Dermatotoxicology

ISBN-13: 9780415288620......Page 1
DERMATOTOXICOLOGY, 6TH EDITION......Page 4
Contents......Page 6
Contributors......Page 14
Foreword from the Fifth Edition......Page 22
Preface to the Sixth Edition......Page 25
PART I: Concepts......Page 27
Contents......Page 29
1.2 METHOD ANALYSES: ATRAZINE......Page 31
1.3 METHOD ANALYSES: BORATES......Page 33
1.4 LIMITATIONS......Page 34
1.5 DISCUSSION......Page 35
REFERENCES......Page 37
Contents......Page 39
2.2 OCCLUSION AND ITS APPLICATION......Page 41
2.3 SKIN BARRIER FUNCTION......Page 42
2.4 EFFECTS OF OCCLUSION ON BARRIER FUNCTION......Page 43
2.5 QUANTIFICATION WITH BIOENGINEERING TECHNIQUES......Page 44
2.6 CONCLUSIONS......Page 45
REFERENCES......Page 48
Contents......Page 55
3.2 LEVELS OF INTERACTION......Page 57
3.3 EXAMPLES OF MIXTURE INTERACTIONS......Page 60
3.4 CONCLUSIONS......Page 64
REFERENCES......Page 65
Contents......Page 69
4.2 GENERAL CHARACTERISTICS......Page 71
4.3 DERMIS......Page 75
4.4 REGIONAL AND SPECIES DIFFERENCES......Page 76
4.5 HAIR FOLLICLES......Page 79
4.6 BLOOD FLOW......Page 81
4.7 AGING......Page 83
4.8 DISEASES......Page 85
4.9 CONCLUSIONS......Page 86
REFERENCES......Page 87
Contents......Page 97
5.2 ALTERATION OF LIPIDS WITH DIFFERENTIATION......Page 99
5.4 LIPID ENVELOPE......Page 100
5.5 CHEMICAL STRUCTURES OF THE STRATUM CORNEUM LIPIDS......Page 101
5.6 ULTRASTRUCTURE OF THE INTERCELLULAR SPACES OF THE STRATUM CORNEUM......Page 103
REFERENCES......Page 104
Contents......Page 109
6.2 SHORT-TERM EXPOSURE TO HAZARDOUS CHEMICALS......Page 111
6.3 LAG TIME......Page 113
6.4 MULTIPLE EXPOSURE IN THE SAME DAY......Page 115
6.5 MULTIPLE DOSING: AZONE SELF-ENHANCED PERCUTANEOUS ABSORPTION......Page 118
6.6 INDIVIDUAL VARIATION: IN VITRO HUMAN SKIN......Page 119
6.7 MODELS: IN VITRO AND IN VIVO......Page 120
6.8 PERCUTANEOUS ABSORPTION FROM CHEMICALS IN CLOTHING......Page 123
6.9.1 Diazinon......Page 124
6.9.2 Pyrethrin and Piperonyl Butoxide......Page 125
6.9.3 Isofenphos......Page 126
6.10 DISCUSSION......Page 127
6.10 REFERENCES......Page 128
Contents......Page 131
7.1 INTRODUCTION......Page 133
7.2 PHSC AND PHYSICAL-CHEMICAL PROPERTIES OF STRATUM CORNEUM......Page 134
7.3 PHSC AND CHEMICAL PARTITIONING......Page 135
7.4 PHSC AND PERCUTANEOUS ABSORPTION......Page 137
7.5 PHSC AND THE SKIN BARRIER FUNCTION......Page 138
7.7 PHSC AND ENVIRONMENTALLY HAZARDOUS CHEMICALS......Page 139
7.8 PHSC AND CHEMICAL DECONTAMINATION......Page 140
7.9 PHSC AND ENHANCED TOPICAL FORMULATION......Page 141
7.10 PHSC AND QSAR PREDICTIVE MODELING......Page 142
7.11 DISCUSSION......Page 144
REFERENCES......Page 145
Contents......Page 149
8.1 INTRODUCTION......Page 151
8.2 FINDINGS IN INDIVIDUALS WITH A SELF REPORTED SENSITIVE SKIN......Page 152
8.3 FINDINGS IN POPULATIONS WITH A DIFFERENT “SENSITIVE SKIN”......Page 155
8.4 DEFINITION OF TERMS CONCERNING SKIN SUSCEPTIBILITY......Page 157
REFERENCES......Page 158
Contents......Page 163
9.2 PERCUTANEOUS DRUG ABSORPTION......Page 165
9.3 TRANSDERMAL DRUG DELIVERY DEVICES......Page 166
9.4 ADVANTAGES OF TRANSDERMAL DRUG DELIVERY......Page 167
9.5 DISADVANTAGES OF TRANSDERMAL DRUG DELIVERY......Page 168
9.7.3 Irritant Contact Dermatitis......Page 169
9.8 SYSTEMIC/IMMUNOLOGIC......Page 170
9.10 FUTURE......Page 171
REFERENCES......Page 173
Contents......Page 177
10.1 INTRODUCTION AND HISTORICAL PERSPECTIVES......Page 179
10.2 THEORY......Page 180
10.3.1 In vitro......Page 183
10.3.2 In vivo......Page 184
10.3.1 Choice of Electrode Materials in Iontophoresis......Page 185
10.4 PATHWAYS OF ION TRANSPORT......Page 186
10.5.1 pH......Page 188
10.5.4 Competing ions......Page 189
10.5.5 Current......Page 190
10.5.6 Species, sex and site......Page 191
10.5.7 Continuous versus Pulsed Current......Page 192
10.6 IN VITRO-IN VIVO CORRELATION......Page 193
10.7 ADVANTAGES OF IONTOPHORESIS......Page 194
10.8 PROBLEMS ASSOCIATED WITH IONTOPHORESIS......Page 195
10.9 APPLICATIONS OF IONTOPHORESIS IN DERMATOLOGY......Page 197
REFERENCES......Page 198
Contents......Page 207
11.1.1 Acute irritant dermatitis (primary irritation)......Page 209
11.1.3 Irritant reaction......Page 210
11.1.5 Suberythematous irritation......Page 211
11.1.6 Cumulative irritant dermatitis......Page 212
11.1.10 Exsiccation eczematoid......Page 213
11.1.11 Friction dermatitis......Page 214
11.2 LOCALIZATION OF IRRITANT CONTACT DERMATITIS......Page 215
11.3.3 Multiple simultaneous exposures......Page 216
11.3.4 Environmental factors......Page 218
11.3.5 Airborne irritation......Page 219
11.4.1 Methodological aspects......Page 220
11.4.2 Regional anatomic differences......Page 221
11.4.3 Age......Page 224
11.4.4 Race......Page 225
11.4.6 Previous and preexisting skin diseases......Page 227
11.5.1 Predictive testing for chemical irritant potential......Page 229
11.5.2 Predictive testing for susceptibility to irritation......Page 231
11.6 HISTOLOGY, HISTOPATHOLOGY, AND PATHOLOGY......Page 232
11.7 MECHANISM OF IRRITANT DERMATITIS......Page 234
11.8 TREATMENT......Page 235
REFERENCES......Page 237
CHAPTER 12: Allergic Contact Dermatitis......Page 255
REFERENCES......Page 260
Contents......Page 263
13.1 INTRODUCTION......Page 265
13.2 CLINICAL DIAGNOSIS......Page 266
13.3 HISTOLOGICAL AND IMMUNOHISTOCHEMICAL STUDIES......Page 269
13.4 CYTOKINES......Page 272
13.5 ALLERGENS AND IRRITANTS IN IMMUNOTOXICOLOGY TESTING......Page 279
REFERENCES......Page 281
Contents......Page 291
14.2 SOME CHEMICAL REMINDERS......Page 293
14.2.2 Strong interactions......Page 294
14.2.3 Mechanisms of bond formation......Page 296
14.4 BACK TO CONTACT ALLERGY......Page 297
14.4.1 Chemical selectivity of haptens for amino acids......Page 299
14.6 METABOLISM AND PROHAPTENS......Page 301
14.7 HAPTENS AND CROSS-ALLERGY......Page 304
14.7.2 Example of conformational analysis. Cross-reaction to corticosteroids......Page 305
14.8 CONCLUSION......Page 307
REFERENCES......Page 308
Contents......Page 311
15.2 IMMUNOLOGY/MECHANISM......Page 313
15.3 CLINICAL FEATURES......Page 315
15.4.1 Antibiotics......Page 317
15.4.3 Para-amino compounds......Page 318
15.4.4 Corticosteroids......Page 319
15.4.5 Miscellaneous medications......Page 320
15.5 NICKEL......Page 321
15.6 CHROMIUM, COBALT AND OTHER METALS......Page 325
15.7 OTHER CONTACT ALLERGENS......Page 327
15.8 RISK ASSESSMENT-ORIENTED STUDIES......Page 330
15.9 DIAGNOSIS......Page 331
REFERENCES......Page 332
Contents......Page 347
16.1 INTRODUCTION......Page 349
Dose......Page 350
Nature of chemical bond and polarity......Page 351
Valence......Page 352
Time interval......Page 353
Anatomical site......Page 354
Oxidation and reduction of xenobiotics in the skin......Page 355
16.3 ROUTES FOR SKIN ABSORPTION OF METALS......Page 356
16.4.1 The permeation coefficient Kp and Fick’s first law of membrane diffusion......Page 358
16.5 ABSORPTION DETERMINED THROUGH STRATUM CORNEUM ANALYSIS......Page 360
REFERENCES......Page 361
Contents......Page 367
17.1 INTRODUCTION......Page 369
17.2 PHOTOTOXIC AGENTS......Page 370
17.3 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS......Page 371
17.4 ELEMENTS OF THE TEST FOR PHOTOTOXICITY......Page 372
17.5 MECHANISMS OF PHOTOTOXICITY......Page 373
17.6 HIGHLIGHTS......Page 374
REFERENCES......Page 375
Contents......Page 379
18.2.1 Toxic oil syndrome......Page 381
18.2.3 Urea formaldehyde foam insulation......Page 382
18.3.2 Trichloroethylene and perchloroethylene......Page 383
18.3.3 Aromatic hydrocarbon solvents......Page 384
18.3.5 Epoxy resins......Page 385
18.3.8 Silica......Page 386
18.3.9 Pesticides......Page 387
18.4 IATROGENIC AGENTS......Page 388
18.4.2 Pentazocine......Page 389
18.4.5 Ergot methysergide......Page 390
18.5.1 Eosinophilia-myalgia syndrome......Page 391
18.5.2 Appetite suppressants......Page 392
REFERENCES......Page 393
Contents......Page 401
19.3 CHEMICAL STRUCTURES CAUSING DEPIGMENTATION......Page 403
19.4 REPIGMENTATION......Page 407
19.5 MECHANISM OF ACTION......Page 408
REFERENCES......Page 411
Contents......Page 415
20.1 BACKGROUND AND MILITARY USE......Page 417
20.2 TOXICITY......Page 418
20.3 BIOCHEMICAL MECHANISM OF SULFUR MUSTARD TOXICITY......Page 419
20.4 HISTOPATHOLOGY, MODELS, AND ULTRASTRUCTURE......Page 422
20.5 IMMUNOHISTOCHEMISTRY OF THE MUSTARD SKIN LESION......Page 423
20.7 CLINICAL MANIFESTATIONS......Page 427
20.9 MANAGEMENT OF SKIN LESIONS......Page 430
REFERENCES......Page 431
Contents......Page 435
21.2.1 Ultraviolet light radiation......Page 437
21.2.2 Viruses......Page 438
21.2.5 Diet......Page 439
21.3 PREVENTION......Page 440
REFERENCES......Page 441
Contents......Page 445
22.2 RETINOID CLASSIFICATION......Page 447
22.3 BASIC ASSUMPTIONS......Page 449
22.4 VARIATIONS OF SYSTEM, SPECIES, AND ROUTE OF DELIVERY......Page 450
22.5 RETINOID ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION......Page 451
22.7 METABOLISM OF RETINOIDS......Page 452
22.9 ADVERSE EFFECTS OF RETINOIDS......Page 454
22.9.1 Mucocutaneous toxicity......Page 455
22.9.2 Dyslipidemias......Page 456
HDL......Page 457
22.9.3 Teratogenicity......Page 458
22.9.4 Bone......Page 459
22.10 SUMMARY AND CONCLUSIONS......Page 460
BIBLIOGRAPHY......Page 461
Contents......Page 467
23.2 COSMETIC CONTACT DERMATITIS......Page 469
23.4 ABNORMAL PIGMENTATION CAUSED BY COSMETICS......Page 470
23.6 HAIR INJURING......Page 471
23.7 NAIL INJURING......Page 472
REFERENCES......Page 473
Contents......Page 475
24.2 STRUCTURE OF THE EYE......Page 477
24.3 TRANSMISSION OF LIGHT THROUGH THE HUMAN EYE......Page 478
24.4 OCULAR PHOTOTOXICITY INDUCED BY XENOBIOTICS......Page 479
24.5 SHORT SCREEN FOR PREDICTING POTENTIAL PHOTOTOXICITY......Page 480
24.6 ADDITIONAL TECHNIQUES......Page 481
24.7 PHOTOCHEMICAL MECHANISM OF PHOTOTOXICITY......Page 483
24.8 BIOPHYSICAL STUDIES......Page 484
24.9.2 Substrates of photooxidative damage......Page 485
Mass spectrometry......Page 486
Normalization for photons absorbed......Page 487
24.10.1 Site of damage......Page 488
24.10.2 In vivo testing......Page 489
REFERENCES......Page 490
CHAPTER 25: Water: Is It an Irritant?......Page 497
REFERENCES......Page 502
Contents......Page 505
26.2 APPLICATION METHODS......Page 507
26.2.2 Quantity and concentration of test solution......Page 508
26.2.3 Evaporation and temperature of test solution......Page 509
26.2.4 Time of evaluation......Page 510
26.3.2 Pathogenesis of SLS reaction......Page 511
26.3.3 Noninvasive bioengineering techniques assessing SLS reaction......Page 514
26.3.4 Recovery of SLS reaction......Page 516
26.4.2 Sex......Page 517
26.4.4 Race and skin color......Page 518
26.4.6 Sensitive skin......Page 519
26.4.7 Hyperirritable skin (Excited skin syndrome)......Page 520
26.4.8 Skin diseases (atopic dermatitis, hand eczema, seborrheic dermatitis)......Page 521
REFERENCES......Page 522
Contents......Page 533
27.2 DEFINITION AND TERMS......Page 535
27.4 MECHANISM OF ACTION AND DURATION......Page 536
27.6 US FOOD AND DRUG ADMINISTRATION MONOGRAPH “SKIN PROTECTANTS”......Page 537
27.7 CONCLUSION......Page 538
REFERENCES......Page 539
PART II: Methods......Page 543
Contents......Page 545
28.3 DIFFUSION CELLS......Page 547
28.4 PREPARATION OF SKIN......Page 549
28.5 RECEPTOR FLUID......Page 550
28.7 DETERMINATION OF ABSORPTION......Page 551
REFERENCES......Page 553
Contents......Page 557
29.2 STRATUM CORNEUM......Page 559
29.3 SC REMOVAL METHODS AND EFFECT OF STRIPPING......Page 560
29.4 EFFECT OF STRIPPING FACTORS ON THE TAPE STRIPPING......Page 562
29.4.1 Tape stripping versus SC thickness......Page 563
29.5 TAPE STRIPPING VERSUS PERCUTANEOUS ABSORPTION AND PENETRATION......Page 565
29.6 TAPE STRIPPING VERSUS PEPTIDE IMMUNIZATION......Page 568
REFERENCES......Page 569
Contents......Page 575
30.2.1 Solvents......Page 577
DDT, Benzo[a]pyrene, Chlordane, Pentachlorophenol, 2, 4-D......Page 579
30.2.3 PCBs......Page 581
Arsenic, cadmium, mercury......Page 582
30.4 SOIL LOAD......Page 583
30.5 DISCUSSION......Page 584
REFERENCES......Page 585
Contents......Page 589
31.1 INTRODUCTION......Page 591
31.2.1 Surgical preparation and perfusion......Page 593
31.3.1 Assessment of flap viability and development of biomarkers for toxicity assessment......Page 596
31.3.2 Absorption studies......Page 598
31.3.3 Dermatopharmacokinetic studies......Page 601
31.3.4 Cutaneous biotransformation......Page 604
31.3.5 Percutaneous absorption of vasoactive chemicals......Page 605
31.4 DISCUSSION......Page 606
31.4.1 Integrated approach to dermal risk assessment using a dermatopharmacokinetic template......Page 607
REFERENCES......Page 608
Contents......Page 615
32.2 WHY USE PB-PK MODELS?......Page 617
32.4 WHAT ARE THE COMPONENTS OF A PB-PK MODEL?......Page 620
32.4.1 Tissue compartments......Page 621
32.4.2 Skin compartment......Page 623
32.4.3 Flux equations......Page 625
Each lumped compartment......Page 626
Skin compartment......Page 627
Simplifying assumptions......Page 628
Full PB-PK model......Page 629
32.4.5 Parameters of a model......Page 630
32.5 HOW DO YOU DEVELOP PB-PK MODELS?......Page 632
32.5.1 Choose compartments......Page 633
32.5.2 Determine physiological parameters......Page 634
32.5.4 Validate model where absorption is absent......Page 635
32.5.6 Extrapolation to humans......Page 636
32.5.8 Value of PB-PK skin models......Page 638
32.7 NOMENCLATURE......Page 639
REFERENCES......Page 640
Contents......Page 647
33.2 REASONS FOR DOING IN VITRO STUDIES......Page 649
33.4 SKIN VIABILITY ASSAYS......Page 650
33.5 SKIN METABOLISM DURING IN VITRO ABSORPTION STUDIES......Page 651
REFERENCES......Page 655
Contents......Page 657
34.2 SCOPOLAMINE......Page 659
34.3 CLONIDINE......Page 660
34.4 NITROGLYCERIN......Page 662
34.5 NICOTINE......Page 663
34.6 ESTRADIOL......Page 664
34.9 FENTANYL......Page 666
34.10 FUTURE......Page 667
REFERENCES......Page 668
ANNEX......Page 676
Contents......Page 679
35.2 TOXICOLOGY EVALUATION PLAN......Page 681
35.3.1 In vivo irritation testing......Page 686
35.3.2 In vitro irritation testing......Page 687
35.3.3 In vitro/in vivo correlation......Page 689
35.4.1 Guinea pig model......Page 690
35.4.2 Murine models......Page 692
REFERENCES......Page 694
Contents......Page 703
36.2.1 Draize rabbit assay......Page 705
36.2.3 Cumulative irritation assays......Page 707
36.2.5 Mouse ear model......Page 709
36.3 IN-VITRO ASSAYS......Page 710
36.4 HUMAN MODELS......Page 712
36.4.2 Cumulative irritation test......Page 713
36.4.4 Immersion tests......Page 714
36.4.6 Protective barrier assessment......Page 715
REFERENCES......Page 716
Contents......Page 721
37.1 INTRODUCTION......Page 723
37.2.1 Principles......Page 724
37.2.2 Electron spin resonance spectrometer......Page 726
37.2.3 Spin labeling method; paramagnetic nitroxide molecules that serve as probes in membranes......Page 727
37.2.4 How to read the EPR spectrum; calculation of order parameter S......Page 729
37.3.1 EPR measurement of stratum corneum from cadaver; spin labeling and surfactant treatment procedure......Page 730
37.4.1 Effect of surfactants on the intercellular lipid fluidity of cadaver stratum corneum......Page 731
37.4.2 Effect of surfactant mixtures (SLS/SLG) on intercellular lipid fluidity of cadaver stratum corneum......Page 735
37.4.3 Correlation between CMC and intercellular lipid fluidization for SLS......Page 737
37.4.4 EPR study utilizing human stripped stratum corneum......Page 738
37.4.5 Water may affect the Order Parameter S......Page 741
REFERENCES......Page 743
Contents......Page 751
38.1 INTRODUCTION......Page 753
38.2 GENERAL PRINCIPLES......Page 755
38.2.3 Evaluation......Page 756
38.3 THE GUINEA PIG MAXIMIZATION TEST......Page 757
38.4 SPLIT ADJUVANT TECHNIQUE......Page 758
38.4.2 Challenge......Page 759
38.5.1 Sequence of induction......Page 760
38.5.3 Assessment......Page 761
38.6 FREUND’S COMPLETE ADJUVANT TEST......Page 762
38.7 THE MODIFIED DRAIZE TEST......Page 763
Induction phase......Page 764
38.8 THE BUEHLER TEST......Page 765
38.9 THE OPEN EPICUTANEOUS TEST......Page 767
38.10 MODIFIED GUINEA PIG MAXIMIZATION TEST......Page 768
38.11 THE CUMULATIVE CONTACT ENHANCEMENT TEST......Page 770
38.12 THE EPICUTANEOUS MAXIMIZATION TEST......Page 771
38.13 SINGLE-INJECTION ADJUVANT TEST......Page 772
38.14 THE TIEREXPERIMENTELLER NACHWEIS (TINA) TEST......Page 774
38.15 THE FOOTPAD TEST......Page 775
38.16.1 Protocol I—Induction by topical route......Page 776
38.16.2 Protocol II—Induction by injection......Page 777
38.17 THE EAR/FLANK TEST (STEVENS TEST)......Page 778
REFERENCES......Page 780
Contents......Page 789
39.1 INTRODUCTION......Page 791
39.2 PREDICTIVE TESTS......Page 792
39.3 DIAGNOSTIC TESTS......Page 793
REFERENCES......Page 798
Contents......Page 801
40.1 INTRODUCTION......Page 803
40.2 COMPLETE FREUND’S ADJUVANT......Page 805
40.3 P. ACNES......Page 806
40.5 LOCAL ANTICANCER DRUGS......Page 807
40.6.1 Gamma-interferon......Page 808
40.6.2 Interleukin-12......Page 810
40.7.2 Plasmids expressing cytokines and chemokines......Page 812
REFERENCES......Page 813
Contents......Page 819
41.1 INTRODUCTION......Page 821
41.2 DEVELOPMENT OF THE LLNA......Page 822
41.3 EVALUATION AND VALIDATION......Page 824
41.5 THE LLNA AND ASSESSMENT OF RELATIVE POTENCY......Page 828
41.6 INTEGRATION OF LLNA DATA INTO RISK ASSESSMENT......Page 831
41.7 CONCLUSIONS......Page 832
REFERENCES......Page 833
Contents......Page 843
42.2 SYMPTOMS......Page 845
42.3 ETIOLOGY AND MECHANISMS......Page 846
42.3.1 Immediate contact urticaria (ICU), IgE-mediated contact reactions (Type I)......Page 852
42.3.2 Protein contact dermatitis......Page 854
42.3.3 Nonimmunologic contact urticaria......Page 855
Role of sensory nerves......Page 856
Animal model for nonimmunologic contact urticarial reactions......Page 857
Specificity of the reaction......Page 858
42.4.2 Tests for immunologic contact urticaria (ICU)......Page 859
REFERENCES......Page 861
Contents......Page 875
43.2 HUMAN EPIDERMIS RECONSTITUTED IN CHEMICALLY DEFINED MEDIUM: CHARACTERISTICS AND ADVANTAGES......Page 877
43.3 IN VITRO ANALYSIS OF EPIDERMAL TOXICITY BASED ON MULTIPLE ENDPOINT ANALYSIS MEA......Page 880
43.3.1 In vitro skin irritation and phototoxicity prediction based on the MEA approach......Page 881
43.3.2 Differentiating skin irritants from skin sensitizers based on the MEA approach......Page 886
43.4 CONCLUSION......Page 887
REFERENCES......Page 888
Contents......Page 897
44.4 PRECAUTIONS......Page 899
44.5 EXPLORATORY STUDIES......Page 900
44.7 LAMP SOURCES......Page 901
REFERENCES......Page 902
ADDITIONAL READING......Page 903
Contents......Page 905
45.1 INTRODUCTION......Page 907
45.1.1 Radiometric quantities......Page 909
45.1.2 Spectral band notations......Page 910
45.1.3 Radiometric principles......Page 911
45.2 OPTICAL RADIATION SOURCES......Page 912
45.3.1 Types of UVR measurement instruments......Page 915
45.3.2 Performing the measurement......Page 916
45.4 GENERAL BIOPHYSICAL AND PHOTOBIOLOGICAL FACTORS......Page 917
45.5.1 Choice of monochromator bandwidth......Page 920
REFERENCES......Page 924
Contents......Page 927
46.2 TEST SYSTEM......Page 929
46.3 FORMULATION AND SKIN PERMEATION STUDIES......Page 930
46.3.2 Radiometric analysis......Page 931
46.3.3 Statistical analysis......Page 933
46.3.4 Results......Page 934
46.3.5 Discussion......Page 935
46.3.6 Conclusions......Page 938
46.4 CHEMICAL TOXICITY STUDIES......Page 939
Release of lactic dehydrogenase (LDH)......Page 940
Mitochondrial oxidative function......Page 941
Analysis and excretion of RNA terminal metabolites in receptor fluids......Page 942
46.4.4 Statistical analysis......Page 945
46.4.5 Results of RNA metabolite feasibility study......Page 948
46.4.6 Results of known toxicants on biochemical measurements and RNA terminal metabolites......Page 950
46.4.7 Discussion......Page 958
46.5 SUMMARY......Page 959
REFERENCES......Page 960
Contents......Page 963
47.1 INTRODUCTION......Page 965
47.2 MEASUREMENT OF SUB-CLINICAL BARRIER CHANGES EVAPORIMETRY (TEWL)......Page 966
47.2.1 Principle of TEWL measurements......Page 968
47.3 ASSESSMENT OF SUB-CLINICAL BARRIER ALTERATIONS BY SQUAMOMETRY......Page 970
47.3.1 Squamometry-methodology......Page 971
47.3.2 Sub-clinical alterations of the stratum corneum with surfactant......Page 973
47.4 CONCLUSIONS......Page 975
REFERENCES......Page 976
General readings......Page 981
Contents......Page 983
48.1 INTRODUCTION......Page 985
48.2.2 Relevance......Page 986
48.3.1 Step 1. Define the performance measures to be confirmed in the validation study (Figure 48.1)......Page 987
48.3.2 Step 2. Design a validation study to test the validity of the prediction model (Figure 48.1)......Page 992
Establishment of common protocols and standard operating procedures......Page 993
Data collection and analysis......Page 994
Distribution of toxicity in the RSTS......Page 995
Number of test substances in the RSTS......Page 996
48.3.4 Step 4. Evaluate the quality of the in vivo toxicity data (Figure 48.1)......Page 1001
48.3.5 Step 5. Conduct the validation study (Figure 48.1)......Page 1002
Definitions (Figure 48.5)......Page 1003
Intralaboratory variability (Figure 48.5)......Page 1005
Interlaboratory variability (Figure 48.5)......Page 1006
Number of participating laboratories......Page 1007
48.4 ASSESSING ALTERNATIVE METHOD RELEVANCE......Page 1009
48.4.1 Assessing the best performance that can be expected from an alternative method......Page 1010
48.4.2 Assess the performance of the in vivo test that will be replaced......Page 1015
48.4.3 Assessing supplemental data available for use in conjunction with the alternative method during a safety assessment......Page 1016
48.5 DISCUSSION......Page 1018
REFERENCES......Page 1019
Contents......Page 1025
49.2 IMMUNOLOGIC CONTACT URTICARIA: MECHANISMS......Page 1027
49.3 RESPIRATORY CHEMICAL ALLERGY AS AN ANIMAL MODEL FOR IMMUNOLOGIC CONTACT URTICARIA......Page 1028
49.5 PROTEIN ALLERGY AS AN ANIMAL MODEL FOR IMMUNOLOGIC CONTACT URTICARIA......Page 1029
49.8 CONCLUSIONS......Page 1030
REFERENCES......Page 1031
Contents......Page 1033
50.2 DRUG ERUPTIONS......Page 1035
50.3 CONTACT DERMATITIS......Page 1041
50.4 CONTACT URTICARIA SYNDROME: IMMEDIATE CONTACT REACTIONS......Page 1043
REFERENCES......Page 1045
Contents......Page 1047
51.1 INTRODUCTION......Page 1049
Objective irritation......Page 1050
Sensory or subjective irritation......Page 1052
51.2.2 Allergic contact dermatitis......Page 1053
51.2.3 Contact urticaria syndrome......Page 1055
Nonimmunologic contact urticaria......Page 1056
Immunologic contact urticaria......Page 1058
51.2.4 Acne and comedones......Page 1059
51.2.5 Pigmentation......Page 1061
51.2.6 Photosensitivity......Page 1063
Photopatch testing......Page 1064
51.2.8 Hair changes......Page 1067
51.3 INGREDIENT PATCH TESTING......Page 1068
51.4.1 Preservatives......Page 1069
51.4.3 Emulsifiers......Page 1072
51.4.5 Eye makeup preparations......Page 1073
Permanents......Page 1075
Shampoos......Page 1077
51.4.7 Hair coloring preparations......Page 1078
51.4.8 Facial makeup preparations......Page 1080
51.4.9 Sunscreen......Page 1082
PABA derivatives......Page 1084
Cinnamates......Page 1085
Miscellaneous......Page 1086
51.4.10 Manicuring preparations......Page 1087
51.4.11 Oral hygiene product......Page 1090
51.4.13 Baby products......Page 1091
Depilatories......Page 1092
51.5 COSMETIC INTOLERANCE SYNDROME......Page 1093
51.6 OCCUPATIONAL DERMATITIS: HAIRDRESSERS......Page 1094
REFERENCES......Page 1097
Contents......Page 1113
52.2.1 In Vitro Methods......Page 1115
52.2.2 In Vivo Methods......Page 1116
52.3 CONCLUSIONS......Page 1121
REFERENCES......Page 1125
Contents......Page 1130
53.1 INTRODUCTION......Page 1132
53.2 LIGHT CHARACTERISTICS......Page 1133
53.3 FUNDAMENTAL CONCEPTS IN PHOTOCHEMISTRY......Page 1138
53.4 CELLULAR TARGETS AND MECHANISMS OF PHOTOTOXICITY......Page 1141
53.5.1 Thymine Photoproducts......Page 1142
53.5.2 DNA-Protein Cross-Links......Page 1147
53.5.3 Phototoxicity......Page 1150
53.5.4 Photosensitized Oxidations......Page 1160
53.5.5 Mutations and Changes in Cellular Phenotype......Page 1164
53.6 CELLULAR MEDIATORS INDUCED BY LIGHT......Page 1166
53.7 PHOTOIMMUNOLOGY......Page 1172
53.8 ALTERATIONS IN GENE EXPRESSION INDUCED BY LIGHT......Page 1176
53.9 EPILOGUE......Page 1179
REFERENCES......Page 1180