brain AChE enzyme activity, 204 f ChE activity determination, 199

Subject Index

Downloaded by 5.62.154.53 on June 3, 2016 | http://pubs.acs.org Publication Date (Web): July 25, 2012 | doi: 10.1021/bk-2012-1099.ix002

A Absorption, metabolism, inhibition and elimination (ADME) modeling, 4, 8f, 9f Acetylcholinesterase (AChE), 167 AChE. See acetylcholinesterase (AChE) Adipose-plasma partition coefficient, 299f ADME. See absorption, metabolism, inhibition and elimination (ADME) modeling A-esterase-mediated hydrolysis, 185f Age-dependent acute neutotoxicity, rats, 56

B Bayesian analysis, PBPK, 293 BBB. See blood-brain barrier (BBB) transportion Bifenthrin, 21f, 22t Blood-brain barrier (BBB) transportion, 58 Brain AChE inhibition, 169, 171f, 172f, 173f, 190f Brain-plasma partition coefficient, 300f, 301f

C Caco-2 cells, 60f, 61f, 62f CAPHRA. See Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA) Carbaryl concentration, plasma, 335f Carbaryl metabolism, 326f, 327f, 328t, 330t Carbaryl tissue partitioning, 331 Carbon dioxide laser skin exposure, 104f Carboxylesterase hydrolysis, 261f Carboxylesterases (CES) catalytic efficiencies, 158f CES1 inhibition, 159 enzymology, 151 esterolytic metabolism, 159 genetics, 151, 151f kinetic constants, 155t lipid metabolism, 157 mass spectrum, 157f OP-modified CES1, 156 overview, 149

proteins, 153f xenobiotic metabolism, 152 CAS numbers, pyrethroid pesticides, 27 CES. See carboxylesterases (CES) Chiral recognition model, 35f Chiral separation, pyrethroid isomers, 34 Chlorpyrifos (CPF), 179, 184f, 185f, 185t, 187t brain AChE enzyme activity, 204f ChE activity determination, 199 concentration, 202f, 203f CYP human exposure assessment, 311f, 312 overview, 309 PBPK/PD modeling, 313, 314t data analysis, 201 GC/MS analysis, 200 metabolic scheme, 197f overview, 195 pup treatment, 199 rat treatment, 199 in vitro metabolism, 200, 205f Chlorpyrifos exposed human hepatocytes, 123f Chlorpyrifos inhibition, human metabolic interactions, 125f Cholinesterase inhibition age-related differences, 172 behavioral toxicity, rats, 169 brain AChE inhibition, 169, 171f, 172f, 173f mode of action considerations, 174 overview, 167 time-course, 174 Chrysanthemic acid moieties, stereochemical configurations, 33f Cloned sodium channel isoforms, heterologous expression, 220 Copper vapor laser skin exposure, 104f Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA), 55 14C-permethrin, 107f, 108f CPF. See chlorpyrifos (CPF) Cyfluthrin, 21f, 26t CYP. See cytochrome P450 (CYP) Cypermethrin isomer separation, 39f Cytochrome P450 (CYP) human exposure assessment, 312 overview, 309 PBPK/PD modeling human data sets, 316

345 Knaak et al.; Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

output, 316, 317f, 318f pharmacodynamic parameters, 315 pharmacokinetic parameters, 313, 314t working assumptions, 315 Cytochrome P450-mediated metabolism, 184f


D DEET, 109f Deltamethrin, 22f, 61f, 62f, 219f, 231f, 235f, 236f, 237f, 238f, 238t, 239t Dermatomed skin, 105f Diastereoisomer, 23, 25f, 25t Differential pyrethroid sensitivity, 223, 225, 225f

E Enantiomer, 23, 25f, 25t Environmental chemical inhibition, human metabolic interactions, 127f

induction, 120 inhibition, 124 pesticide-endogenous metabolite inhibition, 126 pesticide-pesticide inhibition, 125 microarray studies, 122 nuclear receptors, 120 overview, 115 PBPK, 119 PXR mechanism, 121f risk assessment, 118 toxicants, mode of action, 117f Human sodium channels, 225

I In vitro to in vivo extrapolation (IVIVE)., 323 IVIVE. See in vitro to in vivo extrapolation (IVIVE)

L Liquid chemical reservoir, 92f

F M Fipronil cytotoxicity, human metabolic interactions, 123t

G Gastrointestinal (GI) transportation, 58 GI. See gastrointestinal (GI) transportation GMP. See good modeling practices (GMP) Good modeling practices (GMP), 3

H House fly incapacitation, 108f Human carbaryl, 332, 334f Human metabolic interactions chlorpyrifos exposed human hepatocytes, 123f chlorpyrifos inhibition, 125f cytotoxicity, 122 environmental chemical inhibition, 127f enzyme activation, 126 fipronil cytotoxicity, 123t

MacKee model laser pretreatment, 95, 97, 100, 104 Mammalian metabolism, pyrethroids age-dependent, 47, 48f better extrapolation, humans, 49 carboxylesterase, 45 cholesterol esters, 48f conjugations, 46 CYP isomers, 46 development, 42f ester hydrolysis, 45 history, 43, 44f mammalian metabolic reactions, 43 overview, 41 oxidation, 46 rats vs humans, 49 sex-dependent, 47

N Neurotoxic pyrethroid pesticide biochemical data, 232


clearance data, 232 deltamethrin, 231f, 235f, 236f, 237f, 238f, 238t, 239t overview, 229 PBPK model, 234, 235f, 236f, 237f PBPK model development, data, 231, 232t physicochemical parameters, 232 physiological information, 232 in vivo extrapolation, 234 in vivo pharmacokinetic data, 233


O Organophosphate enzyme inhibition molecular graph, 276f overview, 271 QSAR, 273f, 274, 274f, 276f acetylcholinesterase, 282, 283t, 284f, 285t applicability domain, 278 chymotrypsin, 279, 280t, 282f data preparation, 275 descriptor calculation, 275 model generation, 277 model validation, 277 serine proteases trypsin, 279, 280t, 281f Organophosphorus insecticides A-esterase-mediated hydrolysis, 185f cytochrome P450-mediated metabolism, 184f inhibition kinetics, 183t overview, 179 oxon detoxication, 185, 186t, 188f phosphorothionate metabolism, 183 target acetylcholinesterase sensitivity, 182 in vivo experiments, 189 Oxon detoxication, organophosphorus insecticides, 185, 186t, 188f

P Paraoxonase 1 (PON1) AREase hydrolysis, 141f compounds, 135f DZO hydrolysis, 139f in vivo efficacy, 140t knockout mouse, 136 overview, 133 status, 137, 138f substrate hydrolysis, 142t

wild type rodents, 136 Parathion, 179, 184f, 185f, 185t, 187t See also organophosphorus insecticides PBPK. See physiologically based pharmacokinetics (PBPK) PBPK modeling children, 57 date, 57 PBPK/PD. See physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) PBPK/PD modeling parameters ADME modeling, 4, 8f, 9f components, 12f overview, 3 percutaneous disposition determinants, 6, 7t source-to-outcome continuum, 5f Percutaneous absorption, pesticide formulations carbon dioxide laser skin exposure, 104f copper vapor laser skin exposure, 104f 14C-permethrin, 107f, 108f DEET, 109f dermatomed skin, 105f formulation effects, 106 house fly incapacitation, 108f liquid chemical reservoir, 92f MacKee model laser pretreatment, 95, 97, 100, 104 overview, 87 radioactivity disposition, 106f radiochemicals, 90 skin penetration cell, 91f skin permeability constants, 96t skin transport, 88f solvent Kp determinations, 96 solvents, 90 unlabeled counterparts, 90 vapor exposure, excised skin, 93f in vitro disposition, 101f, 105f in vitro measurements, 90, 91f, 100 in vitro penetration, 100t in vitro skin disposition, 97f, 98f, 103f in vitro vs. in vivo, 103f in vitro vs. in vivo dermal residues, 102f in vivo disposition, 102f in vivo measurements, 95 in vivo skin disposition, 99f Percutaneous disposition determinants, 6, 7t Percutaneous penetration, pesticides absorption determining method, 76, 77 mathematical models, 78 in vitro methods, 77 absorption population variability, 71



absorption regional variability, 70 binding, 72 distribution, 73 dose, 69 duration, 69 excretion kinetics, 76 exfoliation, 73 exposure frequency, 69 factors, 68t metabolic transformation, 75 overview, 67 photochemical transformation, 75 physiochemical properties, 68 skin health, 72 skin surface conditions, 71 sub-anatomical pathways, 70 substantivity, 72 surface area, 69 vehicle effects, 69 wash effect, 75 Physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD), 3 Physiologically based pharmacokinetics (PBPK), 57, 133 adipose-plasma partition coefficient, 299f Bayesian analysis, 293 brain-plasma partition coefficient, 300f, 301f carbaryl concentration, plasma, 335f carbaryl metabolism, 326f, 327f, 328t, 330t carbaryl tissue partitioning, 331 chemical-specific parameters, 296 clearance, 302 partition coefficients, 297, 301t human carbaryl, 332, 334f IVIVE data gaps, 333 overview, 291 pharmacokinetic data collection, 325 priors, 294, 294f, 295f regression analysis, 299f, 300f species extrapolation, 303f in vitro data-based parallelogram, 324, 325f in vivo extrapolation, 331 Plasma, carbaryl concentration, 335f PLIF. See protein-ligand interaction fingerprint (PLIF) PON1. See paraoxonase 1 (PON1) Prallethrin isomers, efficacy against houseflies, 34t Protein-ligand interaction fingerprint (PLIF), 255f, 257f

Pyrethroid actions, sodium channels cloned sodium channel isoforms, heterologous expression, 220 deltamethrin, 219f differential pyrethroid sensitivity, 223, 225, 225f human sodium channels, 225 overview, 217 pyrethroid heterogeneity, 218 rat sodium channel isoforms, 223, 224f rats, 221, 221f, 222f, 223f S-bioallethrin, 219f sodium channel isoforms, 219, 220f target heterogeneity, 219 Pyrethroid heterogeneity, 218 Pyrethroid isomers chiral recognition model, 35f chiral separation, 34 chrysanthemic acid moieties, stereochemical configurations, 33f cypermethrin isomer separation, 39f gas chromatogram, 36f HPLC vs. GC, 37t LC chromatogram, 37f overview, 31 prallethrin isomers, efficacy against houseflies, 34t single isomers, 32 structure-activity relationship, 33 Pyrethroid pesticides bifenthrin, 21f, 22t CAS numbers, 27 cyfluthrin, 21f, 26t defined, 20 deltamethrin, 22f diastereoisomer, 23, 25f, 25t enantiomer, 23, 25f, 25t overview, 19 stereoisomers, 22, 25f, 25t technical products, 22 Pyrethroid transport age-dependent acute neutotoxicity, rats, 56 blood-brain barrier (BBB), 58 Caco-2 cells, 60f, 61f, 62f deltamethrin, 61f, 62f gastrointestinal (GI), 58 overview, 55 PBPK modeling, children, 57 PBPK modeling, date, 57


Q

carboxylesterase hydrolysis, 261f chemoinformatics, 258 chirality, 246 computational details, 250 data analysis, 266 dataset preparation, 252 GC peaks, 265 GC/MS, 265 HPLC analysis, 266 inhibition studies, 266 overview, 245 pharmacophore models, 251f, 253f, 254f PLIF, 255f, 257f QSAR model, 251f, 258, 260f, 261f rat serum, incubations, 264 in silico workflow, 248, 249f structural bioinformatics, 252 in vitro dataset, 248, 250f

QSAR. See quantitative structure activity relationships (QSAR) Quantitative structure activity relationships (QSAR), 3


R Radioactivity disposition, percutaneous absorption, 106f Rat serum, incubations, 264 Rat sodium channel isoforms, 223, 224f Rats, age-dependent acute neutotoxicity, 56

S S-bioallethrin, 219f Single isomers, pyrethroid isomers, 32 Skin penetration cell, percutaneous absorption, 91f Skin permeability constants, percutaneous absorption, 96t Skin transport, percutaneous absorption, 88f Sodium channel isoforms, 219, 220f Solvent Kp determinations, percutaneous absorption, 96 Source-to-outcome continuum, 5f Stereoisomers, 22, 25f, 25t Stereoselective metabolism modeling, pyrethroids carboxylesterase activity, 266

T Target heterogeneity, 219

V Vapor exposure, excised skin, 93f

X Xenobiotic metabolism, 152


brain AChE enzyme activity, 204 f ChE activity determination, 199

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