

The Hamner Institutes for Health

Research

P.O. Box 12137

Research Triangle Park, NC 27709

USA

Subhash C. Basak

University of Minnesota Duluth

Center for Water and the Environment

Natural Resources Research Institute

5013 Miller Trunk Hwy.

Duluth, MN 55811

USA

Ronald E. Baynes

North Carolina State University

Center for Chemical Toxicology

Research and Pharmacokinetics

4700 Hillsborough Street

Raleigh, NC 27606

USA

Negash Belay

United States Food and Drug

Administration

Center for Food Safety and Applied

Nutrition

Office of Food Additive Safety

Division of Biotechnology and GRAS

Notice Review

5100 Paint Branch Parkway, HFS-255

College Park, MD 20740

USA

Linda S. Birnbaum

National Institute of Environmental

Health Sciences (NIEHS)

P.O. Box 12233

Mail Drop B2-01

Research Triangle Park, NC 27709

USA

Christopher J. Borgert

Applied Pharmacology and Toxicology,

Inc.

2250 NW 24th Avenue

Gainesville, FL 32605

USA

Laura K. Braydich-Stolle

Wright-Patterson AFB AFRL/HEPB

U.S. Air Force Research Laboratory

P.O. Box 31009

Dayton, OH 45437-0009

USA

Jerry L. Campbell Jr.

The Hamner Institutes for Health

Research

P.O. Box 12137

Research Triangle Park, NC 27709

USA

Ed Carney

The Dow Chemical Company

Toxicology & Environmental Research

and Consulting

1803 Building

Midland, MI 48674

USA

Harvey J. Clewell III

The Hamner Institutes for Health

Research

P.O. Box 12137

Research Triangle Park, NC 27709

USA

Alexander A. Constan

Infinity Pharmaceuticals, Inc.

780 Memorial Drive

Cambridge, MA 02139

USA

Rebecca P. Danam

United States Food and Drug

Administration

Center for Food Safety and Applied

Nutrition

Office of Food Additive Safety

Division of Biotechnology and GRAS

Notice Review

5100 Paint Branch Parkway, HFS-255

College Park, MD 20740

USA

Christopher T. De Rosa

Agency for Toxic Substances and

Disease Registry (ATSDR)

Division of Toxicology and

Environmental Medicine

F-32, 1600 Clifton Road

Atlanta, GA 30033

USA

Kirby C. Donnelly

Texas A&M University System Health

Science Center

School of Rural Public Health

Department of Environmental and

Occupational Health

1266 TAMU

College Station, TX 77843-1266

USA

Hisham El-Masri

U.S. Environmental Protection Agency

National Health and Environmental

Effects Research Laboratory

Experimental Toxicology Division

109 T.W. Alexander Drive

Mail Drop B143-01

Research Triangle Park, NC 27711

USA

Mike Fay

Agency for Toxic Substances and

Disease Registry (ATSDR)

Division of Toxicology and

Environmental Medicine

F-32, 1600 Clifton Road

Atlanta, GA 30033

USA

Jeffrey W. Fisher

University of Georgia

College of Public Health

Department of Environmental Health

Science

102 Conner Hall

Athens, GA 30602

USA

Paulette M. Gaynor

United States Food and Drug

Administration

Center for Food Safety and Applied

Nutrition

Office of Food Additive Safety

Division of Biotechnology and GRAS

Notice Review

5100 Paint Branch Parkway, HFS-255

College Park, MD 20740

USA

Chris Gennings

Virginia Commonwealth University

Department of Biostatistics

1101 E. Marshall St.

Richmond, VA 23298-0032

USA

Panos Georgopoulos

UMDNJ/Rutgers University

Environmental and Occupational

Health Sciences Institute

107 Frelingshuysen Road

Piscataway, NJ 08854

USA

Brian D. Gute

University of Minnesota Duluth

Center for Water and the Environment

Natural Resources Research Institute

5013 Miller Trunk Hwy.

Duluth, MN 55811

USA

Laurie C. Haws

Tox Strategies

3420 Executive Center Drive

Suite 114

Austin, TX 78731

USA

Frank J. Hearl

U.S. Department of Health and Human

Services

Centers for Disease Control and

Prevention

National Institute for Occupational

Safety and Health

395 E Street, S.W.

Suite 9200

Patriots Plaza Building

Washington, DC 20201

USA

Saber M. Hussain

Wright-Patterson AFB AFRL/HEPB

USA

U.S. Air Force Research Laboratory

P.O. Box 31009

Dayton, OH 45437-0009

USA

Mark Johnson

Agency for Toxic Substances and

Disease Registry (ATSDR)

Division of Regional Operations

4770 Buford Hwy NE

Atlanta, GA 30341

USA

Kannan Krishnan

Université de Montréal

Département de santé

environnementale et santé au travail

C.P. 6128, Succ. Centre-ville

Montréal (Québec) H3C 3J7

Canada

UMDNJ/Rutgers University

Environmental and Occupational

Health Sciences Institute

170 Frelinghuysen Road

Piscataway, NJ 08854

USA

Jason C. Lambert

U.S. Environmental Protection Agency

National Center for Environmental

Assessment

Office of Research and Development

Chemical Mixtures Research Team

26 West Martin Luther King Drive

MC-A-110

Cincinnati, OH 45268

USA

Mary E. LaVecchia

United States Food and Drug

Administration

Center for Food Safety and Applied

Nutrition

Office of Food Additive Safety

Stakeholder Support Team

5100 Paint Branch Parkway, HFS-255

College Park, MD 20740

USA

John C. Lipscomb

U.S. Environmental Protection Agency

National Center for Environmental

Assessment

Office of Research and Development

Chemical Mixtures Research Team

26 West Martin Luther King Drive

MC-A-110

Cincinnati, OH 45268

USA

Michael A. Lyons

Colorado State University

Quantitative and Computational

Toxicology Group

1680 Campus Delivery

Fort Collins, CO 80523

USA

Colorado State University

Department of Environmental and

Radiological Health Sciences

1680 Campus Delivery

Fort Collins, CO 80523

USA

Margaret MacDonell

Argonne National Laboratory

Environmental Science Division

9700 South Cass Avenue, EVS/Bldg 240

Argonne, IL 60439

USA

Antonia Mattia

United States Food and Drug

Administration

Center for Food Safety and Applied

Nutrition

Office of Food Additive Safety

Division of Biotechnology and GRAS

Notice Review

5100 Paint Branch Parkway, HFS-255

College Park, MD 20740

USA

Arthur N. Mayeno

Colorado State University

Quantitative and Computational

Toxicology Group

1680 Campus Delivery

Fort Collins, CO 80523

USA

Colorado State University

Department of Environmental and

Radiological Health Sciences

1680 Campus Delivery

Fort Collins, CO 80523

USA

Eva D. McLanahan

University of Georgia

College of Public Health

Department of Environmental Health

Science

102 Conner Hall

Athens, GA 30602

USA

Harihara M. Mehendale

University of Louisiana at Monroe

College of Pharmacy

Department of Toxicology

Bienville Building

700 University Avenue

Monroe, LA 71209

USA

Chander Mehta

Texas Southern University

College of Pharmacy

3100 Cleburn Street

Houston, TX 77004

USA

David Mellard

Agency for Toxic Substances and

Disease Registry (ATSDR)

Division of Health Assessment and

Consultation

1600 Clifton Road

Atlanta, GA 30033

USA

Nancy A. Monteiro-Riviere

North Carolina State University

College of Veterinary Medicine

Center for Chemical Toxicology

Research and Pharmacokinetics

4700 Hillsborough Street

Raleigh, NC 27606

USA

Moiz Mumtaz

Agency for Toxic Substances and

Disease Registry (ATSDR)

Computational Toxicology and Methods

Development Laboratory

Division of Toxicology and

Environmental Medicine

MS-F62, 1600 Clifton Road

Atlanta, GA 30333

USA

Richard C. Murdock

Applied Biotechnology Branch

Human Effectiveness Directorate

Air Force Laboratory

Wright-Patterson AFB Building 837

“R” Street, Area B

Dayton OH 45433-5705

USA

Ziad S. Naufal

Texas A&M University System Health

Science Center

School of Rural Public Health

Department of Environmental and

Occupational Health

1266 TAMU

College Station, TX 77843-1266

USA

Binu K. Philip

Indiana University

School of Medicine

1120 South Drive

Indianapolis, IN 46202

USA

Hana R. Pohl

Agency for Toxic Substances and

Disease Registry (ATSDR)

Division of Toxicology and

Environmental Medicine

F-32, 1600 Clifton Road

Atlanta, GA 30033

USA

Paul S. Price

The Dow Chemical Company

Toxicology & Environmental Research

and Consulting

2030 Dow Center

Midland, MI 48674

USA

Brad Reisfeld

Colorado State University

Department of Chemical and

Biological Engineering

1370 Campus Delivery

Fort Collins, CO 80523

USA

Glenn E. Rice

U.S. Environmental Protection Agency

Office of Research and Development

National Center for Environmental

Assessment

Chemical Risk Assessment Branch

Chemical Mixtures Research Team

26 West Martin Luther King Drive

M.S. A 130

Cincinnati, OH 45268

USA

Jim E. Riviere

North Carolina State University

Center for Chemical Toxicology

Medicine Box 8410

4700 Hillsborough Street

Research and Pharmacokinetics

Raleigh, NC 27606

USA

Craig Rowlands

The Dow Chemical Company

Toxicology & Environmental Research

and Consulting

2030 Dow Center

Midland, MI 48674

USA

Patricia Ruiz

Agency for Toxic Substances and

Disease Registry (ATSDR)

Division of Toxicology and

Environmental Medicine

1600 Clifton Road NE

Mailstop F32

Atlanta, GA 30333

USA

P. Barry Ryan

Emory University

Rollins School of Public Health

Department of Environmental and

Occupational Health

1518 Clifton Road, NE,

Atlanta, GA 30322

USA

Alan Sasso

UMDNJ/Rutgers University

Environmental and Occupational

Health Sciences Institute

170 Frelinghuysen Road

Piscataway, NJ 08854

USA

Jane Ellen Simmons

U.S. Environmental Protection Agency

Office of Research and Development

National Health and Environmental

Effects Research Laboratory

109 T. W. Alexander Drive

Research Triangle Park, NC 27711

USA

Daniele F. Staskal

National Institute of Environmental

Health Sciences (NIEHS)

P.O. Box 12233

Mail Drop B2-01

Research Triangle Park, NC 27709

USA

William A. Suk

National Institute of Environmental

Health Sciences

Division of Extramural Research and

Training

P.O. Box 12233

Research Triangle Park, CO 80523-1681

USA

Linda K. Teuschler

U.S. Environmental Protection Agency

National Center for Environmental

Assessment

Office of Research and Development

Chemical Mixtures Research Team

26 West Martin Luther King Drive

MC-A-110

Cincinnati, OH 45268

USA

Richard Y. Wang

Centers for Disease Control and

Prevention

National Center for Environmental

Health

Division of Laboratory Sciences

4770 Buford Highway, MS-F17

Atlanta, GA 30341

USA

Frank A. Witzmann

Indiana University School of Medicine

Biotechnology Research and Training

Center

Department of Cellular and Integrative

Physiology

1345 W. 16th Street

Indianapolis, IN 46202

USA

Kent Woodburn

Health and Environmental Sciences

Dow Corning

Midland, MI 48686

USA

and

The Dow Chemical Company

Toxicology & Environmental Research

and Consulting

Midland, MI

USA

Raymond S. H. Yang

Colorado State University

Department of Environmental and

Radiological Health Sciences

1680 Campus Delivery

Fort Collins, CO 80523

USA

1

Introduction to Mixtures Toxicology and Risk Assessment

M. Moiz Mumtaz, William A. Suk, and Raymond S.H. Yang

1.1 Chemical Mixtures Exposure

When humans are exposed to chemicals, they are not exposed to just one chemical at a time. A vast number of chemicals pervade our environment. Exposures, whether simultaneous or sequential, are to chemical mixtures. The standard definition of a chemical mixture is any set of multiple chemicals regardless of source that may or may not be identifiable that may contribute to joint toxicity in a target population [1, 2].

By some estimates, up to 6 billion tons of waste is produced annually in the United States. Several years ago, the US Office of Technology Assessment estimated 275 million of those tons were hazardous. Most waste finds its way to more than 30 000 toxic waste disposal sites across the United States, a majority of which the US EPA has categorized as uncontrolled hazardous waste sites [3]. Thus far, traditional risk assessment, even with its inherent shortcomings, has helped to control chemical exposures to that waste reasonably well, as evidenced by statistics on longevity, health status, and world population growth. Yet, new health and environment indicators have raised disquieting questions, and a consequent growing concern is that this success might be short-lived. One reason is an alarming, logarithmic increase in the synthesis, manufacture, and use of chemicals worldwide as “developed” and “developing” countries compete to provide their populations an improved quality of life. To help meet these concerns, the World Health Organization (WHO), as part of its harmonization of approaches project, recently published a report on methods and approaches for risk assessment of chemical mixtures [4, 5].