Reducing, Refining and Replacing the Use of Animals in Toxicity Testing

384 Pages·2013·5.546 MB·English

by  Dave Allen

Reducing, Refining and Replacing the Use of Animals in
Toxicity Testing
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Issues in Toxicology
Series Editors:
Professor Diana Anderson, University of Bradford, UK
1 Dr Michael D Waters, Integrated Laboratory Systems, Inc, N Carolina, USA
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9 Titles in the Series:
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1 1: Hair in Toxicology: An Important Bio-Monitor
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9 2: Male-mediated Developmental Toxicity
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03 3:CytochromeP450:RoleintheMetabolismandToxicityofDrugsandother
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0. Xenobiotics
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oi: 4: Bile Acids: Toxicology and Bioactivity
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g | 5: The Comet Assay in Toxicology
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c. 6: Silver in Healthcare
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p:// 9:BiomarkersandHumanBiomonitoring,Volume1:OngoingProgramsand
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ber 11: Hormone-Disruptive Chemical Contaminants in Food
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Oct 12: Mammalian Toxicology of Insecticides
. n 31 13:TheCellularResponsetotheGenotoxicInsult:TheQuestionofThreshold
o for Genotoxic Carcinogens
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he 14:ToxicologicalEffectsofVeterinaryMedicinalProductsinHumans:Volume1
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Disorders and their Origins in Environmental Exposures
17: Chemical Toxicity Prediction: Category Formation and Read-Across
18: The Carcinogenicity of Metals: Human Risk through Occupational and
Environmental Exposure
19: Reducing, Refining and Replacing the Use of Animals in Toxicity Testing
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Reducing, Refining and
Replacing the Use of Animals in
1 Toxicity Testing
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10. Toxicity testing is performed to assess the safety or hazards presented by
doi: substances such as industrial chemicals, consumer products, and pharma-
g | ceuticals. Many of the test methods currently employed for this purpose use
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c. laboratory animals (e.g., mice, rats, or rabbits). Alternative test methods are
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bs.r proceduresthat,reduce,refine,orreplaceanimalsinregulatorytoxicitytesting.
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http://p Tinejustrymoetrhdoidsesatsheaatrceanviataclcutorahteelayltdheptercottwechtieotnh.erImchpermoviceadlsparnevdepnrtioodnucotfsicnajuursye
n and disease requires effective translation of new knowledge into better test
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13 methods.Newtestmethodsshouldnotonlybemorepredictivebutalsofaster,
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ob still considered necessary, new test methods should not only minimize animal
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d o based technologies to predict responses in humans, typically the species of
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environment, performing as well or better than currently accepted methods.
For this reason, test method validation must demonstrate that an alternative
test method is both scientifically valid and as protective as currently accepted
methods. In this text, readers will see that scientists have succeeded in
developing alternatives for virtually every toxicity endpoint required for
regulatorytesting.Alternativesarenowavailablethatreduceoreveneliminate
the need for animals for certain acute endpoints. Likewise, methods are
available to address some of the mechanisms associated with longer term and
complex processes (e.g., carcinogenicity, reproductive toxicity, and develop-
mental toxicity), but none can account for them all. Therefore, integrated
testing strategies are being developed that will allow for a broader assessment
of the many mechanisms involved in these complex processes.
IssuesinToxicologyNo.19
Reducing,RefiningandReplacingtheUseofAnimalsinToxicityTesting
EditedbyDavidG.AllenandMichaelD.Waters
rTheRoyalSocietyofChemistry2014
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
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vi Preface
In this text, we describe the ever-expanding ‘‘toolbox’’ of test methods
available to the toxicologist to determine the hazards associated with test
materials of interest. Development of such methods has often resulted from
basic science advances that facilitate identification of biochemical and cellular
5 pathwaysthatmediatemechanismsoftoxicity.Thispermitsthetoxicologistto
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79 in vitro, and ex vivo methods, coupled with state-of-the-art mid- and high-
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97 throughputtechnologies that rely almost completelyon biochemical- and cell-
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18 based in vitro assays, toxicologists are moving closer to using mechanistically
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03 Chapter 1 History of the 3Rs in Toxicity Testing: From Russell and
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1.6 Remaining Challenges 27
1.7 Conclusions 29
Appendix A: Citation Search Strategies 29
Databases 29
Search Terms 31
Limitations 32
Appendix B: Literature Search Strategies 33
Databases 34
Search Terms 34
Categorization 37
Limitations 38
IssuesinToxicologyNo.19
Reducing,RefiningandReplacingtheUseofAnimalsinToxicityTesting
EditedbyDavidG.AllenandMichaelD.Waters
rTheRoyalSocietyofChemistry2014
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
vii
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viii Contents
Acknowledgements 39
References 39
Chapter 2 Regulatory Testing To Inform Decisions: National and
07 International Requirements 44
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doi: 2.2 US Regulatory Agencies, Research Agencies and
org | Interagency Bodies 49
sc. 2.2.1 The Environmental Protection Agency (EPA) 49
bs.r 2.2.2 The Food and Drug Administration (FDA) 56
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Chapter 3 Efforts Towards International Harmonization of Acceptable
Alternatives to Animal Testing 99
Chantra Eskes
3.1 Introduction 99
3.2 Acceptable Alternative Methods 100
3.2.1 The Acceptance Process 100
3.2.2 Major Validation Principles 102
3.2.3 The Need for International Harmonization 107
3.3 Efforts Toward International Harmonization 108
3.3.1 The Organisation for Economic Co-operation
and Development 108
3.3.2 The International Cooperation on Alternative
Test Methods 111
3.3.3 Further International Efforts 112
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3.4 Conclusions 113
References 115
Chapter 4 Refinement Alternatives: Minimizing Pain and Distress in
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4.10 Selection of Animals 133
4.10.1 Species 133
4.10.2 Genetic Status 133
4.10.3 Microbiological Status 134
4.10.4 Age 134
4.10.5 Sex 134
4.11 Housing, Husbandry and Care 134
4.11.1 The Physical Environment 135
4.11.2 Environmental Enrichment 135
4.12 Husbandry 137
4.12.1 Handling 137
4.12.2 Transport and Acclimatization 137
4.12.3 Marking and Identification of Animals 137
4.12.4 Diet and Food Intake 137
4.13 Refining Procedures 138
4.13.1 Restraint 138
4.13.2 Procedural Training 138
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4.13.3 Motivational Tools 138
4.13.4 Dosing and Sampling 139
4.13.5 Dosing 139
4.13.6 Blood Sampling 141
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5.2 Conventional Cheminformatics Toxicity Models 165
5.3 Future Directions of Computational
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5.4 Availability of Large Toxicity Databases from
Data-sharing Projects 168
5.4.1 The Available Resources for In Vitro
Toxicity Data 168
5.4.2 The Available Animal Toxicity Data 170
5.5 The use of Quantitative Structure In vitro–In vivo
Relationship (QSIIR) to Develop Enhanced
Computational Animal Toxicity Models 172
5.5.1 The Use of Experimental Parameters in the
Computational Modeling 172
5.5.2 Advance the Traditional QSAR
Approaches to QSIIR Strategy 172
5.6 The Pitfalls of QSIIR Modeling and Potential
Solutions 173