Animal Cloning: A Risk Assessment

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Animal Cloning:
A Risk Assessment

Center for Veterinary Medicine
U. S. Food and Drug Administration
Department of Health and Human Services
7500 Standish Place
Rockville, MD 20855

1/8/2008

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Table of Contents

Preface i
Chapter I: Executive Summary 3
A. Overview 3
B. Technology Overview (Chapter II) 4
C. Risk Assessment Methodology (Chapter III) 5
D. The Implications of Epigenetic Reprogramming for Clones and their Progeny (Chapter IV) 8
E. Risks to Animals Involved in Cloning (Chapter V) 9
F. Food Consumption Risks (Chapter VI) 11
1. Two-Pronged Approach to Identifying and Characterizing Food Consumption Risks 11
2. Conclusions Regarding Potential Food Consumption Risks 11
a. Cattle Clones 11
b. Swine Clones 13
c. Sheep Clones 14
d. Goat Clones 14
e. Clone Progeny 14
G. Concluding Statements (Chapter VII) 15
Chapter II: Technology Overview: Somatic Cell Nuclear Transfer and Other Assisted Reproductive Technologies 19
A. What is Cloning? 20
B. Continuum of Reproductive Technologies 21
1. Natural Service 21
2. Artificial Insemination and Synchronized Estrus 22
3. Embryo Transfer 25
4. In vitro Fertilization 26
5. Embryo splitting 27
6. Blastomere Nuclear Transfer 28
7. Somatic Cell Nuclear Transfer (SCNT) 29
a. Donor cell 30
b. Oöcyte 31
c. Fusion 31
d. Transfer to recipient 32
C. Critical Biological Events in SCNT 33
D. Outcomes Observed in ARTs 35
E. Future of Reproductive Technologies in Modern Agricultural Practice 36 ​
Chapter III: Developing the Risk Assessment Methodology 41
A. Charge 41
B. General Discussion of Risk/Safety Analyses 41
1. Risk and Safety 41
2. Risk Assessment vs. Risk Management 42
C. Risk/Safety Assessment of Cloning 42
D. Transgenic Animal Clones 44
E. Methodology Development 45
1. Hazard Characterization 46
2. Potential Risks 47
3. Proposed Approaches 48
a. Animal Health Risks 48
b. Food Consumption Risks 49
F. Two-Pronged Approach to Assessing Food Consumption Risks 50
1. Critical Biological Systems Approach 51
a. Overview 51
b. Evaluation Nodes 52
G. The Weight of Evidence Approach 54
H. Limitations of the Risk Assessment 55
Chapter IV: Epigenetic Reprogramming: Implications for Clones and their Progeny 59
A. Overview of Epigenetic Reprogramming in Early Embryonic Development 61
1. Preimplantation Reprogramming 63
a. Fusion and Cleavage 63
b. Demethylation and Remethylation in Early Embryos 66
c. Epigenetic Reprogramming in Later Development 70
d. Studies of Gene Expression and Development in Clones and Animals Produced by Other ARTs 73
e. Studies of Technical Contributions to Epigenetic Variability in Clones and Other ARTs 78
2. Gametogenic Reprogramming 79
3. Mitochondrial Heteroplasmy 81
4. Conclusions from Studies of Epigenetic Reprogramming 82
B. Phenotypic Evidence for Gametogenic Reprogramming 83
1. Phenotypic Anomalies Observed in Mouse Clones 83
a. Utility of Mouse Model 83
b. Pregnancy (Developmental Node 1) 84
c. Perinatal Period (Developmental Node 2) 86
d. Juvenile Period to Reproductive Maturity (Developmental Nodes 3 and 4) 86
e. Maturity and Aging (Developmental Node 5) 88
2. Conclusions from Phenotypic Studies of Gametogenic Reprogramming in Mouse Clones and their Progeny for Reprogramming in Domestic Livestock Clones and their Progeny 90 ​
C. Implications of Epigenetic Reprogramming for Animal Health and Food Consumption Risks 91
Chapter V: Animal Health Risks 95
A. Potential Hazards and Risks to Animals Involved in Cloning 95
B. The Critical Biological Systems Approach to the Analysis of Clone Animal Health: Cattle, Swine, Sheep, and Goats 96
1. Pregnancy and Parturition (Developmental Node 1) 96
2. Perinatal Period (Developmental Node 2) 98
3. Juvenile Developmental Node (Developmental Node 3) 99
4. Reproductive Development and Function Node (Developmental Node 4) 100
5. Post-Pubertal Maturation and Aging (Developmental Node 5) 101
a. Telomere Length as an Indicator of Aging 101
C. Data on Animal Health by Species 105
1. Cattle 105
a. Developmental Node 1: Pregnancy and Parturition 109
b. Developmental Node 2: Perinatal Period 123
c. Developmental Node 3: Juvenile Development 135
d. Developmental Node 4: Reproductive Development and Function 145
e. Developmental Node 5: Post-Pubertal Maturation and Aging 150
f. Progeny of Bovine Clones 153
g. Summary for Health of Bovine Clones and Their Progeny 156
2. Swine 157
a. Developmental Node 1: Pregnancy and Parturition 158
b. Developmental Node 2: Perinatal Period 159
c. Developmental Node 3: Juvenile Development 163
d. Developmental Node 4: Reproductive Development and Function 165
e. Developmental Node 5: Post-Pubertal Maturation and Aging 166
f. Progeny of Swine Clones 166
g. Summary for Health of Swine Clones and Their Progeny 167
3. Sheep 168
a. Developmental Node 1: Pregnancy and Parturition 169
b. Developmental Node 2: Perinatal Period 172
c. Developmental Node 3: Juvenile Development 174
d. Developmental Node 4: Reproductive Development and Function 175
e. Developmental Node 5: Post-Pubertal Maturation and Aging 175
f. Progeny of Sheep Clones 176
g. Summary for Health of Sheep Clones 176
4. Goats 176
a. Developmental Node 1: Pregnancy and Parturition 177
b. Developmental Node 2: Perinatal Period 178
c. Developmental Node 3: Juvenile Development 179
d. Development Node 4: Reproductive Development and Function 180
e. Developmental Node 5: Post-Pubertal Maturation and Aging 180
f. Progeny of Goat Clones 180
g. Summary for Health of Goat Clones 181
D. Conclusions 181 ​
Chapter VI: Food Consumption Risks 187
A. Potential Hazards and Food Consumption Risks Associated with Food Products from Animal Clones and their Progeny 187
1. Assumptions 187
2. Critical Biological Systems Approach to Clones of Cattle, Swine, Sheep, and Goats 188
a. Bovine Clones 188
b. Swine Clones 243
c. Sheep Clones 260
d. Goat Clones 264
3. Compositional Analysis Method 268
a. Overview 268
b. Nutritional Risk 269
c. Characterization of Milk from Cow Clones 278
d. Characterization of Meat from Clones and Their Progeny 288
B. Drawing Conclusions Regarding Risks Associated with Consumption of Food Products from Animal Clones 309
1. Approaches for Decreasing Uncertainties 309
2. Bounding the Risk Space 310
3. Developing Conclusions Regarding Food Consumption Risks 310
4. Weight of Evidence Conclusions Regarding Food Consumption Risks for Clones and their Progeny 312
a. Cattle Clones 312
b. Swine Clones 316
c. Sheep Clones 317
d. Goat Clones 318
e. Clone Progeny 319
5. Summary of Risk Hypotheses 319
a. Additional Issues 320
6. How Much (Information) Is Enough? 323
Chapter VII Summary and Conclusions 327
A. Methodology 327
B. Conclusions Regarding Risks to Animal Health 328
C. Conclusions Regarding Food Consumption Risks 329
D. Conclusions Regarding Food Consumption Risks from Clone Progeny 330
E. Weight of Evidence Evaluations 330 ​
Glossary 333
References 349

Appendices

Appendix A: Risk and Safety Assessment Primer for Animal Cloning 425
A. How has Risk Assessment Evolved? 425
B. Thinking About Risk 426
C. How Do We Think About Safety? 428
Appendix B: Overall Reproductive Efficiency and Health Statistics for US Animal Agriculture 431
A. Dairy cattle 431
B. Beef Cattle 433
C. Swine 436
D. Sheep 437
D. Goats 439
Appendix C: Comparisons of Outcomes Among Assisted Reproductive Technologies (ARTs) 443
A. Successes and Failures of AI, IVP, and ET 449
B. Outcomes for BNT, Fetal- and Adult-Cell SCNT 453
C. Conclusions regarding outcomes for ARTs 454
Appendix D Transgenic Clones 457
A. Issues 457
B. Cattle 458
C. Swine 460
D. Sheep 462
E. Goats 463
F. Conclusions Regarding Transgenic Clones 466
Appendix E: The Cyagra Dataset 471
A. Response to CVM Data Requests 471
B. Cyagra Dataset 472 ​
1. Description of Clones 474
2. Evaluations Performed 476
3. CVM's Analysis of Cyagra Data: Method 477
4. CVM's Analysis of Cyagra Data: Results 479
a. Comprehensive Veterinary Examinations 479
b. Conclusions from Veterinary Examinations 480
c. Laboratory Values: Selection of Most Appropriate Comparator 481
d. Conclusions Regarding Clone and Comparator Population Cohorts in Aggregate 482
e. Animal and Analyte Specific Analyses 484
f. Animals with Measurements at Different Developmental Nodes 487
5. Charts and Tables 500
Cyagra Data Chart Interpretations 501
Cyagra Raw Data 523
Appendix F: The ViaGen Dataset 571
A. Background 571
B. Experimental Design 571
1. Study 1: Clones vs. Comparators 573
a. Animal Health, Hematology, Clinical Chemistry, and Urinalysis 574
b. Boar Semen Evaluation 574
c. Farrowing Rate 574
2. Study 2: Progeny of Clone Boars vs. Progeny of Conventional Boars 575
a. Statistical Analysis 575
b. Specific Methods for the Analysis of Animal Health, Hematology, Clinical Chemistry, and Urinalysis Data 578
c. Meat Composition, Carcass Characteristics, and Meat Quality Assessments for Clones, Comparators, and Progeny 578
C. Results 579
1. Study 1 579
a. Survival 579
b. Animal Health, Growth, Blood Clinical Chemistry, Hematology, and Urinalysis 580
c. Carcass Characteristics 588
d. Meat Composition Analysis for Clones and Comparators 589
e. Semen and Breeding Evaluation 591
f. Farrowing Rate 592
2. Study 2: Progeny of Clones vs. Comparators 594
a. Survival 594
b. Growth, Hematology, Clinical Chemistry, and Urinalysis 600
c. Carcass Characteristics 608
d. Meat Composition from the Progeny of Clones and Comparators 609
D. Conclusions from the ViaGen Dataset 614
1. Study 1: Clones vs. Comparators 614
a. Animal Health 614 ​
b. Food Safety 615
2. Progeny of Clone Boars vs. Progeny of Comparator Boars 615
a. Animal Health 615
b. Food Safety 616
E. Addendum 617
ViaGen Data Chart Interpretations 621
ViaGen Raw Data 695
Appendix G: Unpublished Data 857
A. Perinatal Development in Cattle Clones (Node 2) 857
B. Juvenile Development in Cattle Clones (Node 3) 859
C. Reproductive Development and Function in Cattle Clones (Node 4) 865
D. Post-pubertal Maturation in Cattle Clones (Node 5) 867
E. Summary of Cloning Studies at University of Tennessee 868
1. Developmental Node 1: Pregnancy and Parturition 868
2. Developmental Node 2: Perinatal Period 869
3. Developmental Node 3: Juvenile Period 869
4. Developmental Node 4: Reproductive Development and Function 869
5. Developmental Node 5: .Post-pubertal Maturation and Aging 870
F. Perinatal Development in Swine Clones (Node 2) 870
G. Conclusions for unpublished data 872
Appendix H: The Comprehensive Veterinary Examination 877
A. Introduction to the Comprehensive Veterinary Examination 877
B. The Importance of Species-Specific Standards 878
C. How a Veterinarian Performs a Comprehensive Veterinary Examination 878
1. Specific Considerations for Neonatal CVEs 880
2. Specific Considerations for Juvenile CVEs 881
3. Specific Considerations for Mature Animal CVEs 881
4. Specific Consideration for Reproductive Stage Examinations 881
a. Males 881
b. Females 882
D. Interpreting the Comprehensive Veterinary Examination for Animal Clones 883
E. Parameters Evaluated in the Comprehensive Veterinary Exam for a Risk Assessment 883
Appendix I: Investigation on the Attributes of Cloned Bovine Products 895

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