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~ ndex A AADI (adjusted acceptable daily intake), 171 2-AAF (2-acetylaminofluorene), 145 Abbreviations, definitions of, 218-219 Abortions, spontaneous, see Spontaneous abortions Absorption, systemic, 257 Absorption process in GI tract, 210-211 Acceptable daily intake (ADI), 171, 254, 257, 296, 410-411 aldicarb, 309 di(2-ethylhexyl) phthalate, 358, 410 nitrofen, 379 trichlorfon, 408 Acetaldehyde, 50 2-Acetylaminofluorene (2-AAF), 145 Acetylcholinesterase, 306 ACGIH (American Conference of Governmental Industrial Hygienists), 105 Acrylamide, 118, 297-303 ADI, 410 carcinogenic risk estimate, 301-302, 410 443 carcinogenicity, 300 developmental effects, 302 health aspects in humans, 298-299 health aspects in other species, 299- 302 lifetime cancer risk estimate, 410 metabolism, 298 mutagenicity, 300 SNARL, 410 studies needed, 409 tumor incidence, 301 Action potential, 111 A:D ratio (ratio of adult to developmental toxicity), 28, 273 Additive risk, 242 ADI, see Acceptable daily intake Adjusted acceptable daily intake (AADI), 171 Administered dose, 261, 262 Adult to developmental toxicity, ratio of (A:D ratio), 28, 273 Afferent nerve fibers, 107 Aflatoxin Be, 76 AFP (cx-fetoprotein), 47

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444 Index Aged nervous system, 124-125, 126- 127 Agonists, 121 AHH (aryl hydrocarbon hydroxylase), 318 Air exposure through, 260 PCP concentrations in, 384 Aldicarb, 303-309 ADI, 309, 410 carcinogenic risk estimate, 410 carcinogenicity, 305 developmental effects, 305 health aspects in humans, 303-304 health aspects in other species, 304- 305 mutagenicity, 305 SNARL, 410 studies needed, 409 Allometric relationships, 193- 194 Alveolar macrophages, 207 Alveolar sacs, 205 Alveolar Type I cells, 205-206 Alveolar Type II cells, 205, 206, 207 Alzheimer senile dementia, 126 AMEFF (effective concentration of metabolite), 188, 189 American Conference of Governmental Industrial Hygienists (ACGIH), 105 Androgen-binding protein, 56 Androgens, 46-48 Anesthetic gases, 72 Aneuploidy, 142-143 Animal data, 36 bioassays, 5, 151-152 concordance of results from human studies and, 20-22 dose-response patterns in, 15-18 extrapolation of, to humans, 18-22 health aspects in, see Health aspects . . In ot. her species interpretation of, 22-28 interspecies extrapolation, 133, 177, 193-201, 264-266 intraspecies extrapolation, 264-266 male reproductive toxicity in, 57-59 mouse liver model, 145-147 mouse skin model, 143-145 neurotoxicity in, 131- 133 PCP in, 384 quality and quantity of, 22-25 rat liver model, 145-147 rat physiological constants, 169 rat pup, vaginal opening time in, 88- 89 rat sperm production rates, 89-90 using, to predict human risk, 143- 148, 254-255 Antabuse (disulf~am), 364 Antagonists, 121 Antineoplastic agents, 3, 44-45 Area under the rate-of-metabolism curve (AURMC), 175 Area under the target-tissue metabolite- concentration curve (AUTMC), 176 Area under the tissue-concentration curve (AUTC), 174-175 Arsenic poisoning, 230 Arterial blood concentration, 183 Aryl hydrocarbon hydroxylase (AHH), 318 Astrocytes, 111-112 Attributable risk, 241-242 AURMC (area under the rate-of- metabolism curve), 175 AUTC (area under the tissue- concentration curve), 174- 175 AUTMC (area under the target-tissue metabolite-concentration curve), 176 Axons, 107, 110, 111 degeneration of, 122 B B(a)P [benzo(a)pyrene], 149 Barbiturates, 49 Behavioral teratogens, 106 Behavioral toxicology, 131 Benzene (BEN), 186, 188, 190-193 airborne, 209 ,B-Benzene hexachloride, 230, 232 BHT (butylated hydroxytoluene), 148, 207 Biases, 238 Biographies, committee, 439-442 Biological action, mechanisms of, 240- 241 Biological toxins, 129 Biologically effective dose, 228 Blastocyst formation, 13 Brain, 108

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Index 445 Brainstem, 108 Bronchiolar cells, 207 Buccal cavity, 211 Butylated hydroxytoluene (BHT), 148, 207 C Cadmium chloride, 74 Cancer, radiation and, 238 Cancer risk estimates, lifetime, 410-411 Captan, 75 Carbamate pesticides, 303-314; see also Aldicarb; Diallate; Sulfallate Carbaryl, 74 Carbon dioxide, elevated, 75 Carbon disulfide, 72, 76 Carbon tetrachloride, 76, 206, 207, 208 Carcinogenesis, 4-6, 266-271, 282 animal bioassays, 151- 152 cocarcinogenesis, 141-142 effects, 253 evaluation, 151-156 genetic toxicity, 148-149 immune system in, 149-151 initiation, 140 mechanisms of, 139-157 model systems, 143-148 multistage theory of, 139- 142, 147 oncogenes in, 142-143 progression, 141 promotion, 140 risk assessment for, 156-157, 253 short-term tests, 152-155 teratogenesis and, 15 unit risk of, 255 Carcinogenic risk estimates, 301-302, 313, 314, 324, 336, 337, 348-349, 372, 373, 410-411 Carcinogenicity, 1 acrylamide, 300 chloropropanes and chloropropenes, 335-336 conclusions and recommendations, 282-284 diallate, 311 dibromochloropropane, 323-324 di(2-ethylhexyl) phthalate, 344-348, 410 ethylene dibromide, 365-367 nitrofen, 371-372 pentachlorophenol, 391-392 sulfallate, 313 trichlorfon, 405-406 Case-comparison studies, 232-233 "nested," 233 Catechol, 144 Catecholamines, 48 Cells culture, short-term, 5-6 divisions in germ cells, 78 mutation, 140 transformation assays, 153 Central nervous system (CNS), 108 Central-peripheral distal axonopathy, 122 Cerebral cortex, 108-109, 125 Cerebral hemispheres, 108, 110 Cerebrospinal fluid (CSF), 112 Chemical carcinogens, 261 Chemical contaminants, developmental effects of, 11-31 Childhood tumors, 14 Chloramphenicol, 17 Chlordecone, 74 Chloroform, 208-209 Chloroprene, 72, 77 Chloropropanes and chloropropenes (CPs), 326-337 ADI, 410 carcinogenic risk estimate, 336, 337, 410 carcinogenicity, 335-336 developmental effects, 337 health aspects in humans, 328 health aspects in other species, 328- 337 lifetime cancer risk estimate, 410 metabolism, 327 mutagenicity, 334-335 neurotoxicity, 334 reproductive effects, 337 SNARL, 410 studies needed, 409 tumor incidence, 336 Cholinergic system, 121 Cholinesterase erythrocyte, 306-308 serum, 306 trichlorfon and, 40-2 Chromosomes, 38 aberrations, 65

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446 Index abnormalities, 35 damage, 3 macrolesions in germ cells, 69 sperm complement, 64-66 Cigarette smoke condensate (CSC), 144 Cigarette smoking, 44, 72, 148, 155, 238 Clara cells, 205, 206 Clearance intrinsic, 216-217 liver, 216 organ-specific, 210 total, 209 Cleft palate, 26 Clinical observations, 226-227 CNS (central nervous system), 108 Cocarcinogenesis, 141-142 Cohort studies, 233 Colchicine, 116 Colon, 212 Committee biographies, 439-442 Concentration, effective, of metabolite (AMEFF), 188, 189 Confidence limits, 237 Contaminants, selected, toxicity of, 294-412 Contraceptives, oral, 72 Corpus luteum, 45 Cortical atrophy, 124- 125 CPs, see Chloropropanes and chloropropenes CSC (cigarette smoke condensate), 144 CSF (cerebrospinal fluid), 112 Cyclosiloxanes, 76 Cytochrome P450, 214, 215 Cytotoxic agents, 16-17 Cytotoxicity, 153 D Data-based inhalation models, 178- 179 DBCP, see Dibromochloropropane 1,2-pop (1,2-dichloropropane, see Chloropropanes and chloropropenes DDE (dichlorodiphenyldichloroethylene), 230, 231 DDT (dichlorodiphenyltrichloroethane), 75, 230, 231, 282, 283 DDVP (dichlorvos), 75 Death embryo, 25 postimplantation, 87 preimplantation, 87 rates, embryonic, 35 see also Lethality; Mortality Definitions of symbols and abbreviations, 218-219 Degeneration of axons, 122 of germ cells, 38 DEHA [di(2-ethylhexyl) adipate], 346 DEHP, see Di(2-ethylhexyl) phthalate Demyelination, 112 DEN (diethylnitrosamine), 145, 146 DES (diethylstilbestrol), 15, 47, 48, 149, 282, 283 Developmental effects acrylamide, 302 chemical contaminants, 11-31 dibromochloropropane, 324 di(2-ethylhexyl) phthalate, 349-352 nitrofen, 373-376 pentachlorophenol, 392 trichlorfon, 406 Developmental risk estimate, nitrofen, 376-380 Developmental toxicity, 2, 271-272 conclusions and recommendations, 284-286 defined, 11-12 PCP and, 393-394 quantitative assessment of, 28-30 ratio of adult to (A:D ratio), 28, 273 relationship between maternal toxicity and, 25-27 Diallate ADI, 410 carcinogenic risk estimate, 410 carcinogenicity, 311 developmental effects, 312 health aspects in humans, 310 health aspects in other species, 310- 311 metabolism, 310 mutagenicity, 311 neurotoxicity, 311 SNARL, 410 studies needed, 409 tumor incidence, 311 Dibromochloropropane (DBCP), 72, 74, 314-326 ADI, 410

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Index 447 carcinogenic risk estimate, 324, 410 carcinogenicity, 323-324 developmental effects, 324 epidemiological studies of, 243 health aspects in humans, 315-316 health aspects in other species, 316- 325 lifetime cancer risk estimate, 410 LOEL, 320, 325 mutagenicity, 322-323 NOEL, 320, 325 reproductive effects, 324-325 SNARL, 410 spermatogenesis and, 315-316 studies needed, 409 tumor incidence, 324 Dibutyl phthalate, 76, 77 Dichlorodiphenyldichloroethylene (DDE), 230, 231 Dichlorodiphenyltrichloroethane (DDT), 75, 230, 231, 282, 283 1,2-Dichloropropane (1,2-DCP), see Chloropropanes and chloropropenes 1,3-Dichloropropene, see Chloropropanes and chloropropenes Diencephalon, 108, 113 Diethyl adipate, 76 Di(2-ethylhexyl) adipate (DEHA), 346 Di(2-ethylhexyl) phthalate (DEHP), 338-359 ADI, 358, 410 carcinogenic risk estimate, 348-349, 410 carcinogenicity, 344-348 developmental effects, 349-352 health aspects in humans, 340 health aspects in other species, 340- 356 lifetime cancer risk estimate, 410 liver function and, 357 LOEL, 357-358 metabolism, 339-340 mutagenicity, 341-344 NOEL, 357-358 peroxisome proliferation and, 344- 346 reproductive effects, 352-356 SNARL, 410 studies needed, 409 tumor incidence, 349 Diethylnitrosamine (DEN), 145, 146 Diethylstilbestrol (DES), 15, 47, 48, 149, 282, 283 Diffusion-limited models, 181 Dimethylnitrosamine, 65 Dinitrotoluene (DNT), 154-155 Diquat, 75 Diseases, neurological, see Neurological diseases Disulfiram (Antabuse), 364 DNA, 139, 148-149, 282, 283, 361- 362 DNT (dinitrotoluene), 154-155 Dominant lethal test, 73, 78-79 Dose administered, 261, 262 biologically effective, 228 choice of, 268 effective, 261 equivalence, 177 internal, 173, 228 maximum tolerated (MTD), 152 rate of inhalation, 169 target-tissue, see Target-tissue dose teratogenic, 29 tissue, scale-up, 194-196 Dose response, 284 in animal studies, 15-18 log-probit, 29, 273-274 model, multistage, 268-269 relationships, 280 VOCs, 172-173 Dose-route extrapolations, 6-7, 168- 219 examples of, 186-193 E EDB, see Ethylene dibromide Effective concentration of metabolite (AMEFF), 188, 189 Efferent nerve fibers, 107 2-EM, 338; see also Di(2-ethylhexyl) phthalate Elimination, presystemic, 212-214 Embryonic organ susceptibility to teratogens, 13, 14, 116 Embryos death, 24-25 lethality, 11, 24 preimplantation, 12 toxicity, 11, 25, 88

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448 Index see also Developmental toxicity; Fetus End points, 11, 153 historical variability, 24-25 spectrum of, 18-20 Endocrinology, reproductive, alterations in, 45-50 CNS-mediated, in adult, 48-50 in perinatal period, 46-48 ENU (ethylnitrosourea), 14- 15, 270 Enzyme activity, 264-265 Epidemiological observations, 228-234 of human neurobehavioral disorders, 130-131 risk assessment, 7, 241-245 Epidemiology analytical, 230-232 beginning of, 229 descriptive, 229-230 principals, problems, and limitations of, 243 Epididymal sperm numbers, 90 Epigenetic, term, 282 Epigenetic carcinogens, 153 Ely~rocyte cholinesterase, 306-308 Esophagus, 211 Estrogens, 46-48 Estrous syndrome, persistent, 46 Ethanol, 50 Ethoxyethanol, 77 Ethylene dibromide (EDB), 237, 359- 368 ADI, 411 carcinogenic risk estimate, 411 carcinogenicity, 365-367 epidemiological studies on, 244 health aspects in humans, 359-360 health aspects in other species, 360- 367 lifetime cancer risk estimate, 411 mutagenicity, 364-365 reproductive effects, 367 SNARL, 411 studies needed, 409 Ethylene oxide, 77 2-Ethylhexanol, 338; see also Di(2- ethylhexyl) phthalate Ethylnitrosourea (ENU), 14- 15, 270 Excitotoxicants, 113 Exencephaly, 26 Exhalation, pulmonary, 172 Experimental studies, 233-234 Exposure, 228 through air, 260 assessment of, 230 combined, 255-256 estimates of, from different sources and various routes, 257-260 through food, 259 through household, 260 noningestion, 295 timeof,12-15,35 through water, 258-259 through workplace, 260 Extraction ratio, 216 Extrapyramidal pathways, 109 F 2F bodies test, 61, 64 Fabro index, 274 FACE, see Fertility Assessment by Continuous Breeding False-positive or false-negative result, 235 Females fetus, 37 germ cell mutations, 69-82 infertility, 50-53 reproductive impairment, 37-53 reproductive system, 37-41 see also Humans Fertility index, 73, 84 reduced, 37 reproductive performance and, 87-88 subfertility and, 63 Fertility Assessment by Continuous Breeding (FACB), 51-52 details of protocol for, 85-87 Fertilization, 40 a-Fetoprotein (AFP), 47 Fetus, 23-24, 37, 116-117; see also Embryos FHPLs (focal hepatocellular proliferative lesions), 346-347 Fluoridation, 233 Focal hepatocellular proliferative lesions (FHPLs), 346-347 Follicle growth, 41-42 Follicle-stimulating hQrmone (FSH), 40, 45, 54, 55-56 Folliculogenesis, 40

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Index 449 Food additives and contaminants, 76 exposure through, 259 PCP in, 384 Frontal lobe, 109 FSH (follicle-stimulating hormone), 40, 45, 54, 55-56 Fungicides, 75 G Gastric emptying time, 211 Gastrointestinal (GI) mucosa, metabolism by, 213-214 Gastrointestinal tract, 171 - 172, 210- 214 absorption process, 210-211 anatomical regions of, 211-212 Genetic toxicity, 148-149, 155, 282- 283 Germ cells cell divisions in, 78 chromosome macrolesions in, 69 degeneration of, 38 mutagenesis, 3, 155-156 mutagens, 65-66 mutations, 69-82 primordial, 37 Gestation index, 84 Gestation length, 13 GI, see Gastrointestinal entries Glial cells, 111 Glucocorticoids, 15 Glutamic acid, 76 Glutathione (GSH), 317-319 GnRH, see Gonadotropin-releasing hormone Goblet cells, 205 Gonadotropin-releasing hormone (GnRH), 45, 48-50 Gonadotropins, 40-42, 55 Gonads biotransformation, 65 indifferent, 37 sex differentiation, 38 Growth index, 84 Growth retardation, 15-18 intrauterine, 23 measured, 11 GSH (glutathione), 317-319 Gut lumen, metabolism within, 213 H Hair dyes, 77 Hansch-Taft relationship, 156 Health aspects in humans acrylamide, 298-299 aldicarb, 303-304 chloropropanes and chloropropenes, 328 dibromochloropropane, 315-316 di(2-ethylhexyl) phthalate, 340 ethylene dibromide, 359-360 pentachlorophenol, 387-388 trichlorfon, 398-400 Health aspects in other species acrylamide, 299-303 aldicarb, 304-305 chloropropanes and chloropropenes, 328-334 diallate, 310-311 dibromochloropropane, 316-322 di(2-ethylhexyl) phthalate, 340-341 ethylene dibromide, 360-364 nitrofen, 370 pentachlorophenol, 388-390 sulfallate, 312-313 trichlorfon, 400-403 Hemispheres, cerebral, 108, 110 Hepatic elimination, 172 f~rst-pass, 204 Herbicides, 75; see also Diallate; Sulfallate; Nitrofen Heritable mutations, 71 Heritable translocations, 66, 79-81 Heroin, 49 Histological evaluation of testis, 91-92 Human nervous system, 107- 131 cellular structure and function, 110- 113 epidemiological studies, 130- 131 gross structure and function, 107- 110 neurotoxic responses after birth and at maturity, 118- 123 normal developmental structure and function, 113- 115 studies in, 127- 131 susceptibilities of special populations 124-127 Humans adverse pregnancy outcomes in, 19- 20

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450 Index clinical observations and case reports, 226-227 concordance of results from animals and, 20-22 data on, 226-245 epidemiological observations, 228- 234 extrapolation of animal data to, 18-22 health aspects in, see Health aspects in humans Interspecies extrapolation, 133, 177, 193-201, 264-266 intraspecies extrapolation, 264-266 male reproductive toxicity in, 59-68 multiple stages in tumor promotion, 148 PCP and, 384-385 physiological constants, 169 risk to, using animal data to predict, 254-255 see also Females; Males Hydrocarbons, 72 Hypothalamic maturation, 47 Hypothalamus, 108 Immortalizing genes, 142 Immune system, 5, 149- 151 Immunosurveillance, 150 Immunotoxicity, pentachlorophenol, 390-391 Infant mortality, 36 Inference and quantification, 239-240 Infertility, 35, 36, 88 female, 50-53 male, 59 Inhalation studies, 168-170 background, 170-176 data-based, 178-179 dose-rate, 169 models, 178-180, 182-183 pharmacokinetic models, see Pharmacokinetic models toxicity, 6 Inheritance, polygenic, 71 Inhibin, 56 Intercompartmental transfer rate constants, 179 Interspecies extrapolation, 133, 177, 193-201, 264-266 Interspecies PB-PK model simulations. 197-200 Intervention studies, 233-234 Intestinal lumen, metabolism within, 213 Intestine, small, 212 Intraspecies extrapolation, 264-266 Intrauterine growth retardation, 23 Intrinsic clearance, 216-217 Ionizing radiation, see Radiation effect K Kepone, 72 Kinetic modeling, physiological constants in, 169 L Lead, 72 Lead-cadmium interaction, 74 Lethality, 15-18 embryo, 11 teratogenicity and, 29 see also Death; Mortality Leydig cells, 54, 55 LH (Luteinizing hormone), 40, 45, 55 Lifetime cancer risk estimates, 410-411 acrylamide, 410 chloropropanes and chloropropenes, 410 dibromochloropropane, 410 di(2-ethylhexyl) phthalate, 410 nitrofen, 411 sulfallate, 410 Limbic system, 109, 113 Lipid membranes, perturbation of, 386 Lipofuscin, 125 Liver clearance, 216 function, di(2-ethylhexyl) phthalate and, 357 metabolism in, 215-217 Lowest-observed-effect level (LOEL), 2, 10, 27-28, 53, 82, 272, 277-279, 285, 286-287 dibromochloropropane, 320-321, 325 di(2-ethylhexyl) phthalate, 357-358 nitrofen, 378-379 pentachlorophenol,^ 393-395 Lung, elimination of compounds by, 208-210

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Index 451 Lung cells, 205-206 metabolic properties of, 206-207 Luteinizing hormone (LH), 40, 45, 55 M Macrolesions, 69-70 Macrophages, 150 alveolar, 207 Malathion, 75 Males germ cell mutations, 69-82 infertility, 59 reproductive dysfunction, 71, 72, 74- 77 reproductive impairment, 53-68 reproductive system, 53-55 reproductive toxicity, 55-68 see also Humans Malformations, 15-18 major, 23-24, 35 maternal toxicity and, 26 minor, 24 Malnutrition, 119 MAM (methylazoxymethanol), 117 Marijuana, 49 Mass-balance equations, 176, 180 Maternal toxicity embryonic toxicity and, 88 malformations and, 25-26 relationship between developmental toxicity and, 25-27 Mathematical functions and model, 280- 281 Mating index, 73 Maximum likelihood estimates (MLEs), 256 Maximum tolerated dose (MTD), 152 MBK (methyl n-butyl ketone), 130 MEHP [mono(2-ethylhexyl) phthalate], 338; see also Di(2-ethylhexyl) phthalate Meiosis, 38-40 arrest of, 38 initiation of, 38 Men, see Males Menopause, 42 Menstrual cycle, 40, 41 Mercuric chloride, 74 Metabolic changes, time-dependent, 200-201 Metabolism acrylamide, 298 chloropropanes and chloropropenes, 327 di(2-ethylhexyl) phthalate, 339-340 nitrofen, 369 pentachlorophenol, 385-387 trichlorfon, 395, 397 Metabolite, reactive, see Reactive metabolite Metastasis, 142 Methadone, 68 Methoxyethanol, 77 Methyl n-butyl ketone (MBK), 130 Methyl methane sulfonate (MMS), 149 Methylazoxymethanol (MAM), 117 Methylmercury hydroxide, 74 Methylphenyltetrahydropyridine (MPTP), 112 Microlesions, 70 Microsomal detoxification, disturbance of, 386 Microwaves, 72 MLEs (maximum likelihood estimates), 256 MMS (methyl methane sulfonate), 149 Mono-n-butyl phthalate, 77 Monocytes, 150 Mono(2-ethylhexyl) phthalate (MEPH), 338, 411; see also Di(2-ethylhexyl) phthalate Monosodium glutamate, 76 Monosomies, 70 Moolgavkar-Knudson model, 9 Morphine, 49 Mortality infant, 36 M ratio, standard (SMR), 241 see also Death; Lethality Motor area, 109 Motor nerve fibers, 107 MPTP (methylphenyltetrahydropyridine), 112 MRFIT (Multiple Risk Factor Intervention Trial) studies, 233 MTD (maximum tolerated dose), 152 Mucosal cells, 213 Multigeneration studies, 51-53 details of protocol for, 83-85 Multiple Risk Factor Intervention Trial (MRFIT) studies, 233

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452 Index Multistage dose-response model, 268- 269 Multistage theory of carcinogenesis, 139-142, 147 Mutagenesis, germ cell, 3, 65-66, 155- 156 Mutagenicity, 3, 253 acrylamide, 300 aldicarb, 305 chloropropanes and chloropropenes, 334-335 diallate, 311 dibromochloropropane, 322-323 di(2-ethylhexyl) phthalate, 341-344 ethylene dibromide, 364-365 pentachlorophenol, 391 sulfallate, 312-313 trichlorfon, 403-405 Mutations cellular, 140 heritable, 71 point, 81 recessive, 71 replication-dependent, 78 somatic cell, 283 myc-type oncogenes, 142 Myelination, 112 Myopathies, 123 N National Health and Nutrition Examination Survey, Second (NHANES II), 230 Neoplasms, 150 Nerve conduction, 111 Nervous system, 105-134 in aged, 124-125, 126-127 central (CNS), 108 diseases and, 125-127 human, see Human nervous system peripheral (PNS), 107 "Nested" case-comparison studies, 233 Neuroactive agents, 106 Neurobehavioral changes, 105 Neurological diseases, 125- 130 Neurons, 107, 110- 111 cerebral cortical, 125 sympathetic, 115 Neuroteratology, 106, 115-118 Neurotoxicity, 3-4, 105- 134 in animal data, 131-133 chloropropanes and chloropropenes, 334 chronic, 277 common clinical manifestations of human, 128 conclusions and recommendations, 286-287 diallate, 311 effects of, 105-134 pentachlorophenol, 391 responses, 106-107, 118-123 risk assessment of, 133-134, 276- 281 trichlorfon, 403 NHANES II (Second National Health and Nutrition Examination Survey), 230 Nickel sulfate, 74 Nitrofen, 368-382 ADI, 379, 410-411 carcinogenic risk estimate, 372, 373, 410-411 carcinogenicity, 371-372 developmental effects, 373-376 developmental risk estimate, 376-380 health aspects in humans, 369 health aspects in other species, 370 LOEL, 378-379 metabolism, 369 NOEL, 376-379, 381, 382 reproductive effects, 381 SNARL, 410-411 studies needed, 412 tumor incidence, 372 Nitrofuran compounds, 76 Nitrous oxide, 77 No-observed-effect level (NOEL), 2, 10, 22, 27-28, 53, 257, 266-267, 272-273, 277-279, 285, 286, 296 dibromochloropropane, 320-321, 325 di(2-ethylhexyl) phthalate, 357-358 nitrofen, 376-379, 381, 382 pentachlorophenol, 393-396 Noncarcinogenic effects, 253 Nongenetic carcinogens, 153 Nongenotoxic, term, 282 Noningestion exposure, 295 Nutritional status, 117

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Index 453 o Oligodendrocytes, 112 Oncogenes, 5, 142-143 Oocytes, 37 destruction, 41, 89 maturation, 38, 39 preovulatory, 43 primary, 37-38, 40 radiosensitivity, 42-43 secondary, 38, 40 toxicity, 41-42 Oogenesis completion of, 38 radiation effects on, 42-43 xenobiotic compounds and, 43-45 Oogonia, 37-40 Opioid peptides, 48 Oral contraceptives, 72 Oral model, 183-186 Organ-specific clearance, 210 Organogenesis, 13 Ovarian failure, premature, 42 Ovarian life span, 42 Ovary, 41 radiation effect on, 43 Ovulation, 41 Oxidative phosphorylation, uncoupling of, 386 Oxidative reactions, 213 Oxygen tension, high, 75 p PAHs (polycyclic aromatic hydrocarbons), 43-44 Papillomas, 144-145 Paraquat, 75, 206 Parasympathetic system, 115 PBBs (polybrominated biphenyls), 319 PB-PK, see Pharmacokinetic models PCBs (polychlorinated biphenyls), 21 PCP, see Pentachlorophenol Pentachlorophenol (PCP), 382-396 ADI, 411 in air, 384 in animals, 384 carcinogenic risk estimate, 411 carcinogenicity, 391-392 developmental effects, 392 developmental toxicity and, 393-396 epidemiological studies on, 244 in food, 384 health aspects in humans, 384-385, 387-388 health aspects in other species, 388- 390 immunotoxicity, 390-391 LOEL, 394-395 metabolism, 385-387 mutagenicity, 391 neurotoxicity, 391 NOEL, 394-395, 396 in sediment, 384 SNARL, 396, 411 in soil, 384 studies needed, 412 in water, 384 Perinatal period, 14 endocrine alterations in, 46-48 Peripheral nervous system (PNS), 107 Permeability barriers, 112 Persistent estrous syndrome, 46 Pesticides, 106, 129 carbamate, 303-314 reproductive effects in males, 74-75 see also Aldicarb, Diallate; Dibromochloropropane; 1,2-Dichloropropane; 1,3-Dichloropropene; Ethylene dibromide; Nitrofen; Pentachlorophenol; Sulfallate; Trichlorfon Pharmacokinetic models (PB-PK), 176- 186 data-based inhalation models, 178- 179 extending, to accommodate reality, 202-204 interspecies model simulations, 197- 200 physiologically based models, 180- 186 in risk assessment, 201-204 Pharmacokinetic parameters, 65 Pharmacokinetics, 9-10, 65, 177, 260- 264 Phencyclidine hydrochloride, 49-50 Phenobarbital, 145, 147 Phorbol myristate acetate (PMA), 143, 144, 145 Phosphorylation, oxidative, uncoupling of, 386

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454 Index Phthalate esters, 77 Physiological changes, time-dependent, 200-201 Physiological constants in kinetic modeling, 169 Physiologically based models, 180- 186 Pituitary gland, 113 PMA (phorbol myristate acetate), 143, 144, 145 Pneumocytes, Type II, 207 PNS (peripheral nervous system), 107 Point mutations, 81 Polybrominated biphenyls (PBBs), 319 Polychlorinated biphenyls (PCBs), 21 Polycyclic aromatic hydrocarbons (PAHs), 43-44 Polygenic inheritance, 71 Population, study and control, 234, 240 Postimplantation death, 87 Pregnancy, adverse outcomes in humans, 19-20 Preimplantation death, 87 Preimplantation embryo, 12 Preovulatory oocytes, 43 Prespermatogonial cells, 53-54 Presystemic elimination, 212-214 Primordial germ cells, 37 Primordial oocyte destruction, 89 Prolactin, 55 Promoters, 5, 140-141 Prostate function, 68 Psychoteratology, 115-118 Pulmonary exhalation, 172 Pulmonary structure and cell types, 205- 206 Pyramidal tracts, 109 Q QRA, see Quantitative risk assessment Qualitative risk assessments, 7, 8 Quantification and inference, 239-240 Quantitative risk assessment (QRA), 7, 8, 9, 28-30, 251-252, 267-268, 273-275, 279-281 R Radiation effect, 72, 76 cancer and, 238 on oogenesis, 42-43 on ovaries, 43 on spermatogenesis, 56-57 rag-type oncogenes, 142 Rate-of-metabolism curve, area under the (AURMC), 175 Reactive metabolite, 175 short-lived, 196-197, 204 Recall bias, 238 Receptor binding constant, 174 Recessive mutation, 71 Reductive enzymes, 213 Relative risk, 241 Relative teratogenic index (RTI), 29, 274 Reliability of risk estimation, 256 Replication-dependent mutations, 78 Reproductive dysfunction defined, 35 male, 71, 72, 74-77 Reproductive effects chloropropanes and chloropropenes, 337 dibromochloropropane, 324-325 di(2-ethylhexyl) phthalate, 352-356 ethylene dibromide, 367 nitrofen, 381 trichlorfon, 406-407 Reproductive endocrinology, see Endocrinology, reproductive, alterations in Reproductive impairment female, 37-53 male, 53-68 Reproductive performance, 86-88 Reproductive system female, 37-41 male, 53-55 Reproductive toxicity, 2-3, 35-92, 271-272 conclusions and recommendations, 284-286 male, 57-68 Reproductive toxicity testing, 50-51 details of protocols for, 83-92 Reproductive toxicology, risk assessment in, 82 Respiratory tract, 205-210 pulmonary structure and cell types, 205-206 Response bias, 238 Rhabdomyolysis, 123

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Index 455 Ribs, supernumerary, 26-27 Risk additive, 242 attributable, 241-242 computation of, 295-296 defining term, 31 relative, 241 unit, 255 Risk assessment, 1-2, 28-31, 250-287 for carcinogenesis, 156-157, 284 epidemiological studies, 7, 241-245 framework for, 7-9 neurotoxicants, 133-134 neurotoxicity, 276-281 PB-PK models in, 201-204 pharmacokinetic, 177 qualitative, 7, 8 quantitative, see Quantitative risk assessment reliability of, 256 in reproductive toxicology, 82 see also individual compounds Risk estimate(s) carcinogenic, see Carcinogenic risk estimates lifetime cancer, 410-411 RNA, 283, 361 RTI (relative teratogenic index), 29, 274 S Safety factors, 8, 30-31, 253, 275, 286-287 SCE (sister-chromatic exchange), 322 Schwann cells, 112 Segment I studies, 52-53 details of protocol for, 87-88 Semen, 67 analysis, 63 drugs in, 68 fluid examination, 67-68 plasma, 67-68 Senile dementia, Alzheimer, 126 Studies needed Sensitivity, species, 194 Sensory nerve fibers, 107 Sertoli cells, 54, 56 Sex differentiation, gonadal, 38 Sex ratio, 84 Sexual development, 3 Shape parameter, 269, 270 Short-term cell culture, 5-6 Significance, statistical, 235-237 Sister-chromatid exchange (SCE), 322 Skeletal variants, 27 Skin absorption rates, 259 Small intestine, 212 Smoking, cigarette, see Cigarette entries SMR (standard mortality ratio), 241 SNARLs, see Suggested no-adverse- response levels Sodium-channel toxins, 121 Sodium intake, 245 Somatic cell mutations, 283 Species sensitivity, 194 Specific locus test, 66, 81-82 Sperm abnormalities, 60 chromosome complement, 64-66 concentration, 63-64 epididymal, 90 interaction with cervical mucus, 66- 67 interaction with oocytes, 67 morphology, 60-62, 1$5 motility, 61, 62-63, 90-91 production rate, 56, 59, 89-90 toxicity, 55-56 Spermatocytes, 54 primary, 54, 55 secondary, 54-55 Spermatogenesis, 54-55, 56 dibromochloropropane and, 315-316 radiation effect on, 56-57 Spinal cord, 114-115 Spontaneous abortions, 19-20 early, 35-36 Standard mortality ratio (SMR), 241 Statistical significance, 235-237 Sterility, 36 Steroid hormones, 46-48 Stomach, 211 Structure-activity considerations, 156, 277 acrylamide, 409 aldicarb, 409 chloropropanes and chloropropenes, 409 di(2-ethylhexyl) phthalate, 409 diallate, 409 dibromochloropropane, 409 ethylene dibromide, 409

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456 Index nitrofen, 412 pentachlorophenol, 412 sulfallate, 412 trichlorfon, 412 Styrene model, 184 Subfertility, fertility and, 63 Substrate concentration, 263 Suggested no-adverse-response levels (SNARLs), 10, 257, 396, 410-411 pentachlorophenol, 396, 411 Sulfallate, 312-314 ADI, 410 carcinogenic risk estimate, 313, 314, 412 carcinogenicity, 313 developmental effects, 314 health aspects in humans, 312 health aspects in other species, 312 lifetime cancer risk estimate, 410 metabolism, 312 mutagenicity, 312-313 SNARL, 410 studies needed, 412 tumor incidence, 313 Supernumerary ribs, 26 Symbols, definitions of, 218-219 Sympathetic neurons, 115 Sympathoadrenal system, 115 Systemic absorption, 257 T Target-tissue dose, 173 measurement of, 173- 176 Target-tissue metabolite-concentration curve, area under the (AUTMC), 176 TCA (trichloroacetic acid), 202-203 TCCD (tetrachlorodibenzo-p-dioxin), 146, 147, 174, 283-284 TCE (trichloroethylene), 186-188, 189 1,2,3-TCP (1,2,3-trichloropropane), see Chloropropanes and Chloropropenes TEAM (Total Exposure Assessment Measurement) study, 260 Telone II, see Chloropropanes and Chloropropanes Temperature, elevated, 75 Teratogenesis, 274 carcinogenesis and, 15 dose, 29 hazard potential, 28, 273 index, relative (RTI), 29, 274 lethality and, 29 Teratogens, 11-12 behavioral, 106 embryonic organ susceptibility to, 14 neuroteratogens, 106, 117 psychoteratogens, 118 Teratology neuroteratology, 115-117 psychoteratology, 118 Testis function, 55 histological evaluation of, 91-92 Tetrachlorodibenzo-p-dioxin (TCCD), 146, 147, 174 Tetrachloroethylene, 209 Tetradecanoyl-phorbol-13-acetate (TPA), 264, 283 Tetrahydrocannabinol (THC), 49 Thalidomide, 21, 68 THC (tetrahydrocannabinol), 49 Theoretical maximum residue contribution (TMRC), 259 Thiamphenicol, 17 Threshold, issues concerning, 252-253, 283 Threshold limit values (TLVs), 4, 106, 170 Threshold models, 269-271 Time-dependent physiological and metabolic changes, 200-201 Time of exposure, influence of, 12-15 Tissue-concentration curve, area under the (AUTC), 174-175 Tissue culture systems, 277 Tissue dose scale-up, 194-196 Tissue partition coeff~cients, 182 TLVs (threshold limit values), 4, 106, 170 TMRC (theoretical maximum residue contribution), 259 Total Exposure Assessment Measurement (TEAM) study, 260 Toxic dose, maternally, 25 Toxic metabolites, short-lived, 204 Toxicants, genetic, 155 Toxicity developmental, see Developmental toxicity genetic, 148-149

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Index 457 immunotoxicity, pentachlorophenol, 390-391 inhalation, 6 maternal, see Maternal toxicity neurotoxicity, see Neurotoxicity oocyte, 41-42 reproductive, see Reproductive toxicity of selected contaminants, 294-412 sperm, 55-56 testing procedures, 36, 83-92 TPA (tetradecanoyl-phorbol- 13-acetate), 264, 283 Transforming genes, 142 Translocations, 80 heritable, 80-81 Trichlorfon, 396-397, 398-408 ADI, 408, 411 carcinogenic risk estimate, 411 carcinogenicity, 405-406 cholinesterase activities, 402 developmental effects, 406 epidemiological study on, 244 health aspects in humans, 398-400 health aspects in other species, 400- 403 metabolism, 397-398 mutagenicity, 403-405 neurotoxicity, 403 reproductive effects, 406-407 SNARL, 411 studies needed, 412 Trichloroacetic acid (TCA), 202-203 Trichloroethylene (TCE), 186-188, 189 1,2,3-Trichloropropane (1,2,3-TCP), see Chloropropanes and chloropropenes Tris, 77 Trisomies, 70 True-positive or true-negative result, 235 Tubular cross sections, 92 Tumor incidence acrylamide, 301 chloropropanes and chloropropenes, 336 diallate, 311 dibromochloropropane, 324 di(2-ethylhexyl) phthalate, 349 nitrofen, 372 sulfallate, 313, 314 Tumors childhood, 14 induction, 5 promotion, human, multiple stages in, 148 U Uncertainty factors, 8, 253 Unit risk, 255 Uterine epithelial hypertrophy, 89 V Vaginal opening time in rat pup, 88-89 Venous blood concentration, 183 Viability index, 84 Vial equilibration, 182 Vincristine, 118 Vinyl chloride, 72 Vinylidene chloride, 209 Visual system, 109 Volatile organic compounds (VOCs), 168-169 dose-response curves, 172-173 routes of exposure, 171-172 W Weaning index, 84 Weibull model, 269-270 Women, see Females X X chromosomes, 78 Xenobiotic substances, 3 effect on oogenesis, 43-45 y Y chromosomes, 64 YFF test, 63, 64-65 Zona pellucida, 40 z

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