Index
A
Abortion (spontaneous), early fetal/embryo loss, 7, 11, 18, 19, 23, 38, 62, 103, 185, 233
Acceptable daily intake, 26, 40, 55
defined, 281
pharmaceutical agents, 41
Acetylaldehyde dehydrogenase, 103
Adenosine triphosphate, 114
Agency for Toxic Substances and Disease Registry, 217
Alcohol dehydrogenase, 103
Alcohol use and abuse, 20, 22, 41, 60, 103, 233
dose-response, 41
historical perspectives, 60
American Chemical Society, 24
Ames test, 176-177
Aminopterin, 23
Angiotensin-converting enzymes, 23, 69-70
Animal models, 76, , 16, 21, 24-25, 27, 28, 29-34 (passim), 70, 83, 149, 150, 151-195, 198-199, 203, 204, 210, 225-227, 233, 234, 296-306
Ames test, 177
bioassays, 3, 5, 6, 12, 16, 24, 28, 32, 34-37, 40, 54, 100, 153, 164, 167, 170, 176, 177, 186-187, 191, 200, 203-208 (passim), 221, 236, 237, 239-240
cell differentiation, 149, 150, 152, 168, 185
committee charge and methodology, 3, 4-6, 225-226
cost of research, 27, 152, 153, 167, 176, 177, 191, 203, 205-206, 208, 224, 225-226, 238
databases, 8, 15, 31, 40, 155, 157, 216, 218, 292, 293, 294
dose and dose-response, 7, 8, 38, 34, 35, 40-41, 178, 182, 197, 200, 201, 206, 209
extrapolation from high to low doses, 8, 34, 35, 40-41, 55-57, 197, 225, 226, 231, 238, 241
epidemiological studies and, 38, 233, 234
exposure indices, 34, 36, 207, 236
extrapolation, interspecies, 6, 7-8, 12, 34, 35, 40-41, 42, 45-46, 50, 54, 55, 56-57, 120, 141-143, 157, 159, 178, 187-188, 195-201 (passim), 206, 214, 215, 216, 222, 224, 229, 236, 238, 240-241, 242-243
from high to low doses, 8, 34, 35, 40-41, 55-57, 197, 225, 226, 231, 238, 241
toxicokinetics, 7-8, 45-46, 225
forward genetics, 154-156, 161, 284
gene expression and regulation, 4, 5, 115, 116-119, 128, 157, 165, 168, 170, 171, 188-189, 223, 224, 237
genetic factors, general, 153-195, 180, 223-224, 234-235
genomics, 4, 5, 8, 13, 14, 15, 92, 97, 101, 104, 106, 114-115, 123, 127-128, 143, 153, 155-157, 159-160, 163, 168, 169, 171, 172, 182, 195, 209, 216, 217-218, 227, 233, 292
historical perspectives, 11, 12, 35, 113-114, 115, 120-121, 123, 145-146, 151-152, 153, 161-163
mechanism-based toxicity results, 6-7, 63, 65, 70, 73-81 (passim), 195, 198-199, 225, 227
methylmercury, 75
musculoskeletal system, 34, 180
retinoids, 77
reverse genetics, 94, 156-157, 287
single-celled organisms, 151-152
bacteria, 151, 158, 163, 174, 176, 193, 204, 227
yeast, 14-15, 41, 92, 93, 94-97, 114, 143, 151-152
valproic acid, 82
see also Knockout mutations;
Mouse and rat models;
Nonmammalian models;
Sensitization;
Transgenics
Antiarrhythmic drugs, 72
diphenylhydantoin, 4, 23, 66, 73-74, 87, 102-103, 210
valproic acid, 23, 46, 48, 60, 82-83, 85-86
Apoptosis, 8, 61, 52, 71, 77-78, 83-84, 87, 134, 139, 140, 180, 189, 231, 302
Aryl hydrocarbon hydroxylase, 53
Aryl hydrocarbon receptor (AHR), 65, 80-82, 106, 182
B
Bacteria, 114, 158, 163, 174, 176, 193, 204, 227
transfection, 174, 193-195, 205
Basic Local Alignment Search Tool, 115, 293
Behavioral assays, 113, 180-181, 185-186, 187, 190, 200, 207, 209
Behavioral factors, see Life-style risk factors
Benchmark dose, 40, 54, 55-56, 281
Benzo[a]pyrene, 28, 51, 53, 63
Bioinformatics, 15, 99-100, 214-215, 216
defined, 281
see also Databases
Biologic Markers in Reproductive Toxicology, 49
databases, 214-215
defined, 49-50, 53, 214, 281-282
effect, 49, 51, 52, 53, 214, 215, 281
birth weight, 1, 18, 34, 40, 52, 74
exposure, 42, 49, 50-52, 53, 214, 281
gene expression and regulation, 51, 52, 214
susceptibility, 49, 50, 53-54, 214, 215, 281-282
see also Drug-metabolizing enzymes
Biotechnology, see Genetic engineering
Bipolar disorder, lithium, 23
dose-response, 40
methotrexate, 74
alternatives to testing pregnant mammals, 33
autism, 85
methylmercury, 74-75
neural tube defects, 19, 23, 48, 52, 62-63, 82, 84, 144
C
Caenorhabditis elegans, 14-15, 63, 101, 104, 113, 114, 123, 124, 143, 150, 152-153, 154, 156-161 (passim), 163, 167, 178-182, 191, 195, 216, 224, 178-182, 206-207, 226, 231, 234, 293, 297-298, 300, 303
genomics, 14-15, 88, 93, 94, 101, 104, 195, 216, 226, 234
Cancer and carcinogenesis, 48, 133, 134, 209, 213, 217, 234
Ames test, 176-177
DES, 73
methotrexate, 74
Cancer Genome Anatomy Project, 98, 217, 294
Cardiovascular system, 17, 18, 23, 130, 132, 133, 145
antiarrhythmic drugs, 72
retinoids, 77-78
Case-control studies, 38
Case series, 37
Cell cultures, 3, 6, 7, 12, 28-34, 77, 192-195, 197, 198, 200, 204, 205, 237
methylmercury, 75
retinoids, 78
Cell death, see Apoptosis
Cell differentiation, 12, 19, 64, 99, 101, 109, 112, 124, 127, 128, 129, 149-150
animal models, 149, 150, 152, 168, 185
retinoids and, 79-80
risk assessment, 33, 52, 224, 228-229
stem cells, 32, 111, 172, 173-174, 283
see also Organogenesis
Cell proliferation, 4, 14, 28, 32, 33, 34, 52, 64, 66, 71, 87, 148, 149, 228
see also Cancer and carcinogenesis
Cell-to-cell signaling, 4, 5, 6-7, 8, 13, 14, 16, 87, 111-112, 126-136, 143, 149-150, 158-159
history of developmental biology, 110, 111
in vitro models, 30
see also Checkpoint pathways;
Molecular-stress pathways;
Receptor-mediated actions;
Signaling pathways;
Transduction
Cellular processes, general, 14, 28-29, 64, 65-71, 86, 88, 109-113, 143, 185, 222, 225
apoptosis, 8, 61, 52, 71, 77-78, 83-84, 87, 134, 139, 140, 180, 189, 231, 302
cleavage, 72, 83-84, 109, 116, 140, 170, 228
cytochrome P450, 66, 74, 80, 104, 293
epidermal cells, general, 142, 146
epidermal growth factor, 63, 81, 179
eukaryotic, 93, 127, 138, 139, 143, 152, 161, 192, 193, 194, 283
history of developmental biology, 109-110, 111
methylmercury, 75
stem cells, 32, 111, 172, 173, 283
transduction, 14, 16, 55, 71, 72-73, 84, 86-87, 126, 150, 151, 237, 294
transfection, 174, 193-195, 205
transplantation technologies, 109. 111
see also Bacteria;
Gene expression and regulation;
Genetic factors, general;
Intracellular signaling;
Molecular-stress pathways;
Oocytes;
Receptor-mediated actions;
Secretion and secretory processes;
Signaling pathways;
Yeast;
Zygotes
Center for the Evaluation of Risks to Human Reproduction
Centers for Disease Control and Prevention, 211
Central nervous system, 23, 109, 132, 149, 187, 190
autism, 84
fetal alcohol syndrome, 103
methylmercury, 74
see also Brain
Cerebral palsy, 18
Checkpoint pathways, 7, 8, 16, 25, 75, 87, 127, 136-141, 152, 185, 189, 204, 208-209, 225, 227, 228, 229, 231, 233, 235, 238, 239, 241, 295, 231, 233, 235, 238, 239, 241, 295, 296, 302
Chickens, 33, 58-59, 125, 153, 216, 292
Chromosomes, 7, 17, 19, 20, 88, 93, 122, 139, 160, 161-162, 163, 168, 170
see also Genomics
Cleavage, 72, 83-84, 109, 116, 140, 170, 228
Clefting, see Oral clefting
Clinical trials, 37
Cloning, 13, 86, 94, 97, 111, 115, 153-157 (passim), 159-166 (passim), 168, 169, 173, 174, 176, 183, 184, 186, 192, 193
Cmax see Peak threshold concentration
CNS, see Central nervous system
Cohort studies, 37-38
Computer applications
extrapolation from animal models to humans, 242
forward genetics, 156
genetics, general, 157
see also Bioinformatics;
Databases;
Internet
Connective tissue, 23, 145, 148
fibroblasts, 145, 176, 185, 193
Convulsions, see Anticonvulsants
Cost factors, see Economic factors
Covalent binding, 66
Craniofacial defects, 23, 71, 73, 74, 76, 77, 78, 79, 80, 85, 103
see also Oral clefting
Cyclopamine, 72-73, 87, 223, 229, 232
Cyclophosphamide, 23
Cytochrome P450, 66, 74, 80, 104, 293
Cytomegalovirus, 194
D
Danio rerio, see Zebrafish
Databases, 8, 12, 27, 31, 201-202, 210-219, 229, 243-244, 290-295
animal models, 8, 15, 31, 40, 155, 157, 216, 218, 292, 293, 294
bioinformatics, 15, 99-100, 214-215, 216, 281
biomarkers, 214-215
dose and dose-response, 201, 214
genetics, general, 16, 97, 98-100, 114-115, 155, 212-214, 216, 217-218, 243, 290-295
genomics, 16, 97, 98-100, 114-115, 155, 212-214, 216, 217-218, 243, 290, 292, 293, 294
bioinformatics, 15, 99-100, 214-215, 216, 281
Internet, 92, 218, 290, 292, 293. 294-295
minor defects, 18
multidisciplinary linkages, 100, 216-219, 229, 243-244, 290
organogenesis, 150
polymorphisms, 8, 98-99, 212-214, 216, 243, 291, 293, 294
proteomics, 15, 97, 114, 218, 290, 291, 293, 294
see also Internet
Death, see Mortality
Delta pathways, 66, 127, 129, 179-180, 300
Δ7-dehydrocholesterol, 72-73
Department of Energy, 93, 99-100
Department of Health and Human Services, see Agency for Toxic Substances and Disease Registry;
Centers for Disease Control and Prevention;
National Cancer Institute;
National Institutes of Health
DES (diethylstilbesterol), 23, 73, 223
Developmental and Reproductive Toxicological Database, 217
Diabetes, 38
Diet, see Nutrition
Diethylstilbesterol, see DES
Diphenylhydantoin (DPH), 4, 23, 66, 73-74, 87, 102-103, 210
DNA, 4, 65, 66, 70, 87, 123, 139, 151, 155, 156, 157, 159-160, 162-163, 166, 172-175, 192-193, 293, 296
adducts, 51, 52, 53, 66, 87, 204, 302
Ames test, 176-177
defined, 284
diphenylhydantoin, 73-74
introns, 88, 174, 175, 194, 217, 284
microarray technology, 93-98, 100, 159-160, 205, 207, 210, 214, 216
molecular-stress pathways, 138, 139, 140
retinoids, 78-79
transfection, 174, 193-195, 205
see also Chromosomes;
Genomics;
Transcription
DNA Data Bank of Japan, 99
Dose and dose-response, 3, 7, 27, 28, 30-31, 32, 39-41, 45, 46, 61, 229
acceptable daily intake, 26, 40, 41, 55, 281
alcohol, 41
animal models, general, 7, 8, 38, 34, 35, 40-41, 178, 182, 197, 200, 201, 206, 209
extrapolation from high to low doses, 8, 34, 35, 40-41, 55-57, 197, 225, 226, 231, 238, 241
toxicokinetics, 7-8, 45-46, 225
benchmark dose, 40, 54, 55-56, 281
birth weight, 40
maximum tolerated dose, 36, 45
peak threshold concentration (Cmax), 46, 48, 49
reference dose, 39, 40, 41, 54, 55, 287
wild-type, 115
see also Exposure
DPH, see Diphenylhydantoin
Drosophila melanogaster, 14-15, 63, 89-90, 93, 101, 104, 113-114, 115-128, 141, 142, 143, 153, 159, 161-166, 182-186, 191, 195, 206-207, 216, 224, 226, 230-235 (passim), 296, 297-304 (passim)
embryos, 115-128, 161, 159, 161, 182, 183, 185
genome, 14-15, 93, 101, 104, 233-234, 292
mutation, 113-114, 115-128, 161, 183, 184, 185, 186, 235
structural defects, 14-15, 89-90, 93, 101, 104, 113-114, 115-127
Drug-metabolizing enzymes (DMEs), 6, 7, 8, 44, 49, 53-54, 66, 99, 102, 103-106, 107, 141, 177, 188, 188-189, 194-195, 197, 200-208 (passim), 213, 214, 215, 222, 227, 228, 231-232, 234, 236-237, 239-240, 243
defined, 283
Drugs, see Pharmaceuticals
E
Ecogenetics, 103-104, 105-106, 198, 232
genotype-environment interactions, 6, 25, 88, 175, 220, 228, 233, 234, 235
epidemiology and, 89, 99, 100-106, 215-216
defined, 283
Economic factors
developmental defects, costs of, 17-18
research costs, 27, 152, 153, 167, 176, 177, 191, 203, 205-206, 208, 224, 225-226, 238
risk assessment paradigm, 27, 198
Ectopic expression, 79, 170, 188, 234, 283
Effect (biomarkers), 49, 51, 52, 53, 214, 281
birth weight, 1, 18, 34, 40, 52, 74
Electroporation, 172, 173, 283
Embryos, 3, 4, 8, 10, 12, 14, 19, 32, 44, 47-49, 98, 111-112, 221, 223, 238
abortion (spontaneous), early fetal/embryo loss, 7, 11, 18, 19, 23, 38, 62, 103, 185, 233
animal models, 34, 62-63, 123, 124, 153, 158, 159-160, 161, 167, 169-170, 187, 188
autism, 85
gastrulation, 107, 116, 144, 145, 228, 232
history of developmental biology, 109, 110
history of developmental toxicology, 58-59
in vitro assessments, 28, 29, 30, 33
molecular-stress/checkpoint pathways, 141
neurulation, 109, 144, 228, 232
nonmammalian models, 6, 7, 28, 32, 33, 153, 115-128
Caenorhabditis elegans, 123, 124, 158, 159-160
chick embryotoxicity test, 33, 58-59
Drosophila melanogaster, 115-128, 161, 159, 161, 182, 183, 185
larvae, 127, 158, 159, 161, 179, 181, 182, 183, 185, 293
see also specific species
TCCD, 81-82
see also Organogenesis
Embryonic stem cells, see Stem cells
Employment, see Occupational health and safety
Endocrine Disruption Screening Program (EDSP), 198, 203, 205
Education and training, 9, 293
Environmental agents, general, 4, 8, 10, 11, 28, 35, 52, 61-64
committee charge and methodology, 1-2, 20
ecogenetics, 103-104, 105-106, 198, 232, 283
genotype-environment interactions, 6, 25, 88, 175, 220, 228, 233, 234, 235
epidemiology and, 89, 99, 100-106, 215-216
see also Risk assessment;
specific agents
Environmental Genome Project, 98-99, 217, 294-295
Environmental Health Commission, 211
Environmental Protection Agency (EPA), 26, 34, 64, 221
Environment and Birth Defects, 60, 110
Enzymes, 24, 53, 103, 105, 188, 193, 197, 233, 234, 290-291
see also Drug-metabolizing enzymes
Epidemiology, 7, 28, 36, 37-39, 57, 202, 210-212, 213, 219, 233-234
animal studies and, 38, 233, 234
biomarkers of effect, 52
biomarkers of exposure, 42, 51
cohort studies, 37-38
dose-response, 40
genomics and, 7, 89, 99, 100-106
historical perspectives, 11, 37
molecular genetics and, 89, 99, 100-106, 107, 286
natural toxins, 1, 10, 13, 20, 24, 203, 223, 224-225, 238
professional education, 9
Epidermal cells, general, 142, 146
Epidermal growth factor, 63, 81, 179
Epigenetic factors, 6, 25, 88, 175, 220, 228, 233, 234, 235
epidemiology and, 89, 99, 100-106, 215-216
Epstein-Barr virus, 194
Estrogen, 23, 34, 65, 67, 73, 105, 204
Ethical issues, see Legal and ethical issues
Ethnicity, see Race/ethnicity
Ethylene glycol ethers, 47
Ethylene oxide, 40
Etretinate, 23
Eukaryote, 93, 127, 138, 139, 143, 152, 161, 192, 193, 194, 283
European Bioinformatics Institute, 100
European Molecular Biology Library, 99
Exposure, 4, 16, 27, 28, 30, 32, 38, 41-42, 43, 45, 220, 222, 226
animal bioassays, 34, 36, 207, 236
biomarkers, 49, 50-52, 53, 214, 281
defined, 281
risk assessment paradigm, 27, 198, 200, 204, 207
timing and duration of, 5, 8, 27, 31, 41, 46, 48, 50, 51, 61, 221
see also Dose and dose-response
Expressed sequence tag (EST) libraries, 92, 94-95, 97, 99, 157, 168, 218, 284, 293, 294
Eye defects, 77, 83, 87, 106, 109, 124, 140, 144, 145, 164, 182, 184, 185, 187, 206, 207, 232, 233
F
Federal government, see Legislation;
Regulatory issues;
specific departments and agencies
Fetal alcohol effects, see Alcohol use and abuse
Fetuses, 3, 4, 10, 12, 14, 19, 34, 40, 44, 98, 132, 221
abortion (spontaneous), early fetal/embryo loss, 7, 11, 18, 19, 23, 38, 62, 103, 185, 233
diphenylhydantoin, 73-74
fetal alcohol syndrome, 20, 22, 41, 60, 103, 233
protein function, 69-70
Fibroblasts, 145, 176, 185, 193
Food and Drug Administration (FDA), 26, 34, 59
Food Quality Protection Act, 40
Forward genetics, 154-156, 161, 284
Frogs, 4, 32, 33, 111, 113, 121, 123, 124, 129, 142, 153, 178, 216
Fruit fly, see Drosophila melanogaster
Functional deficits, general, 7, 18, 27, 34, 35, 39, 61, 63, 87, 129, 130, 149, 180-181, 185-186, 200, 222, 232
behavioral assays, 113, 180-181, 185-186, 187, 190, 207, 209
see also Neurological defects;
specific deficits
G
Gastrulation, 107, 116, 144, 145, 228, 232
GenBank, 99-100
Gene expression and regulation, 5, 13-14, 29, 63, 71, 86-87, 111, 112, 148, 174, 192-195, 204, 207-208, 229, 230, 237, 244
animal models, 4, 5, 115, 116-119, 128, 157, 165, 168, 170, 171, 188-189, 223, 224, 237
ectopic expression, 79, 170, 188, 234, 283
expressed sequence tag (EST) libraries, 92, 94-95, 97, 99, 157, 168, 218, 284, 293, 294
genomics, 88, 92, 94, 98, 107, 216, 217-218
history of developmental biology, 110, 111
Hox genes, 79, 86, 87, 116-117, 120-123, 141, 213
microarray technology, 93-98, 100, 159-160, 205, 210, 214, 216
proteomics, 15, 92-93, 97-98, 114, 291, 293, 294
valproic acid, 85-86
see also Transcription
Genetic engineering, 5, 49. 92, 169-176, 289
transfection, 174, 193-195, 205
see also Transgenics
Genetic factors, general, 10, 13, 16, 21, 22, 25, 64, 88-107 (passim), 223-224, 233-234
animal models, 153-195, 180, 223-224, 234-235
autism, 84
cytochrome P450, 66, 74, 80, 104, 293
databases, 16, 97, 98-100, 114-115, 155, 212-214, 216, 217-218, 243, 290-295
epidemiological studies, 38, 89, 99, 100-106
history of developmental biology, 110
environment-genotype interactions, 6, 25, 88, 175, 220, 228, 233, 234, 235
ecogenetics, 103-104, 105-106, 198, 232, 283
epidemiology and, 89, 99, 100-106, 215-216
Mendelian rules, 21
multifactoral inheritance, 10, 21, 22, 89, 90, 101-102, 216, 220
pharmacogenetic factors, 94, 103-104, 105-106
see also Chromosomes;
Cloning;
DNA;
Gene expression and regulation;
Genomics;
Multidisciplinary approaches;
Mutation and mutants;
Polymorphisms;
RNA;
Transcription;
Transduction
Genomics, 1, 5, 13, 14-15, 16, 21, 88, 89, 91, 92-107, 111, 114-115, 195, 223, 233-234, 235
animal models, 4, 5, 8, 13, 14, 15, 92, 97, 101, 104, 106, 114-115, 123, 127-128, 143, 153, 155-157, 159-160, 163, 168, 169, 171, 172, 182, 195, 209, 216, 217-218, 227, 233, 292
bioinformatics, 15, 99-100, 214-215, 216, 281
Caenorhabditis elegans, 14-15, 88, 93, 94, 101, 104, 195, 216, 226, 234
Cancer Genome Anatomy Project, 98, 217, 294
committee charge and methodology, 2, 4, 11, 226
databases, 16, 97, 98-100, 114-115, 155, 212-214, 216, 217-218, 243, 290, 292, 293, 294
bioinformatics, 15, 99-100, 214-215, 216, 281
Internet, 92, 218, 290, 292, 293. 294-295
DNA Data Bank of Japan, 99
Drosophila melanogaster, 14-15, 93, 101, 104, 233-234, 292
Environmental Genome Project, 98-99, 217, 294-295
epidemiology, 7, 89, 99, 100-106
gene expression regulation, 88, 92, 94, 98, 107, 216, 217-218
expressed sequence tag (EST) libraries, 92, 94-95, 97, 99, 157, 168, 218, 284, 293, 294
Genome Sequence Database, 99, 100
historical perspectives, 14-15, 92, 93, 98, 99-100
Human Genome Project, 14-15, 92-100, 212-213, 214, 284
infectious diseases, 93
legal and ethical issues, 93
microarray technology, 93-98, 100, 159-160, 205, 207, 210, 214, 216
mouse and rat models, 8, 13, 15, 97, 124, 169, 226, 292
multidisciplinary/multilevel approaches to risk assessment, 197, 198, 205, 207, 210, 212-214, 216, 218, 243
National Center for Genome Resources, 100
National Human Genome Research Institute, 93
professional education, 9
proteomics, 15, 92-93, 97-98, 114, 291, 293, 294
risk assessment, 100, 101-104 (passim), 107, 197, 198, 205, 207, 210, 212-214, 216, 218, 243
Genome Sequence Database, 99, 100
Glucocorticoids, 34, 62, 65-66, 67, 81, 105, 194
Good Laboratory Practices, 35
Growth retardation, 1, 23, 26, 34, 35, 39, 61, 63, 70, 132, 133, 134, 206, 222, 225
see also Transforming growth factor
H
“Healthy from the Start: Why Americans Need a Better System to Track and Understand Birth Defects and the Environment,” 211
Heart, see Cardiovascular system
Heat shock, 1, 10, 20, 25, 83, 84, 105, 138, 141
neural tube defects, 62-63
Hedgehog pathways, 66, 115, 123, 126, 127, 129, 145, 161, 167, 184, 191, 203, 206, 213, 223, 229, 232, 235, 237, 298
Herpes virus, 194
His, W., Sr., 109
Historical perspectives, 11, 16, 17, 58-60
alcohol abuse, 60
animal models, 11, 12, 35, 113-114, 115, 120-121, 123, 145-146, 151-152, 153, 161-163
costs of developmental defects, 17-18
developmental biology, 16, 108-111, 113-114, 115, 120-121, 123, 145-146
developmental toxicology, 11, 58-60, 62, 86, 220
genomics, 14-15, 92, 93, 98, 99-100
government regulation, 26
Human Genome Project, 92
Mendelian theory, 89
regulatory issues, 59
risk assessment, 11-12
thalidomide, 11, 23, 36, 38-39, 59, 60, 85, 87, 149
Hox genes, 79, 86, 87, 102, 116-117, 120-123, 141, 213
Human Genome Project, 14-15, 55, 92-100, 212-213, 214, 284
Hydra assay, 32
Hyperthermia, see Heat shock
I
Immune system effects, 52, 53, 130, 303
In vitro systems, 3, 6, 12, 24, 28-34, 77, 192-193, 197, 198, 199, 219, 221
see also Cell cultures;
Tissue assays
In vivo systems, see Animal models
Infectious diseases, 20, 58, 106
genomics, 93
herpes, 194
Information dissemination, see Computer applications;
Databases;
Education and training;
Internet
Integrated Risk Information System, 217
Interagency Center for Evaluation of Alternative Toxicological Methods, 32
Intercellular signaling, see Cell-to-cell signaling;
Signaling pathways
Interdisciplinary approaches, see Multidisciplinary approaches
International Agency for Research, 217
International perspectives
birth defect surveillance, 211
genomics, 93
International Programme on Chemical Safety, 64, 221
Internet, 290-295
Basic Local Alignment Search Tool, 115
biomarker database, 214
genomics, 92, 218, 290, 292, 293. 294-295
signal transduction, 244
Intracellular signaling, 13, 66, 74, 83, 84, 112, 126, 134, 185
see also Molecular-stress pathways
Introns, 88, 174, 175, 194, 217, 284
K
Knockout mutations, 124, 126, 128, 154-155, 156, 161, 178, 189, 230, 234-235
embryonic stem cell technology, 104, 173-174
mouse, 73, 76, 77-78, 85, 104, 105, 112, 121, 123, 124, 129, 169, 173-174, 188, 189, 190, 209, 218, 232-235 (passim), 244, 292
yeast, 94
L
Larvae, 127, 158, 159, 161, 179, 181, 182, 183, 185, 293
Lead, 1, 20, 22, 23, 60, 106, 214, 215
Legal and ethical issues
genomics, 93
risk assessment paradigm, 27
see also Ethical issues
Legislation, 40
see also Regulatory issues
Life-style risk factors, 20, 22
see also Alcohol use and abuse;
Smoking
Ligands, 78, 86, 115, 116, 127, 136, 137, 297. 300, 301, 306
environmental agents, metabolism of, 24
methylmercury, 74
receptor interactions, general, 65-66, 70, 126, 137
tyrosine kinase, 95, 102, 116, 165
WNT (Wnt) pathways, 66, 73, 74, 126, 129, 136, 141, 145, 148, 180, 184, 206, 213, 234, 297
Lithium, 23
Los Alamos National Laboratory, 99-100
M
Mass media, 59
Maximum tolerated dose, 36, 45
Mechanistic information, general, 6-7, 63-87, 195, 198-199, 201, 220-224, 225, 227, 228, 236, 238
Medical treatment, see Treatment
Mercury, 20, 23, 50-52, 69, 74-75
Metabolic processes, 3, 4, 5, 8, 20, 31, 32, 51, 178, 203, 216, 222, 228, 233-234, 236-237
see also Drug-metabolizing enzymes;
Enzymes;
Toxicokinetics
Methylmercury, 23, 50-52, 69, 74-75
Mice, see Mouse models
Microarray technology, 93-98, 100, 159-160, 205, 210, 214, 216
Minor defects, general, 18
Molecular-stress pathways, 7, 8, 16, 69, 136, 138-141, 180-181, 185, 189, 197, 200, 204, 208-209, 215, 225, 227, 228, 229, 231, 235, 238, 241, 299
Mortality, 17, 19, 39, 61, 63, 130, 134, 162, 206
abortion (spontaneous), early fetal/embryo loss, 7, 11, 18, 19, 23, 38, 62, 103, 185, 233
Mouse and rat models, 3-7 (passim), 8, 13, 22, 35, 40, 45, 48, 54, 55, 62, 125, 128-136, 141-142, 153-154, 184, 187-191, 195, 208, 209, 216, 217, 218, 225, 231, 234, 235, 237, 238, 239-240
Ames test, 177
autism, 85
diphenylhydantoin, 74
genomics, 8, 13, 15, 97, 124, 169, 226, 292
knockout mutations, 73, 76, 77-78, 85, 104, 105, 112, 121, 123, 124, 129, 169, 173-174, 188, 189, 190, 209, 218, 232-235 (passim), 244, 292
methylmercury, 74-75
polymorphisms, 4, 7, 104, 106, 225, 234
retinoids, 77-78
single-gene defects, 101
TCCD, 80-82
transgenic, 159, 168-176, 187-191, 208, 237-238, 244, 294
Multidisciplinary approaches, 8-9, 16, 86, 176, 196-219, 220, 221, 229, 243-244
committee study, methodology, 15
databases, 100, 216-219, 229, 243-244, 290
genomics in, 197, 198, 205, 207, 210, 212-214, 216, 218 , 243
historical perspectives, 59
Multifactoral inheritance, 10, 21, 22, 63, 89, 90, 101-102, 216, 220
Musculoskeletal system, 17, 18, 27, 47-48, 34, 56, 102, 130-134 (passim), 145, 180, 187
craniofacial, 23, 71, 73, 74, 76, 77, 78, 79, 80, 85, 103
diphenylhydantoin, 73-74
history of developmental toxicology, 59, 62
methotrexate, 74
oral clefting, 21, 38, 54, 62, 63, 80, 81, 102, 213, 242
thalidomide, 11, 23, 36, 38-39, 59, 60, 85, 87, 149
Mutation and mutants, 20, 124, 148, 164, 167-168, 171, 172, 174-175, 177-178, 187, 189, 229, 232-233, 240, 291
Ames test, 176-177
biomarkers of exposure, 51-52
Drosophila melanogaster, 113-114, 115-128, 161, 183, 184, 185, 186, 235
forward genetics, 154-156, 161, 284
Hox genes, 79, 86, 87, 116-117, 120-123
molecular-stress pathways, 138-140
reverse genetics, 94, 154, 156-157, 178-179, 287
signaling pathways, 8, 126-136, 137, 139, 177-178, 183, 184, 185, 187
see also Knockout mutations;
Polymorphisms;
Sensitization;
Transgenics
N
National Cancer Institute, 98-99, 212, 213, 217
National Center for Biotechnology Information, 100, 290
National Center for Genome Resources, 100
National Center for Human Genome Research, 93
National Center for Toxicological Research, 35
National Human Genome Research Institute, 93
National Institute of Environmental Health Sciences, 98, 217, 242
National Institute of General Medical Sciences, 100
National Institutes of Health, 290
see also Human Genome Project;
National Cancer Institute
National Library of Medicine, 100, 290
National Toxicology Program, 32, 35, 217
Natural toxins, 1, 10, 13, 20, 24, 203, 223, 224-225, 238
Nematodes, see Caenorhabditis elegans
Neurological defects, 1, 10, 17, 18, 23, 47-48, 130, 134, 145-146, 180-181, 190
cerebral palsy, 18
cyclopamine, 72-73
fetal alcohol syndrome, 103
methotrexate, 74
methylmercury, 74-75
neural tubes, 1, 19, 23, 48, 52, 62-63, 82, 84, 130, 144
spina bifida, 18
see also Anticonvulsants;
Brain;
Central nervous system
Neurulation, 109, 144, 228, 232
Nicotine, see Smoking
Nonmammalian models, 6, 7, 28, 32, 33, 63, 153, 198, 200, 205-208, 216, 224-226, 230, 236, 240
Ames test, 177
bioassays, 32, 153, 178, 180, 181, 182, 183, 206, 218, 221, 237
Caenorhabditis elegans, 63, 101, 104, 113, 114, 123-124, 143, 150, 153, 154, 156-161 (passim), 163, 167, 178-182, 191, 195, 216, 224
genomics, 14-15, 88, 93, 94, 101, 104, 195, 216, 226, 234
chick, 33, 58-59, 125, 153, 216, 292
Drosophila melanogaster, 63, 89-90
genomics, 14-15, 93, 101, 104, 233-234, 292
frog, 4, 32, 33, 111, 113, 121, 123, 124, 129, 142, 153, 178, 216
larvae, 127, 158, 159, 161, 179, 181, 182, 183, 185, 293
puffer fish, 153
pupae, 161, 182, 183, 185, 191
single-celled organisms, 151-152
yeast, 14-15, 41, 94, 92, 93, 94-97, 114, 143, 151-152
zebrafish, 3-7 (passim), 33, 93, 101, 113, 142, 150, 153, 154, 158, 159, 167, 168, 186-187, 191, 206, 207, 216, 217, 225, 226, 230, 231, 234, 237, 239, 240, 241, 292-293
North American Registry for Epilepsy and Pregnancy, 211
Notch pathways, 126, 127, 129, 164, 179-180, 184, 206, 300
Nuclear-hormone receptors, 30, 63, 65, 66, 77, 86, 126, 127, 203, 204, 219, 223, 229, 301
Null mutations, see Knockout mutations
Nutrition, 1, 10, 20, 53, 58, 64, 70, 75, 90, 139, 197, 220, 233, 235
O
Occupational health and safety, 21
On Line Mendelian Inheritance in Man, 211
Oocytes, 13
Drosophila melanogaster, 115, 116, 119, 120
early death, 62
gastrulation, 107, 116, 144, 145, 228, 232
transgenic technology, 159-160
Oral clefting, 21, 38, 54, 62, 63, 80, 81, 102, 213, 242
Organization for Economic Cooperation and Development (OECD), 34
Organogenesis, 36, 62, 87, 110-111, 124, 126, 142, 144-150, 167-168, 207, 209, 226, 228, 230-231, 232, 233, 239
defined, 286
eyes, 77, 83, 87, 106, 109, 124, 140, 144, 145, 164, 182, 184, 185, 187, 206, 207, 232, 233
history of developmental biology, 109
Oxidants and oxidation, 51, 69, 76, 83, 91, 103, 104, 105, 138, 139, 140-141, 188, 204-205, 208-209, 233, 236
P
PAHs, see Polycyclic aromatic hydrocarbons
PCR, see Polymerase chain reaction
Peak threshold concentration (Cmax), 46, 48, 49
Penicillamine, 23
Pharmaceuticals, general, 20, 24, 31, 36, 204
cohort studies, 38
dose-response, 41
public opinion, 59
see specific drugs
Pharmacogenetics, 94, 103-104, 105-106
Pharmacokinetics, 44, 46, 73, 77, 83
see also Drug-metabolizing enzymes
Phenytoin, see Diphenylhydantoin
Placenta, 11, 28, 30, 33, 61, 90, 94, 132, 133, 142, 152, 153, 159, 168
retinoids, 78
Polychlorinated biphenyls, 20, 23
Polycyclic aromatic hydrocarbons, 52, 53
benzo[a]pyrene, 28, 51, 53, 63
Polymerase chain reaction, 94, 214
Polymorphisms, 4, 7, 90-91, 102, 103, 104-106, 141, 192, 195, 200, 202, 215, 225, 234
biomarkers of susceptibility, 53
databases, 8, 98-99, 212-214, 216, 243, 291, 293, 294
defined, 287
mouse and rat models, 4, 7, 104, 106, 225, 234
RNA, 91
zygotes, 90
see also Transforming growth factor
Polyphodiersterase (PDE), 291
Prenatal period, 1, 3, 4, 19-20, 21, 31, 34, 35, 60-61, 190
alcohol use and abuse, 20, 22, 41, 60, 103, 233
exposure assessment, 41-42, 50-52
mechanisms of toxicity, 64, 70
placenta, 11, 28, 30, 33, 52, 53, 61, 90, 94, 142, 152, 153, 159, 168
smoking, 21, 23, 38, 54, 63, 102, 213, 230, 233
timing and duration of exposure, 5, 8, 27, 31, 41, 46, 48, 50, 51
uterine factors, 20, 21, 34, 35, 41, 50-52, 70, 73-74, 168
see also Embryos;
Fetuses;
Oocytes;
Organogenesis;
Placenta;
Zygotes
Professional education, see Education and training
Proteins and protein function, 4, 5, 15, 25, 53, 63, 66, 69-70, 108, 112, 114, 116, 119, 120, 126, 128, 135, 142, 193, 208, 297-308 (passim)
cytochrome P450, 66, 74, 80, 104, 293
databases, 15, 97, 114, 218, 290, 291, 293, 294
fetal protein function, 69-70
methylmercury, 74
translation, 88
see also Drug-metabolizing enzymes;
Transforming growth factor
Proteomics, 15, 92-93, 97-98, 114, 291, 293, 294
Puffer fish, 153
Q
Qualitative risk assessment, 2, 5, 11, 34, 44, 56, 151, 176, 195, 196, 224-226, 229, 238-239
R
Rat models, see Mouse and rat models
Receptor-mediated actions, 41, 53, 56, 86, 114, 126, 128, 133-134, 137, 199, 204
aryl hydrocarbon receptor (AHR), 65, 80-82, 106, 182
Drosophila melanogaster, 116, 117, 119, 165
mechanisms of toxicity, 65-68
molecular-stress pathways, 139
see also Ligands;
Signaling pathways
Receptor tyrosine kinase (RTK), 95, 102, 114, 116, 126, 129, 136, 165, 179, 185, 204, 206, 230, 298, 299, 300
Red Book, see Risk Assessment in the Federal Government: Managing the Process
Reference concentration, 39, 40, 41, 54, 55, 287
Registry of Toxic Effects of Chemical Substances, 217
acceptable daily intake, 26, 40, 41, 55, 281
Environmental Protection Agency (EPA), 26, 34, 64, 221
Food and Drug Administration (FDA), 26, 34, 59
Food Quality Protection Act, 40
historical perspectives, 59
reference concentration, 39, 40, 41, 54, 55, 287
risk assessment paradigm, 27
Reproductive system and behavior, 2, 15, 18, 20, 34, 131, 135, 162, 186, 217
retinoids, 77-78
see also Prenatal period
Reproductive Toxicology, 2, 15
REPROTEXT, 217
REPROTOX, 217
Respiratory system, 17, 90, 106, 129, 145
Retinoids, 23, 44, 51, 60, 65-66, 67, 75-80, 86, 148, 204, 223, 229-230
Reverse genetics, 94, 154, 156-157, 178-179, 287
Risk assessment, general, 2, 12-13, 15-16, 26-58, 195, 221-222, 224-226, 228-229, 235-236, 239-243
cell differentiation, 33, 52, 224, 228-229
committee study, charge and methodology, 2-3, 6-9, 11, 15, 224, 226
cost factors
research costs, general, 27, 152, 153, 167, 176, 177, 191, 203, 205-206, 208, 224, 225-226, 238
risk assessment paradigm, 27, 198
exposure, 27, 198, 200, 204, 207
extrapolation, interspecies, 6, 7-8, 12, 34, 35, 40-41, 42, 45-46, 50, 54, 55, 56-57, 120, 141-143, 157, 159, 178, 187-188, 195-201 (passim), 206, 214, 215, 216, 222, 224, 229, 236, 238, 240-241, 242-243
from high to low doses, 8, 34, 35, 40-41, 55-57, 197, 225, 226, 231, 238, 241
toxicokinetics, 7-8, 45-46, 225
framework, diagram, 43
genomics, 100, 101-104 (passim), 107, 197, 198, 205, 207, 210, 212-214, 216, 218, 243
historical perspectives, 11-12
in vitro systems, 3, 6, 12, 24, 28-34;
see also Cell cultures;
Tissue assays
legal and ethical issues, 27
mechanisms of toxicity, 63-65
multilevel/multidisciplinary approach, 6, 8-9, 16, 59, 86, 100, 176, 196-219
paradigm, 27
professional education, 9
qualitative, 2, 5, 11, 34, 44, 56, 151, 176, 195, 196, 224-226, 229, 238-239
relative risk, 287
uncertainty, 3, 6, 12, 15-16, 23, 27, 34, 37-38, 238
see also Animal models;
Biomarkers;
Cell cultures;
Dose and dose-response;
Epidemiology;
Exposure;
Susceptibility;
Toxicokinetics
Risk Assessment in the Federal Government: Managing the Process (Red Book), 26, 27
Risk characterization, 3, 27, 41, 42, 59, 64
bioassays used for regulatory assessment, 54
defined, 288
DNA microarrays, 95-96, 205, 207, 210, 214, 216
methylmercury, 75
retinoids, 77
see also Biomarkers;
Exposure
RNA, 13, 94, 95, 96, 97, 98, 111, 116, 155, 156-157, 160-161, 178, 182, 192, 207
anti-sense, 29
defined, 287
methylmercury, 75
molecular-stress pathways, 139
organogenesis, 144
polymorphism, 91
see also Transcription
Rodent models, see Mouse and rat models
S
SARs, see Structure-activity relationships
Science and Judgment, 199, 243
Secretion and secretory processes, 4, 69, 71, 80, 112, 114, 115, 116, 126, 141, 146, 148, 150, 228
see also Transforming growth factor
Seizures, see Anticonvulsants
Sensitization, 7, 39, 45, 50, 54, 61, 76, 104, 202, 208, 234, 242
animal models, 8, 12, 34, 35, 40, 62-63, 81, 154, 155, 163-164, 176-180, 183-185, 186, 187, 189, 191, 197, 206, 209, 226, 229, 233-239 (passim), 242
methylmercury, 75
placenta, 53
temporal, 50, 51, 56, 191, 220-221, 227
valproic acid, 82
see also Knockout mutations
Signaling pathways, 4, 5, 6-7, 8, 13, 14, 16, 30, 34, 63, 80, 87, 111-113, 123, 124, 126-136, 137, 139, 140, 145, 148, 149-150, 151, 159, 161, 163-166, 177-178, 179-181, 183-184, 185, 187, 189, 197-209 (passim), 214, 215, 223, 227, 228-231, 234, 237-238, 241, 244
apoptosis, 8, 61, 52, 71, 77-78, 83-84, 87, 134, 139, 140, 180, 189, 231, 302
checkpoint pathways, 7, 8, 16, 25, 75, 87, 127, 136-141, 152, 185, 189, 204, 208-209, 225, 227, 228, 229, 231, 233, 235, 238, 239, 241, 295, 231, 233, 235, 238, 239, 241, 295, 296, 302
Delta pathways, 66, 127, 129, 179-180, 300
epidermal growth factor, 63, 81, 179
Hedgehog pathways, 66, 115, 123, 126, 127, 129, 145, 161, 167, 184, 191, 203, 206, 213, 223, 229, 232, 235, 237, 298
illustrations of 17 currently known, 296-308
molecular-stress pathways, 7, 8, 16, 69, 136, 138-141, 180-181, 185, 189, 197, 200, 204, 208-209, 215, 225, 227, 228, 229, 231, 235, 238, 241, 299
mutations, 8, 126-136, 137, 139, 177-178, 183, 184, 185, 187
Notch pathways, 126, 127, 129, 164, 179-180, 184, 206, 300
nuclear hormone, 30, 63, 65, 66, 77, 86, 126, 127, 203, 204, 219, 223, 229, 301
receptor tyrosine kinase (RTK), 95, 102, 114, 116, 126, 129, 136, 165, 179, 185, 204, 206, 298, 299, 300
transforming growth factor, 21, 63, 102, 126, 129, 179, 184, 206, 298
WNT (Wnt) pathways, 66, 73, 74, 126, 129, 136, 141, 145, 148, 180, 184, 206, 213, 234, 297
see also Cell differentiation;
Cell proliferation;
Secretion and secretory processes;
Transcription
Signal transduction, see Transduction
Simian virus 40 (SV40), 194
Skeletal system, see Musculoskeletal system
Smoking, 21, 23, 38, 54, 63, 102, 213, 230, 233
Society of Toxicology, 205
State government
California EPA Hazard Identification Documents, 217
tracking systems, 211
Statistics
causes of defects, 20-21
chemicals in use, 24
costs of developmental defects, 17-18
developmental defects, general, 1, 10, 17, 25
in vitro testing, 30
see also Epidemiology
Stem cells, 32, 111, 172, 173-174, 283
Structure-activity relationships (SARs), 28, 29, 201, 204, 207, 209, 216, 217
Structural defects, general, 1, 7, 10, 18, 23, 34, 54, 56, 148-149, 232-233
dose-response, 39
Drosophila melanogaster, 14-15, 89-90, 93, 101, 104, 113-114, 115-127
mechanisms of toxicity, 63
principles of teratology, 61, 62
see also Musculoskeletal system;
specific defects and anatomical categories
Surveillance, see Epidemiology
Susceptibility, 48, 61-62, 101-102, 202, 222, 226, 236
biomarkers, 49, 50, 53-54, 214, 215, 281-282
dose-response, 40
environment-genotype interactions, 6, 25, 88, 175, 220, 228, 233, 234, 235
epidemiology and, 89, 99, 100-106, 215-216
toxicokinetics, species concordance, 44-45
see also Drug-metabolizing enzymes;
Sensitization
SV40, see Simian virus 40
T
TCDD (2,4,5-trichlorophenoxyacetic acid), 28, 66, 80-82, 86
Teratogen Information Service, 217
Teratology Society, 59
TGF, see Transforming growth factor
Thalidomide, 11, 23, 36, 38-39, 59, 60, 85, 87, 149
Therapeutic measures, see Treatment
Thyroid hormones, 34, 67, 107, 145
Timing and duration of exposure, 5, 8, 27, 31, 41, 46, 48, 50, 51, 61, 221
Tissue assays, 12, 28, 42, 46, 83, 94, 95, 97, 205, 207, 217-218
Tissue transplantation, 109, 146, 148, 153
Tobacco use, see Smoking
Toxicodynamics, 3, 5, 43, 45, 196, 198, 199, 203, 215, 222-229 (passim), 234-235, 237-238, 242
Toxicokinetics, 3, 5, 7, 32, 42-49, 87, 196, 197, 198, 199, 200, 203, 208, 214, 222, 226, 228, 229, 231-232, 233-234, 236-237, 239, 242
defined, 289
exposure assessment, 41-42, 214
extrapolation from animal models, 7-8, 45-46, 225
see also Drug-metabolizing enzymes;
Pharmacokinetics
TOXNET, 294
Training, see Education and training
Transcription, 6-7, 15, 66, 88, 91, 92, 94, 112, 126, 137, 151, 174, 197, 199, 223, 229-230, 298, 299, 301-308 (passim)
defined, 289
Drosophila melanogaster, 116, 117, 121
history of developmental biology, 110
molecular-stress pathways, 139
retinoids, 79
Transduction, 14, 16, 55, 71, 72-73, 84, 86-87, 126, 150, 151, 237, 294
see also Signaling pathways
Transfection, 174, 193-195, 205
Transforming growth factor (TGF), 21, 63, 102, 126, 129, 179, 184, 206, 213, 230
receptor tyrosine kinase (RTK), 95, 102, 114, 116, 126, 129, 136, 165, 179, 185, 204, 206, 230, 298, 299, 300
Transgenics, 5, 49. 92, 159-161, 163, 169-176, 178, 203, 206, 208, 237-238, 289, 240
mouse and rat models, 159, 168-176, 187-191, 208, 237-238, 244, 294
see also Knockout mutations;
Sensitization
Transplantation technologies
Treatments
animal models, 176
see also Pharmaceuticals;
specific drugs
2,4,5-Trichlorophenoxyacetic acid, see TCDD
U
Ultrasound, 60
Ultraviolet radiation, 1, 20, 139
Uterine factors, 20, 21, 34, 35, 41, 50-52, 70, 73-74, 168
V
Valproic acid, 23, 46, 48, 60, 82-83, 85-86
Viruses, 33
baculoviruses, 193
herpes, 194
simian virus 40 (SV40), 194
transduction, 14, 16, 55, 71, 72-73, 84, 86-87, 126, 150, 151, 237, 294
transfection, 174, 193-195, 205
Vitamin A, see Retinoids
W
WNT (Wnt) pathways, 66, 73, 74, 126, 129, 136, 141, 145, 148, 180, 184, 206, 213, 234, 297
Workers, see Occupational health and safety
World Wide Web, see Internet
X
Y
Yeast, 14-15, 41, 94, 92, 93, 94-97, 114, 143, 151-152, 195, 216 217, 293
Z
Zebrafish, 3-7 (passim), 33, 93, 101, 113, 125, 142, 150, 153, 154, 158, 159, 166-168, 186-187, 191, 206, 207, 216, 217, 225, 226, 230, 231, 234, 237, 239, 240, 241, 292-293
defined, 289
mutant, 113
polymorphisms, 90