Issues and Reviews in Teratology

1. Problems in Human Teratology.- 1. Introductory Remarks.- 2. Advances in Knowledge and Technology during the Past 30 Years.- 2.1. Discovery of Human Chromosomal Aberrations and Advances in Cytogenetics.- 2.2. Documentation of Human Genetic Diseases Caused by Single Defective Mutant Genes.- 2.3. Detection of Human Teratogens.- 3. Clinical Progress through Application of Practical Procedures.- 3.1. Exchange Transfusion.- 3.2. Amniocentesis.- 3.3. Dietary Treatment of Infants with Biochemical Abnormalities.- 3.4. Rubella Vaccination.- 3.5. Screening for Fetal Neural Tube Defects by the Measurement of Alphafetoprotein in the Mother's Blood.- 3.6. Conclusion.- 4. Present-Day Problems.- 4.1. Is There a Way of Effectively Preventing Spontaneously Occurring Birth Defects of Multifactorial Origin?.- 4.2. Is It Possible to Screen Clinically Malformed Embryos at Early Stages?.- 4.3. Can We Predict the Risk of Teratogenicity of Chemicals in Humans from Available Animal Data?.- 5. Future Perspectives.- 5.1. Certain Types of Birth Defects Will Be Prevented, But There Will Be No Substantial Change in the Overall Rate of Affected Children Born.- 5.2. New Human Teratogens Will Be Discovered, Although They Will Be Few in Number.- 5.3. There Will Be New Methodologies in Teratological Research.- 6. Conclusion.- 7. Summary.- 7.1. Past Progress.- 7.2. Unsolved Problems.- 7.3. The Future.- References.- 2. Teratology: Spectrum of a Science.- 1. Ancient Records.- 2. Portents.- 3. Hybrids.- 4. Teratology and Superstition.- 5. Natural Philosophy.- 6. Anatomy and Pathology.- 7. Embryology and Experimental Teratology.- 8. Genetics.- 9. Surgery.- 10. Obstetrics.- 11. Law.- 12. Prevention.- References.- 3. Cytogenetics of Human Reproductive Wastage.- 1. History and Definition of Abortion.- 2. Historical Aspects of Cytogenetics.- 3. Frequency of Chromosome Anomalies in Miscarriages.- 4. Techniques of Study.- 5. Relative Frequency of Types of Chromosome Anomalies.- 5.1. Trisomy.- 5.2. Sex Chromosome Anomalies.- 5.3. Polyploidy.- 6. Cystic Changes of the Chorionic Villi.- 7. Cytogenetic Studies of Stillbirth and Neonatal Death.- 8. Translocations in Miscarriages.- 9. Chromosome Anomalies and Recurrent Abortion.- 9.1. Introduction.- 9.2. Karyotypes of Multiple Abortions.- 10. Etiology of Chromosome Anomalies.- 10.1. Maternal Age.- 10.2. Radiation Exposure.- 10.3. Hormonal Factors.- 11. Sex Ratio.- 12. Significance of the Cytogenetic Findings in Pregnancy Wastage.- 13. The Future for Cytogenetic Studies of Abortuses.- References.- 4. Twenty Years of Study of the Etiology of Congenital Malformations in Finland.- 1. Introduction.- 2. The Study Population.- 3. The Finnish Register of Congenital Malformations.- 3.1. Notification of Malformations.- 3.2. Matched-Pair Register.- 3.3. Maternal and Child Health Organization.- 3.4. Interview.- 3.5. Controls.- 3.6. Blood Samples.- 3.7. Treatment of Material.- 3.8. Special Studies.- 4. Incidence of Congenital Malformations.- 4.1. Pilot Study.- 4.2. Malformations Registered in 1963-1980.- 4.3. Follow-Up Studies.- 4.4. Failures in Reporting and Detection.- 4.5. Trends and Seasonal Variations.- 4.6. Geographic Distribution.- 5. The Matched-Pair Register.- 5.1. Indicator Defects.- 5.2. Risk Indicators.- 6. Special Studies.- 6.1. Occunational Hazards.- 6.2. Leisure Time.- 6.3. Infectious Diseases.- 7. Limitations and Pitfalls of Epidemiologic Studies.- 7.1. Definitions.- 7.2. Maternal Memory Bias.- 7.3. Confounding Factors.- 7.4. Chance Correlations.- 7.5. Controls.- 8. Concluding Remarks.- References.- 5. Genome and Chromosome Mutations: Balance between Appearance and Elimination.- 1. Introduction.- 2. Numerical Chromosome Anomalies or Genome Mutations.- 2.1. Overall Frequency.- 2.2. Types of Numerical Chromosome Anomalies.- 2.3. Nondisjunction of Chromosomes during Meiosis.- 2.4. Errors of Chromosome Haploid Set.- 2.5. Frequency of Numerical Chromosome Mutations at Fertilization and Natural Selection.- 2.6. Are Genome Mutations Dominant Lethal Mutations?.- 2.7. Are There Genes Favoring Nondisjunctions?.- 3. Chromosome Structural Rearrangements or Chromosome Mutations.- 3.1. Robertsonian Translocations.- 3.2. Reciprocal Translocations.- 3.3. Inversions.- 3.4. Conclusions.- 4. Human Chromosome Heteromorphisms (Variants, Polymorphisms).- 5. Minor Deletions and Mutation.- 6. Chromosomal Mutations and Evolution.- 7. Population Genetics of Structural Chromosome Rearrangements.- 7.1. Notation of Karyotypes and Haplokaryotypes.- 7.2. The Proposed Model.- 7.3. Equilibrium with Polymorphism.- 7.4. Frequency of Balanced Carriers (A1A2) at Equilibrium.- 7.5. Incidence of Unbalanced Individuals at the End of the Third Month of Pregnancy and Its Estimation.- 7.6. Estimation of , the Segregation Distortion, and s, the Reduction of Fertility..- 7.7. Analysis of the Data.- 7.8. Equilibrium Frequencies.- 8. Conclusion.- References.- 6. Developmental Toxicity and Nonhuman Primates: Interspecies Comparisons.- 1. Introduction.- 2. Thalidomide.- 3. Fungicides.- 4. Cytotoxic Agents.- 4.1. Methotrexate.- 4.2. Cyclophosphamide.- 4.3. Hydroxyurea.- 5. X-Irradiation.- 6. Hyperthermia.- 7. Androgens and Progestins.- 8. Glucocorticoids.- 9. Summary.- 10. Experimental Protocols.- 11. Comparative Embryology.- 12. Conclusion.- References.- 7. Teratogenic Risk Assessment: Past, Present, and Future.- 1. Introduction.- 2. Present Testing Strategy: Tolerance Levels/Risk-Benefit Analysis and the Concept of "Thresholds".- 2.1. The Problem of Variability.- 2.2. The Sensitivity Factor.- 3. The Past in Risk Assessment of Teratogens.- 3.1. Maternal LD50 and Teratogenic Dose Ratios.- 3.2. Teratogenic Dose to Therapeutic Dose Ratios.- 3.3. Structure-Activity Relations.- 3.4. Embryolethal Dose to Teratogenic Dose Ratio.- 4. New Concepts of Toxicity Which May Have Application in Risk Assessment of Potential Teratogens.- 4.1. Surveillance Index.- 4.2. One-Third Maximum Tolerable Dose Rule.- 4.3. Enslein Mathematical Model.- 4.4. Adult Toxic/Developmental Toxic (A/D) Ratio and Relative Teratogenic Index (RTI).- 4.5. Genotoxicity Tier.- 4.6. In Vitro Systems.- 4.7. Animal-to-Animal Extrapolation.- 5. Appropriate Present-Day Approaches to Teratogenic Risk Assessment.- 5.1. Improvements in Existing Screening Methods or Testing Strategy.- 5.2. Surveillance and Epidemiology.- 5.3. Pharmacokinetic Applications.- 5.4. Change in Emphasis in Testing: Developmental Toxicity versus Malformation.- 6. Summary and Conclusions.- References.- 8. Thalidomide and Embryonic Sensory Peripheral Neuropathy: An Appraisal of the Neuropathic Theory of Limb Reduction Defects.- 1. Introduction.- 2. Statement of the Neuropathic Theory of Limb Reduction Defects.- 3. Premises of the Theory.- 4. Analysis of the Premises and Supporting Arguments and Observations.- 4.1. First Premise: Embryonic Limb Development Is Dependent on Neurotrophic Influences.- 4.2. Second Premise: Limb Deformities Produced by Thalidomide Are the Result of Interference with Neurotrophic Influence.- 5. Summary.- 6. Other Theories of the Mechanism of Thalidomide Teratogenicity.- References.- 9. Restorative Growth in Mammalian Embryos.- 1. Introduction.- 2. Embryologic Studies.- 3. Teratologic Studies.- 3.1. Restorative Growth in the Nervous System.- 3.2. Restorative Growth Following Damage by Ionizing Radiation.- 3.3. Restorative Growth Following Damage by Other Agents.- 4. Conclusions and Discussion.- References.- 10. Functional Teratology of the Cardiovascular and Other Organ Systems.- 1. Introduction.- 2. Effects of the Pesticide Mirex on the Fetal Cardiovascular System-A Case Study.- 2.1. Embryonic and Fetal Electrocardiography.- 2.2. Effects of Mirex Exposure on the Fetal Electrocardiogram.- 2.3. Cardiovascular Effects and Postnatal Death.- 2.4. Blood Parameters.- 2.5. The ECG Method and Functional Teratology.- 2.6. Relation to Human Experience.- 3. Functional Teratology of Other Organ Systems.- 3.1. Nervous System.- 3.2. Pulmonary System.- 3.3. Immune System.- 3.4. Renal System.- 4. Concluding Comments.- References.- 11. Searching for the Mechanism of Acetazolamide Teratogenesis.- 1. Acetazolamide Teratology.- 1.1. Species and Strain Susceptibility.- 1.2. Critical Periods.- 2. Carbonic Anhydrase.- 3. Carbonic Anhydrase Inhibition by Acetazolamide.- 4. Carbonic Anhydrase during Development.- 5. Studies of the Mechanism of Acetazolamide Teratogenesis.- 5.1. Earlier Efforts.- 5.2. Other Approaches.- 6. Recent Studies on the Teratogenic Mechanism of Acetazolamide.- 6.1. Teratology.- 6.2. Pharmacokinetics.- 6.3. Histochemical Studies.- 6.4. ImmunodifTusion Analysis.- 6.5. Purification of Carbonic Anhydrase.- 6.6. Immunoprecipitation Analysis.- 7. Comparative Studies in Rats, Rabbits, and Monkeys.- 8. Discussion.- References.