INDEX

Page references in boldface type refer to tables.

Abamectin, 503Abate, 316Abortion, 448Acceptable daily intake (ADI), 317, 575Acceptable Operator Exposure Levels (AOEL), 576Accidental poisonings, 343, 347–348, 349

children, 347–348Chile, 362China, 372India, 349Iran, 436–440Japan, 349, 458–459, 459prevention, 351Serbia, 483Spain, 500Taiwan, 349, 512, 517Thailand, 528Turkey, 349, 535–537worldwide, 237, 349, 482, 583

Acephate, and aluminum, 330Acetaminophen

and fenitrothion, 321and organophosphates, 321

Acetylcholine (ACh)accumulation, 4, 11, 136, 150, 151–152, 484, 543

and seizures, 156determination, head-focused microwave

irradiation, 11and glutamate, 156–157homeostatic mechanisms, 10hydrolysis, 4, 9–10

butyrylcholinesterase, 26, 29, 30steps in, 58

insufficient, 31storage, 4synthesis, 9–10turnover time, 268

Acetylcholine receptors, See also Muscarinic acetylcholinereceptors; Nicotinic acetylcholine receptors

direct effects of organophosphates, 244–245long-term acetylcholinesterase inhibition, 5mechanism of acetylcholine binding, 4overstimulation of, cholinergic signs, 30, 31plant-produced, 20

Acetylcholinesterase (AChE)aging reaction, 5, 58, 268, 484, 584as biomarker of exposure, 278–279, 404, 485as bioscavenger, 27, 255brain, measuring, 5carbamate effects, 5–9erythrocyte, 278–279, 485, 585functions of, 27, 58gene, 20, 31, 31

alterations in expression, 31, 183deletions, 31polymorphisms, 20

interindividual variations, 485knockout mice, 5, 30organophosphate effects on, 5–9, 584–585reactivation, 19, 150–151, 268, 484, 487–488, 585role of, 584sarin-bound, 458similarity with carboxylesterases, 60upregulation, and response to exposure, 20

Acetylcholinesterase inhibitionage and, 6–7antioxidants and, 141–142brain acetylcholinesterase activity and, 5–7carbamates, 5–9, 63, 242, 584–585cholinergic signs, 30, 31cholinergic targets, 14in chronic neurotoxicity, 246direct, 5, 14exposure pathways, 19–20

Anticholinesterase Pesticides: Metabolism, Neurotoxicity, and Epidemiology. Edited by Tetsuo Satoh and Ramesh C. GuptaCopyright # 2010 John Wiley & Sons, Inc.

599

Acetylcholinesterase inhibition (Continued)extrapyramidal signs of, 136genetic polymorphisms and, 20–23high-energy phosphate depletion, 139–140inhibition rate constant, 5mechanism of, 5, 58memantine pretreatment, 142–143nitric oxide and, 139–140noncholinergic effects, 13–14organophosphates, 5–9, 242, 584–585paraoxonase 1 activity

and acute exposure, 23and chronic exposure, 22–23

pesticides, 3–4; See also Anticholinesterase pesticides;Carbamates; Organophosphates

striatum, 6–7therapeutic purposes, 4

Acetylcholinesterase reactivators, 253, 268, 584;See also individual agents

Acetylcholine synthesis, blockade of, 255–256Activated charcoal, 487, 589Acute pesticide poisonings

Central America, 506defined, 343, 496global rates, 19, 343–344, 351–352, 495, 541Greece, 406–408India, 420–422Iran, 436–440Israel, 452–453Korea, 464–466Mexico, 475neurobehavioral effects, 559Serbia, 484–486signs/symptoms, 496, 542–543, 585Spain, 506Taiwan, 511, 516Thailand, 523, 525–526treatment, 585–588, 589–591Turkey, 538underreporting, 506United States, 506WHO estimates, 343–344, 380, 405, 571

Acute reference dose (ARfD), 576–577Addiction, 14Adenosine, in seizures, 154A1 Adenosine receptor, nerve agent binding, 154A1 Adenosine receptor agonists, 154Adenosine receptor antagonists, 154, 255Adenylyl cyclase signaling, 214

anticholinesterases effects, 208–209, 249, 250chlorpyrifos exposure and, 249organophosphate effects on, 250

ADME (absorption, distribution, metabolism, and excretion),267, 269

Adolescents, neurobehavioral effects in, 232–233Adults, paraoxonase activity, 206Aerial spray workers, Israel, 450–451A-esterases, 77

age-related differences in activity, 206organophosphate detoxication, 126

Affective disorders, 104, 350Africa, self-poisonings, 346Age

and acetylcholinesterase activity, 6–7and brain, acetylcholinesterase inhibitors, 6–7and paraoxonase 1 status, 90–91

Agent Orange, 403Aging reaction

acetylcholinesterase, 5, 58, 268, 484, 584neuropathy target esterase, 114–115, 136resistance of carboxylesterases to, 58–59soman, 484, 585

Agricultural and Cattle Service, 357–363Agricultural workers

anticholinesterase exposure, 238, 346–347, 349chronic, 103–104long-term effects, 238routes, 435

biomonitoring, 268, 279–280children of

neurobehavioral effects in, 232pesticide exposure, 226

genotoxicity, 305–306, 477–478paraoxonase 1 status, 22reproductive toxicity, 477–478

Agrochemicals, WHO classifications, 359Alachlor, carcinogenicity, 306–307Albumin

carbamate detoxication, 129–130organophosphate detoxication, 126–127paraoxon metabolism, 88

Aldicarbbiomarkers, 282LD50, 570neurobehavioral effects, 215oxidative biotransformation, 128toxicity, 436

Aldo-keto reductases, 181Alexandria Poison Center (APC), 384–385Allergic rhinitis, 410–411Allethrin, 66, 67All-trans retinoic acid (ATRA), 185N-Allylquinuclinidol, 256Almerı́a, Epidemiological Surveillance Program on Acute

Pesticide Poisoning (ESPAPP), 496–508a-Adrenergic agonists, 155a,b-hydrolase-fold families, 43, 47Alpha-synuclein, 171Aluminum, and acephate, 330Aluminum phosphide, suicide attempts, 344, 422Alzheimer’s disease

donepezil for, and cytochrome P450 polymorphisms, 21loss/alteration of nicotinic receptors, 14protective effects of PBN, 141and silent butyrylcholinesterase genotype, 29

Aminopyrine N-demethylase, 332–333

600 INDEX

Amitraz poisoning, Turkey, 537–538AMPA/kainate, seizures and, 154Amphibians, endocrine disruption in, 194–195Amyotrophic lateral sclerosis (ALS), in Gulf War

veterans, 242Andalusia, Epidemiological Surveillance Program on Acute

Pesticide Poisoning (ESPAPP), 496–507Androgen receptor, 197Androgen receptor-associated protein 54 (ARA54), 114Anectine, 32Angiotensin-converting enzyme inhibitors, 44Aniline hydrolase, 332–333Animal poisonings, Greece, 411–412Annexin-V, 166Annexin-V/propidium iodide, 169Antagonism, anticholinesterases, 320–321Antiatherogenic compounds, 587Anticholinergic drugs, antiseizure effects, 153Anticholinesterase pesticides, See also Acetylcholinesterase

inhibition; Carbamates; Organophosphatesabsorption, 269antagonism, 320–321apoptosis and, 166–172, 180, 215, 251, 334–335as carboxylesterase substrates, 318environmental residues, 175–176excretion, 269exposure routes, 269, 435gene expression and, 250–252global poisonings, 150-induced seizures, 151–158interactions with metals, 330–336interaction with non-cholinesterase inhibitors, 317–318metabolism, 269neurobehavioral effects. See Neurobehavioral effectsoccupational exposure. See Occupational poisoningspharmacokinetics, 268–270potentiation between, 316–317sensitivity, age-related differences, 205–207tissue distribution, 269tolerance to, 248toxicity, See also Neurotoxicity

CNS effects, 239, 542, 543complications, 490developmental neurotoxicity, 205–218and heavy metals, 335immunotoxicity, 333–334mechanism of, 484muscarinic effects, 150, 239, 542, 543nicotinic effects, 150, 239, 542, 543oxidative stress in, 442signs/symptoms, 239, 542–543

treatment, 150–151Anticonvulsants, 19, 150–151, 254–255, 586Antidementia drugs, 4Antidotes, organophosphate poisoning, 585–588, 589–591;

See also individual agentsAntioxidants

apoptosis prevention, 166–167

organophosphate-induced impairments, 246–247suppression of oxidative injury, 141–142

Antipyrine, 333Antitumor drugs, 44Anxiety, 104, 136, 405Apnea, 27, 28, 32, 33Apolipoprotein A1, paraoxonase and, 123–125Apoptosis

carbamates-induced, 170–172defined, 165–166disruption of, 334and DNA fragmentation, 247and immunotoxicity, 333–334and metals, 334–335organophosphate-induced, 166–170, 215, 251, 334–335

neurodevelopmental effects, 180role of, 334rotenone-induced, 251

Aquatic ecosystems, pesticide residues, Egypt, 392, 393Aquatic invertebrates, carbamate metabolism, 65–66Arachidonic acid, 138Ariceptw. See DonepezilAromatase, 191Aromatic plants, contaminated, 395Arsenic, 329

-induced apoptosis, 334–335-induced septal defects, 335interactions with pesticides, 330, 332, 333and malathion, 333and parathion, 330and pefloxacin, 333

Artemisinin, 211Aryl acylamidase activity, butyrylcholinesterase, 33Aryl hydrocarbon receptor (AhR), 191Asia, suicide by pesticides, 344–345Asians, paraoxonase 1 polymorphisms, 86Asoxime. See HI-6Aspartate, in soman poisoning, 154Astrocytes

development, 214role of, 137in seizures, 157

Atherosclerosis, 60Atmosphere, organophosphates in, 454ATP, depletion of, 139–140Atropine

antagonism at muscarinic receptors, 151for anticholinesterase pesticide poisoning, 150–151, 252, 487,

585–586, 589anticonvulsant effects, 586and benzodiazepines, 254and diazepam, 488and dizocilpine, 153dosing, 487, 589and memantine, 255with methylprednisolone and trimedoxime, 256, 594oxime interactions, 151, 253, 585–586and pyridostigmine, 151

INDEX 601

“Attention” battery, NEPSY, 451Attention deficit, 136Attention deficit hyperactivity disorder (ADHD), 451Avizafone, 254Axonal-enriched proteins, 211Axons, degeneration, 240

Bangladesh, pesticide-related fatalities, 344–345Barbiturates, 254Bayley Scales of Infant Development, 231, 233Beekeepers, 411Behavior, 97, 98–100; See also Neurobehavioral effectsBenactizine, 153Benzene, carcinogenicity, 417Benzene hexachloride, 448Benzodiazepines, 254, 586

for anticholinesterase pesticide poisoning, 150–151and atropine, 254mechanisms of action, 488site of action, 254–255

Beryllium, 334–335B-esterases, 46

organophosphate detoxication, 126sensitivity, 278–279

Bhopal, India, plant disaster, 423–425Binding Occupational Exposure Limit Values (BOELV), 576Biological Limit Values (BLV), 576Biomarkers

butyrylcholinesterase, 278–279, 280, 282, 404, 410carbamates, 281–282, 282and carcinogenesis, 304–305choline acetyltransferase, 212–213citrulline, 140defined, 305dimethyl phosphate, 294erythrocyte acetylcholinesterase, 278–279, 404, 485, 585of exposure, 280, 282F2 isoprostanes, 138, 141, 142glucuronide, 2811-naphthol, 281organophosphate exposure, 277–278

adducts of phosphorylated albumin, 127b-glucuronidase, 289–300, 436

oxidative stress, 138, 141, 142of response, 280

Biomarkers of Oxidative Stress Study (BOSS), 138Biomonitoring

butyrylcholinesterase, plasma, 278–279, 404, 410cholinesterase biomarkers, 278–279, 404, 485, 585exposure pathways, 268b-glucuronidase, 289–300, 436goal of, 267guidelines for, 268pharmacokinetic models, 270, 276–277protein adducts, 282strategy, 267

Biomonitoring programsChile, 360–361

China, 367–369, 373Egypt, 394–395Spain, 496–507Thailand, 525–526U.S., 544–546

Bioscavengerscarboxylesterases, 255catalytic, 27–28, 91melatonin, 171organophosphates

acetylcholinesterase, 27, 255butyrylcholinesterase, 20–21, 26, 27–28, 33, 35, 91, 255paraoxonase 1, 91requirements for, 27

stoichiometric, 91Biotransformation

activation to detoxification ratio, 270carbamates, 270detoxication, 121organophosphates, 269–270phosphates, 122phosphorothioates, 121prenatal toxin exposure, 205toxic activation, 121xenobiotics, 121

Biperiden, 153Bipyridyls, 503, 506Birds

organophosphate sensitivity, 125paraoxonase 1 activity, 87phosphotriesterases, 123

Birth defects, 448Birth weight, 231, 232Blood, organophosphates in, 196Blood alkalinization, sodium bicarbonate, 254, 441, 488–489Blood-brain barrier (BBB)

carbamates and, 592and developmental neurotoxicity, 207disruption of permeability, 207organophosphate-induced damage, 158oximes and, 587sarin and, 587and toxin exposure, 204, 205

Blood disorders, 405Blowflies, dichlorvos toxicity, 184, 185Bouillon theory, 156BPMC

and fenitrothion, 317and malathion, 317potentiation of, 320

Brainacetylcholinesterase, 585age and acetylcholinesterase inhibitors, 6–7Ca2þ/cAMP response element binding protein

(CREB) in, 250cholinergic regulation of, 4development, 195–196GABA levels during seizures, 155

602 INDEX

neurodevelopmental effects, 176, 177–180, 180–185neuropathy target esterase activity, 112–113nicotinic receptors, 243oxidative injury, 137–139, 245

Brain-derived neurotrophic factor (BDNF), 176, 209–210Brazelton Neonatal Behavioral Assessment Scale (BNBAS), 231Breast cancer

Greece, 409–410pesticide and estrogen effects, 182, 310

Breast cancer resistance protein (BCRP), 44, 46Breast milk, organophosphates in, 196Brodifacoum poisoning, sheep/goats, 391Butyrylcholinesterase

acetylcholine hydrolysis, 29, 30affinity of oxons for, 79aryl acylamidase activity, 33“atypical” (silent), 21, 26, 28

and donepezil, 29as biomarker of exposure, 278–279, 280, 282, 404, 410biomonitoring and, 278–279, 404, 410characteristics of, 25–26and cholinergic syndrome, 246detoxication

acetylcholinesterase inhibitors, 28, 32cocaine, 26–27, 28, 29, 33, 35mivacurium, 27, 28, 32, 33succinylcholine, 27, 28, 32, 33

esterase activity of, 26functions of

detoxication, 26, 28–33, 34–35fat metabolism, 28, 33knockout mouse studies, 28–29

gene, 26, 31, 31deletions, 31polymorphisms, 20

history, 26–27human

clinical use of, 33Gly117 His mutant, 29native, 26plasma-derived, 256recombinant, 26structure of, 34tissue distribution, 33

human studies, 28knockout mice, 29limitations of, 28mouse studies, 28–33nomenclature, 26as organophosphate scavenger, 20–21, 27–28, 33,

91, 255regulation of acetylcholine release, 30role in neurotransmission, 31–32role in thermoregulation, 31, 33substrate specificity, 27subunits, 31, 34

Butyrylcholinesterase inhibitors, 317Bystander exposure, 574, 577

Cadmium, 329and anticholinesterases, developmental toxicity, 335-induced apoptosis, 334–335

Ca2þ ATPase, 249Ca2þ/calmodulin-dependent protein kinase II (CaM kinase II),

180–181activation of, 249, 250in OPIDN, 240

Ca2þ/cAMP response element binding protein (CREB)activation of, 250–251anticholinesterases effects, 204, 214, 215role of, 250

Ca2þ uptake, mitochondrial, 246Calcium channel blockers, 255, 594California

cholinesterase monitoring program, 551occupational poisonings, 347

California Pesticide Illness Reporting (Cal-PIR),545, 549

California Pesticide Illness Surveillance Program (Cal-PISP),544–545, 548–549

Calmodulin, 140Calpain, 249Calreticulin, 181cAMP

neuropathy target esterase binding, 114, 117, 118organophosphate inhibition of, 248signaling

anticholinesterases effects, 209and developmental neurotoxicity, 248

“Campo Limpio,” 473Cancer

epidemiology, 311stages of, 304–305

Caramiphen, 153Carbamates

acetylcholinesterase inhibition, 5–9, 63, 242, 584–585albumin hydrolysis of, 129–130biomarkers, 281–282, 282biotransformation, 270blood-brain barrier (BBB) and, 592carboxylesterase hydrolysis of, 63–66, 81, 127, 128–129,

317–318cholinergic targets, 14classification of, 436cytochrome P450 metabolism, 63–64, 65delayed intermediate syndrome, 136detoxication, 127–130environmental persistence, 136exposure, 101, 238, 280–282formulations, 436fungicides, 63, 136, 165in hemoglobin, 238herbicides, 63, 136-induced apoptosis, 170–172-induced reactive oxygen species (ROS), 247insecticides, 63mechanism of action, 4, 63, 268, 542–543, 583

INDEX 603

Carbamates (Continued)metabolism

aquatic invertebrates, 65–66by carboxylesterases, 63–64

in invertebrates, 65–66in vertebrates, 64–65

metabolites, 63–64muscarinic receptors and, 13, 244neurobehavioral effects, 101, 239nicotinic receptors and, 13, 244noncholinergic effects, 13–14oxidation of, 127–128and oxidative stress, 247, 442pharmacokinetics, 268–270placental transfer of, 206poisoning

children, 469pralidoxime for, 254signs/symptoms, 436, 542treatment, 254, 591–592

potency of inhibition, 13potentiation

between, 316–317by carboxylesterase inhibitors, 318of organophosphates, 317

resistance, insects, 65sensitivity, age-related differences, 205–207structure, 63, 127, 136, 150sulfoxidation, 127–128therapeutic uses, 4, 238toxicity, 127

developmental neurotoxicity, 205mechanism of, 4, 63neurotoxicity, 101, 136–137, 239reproductive, 65signs/symptoms, 239

and transient receptor potential (TRP) family, 244tumor-initiating potency, 306–307types of, 175uses, 238

Carbarylalbumin hydrolysis of, 129biomarkers, 282biomonitoring, 128, 280–282carboxylesterase hydrolysis of, 128–129delayed neurotoxicity, 240-induced alterations in gene expression, 180metabolism, 64metabolites, 128, 280–282neurite inhibition, 211neurobehavioral effects, 215poisoning, pralidoxime for, 254reproductive toxicity, 65, 185

Carbendazim, -induced apoptosis, 170Carbofuran

brain acetylcholinesterase and, 8, 9carboxylesterase hydrolysis of, 65delayed neurotoxicity, 510

-induced apoptosis, 170–171neurobehavioral effects, 215oxidative injury, 138reproductive toxicity, 65

Carbohydrate metabolism, 182Carbosulfan, 81Carboxylesterases

acetylcholinesteraseaffinity for, 318similarity to, 58, 60

activity in reproductive organs, 65affinity of oxons for, 79as bioscavengers, 255carbamate metabolism, 63–66, 81, 127, 128–129, 317–318

interspecific sensitivities, 66invertebrates, 65–66vertebrates, 64–65

catalytic mechanisms, 47, 48, 58characteristics of, 126in children, 226cholesterol hydrolysis, 60classification, 43cocaine metabolism, 44, 49drug metabolism, 44, 49in endoplasmic reticulum, 43functions of, 43, 60genes

human, 49–50male-dependent overexpression, 184–185mouse, 49–50polymorphisms, 51–52

human, identity with acetylcholinesterase, 58inhibitors, 66

chloramphenicol, 322molinate, 65potentiation of anticholinesterases, 317–318

malathion metabolism, 80mammals, 126mechanism of action, 47organophosphate metabolism, 46, 58–59, 126

insects, 60–62vertebrates, 59–60

protective effects, 79–80pyrethroids metabolism

structural and chemical basis, 66–68vertebrates, 68–69

resistance to aging, 58–59species differences, 43–44tissue expression, 44, 126xenobiotic metabolism, 182

Carboxylesterases isozymesaE7, 61–62, 69catalytic mechanism, 46–49CES1-5, 46–52E4/FE4, 60–61esta/b, 61families, 45, 46–52gene structure, 49–51

604 INDEX

genetic polymorphisms, 51–52glycosylation site, 49hCE-1, 68hCE-2, 68hepatocarcinogenesis, 43human, 68regulation of, 49–51single nucleotide polymorphisms (SNPs), 51–52structure of, 46–49substrate specificity, 49tissue expression, 49, 50

Carcinogenesisbenzene, 417and biomarkers, 304–305carboxylesterases isozymes and, 43course of, 303–304hormonal, 310malathion, 181–182pesticides, 304, 405

Carcinogenicity testing, 573Carcinogenic, mutagenic, and reproductive toxic (CMR)

compounds, 577Carcinogens, complete, 305Cardiotoxicity, organophosphates, 426Caspase-3, 167–168

activation, 169in apoptosis, 166

Caspase-8 inhibitors, 168Caspase-9, activation, 169Caspase family, 166Caucasians, paraoxonase 1 polymorphisms, 86, 89Cell growth, organophosphate-induced alterations, 176Cell membrane, role of neuropathy target esterase, 113Cell replication, anticholinesterases effects, 207–208Cell signaling, anticholinesterases effects, 208–210Central America, acute pesticide poisoning, 506Central nervous system

anticholinesterase effects, 239, 240, 241, 542, 543;See also Neurotoxicity

endocrine disruption and, 196–197nicotinic receptors, 243

Centromere protein F, 181c-fos, 251–252cGMP, neuropathy target esterase binding, 117, 118CHAMACOS study, 227, 230, 231c-Ha-ras oncogene, 310Children

accidental poisonings, 347–348carbamates poisoning, 469carboxylesterase levels, 226delayed neurotoxicity, 451farm work and pesticide exposure, 397food to body mass ratio, 226neurobehavioral effects in, 215–216, 451organophosphate exposure, 196paraoxonase activity, 226pesticide exposure, 196, 226

acute, 231

longitudinal studies, 227, 230, 231and performance, 227, 228–229

pralidoxime in, 253vulnerability to toxicants, 225–226

Chileaccidental poisonings, 362agriculture activity, 361carbamate use, 359–360, 360congenital malformations, 362–363epidemiology, 361–363, 361monitoring system, 360–361occupational poisonings, 362organophosphate use, 359–360, 360pesticides regulations, 357–361residue regulations, 359

Chinaaccidental poisonings, 372agriculture activity, 366epidemiology, 366, 367–369, 367fatality rates, 366, 372, 373monitoring system, 367–369, 373non-occupational pesticide poisonings, 371, 372–376occupational poisonings, 347, 369–372pesticide category distribution, 370–371, 371pesticide regulations, 373–374pesticide use, 366poisoning prevention, 373–374safety education, 374suicide attempts, 372–373, 506

Chloramphenicol, 322Chlordane, carcinogenicity, 306–307, 405Chlorfenvinphos, O-dealkylation, 123Chlorpyrifos

activation of, 21adenylyl cyclase signaling effects, 249B-esterase sensitivity, 278–279bioactivation of, 80brain acetylcholinesterase activity and, 6carcinogenicity, 306–307and cell signaling, 208–210developmental neurotoxicity, 194, 196and diazinon, 316fertility and, 194gene expression alterations, 176, 177, 178glial cell development and, 137, 213–215-induced apoptosis, 167–168, 169, 180, 196, 215, 335induction of heat shock proteins, 184inhibition of cell replication, 207–208inhibition of DNA synthesis, 214and lung cancer, 405metabolic pathways, 270neurite inhibition, 210neurobehavioral effects, 101, 215–216neurotoxicity, 185, 241nicotinic receptors and, 13OPIDN, 350PBPK/PD modeling, 273–276prenatal exposure to, 10, 91

INDEX 605

Chlorpyrifos (Continued)protective effects of zinc, 331synaptic development and, 212–213toxicity

acute long-term effects, 98age and, 90–91chronic, 101neural tube, 168neurotoxicity, 185, 194, 196, 215–216, 241paraoxonase 1 status and, 87, 88, 90

urinary metabolites, 280U.S. regulations, 572

Chlorpyrifos-methyl, endocrine effects, 191, 193Chlorpyrifos-oxon, 21

albumin hydrolysis of, 126cAMP inhibition, 248detoxication, paraoxonase, 124glial development and, 214-induced apoptosis, 168, 180, 196metabolism of, 270neurite inhibition, 211

Cholesterol, carboxylesterase hydrolysis of, 60Choline, transport, 10Choline acetyltransferase (ChAT), 10, 212–213Cholinergic neurons

anticholinesterase effects, 243distribution of, 404overstimulation, 484

Cholinergic syndrome, 238–239, 484–485and butyrylcholinesterase, 246CNS symptoms, 485, 506early phase, 100later stages, 100muscarinic effects, 485, 506nicotinic effects, 485, 506signs, 136

Cholinergic systemanticholinesterase effects, 212–213and glutamatergic system, 156–157major functions, 4

Cholinesterase monitoring programs, U.S.,551–552

Cholinesterases, 584as biomarkers, 278–279, 404, 485, 585ChEs isoform, 213inhibition

and motor activity, 242organophosphates, 176

inhibitors. See Anticholinesterase pesticides; Carbamates;Organophosphates

interindividual variations, 485role of, 436, 584serum, 26types of, 584

Chromium, -induced apoptosis, 334–335Chromosomal aberrations

methyl isocyanate, 425pesticide-induced, 305–310, 408

Chronic fatigue syndrome, 137Chronic organophosphate-induced neuropsychiatric disorder

(COPIND), 136Chrysanthemic acid, 66, 81Cimetidine, 321Citrulline, 140c-Jun, 251, 252c-Jun N-terminal protein kinase (JNK), 251Clonazepam, 154, 254Clonidine, 254Coagulation defects, 319, 405Coal combustion, 417–418Cocaine metabolism

butyrylcholinesterase, 26–27, 28, 29, 33, 35carboxylesterases, 44, 49cytochrome P450 system, 29

Cockroaches, organophosphate resistance, 126Cognitive dysfunction

adolescents, 232carbamates, 215–216childhood pesticide exposure, 227malaise and, 241organophosphate poisoning

acute, 215–216, 451chronic, 102–104, 102, 103, 215–216

COLQ gene, 31, 32Coma, delayed onset, 240Compartmental pharmacokinetic models, 270–272Conditioned behavior, chronic organophosphate

exposure and, 101Congenital defects

Chile, 362–363metals and anticholinesterases, 335

Containersdermal exposure from, 419recycling, 351residue regulations

Chile, 359Egypt, 397, 398Greece, 409Mexico, 473–474

Convulsionsbenzodiazepines for, 488and increased gene expression, 251–252and oxidative stress, 245pretreatment with PBN, 142

Costa Rica, agricultural worker poisonings, 238Cotton production

Egypt, 380–381, 381, 382Israel, 448, 449–450

CPP, 153Crete, 405

carbamate poisonings, 407organophosphate poisonings, 406

Crop losses, due to insects, 570–571CTP-phosphocholine cytidylyltransferase (CCT), 114Culex pipens, 61Cumulative risk assessment (CRA), U.S., 560–561

606 INDEX

Cyclic nucleotide phosphorylase, 213Cyclins, 310Cycloate, -induced apoptosis, 170Cyclooxygenase (COX), organophosphate

induction of, 137Cycloprothrin, 67Cyclosporinecytoprotective effects, 168interactions with pesticides, 332Cypermethrin, 67, 68Cysteine proteases, in apoptosis, 166Cytochrome c oxidase (COx), 139, 140Cytochrome P450 monooxygenase system, 44, 77

arsenic-mediated effects, 333carbamate metabolism, 63–64, 65, 81carbofuran metabolism, 128cocaine metabolism, 29drug metabolism, 44ethyl carbamate metabolism, 65genetic polymorphisms, 21inhibition by chloramphenicol, 322–323and insecticide tolerance, 182metals and, 331organophosphate bioactivation, 78–79, 125, 270xenobiotic metabolism, 182

Cytokines, role in seizures, 158Cytoskeletal proteins, 211, 240Cytotoxic T-lymphocyte (CTL) activity,

organophosphate-induced inhibition, 170

2,4-D, 403Dasanit, 320DDT, 344

cancer and, 405use of, 571

DDVP. See DichlorvosDelayed effects, epidemiology of, 348–350Delayed neurotoxicity

children, 451farm animals, 391

Deltamethrin, 67Demeton-S-methyl toxicity, 88Depression

in COPIND, 136and organophosphate exposure, 100, 103–104, 350, 405

Dermal exposure, 269pharmacokinetic models, 276–277risk assessment, 574

Desert Storm, 242Destruction-box (D-Box), 114Developmental neurotoxicity

absorption of toxins, 204–205age differences in, 205–207anticholinesterase pesticides, 205–218apoptosis and, 215cadmium and anticholinesterases, 335and cAMP signaling, 248carbamates, 205

disruption of neurodevelopment processes, 207effects, 204and exposure timing, 204findings, 242glial development and, 213–215inhibition of neurite outgrowth, 210–212neurobehavior and, 215–216neuronal cells, 207–210organophosphates, 90, 205–218paraoxonase 1 status and, 90PC12 model, 248postnatal exposure, 204prenatal exposure, 204prevalence of, 203pyrethroids, 68synaptic development and, 211–212testing for, 216–217

DFP. See Diisopropyl fluorophosphateDFPase, 255Diabetes, 182, 443Diacylglycerol, 11, 249, 250Dialkyl phosphates (DAP)

as biomarkers, 277–278, 294elimination half-lives, 297reference values, 297, 298urinary clearance, 276–277

Diazepam, 20, 254, 255antiseizure effects, 152, 154and atropine, 488dosing, 586

Diazinonactivation of, 21and chlorpyrifos, 316chronic exposure, 443developmental neurotoxicity, 208glial cells and, 137, 214–215-induced alterations in gene expression, 178-induced apoptosis, 215inhibition of DNA synthesis, 214Medfly eradication, 553–554neurite inhibition, 210neurobehavioral effects, 216synaptic development and, 213toxicity, and paraoxonase 1 status, 90

Diazinon-oxon, 21albumin hydrolysis of, 126neurite inhibition, 211toxicity, paraoxonase 1 activity and, 88

Dichlorvosbrain acetylcholinesterase activity and, 6delayed neurotoxicity, 240, 391-induced alterations in gene expression, 178-induced apoptosis, 169, 335-induced oxidative stress, 305muscarinic receptors and, 12, 245neurotoxicity, chronic exposure, 241OPIDN, 350reproductive toxicity, flies, 184, 185

INDEX 607

Dieldrin, 448N,N-Diethyldithiocarbamate, 250Diethyl maleate, 183Diethylphosphate (DEP), 270

as biomarker, 277–278, 294and sperm DNA, 478

Diethylthiophosphate (DETP)as biomarker, 277–278, 294and sperm DNA, 478

Diethylumbelliferyl phosphate, 249Digit-Symbol test, 99Dihydrotestosterone (DHT), parathion inhibition of, 190Diisopropylfluorophosphate (DFP), 149–150

delayed neurotoxicity, 180, 594dopaminergic effects, 239for glaucoma, 435-induced alterations in gene expression, 179,

180–181oxidative injury, 138somatostatinergic effects, 239therapeutic uses, 4, 435

Diisopropyl phosphates, O-dealkylation, 123Dimethoate

immunotoxicity, 334and metals, 330neurobehavioral effects, 215treatment, 590

N,N-Dimethyldithiocarbamate (DMDC), 250Dimethyl phosphate (DMP)

as biomarkers, 294intermediate syndrome, 592O-dealkylation, 123

Disulfoton, and OMPA, 316Dithiocarbamates

changes to cell systems, 252delayed neurotoxicity, 240endocrine disruption, 240immune system effects, 252-induced apoptosis, 171–172neurotoxicity, 250and oxidative stress, 248and Parkinson’s disease risk, 243

Dizocilpine, 13, 153, 254, 255DNA damage

in apoptosis, 166, 247malathion-induced, 181pesticide-induced, 305–310

DNA synthesis, inhibition by anticholinesterases, 207–210,213, 214

Docosahexaenoic acid (DHA), 138Domestic animals

pesticide exposure, 435poisonings, Greece, 411–412

Donepezil, 4metabolism, 21and silent butyrylcholinesterase genotype, 26, 29specificity of, 29toxic side effects, 26

Dopamineactivity in Gulf War veterans, 242auto-oxidation of, 245cytoxicity, 155

Dopamine quinones, 247Dopamine receptor antagonists, 157Dopaminergic neurons, 243, 247Dopaminergic systems, in seizures, 155Dose-effect relationships, risk assessment, 574Dose-response relationships, risk assessment, 573–574Down syndrome, 363Drug metabolism

carboxylesterases in, 44–46enzymes, 44, 45–46

Drug seeking, blocking with butyrylcholinesterase, 27

Echothiophateand muscarinic receptors, 244and nicotinic receptors, 245

Ectoparasiticides, 433Egasyn, 47Egasyn-b-glucuronidase complex, 290Egypt

acute pesticide poisonings, 383, 384–391agriculture activity, 379chemical industry, 379child workers, pesticide exposure, 397contaminated food, 392–395cotton production, 380–381, 381, 382environmental pesticide residues, 392–395farm animals, incidental poisoning, 391indoor pesticide use, 392monitoring programs, 394–395occupational poisonings, 382–384organochlorine insecticides, 380, 381pesticide regulations, 381, 392pesticide use, 380–381pest resistance, 391–392phosfolan poisonings, 383poison control centers, 384–388poverty line, 379safety education, 396toxaphene use, 391

Electron transport chain, inhibitors/uncouplers, 245Encephalopathy, delayed onset, 240Endemic familial arthritis, 426Endocrine disruption

in animals, 191–195central nervous system and, 196–197dithiocarbamates, 240organophosphates, 190–191

Endoplasmic reticulum, carboxylesterases in, 43Endosulfan, 448

restrictions, 441use in Mexico, 473

Endrin, 448carcinogenicity, 306–307-induced oxidative stress, 307–310

608 INDEX

England, accidental poisonings, 348Environment, residues in, 571Environmental exposure, pharmacokinetic models, 276–277Environmental Genome Project, paraoxonase 1 polymorphisms, 86Environmental monitoring, workplace exposure, 279Environmental Protection Agency (EPA)

neurotoxicity testing, 216–217Office of Pesticide Programs, 571registered organophosphates, 225

Epidemiological studies, limitations of, 404Epidemiological Surveillance Program on Acute Pesticide

Poisoning (ESPAPP), Spain, 496–507Epileptic seizures

excitatory amino acids in, 13–14loss/alteration of nicotinic receptors, 14monoamines in, 155

EPNbioactivation of, 80delayed neurotoxicity in farm animals, 391potentiation of procaine, 320toxicity potentiation, 316, 320

Erythrocytes, annealed, 254E-screen assay, 190Eserine, and breast cancer, 310Esterasesa,b-hydrolase-fold structure, 47classification of, 46pyrethroid resistance, 68–69substrate specificity, 46

Estrogenand malathion/parathion, 182prolonged exposure, and breast cancer, 310

Estrogen receptor (ER) competitive binding assay, 190Estrogen-responsive gene (EBBP), 181Ethacrynic acid (EA), 183Ethyl carbamate

carcinogenicity, 306detoxication, 65

Ethyl octylphosphonofluoridate (EOPF), 115Ethyl parathion

brain acetylcholinesterase activity, 6–7treatment, 591

Etofenprox, 67European Commission (EC), 571

Pesticides Directive, 575European Food Safety Authority (EFSA), 571, 575European Pesticide Cooperation (EPCO), 571European Union (EU)

carcinogenic, mutagenic, and reproductive toxic (CMR)compounds, 577

Council Directive, 571neurotoxicity testing, 216pesticide regulations, 571residue limits, 574risk assessment, 575risk management, 575–577SCOEL, 575–576self-poisonings, 346

Excitatory amino acids, 13–14in anticholinesterase neurotoxicity, 153neurite inhibition, 211

Excitotoxicityglutamate in, 157, 246hippocampus, 141initiating mechanism, 245–246pretreatment with PBN, 142reactive nitrogen species (RNS) in, 245reactive oxygen species (ROS) in, 245

Exposureassessment, 573, 574multiple pesticides, 315pathways, 19–20, 196–197, 238quantifying

carbamates, 280–282organophosphates, 279–280

Exterminators, paraoxonase 1 genotypes, 22Extracellular signal-regulated kinases (ERKs), 180, 249–250

F2-isoprostanes, 138, 141, 142F4-neuroprostanes, 138–139, 141, 142Farm animals, incidental poisoning, Egypt, 391Farmers

biomonitoring, 281–282suicide rates, 103

Farm workers. See Agricultural workersFat metabolism, butyrylcholinesterase in, 28, 33FB642, 172Federal Food, Drug, and Cosmetic Act (FFDCA), U.S., 560, 571Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA), U.S., 560, 571Felbamate, 254Fenitrothion

and acetaminophen, 321and BPMC, 317endocrine disruption, 190, 191, 193, 194, 195-induced alterations in gene expression, 179resistance, 183self-poisoning, Japan, 459–461toxicokinetics, 460–461urinary metabolites, 436

Fenthioncarcinogenicity, 306–307endocrine effects, 191potentiation of BPMC, 320treatment, 590

Ferric-reducing ability of plasma (FRAP), 442Fertility

and acetylcholine overexpression, 184–185and chlorpyrifos exposure, 194organophosphates and, 194, 197, 477–478

Fetotoxicity, in lipid peroxidation, 308Fetus

brain, neurotoxicity, 206endocrine disruption in, 194neurobehavioral effects in, 215–216paraoxonase 1 activity, 227

INDEX 609

Fibroblast growth factor (FGF), 176Fish

endocrine disruption in, 194–195methyl parathion bioaccumulation, 391pesticide residues, 391, 392pyrethroids sensitivity, 67

Flavin-containing monooxygenases (FMOs), 44, 77in carbamate metabolism, 63–64fonofos bioactivation, 79

Flea-control products, 557Flies

dichlorvos toxicity, 184, 185organophosphate resistance, 126Swiss cheese protein (SWS), 111, 112

Flufenamic, -induced apoptosis, 171Flufenprox, 67Flutamide, endocrine disruption, 190, 193Follicle-stimulating hormone (FSH), 477Fonofos, flavin monooxygenase activation of, 79Food and Agriculture Organization (FAO), 570

goals of, 472Integrated Pest Management System, 374International Code of Conduct on the Distribution and

Use of Pesticides, 351Food poisoning, 435Food Quality Protection Act (FQPA), U.S., 560Free radical intermediates, 138Fruits, contaminated

Egypt, 392–395Israel, 449

Fumigants, characteristics of, 434Fungicides

benefits of, 570carbamates, 63, 136toxicological characteristics of, 434

G137D substitution, aE7 gene, 61, 62Gacyclidine, antiseizure effects, 153Galantamine, 4Gamma-aminobutyric acid (GABA), 586

brain levels during seizures, 154–155effects of organophosphates on, 14

Gamma-aminobutyric acid (GABA)-ergicneurons, 247

Gamma-aminobutyric acid (GABA) receptor,benzodiazepines at, 586

Gamma-aminobutyric acid (GABA)-regulated chloride channels,leptophos and, 239

Gamma glutamyl transpeptidase (GGT), 442Gangliosides, 594Gastric aspiration, 589Gastric lavage, 486, 589Gene expression

anticholinesterase effects on, 250–252increases, convulsions and, 251–252

Genotoxicityagriculture workers, Mexico, 477–478and chronic pesticide exposure, Iran, 442

and occupational exposure, India, 428and oxidative stress, 183–184

Genotoxicity testing, 573Ginger Jake paralysis, 109, 391, 543Glasgow coma score, 240Glaucoma, DFP for, 435Glial cells

anticholinesterase effects, 137, 213–215neuropathy target esterase expression, 112–113, 116

Glial fibrillary acidic protein (GFAP), 176, 180–181, 213, 214Glioma, 405Gliosis, 137Glucokinase, 182Glucose-6-phosphate dehydrogenase (G-6PDH), 330Glucose homeostasis, organophosphates and, 182, 184, 442b-Glucuronidase, as biomarker, 289–300

acute exposure, 292–294, 436chronic exposure, 292Malaysian population, 291–294in rats, 290–291

b-Glucuronidase assay, 290Glucuronide, as biomarker, 281Glutamate

and acetylcholine, 156–157in excitotoxicity, 157, 246NMDA receptor activation, 137in seizures, 254in soman poisoning, 153–154

Glutamate-receptor antagonists, 254Glutamate receptors

effects of long-term organophosphate poisoning, 98overstimulation of, 137

Glutamatergic system, and cholinergic system, 156–157Glutamine synthase, 213Glutathione-S-transferases (GSTs)

in carbamate metabolism, 64genes, 176-mediated O-dealkylation, 183in organophosphate resistance, 183xenobiotic metabolism, 182

Gly117 His mutant, butyrylcholinesterase, 29Glyceraldehyde-3-phosphate dehydrogenase, 180–181Glycerophosphocholine, 111Glycopyrrolate, 253Goats, brodifacoum poisoning, 391Golfers, carbamate exposure, 282Gonadotropin-releasing hormone (GnRH), 191, 195G-protein coupled receptors, 11G-protein signaling, anticholinesterase impairment of, 214Grape farmers, 410–411Greece

acute pesticide poisonings, 406–408breast cancer incidence, 409–410chromosomal aberrations, 408domestic animal poisonings, 411–412honeybee poisoning, 411occupational poisonings, 406–411residue regulations, 409

610 INDEX

self-poisonings, 406, 407tobacco farmers, 410

Greek Poison Control Center, 406, 407Greenhouses

Greece, 409Israel, 448, 450Spain, 496

Greenhouse workers, Greece, 406–411Green Revolution, 472Groomers, 435Ground crews, pesticide exposure, 450–451Guanine nucleotide binding protein beta polypeptide 2 (GNB2),

113–114Gulf War syndrome

and organophosphates, 242–243and paraoxonase 1 status, 89–90

Gulf War veteransautonomic nervous system, 242dopamine activity, 242neurological disorders, 242paraoxonase 1 status, 242–243

Hair analysis, biomonitoring, 411Hazard characterization, 573–574Hazard identification, 573Head circumference, 231Head-focused microwave irradiation, 11Healthcare workers

occupational exposure, 435pesticide exposure, 556

Heat shock proteins (Hsp)organophosphate-induction of, 184pesticide and estrogen effects, 310reactive oxygen species generation, 169

Heavy metals, 329Heme-oxygenases, arsenite-induced, 333Hemoglobin, carbamates in, 238Hemostatic disorders, 319Hen model, OPIDN, 110Hepatocarcinogenesis, carboxylesterases isozymes and, 43Hepatocellular carcinoma, and pesticides, 383Hepatocyte nuclear factor-3 (HNF3), 20Hepatocyte nuclear factor-4 alpha (HNF-4a), 50Heptachlor, 448Herbicides

benefits of, 570carbamates, 63, 136toxicological characteristics of, 434

Herbs, contaminated, 395Heroin, carboxylesterases metabolism of, 44Hexachlorobenzene poisoning, Turkey, 538O-Hexyl,O-2,5-dichlorophenyl phosphoramidate (HDCP), 126HI-6, 151, 253, 590–591

dosing, 590interaction with nicotinic receptors, 587mechanism of action, 587use in Serbia, 488

High-affinity choline uptake, 10, 157, 249

High density lipoproteins (HDLs), paraoxonase and, 86,123–125, 127

High-energy phosphates, depletion of, 139–140Hippocampus

acute soman poisoning, 98excitotoxicity, 141

Honeybee poisoning, Greece, 411Hormone disruption, pesticides, 405Human health, pesticides and, 570–571Human plasma-derived butyrylcholinesterase, 256Huperzine A

antiseizure activity, 154and silent butyrylcholinesterase genotype, 26, 29specificity of, 29toxic side effects, and butyrylcholinesterase genotype, 26

Hydrocephaly, 335, 363Hydrolase-A

ethyl carbamate metabolism, 65in testicular toxicity, 65

N-Hydroxymethylnapthylvinylpyridine, 255Hyperglycemia, 182Hypothalamic-pituitary-gonadal axis, 195, 478

Illiteracy, and pesticide risks, 397–398, 425, 475Imidazenil, 154Imidrapil, 49Immunotoxicity

and apoptosis, 333–334dithiocarbamates, 252metals, 334methyl isocyanide, 425organophosphate-induced, 169–170

Indiaaccidental poisonings, 347–348, 349acute pesticide poisoning, 349, 420–422cancer, and pesticide exposure, 428carbamate use, 420exposure routes, 419–420genotoxicity, exposed farmers, 428Insecticide Act, 418mass pesticide poisonings, 422–423National Malaria Control Program, 418occupational poisonings, 425–428organophosphate use, 418, 419pesticide manufacturing, 418pesticide regulations, 418Prevention of Food Adulteration Act, 418residue regulations, 428–429suicide attempts, 349, 419, 420, 421, 422, 422, 423

Indicative Occupational Exposure Limit Values (IOELV), 576Infants

neurobehavioral effects, 231–232organophosphate exposure, 196paraoxonase activity, 206

Inflammatory cytokines, role in seizures, 158Inhalation exposure, 268, 574Inositol 4,5-3 phosphate (IP3), 11Insect growth regulator (IGR) insecticides, 503, 507

INDEX 611

Insecticide Act, India, 418Insecticides, characteristics of, 434; See also Anticholinesterase

pesticides; Carbamates; Organophosphates; PesticidesInsect resistance

carbamates, 65carboxylesterase-mediated, 60and cytochrome P450 activity, 182Egypt, 391–392Israel, 454malathion, and W251L aE7 substitution, 62organophosphates, heat shock proteins in, 184

Insectscrop losses due to, 570–571malathion toxicity, 80, 318organophosphate sensitivity, 125sodium channel sensitivity, 67

Institute of Public Health (ISP), 357–358Insulin resistance, 442Integrated Pest Management System, FAO, 374Intentional poisonings, 343, 344; See also Self-poisoning;

Suicide attemptsIndia, 419, 423Iran, 436–440Israel, 453Japan, 459Korea, 463, 464–466Serbia, 482–483Spain, 500Taiwan, 511, 512, 517Thailand, 529–530Turkey, 535–537

InterleukinsIL-10, 252role in seizures, 158

Intermediate syndromedelayed, 136dimethylphosphates, 592epidemiology of, 348mechanism of, 348Serbia, 490–491signs/symptoms, 109, 136, 543, 592treatment, 592

International Agency for Research on Cancer (IARC), 303International Classification of Diseases, WHO, 525International Code of Conduct on the Distribution and Use of

Pesticides, FAO, 351International Program for Chemical Safety (IPCS), 570Invertebrates

carbamate metabolism, 65–66pyrethroids metabolism, 68–69

Ipecacuanha, 487Iran

accidental poisonings, 436–440acute pesticide poisonings, 436–440biomonitoring, b-glucuronidase, 293–294fatality rates, 345occupational exposure, 442–443opioid self-poisonings, 439

pesticides residues, 443registered pesticides, 436, 437self-poisonings, 436–440treatment protocols, 440

Isofenphos, OPIDN, 350Isomalathion, 318

-induced alterations in gene expression, 181potentiating impurities, 318

Israelacute pesticide poisonings, 452–453aerial spray workers, 450–451agriculture activity, 448contaminated fruits/vegetables, 449cotton production, 448, 449–450greenhouses, 448, 450groundwater contamination, 454insect resistance, 454migrant workers, 448mosquito control, 448neurotoxic effects, 449occupational poisoning, 449–452organophosphate use, 448–449Parkinson’s disease in kibbutz farmers, 452pediatric poisoning cases, 453pesticide regulations, 454pesticide use, 448–449self-poisonings, 453

Israel National Poison Control Center, 452–453

Jamaica Ginger, 109, 391, 543Japan

accidental poisonings, 349, 458–459, 459carbamates poisoning, 461carbamate use, 458fatality rates, 345fenitrothion self-poisoning, 459–461“gyoza” dumplings, 458, 459Ministries of Agriculture, Forestry, and Fisheries (MAFF), 457National Research Institute of Police Science, 345organophosphate use, 457–458paraquat poisoning, 459parathion regulations, 457, 458suicide attempts, 349, 458, 459–461

Japanese, paraoxonase 1 polymorphisms, 89Japan Poison Information Center (JPIC), 458–459Joint Meeting on Pesticide Residues (JMPR), 570, 576–577c-Jun N-terminal kinases, 180Jurkat human T cells, 170

Kainate, neurite inhibition, 211Kainic acid, 142KDEL receptor, 46Kerala, India, ethyl parathion poisoning, 422Kibbutz farmers, 448–450, 452Kidneys, neuropathy target esterase activity, 112Knock Tap test, 451Korea

acute pesticide poisoning, 464–466

612 INDEX

carbamates poisoning, 468–469epidemiology, 464–466fatality rates, 463, 464, 467, 468organophosphate poisonings, 466–468organophosphate/pyrethroid poisonings, 466–468suicide attempts, 463, 465–466

L/M polymorphism, paraoxonase 1, 86Lactate dehydrogenase (LDH) release assays, 169Langerhans islets, 442Latin America, self-poisonings, 346Lead, 329, 334–335Learning deficits, childhood pesticide exposure, 227Legge’s principle, 448Leptophos

delayed neurotoxicity in farm animals, 391GABA-regulated chloride channels and, 239neurite inhibition, 210–211

Leukemia, 408Ligand-gated ion channels, 11Limbic region, 22Lindane

-induced oxidative stress, 308use of, 571

Lipases, a,b-hydrolase-fold structure, 47Lipid metabolism, and neuropathy target esterase, 116Lipid peroxidation

brain, 137–139in chronic pesticide exposure, 442in fetotoxicity, 308protective effects of zinc, 330–331

Lipopolysaccharide (LPS), 142Lithium, 249Liver

activation/detoxification reactions, 269carboxylesterases activity, 44

Loqman Hakim Hospital Poison Center, 293Low affinity choline uptake, and chlorpyrifos exposure, 249Lung cancer, 405Luteinizing hormone (LH), 477Lymphocytes, neuropathy target esterase activity, 112Lymphoma, 408Lysosome pathway, neuropathy target esterase

degradation, 117

Magnesium sulfate, with atropine/oximes, 440–441Malaise, 241Malaoxon, 80

-induced alterations in gene expression, 181persistence of, 316potentiating impurities, 318toxicity, organophosphates potentiation of, 89

Malaria preventionDDT for, 571Israel, 448

Malathionaerial application, 553–554arsenic and, 333

and BPMC, 317and breast cancer, 310carboxylesterase detoxication of, 80and carcinogenesis, 181–182chromosomal damage, 176chronic exposure, 101, 443endocrine disruption, 190, 194estrogen and, 182, 310immunotoxicity, 334-induced alterations in gene expression, 179-induced apoptosis, 168, 169Medfly eradication, 553–554mosquito-control, 554neurobehavioral effects, 101, 215potentiating impurities, 318protective effects of zinc, 330–331resistance, and W251L aE7 substitution, 62toxicity

EPN potentiation of, 316insects, 80, 318mammals, 80potentiation of, 318, 319

urinary metabolites, 436Malaysia, biomonitoring, b-glucuronidase, 291–294Mammals

carboxylesterases, 126endocrine disruption in, 191, 193–194paraoxonase 1 activity, 87phosphotriesterases, 123pyrethroid toxicity, 67, 68

Mammary glands, organophosphate-induced changes, 310Mancozeb

-induced apoptosis, 171neurotoxicity, 245

Maneb, neurotoxicity, 245Manganese, interactions with pesticides, 331–332Manzanate/foley, 472MAP, 180MAP kinase, 251Maximum residue limits, 575Medicinal plants, contaminated, 395Mediterranean fruit fly, 553–554Mediterranean Sea, methyl parathion spill, 391Melatonin, bioscavenging, 171Memantine, 14

antiseizure effects, 152, 153atropine and, 255mechanisms of action, 142pretreatment, 143–144

Memory, Ca2þ/cAMP response element binding protein(CREB) in, 250

Memory impairmentchildhood pesticide exposure, 232in COPIND, 136from soman poisoning, 98

Meperidine, 44, 49Mercury, 329Metabolites, toxicity of, 319

INDEX 613

Metalsand anticholinesterase toxicity, 335and apoptosis, 334–335immunotoxicity, 334pesticide interactions, 330–336

Methamidophos-contaminated vegetables, 435in “gyoza” dumplings, 458, 459as an index chemical, 560neurobehavioral effects, 101OPIDN, 350restrictions, 441use in Mexico, 473

Methanesulfonyl fluoride, 4Methiocarb, oxidative biotransformation, 128Methocramine, 157Methomyl

acute poisoning, 506biomarkers, 282food-related exposure, 510self-poisoning, Japan, 461

b-N-Methylaminoalanine, 211Methyl carbamates

activation of, 81carcinogenicity, 306detoxication of, 81

N-Methyldithiocarbamate, 250Methyl isocyanate

acute poisoning symptoms, 424Bhopal disaster, 423–425chromosomal aberrations, 425decomposition products, 423inhalation exposure, 425post-traumatic stress disorder (PTSD), 425

Methyl paraoxon, 79Methyl parathion

accidental ingestion, 558–559atmospheric transformations, 454bioactivation of, 90brain acetylcholinesterase activity and, 6, 9brain choline acetyltransferase and, 212endocrine effects, 193illegal spraying, 558-induced alterations in gene expression, 179-induced apoptosis, 180mammalian toxicity, 457Mediterranean Sea spill, 391muscarinic receptors and, 12neurobehavioral effects, 451treatment, 591use in Mexico, 473

Methylprednisolonein OPIDP treatment, 594with trimedoxime and atropine, 256, 594

Methyl thiophanate, -induced apoptosis, 170Mevinphos

LD50, 570OPIDP, 491

Mexicoacute pesticide poisonings, 475agriculture activity, 472genotoxic effects of pesticides, 477–478Green Revolution, 472occupational poisonings, 475–477paraoxonase 1 polymorphisms, 478pesticide regulations, 474pesticide use, 472reproductive effects of pesticides, 477–478socioeconomic status and pesticide use, 473, 474tobacco farmers, 477Toxicological Information Centers (TIC), 474–475

Microdialysis, intracerebral, 10–11Microglia, in seizures, 157Microtubule-associated protein-2 (MAP-2), 240Midazolam, 254Middle East, suicide attempts, 441–442Migrant farm workers, pesticide exposure, 557Milk

contraindications, 487parathion contaminated, 348toxins in, 204

Ministries of Agriculture, Forestry, and Fisheries (MAFF),Japan, 457

Mipafoxneurite inhibition, 210OPIDN, 350

Mitochondria, organophosphate-induced impairments, 246Mitochondrial electron transport chain, inhibitors/uncouplers, 245p38mitogen-activated protein (MAP), 180p38mitogen activated protein (MAP) kinase, 251Mivacronw, 32Mivacurium

detoxication by butyrylcholinesterase, 27, 28, 32, 33uses, 28, 32

Mivacurium apnea, 27, 28, 32, 33Molinate, 65Monitoring programs. See Biomonitoring programsMonoamines, in seizures, 155Monoaminooxidases, anticholinesterase inhibition of, 157Monocrotophos

-induced alterations in gene expression, 179restrictions, 441

Monomethyl carbamate, 592Moshav farmers, 448–450Mosquitoes

carboxylesterases polymorphisms, 61control

DDT, 571Israel, 448malathion, 554

Mothers’ and Newborns Cohort Study, 227, 230, 231Motor impairment, 99, 22, 42Motor neuron disease, 116Mt. Sinai Children’s Environmental Health Study, 227, 230, 231Muda Agricultural Development Authority (MADA), 292Multi-drug resistance-associated protein 2 (MRP2), 44, 46

614 INDEX

Multiple myeloma, 405Muscarinic acetylcholine receptors, 11, 14

acetylcholine accumulation, 4, 11, 136, 150, 151–152, 484antagonists, 152, 244, 252–253anticholinesterase effects, 11–13, 157, 243–245, 248, 543carbamates and, 244, 543downregulation of, 11, 12, 248location, 157organophosphates and, 11–13, 243–245, 248, 543

direct effects, 244, 248overstimulation of, 136, 151–152, 243stimulation of, 11subtypes, 11, 14

Muscarinic mechanism, seizures and lethality, 151–152Myelin, degeneration, 240Myelin-associated glycoprotein (MAG), 176, 214Myzus persicae, 60–61

1-Naphthol, 281Narcotics, carboxylesterases metabolism of, 44National Environmental Center for Toxicology Research (NECTR),

Egypt, 389–391National Epidemiological Surveillance System, Thailand, 525National Health and Nutrition Examination Survey

(NHANES), 305National Malaria Control Program, India, 418National Pesticide Information Center (NPIC), U.S., 545,

549–551National Poison Center, Turkey, 535–536National Poison Control Center, Serbia, 482National Poison Data System (NPDS), U.S., 546–547, 551National Research Institute of Police Science, Japan, 345Natural killer (NK) cells, 169NBQX, 154Necrosis, 165Neonates, endocrine disruption in, 194Neonicotinoids, 507Neostigmine, therapeutic uses, 4NEPSY, “Attention” battery, 451Neramexane, 153Nerve agents

acetylcholinesterase inhibitors, 3detoxication

butyrylcholinesterase, 28, 32paraoxonase 1 in, 124, 256

pretreatment/protection, butyrylcholinesterase, 26toxicity, 80

acute long-term effects, 98–100and paraoxonase 1 status, 89–90phosphotriesterase prevention of, 125

Nerve growth factor (NGF), 176, 209–210Nervous system, developing

processes in, 204sensitivity to toxic injury, 204–205

NEST, 111, 112, 115Netherlands, occupational poisonings, 347Neural tube, chlorpyrifos cytotoxicity, 168Neurite outgrowth, anticholinesterases effects, 210–212

Neurobehavioral effectsacute pesticide poisoning, 98–100, 559adolescents, 232–233carbamates, 215–216, 239children, 215–216, 231–232, 451functional areas, 102–104, 102, 103infants, 231–232organophosphate poisoning, 215–216

acute, 98–100, 559chronic, 101–104, 241low level, 227, 449–450, 451–452

Neurobehavioral tests, demographic variables, 231Neurodegeneration

excitatory amino acids in, 13–14and neuropathy target esterase, 113and pesticide exposure, 405

Neurodevelopmental toxicity, anticholinesterase pesticides, 176,177–180, 180–185

Neuroinflammation, in neurotoxicity, 155–156, 157–158Neurological disorders, Gulf War veterans, 242Neuromuscular junction, acetylcholinesterase reactivation at, 253Neurons

neuropathy target esterase activity, 112–113, 115replication/differentiation, 207–210

Neuropathy esterase, 110, 240Neuropathy target esterase (NTE)

active site, 593aging of, 114–115, 136altered gene expression, 185biochemistry, 110–111in cell membrane regulation, 113discovery of, 110, 593function of, 112–113, 593knockout mice, 113and lipid metabolism, 116lysophospholipase activity, 111molecular structure of, 111–112molecular toxicology, 117–118NTE1, 111in OPIDN, 114, 115–116, 240in OPIDP, 491, 593in predictive toxicity testing, 116–117regulation of expression, 113–114tissue distribution, 112–113

Neuropathy target esterase (NTE)-related esterase (NRE),111–112

Neuropsychiatric disorders, 528organophosphate poisoning, acute long-term, 99–100sheep dippers, 241–242

Neurosteroids, antiseizure activity, 154–155Neurotoxicity

acute, 98–100, 238–240altered gene expression, 176, 177–180, 180–185carbamates, 136–137chronic, 241, 246, 449

mechanism of, 246delayed. See Organophosphate-induced delayed neuropathy;

Organophosphate-induced delayed polyneuropathy

INDEX 615

Neurotoxicity (Continued)developmental differences, 205, 226–227mechanisms, 151–158NMDA receptors in, 141organophosphates, 136–137

acute exposure, 98–100, 238–240, 239chronic exposure, 241–242, 449

and oxidative stress, 245–247protective effects of PBN, 141–142severe effects, 226and signaling pathways, 248–250subtle effects, 226

Neurotransmission, role of butyrylcholinesterase in, 26,31–32

Neurotransmittersin anticholinesterases poisoning, 151–155noncholinergic, inactivation of, 4

Neurotrophic factors, anticholinesterases effects, 208–210Neurotrophins, 176Newborns

congenital malformations, 362–363paraoxonase 1 levels, 91, 206

Nicaragua, occupational poisonings, 347Nickel, -induced apoptosis, 334–335Nicotinic acetylcholine receptors, 11

acetylcholinesterase inhibitors, 13antagonists, 253–254anticholinesterase effects, 13, 157carbamates and, 244downregulation, 11, 12HI-6 interaction, 587loss/alteration of, 14organophosphates and, 13, 243–244

direct effects, 245overstimulation of, 136, 243potencies of inhibition, 13pralidoxime interaction, 587stimulation of, 11subunits, 11, 14

Nicotinic mechanisms, seizures and lethality, 152Nimodipine, 255Nitric oxide

cytochrome c oxidase inhibition, 140in lipid peroxidation, 140NMDA activation of, 137in seizures, 140

Nitric oxide synthase, 1404-Nitrophenol, endocrine effects, 193N-Nitrosocarbofuran, -induced apoptosis, 171NMDA. See N-methyl-D-aspartateN-methyl-D-aspartate (NMDA)

activation of nitric oxide synthesis, 137in neurodegeneration, 13–14

N-methyl-D-aspartate (NMDA) receptor, 14, 255activation, apoptosis blocking, 168glutamate activation of, 137location, 157role in neurotoxicity, 141

N-methyl-D-aspartate (NMDA) receptor antagonistsantiseizure effects, 152–154, 156memantine, 14properties of, 255

N-methyl-D-aspartate (NMDA)-receptor-channel blockers, 254Non-Hodgkin’s lymphoma, 311, 403, 405Non-protein sulfhydryls (NPSH), 321–322Noradrenaline, 155Noradrenergic systems, in seizures, 155Norocaine nitroxide, 29N-tert-butyl-a-phenylnitrone (PBN), 141–142Nuclear factor kappaB (NF-kappaB), 171–172

Obesity, and butyrylcholinesterase deficiency, 28Obidoxime, 253, 588

dosing, 590, 591Occupational exposure levels (OELs), 575Occupational poisonings, 150, 238, 343, 346–347, 349

biomonitoring, 279–280, 411Chile, 359, 362China, 369–372data collection, 346Egypt, 382–384epidemiological studies, 404Greece, 406–411hair analysis, 411healthcare workers, 435India, 425–428Iran, 442–443Israel, 449–452Mexico, 475–477migrant farm workers, 557and Parkinson’s disease risk, 243pesticide applicators, 557–558pharmacokinetic models, 276–277prevention, 351risk assessment, 574risk of, 346self-reporting, 346–347signs/symptoms, 506Spain, 498, 500Taiwan, 512, 517Thailand, 529Turkey, 536, 537–539underreported, 34–37U.S., 554–558veterinarians, 435

Octamethylpyrophosphoramide. See OMPAOctanoyl ghrelin, 28O-dealkylation, organophosphates, 122–123O-dearylation, organophosphates, 125–126Omethoate, use in Mexico, 473iso-OMPA, 4, 317–318OMPA, and disulfoton, 316Ophthalmic disorders, methyl isocyanide poisoning, 424–425OPIDN. See Organophosphate-induced delayed neuropathyOPIDP. See Organophosphate-induced delayed polyneuropathyOpioids, self-poisoning, 439

616 INDEX

Organization for Economic Cooperation and Development(OECD), 216–217

Organochlorine insecticides, 175Egypt, 380, 381in medicinal/aromatic plants, 395restrictions, 404use in Israel, 448use in Mexico, 473

Organonitrogens, 507Organophosphate-induced delayed neuropathy (OPIDN),

239–240CaM kinase II in, 240characteristics of, 239–240compounds causing, 240DFP, 180epidemiology of, 348–349, 349hen model, 110in vitro testing, 116–117and neuropathy target esterase, 114, 115–116, 240tri-o-tolyl phosphate (TOTP), 543

Organophosphate-induced delayed polyneuropathy (OPIDP), 109characteristics of, 109DFP-induced, 594electrophysiological evaluation, 593neuropathy target esterase (NTE) in, 491, 593prevention and treatment of, 256Serbia, 491signs/symptoms, 136, 593treatment, 592–594

Organophosphate poisoningacute, 496, 542–543, 585chronic, 100–104

and carboxylesterases inhibition, 60markers of, 442and paraoxonase 1 status, 90

confirming, 544exposure routes, 19–20, 196–197, 238, 279–280, 315global rates, 19, 343–344, 351–352, 495, 541Gulf War Syndrome, 89–90, 242–243intermediate syndrome. See Intermediate syndromeneurobehavioral effects, 98–100, 101–104, 215–216, 227,

241, 449–450, 451–452, 559occupational exposure, long-term effects, 99sensitivity to, species differences, 59–60signs/symptoms, 239, 434, 542–543, 585treatment, 19–20, 252–256, 434, 544

paraoxonase 1 scavenging, 91supportive, 588–589

underestimating, 510Organophosphate resistance

glutathione-S-transferases (GSTs) in, 183heat shock proteins in, 184

Organophosphates, 175absorption, 486, 543and acetaminophen, 321acetylcholine receptors, direct effects, 244–245acetylcholinesterase and, 5–9, 584–585agricultural uses, 149–150

albumin hydrolysis of, 126–127antiandrogenic actions, 190–191, 197atmospheric transformations, 454bioactivation, 78–79, 122biomarkers, 277–278

adducts of phosphorylated albumin, 127b-glucuronidase, 289–300, 436

bioscavengersacetylcholinesterase, 27, 255butyrylcholinesterase, 20–21, 26, 27–28, 33, 35, 91, 255paraoxonase 1, 91requirements for, 27

biotransformation, 269–270brain acetylcholinesterase and, 5–7cardiotoxicity, 426characteristics, 58–59choline acetyltransferase and developmental stage, 10cholinergic effects, 14, 243–244cholinesterases and, 5–9, 584–585classification, 269, 543commonly used, 434–435detoxication, 122–127

butyrylcholinesterase, 28, 32carboxylesterases, 46, 58–62, 126hydrolysis reactions, 123–125insects, 60–62paraoxonase 1 in, 21, 60species differences, 125, 130vertebrates, 59–60

developmental neurotoxicity, 90, 205–218effects on GABA, 14environmental residues, 136, 175–176estrogenic/antiestrogenic actions, 190formulations, 175, 434gastrointestinal absorption, 486and glucose homeostasis, 182, 184, 442history of, 403in vitro testing, neuropathic vs. nonneuropathic, 117mechanism of action, 4, 19, 27, 268, 542–543, 583metabolites, 294, 295

biomarkers, 277–278detecting, 294–300pharmacokinetics, 276–277

muscarinic receptors and, 11–13, 243–245, 248, 543nerve gases, 150; See also individual agentsneurotoxicity, 136–137

acute exposure, 98–100, 238–240, 239altered gene expression, 176, 177–180, 180–185chronic exposure, 241–242, 449developmental, 205, 226–227fetal brain, 206glial cells in, 137

nicotinic receptors and, 13, 243–244, 245noncholinergic effects, 13–14O-dealkylation, 122–123O-dearylation, 125–126and oxidative stress, 442oxon-type, 5, 78–79, 122

INDEX 617

Organophosphates, 175 (Continued)and Parkinsonism, 100pharmacokinetics, 268–270, 279–280phosphorothioate form, 122phosphotriesterase hydrolysis of, 123–125photochemical degradation, 454placental transfer of, 206potency of inhibition, 13potentiation

between, 316–317of carbamates, 317by carboxylesterase inhibitors, 318impurities, 318of pyrethroid toxicity, 82–83

prophylaxis, 20racemic mixtures, phosphotriesterase resolution, 124reactivation rates and aging reaction, 584resistance

cockroaches, 126flies, 126

sensitivity, age-related differences, 205–207serum protein binding, 248–249structure, 58–59, 78, 122, 135–136suicide and, 103–104, 175, 344, 405therapeutic uses, 4thion-type, 5tissue protein binding, 248–249toxicity, See also Organophosphate poisoning

acute, 98–100, 496, 542–543, 585age and, 90chronic, 60, 90, 100–104, 442delayed onset, 240depression and, 100, 103–104developmental, 90–91effects of carboxylesterase, 79–80mechanism of, 4, 27, 137neurotoxicity, See Neurotoxicity; Organophosphates,

neurotoxicitynoncholinergic mechanism, 137oxon form, 58paraoxonase 1 and, 21–22, 86–91phosphotriesterase prevention of, 125reproductive, 195signs/symptoms, 239, 434, 542–543, 585species differences in sensitivity, 125, 130variations in, 584–585

uses, 238, 433veterinary use, 433

Oseltamivir, carboxylesterases hydrolysis of, 49O,S,S-trimethylphosphorodithionate (OSS-Me), 319Oxidative stress, 245–247

in anticholinesterase toxicity, 442and chronic pesticide exposure, 442and dopaminergic neurons, 247genotoxicity and, 183–184markers of, 306neuronal, 137–139pesticide-induced, 184, 305–310

and seizures, 247–248suppression of, 141–143

Oximes, 150–151, 253, 586–588, 589antidotal potency, 487–488and atropine, 151, 253, 585–586and blood-brain barrier (BBB), 587contraindications, 592dosing, 587–588, 589–590limitations of, 150mechanism of action, 253, 586–587toxicity of, 150

Oxonases, age-related differences in activity, 206Oxons, affinity for serine esterases, 79

p53 tumor suppressor gene, 309Packaging, residue regulations, 359Pakistan, pesticide-related fatalities, 344Pan American Health Organization (PAHO), 238Pancreatic cancer, 405Paraoxon

albumin hydrolysis of, 88, 126detoxication of, 88, 126-induced apoptosis, 167, 168, 169, 334–335LD50, 570modulation of signal transduction, 249protective effects of carboxylesterase, 79toxicity

acute long-term effects, 98paraoxonase protection, 87

Paraoxonase 1, 123–125age and, 90–91, 206albumin-associated, 127catalytic activity of alloforms, 88in children, 226chronic pesticide exposure and, 22–23fetal, 227genes, 85–86knockout mice, 87–88lipoprotein-associated, 86, 123–125, 127in nerve agent poisoning, 256in organophosphate metabolism, 60, 91organophosphates toxicity

animal studies, 87–88developmental, 90–91modulation of, 88–89protective effects, 86–87

polymorphisms, 21–23, 85–87Gulf War veterans, 242–243Mexican workers, 478Q192R, 243

pregnancy and, 91protective effects, 87–88status, 86–87, 88, 89–90structure, 85–86substrates, 86therapeutic uses, 87–88tissue expression, 86transgenic mice, 88

618 INDEX

Paraoxonase 2, 85Paraoxonase 3, 85Paraquat

and oxidative stress, 248suicide and, 344, 459use in Mexico, 473

Parathionand arsenic, 330bioactivation of, 80and breast cancer, 310chronic exposure, neurobehavioral effects, 101-contaminated milk, 348developmental neurotoxicity, 208endocrine effects, 190, 193estrogen and, 182, 310-induced alterations in gene expression, 179-induced apoptosis, 167, 169inhibition of DNA synthesis, 214LD50, 570mammalian toxicity, 457regulations, Japan, 457, 458

Parkinson’s diseaseextrapyramidal signs, 100kibbutz farmers, 452organophosphates and, 100, 428and pesticide exposure, 171, 243, 405, 448

and acetylcholinesterase inhibitors sensitivity, 22protective effects of PBN, 141protective effects of smoking, 452reactive oxygen species (ROS) in, 243

PBN, 141–142Peach-potato aphid, carboxylesterase-mediated resistance, 60–61Pediatric Environmental Neurobehavioral Test (PENBT), 233Pefloxacin

arsenic and, 333interactions with pesticides, 332, 333

Percutaneous absorption studies, 276–277Peripheral nervous system, 240, 241Permethrin, 66

metabolism of, 82–83resistance, 183stereospecific toxicity, 67

Permissible exposure limits (PEL), 575Peroxisome proliferator-activated receptor a (PPARa), 191Peroxynitrite radicals, 140Persian Gulf veterans, paraoxonase 1 status, 89–90Personal external monitoring, 279Personal protective equipment (PPP)

agricultural workers, 500, 503, 508health-care workers, 556

Peru, accidental poisonings, 348Pest control operators, biomonitoring, 279–280Pest eradication programs, U.S., 552–554, 564Pesticide applicators, occupational exposure, 557–558Pesticide Hazard Classes, WHO, 512, 513, 516Pesticide regulations

carcinogenic, mutagenic, and reproductive toxic (CMR)compounds, 577

Chile, 357–361China, 373–374Egypt, 381, 392EU, 571goal of, 570India, 418Israel, 454Mexico, 474risk assessment, 572–575risk management, 575–577U.S., 571–572

cholinesterase monitoring programs, 551–552cumulative risk assessment (CRA), 560–561organophosphates, 559–560pest eradication programs, 552–554, 564public health impact, 562–563risk management, 561–562surveillance programs, 544–551

WHO. See World Health OrganizationPesticide residues. See Residue regulationsPesticides

acceptable daily intake (ADI), 317availability of, 350benefits of, 570–571carcinogenicity, 304, 383, 405contaminants in, 507environmental persistence, 381–382, 571; See also Residuesand hepatocellular carcinoma, 383history of, 403metals interactions, 330–336and Parkinson’s disease, 243risk assessment, 351safety programs, 351storage, 507synergism, 315tolerance, and cytochrome P450 activity, 182toxicological characteristics of, 434in veterinary medicine, 433WHO classification, 441

Pets, pesticide exposure, 435P-glycoprotein

in drug metabolism, 44organophosphate-induced alterations in expression, 183

Pharmacodynamic (PD) response modeling, 272–276Pharmacokinetics

modelscompartmental, 270–272organophosphate exposure, 276–277PBPK, 272–273PBPK/PD, 273–276

principles of, 270Phase I reactions, 44, 45, 63–64, 77Phase II reactions, 44, 45, 64, 77Phenobarbital

antagonism of anticholinesterases, 320–321fetoprotective effects, 321induction of hepatic microsomal enzymes,

320, 321

INDEX 619

Phenothrin, 67Phenthoate, potentiating impurities, 319Phenthoate acid, 319Phenylisopropyl adenosine, 154Phenyl saligenin phosphate, -induced apoptosis, 167Phenytoin, 254Phosfolan, occupational exposure, Egypt, 383Phosphamidon

-induced apoptosis, 166-induced oxidative stress, 305OPIDN, 350

Phosphates, biotransformation, 122–123Phosphatidylcholine, 111Phosphatidyl inositol (PI), 249Phosphatidyl inositol 4,5-2 phosphate (PIP2), 11, 249Phosphocholine, neuropathy target esterase interaction, 114Phosphocreatine, depletion of, 139–140Phospholipase C, 11Phospholipid phosphatidylserine (PS), 166Phosphoramidates, 135–136Phosphoroamidothiolates, 269Phosphorodithioates, 269Phosphorothionates, 78–80, 269

biotransformation, 121metabolic activation of, 270

Phosphorylation, serine esterases, 79–80Phosphotriesterases, 255

albumin-associated activity, 127applications, 124–125bacterial, 124hydrolysis of organophosphates, 123–125stereoselectivity, 124–125

Physiologically-based pharmacokinetic (PBPK) models,272–273

Physiologically-based pharmacokinetic (PBPK)/pharmacodynamic(PD) modeling, 273–276

Physostigmine, 150developmental neurotoxicity, 208glial development and, 214and muscarinic receptors, 244therapeutic uses, 4

Pilots, pesticide exposure, 450–451Piperonyl butoxide, 322Pirenzepine, 157Placenta, and toxin exposure, 204–205Placental transfer

carbamates, 206organophosphates, 206

Plasminogen activator, 181Points of departure (PoDs), 560Poison Center Surveillance System, Thailand, 525–526Poison Control Center, Taiwan, 510–511, 516Poison Control Center of Ain Shams University (PCCA),

385–388Poison control centers, Egypt, 384–388Poisoning Severity Score, Serbia, 489–490Polyhalogenated cyclic hydrocarbons (PCH), carcinogenicity,

306–307

Polyunsaturated fatty acids (PUFAs), 137–139PON1. See Paraoxonase 1Porphyria cutanea tarda-like syndromes (PCT), 538Post-traumatic stress disorder (PTSD), 100, 425Potency of inhibition

carbamates, 13organophosphates, 13

Potentiation, 316between anticholinesterases, 316–317anticholinesterases and non-cholinesterase inhibitors,

317–318anticholinesterases as carboxylesterase substrates, 318blockage of detoxification pathway, 320by impurities, 318–319metabolism-based interactions, 319–323models for, 323

Potentiometric biosensors, phosphotriesterases-based, 124Pralidoxime (2-PAM), 19, 253–254, 590–591

and blood-brain barrier, 587dosing, 589–590interaction with nicotinic receptors, 587pharmacokinetics, 253WHO recommendations, 488

Pralidoxime methylsulphate, 488Prefrontal brain region, 22Pregnancy

and carbamates exposure, 196–197and organophosphate exposure, 196–197and paraoxonase 1 status, 91

Pregnane X receptor (PXR), 191Pregnenolone, antiseizure activity, 154–155Preschool children, neurobehavioral effects in, 232Prevention of Food Adulteration Act, India, 418PRiMA gene, 31–32, 33Primicarb, 247, 282Pro-2PAM, 254Procainamide, 49Procaine, potentiation by EPN, 320Procyclidine, 254Profenofos, 588Proliferating cell nuclear antigen (PCNA), 310Prophylaxis, organophosphates, 20Propoxur

biomarkers, 282brain acetylcholinesterase and, 8–9immunotoxicity, 334

Prostaglandins, cyclooxygenase-derived, 138Protein adducts, biomonitoring of, 282Protein kinase A (PKA), similarity to neuropathy target esterase,

112, 113Protein kinase C (PKC)

activation of, 11, 157, 308–309in neuropathy target esterase expression, 114role of, 308

Protein phosphorylation, and pyrethroids, 67Protein synthesis, anticholinesterases effects, 207–210Prothiofos, -induced alterations in gene expression, 179Pseudocholinesterase, 26

620 INDEX

Psychological disorderschronic organophosphate poisoning and, 102–104, 102, 103methyl isocyanide poisoning, 425

Psychomotor functions, chronic organophosphate poisoning and,102–104, 102, 103

Public health regulations, U.S., 562–563Pyramidal neurons, excitotoxicity, 141Pyrethroids

developmental toxicity, 68-induced oxidative stress, 305metabolism, 81–82

carboxylesterases, 66–68invertebrates, 68–69mammals, 67, 68–69

optical isomers, 67, 81–82reproductive toxicity, 68resistance, esterase-mediated, 68–69sensitivity of fish to, 67site of action, 67, 81structure, 66, 81toxicity

acute signs, 81mammalian, 68potentiation by organophosphates, 82–83species, differences, 67stereospecificity, 67–68, 81–82

type I, 66, 67, 81type II, 66–67, 81

Pyrethrum, neurite inhibition, 211Pyrethrum extract, 66Pyridinium oximes, 487–488, 586–588, 589; See also OximesPyridostigmine, 20

atropine and, 151prophylaxis, and ‘atypical’ butyrylcholinesterase, 21

Q/R polymorphism, paraoxonase 1, 86Quinalphos, endocrine effects, 191, 193–194, 195

Rabbits, paraoxonase 1 activity, 87REACH (Registration, Evaluation, Authorization and Restriction

of Chemicals), 216Reactive nitrogen species (RNS)

in excitotoxicity, 245generation of, 137

Reactive oxygen species (ROS)carbamate-induced, 247in excitotoxicity, 245and heat shock protein expression, 169, 184mediators of apoptosis, 167in oxidative injury, 137–139in Parkinson’s disease, 243

Relative potency factors (RPFs), 560Replication factor C, 181Reproductive organs, carboxylesterases activity in, 65Reproductive toxicity

and acetylcholine overexpression, 184–185agriculture workers, Mexico, 477–478carbamates, and carboxylesterases inhibition, 65

carbaryl, 185dichlorvos, 184, 185organophosphates, 195pyrethroids, 68

Reproductive toxicity testing, 573Reptiles, endocrine disruption in, 194–195Residential risk assessment, 561–562Residue regulations

Chile, 359EU, 574India, 428–429Iran, 443

Residuesenvironmental, 381–382, 571in food, 574

Resmethrin, 66, 67Respiratory disorders

methyl isocyanide poisoning, 424and pesticide exposure, 239, 405

Rift Valley fever, 391Risk assessment

accuracy of data, 572–573EU, 575exposure assessment, 573, 574harmonizing, 351principles, 572–573steps in, 573–575U.S., 560–561

Risk characterization, 575–576Risk management

EU, 575–577U.S., 561–562

Rivastigminebrain acetylcholinesterase and, 9therapeutic uses, 4

RNA synthesis, anticholinesterases effects, 207–210Rodenticides

accidental poisonings, 347–348toxicological characteristics of, 434

Rodents, endocrine disruption in, 191, 193–194Rotenone

-induced apoptosis, 251and Parkinson’s disease risk, 243

Rotterdam Convention, 373, 474

Safety programs, pesticide use, 351Sample collection, urine, 296–297Sarin, See also Tokyo subway sarin attacks

acute exposure, 241long-term effects, 98, 100neurotoxic effects, 10

A1 adenosine receptor binding, 154and blood-brain barrier (BBB), 587-bound acetylcholinesterase, 458choline acetyltransferase activity and, 10chronic exposure, 241direct reaction with oximes, 253Japanese terrorist attacks, 242

INDEX 621

Sarin, See also Tokyo subway sarin attacks (Continued)low-dose exposure, 242nicotinic receptors and, 13sensitivity to, and paraoxonase 1 polymorphisms, 23toxicity, and paraoxonase 1 status, 89

SCH 23390, 155, 157Schizophrenia, 14School-age children, neurobehavioral effects in, 232Schools, pesticide exposure, 559SCOEL, EU, 575–576Scoline, 32Seizures

adenosinergic mechanism, 154AMPA/kainate-related mechanisms, 154anticholinesterase-induced, 247

mechanisms, 151–158neurotransmitter systems in, 151–155

atropine protection, 151GABA-ergic mechanisms, 154–155glutamate in, 254monoaminergic mechanism, 155muscarinic mechanisms, 151–152neuroinflammation in, 155–156, 157–158nicotinic mechanisms, 152nitric oxide in, 140NMDA antagonists, 152–154, 156organophosphate-induced, 100

cyclooxygenase (COX) induction, 137and oxidative stress, 247–248pretreatment with PBN, 142

Selenium, immunoprotective effects, 334Self-harming, characteristics of, 350Self-poisonings, 344–346, 349; See also Intentional poisonings;

Suicide attemptsChina, 372, 506Greece, 406, 407India, 420, 421, 422, 422, 423Iran, 436–440Israel, 453Japan, 458, 459–461Korea, 463, 465–466Serbia, 482–483Spain, 500Sri Lanka, 506Taiwan, 511, 512, 517Thailand, 529–530Turkey, 535–537worldwide rates, 344–346, 349, 441–442, 463

Semen, 477, 478Sensory impairment, 99Sensory-motor functions, 102–104, 102, 103Sentinel Event Notification System for Occupational Risk

(SENSOR), 544, 548Septal defects, arsenic, 335Serbia

accidental poisonings, 483acute pesticide poisoning, 484–486intermediate syndrome, 490–491

National Poison Control Center, 482OPIDP, 491Poisoning Severity Score, 489–490suicide attempts, 482–483treatment protocols, 486–489

Serine esterasesorganophosphate detoxication, 126phosphorylation, 79–80

Serine hydrolase KIAA 1363, 126Serine hydrolase superfamily, 58Serine protease inhibitor, 168Serotonin receptors, chlorpyrifos and, 196Serotonin systems, 155

anticholinesterase effects on, 215–216organophosphate effects on, 196in seizures, 155

Serum proteins, 248–249Sex steroids, and brain development, 195–196Sexually dimorphic nucleus of the medial preoptic area

(SDN-POA), 195Sheep, brodifacoum poisoning, 391Sheep dippers

chronic neuropsychological effects, 241–242paraoxonase 1 status, 90

Sheep farmers, occupational exposure, 558SH-SY5Y cells, 117Signaling pathways

organophosphate modulation of, 248–250reduction in, 251

Silafluofen, 67Single nucleotide polymorphisms (SNPs)

acetylcholinesterase gene, 20carboxylesterases isozymes, 51–52

SKF 525-A, 321Smoking, protective effects in Parkinson’s disease, 452Sodium bicarbonate, blood alkalization with, 254, 441,

488–489Sodium channels, pyrethroids and, 67, 81Sodium methyldithiocarbamate (SMD), 238Sodium pentobarbital, 321Soil

pesticide persistence, 381–382toxaphene residues, 381–382

Solanaceous plants, butyrylcholinesterase inhibitors in, 21Soman

acute long-term effects, 98A1 adenosine receptor binding, 154aging reaction, 484, 585albumin hydrolysis of, 126direct reaction with oximes, 253muscarinic receptors and, 245nicotinic receptors and, 245toxicity

brain aspartate levels, 154brain glutamate levels, 153–154

Spainaccidental poisoning, 500acute pesticide poisoning, 506

622 INDEX

Epidemiological Surveillance Program on Acute PesticidePoisoning (ESPAPP), 496–507

greenhouses, 496mortality rates, 499, 506occupational poisoning, 498, 500personal protective equipment, 500, 503, 508suicide attempts, 500

Sperm, 477–478Sperm aneuploidy, 478Spermatogenesis, parathion effects on, 193Spermatozoids, 65Spina bifida, 363Spin trapping agents, 141–142Sri Lanka

organophosphate poisoning, 512pesticide-related fatalities, 345self-poisoning, 506

Statue test, 451Steroid hormones, receptors involved with, 195Steroidogenesis, disruption of, 191Steroidogenic acute regulatory protein (StAR), 185Stress proteins, organophosphate-induction of, 184;

See also Heat shock proteinsStress response, p53 in, 309Striatum

cholinergic markers, 4sensitivity to acetylcholinesterase inhibitors, 6–7

Substantia nigra, vulnerability to oxidative stress, 245Substantia nigra pars compacta (SNpc), 243Succinylcholine

butyrylcholinesterase detoxication, 21, 25–26, 27, 28, 32, 33hypersensitivity to, 21uses, 28, 32

Succinylcholine apnea, 27, 28, 32, 33Sugar oximes, 254Suicide attempts

aluminum phosphide, 422bipyridyls, 506China, 372–373, 506common chemicals used in, 344Greece, 406, 407India, 420, 421, 422, 422, 423Iran, 436–440Israel, 453Japan, 458, 459–461Korea, 463, 465–466and organophosphate exposure, 103–104, 175, 344, 405Serbia, 482–483Spain, 500Sri Lanka, 506Taiwan, 511, 512, 517Thailand, 529–530Turkey, 535–537WHO estimates, 237, 482worldwide rates, 344–346, 349, 441–442, 463

Suicide prevention, 350Sulfotransferase, in drug metabolism, 44Sulfoxidation, carbamates, 127–128

Surveillance systems. See Biomonitoring programsSuxamethonium, 32Swiss cheese protein (SWS), fly, 111, 112Synaptic development, anticholinesterase effects, 212–213Synergism, pesticides, 315Synthetic pyrethroids. See Pyrethroids

TabunA1 adenosine receptor binding, 154direct reaction with oximes, 253

Taiwanaccidental poisonings, 348, 349, 512, 517acute pesticide poisoning, 511, 516carbamates poisoning, 516–520fatality rates, 345–346, 513, 516, 518occupational poisoning, 512, 517organophosphate poisoning, 510–516Poison Control Center, 510–511, 516suicide attempts, 349, 511, 512, 517

Tamaron/lannate, 472Target organs, identifying, 573TCDD, -induced oxidative stress, 307–310Tehran Legal Medicine Center (TLMC), 439Temocapril, carboxylesterases hydrolysis of, 49Tengku Ampuan Rahimah Hospital, 292–293Testicles, neuropathy target esterase activity, 112Testosterone

metabolism, 191pyrethroids and, 68

Tetrachlovinfos, -induced alterations in gene expression, 179Tetra ethyl pyrophosphate (TEPP), 165, 457Tetra hydroamino acridine (THA), 4Tetraisopropyl pyrophosphoramide (iso-OMPA),

therapeutic uses, 4, 317–318TGF-b3, 181Thailand

accidental poisonings, 348, 528acute pesticide poisoning, 523, 525–526carbamates available in, 528epidemiology of pesticide poisoning, 526–527fatality rates, 344, 525intentional poisoning, 525medical outcomes, 530–531National Epidemiological Surveillance System, 525occupational poisoning, 529organophosphates available in, 527pesticide poisoning in children, 528pesticides imported into, 524, 526Poison Center Surveillance System, 525–526severity of pesticide poisoning, 530suicide attempts, 529–530

Thermoregulation, 31, 33Thiobarbituric acid-reactive substances (TBARS), 330, 442Thiram

-induced alterations in gene expression, 180-induced apoptosis, 170, 171

Threshold limit values (TLV), 575Threshold of toxicological concern (TTC), 574

INDEX 623

Thrombocytopenia, 405Thymidylate synthetase, 181Thyroid hormones

and brain development, 195–196disruption by organophosphates, 194and occupational exposure, 426

Tiagabine, 254Tissue proteins, OP binding, 248–249T-lymphocytes, dithiocarbamate activation of, 252Tobacco farmers

Greece, 410Mexico, 477

Toddlers, neurobehavioral effects, 231–232Tokyo subway sarin attacks, 457–458

long-term effects, 100paraoxonase 1 polymorphisms in victims, 23treatment, 589–590

Tolerance, to anticholinesterase pesticides, 248Toxaphene

in soil, 381–382use in Egypt, 391

Toxic Exposure Surveillance System (TESS), 544, 546–548Toxicity testing, 573Toxicological Information Centers (TIC), Mexico, 474–475Toxicology Unit in Mansoura Emergency Hospital (TUMEH),

388–389Trail Making test, 232Transcription factors

anticholinesterases effects, 208–210AP-1, 209Sp1, 2209

Transient receptor potential (TRP) family, 244Triamcinolone, in OPIDP treatment, 594Trichlorfon

-induced oxidative stress, 305OPIDN, 350

Trichlormat, OPIDN, 350Trichlorpyridinol, 270

pharmacokinetics, 277–278urinary clearance, 276–277, 280

Trienylcyclohexylpiperdine (TCP), 152–153Trimedoxime, with atropine and methylprednisolone, 256, 594Tri-o-cresyl phosphate (TOCP), 109

Jamaica Ginger, 109, 391, 543OPIDP, 593

Tri-o-tolyl phosphate (TOTP)-induced apoptosis, 167OPIDN, 543

Triphenyl phosphite, -induced apoptosis, 167Tubulin, 180, 214, 240Tumor necrosis factor-a (TNF-a), role in seizures, 158Turkey

accidental poisoning, 349, 535–537acute pesticide poisoning, 538agriculture activity, 533–534amitraz poisoning, 537–538crop production, 534fatality rates, 345, 538

hexachlorobenzene poisoning, 538National Poison Center, 535–536occupational poisoning, 536, 537–539pesticide use, 533–535pesticide consumption, 534–535poisoning studies, 537–538self-poisoning, 349, 535–537

Ubiquitin-protease pathwayneuropathy target esterase degradation, 117in neuropathy target esterase expression, 114

UDP-glucuronylsyltransferase (UGT)in carbamate metabolism, 64in drug metabolism, 44

Unconditioned behavior, 101Union Carbide, 423–425United Kingdom, accidental poisonings, 348United States

acute pesticide poisoning, 506cholinesterase monitoring programs, 551–552cumulative risk assessment (CRA), 560–561Environmental Protection Agency (EPA), 216–217,

225, 571illegal methyl parathion spraying, 558occupational poisoning, 554–558organophosphate regulations, 559–560organophosphate use, 225pest eradication programs, 552–554, 564pesticide regulations, 571–572pesticide use, 135poison centers, 463public health regulations, 562–563risk management, 561–562schools, pesticide exposure, 559surveillance programs, 544–546

URB597, 244Urethane, 65Urine

metabolites, 196, 279–280, 436sample collection, 296–297

Vegetables, contaminatedEgypt, 392–395Iran, 443Israel, 449methamidophos, 435

Verapamil, 594Vertebrates

carbamate metabolism, 64–65organophosphate metabolism, 59–60pyrethroids metabolism, 68–69

Vesamicol, 10Vesicular acetylcholine transporter (VAChT), 10Veterinarians, occupational exposure, 435Vimentin, 180–181Vinyl carbamate, 65Visual Motor Integration Test (VMI), 233Vitamin C, apoptosis prevention, 166–167

624 INDEX

Vitamin Eapoptosis prevention, 166–167suppression of oxidative injury, 141–142

Vitellogenin assay, 194–195Voltage-dependent sodium channel, pyrethroids and, 67, 81VX, direct effects on muscarinic acetylcholine receptors, 244

W251L substitution, aE7 gene, 61, 62Washington, U.S., cholinesterase monitoring rule,

551–552Waste materials, phosphotriesterase detoxication of, 124Water

EU residue limits, 574pesticide residues, Iran, 443

Wheat flour, ethyl parathion in, 422Wisconsin Card Sorting Test, 232Workplace exposure, environmental monitoring, 279World Health Organization (WHO)

accidental poisonings, 237, 482acute pesticide poisonings, 380, 405, 571agrochemical classifications, 359, 441fatality rates, 19, 344, 405International Classification of Diseases, 525Pesticide Hazard Classes, 512, 513, 516pesticide regulations, 569–570

pralidoxime chloride recommendations, 488public health initiative, 463self-reported poisonings, 380suicide attempt statistics, 237, 344, 482

Xenobioticsabsorption of, 121biotransformation, 121excretion, 121lipophilicity, 121

Xenobiotics metabolismcarboxylesterases, 182chloramphenicol inhibition of, 322–323cytochrome P450 system, 182glutathione-S-transferases (GSTs), 182organophosphate-inhibited carboxylesterases, species

differences, 60phase I reactions, 44, 77phase II reactions, 44, 77

yTb rare blood group, 20

Zinc, antioxidant properties, 330–331, 335–336Zineb, -induced apoptosis, 171Ziram, -induced apoptosis, 171

INDEX 625