k

Index

abnormal mitotic spindles 180 adaptive immune system 332 abrin 758 adenosine 5′-phosphosulfate (APS) 76 absorption, distribution, metabolism, and adenosine triphosphate (ATP) 271 elimination (ADME) 10 adverse effects, endocrine active compounds acceptable daily intake (ADI) 13, 16, 649–650 29 adverse outcome pathway (AOP) 26, 469 acceptable exposure level (AEL) 342 aerodynamic diameter 628

acceptable risk 529 aflatoxin B1 (AFB1) 246, 247 acetamidofluorene 86 Agency for Toxic Substances and Disease Registry acetaminophen (APAP) 242 (ATSDR) 570–571 aconitines 753 AhR nuclear translocator (ARNT) 600 acrylamide (ACR) 277 airborne systemic poisons k acrylonitrile 128–130 carbon monoxide 686–689 k action potential 273 cyanide 689–691 activated glucuronic acid 74, 75 hydrogen sulfide 691–692 active substance, pesticides ALARA see as low as reasonably achievable molluscicides 715 (ALARA) regulatory toxicology of 716–717 alcohol dehydrogenase (ADH) 71 rodenticides 715–716 alcohol biotransformation 682 target organisms 706 ethanol 681–684 toxicity 707–709 methanol 680–681 toxicological effects 717 aldehyde dehydrogenase 71–72 acute damage 369 aldo-keto reductases (AKR) 72 acute methanol poisoning 360 aliphatic alcohol, solvents acute toxicity ethanol diesel engine emissions 736, 739 acute, chronic effects 682–684 metals 609 toxicokinetics 681–682 OECD TGs for in vivoCOPYRIGHTEDtests glycols MATERIAL684–685 dermal toxicity 393–394 methanol 680–681 examinations 394 alkaline single-cell gel electrophoresis 417–418 inhalation toxicity 394 alkaloids toxin limit test 394 aconitines 753 oral toxicity test 392–393 belladonna alkaloids 752 significance of 392 colchicine 754–755 PAHs 726 strychnine 753–754

Toxicology and Risk Assessment: A Comprehensive Introduction, Second Edition. Edited by Helmut Greim and Robert Snyder. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

k k

770 Index

allergic contact dermatitis (ACD) 302–303, 341 in vivo 664–666 α–Latrotoxin (A-LTX) 749 weight of evidence 666–667 alveolar macrophage (AM) 250, 629 xenoantiandrogens 661–662 Amanita muscaria 278 xenoestrogens 661–662 American Conference of Governmental Industrial antidotes 609 Hygienists (ACGIH) 18, 444–446 antiestrogens 664–665 2-amino-1-methyl-6-phenylimidazo- antivenom therapy 746 [4,5-b]pyridine (PhIP) 134 apoptosis aminomethylphosphonic acid (AMPA) 707 DNA repair 178 amyl nitrite 690 extrinsic pathway of 179 anaplerosis 105 intrinsic pathway of 178–179 androgen receptor (AR) 380, 385 p53 protein 178 agonists 657 premature senescence 177 antagonists 657 Arking’s theory of IGF-1 598 modes of actions 662 aromatase inhibitors 657–658, 665 androgens 665 aromatic amines 161 aneuploidy 174 arsenic metal 309, 611–613 animal testing arteriosclerosis 370 aspirin 467 aryl hydrocarbon receptor (AhR) 600–601 ban for cosmetics, in Europe 467–468 as low as reasonably achievable (ALARA) 27, cell cultures 468 32, 530 computer-aided methods 468 astrocytes 271 consumer safety 466–467 ataxia telangiectasia (AT) 174 ECVAM validations 463–465 ataxia-telangiectasia mutated (ATM) 190 experiments 461–462 Atomic Energy Act 570 IATA 466 Atomic Energy Commission (AEC) 570 k in vitro and in silico approaches 469 ATRad-3 related (ATR) protein 190 k OECD test guidelines 463–465 ATR-interacting protein (ATRIP) 170, 190 organo-typic cultures 468 atropine 226

reduce, refine, replace (3Rs-principle) 463 α2u-globuline-mediated effects 316 toxicological ignorance 468 Australian funnel-web spiders venoms 748–749 animal toxins autophagy 179 scorpions 747–748 axonopathy 275–277 snakes azole fungicides 710 bites 743 first aid 746 barbiturates 83, 84 hematotoxins 744–745 base excision repair (BER) system 165–167, hospital treatment 746 188–190 local damage 745 Bcl-2 family 178 myotoxins 744 behavioral neurotoxicology neurotoxins 743–744 exposure assessment 283–284 symptoms 745 neurobehavioral effects in humans spiders lead 293–294 Australian funnel-web 748–749 mercury 294–295 latrodectus 749–750 solvents 292–293 loxosceles 750–751 neurobehavioral methods antiandrogens see also endocrine active batteries 291, 292 compounds (EACs) cognitive functions 286–289 diethylstilbestrol 661 evaluation of 291 limited evidence 667 executive functions 286 modes of action personality characteristics 289, 290 in vitro 663 personality or emotional changes 287

k k

Index 771

psychomotor functions 286–289 occupational exposure 442 sensory functions 291 parameters symptom measurements 289, 290 high biological persistence 448 neuromorphological method 284–285 high vapour pressure substances 447 neuropathological methods 284–285 Phase I and Phase II products 447–448 neurophysiological methods 285 protein and DNA adducts 444 sensory evoked potentials 285 toxic effects 441 belladonna alkaloids 752 biotransformation of xenobiotics benchmark dose (BMD) 24 barbiturates 83, 84 benchmark-dose level (BMDL) 653 bioactivation reactions 87–90 Benton test 288 hepatic first-pass effect 81 β-lyase-mediated carcinogenicity 316 inhibition of biotransforming β-N-acetyl-glucosaminidase (NAG) 257 enzymes 84–85 bile salt export pump (BSEP) 240 metabolic enzymes induction 82–84 bioaccumulation potential 215 Phase II reactions bioavailability 41 acetylation 78 biocidal products, EU legislation 541–542 amino acid conjugation 77–78 bioconcentration 215 functionalization 62, 63 biological exposure indices (BEI) 444, 445 glucuronidation 74–76 biological guidance values (BLW) 445 glutathione S-transferases 78–80 biological limit values (BLV) 445 methylation 80 biological membrane sulfatation 76–77 active transport 37 Phase I reactions convective transport 37 ADH 71 facilitated diffusion 37 carbonyl-reducing enzymes 72 passive diffusion 36, 37 cytochrome P450 enzymes 63–69 k pinocytosis 37 epoxid hydrolases 73–74 k biological origin substances esterases and amidases 70–71 microorganisms active compounds 714 FMO 68–69 neem tree extracts 713–714 functionalization 62, 63 rotenone 713 prostaglandin synthase 69–70 viruses 714 reductive reactions 72–73 biological tolerance values (BAT) 445 reactive intermediates biomagnification 215 detoxifications 90–91 biomonitoring DNA interactions 92–96 analytical methods 444 lipids interactions 92 application of 440 proteins interactions 91–92 biochemical effect 440 species differences in 86–87 biological assessment values TCDD 62, 83 descriptive values 446–447 toxic effects 87, 88 health-based values 445–446 bipyridylium herbicides 709 reference values 446–447 bisphenol A (BPA) 656 risk-based values 446 bladder cancer 130–133, 315, 318–319 biological effect 440 blood-brain barrier (BBB) 268–269 biological material for 441–443 bloom syndrome 174 definition 440 Botulinum toxin (Botox) 279 of effects 5 Bowman’s capsule 312 of exposure 5 brainstem 268 external exposure 441 brain stem auditory-evoked responses 285 fundamental requirements 442 bromism 307 health risks 441 bronchoalveolar lavage fluid (BALF) internal exposure 441 256, 257

k k

772 Index

cadmium metal 613–614 carcinogenic natural products 161 Ca2+-independent receptor (CIRL) 749 Carcinogenic Risk Assessment 186 calmodulin 608 cardiac glycoside poisoning 755–756 carbamate insecticides 712 cardiomyopathy 368 carbon monoxide (CO) poisoning cardiovascular effects chronic, delayed effects 688–689 diesel engine emissions 740 effects 688 special particle effects 638–640 hypoxia 275, 279 cardiovascular system mechanism of action 687 structure and function pharmacokinetics 687–688 coronary blood vessels 366 signs and symptoms 688 excitation and conduction system 365 sources 686–687 myocardium 364, 365 therapeutic principles 688 vascular system 366

carbon tetrachloride (CCl4) 242, 673 toxic damage to carbonyl-reducing enzymes 72 coronary arteries and blood vessels carboxyhemoglobin (COHb) 686 369–371 carcinogen 595–596 excitation and conduction system 368–369 diesel engine emissions 737–738 myocardium 367–368 lead effects of 616 caretakers 173 metals classification of 611 caspases 178 PAHs 728–729 catalase 163 particle effects 637–639 cataract formation 360 vs. non-carcinogen fibers 633 cationic amphiphilic drugs (CAD) 260 carcinogenic aromatic amines 130 celiac disease 227–228 carcinogenicity cell nucleus 105 animal experiments 511 cellular defence mechanisms 194 k assumptions and limits of extrapolation cellular membranes 107–108 k accumulation of dose 522–523 Centers for Disease Control (CDC) 571 additivity 522 central nervous system (CNS) 267–269, 602 linearity 521–522 cerebellum 268 proportionality 522 ceruloplasmin 608 dose-response relations (DRRs) 511 chelates 609 epidemiological studies 511 chemical carcinogenesis linear extrapolation cancer development biological knowledge empirical data 513 aneuploidy 180 EPA method 514 apoptosis 177–179 extrapolation with straight lines 512 carcinogen-induced immortalization of cells ICRP method 514 179–180 straight lines, upper boundary estimates chromosomal instability 174–175 512–513 chromosome segregation 180 WHO method 514 colon cancer 172–173 multihit multistage models initiation 171–172 empirical evidence for 520 mutator phenotype 173–174 expansions and alternative models 520 neoangiogenesis 181 extrapolation to small doses 520–521 oncogenes 175–176 graphical representation of 519 progression 172 of time aspects promotion 172 dose-effect function 517 tumor suppressor genes 176–177 dose specification 516–517 two-hit hypothesis 173 environment carcinogenesis 515–516 DNA damage 160 non-linear extrapolation 518 aberrant non-duplex DNA forms 161 risk and survival 515 antioxidant mechanisms 163

k k

Index 773

cross-links 161 chromosome aberrations 414 damage to DNA bases 161 chronic damage 369 definition 160–161 chronic obstructive pulmonary diseases (COPD) endogenous 162 625, 736 exogenous 161 chronic organ toxicity 610 halting cell cycle progression 170–171 chronic toxic encephalopathy 292 lesions, DNA backbone 161 chronic toxicity 736, 739 prevention and repair of 162 cigarette smoking 370 tolerance 169–170 citric acid cycle 105 DNA repair clara cells 250 base excision repair 165–167 classification and labeling (C&L) of chemicals damage reversal mechanisms 164–165 17–18 definition 163 classification, labelling and packaging (CLP) 15, DSBs 168–169 536 MMR 168 clastogenic 423 nucleotide excision repair 167–168 Clean Air Act (CAA) 564–565, 585 non-genotoxic mechanisms Clean Water Act (CWA) 565, 585 definition 181 clonal selection 174 epigenetics 181–182 coal tar 309 tumor promoters 183–184 cocarcinogens 172 risk assessment 184–185 Codex Alimentarius Commission 532 tumor initiation 159 colchicine 754–755 tumor progression 160 colon cancer 172–173 tumor promotion 159–160 colony-forming units (CFU) 321, 322 chemically-induced cell death 115 colorectal cancer 133–135 chemical substances, defined 530 combustion-derived NP (CDNP) 371, 639 k chemical substances regulations, in EU comet assay 417–418 k EU legislation 525–528 Commission Regulation (EC) No. 440/2008 15 hazard potential 528–529 Committee for Risk Assessment (RAC) 580 precautionary principle 529–530 Committee for Socio-Economic Assessment risk assessment 528 (SEAC) 580 risk communication 528 compartment models risk governance 528 one-compartment model risk management 528 apparent volume of distribution 49 risk types 529 area under the concentration 52–54 Chemical Weapons Convention (CWC) 535 Bateman function 51–52 chloracne 306–307, 595 continuous administration 54 chlorinated methanes 673–674 definition 48 chlorine 695–696 extravascular administration 51–52 chloro acetaniline herbicides 708 intravascular administration, elimination, chloroform 675 total clearance, and half-life 50, 51 chloroquine 361 repeated administration 54–56 cholestasis 240 saturation kinetics 55–57 choreoathetosis 712 physiologically-based toxicokinetic models choroid 354 59–61 chromium metal 618–619 two-compartment model 56–59 chromosomal aberrations 423 competitive inhibition 44 chromosomal instability (CIN) 180 Comprehensive Environmental Response, amplifications 175 Compensation, and Liability Act deletions 175 (CERCLA) 565–566 inversions 175 consolidated legislation documents 528 translocations 174–175 constitutive androstane receptor (CAR) 83, 377

k k

774 Index

Consumer Product Safety Act (CPSA) 569 critical enzymes inhibition, signal Consumer Product Safety Commission (CPSC) transduction 114, 115 568–569 lipid peroxidation 108–110 contact dermatitis 463 redox systems disturbance 110–112 convective transport 37 synthesis of macromolecules 114 copper metal 619–620 transporters inhibition 114–117 coronary blood vessels toxin targets 98–99 structure and function 366 toxic damage to daidzein 656 cadmium 371 Dangerous Substances Directive 574 carbon disulfide 369 DDT see dichlorodiphenyltrichloroethane (DDT) carbon monoxide 370 death-associated proteins (DAPs) 179 cigarette smoking 370 death effector domain (DED) 118 fibers and particles 371 death-inducing signal complex (DISC) 179 lead 370 death receptors 117 nitrate esters 369–370 degradation of fatty acids 105 water hardness 370 Delaney Clause 563 cosmetic products 547–548 delayed-type hypersensitivity (DTH) reactions cross-linking and alkylating agents 161 337 cyanide (CN−) poisoning demyelination 276, 277 hypoxia 279–280 dendrites 269 intoxications 690 dendrotoxins 744 mechanism of action 689 deoxyribonucleic acid (DNA) 106 sources 689 derivation of no-effect levels (DNEL) 445 therapeutic principals 690–691 derived minimal effect levels (DMELs) 29–31 toxicokinetics 689–690 derived no effect level (DNEL) 16, 29–31 k cyanogenic glycosides 756–757 dermal irritation 8 k cycasin 228 dermal sensitization threshold (DST) 702 CYP1A2 133, 134 descriptive statistics 488–491 CYP2E1-mediated metabolism 128, 130 detoxifications 90–91 cytochrome c 178 diacylglycerole (DG) 172 cytochrome P450 (CYP) 63–69, 83, 85, dicarboximides fungicides 710 224 dichlorodiphenyltrichloroethane (DDT) 108 cytochrome P450-2E1 82 central nervous system 602–603 cytochrome P450 enzyme (1A1) 87 definition of 589 cytoskeleton 105 effect of 590 cytotoxicity 315–316 estrogen receptor antagonists 654–656 cell metabolites 599 cytoplasm components 105–106 dichloromethane 675–676 membrane system 103–104 diesel engine emissions structural elements 102, 104 carcinogenic effects 738–740 cell death gas phase of 734 apoptosis 115, 117, 118 humans exposure of 740 calcium homeostasis 118–120 international organizations 740–741 DED 118 mechanisms of 738–740 necrosis 115, 117, 118 new diesel 734 cell functions old diesel 734 animal and plant poisons 99–102 toxicity 737 chemicals 99, 102 acute 736 cellular targets of toxins carcinogenicity 737–738 ATP formation inhibition 112–114 chronic 736 cellular membranes 107–108 development/reproductive 737

k k

Index 775

genotoxicity 737 cascading effects 212 irritation/immunotoxicity 736 damping effects 212 toxicokinetics 735 definition 209–210 diesel engine exhaust fumes 738 dose/concentration-effect relationships 211 di-(2-ethylhexyl) phthalate (DEHP) 658 exposure assessments 214–215 diethylstilbestrol (DES) 661 fast-track and short-cut techniques 217–218 diflubenzuron 714–715 LOAEL 211 Digit Symbol Test (DST) 287 NOAEL 211 2,3-dimercaptopropanesulfonate (DMPS) 609 protection targets 210–211 4-dimethylaminophenol (4-DMAP) 690 risk assessment 216–217 dioxin response element (DRE) 600 test systems diphtheria toxin 277 freshwater systems 212–213 Dirty Dozen 585–586, 589 marine systems 213 disorders of movement 280 micro-, meso/macrocosm studies 214 disseminated intravascular clotting (DIC) 745 terrestrial systems 213, 214 dissimilar joint action 149–150, 157 EC regulation distal axonopathy 276 biocides 707 DNA damage response (DDR) system 188 PPPs 703–705 DNA polymerase I (Pol I) 170 toxicology 716 DNA polymerases 173 electron transport chain of mitochondria 105, DNA repair 106 apoptosis 178 electroretinograms 285 cellular reaction to DNA damage EMA committees, for medicinal products 538, apoptosis and necrosis 192 539 ATM and ATR 190–191 encephalopathy 280 base excision repair system 188–190 endocrine active compounds (EACs) k DNA adducts 191–192 adverse effects 649–650 k epigenetic mechanisms 192 dose–effect 659 intercellular communication, gap junctions low dose 659 192–193 perchlorate 651 chemical carcinogenesis sex hormones base excision repair 165–167 androgen receptor antagonists 657 damage reversal mechanisms 164–165 aromatase inhibitors 657–658 definition 163 compounds with combined effects 658 DSBs 168–169 estrogen receptor 654–657 MMR 168 thyroid hormones nucleotide excision repair 167–168 in blood 651–653 genes 173 in liver 653 DNA-strand breaks 111 PBDEs 653–654 dominant lethal test 423 TBBPA 654 domoic acid 278 thyroid gland 651 dose-effect relation 659, 662 thyroid peroxidase 651 dose-response relations (DRRs) endocrine disruptors 199 linear extrapolation 512–514 compounds 667 non-linear extrapolations 518, 521 definition 661 double-strand breaks (DSBs) 168–169, 190 potential 661 D-penicillamine 609 endocrine modes of action drug-induced ocular cicatricial pemphigoid 358 in vitro studies dying-back neuropathy 276 direct receptor binding 663 disadvantages 662 EACs see endocrine active compounds (EACs) steroid biosynthesis 663 ecotoxicology thyroid hormone metabolism 663–664

k k

776 Index

endocrine modes of action (continued) history of 450–451 in vivo indirect standardization 453–454 androgens and antiandrogens 665 meta-analysis 457–458 5α-reductase 665 observational study 454–455 aromatase 665 risk of disease 450–451 estrogens and antiestrogens 664–665 statistics 456–457 steroid and thyroid hormone metabolism epigenetic mechanisms for carcinogenesis 666 181–182 steroidogenesis 665 epoxid hydrolases 73–74 thyroid toxicity 665 error propagation 491–492 wildlife 666 erythrocytes endocrine system carbon monoxide poisoning 325 foetal development, HPG axis 381–383 erythropoiesis 323–324 hazard identification 386 hemoglobin function 324 hormones 372 hemolytic anemias 324–325 HPG axis 381–383 Escherichia coli 409, 410 risk assessment 386 estrogen receptor 654–657 risk assessment of 386 1,2-ethane diol see ethylene glycol sexual function in ethylene bis-dithiocarbamate 651 endocrine active substances 384–386 ethylenediaminetetraacetic acid (EDTA) 609 regulatory in vivo studies 383–384 ethylene glycol 684–685 structure and function ethylene thiourea (ETU) 651 hormonal balance in mammals 373, 374 EU Chemicals Agency (ECHA) 201 sex hormones 379–381 EU laws 527, 528 steroid hormone 373 EU legislation 544–545 thyroid (see thyroid hormones) biocidal products 541–542 k tissue hormones 373 on chemical substances in environment k endoplasmic reticulum (ER) 105, 385 air quality standards 553, 554 end replication problem 179 avoidance principle 552 5-enol pyruvyl shikimate 3-phosphate (EPSP) high level of protection 552 707 polluter pays principle 552–553 enterohepatic circulation 10, 46 precautionary principle 552 Environmental Protection Agency (EPA) 14, soil protection 556 514, 563 waste management 555–556 CAA 564–565 Water Framework Directive 553–555 CERCLA 565–566 on consumer products 546, 547 CWA 565 cosmetic products 547–548 FIFRA 567 dangerous chemicals, import and export of FQPA 567–568 537 RCRA 567 dangerous substances, groups of 537 TSCA 566–567 drinking water 543 environment carcinogenesis 515–516 EU laws 527, 528 enzyme induction, PHAHs 603–604 European legal acts, features of 526, 527 EPA see Environmental Protection Agency (EPA) food 542–543 epidemiology medicinal products, for human/veterinary use bias 459 537–540 British-doctor study 451–452 plant protection products 541 causality 459–460 primary legislation 526 chance 459 protection from ionizing radiation, by confounding 459 radioactive materials 550–551 direct standardization 452–453 safety of experimental study 455–456 chemical substances 535–536

k k

Index 777

medical devices 540, 541 lens 353–354 medicinal products 538, 539 metabolism 300 secondary legislation 526 ocular absorption 299 transport of dangerous goods 551–552 structure 297 Euratom Treaty 525 tear film 352 European Centre for the Validation of Alternative toxicology of Methods (ECVAM) 466 lids 352 European Chemicals Agency (ECHA) 15, 29, OECD TGs for in vivo tests 395–397 573, 708 posterior segment 354 European Commission 527 routes of delivery of xenobiotics European Commission Pesticides Database 706 blood flow 355 European Council 527 lacrimal drainage 355 European Food Safety Authority (EFSA) 186, ocular absorption 354–355 706 toxicology of European legal acts, features of 526, 527 acids 356–357 European Medicines Agency (EMA) 15 alkalis 356 European Parliament 527 cataract formation 360, 361 EUROQUEST 289 chemical injuries 355–356 EU Scientific Committee on Food in 2002 731 conjunctival irritation 357 EU Technical Guidance Document on Risk contact allergy 357–358 Assessment 5 cornea 358–360 excitation and conduction system inflammation 357 structure and function 365 mucocutaneous disease 358 toxic damage to retinal toxicity (see retinal toxicity) barium 369 toxic optic neuropathy 363 cadmium 368 k halogenated hydrocarbons 368 Fas-associated death domain protein k mercury 368–369 (FADD/Mort1) 179 excitatory amino acids 278 fasciculins 744 excretion 36 fatty acid hydroperoxides (FS-OOH) 163 intestinal tract 46 fatty liver/steatosis 241 kidneys 44–46 Federal Insecticide, Fungicide, and Rodenticide lung 46–47 Act (FIFRA) 567 mammary glands 47 ferric III phosphate 716 skin 47 ferritin 608 executioner caspases 178 fiber dimensions 633–634 existing active substance, EU legislation 541 fibre toxicity 645 exogenous DNA damaging agents 161 fibrosis 238–240 expanded single tandem repeat assay (ESTR) Fick’s first law 41 435 first-order kinetics 44 exposure guide value (ELW) 696 first-pass effect 40, 41 Extended One-Generation Reproductive Toxicity 5α–reductase 665 Study (EOGRTS) 577 flash-evoked potentials 285 eye flavin adenine dinucleotide (FAD) 68 anterior segment flavin-dependent monooxygenases (FMOs) 68, acidic and alkaline corrosion 301 69 ciliary body 353 follicle-stimulating hormone (FSH) 197, 380 conjunctiva 352 Food and Agriculture Organization (FAO) 531, cornea 353 532, 706 corneal limbus 352–353 Food and Drug Administration (FDA) 561–562 iris and chamber 353 food contact materials (FCMs) 546 irritation and contact dermatitis 301–302 Food, Drug, and Cosmetic Act (FDCA) 562–563

k k

778 Index

food-induced allergy 227 genetic endpoints of 408 Food Quality Protection Act (FQPA) 567–568 mammalian cells (see mammalian cells) formaldehyde (HCHO) 694–695 xenobiotic metabolism 420–421 formaldehyde dehydrogenase (FOD) 681 in vivo mutagenicity tests fractional factorial design 152 germ cells 429–437 fragrance materials somatic cells 424–429 chemical senses 699 PAHs 727 risk assessment of 700–702 germ cells toxicity 699–700 chromosome mutations in 429–433 Friedel–Crafts catalyst 591 gene mutations in 433–437 full factorial design 152 GI tract see gastrointestinal (GI) tract fungicides 709–710 global genomic repair (GGR) 167 Globally Harmonised System of Classification and gamma-aminobutyric acid (GABA) 273 Labelling of Chemicals 536 gastrointestinal (GI) tract Globally Harmonized System (GHS) 17, 340 definition 221 gluconeogenesis 105 function 222–223 glucose-6-phophate dehydrogenase 122, 163 microbiota 223 glucose-6-phosphate dehydrogenase deficiency structure 221–222 (G6PD) 325 tissue repair 223 glucuronidation 74–76 toxicology glutamic acid 278 cytotoxic effects 226–227 glutathione (GSH) 111, 112 disturbance of function 226 glutathione peroxidases 163 experimental methods 229–230 glutathione reductase 163 immune reactions 227–228 glutathione S-transferase (GST) 78–80, 129, 163 toxic damage 230, 231 glycols 684–685 k xenobiotics in glycosides 755–757 k absorption of 223–224 glycosylphosphatidylinositol (GPI) biosynthesis biotransformation of 224–225 413 enterohepatic circulation of 225–226 glyphosate herbicides 707–708 Gatekeeper genes 174 gonadotropin-releasing hormone (GnRH) 197, General Food Law regulation 542 380 General Product Safety Directive (GPSD) 546, good laboratory practice (GLP) 14, 15, 390, 547 534 general steroidogenesis 665 G-protein-coupled receptors (GPCR) 144–145 Genetic Susceptibility to Environmental granular bio-durable particles (GBP) 635, 646 Carcinogens (GSEC) 136 granular nanoparticles 646–648 genistein 657 granulocytes 326–327 genome-wide association studies (GWASs) 137, gut-associated lymphoid tissue (GALT) 227 138 genotoxic carcinogens, threshold effects 25, 27 Haber–Weiss reaction 255 cellular reaction to DNA damage halogen acne 306–307 DNA repair 188–193 halogenated aliphatic hydrocarbons 672–673 mechanism 187, 188 halting cell cycle progression 170–171 development of cancer 187 haplotype 125–126 dose-dependent reactions 193 Hashimoto thyroiditis 346 genotoxicity hazard identification definition 408 acute toxicity studies 8 diesel engine emissions 737, 739 carcinogenicity 9–10 in vitro test systems chronic studies 8 bacterial test systems 409–411 genotoxicity 9 cell transformation assays 420 institutions 6, 7

k k

Index 779

irritation 8–9 exposure assessment 28 phototoxicity 9 genotoxic carcinogens 27 qualitative description 22 hazard characterisation 22, 24–25 reproduction and development 10 human data 25–26 toxicokinetics 10–11 non-genotoxic carcinogens 28 Hazardous and SolidWaste Amendments (HSWA) qualitative and quantitative method 22 567 risk characterisation 28–29 hazard potential, of chemical substances in silico tools 26 528–529 terminology 22–24 headache 369 in vitro models 26 health-based limit values 717 human repeat insult patch test (HRIPT) 342 health hazards, classification of 529–531 hydrocarbons hematopoietic system (bone marrow and blood) partition coefficients for 36, 37 bone marrow niche 323 solvents for CFU 320, 321 benzene 678–679 components of 320, 321 gasoline and kerosene 677 depression of bone marrow function 329 n-Hexane 677 leucocytes 326–328 toluene 679–680 leucocytosis and leukemias 329–330 hydrochloroquine 361 platelets/thrombocytes 328 hydrogen chloride (HCl) 694 toxicological features, circulating blood cells hydrogen fluoride (HF) 694

methemoglobinemia 325–326 hydrogen sulfide (H2S) poisoning red blood cells 323–325 effects 692 hematotoxins 744–745 mechanism of action 691 hepatocyte growth factor (HGF) 235 pharmacokinetics 691–692 hepatocytes 232 sources 691 k hepatotoxicants 482 therapeutic principals 692 k herbicides hydroxocobalamine 691 bipyridylium herbicides 709 hypothalamic–pituitary–gonadal (HPG) axis chloro acetaniline herbicides 708 compound structures, effects 655 glyphosate 707–708 foetal development of 381–383 phenoxy herbicides 709 human drugs 649–650 triazine herbicides 708–709 hypothalamus-pituitary-thyroid (HPT) axis urea herbicides 709 foetal development of 377 hereditary non-polyposis colon cancer (HNPCC) human drugs 649–650 173 hypoxanthine guanine phosphoribosyl transferase heritable translocation assay 423 (HPRT) activity 411–412 heterocyclic amine metabolism 134, 135 hypoxia 279 hexachlorobenzene (HCB) 346, 590–591, 599 hexachloro butadiene (HCBD) 317 immune system hexachlorophene 277 adaptive 332 2,5-Hexanedione (HD) 277 advantage 332 hormone responsive elements (HREs) 380 antigen recognition 333–334 hormones 372 B lymphocytes 336 human health risk assessment 718–720 chemical immunosuppression 348–350 feasibility and achievability issues 32 chemical-induced autoimmunity 345–347 importance of 32 elicitation thresholds 340–342 OELs 30–32 human studies 340 precautionary principle 31–32 immunologic tolerance 336–337 principles of immunostimulation by chemicals 346–348 animal data 26 innate 332 application of assessment factors 29 neutrophils 332–333

k k

780 Index

immune system (continued) International Programme on Chemical Safety risk assessment of (IPCS) 531 oral and parenteral sensitization 345 International System of Radiological Protection respiratory tract sensitization 343, 344 533 skin sensitization 342–343 International Uniform Chemical Information sensitization and allergy 337–339 Database (IUCLID) 533 T lymphocytes 334–335 Inter-Organization Programme for the Sound in vitro studies 339–340 Management of Chemicals (IOMC) immunosuppression 596–597 533 immunotoxicity, diesel engine emissions 740 intoxications 690 inferential statistics 496–504 ionized organic substances 36 inflammatory phagocytes 632 iron metal 620–622 initiator caspases 178 irritant gases innate immune system 332 chlorine 695–696 inorganic lead 277 formaldehyde 694–695 insect growth regulators 714–715 hydrogen chloride 694 insecticides 711–712 hydrogen fluoride 694 insulin-like growth factor-1 (IGF-1) 598 isocyanates 696 Integrated Approaches to Testing and Assessment nitrogen oxides 696–697 (IATA) 466 ozone 697–698 for Serious Eye Damage and Eye Irritation phosgene 697 397 smoke inhalation 698 for Skin Irritation/corrosion 395 sulfur dioxide 695 International Agency for Research on Cancer ischemia 280 (IARC) 531, 597, 730, 734, 740 isocyanates 696 International Atomic Energy Association (IAEA) isoflavonoids 657 k 533, 535 k International Chemical Safety Cards (ICSC) Joint FAO/WHO Expert Committee on Food project 532 Additives (JECFA) 532 International Civil Aviation Organization (ICAO) Joint Meeting on Pesticide Residues (JMPR) Technical Instructions 552 532, 706 International Commission for Ray Protection (ICRP) 514 kainic acid 278 International Commission on Radiological kerosene 677 Protection (ICRP) 533 kidneys International Conference on Harmonisation of blood filtration 312–313 Technical Requirements for Registration carcinogenic effects 318 of Pharmaceuticals for Human Use phase I and phase II enzymes 311 (ICH) 15, 535, 540 toxicology International Conference on Harmonization (ICH) glomerulus 314 199 heavy metals 316–317 international co-operation, EU role 531–533 hydrocarbons 315–316 International Council of Chemical Associations intoxication 313–314 (ICCA) program 14 polyvalent alcohols 317 International Fragrance Association (IFRA) 701 tubular system 314 International Labour Office (ILO) 532 tumors of 318 International Maritime Dangerous Goods (IMDG) kinetics 604–605 Code 552 Kupffer cells 232 International Maritime Organization (IMO) 532 lactate dehydrogenase (LDH) 257 International Organization for Standardization Langerhans cells 340 (ISO) 642 latrodectus spiders venoms 749–750

k k

Index 781

lead metal 614–616 risk assessment process 6 lectins 757 lowest observed effect concentrations (LOECs) leucocytes 211, 342 granulocytes 326–327 loxosceles spiders venoms 750–751 lymphocytes 327 lung cancer 262–263 monocyte/macrophage system 328 luteinizing hormone (LH) 380 lifetime weighted average exposure (LWAE) Lyell Syndrome 303 283–284 lymphocytes 327 Li Fraumeni syndrome 174 lysosomes 105 ligand-receptor interactions biological consequences of major histocompatibility complex (MHC) 228, agonistic effects 143 333–334 antagonistic effects 143–144 malignant transformation 420 law of mass action 141 mammalian cells membrane-bound hormone 141 alkaline elution 417 neurotransmitter receptors 141 chromosome aberrations 414 linuron 657 comet assay 417–418 lipid peroxidation 108–110 DNA binding 416 lipid-soluble steroid hormones 380 DNA repair assays 419 lipopolysaccharides (LPS) 232 DNA strand breaks Induction 416–417 liver gene mutation tests 411–412 acetaminophen 242 HPRT gene mutation test 412–413 bile formation 234–235 indicator tests 416 cell death 237–238 micronucleus test 415–416 cell types 232 SCEs 418–419 cholestasis 240 TK+/−gene mutation test 413–414 k cirrhosis 238 UDS 419 k concentration dependent vs. idiosyncratic mammalian reproductive cycle 196 hepatotoxicity 245–246 manganese metal 622–623 endogenous metabolism 234–235 margin of exposure (MOE) 6, 653 fibrosis 238–240 margin of safety (MOS) 216, 666 hepatotoxic compounds maximal tolerated dose 9, 10 allyl alcohol 244 maximum residue level (MRL) 543 APAP 242–244 mechanism of action CCl4 242–244 aryl hydrocarbon receptor 600–601 ethanol 244–245 carbon monoxide 687 increased liver weight 246–247 central nervous system 603 inflammation 241–242 cyanide 689 interspecies differences 247 hydrogen sulfide 691 in vitro systems 247 PAHs 729–730 liver tumors 246 PEPCK 601–602 microstructure 232, 233 UROD 602–603 myths of 247–248 membrane-bound sulfotransferases 76 local lymph node assay (LLNA) 9, 339 Mendelian diseases 136 loss of hearing 280 mercury and mercury compounds, exports of loss of heterozygosity (LOH) 173 537 low acute toxicity 635 mercury metal 616–618 lowest observed adverse effect level (LOAEL) messenger-ribonucleic acid (mRNA) 106 in behavioural toxicology 284 metabolites biological assessment values 445–446 DDT 599 ecotoxicology 211 saturation kinetics 43–44 POD 25, 29 toxicokinetics 43–44

k k

782 Index

metaldehyde 716 cumulative exposure 149 metallothionein 608 joint action metals direct chemical-chemical interaction 150 acute toxicity 609–610 dissimilar 149–150 aspects 607–608 similar 150 bioavailability importance 608–609 toxicokinetic interaction 150 carcinogenicity 610–611 polycyclic aromatic hydrocarbons 157 chronic organ toxicity 610 safety evaluation proteins 607 dissimilar joint action 157 toxic effects of 607 flow chart for 154 toxicology of individual constituents 155–156 arsenic 611–613 interaction 157 cadmium 613–614 number of fractions 155 chromium 618–619 similar joint action 156–157 copper 619–620 single entity mixture 154–155 iron 621–622 toxicity study design of lead 615–616 mixtures/combinations 151–152 manganese 622–623 simple mixture 148–149 mercury 616–618 specified combination 149 nickel 623–624 molluscicides 715 methoxychlor (MXC) 654–656 monoamine oxidase (MAO) 224 methylation 80 morphine 226 methylbenzene see toluene mucociliary clearance 629–631 methylguanine-DNA methyltransferase (MGMT) muscimol 278–279 163 mutator phenotype 173–174 methyl mercury (MeHg) 274 myocardium 364, 365 k methyl methanesulfonate (MMS) 184 structure and function 364, 365 k 1-methyl 4-phenyl 4-propionoxypiperidine toxic damage to (MPPP) 274–275 antimony 367 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine arsenic 367 (MPTP) 274–276 arsines 367 methyl tert-butyl ether (MTBE) 677 cadmium 367 Michaelis-Menten equilibrium 141 cobalt 367 Michaelis-Menten kinetics 43, 44 ethanol 367 microcystins (MCs) 114 lead 367 microglia 271 myotoxins 744 micro RNAs (miRNAs) 475 microsatellite instability (MIN) 180 N-acetylation 78 microsomal epoxide hydrolases 73–74 N-acetyl-p-benzoquinone imine (NAPQI) 244 microsomes 63 nanomaterials toxicology midbrain 268 granular nanoparticles 646–648 minimal risk level (MRL) 29 mode of toxic action 646 Minimum Information About a Microarray nanotoxicodynamics 645–646 Experiment (MIAME) 480 nanotoxicokinetics 644–645 miRNAs 475 types of 647 mismatch repair (MMR) 168 nanoparticles (NPs) mitochondria 105, 178 deposition of 636 mitogen activated protein (MAP) 739 fibrous 645–646 mitotic spindle checkpoints 180 granular 646–648 mixture, defined 530 toxic mechanisms of 637 mixtures and combinations of chemicals nanotoxicodynamics 645–646 complex mixture 149 nanotoxicokinetics 644–645

k k

Index 783

narcotic effect 107 nonylphenol (NP) 656 nasopharyngeal (NP) region 249–250 no observed adverse effect level (NOAEL) 596, National Adult Reading Test (NART) 287 659 National Institute for Occupational Safety and ADI 13, 14 Health (NIOSH) 560–561 animal test 469 NAT2 polymorphism 131 in behavioural toxicology 284 natural toxins 99–101 biological assessment values 445–446 neoangiogenesis 181 ecotoxicology 211 nephrotoxicants 482 non-genotoxic carcinogens 18 nervous system OECD TGs for in vivo tests 398–400 neurotoxins pesticidal active substances 716–717 axonopathy 275–277 POD 29 clinical signs and symptoms 279–281 threshold 24 demyelination 276, 277 uncertainty analysis 16 neuropathy 274–276 no observed effect concentrations (NOECs) 211, neurotransmission effects 277–279 342 structure and function of no observed genotoxic effect (NOGEL) 193 cells of 269–273 noxious gases central nervous system 267–269 airborne systemic poisons peripheral nervous system 265–267 carbon monoxide 686–689 transmission of neuronal information cyanide 689–691 264–265 hydrogen sulfide 691–692 Neurobehavioral Evaluation System (NES) 291 irritant gases neurogenic inflammation 637 chlorine 695–696 neurons 269, 270 formaldehyde 694–695 neuropathy 274, 275 hydrogen chloride 694 k MeHg 274 hydrogen fluoride 694 k MPTP 274–275 isocyanates 696 TMT 276 nitrogen oxides 696–697 neurotoxicity of lead 616 ozone 697–698 neurotoxins 744–745 phosgene 697 neurotransmission 272–273 smoke inhalation 698 neurotransmitters 273 sulfur dioxide 695 neutrophils 332–333 respiratory tract irritants 692–694 new active substance, biocidal product 541 Nuclear Regulatory Commission (NRC) 569 n-Hexane 677 nucleotide excision repair (NER) 163, 167–168 nickel metal 623–624 nicotinamide adenosine dinucleotide (NAD) 105 occupational exposure limits (OELs) nitrilotriacetic acid (NTA) 317 acceptability of risk 30–31 nitrogen oxides (NO2) 696–697 margins of safety 30–31 nitrosamine formation, stomach 224, 225 SCOEL 30 N-nitroso compounds 161 Occupational Safety and Health (OSH) Act 560 NOAEL see no observed adverse effect level Occupational Safety and Health Administration (NOAEL) (OSHA) 14 no-expected sensitization induction level (NESIL) octachlorodibenzo-p-dioxin (OCDD) 587 342 ocular absorption 354–355 non-alcoholic steatohepatitis (NASH) 238 oestrogen receptors 385 non-genotoxic carcinogens 27, 28 oestrogens 381, 382 non-genotoxic mechanisms 181–184 okadaic acid (OA) 114 non-homologous end joining (NHEJ) 163, 169 oligodendrocytes 271 non-steroidal anti-inflammatory drugs (NSAIDs) oocyte maturation 197 227 optic nerve 354

k k

784 Index

oral sensitization 345 cytotoxic effects 226–227 oral toxicity test 392–393 definition 221 Organisation for the Prohibition of Chemical disturbance of function 226 Weapons (OPCW) 535 experimental methods 229–230 Organization for Economic Co-operation and function 222–223 Development (OECD) 199–201, 337, immune reactions 227–228 340, 533 microbiota 223 Organization for Economic Cooperation and structure 221–222 Development test guidelines (OECD tissue repair 223 TG) 385, 386, 534 toxic damage 230, 231 animal testing 463–465 xenobiotics in 223–226 in vivo tests kidneys 311–319 acute toxicity 392–394 liver control animals 391–392 acetaminophen 242 exposure route 391 bile formation 234–235 eye irritation 395–397 cell death 237–238 healthy animals 391 cell types 232 OECD TG 424 406 cholestasis 240 OECD TG 426 406 cirrhosis 238 OECD TG 440 406 concentration dependent vs. idiosyncratic reproductive toxicity 401–406 hepatotoxicity 245–246 skin irritation 395, 396 endogenous metabolism 234–235 skin sensitization 397 fibrosis 238–240 statistical evaluation 392 hepatotoxic compounds 242–245 test substance 391 increased liver weight 246–247 toxicity after repeated dosing 398–401 inflammation 241–242 k OECD TG 401 392 interspecies differences 247 k OECD TG 407 378 liver tumors 246 OECD TG 420 392, 393 microstructure 232, 233 OECD TG 423 392, 393 myths of 247–248 OECD TG 425 392, 393 porphyria 241 OECD TG 433 394 regeneration 235–237 OECD TG 436 394 steatosis 241 OECD TG 440 385, 406 in vitro systems 247 OECD TG 441 385, 406 xenobiotic metabolism 234–236 organophosphate derivatives (OPDs) 278 nervous system (see nervous system) organophosphates (Ops) 226, 361, 711–712 respiratory system organ toxicology allergy and asthma 261–262 behavioral neurotoxicology (see behavioral anatomy 249 neurotoxicology) epithelia and cell types 252, 254 cardiovascular system 364–371 function 252–254 endocrine system lung cancer 262–263 hazard identification 386 nasopharyngeal (NP) region 249–250 hormones 372 protective systems 254–256 HPG axis 381–383 pulmonary (P) region 250–252 risk assessment 386 target for toxicity 256–261 sexual function 383–386 toxic effects, inhaled materials 263 structure and function 373–381 tracheobronchial (TB) 250 tissue hormones 373 skin (see skin) eye 355–363 oxidative phosphorylation 105 gastrointestinal tract oxidative stress 110, 631–633

cancer 228–230 ozone (O3) 697–698

k k

Index 785

PAHs see polycyclic aromatic hydrocarbons target organisms 706 (PAHs) toxicity 707–709 painter’s syndrome 292 biological origin substances 713–714 parasympathetic nervous system 266 classification 718 parenteral sensitization 345 fungicides 709–710 particle deposition 626–628 human health risk assessment 718–720 particle surface with polymers (PVNO) 635 insect growth regulators 714–715 particle toxicology insecticides 711–713 deposition 626–628 plant protection products 710 and effects 627 toxicological effects 717 inflammation 631–633 phagocytic cells 332 lung overload 629–631 PHAHs see polyhalogenated aromatic mucociliary clearance 629–631 hydrocarbons (PHAHs) nanoparticles 636–637 pharmacokinetics oxidative stress 631–633 carbon monoxide 687–688 properties 627 hydrogen sulfide 691–692 absorbed components 635–636 phenobarbital 172 bio-persistence 633 phenols 757 dimensions 633–634 phenothiazines 362–363 soluble components 635–636 phenoxy herbicides 709 surface area 634–635 phenylpropanoids 757

surface reactivity 635 phosgene (COCl2) 697 shape and density 628–629 3′-phosphoadenosine-5′-phosphosulfate (PAPS) special particle effects 76, 77 carcinogenicity 637–639 phosphoenolpyruvate carboxykinase (PEPCK) cardiovascular effects 639–640 601–602 k translocation 631 physiologically based pharmacokinetic (PBPK) k particulate matter (PM) 371 models 389 passive diffusion 36, 37, 47 physiologically-based toxicokinetic models pathogen-associated molecular patterns (PAMP) 59–61 227, 332 phytoestrogens 656 pattern-recognition receptors (PRR) 332 Pig-a assay 413, 423, 424 pentachlorophenol (PCP) 581–582, 651–653 plant protection products 541 PEPCK see phosphoenolpyruvate carboxykinase plant protection products (PPPs) (PEPCK) active substances 704 perchlorate 651 consumer protection 719–720 perchlorethene 673 EC regulation 703–705 perfusion limited model 60 herbicides 705 peripheral distal axonopathy 276 regulatory toxicology 716 peripheral nervous system (PNS) 265–267, 269, plant toxins 272 alkaloids 752–755 peroxidase 69 glycosides 755–757 peroxisomes 105 lectins 757 persistent, bioaccumulative, and toxicity (PBT) phenols and phenylpropanoids 757 criteria 218 terpens and terpenoids 758–759 persistent organic pollutants (POPs) 537, 585 plate incorporation assay 410 Pesticide Residue Intake Model (PRIMo) 719 podophyllin/podophyllotoxin 757 pesticides point of departure (POD) 24, 25 active substances polybrominated diphenyl ethers (PBDEs) molluscicides 715 653–654 regulatory toxicology of 716–717 polychlorinated biphenyls (PCBs) 588–589, rodenticides 715 654

k k

786 Index

polychlorinated dibenzodioxins (PCDDs) 47 porphyria 241 biotransformation 603 positive endexpiratory pressure (PEEP) 693 PHAHs 586–588 postsynaptic neurotoxins 743–744 toxicity 592 PPPs see plant protection products (PPPs) polychlorinated dibenzofurans (PCDF) 47 pre-and postnatal toxicology PHAHs 586–588 congenital human malformations 205–207 toxicity 592 drug effects principles, pregnancy 201–204 polycyclic aromatic hydrocarbons (PAHs) 161 drug metabolism in pregnancy 204 biological monitoring 725–726 embryonic and fetal toxicology 204–205 classifications of 727 endocrine disrupters 208 environment occurrence 723–724 lactation 207–208 mechanisms of action 729–730 predicted no-effect concentrations (PNECs) 216 molecular structures of 723 predictive toxicogenomic 481–483 national and international organisations PredTox 484 730–731 Pregnan X receptor (PXR) 83, 377 particles 635 preincubation assay 410 physico-chemical properties 722 premature cataract formation 359 skin cancer 309 presynaptic neurotoxins 743 toxicity primary carcinogens 172 acute toxicity 726 principle of proportionality 527 after repeated exposure 726 principle of subsidiarity 526–527 carcinogenicity 727–728 Prior Informed Consent (PIC) Regulation 537 equivalency factors for 731–732 probability distribution 492–496 genotoxicity 727 probit analysis 506–507 local toxicity and irritancy 726 proliferation-dependent nuclear antigen (PCNA) reproductive 729 166 k sensitisation and immunotoxicity 726 promoters 172 k polyethoxylated (POE) 708 1,2-propane diol see propylene glycol polyhalogenated aromatic hydrocarbons (PHAHs) propionibacterium acnes 307 DDT 589–590, 599 propylene glycol 684–685 Dirty Dozen 585 prostaglandin G2 (PGG2) 69 enzyme induction 603–604 prostaglandin H2 (PGH2) 69 hexachlorobenzene 590–591, 599 prostaglandin synthase 69, 70 kinetics 604–605 protein kinase C (PKC) 172 mechanisms of action protein phosphatases (PPPs) 114 aryl hydrocarbon receptor 600–601 proto-oncogenes 172, 176 central nervous system 602 pulmonary circulation 366 PEPCK 601–602 pulmonary (P) region 250–252 UROD 602–603 purified cytochrome P450 enzymes 65 metabolism 603 pyrethrins 712–713 PCDDs/PCDFs 586–588 pyrethroids 712–713 physico-chemical properties 591–592 polychlorinated biphenyls 588–589 quantitative reverse transcriptase polymerase chain toxicity reaction (qRT-PCR) 477 carcinogenicity 595–596 quantitative structure activity relationships chloracne 595 ((Q)SARs) 26, 27 chlorinated dibenzodioxins 592–595 immunosuppression 595 REACH see Registration, Evaluation, reproductive toxicity 596–597 Authorization and Restriction of polymorphism 123 Chemicals (REACH) polyvinyl chloride (PVC) 656 REACH Registration process 29 poorly soluble particles (PSP) 631, 635, 646 reactive nitrogen species (RNS) 162, 631

k k

Index 787

reactive oxygen species (ROS) 607, 631, 737 oocyte maturation 197 receptor-mediated mechanisms spermatogenesis 197–198 ligand-receptor interactions 141–144 international test methods 199–200 Michaelis-Menten equilibrium 141 pre-and postnatal toxicology signal transduction congenital human malformations 205–207 GPCR 144–145 drug effects principles, pregnancy 201–204 ion channels 145–146 drug metabolism in pregnancy 204 nuclear receptors 146–147 embryonic and fetal toxicology 204–205 RTK 146 endocrine disrupters 208 receptors tyrosine kinases (RTK) 146 lactation 207–208 reciprocal translocations 423 Research Institute for Fragrance Materials (RIFM) recommended exposure levels (RELs) 29 701 red blood cells see erythrocytes Resource Conservation and Recovery Act (RCRA) reference concentration (RfC) 29 567, 571 reference dose (RfD) 29, 653 respiratory system Registration, Evaluation, Authorization and allergy and asthma 261–262 Restriction of Chemicals (REACH) anatomy 249 14, 15, 31, 445, 468, 573, 583, 699 function 252–254 authorization 579 lung cancer 262–263 downstream users 582 protective systems 254–256 ECHA, status and function of 580 structure European Commission, role of 581 nasopharyngeal (NP) region 249–250 evaluation process pulmonary (P) region 250–252 compliance check 578 tracheobronchial (TB) 250 decision-making procedure 579 target for toxicity examination of testing proposals 578 BALF 256, 257 k substance evaluation 579 gases 260 k historical development 574 particles 257–260 joint registration of same substances 576–577 substance-specific pulmonary toxicity Member States, role of 581–582 260–261 registration dossiers 576 toxic effects, inhaled materials 263 Regulation (EC) No 1907/2006 29 respiratory tract irritants 692–694 restriction process 579–580 respiratory tract sensitization 343, 344 safety concept 575 retina 354, 359–360 substances, mixtures and articles 574–575 retinal toxicity 360 testing and assessment strategy 577–578 chloroquine 361 regression analysis 504–506 clofazimine and methanol ingestion 363 Regulation (EC) No. 1223/2009 15 desferrioxamine 363 renal clearance 45 hydrochloroquine 361 repeated open application tests (ROATs) 341 ibuprofen 363 replication protein A (RPA) 191 indomethacin 363 reproductive toxicity 596–597 isoretinoin 362 developmental toxicity 401–402 lead 360 fertility 401–406 methanol 360–361 reproductive toxicology organophosphates 361 characteristics of 196–197 phenothiazines 362–363 definition 195 sildenafil 362 female and male fertility, adverse effects solvent 361 cleavage divisions and implantation tamoxifen 362 198–199 vigabrantin 362 fertilization 198 rheumatoid arthritis 346 OECD 199 ricin 758

k k

788 Index

Rio Conference on Environment and Development biosynthesis 379–380 16 biosynthesis of 663 risk assessment process compounds with combined effects 657–658 acute toxicity studies 8 estrogen receptor 654–657 ADI 13 estrogens 664–665 carcinogenicity 9–10 metabolism 381, 382 chronic studies 8 regulation of synthesis 380–381 dose-response curves 3, 6 target cells effect 380 exposure assessment 4–5 short-chain dehydrogenase/reductases (SDR) 72 genotoxicity 9 sildenafil 362 hazard identification 2–3 similar joint action 150, 156–157 institutions 6, 7 single nucleotide polymorphism (SNP) 125 irritation 8–9 sinusoidal endothelial cells 240 LOAEL 6 sister chromatid exchanges (SCEs) 418–419 NOAEL 6 skin phototoxicity 9 function reproduction and development 10 dermal absorption 298–299 reversible and irreversible effects 6 excretory function 299–300 toxicokinetics 10–11 metabolism 300 toxic potency 3 OECD TGs for in vivo tests 395 risk, defined 529 sensitizers 341 risk management measures (RMM) 22 structure 296–297 RNA-induced silencing complex (RISC) 475 toxicology of rodenticides 715 acidic and alkaline corrosion 301 rough endoplasmic reticulum (rER) 105 allergic contact dermatitis 302–303 chloracne 306–307 k Saccharopolyspora spinosa 714 disturbances of pigmentation 307–309 k Salmonella gene mutation test 411 hair loss 306 Salmonella typhimurium 409, 410 irritation and contact dermatitis 301–302 saturnine angina pectoris 370 photoallergy 304, 305 Schwann cells 271, 272 phototoxic reactions 304 Scientific Committee on Consumer Safety (SCCS) toxic epidermal necrolysis 303 701 tumors 309 Scientific Committee on Emerging and Newly urticaria 305 Identified Health Risks (SCENIHR) skin sensitization 397 701 slow acetylators 122 Scientific Committee on Health and small ubiquitin-related modifier (SUMO) 192 Environmental Risks (SCHER) 701 smoke inhalation 698 Scientific Committee on Occupational Exposure snakes venoms 743 Limits (SCOEL) 18, 30, 444, 445, 549 bites 743 sclera 354 first aid 746 SCOEL, see Scientific Committee on hematotoxins 744–745 Occupational Exposure Limits (SCOEL) hospital treatment 746 scorpions venoms 747–748 local damage 745 scrotal squamous cell cancer 309 myotoxins 744 secondary carcinogens 172 neurotoxins 743–744 second cancer 330 symptoms 745 serious adverse effects 280 sodium iodide symporter (NIS) 375, 651 sex hormones sodium nitrite 690 androgen receptor antagonists 657 solar retinopathy 360 androgens 665 solvent-induced psycho organic syndrome 292 aromatase inhibitors 657–658 solvents

k k

Index 789

aliphatic alcohols Stockholm Convention of 2001 585–586 ethanol 681–684 Strategic Approach to International Chemicals glycols 684–685 Management (SAICM) 533 methanol 680–681 Streptomyces avermitilis 714 hydrocarbons strobilurins fungicides 710 benzene 678–679 structural changes in sperm chromatin (SCSA) gasoline and kerosene 677 435 n-Hexane 677 structure-activity relationships 663 toluene 679–680 strychnine alkaloid 279, 753–754 intoxications 671 substance, defined 530 toxicology substance of concern 541 chlorinated methanes 673–674 Substances of Very High Concern (SVHC) 201 chloroform 675 sulfotransferases 76–77

dichloromethane 675–676 sulfur dioxide (SO2) 695 halogenated aliphatic hydrocarbons Superfund Amendments and Reauthorization Act 672–673 (SARA) 566 perchlorethene 673 superoxide dismutase (SOD) 256 tetrachloromethane 673–674 Swedish Performance Evaluation System (SPES) trichloroethene 673 291 somatic cells Switching Attention 287 chromosomal mutations in 424–427 Symbol Digit Substitution Test (SDST) 287, 288 gene mutations 427–429 sympathetic nervous system 266 space of Dissé 232 Syrian hamster embryo (SHE) assay 420 species sensitivity distribution (SSD) 216, 217 systemic circulation 366 specific estrogen receptor modulators (SERM) systemic lupus erythematosus (SLE) 346 146 spermatogenesis 197–198 k tamoxifen 362 k spiders venoms 2,3,7,8-TCDD see Australian funnel-web 748–749 2,3,7,8-tetrachlorodibenzo-p-dioxin latrodectus 749–750 (2,3,7,8-TCDD) loxosceles 750–751 T-cell receptor (TCR) 333 spinosad 714 TDI see tolerable daily intake (TDI) statistical analysis tebufenozide 715 descriptive statistics 488–491 technical regulations for hazardous materials error propagation 491–492 (TRGS) 694–695 experimental designs 507–508 telomerase 172, 179–180 inferential statistics 496–504 terpenoids 758–759 population and sample relationship 487–488 terpens 758–759 probability distribution 492–496 Test Digit Span 288 probit analysis 506–507 tetrabromobisphenol A (TBBPA) 654 regression analysis 504–506 2,3,7,8-tetrachlorodibenzo-p-dioxin Sprague-Dawley rats 487 (2,3,7,8-TCDD) 83, 151 statistical software 508–509 acute toxicity of 601 systematic errors 488 biotransformation reactions 62 steatosis 241 enzyme induction 603–604 stellate cell 232, 239 LD values for 594 stem cell model 322 50 metabolism 602 steroid biosynthesis 663 PCDDs/PCDFs 587 steroidogenic acute regulatory (StAR) protein TEFs 592 379 total body fat 594 steroid synthesis 385 tetrachloromethane 673–674 Stevens–Johnson syndrome (SJS) 303, 358 tetradecanoyl phorbol acetate (TPA) 172 stimulation index (SI) 339

k k

790 Index

tetraiodothyroacetic acid (TETRAC) 377 fragrance materials 699–700 Tetrodotoxin (Tedox) 279 iron 621–622 thalidomide 461 lead 615–616 6-thioguanine (6-TG) 413 manganese 622–623 thorotrast 246 mercury 617–618 three-pillar approach to risk governance 528 nickel 623–624 threshold of toxicological concern (TTC) 17 PAHs thyroglobulin (TG) 375 acute toxicity 726 thyroid gland 651 after repeated exposure 726 thyroid hormones carcinogenicity 727–728 biosynthesis 374–375 equivalency factors for 731–732 in blood 651–653 genotoxicity 727 HPT axis 377 local toxicity and irritancy 726 in liver 653 reproductive 729 metabolism 377, 663–664 sensitisation and immunotoxicity 726 PBDEs 653–654 PCDDs/PCDFs 592 receptor 654 pesticides active substance 707–709 regulation of synthesis 376–377 PHAHs target cells effect 375–376 carcinogenicity 595–596 thyroid gland 651 chloracne 595 thyroid peroxidase 651 chlorinated dibenzodioxins 592–595 in vitro screens 378 immunosuppression 596 in vivo toxicology studies 377–378 reproductive toxicity 596–597 thyroid peroxidase inhibition 651 toxicity equivalent (TEQ) 593, 598 thyroid-stimulating hormone (TSH) 376, 377 toxicity exposure ratio (TER) 216 thyroid toxicity 665 toxicodynamics (TD) 215 k thyroperoxidase (TPO) 375, 378 toxicogenetics k thyrotropin-releasing hormone (TRH) 376 favism 122 thyroxine binding globulin (TBG) 651 genotyping 124–127 tissue hormones 373 phenotyping 125–127 tolerable concentration (TC) 29 polymorphic xenobiotic-metabolising enzymes tolerable daily intake (TDI) 29, 613, 651, 657 acrylonitrile 128–130 toluene 679–680 bladder carcinogens 130–133 toxic epidermal necrolysis (TEN) 303 colorectal cancer 133–135 toxic equivalency factor (TEF) method 156, 592, CYP2C9*2 127 731–732 NAT2 128 toxic gases, fires 698 slow acetylators 122 toxicity study numbers and effect size 135–138 active substance, pesticides 707–709 toxicogenomics 123 acute (see acute toxicity) toxicogenomics 123 arsenic 612–613 bioinformatics 479–480 cadmium 614 biostatistics 479–480 cardiac glycosides 756–757 concept of 472–473, 475 chromium 618–619 genomics copper 619–620 methods 476 diesel engine emissions 737 microarrays 476 acute 736 next-generation sequencing 476–477 carcinogenicity 737–738 qRT-PCR 477 chronic 736 mechanistic analyses 483–485 development/reproductive 737 metabolomics 479 genotoxicity 737 predictive 481–483 irritation/immunotoxicity 736 proteomics 477–478

k k

Index 791

toxicokinetics 10–11 test guidelines 14–15 absorption TTC concept 17 definition 35 uncertainty analysis 16 gastrointestinal tract 40–41 Toxic Substances Control Act (TSCA) 468, intraperitoneal injection 42 566–567, 588 intravascular 42 tracheobronchial (TB) 250 oral cavity 40–41 transcription-coupled repair (TCR) 167 respiratory tract 38–40 transferrin 608 skin 41 translesions synthesis 170 subcutaneous/intramuscular injection 42 transport of dangerous goods (TDG) arsenic 611–613 551–552 biological membrane (see biological membrane) triazine herbicides 708–709 cadmium 614 tributyltin 657–658 chromium 618 trichloroethene 673 see also chloroform

compartment models (see compartment models) trichloromethyl radical (CCl3) 108 copper 619–620 triiodothyroacetic acid (TRIAC) 377 cyanide 689–690 tumor necrosis factor (TNF) receptor 118 definition and purpose 34–35 tumor suppressor genes 172 diesel engine emissions 735 ras proto-oncogenes 176–177 distribution 42–43 TP53 177 elimination type II cell death 179 excretion 44–47 type II pneumocytes 250 metabolites 43–44 type I pneumocytes 250 ethanol solvents 681–682 tyramine 224, 225 iron 621 lead 615 UDP-glucuronic acid 74, 75 k manganese 623–624 UDP-glucuronyltransferases 75, 76 k mercury 617 United Nations Economic Commission for Europe nickel 623–624 (UNECE) 532 PAHs 724–725 United Nations Environment Programme (UNEP) toxicokinetics (TK) 215 532–533 toxicological concern (TTC) 700–701 United Nations Scientific Committee on the toxicological evaluation Effects of Atomic Radiation animal experiments 15 (UNSCEAR) 535 C&L of chemicals 17–18 United States regulations 557 evaluation of mixtures 15–16 ATSDR 570–571 existing chemicals 14 CDC 571 hazard identification and risk assessment CPSA 569 acute toxicity studies 8 CPSC 568–569 ADI 13 environmental regulations 563–568 carcinogenicity 9–10 Food and Drug Administration 561–562 chronic studies 8 litigation 571–572 genotoxicity 9 on occupational and environmental health institutions 6, 7 558, 559 irritation 8–9 OSHA 558–560 phototoxicity 9 radionuclides regulations 569–570 reproduction and development 10 unscheduled DNA synthesis (UDS) 419 toxicokinetics 10–11 urea herbicides 709 issues 13–14 urinary tract 313, 317–319 mode and/or mechanism of action 10–11 bladder tumors 315, 318–319 precautionary principle 16 collection and excretion 313 sensitization and photosensitization 9 toxicology of 317–318

k k

792 Index

uroporphyrinogen decarboxylase (UROD) warfarin 715 602–603 Wechsler Intelligence Scale 287 urticaria 305 Werner syndrome 174 US Environmental Protection Agency (EPA) white blood cells 326–328 186, 741 WHO Core Assessment Group 532 US National Toxicology Program (NTP) 741 whole-mixture study 152 uterotrophic assay 385 wildlife toxicology see ecotoxicology Wiley Act 562 very low density lipoprotein (VLDL) formation Wnt factors 235 241 World Health Organization (WHO) 514, 531, vessel cooption 181 706, 741 Veterinary International Conference on Harmonization (VICH) 535, 540 xenoantiandrogens see antiandrogens vigabrantin 362 xenoestrogens see antiandrogens vinclozolin 657 Xeroderma pigmentosum 173, 309 viral oncogenes 175 visual system 280 zearalenone 657 vitellogenin (VTG) 666 zero-order kinetics 44 vitreous body, eye 354 zonation of liver lobules 235, 236

k k

k