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OCR for page 443
~ 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
OCR for page 444
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
OCR for page 445
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
OCR for page 450
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
OCR for page 451
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
OCR for page 452
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
OCR for page 453
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
OCR for page 454
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
OCR for page 455
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
OCR for page 456
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
OCR for page 457
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
OCR for page 458
Representative terms from entire chapter:
risk estimate
