Index

A

Abortion (spontaneous), early fetal/embryo loss, 7, 11, 18, 19, 23, 38, 62, 103, 185, 233

DES, 23, 73, 223

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

Androgen, 34, 66, 67, 105

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



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Scientific Frontiers in Developmental Toxicology and Risk Assessment Index A Abortion (spontaneous), early fetal/embryo loss, 7, 11, 18, 19, 23, 38, 62, 103, 185, 233 DES, 23, 73, 223 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 Androgen, 34, 66, 67, 105 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

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 toxicokinetics, 42, 44-47 valproic acid, 82 see also Knockout mutations; Mouse and rat models; Nonmammalian models; Sensitization; Transgenics Antiarrhythmic drugs, 72 Anticonvulsants, 23, 73, 80 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 Autism, 18, 84-86 B Bacteria, 114, 158, 163, 174, 176, 193, 204, 227 bacteriophages, 110, 151, 210 genomics, 93, 143 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 Biomarkers, 49-54, 202, 242 carcinogenesis, 51-52, 215 databases, 214-215 defined, 49-50, 53, 214, 281-282 dose and, 50, 214, 215 effect, 49, 51, 52, 53, 214, 215, 281 birth weight, 1, 18, 34, 40, 52, 74 exposure, 42, 49, 50-52, 53, 214, 281 functional deficits, 51, 214 gene expression and regulation, 51, 52, 214 placental, 52, 53 smoking, 51, 52, 53 susceptibility, 49, 50, 53-54, 214, 215, 281-282 see also Drug-metabolizing enzymes Biotechnology, see Genetic engineering Bipolar disorder, lithium, 23 Birth weight, 1, 18, 34, 52 dose-response, 40 methotrexate, 74 Brain, 130, 133, 135, 145-146 alternatives to testing pregnant mammals, 33 autism, 85 mental defects, 1, 18, 19, 23 methylmercury, 74-75 neural tube defects, 19, 23, 48, 52, 62-63, 82, 84, 144 retinoids, 76, 79 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 biomarkers, 51-52, 215 DES, 73

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Scientific Frontiers in Developmental Toxicology and Risk Assessment methotrexate, 74 ovarian cancer, 32, 33 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 organogenesis, 144, 146 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 retinoids, 76, 79 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 cystic fibrosis, 106, 153 fibroblasts, 145, 176, 185, 193 Convulsions, see Anticonvulsants Cost factors, see Economic factors

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Coumarin derivatives, 23, 105 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 Cystic fibrosis, 106, 153 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 polymorphism, 90-91, 291 retinoids, 78-79 transfection, 174, 193-195, 205 transposons, 115, 157, 163 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 biomarkers, 50, 214, 215 birth weight, 40 databases, 201, 214 maximum tolerated dose, 36, 45 peak threshold concentration (Cmax), 46, 48, 49 reference dose, 39, 40, 41, 54, 55, 287 regulatory issues, 40, 45, 54 toxicokinetics, 40-41, 45, 46 wild-type, 115 see also Exposure DPH, see Diphenylhydantoin

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 oocytes, 115, 116, 119, 120 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 DES, 23, 73, 223 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 retinoids, 75-76, 79-80 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 number of, 11, 21-22, 36, 238 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

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 race/ethnicity, 213, 233 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 Epistasis, 113, 155, 163, 283 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 Exons, 194, 217, 284 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 DES, 23, 73, 223 diphenylhydantoin, 73-74 fetal alcohol syndrome, 20, 22, 41, 60, 103, 233 protein function, 69-70 Fibroblasts, 145, 176, 185, 193 Food additives, 20, 22, 26 Food and Drug Administration (FDA), 26, 34, 59 Food Quality Protection Act, 40 Forward genetics, 154-156, 161, 284 Free radicals, 69, 139 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 biomarkers, 51, 214 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 biomarkers, 51, 52, 214 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

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Scientific Frontiers in Developmental Toxicology and Risk Assessment proteomics, 15, 92-93, 97-98, 114, 291, 293, 294 retinoids, 79, 86 TCCD, 81-82, 86 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 bacterial, 93, 143 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 defined, 92, 284 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

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 DES, 23, 73 developmental biology, 16, 108-111, 113-114, 115, 120-121, 123, 145-146 developmental toxicology, 11, 58-60, 62, 86, 220 epidemiology, 11, 37 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 teratology, 11, 58-63 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 defined, 156, 284 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

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 hormone-dependent, 30, 77 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 Mendelian rules, 21, 291 Mental defects, 1, 18, 19, 23 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 2-Methoxyacetic acid, 47, 48 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 DES, 23, 73, 223 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 Hox genes, 121, 123, 141 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 ovarian tumors, 32, 33 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 retinoids, 78, 79, 80 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

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Scientific Frontiers in Developmental Toxicology and Risk Assessment forward genetics, 154-156, 161, 284 genomics, 92, 218 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 autism, 18, 84-86 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 retinoids, 76, 79 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 Hox genes, 116-117, 120-123 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

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 retinoids, 79, 87 Ovarian cancer, 32, 33 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 Pesticides, 20, 26, 40 Pharmaceuticals, general, 20, 24, 31, 36, 204 cohort studies, 38 dose-response, 41 public opinion, 59 toxicokinetics, 44, 46 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 biomarkers, 52, 53 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 DNA, 90-91, 291 mouse and rat models, 4, 7, 104, 106, 225, 234 proteins, 8, 90-91 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 biomarkers, 50, 52 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 biomarkers, 51, 52, 53 timing and duration of exposure, 5, 8, 27, 31, 41, 46, 48, 50, 51 toxicokinetics, 42, 44-48 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 fetoproteins, 50, 52 methylmercury, 74 polymorphisms, 8, 90-91 translation, 88 see also Drug-metabolizing enzymes; Transforming growth factor Proteomics, 15, 92-93, 97-98, 114, 291, 293, 294 Puffer fish, 153 Pupae, 161, 182, 183, 185, 191

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Q Qualitative risk assessment, 2, 5, 11, 34, 44, 56, 151, 176, 195, 196, 224-226, 229, 238-239 R Race/ethnicity, 213, 233 Radiation, 1, 20, 60, 69, 187 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 in vitro models, 30, 32, 34 mechanisms of toxicity, 65-68 molecular-stress pathways, 139 retinoids, 76, 77-78, 86, 223 TCCD, 80-82, 86 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 Regulatory issues, 10, 26, 30 acceptable daily intake, 26, 40, 41, 55, 281 animal studies, 34, 45, 54 dose, 40, 45, 54 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 ovarian cancer, 32, 33 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 defined, 26-27, 288 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

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 toxicokinetics and, 44, 49 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 biomarkers, 51, 52, 53 Society of Toxicology, 205 Spemann organizer, 141, 288 Spina bifida, 18, 134 State government California EPA Hazard Identification Documents, 217 tracking systems, 211

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 Sulfhydryl groups, 69, 74 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 dose-response, 40-41, 45 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 exons, 194, 217, 284 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 viruses, 106, 169 see also Knockout mutations; Sensitization Transplantation technologies cell, 109. 111 tissue, 109, 146, 148, 153 Transposons, 115, 157, 163 Treatments animal models, 176 see also Pharmaceuticals; specific drugs 2,4,5-Trichlorophenoxyacetic acid, see TCDD

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Scientific Frontiers in Developmental Toxicology and Risk Assessment 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 bacteriophages, 110, 151, 210 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 transgenic, 106, 169 Vitamin A, see Retinoids W Wild types, 115, 289 Wilson, J. G., 60-63, 110 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 X-rays, 1, 20 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 Zygotes, 62, 103, 111, 171 defined, 289 mutant, 113 polymorphisms, 90