Description
Book SynopsisA guide to the issues relevant to the design, analysis, and interpretation of toxicity studies that examine chemicals for use in the environment Statistical Analysis of Ecotoxicity Studies offers a guide to the design, analysis, and interpretation of a range of experiments that are used to assess the toxicity of chemicals. While the book highlights ecotoxicity studies, the methods presented are applicable to the broad range of toxicity studies. The text contains myriad datasets (from laboratory and field research) that clearly illustrate the book's topics. The datasets reveal the techniques, pitfalls, and precautions derived from these studies. The text includes information on recently developed methods for the analysis of severity scores and other ordered responses, as well as extensive power studies of competing tests and computer simulation studies of regression models that offer an understanding of the sensitivity (or lack thereof) of various methods and the quality of parameter
Table of ContentsPreface ix Acknowledgments xi
About the Companion Website xiii
1. An Introduction to Toxicity Experiments 1
1.1 Nature and Purpose of Toxicity Experiments 1
1.2 Regulatory Context for Toxicity Experiments 7
1.3 Experimental Design Basics 8
1.4 Hierarchy of Models for Simple Toxicity Experiments 12
1.5 Biological vs. Statistical Significance 13
1.6 Historical Control Information 15
1.7 Sources of Variation and Uncertainty 15
1.8 Models with More Complex Structure 16
1.9 Multiple Tools to Meet a Variety of Needs or Simple Approaches to Capture Broad Strokes? 16
2. Statistical Analysis Basics 19
2.1 Introduction 19
2.2 NOEC/LOEC 19
2.3 Probability Distributions 24
2.4 Assessing Data for Meeting Model Requirements 29
2.5 Bayesian Methodology 30
2.6 Visual Examination of Data 30
2.10 Time‐to‐Event Data 37
2.11 Experiments with Multiple Controls 38
3. Analysis of Continuous Data: NOECs 47
3.1 Introduction 47
3.2 Pairwise Tests 47
3.3 Preliminary Assessment of the Data to Select the Proper Method of Analysis 53
3.4 Pairwise Tests When Data do not Meet Normality or Variance Homogeneity Requirements 62
3.5 Trend Tests 67
3.6 Protocol for NOEC Determination of Continuous Response 75
3.7 Inclusion of Random Effects 75
3.8 Alternative Error Structures 76
3.9 Power Analyses of Models 77 Exercises 81
4. Analysis of Continuous Data: Regression 89
4.1 Introduction 89
4.2 Models in Common Use to Describe Ecotoxicity Dose–Response Data 92
4.3 Model Fitting and Estimation of Parameters 95
4.4 Examples 104
4.5 Summary of Model Assessment Tools for Continuous Responses 112
Exercises 114
5. Analysis of Continuous Data with Additional Factors 123
5.1 Introduction 123
5.2 Analysis of Covariance 123
5.3 Experiments with Multiple Factors 135
Exercises 41
6. Analysis of Quantal Data: NOECs 157
6.1 Introduction 157
6.2 Pairwise Tests 157
6.3 Model Assessment for Quantal Data 160
6.4 Pairwise Models that Accommodate Overdispersion 162
6.5 Trend Tests for Quantal Response 165
6.6 Power Comparisons of Tests for Quantal Responses 168
6.7 Zero‐Inflated Binomial Responses 172
6.8 Survival‐ or Age‐Adjusted Incidence Rates 175
Exercises 179
7. Analysis of Quantal Data: Regression Models 181
7.1 Introduction 181
7.2 Probit Model 181
7.3 Weibull Model 188
7.4 Logistic Model 188
7.5 Abbott’s Formula and Normalization to the Control 190
7.6 Proportions Treated as Continuous Responses 197
7.7 Comparison of Models 198
7.8 Including Time‐Varying Responses in Models 199
7.9 Up‐and‐Down Methods to Estimate LC50 204
7.10 Methods for ECx Estimation When there is Little or no Partial Mortality 206
Exercises 215
8. Analysis of Count Data: NOEC and Regression 219
8.1 Reproduction and Other Nonquantal Count Data 219
8.2 Transformations to Continuous 219
8.3 GLMM and NLME Models 223
8.4 Analysis of Other Types of Count Data 228
Exercises 237
9. Analysis of Ordinal Data 243
9.1 Introduction 243
9.2 Pathology Severity Scores 243
9.3 Developmental Stage 249
Exercises 255
10. Time‐to‐Event Data 259
10.1 Introduction 259
10.2 Kaplan–Meier Product‐Limit Estimator 261
10.3 Cox Regression Proportional Hazards Estimator 266
10.4 Survival Analysis of Grouped Data 268
Exercises 271
11. Regulatory Issues 275
11.1 Introduction 275
11.2 Regulatory Tests 275
11.3 Development of International Standardized Test Guidelines 276
11.4 Strategic Approach to International Chemicals Management (SAICM) 279
11.5 The United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS) 279
11.6 Statistical Methods in OECD Ecotoxicity Test Guidelines 279
11.7 Regulatory Testing: Structures and Approaches 279
11.8 Testing Strategies 287
11.9 Nonguideline Studies 291
12. Species Sensitivity Distributions 293
12.1 Introduction 293
12.2 Number, Choice, and Type of Species Endpoints to Include 294
12.3 Choice and Evaluation of Distribution to Fit 294
12.4 Variability and Uncertainty 300
12.5 Incorporating Censored Data in an SSD 302
Exercises 307
13. Studies with Greater Complexity 309
13.1 Introduction 309
13.2 Mesocosm and Microcosm Experiments 310
13.3 Microplate Experiments 316
13.4 Errors‐in‐Variables Regression 321
13.5 Analysis of Mixtures of Chemicals 323
13.6 Benchmark Dose Models 326
13.7 Limit Tests 327
13.8 Minimum Safe Dose and Maximum Unsafe Dose 329
13.9 Toxicokinetics and Toxicodynamics 331
Exercises 343
Appendix 1 Dataset 345
Appendix 2 Mathematical Framework 347
A2.3 Method of Maximum Likelihood 350
A2.4 Bayesian Methodology 352
A2.5 Analysis of Toxicity Experiments 354
A2.6 Newton’s Optimization Method 358 Table A3.3 Linear and Quadratic Contrast
A2.7 The Delta Method 359 Coefficients 366
A2.8 Variance Components 360 Table A3.4 Williams’ Test tᾱ ,k for α = 0.05 367
Appendix 3 Tables
Table A3.1 Studentized Maximum Distribution 364
Table A3.2 Studentized Maximum Modulus Distribution 365
Table A3.3 Linear and Quadratic Contrast Coefficients 366
Table A3.4 Williams’ Test t̅α,k for α = 0.05 367
References 371
Author Index 385
Subject Index 389
