Toxicological Risk Assessment of Chemicals: A Practical Guide - Chapter 1 ppt

2.1 World Health Organization2.1.1 International Programme on Chemical Safety 2.1.2 Food and Agriculture Organization of the United Nations 2.1.3 Joint FAO=WHO Expert Committee on Food A

Toxicological Risk Assessment

of Chemicals

A Practical Guide

Risk Assessment

of Chemicals

A Practical Guide Elsa Nielsen • Grete Østergaard • John Christian Larsen

New York London

Cover: Theophrastus Phillippus Aureolus Bombastus von Hohenheim, known as “Paracelsus” 1493–1541 (“the equal of

Celsus”, an early Roman physician) Paracelsus is often called “the father of toxicology.” His famous quotation forms the central dogma of regulatory toxicology:

“All substances are poisons; there is none that is not a poison The right dose differentiates a poison and a

remedy.”—Paracelsus

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Library of Congress Cataloging-in-Publication Data

Ostergaard, Grete.

Toxicological Risk Assessment of Chemicals : a practical guide / Elsa Nielsen, Grete Ostergaard, and

John Christian Larsen.

p ; cm.

Includes bibliographical references and index.

ISBN-13: 978-0-8493-7265-0 (hardcover : alk paper)

ISBN-10: 0-8493-7265-8 (hardcover : alk paper)

1 Toxicology 2 Toxicity testing 3 Health risk assessment 4 Environmental risk assessment I

Nielsen, Elsa II Larsen, John Christian III Title

[DNLM: 1 Hazardous Substances toxicity 2 Environmental Exposure prevention & control 3

Risk Assessment methods 4 Risk Assessment standards WA 670 O845p 2008]

2.1 World Health Organization

2.1.1 International Programme on Chemical Safety

2.1.2 Food and Agriculture Organization of the United Nations

2.1.3 Joint FAO=WHO Expert Committee on Food Additives

2.1.4 Joint FAO=WHO Meeting on Pesticide Residues

2.1.5 Inter-Organization Programme for the Sound Management of Chemicals2.1.6 International Agency for Research on Cancer

2.1.7 IPCS: Chemicals Assessment

2.1.7.1 Environmental Health Criteria

2.1.7.2 Concise International Chemical Assessment Document

2.1.7.3 Health and Safety Guide

2.1.7.4 International Chemical Safety Card

2.1.7.5 Pesticide Safety Data Sheet

2.1.7.6 The WHO Recommended Classification of Pesticides by Hazard2.2 Organisation for Economic Co-operation and Development

2.2.1 The OECD Chemicals Program

2.2.2 Mutual Acceptance of Data

2.2.3 The OECD Existing Chemicals Program

2.2.4 The OECD New Chemicals Program

2.2.5 The OECD Pesticides and Biocides Program

2.2.6 OECD Test Guidelines

2.3 United States of America

2.3.1 United States Environmental Protection Agency

2.3.1.1 Office of Pollution Prevention and Toxics

2.3.1.2 Toxic Substances Control Act

2.3.1.3 Existing Chemicals

2.3.1.4 High Production Volume Challenge Program

2.3.1.5 New Chemicals

2.3.1.6 Integrated Risk Information System

2.3.1.7 Harmonization of US-EPA Risk Assessment

2.3.1.8 US-EPA Risk Assessment Guidelines

2.3.1.9 US-EPA Test Guidelines

2.3.2 Agency for Toxic Substances and Disease Registry

2.3.3 National Toxicology Program

2.3.4 United States Food and Drug Administration

2.4 The European Union

2.4.1 EU Chemicals Program

2.4.1.1 Actors Involved in Chemical Legislation

2.4.1.2 Current EU Regulatory Framework for Chemicals

2.4.1.3 New EU Regulatory Framework for Chemicals

2.4.2 Harmonization of Risk Assessment in DG SANCO

2.4.2.1 Scientific Committee on Health and Environmental Risks2.4.2.2 Scientific Committee on Consumer Products

2.4.2.3 Scientific Committee on Emerging and Newly Identified

Health Risks2.4.2.4 EFSA Committees

2.5 Globally Harmonized System of Classification and Labeling of Chemicals2.6 Precautionary Principle

3.3 Data from Studies in Experimental Animals

3.3.1 Animal Toxicity Studies

3.3.2 Test Guidelines for Animal Toxicity Studies

3.3.3 Good Laboratory Practice

3.3.4 OECD Test Guidelines

3.3.5 US-EPA Test Guidelines

3.4.3 ICCVAM Review Process

3.4.4 In Vitro Tests Undergoing Validation by ICCVAM

3.4.5 European Center for the Validation of Alternative Methods

3.4.6 In Vitro Tests Undergoing Validation by ECVAM

3.4.7 In Vitro Test Guideline Methods

3.4.7.1 OECD In Vitro Test Guideline Methods

3.4.7.2 EU In Vitro Test Guideline Methods

3.5 Nontesting Data

3.5.1 Physico-Chemical Properties

3.5.2 Use of Structure–Activity Relationships

3.5.3 Quantitative Structure–Activity Relationship

3.6 Data Collection

3.6.1 Criteria Documents and Monographs from International Bodies

3.6.1.1 Environmental Health Criteria

3.6.1.2 Monographs from the International Agency for Research on Cancer3.6.1.3 Monographs from the Joint FAO=WHO Expert Committee

on Food Additives and from the Joint FAO=WHO Meeting

on Pesticide Residues3.6.1.4 WHO Guidelines for Drinking-Water Quality

3.6.1.5 WHO Air Quality Guidelines for Europe

3.6.1.6 Toxicological Profiles from Agency for Toxic Substances

and Disease Registry3.6.1.7 EU Risk Assessment Reports on Existing Chemicals

3.6.1.8 Publications from the International Life Sciences Institute

3.6.1.9 Publications from the European Centre for Ecotoxicology

and Toxicology of Chemicals3.6.1.10 BUA Reports from the German Chemical Society

3.6.1.11 American Conference on Governmental Industrial Hygienists3.6.1.12 Criteria Documents from the Nordic Expert Group

3.6.2 Databases

3.6.2.1 IPCS INCHEM

3.6.2.2 International Uniform ChemicaL Information Database

3.6.2.3 US-EPA Integrated Risk Information System

3.6.2.4 U.S National Library of Medicine TOXNET

References

Chapter 4 Hazard Assessment

4.1 Introduction

4.2 General Aspects

4.2.1 Systemic Effects versus Local Effects

4.2.2 Adverse Effects versus Non-Adverse Effects

4.2.3 Dose–Response Relationships

4.2.4 No-Observed-Adverse-Effect Level, Lowest-Observed-Adverse-Effect Level4.2.5 The Benchmark Dose Concept

4.2.6 Toxicological Modes of Action

4.3.5 Use of Toxicokinetics in Hazard Assessment

4.3.5.1 Human and Animal Data

4.6.3.1 In Vivo Tests for Skin Sensitization

4.6.3.2 In Vivo Tests for Respiratory or Oral Sensitization

4.7.6.4 Use of Information from Repeated Dose Toxicity Studies

in the Hazard Assessment of Immunotoxicity4.7.7 Neurotoxicity

4.7.7.1 Definitions

4.7.7.2 Test Guidelines

4.7.7.3 Guidance Documents

4.7.7.4 Use of Information from Repeated Dose Toxicity Studies

in the Hazard Assessment of Neurotoxicity4.7.8 Nasal Toxicity

4.9.6 Effects in Experimental Animals of Disputed Relevance for Humans

4.9.6.1 Leukemia (Mononuclear Cell Type) in the Fischer Rat4.9.6.2 Kidney Tumors in Male Rats

4.9.6.3 Liver Tumors in Mice and Rats

4.9.6.4 Leydig Cell Tumors in Rats

4.9.6.5 Thyroid Tumors in the Rat

4.9.6.6 Urinary Bladder Tumors in the Rat and Mouse

4.9.6.7 Forestomach Tumors in Mice and Rats

4.9.6.8 Other Types of Tumors

4.9.7 Categorization for Carcinogenicity

4.11.2 Strategies for Assessment of Endocrine Disrupters

4.13.2 Structure-Based, Tiered TTC Concept

4.13.3 Enhanced Structure-Based, Tiered TTC Concept

4.13.4 TTC Concept, Industrial Chemicals within REACH

4.13.4.1 Tiered TTC Concept: ECETOC

4.13.4.2 Nordic Project: Applicability of TTC within REACH

4.13.4.3 TTC Concept within EU REACH: Dutch Document

4.14 Probabilistic Methods for Hazard Assessment

References

Chapter 5 Standard Setting: Threshold Effects

5.1 Introduction

5.2 Assessment Factors: General Aspects

5.2.1 Assessment Factors: Various Approaches

5.2.1.10 Swedish National Chemicals Inspectorate’s Approach

5.2.1.11 Danish EPA’s Approach

5.2.1.12 Chemical-Specific Assessment Factors

5.2.1.13 Children-Specific Assessment Factor

5.3 Interspecies Extrapolation (Animal-to-Human)

5.3.1 Biological Variation

5.3.2 Adjustment for Differences in Body Size: Allometry=Scaling

5.3.2.1 Adjustment for Differences in Body Size: Body Weight

Approach5.3.2.2 Adjustment for Differences in Body Size: Body Surface

Area Approach5.3.2.3 Adjustment for Differences in Body Size: Caloric Requirement

Approach5.3.2.4 Adjustment for Differences in Body Size: Exposure Route5.3.2.5 Adjustment for Differences in Body Size: PBPK Models5.3.3 Remaining Species-Specific Differences

5.3.4 Assessment Factor for Interspecies Variation (Animal-to-Human):

Default Value

5.3.5 Interspecies Extrapolation (Animal-to-Human): Summary

and Recommendations

5.4 Intraspecies Extrapolation (Interindividual, Human-to-Human)

5.4.3 Intraspecies Extrapolation (Human-to-Human):

Summary and Recommendations

5.7 Dose–Response Curve (LOAEL-to-NOAEL Extrapolation)

5.7.1 Dose–Response Curve (LOAEL-to-NOAEL Extrapolation):

Summary and Recommendations

5.8 Nature and Severity of Effects

5.8.1 Nature and Severity of Effects: Summary

and Recommendations

5.9 Confidence in the Database

5.9.1 Confidence in the Database: Summary and Recommendations5.10 Overall Assessment Factor

5.10.1 Overall Assessment Factor: Summary and Recommendations5.11 Assessment Factors: Probabilistic Approach

5.12 Tolerable Intake

References

Chapter 6 Standard Setting: Non-Threshold Effects (Carcinogenicity)

6.1 Introduction

6.2 Quantitative Dose–Response Assessment: General Aspects

6.2.1 Low-Dose Risk Extrapolation

6.2.1.1 Linear Extrapolation

6.2.1.2 Linearized Multistage Model

6.2.2 Relative Ranking of Potencies

6.2.3 Division of Effect Levels by an Uncertainty Factor

6.2.4 Acceptable/Tolerable Lifetime Cancer Risk

6.3 Quantitative Dose–Response Assessment: Currently

Used Approaches

6.3.1 WHO Approach: Drinking Water and Air Quality Guidelines

6.3.1.1 Drinking-Water Guidelines

6.3.1.2 Air Quality Guidelines

6.3.2 US-EPA: General Approach

6.3.3 EU Approach: Industrial Chemicals

6.4 JECFA and EFSA: New Approach, Margin of Exposure

References

Chapter 7 Exposure Assessment

7.2.3.1 US-EPA Guidelines for Exposure Assessment

7.2.3.2 US-EPA Guidance for Exposure Assessment

7.2.3.3 Other US-EPA Guidelines for Exposure Assessment

8.2 Risk Characterization: General Aspects

8.2.1 Toxicity Exposure Ratio Approach

8.2.2 Standard Setting Approach

Chapter 9 Regulatory Standards Set by Various Bodies

9.1 Guidance Values: Development

9.2 Guidance Values: Examples

10.2 Basic Concepts and Terminology Used to Describe

the Combined Action of Chemicals in Mixtures

10.2.1 No Interaction

10.2.1.1 Simple Similar Action (Dose Addition, Loewe Additivity)10.2.1.2 Simple Dissimilar Action (Response or Effect Additivity,

Bliss Independence)10.2.2 Interactions: Complex Similar Action and Complex Dissimilar Action

10.2.2.1 Complex Similar Action

10.2.2.2 Complex Dissimilar Actions

10.3 Test Strategies to Assess Combined Actions and Interactions

of Chemicals in Mixtures

10.3.1 Testing of Whole Mixtures

10.3.2 Physiologically Based Toxicokinetic Modeling

10.3.3 Isobole Methods

10.3.4 Comparison of Individual Dose–Response Curves

10.3.5 Response Surface Analysis

10.3.6 Statistical Designs

10.4 Toxicological Test Methods

10.5 Approaches Used in the Hazard Assessment of Chemical Mixtures

10.5.1 Procedures Used to Assess Cumulative Effects of Chemicals That Act

by a Common Mechanism of Action: Cumulative Risk Assessment

10.5.2 Procedures Used to Assess Cumulative Effects of Chemicals

That Do Not Act by a Common Mechanism of Action

10.5.2.1 Interactions in Toxicokinetics

10.5.3 Use of Response=Effect Addition in the Risk Assessment of Mixtures

of Carcinogenic Polycyclic Aromatic Hydrocarbons

10.5.4 Approach to Assess Simple and Complex Mixtures Suggested

by the Dutch Group

10.6.1 Chemicals with Different Target Organs and=or Different Modes of Action

10.6.1.1 Dutch Group

10.6.1.2 Other Studies

10.6.2 Same Target Organ with Dissimilar or Similar Modes of Action

10.6.2.1 Nephrotoxicants with Dissimilar Modes of Action

10.6.2.2 Nephrotoxicants with Similar Modes of Action

10.6.2.3 Mixtures of Chemicals Affecting the Same Target Organ

but with Different Target Sites10.6.3 Conclusions of the Dutch Studies

References

Risk assessment of chemical substances is an ever-developing discipline Transparent and accuraterisk assessments are necessary for decision-makers to make wise risk management decisions Theoutcome of risk assessments may have enormous economical consequences, in addition to theconsequences for human health and the environment Globalization is a fact, with huge possibilitiesfor economic and social prosperity Food and consumer products are produced in one part of theworld and put on the market in another Fair competition rests upon global similarity of regulations.Environmental chemical pollution does not stay within the borders of a country, but moves to eventhe most remote and isolated places on Earth Therefore, regulation of chemicals cannot be keptwithin individual states, and consequently the demand for international agreement on regulation isincreasing Toxicology and chemical risk assessments are important parts of this movement from anational to an international world, and must assist in the development of tools to ensure humansafety while free trade is not compromised The key is science, harmonization, mutual agreement,and acceptance

Our aim with this book is to provide the reader with a useful guide and a valuable tool forworking as a toxicologist and risk assessor in thefield of human health risk assessments The bookhas been written with emphasis on international harmonization through the United Nations and theOrganisation for Economic Co-operation and Development, and taking major federal bodies such asthe United States and the European Union into consideration National programs and methods arementioned, but only to a very limited extent The book is mainly concerned with industrial chemicals,but other chemical use categories, for example pesticides, food additives, veterinary drugs, etc., arealso mentioned in recognition of the wide use of chemicals for different purposes

The focus of this book is on the description of the existing risk assessment methodologies forhuman health New developments in these methodologies are also mentioned The major subjects ofthe book include a description of the various institutions, agencies, and programs involved inchemicals regulation; data used for hazard assessment; the various toxicological endpoints andthe associated test methods used in hazard assessment; the process of standard setting for thresholdand non-threshold effects with focus on the assessment factors applied for threshold effects; theexposure assessment, the risk characterization, regulatory standards by various bodies; and the riskassessment of chemicals in mixture

We have attempted to present the state of the art and scientific consensus in an unbiased way;however, what is believed to be true today may not hold tomorrow - politics may change, andscience may progress Fortunately, while methods and techniques are continuing to improve, thebasic concepts of toxicological risk assessment remain stable and form the core in this book.The book has been based primarily on our experiences achieved through many years of practicalwork as risk assessors within different areas of toxicological risk assessments of chemicals We havealso consulted essential key references for the state of the art as well as relevant Web sites Links toWeb sites were checked right before we forwarded the manuscript to the publisher (1 July 2007);however, as Web sites are undergoing continuing development, links might have changed since then.Elsa Nielsen and Grete Østergaard are the authors of Chapters 1 through 9, while John ChristianLarsen is the author of Chapter 10

The book is primarily intended for students in health and environmental sciences as well as forrisk assessors who are involved in toxicological risk assessments of chemicals We hope that thisbook will serve as a fundamental basis for students in their toxicological training and as a usefulguide and a valuable tool for risk assessors in their daily work