Investigative Immunotoxicology

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ISBN: 9780415308540 | 0415308542
Cover: Hardcover
Copyright: 1/27/2005

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Investigative Immunotoxicology provides a critical evaluation of proposed experimental animal models and approaches, and discusses the contribution that immunotoxicity can make to the overall assessment of chemical-induced adverse health effects on humans and the ecosystem. Following a review of general concepts in immunotoxicology, the book discusses emerging methodologies at the cellular and molecular levels, and describes advances in and requirements for animal model development in testing the allergenicity of foods and genetically modified products. It presents animal models of autoimmunity associated with chemical exposure, includes recommendations for the selection of sentinel species in ecotoxicology, and presents an in-depth review of immunotoxicology as it relates to a variety of wildlife species. Finally, the book explains the role of immunotoxicology in human health risk assessment and the regulatory process.Outlining the potential chemical hazards facing human and ecosystem health, this is a valuable reference for professionals and researchers in immunotoxicology and risk assessment. It also deserves the attention of the pharmaceutical industry and environmental toxicologists who are concerned about the effects of xenobiotics on ecosystems.

Section I The Immune System

(10)

Structural and Functional Complexity of the Immune System and Its Relationship to Immunotoxicology

(8)

Barry R. Blakley

Edward Kouassi

Introduction

(1)

Structural and Functional Components of the Immune System

(1)

Immune System Regulation

(1)

The Neuro--Endocrine--Immune Connection

(1)

Consequences of Immune Alteration

(2)

Compensation Associated with Immunotoxicants

(1)

Summary

(3)

Acknowledgments

(1)

References

(2)

Section II Approaches and Models Relevant to the Assessment of Chemical-Induced Immunotoxic Effects in Species of the Ecosystem

(152)

Ecoimmunotoxicology: State of the Science

(16)

Michael R. Woolhiser

Kevin S. Henry

Michael P. Holsapple

Introduction: What Is Ecoimmunotoxicology?

(1)

Background on Current Immunotoxicology Guidelines

(1)

Background on the Immune System in Context of Alternative, Nontraditional Laboratory Species

(2)

Mammalian Immune System

(1)

Avian Immune System

(1)

Aquatic Vertebrate Immunology

(1)

Invertebrate Immunology

(1)

Assessment of Immune Endpoints in Wildlife Species

(3)

Ecoimmunotoxicology Experimental Design

(4)

Advantages

(1)

Complications

(3)

Summary: State of the Science

(5)

References

(4)

Bivalves as Models for Marine Immunotoxicology

(20)

Michel Auffret

Introduction

(1)

The Immune System of Bivalve Mollusks

(1)

Evidence for Immunotoxicity of Chemicals in Bivalve Mollusks: An Overview

(5)

Experimental Design

(5)

In Vitro Exposure

(1)

In Vivo Controlled Exposure Regimens

(1)

Microbial Infectivity Models

(1)

Field Studies

(1)

Site Comparison

(1)

Caging Bivalves

(2)

Bivalves as Sentinel Species in Marine Ecosystems: Biomarker Approach

(1)

Future Perspectives

(2)

Summary

(5)

Acknowledgments

(1)

References

(4)

Approaches and Models for the Assessment of Chemical-Induced Immunotoxicity in Fish

(14)

Jessica E. Duffy

Judith T. Zelikoff

Introduction

(1)

Chemical-Induced Immunotoxicity in Fish: An Overview

(7)

Innate Immunity

(1)

In Vivo Exposure Studies

(3)

In Vitro Exposure Studies

(1)

Cell-Mediated Immunity

(1)

In Vivo Exposure Studies

(1)

In Vitro Exposure Studies

(1)

Humoral-Mediated Immunity

(1)

In Vivo Exposure Studies

(1)

Overall Host Immunocompetence (Host Resistance Studies)

(1)

Metals

(1)

Halogenated Aromatic Hydrocarbons and Polycyclic Aromatic Hydrocarbons

(1)

Summary and Conclusions

(1)

Future Perspectives

(6)

Acknowledgments

(1)

References

(5)

Immunotoxicology in Marine Mammals

(14)

Sylvain De Guise

Introduction

(1)

Marine Mammal Immunology

(3)

Marine Mammal Immunotoxicology

(3)

Coincidental Evidence

(1)

In Vitro Immunotoxicology

(1)

Animal Models of Marine Mammal Immunotoxicology

(1)

Marine Mammal Experimental Immunotoxicology

(1)

Research Needs

(1)

Marine Mammal Immunology

(1)

Models for Marine Mammal Immunotoxicology

(1)

Summary

(6)

Acknowledgments

(1)

References

(6)

Amphibian Models and Approaches to Immunotoxicology

(14)

Louise A. Rollins-Smith

Judit E.G. Smits

Introduction

(1)

Overview of Amphibian Immune Defenses

(1)

Innate Immunity

(1)

Adaptive Immunity

(1)

Effects of Environmental Chemicals on Amphibian Immune Defenses

(4)

Altered Development of the Immune System in Embryos

(1)

Altered Development of the Immune System in Tadpoles

(1)

Effects of Ultraviolet Irradiation on Tadpole Immunity

(1)

Effects of Agricultural Chemicals on Immune Defenses of Juvenile and Adult Frogs and Salamanders

(2)

Association of Global Amphibian Declines with Disease and Concerns About Skin Exposure to Pesticides

(2)

The Problem of Global Amphibian Declines

(1)

Effects of Pesticides on Release of Antimicrobial Peptides Released from Amphibian Skin

(2)

Research Needs

(1)

Summary

(6)

Acknowledgments

(1)

References

(6)

Earthworms as Ecosentinels for Chemical-Induced Immunotoxicity

(16)

Arthur J. Goven

Barney J. Venables

Lloyd C. Fitzpatrick

Introduction

(1)

Earthworm Credentials as Ecosentinels of Immunotoxicity

(1)

Earthworm Immune System

(2)

Innate Immune Functions in Earthworms

(1)

Cell-Mediated Immune Functions in Earthworms

(1)

Humoral Immunity in Earthworms

(2)

Earthworm Immunemarkers

(2)

Potential Earthworm Immunomarker Candidates

(1)

Recommended Earthworm Immune Marker Candidates

(1)

Interaction of Exogenous Chemicals with Earthworm Immune Marker Candidates

(2)

Heavy Metals

(1)

Polycyclic Aromatic Hydrocarbons

(1)

Halogenated Aromatic Hydrocarbons

(1)

Pesticides

(1)

Research Directions

(3)

Exposure Metrics: Normalization of Immunotoxicokinetics Across Taxa

(1)

Control of Natural Sources of Variability in Immune Marker Response

100

(1)

Linkage of Immune Marker to Ecologically Significant Endpoints

100

(2)

Summary

102

(5)

References

102

(5)

Reptiles: The Research Potential of an Overlooked Taxon in Immunotoxicology

107

(22)

Andrew A. Rooney

Introduction

108

(1)

Reptile Phylogeny/Evolutionary Relationships

108

(1)

Reptilian Toxicology and Immunology: Background Data Needed for Immunotoxicology Studies

109

(9)

Tier 1: Present Status and Research Needs

111

(1)

Structural Measurements/Major Organs of Reptile Immune System

111

(1)

General Parameters of Immune System

112

(1)

Tier 2: Present Status and Research Needs

113

(1)

Cell-Mediated Immune Assays

113

(3)

Nonspecific Immune Assays

116

(2)

Tier 3: Present Status and Research Needs

118

(1)

Host Resistance (Infectivity) Models

118

(1)

Life History (Does It Help or Hinder Immunotoxicity Studies?)

118

(2)

Seasonality

118

(1)

Gender and Immunotoxicity

119

(1)

Viviparity, Oviparity, and Developmental Immunotoxicology

119

(1)

Critical Needs for Standard Reptilian Models

120

(1)

The Reptilian Lab Rat

120

(1)

Egg Treatment and Developmental Studies

120

(1)

Generational Studies

120

(1)

Conclusions

121

(8)

Acknowledgments

122

(1)

References

122

(7)

Immunotoxicology in Terrestrial Wildlife

129

(18)

Judit E.G. Smits

David Janz

Introduction

129

(1)

Background

129

(1)

Molecular Techniques in Wildlife Species

130

(1)

In Vivo Tests in Current Use

130

(7)

Birds

130

(6)

Mammals

136

(1)

Rodents

136

(1)

Mink

137

(1)

Cervids

137

(1)

In Vitro Tests in Current Use

137

(2)

Birds

137

(1)

Rodents

138

(1)

Mink

139

(1)

Cervids

139

(1)

Limitation and Relevance of Immunotoxicity Tests

139

(1)

Limitations in Application or Interpretation

139

(1)

Sex-Specific Considerations

140

(1)

Summary

140

(7)

References

141

(6)

Immune Markers in Ecotoxicology: A Comparison across Species

147

(16)

Harri Salo

Claire Dautremepuits

Judit E.G. Smits

Pauline Brousseau

Michel Fournier

Introduction

147

(1)

Immune Markers in Ecotoxicology

148

(2)

Innate Immunity

149

(1)

Evolution of Adaptive Immunity

149

(1)

Immunological Markers

150

(1)

Immunotoxicity of Selected Substances across Species

150

(8)

Heavy Metals

150

(6)

Pesticides

156

(1)

Polycyclic Aromatic Hydrocarbons

157

(1)

Halogenated Aromatic Hydrocarbons

158

(1)

Summary and Conclusions

158

(5)

Acknowledgments

159

(1)

References

159

(4)

Section III Approaches and Models Relevant to the Assessment of the Impact of Chemical-Induced Immunotoxicity on Human Health

163

(104)

Are Changes in the Immune System Predictive of Clinical Diseases?

165

(18)

Michael I. Luster

Dori R. Germolec

Christine G. Parks

Laura Blanciforti

Michael Kashon

Robert W. Luebke

Introduction

165

(1)

Diseases Associated with Immunosuppression

166

(2)

Social and Economic Impact of Infectious Diseases and the Risk Assessment Process

168

(1)

Issues in Using Human Data in Immunotoxicology Risk Assessment

169

(1)

Immunodeficiency and Relationship to Infectious Disease

170

(4)

Environmental Chemicals

170

(1)

Chronic Stress

171

(1)

Hematopoietic Stem Cell Transplantation

172

(1)

Organ Transplants

173

(1)

Experimental Animal Models

174

(3)

Conclusions

177

(6)

Acknowledgments

178

(1)

References

178

(5)

Developmental Immunotoxicology in Rodent Species

183

(14)

Barry R. Blakley

Patricia M. Blakley

Introduction

183

(1)

Fetal Susceptibility to Teratogens

184

(1)

Significance with Respect to Immune Development

185

(1)

Model Systems for Developmental Immunotoxicology

186

(2)

Time of Exposure

186

(1)

Route of Exposure

187

(1)

Animal Monitoring During Pregnancy

187

(1)

Animal Monitoring After Pregnancy

188

(1)

Evaluation of Immunotoxicologic Data in a Developmental Model System

188

(1)

Immunotoxicants Associated with Prenatal Exposure

189

(3)

Summary

192

(5)

References

193

(4)

Gut Mucosal Immunotoxicology in Rodents

197

(14)

Genevieve S. Bondy

James J. Pestka

Introduction

197

(1)

Brief Overview of the Gut Mucosal Immune System

198

(1)

Biomarkers of Changes in Gut-Associated Lymphoid Tissues

199

(7)

Nonfunctional Assessment of Changes in GALT

200

(1)

Histopathology and Immunohistopathology

200

(2)

Functional Assessment of GALT

202

(1)

Basal Circulating IgA Levels

202

(1)

Antigen-Specific Humoral Responses

203

(1)

Lymphocyte Proliferation in Response to B- and T-Cell Mitogens

204

(1)

Cellular Responses

204

(1)

Cytokines

205

(1)

Host Resistance Assays

205

(1)

Specialized Rodent Models

206

(1)

Conclusions and Directions for Future Research

206

(5)

Acknowledgments

207

(1)

References

207

(4)

The Use of Old World Nonhuman Primates as Models for Evaluating Chemical-Induced Alterations of the Immune System

211

(18)

Helen Tryphonas

Douglas L. Arnold

Introduction

212

(1)

Toxicologic Considerations

212

(3)

General Comments

212

(1)

Experimental Considerations

213

(1)

Dosing

213

(1)

Specimens

214

(1)

Housing

214

(1)

Clinical Parameters

215

(1)

Immune Parameters Available for Use in Nonhuman Primates

215

(7)

General

215

(1)

Total White Blood Cell Counts

216

(1)

Immunophenotyping of Peripheral Blood Leukocytes

216

(1)

Quantification of Total Serum Immunoglobulin Levels

216

(1)

Humoral Immunity

217

(1)

Challenge with Specific Antigens

217

(2)

Cell-Mediated Immunity

219

(1)

Lymphocyte Transformation

219

(1)

Mixed-Lymphocyte Cell Cultures

220

(1)

Delayed-Type Hypersensitivity Response

220

(1)

Nonspecific Immunity

221

(1)

Natural Killer Cell Activity

221

(1)

Phagocytosis

221

(1)

Measurement of Serum Hydrocortisone Levels

222

(1)

Nonhuman Primates Used in Immunotoxicity Studies: Examples

222

(1)

PCBs and Toxaphene

222

(1)

Relevance to Humans

223

(1)

Application of Data to Regulatory Issues

223

(1)

Summary

224

(5)

References

225

(4)

Practical Considerations for Toxicologic Pathology Assessment of the Immune System in Rodents and Nonhuman Primates

229

(18)

Olga Pulido

Don Caldwell

Meghan Kavanagh

Santokh Gill

Introduction

229

(1)

Enhanced Toxicologic Pathology of the Immune System

230

(5)

Background

230

(1)

Methods and Procedures

231

(1)

Tissue Sampling

231

(1)

Histopathology Evaluation

231

(3)

Grading of Lesions

234

(1)

Histomorphometry

235

(1)

Immunohistochemical Phenotyping of Lymphoid Tissues

235

(6)

Methods

237

(1)

Microwave Antigen Recovery Method

237

(1)

Streptavidin-Biotin Complex Indirect Method

237

(1)

Biotin-Free Secondary Amplification Indirect Method

238

(1)

Immunotyping Using Clusters of Differential on Markers

238

(2)

Immunohistochemistry of Glutamate Receptors and Neural Markers

240

(1)

Practical Application to Rodents and Nonhuman Primates Studies

241

(2)

Rat

241

(1)

Nonhuman Primates

242

(1)

Summary and Conclusion

243

(4)

Acknowledgments

243

(1)

References

243

(4)

Approaches to Immunotoxicology in Human Population Studies

247

(20)

Frederic Dallaire

Eric Dewailly

Pierre Ayotte

Introduction

248

(1)

Epidemiologic Considerations

248

(4)

Study Design

248

(1)

Cohort Studies

249

(1)

Case-Control Studies

249

(1)

Cross-Sectional Studies

250

(1)

Confounding

251

(1)

Exposure Assessment and Classification

251

(1)

Exposure Assessment

251

(1)

Exposure Classification

252

(1)

Human Studies Specificities

252

(2)

Factors Influencing Immune Response in Humans

252

(1)

Clinical Immunodeficiency, Pre-Existing Diseases, and Medication Use

253

(1)

Assays in Human Immunotoxicology

254

(4)

Total and Differential Blood Counts

254

(1)

Inflammation and Nonspecific Immunity

255

(1)

Neutrophil and Monocyte Function

255

(1)

Complement

256

(1)

Natural Killer Cells

256

(1)

Cellular Immunity

256

(1)

Immunophenotyping of Lymphocytes

256

(1)

Delayed-Type Hypersensitivity Reactions

256

(1)

Lymphocyte Proliferation

257

(1)

Humoral Immunity

257

(1)

Serum Immunoglobulin Concentrations

257

(1)

Antibodies to Ubiquitous Antigen

257

(1)

Antibodies to Self-Antigen

258

(1)

Antibody Response to Immunization

258

(1)

Clinical Endpoints

258

(3)

Infections

259

(1)

Incidence of Acute Infections

260

(1)

Prevalence and Average Risk of Acute Infections

260

(1)

Chronic and Opportunistic Infections

261

(1)

Other Clinical Endpoints

261

(1)

Allergy

261

(1)

Autoimmunity and Neoplasic Changes

261

(1)

Research Needs

261

(1)

Summary

262

(5)

Acknowledgments

262

(1)

References

262

(5)

Section IV Models and Approaches to Chemical-Induced Allergenicity

267

(58)

Guinea Pig, Mouse, and Rat Models for Safety Assessment of Protein Allergenicity

269

(12)

Katherine Sarlo

Rebecca J. Dearman

Ian Kimber

Introduction

269

(1)

Assessment of Proteins as Respiratory Allergens

270

(4)

Guinea Pig Models

270

(2)

Mouse Models

272

(2)

Assessment of Proteins as Food Allergens

274

(3)

Rat Models

274

(2)

Mouse Models

276

(1)

Summary

277

(4)

References

278

(3)

Hypersensitivity Reactions: Nonrodent Animal Models

281

(10)

Ricki M. Helm

Introduction

281

(1)

Mechanistic Studies

282

(1)

Predictive Studies

283

(1)

Therapeutic Options

283

(1)

Animal Models

283

(4)

Guinea Pig Model

283

(1)

Atopic Dog Models

284

(2)

Neonatal Swine Model

286

(1)

Advantages of Using Large Animals

287

(1)

Disadvantages of Using Large Animals

287

(1)

Conclusions

288

(3)

References

288

(3)

Recent Developments in Allergic Contact Dermatitis

291

(12)

Ian Kimber

Rebecca J. Dearman

Introduction

291

(1)

Recent Developments in the Immunobiology of Allergic Contact Dermatitis

291

(2)

Recent Developments in Methods for Hazard Characterization

293

(5)

Local Lymph Node Assay for Hazard Identification

293

(2)

Local Lymph Node Assay for Risk Assessment

295

(2)

Alternative Endpoints for the Local Lymph Node Assay

297

(1)

Conclusions

298

(5)

References

299

(4)

Predictive Methods Specific for Human Immune Response

303

(22)

Fiona A. Harding

David L. Wong

Donald P. Naki

Introduction

304

(1)

Epitope Determination Using Computational Methods

305

(5)

Motif Methods

306

(1)

Matrix Methods

306

(1)

Machine Learning Approaches

307

(1)

Artificial Neural Networks

307

(1)

Hidden Markov Models

308

(1)

Structure Based Methods

308

(1)

Conclusions

309

(1)

Epitope Determination Using In Vitro Methods

310

(5)

Identification of Presented Peptides by Mass Spectral Analysis

310

(1)

Basics of Mass Spectrometry

311

(1)

Identification of Peptide Epitopes by Mass Spectrometry

311

(1)

Applications

312

(1)

Identification of Functional Epitope Determinants by Cell-Based Analysis

312

(1)

Tetramer Binding Analysis

312

(1)

ELISPOT Analysis

313

(1)

Proliferation Responses

314

(1)

I-mune® Assay

314

(1)

Comparative Immunogenicity Assessments

315

(2)

Quantitative Assessment of Immunogenicity from Human Cell Data

315

(1)

In Vivo Testing

316

(1)

The Proof is in the Pudding

317

(1)

Future Perspectives

317

(8)

References

318

(7)

Section V Autoimmunity

325

(18)

Chemical-Induced Animal Models of Human Autoimmunity

327

(16)

Pierluigi E. Bigazzi

Introduction

327

(1)

Systemic Lupus Erythematosus

328

(1)

Drug-Related Lupus

329

(1)

Systemic Sclerosis

330

(1)

Rheumatoid Arthritis

331

(1)

Type 1 Diabetes Mellitus

332

(1)

Autoimmune Thyroiditis

332

(1)

Nephrotic Syndrome

333

(1)

Primary Biliary Cirrhosis

334

(1)

Inflammatory Bowel Disease

335

(1)

Conclusions and Future Needs

335

(8)

Acknowledgments

338

(1)

References

338

(5)

Section VI Emerging Issues in Immunotoxicology

343

(40)

Transgenic Rodent Models in Immunotoxicology

345

(18)

Robert V. House

Introduction

345

(1)

Paradigms of Immunotoxicology

346

(2)

Transgenic Technology

348

(2)

Nonhomologous Recombination (Random Integration) Transgenesis

348

(1)

Homologous Recombination Transgenesis

348

(1)

Knockout Mice

349

(1)

Knockin Mice

349

(1)

Conditional Mutation

350

(1)

Specific Transgenic Models with Potential Utility for Immunotoxicology

350

(8)

Cytokines and Immunomodulation

350

(1)

Host Resistance

351

(1)

Evaluating Immunotoxicology of Recreational Adjuncts (Abused Drugs)

352

(2)

Autoimmunity

354

(1)

Diabetes

355

(1)

Rheumatoid Arthritis

355

(1)

Hypersensitivity

355

(1)

Humanized Mice for Assessment of Human Biologies

356

(1)

Transgenic Rats

357

(1)

Summary

358

(5)

References

358

(5)

Applications of Genomics in Immunotoxicology

363

(20)

Sami Haddad

Michele D'Elia

Jacques Bernier

Alain Fournier

Daniel G. Cyr

Introduction

363

(1)

Flow of Genetic Information

364

(1)

Genomics

364

(1)

Functional Genomics

364

(1)

Technological Advances for Analyzing Functional Genomics

365

(2)

DNA Arrays

365

(1)

Macroarrays

365

(1)

Microarrays

365

(2)

Bioinformatics

367

(6)

Image Acquisition and Analysis

368

(3)

Data Analysis

371

(1)

Differential Gene Expression

371

(1)

Pattern Recognition

371

(1)

Microarray Information Necessary for Data Storage

372

(1)

Proteomics

373

(1)

Applications for Immunotoxicology

374

(4)

Applications of Genomics in Immunotoxicology

374

(1)

Cytokine Analysis in Immunotoxicology

375

(1)

Genomic-Scale Analysis of Gene Expression in Immune System

376

(2)

Research Needs

378

(1)

Summary

378

(5)

Acknowledgment

379

(1)

References

379

(4)

Section VII The Role of Immunotoxicology in Risk Assessment and the Regulatory Process

383

(68)

Biomarkers of Immunotoxic Effects in the Context of Environmental Risk Assessment

385

(22)

Stephane Pillet

Jean-Marc Nicolas

Introduction

386

(1)

Concepts in Environmental Risk Assessment

386

(1)

Definition of Biomarkers

386

(3)

The Immune System

389

(1)

Immunotoxic Effects of Chemical Substances

389

(1)

Immunomarkers of Effects

390

(6)

Weight, Organ:Body Weight Ratio, and Cellularity of Immune Organs

392

(1)

Hematology

392

(1)

Nonspecific Immune Response Immunomarkers

392

(1)

Phagocytic Activity of Macrophages and Other Phagocytes

392

(1)

Oxydative Burst

392

(1)

Cytotoxic Activity of Natural Killer Cells

392

(1)

Specific Immune Response Immunomarkers

392

(1)

Delayed-Type Hypersensitivity

392

(1)

Lymphoblastic Proliferation

393

(1)

Mixed Lymphocyte Reaction

393

(1)

Humoral-Mediated Immunity

393

(1)

Phenotyping

393

(1)

Challenge Against Infectious Agents

393

(1)

New Potential Immunomarkers: Emergence of Genomic and Proteomic Techniques

394

(1)

Confounding Factors

395

(1)

Genetics

395

(1)

Gender and Age

396

(1)

Nutritional Status

396

(1)

Interactions between Toxic Pathways of Chemicals

396

(1)

Immunomarkers of Effects in Wildlife Species

396

(4)

Contaminant-Induced Immunodeficiency in Marine Mammals: Illustration of Complexity of Risk Evaluation in Wildlife Species

397

(2)

Tier Approach for Immunotoxicity Studies in Wildlife Species

399

(1)

Research Needs

400

(1)

Summary

400

(7)

Acknowledgments

401

(1)

References

401

(6)

Toxicological Considerations: Making the Connection between Toxicologic and Immunotoxicologic Studies as These Relate to Human and Ecosystem Health

407

(14)

Michel Fournier

Barry R. Blakley

Herman J. Boermans

Pauline Brousseau

Introduction

407

(1)

Shape of the Dose-Response Curve

408

(2)

Comparison of Tissue Sensitivity

410

(1)

Differences of Sensitivity Associated with Age

411

(2)

Differences of Sensitivity Associated with Sex

413

(1)

Differences in Sensitivity between Cell Type and Cell Activation Status

414

(3)

Comparisons of In Vitro-In Vivo Responses

417

(1)

Conclusions

418

(3)

References

419

(2)

Approaches to Immunotoxicity Testing: The Need for National and International Harmonization/Standardization of Immunotoxicity Methods

421

(10)

Pauline Brousseau

Barry R. Blakley

Herman J. Boermans

Michel Fournier

Introduction

421

(1)

Harmonization Studies

422

(6)

International Collaborative Immunotoxicity Study

422

(1)

Canadian Collaborative Immunotoxicity Study

423

(1)

Experimental Design

423

(1)

Materials and Methods

424

(1)

Results

425

(1)

Other Harmonization Studies

426

(1)

Tangible Outcomes from Harmonization Studies

427

(1)

Validation Issues

427

(1)

Summary

428

(3)

References

428

(3)

Approaches to the Statistical Analysis of Immunotoxicologic Data in Support of Risk Assessment

431

(20)

Stephen Hayward

Introduction

432

(1)

Experimental Design

432

(2)

Choice of Doses

432

(1)

Sample Size and Randomization

433

(1)

Level of Significance

434

(1)

Outliers and Transformations

434

(2)

Univariate Analysis of Immunotoxicologic Assays

436

(4)

Test for Trend

437

(2)

Multiple Comparisons

439

(1)

Analysis of Multivariate Outcomes

440

(9)

Repeated Measures Data

441

(1)

Profile Analysis

441

(2)

Orthogonal Polynomials

443

(2)

Other Multivariate Outcomes

445

(2)

Application of Statistical Methods to Immunotoxicity Data

447

(1)

Cell Surface Markers

448

(1)

Natural Killer Cell Assay

448

(1)

Lymphocyte Transformations

448

(1)

Listeria monocytogenes Assay

448

(1)

Immunization of Monkeys with SRBC, Tetanus Toxoid, and Pneumococcal Antigens

448

(1)

Plaque-Forming Cell Assay

449

(1)

Summary

449

(2)

References

449

(2)

Index

451

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Investigative Immunotoxicology

Summary

Table of Contents

Supplemental Materials