Combined Actions and Interactions of Chemicals in Mixtures

More documents

Recommendations

Info

4.1 INTRODUCTION 38 4.2 PROCEDURES USED TO ASSESS CUMULATIVE EFFECTS OF CHEMICALS THAT ACT BY A COMMON MECHANISM OF ACTION 38 4.2.1 Hazard index (HI) 40 4.2.2 Point of Departure Index (PODI) 41 4.2.3 Toxicity equivalency factors (TEF) 41 4.2.4 Margin of exposure (MOE) 44 4.2.5 Cumulative risk index (CRI) 45 4.3 USE OF RESPONSE ADDITION (SIMPLE DISSIMILAR ACTION) IN THE RISK ASSESSMENT OF MIXTURES OF POLYCYCLIC AROMATIC HYDROCARBONS (PAH).45 4.4 APPROACH TO ASSESS SIMPLE AND COMPLEX MICTURES SUGGESTED BY THE DUTCH GROUP 48 4.4.1 Simple mixtures 48 4.4.2 Complex mixtures 49 4.5 APPROCH FOR ASSESSMENT OF JOINT TOXIC ACTION OF CHEMICAL MIXTURES SUGGESTED BY ATSDR 53 4.5.1 ATSDR strategy for noncarcinogenic effects 53 4.5.2 ATSDR strategy for carcinogenic effects 54 4.6 APPROACHES CURRENTLY USED BY REGULATORY AGENCIES IN DENMARK 55 4.6.1 Danish Working Environment Authority 55 4.6.2 The Danish Environmental Protection Agency 55 4.6.3 The Danish Veterinary and Food Administration 56 5 EXPERIMENTAL STUDIES USING SIMPLE, WELL-DEFINED MIXTURES 61 4 5.1 INTRODUCTION 61 5.2 CHEMICALS WITH DIFFERENT TARGET ORGANS AND/OR DIFFERENT MODES OF ACTION 61 5.2.1 Other studies 64 5.3 SAME TARGET ORGAN WITH DISSIMILAR OR SIMILAR MODES OF ACTION66 5.3.1 Nephrotoxicants with dissimilar modes of action 66 5.3.2 Nephrotoxicants with similar mode of action 67 5.4 MIXTURES OF CHEMICALS AFFECTING THE SAME TARGET ORGAN BUT WITH DIFFERENT TARGET SITES 68 5.5 CONCLUSIONS OF THE DUTCH STUDIES 68 6 INTERACTIONS IN TOXICOKINETICS 70 6.1 TOXICOKINETICS 70 6.1.1 Interactions with absorption 70 6.1.2 Interference with distribution 70 6.1.3 Interference with biotransformation 70 6.1.4 Interference with excretion 72 7 COMBINED ACTIONS IN DIFFERENT TOXICOLOGICAL EFFECT AREAS 73 7.1 LOCAL IRRITATION 73 7.1.1 Introduction 73 7.1.2 Skin irritation 73 7.1.3 Ocular irritancy 76 7.1.4 Irritancy to the respiratory tract 78 7.1.5 Conclusions 80 7.2 GENOTOXICITY 81 7.2.1 Introduction 81 7.2.2 Types of damages to the hereditary material (DNA) 82 7.2.3 Types of mutations 83
7.2.4 Test systems 85 7.2.5 In vitro assays 85 7.2.6 In vivo assays 88 7.2.7 Interactions between genotoxic substances 89 7.2.8 Conclusion 96 7.3 CARCINOGENICITY 97 7.3.1 Introduction 97 7.3.2 Combination effects in initiation 97 7.3.3 Combination effects in promotion 99 7.3.4 Combination effect at later stages 101 7.3.5 Anticarcinogenesis 101 7.3.6 Conclusions: Over-all effects and complex mixtures 102 7.4 REPRODUCTIVE TOXICITY 103 7.4.1 Introduction 103 7.4.2 In vitro studies for testing interaction of teratogenic compounds 104 7.4.3 Examples of interaction of reproductive toxicants in vivo 105 7.4.4 Evaluation of the in vivo studies 108 7.4.5 Conclusions 109 7.5 ENDOCRINE DISRUPTING CHEMICALS 109 7.5.1 Introduction 109 7.5.2 Examples of studies on interaction of endocrine disrupting chemicals (EDCs) 110 7.5.3 Comments on studies dealing with interactions of EDCs 113 7.5.4 The isobole method – a practical approach 115 7.5.5 Conclusion 116 7.6 NEUROTOXICITY 117 7.6.1 Introduction 117 7.6.2 Complexity of the nervous system 117 7.6.3 Developmental neurotoxicity 118 7.6.4 Consequences of adverse effects on the nervous system 119 7.6.5 Examples of interactions: Mechanisms 119 7.6.6 Examples of interactions: Agents 121 7.6.7 Conclusion 125 7.7 IMMUNOTOXICITY 125 7.7.1 Direct toxic effect on the immune system 125 7.7.2 Allergy 127 7.7.3 Patch test results with mixtures of chemicals 127 7.7.4 Experimental studies on the elicitation of allergic response to mixtures of chemicals. 128 7.7.5 Sensitisation 129 7.7.6 Conclusion 129 8 BOOKS, ARTICLES AND REPORTS 131 8.1 BOOKS 131 8.2 REVIEW ARTICLES 131 8.3 CONFERENCE PROCEEDINGS 132 8.4 REPORTS 132 9 REFERENCES 133 5
Page 1 and 2: Combined Actions and Interactions o
Page 3: Contents CONTENTS 3 PREFACE 6 SAMME
Page 7 and 8: Sammenfatning og konklusioner Indle
Page 9 and 10: er ingen viden om, hvorledes den ko
Page 11 and 12: estemt biologisk respons (ED10, ED2
Page 13 and 14: vivo. The COMET-assay in vivo and g
Page 15 and 16: and antagonistic effects may be see
Page 17 and 18: 1 Introduction Prepared by John Chr
Page 19 and 20: Table 1.3.1: Classification of comb
Page 21 and 22: Physicochemical interactions will t
Page 23 and 24: US EPA (1986) applied the concept o
Page 25 and 26: 2.4 Test strategies to assess combi
Page 27 and 28: Figure 2.4.3.1. Isobologram of two
Page 29 and 30: CI = d1 /D1 = 1 In this case the is
Page 31 and 32: 2.5 Toxicological test methods When
Page 33 and 34: 3 General concepts in the risk asse
Page 35 and 36: NOAEL, this indicates that the subs
Page 37 and 38: of uncertainty i.e. differences in
Page 39 and 40: describe toxicities that appears to
Page 41 and 42: should be estimated for all endpoin
Page 43 and 44: 1,2,3,6,7,8-HxCDF 0.1 1,2,3,7,8,9-H
Page 45 and 46: shows the pronounced influence of t
Page 47 and 48: Table 4.3.1 Estimates of carcinogen
Page 49 and 50: Figure 4.4.1.1. Scheme for safety e
Page 51 and 52: obvious ranking of individual const
Page 53 and 54: 4.5 Approach for assessment of join
Page 55 and 56:
4.6 Approaches currently used by re
Page 57 and 58:
no internationally accepted procedu
Page 59:
Figure 4.6.3.1 Flow chart of the ri
Page 62 and 63:
octyltin dichloride). A number of a
Page 64 and 65:
stannous chloride and cadmium chlor
Page 66 and 67:
seen in the animals from the 1000x
Page 68 and 69:
c TCTFP = 1,1,2-trichloro-3,3,3-tri
Page 70 and 71:
6 Interactions in toxicokinetics Pr
Page 72 and 73:
once more exposed and the kinetics
Page 74 and 75:
Dermis The dermis consists of a sup
Page 76 and 77:
7.1.3 Ocular irritancy 7.1.3.1 Comp
Page 78 and 79:
Another in vitro test for ocular ir
Page 80 and 81:
lipid peroxidation was observed, wh
Page 82 and 83:
mixture. These interactions may dev
Page 84 and 85:
0.6% of live births in humans. In s
Page 86 and 87:
DNA, and that the cell was capable
Page 88 and 89:
(Sorsa et al. 1994, Myslak & Kosmid
Page 90 and 91:
Four inhibitors of DNA topoisomeras
Page 92 and 93:
cyclophosphamide-metabolising enzym
Page 94 and 95:
Nickel compounds are carcinogenic t
Page 96 and 97:
7.2.8 Conclusion As shown in this r
Page 98 and 99:
Since no compounds are known to cau
Page 100 and 101:
In a more mechanistic sense, promot
Page 102 and 103:
Several inhibitors of tumour promot
Page 104 and 105:
Table 7.4.1.1 Overview of in vivo t
Page 106 and 107:
analysis was used to predict the hi
Page 108 and 109:
interaction of TCDD and retinoic ac
Page 110 and 111:
and now includes compounds as diver
Page 112 and 113:
Furthermore, the estrogenic effects
Page 114 and 115:
Dose of A (arbitrary units) 10 8 6
Page 116 and 117:
chance or experimental error. One w
Page 118 and 119:
7.6.2.3 Receptors A receptor is a b
Page 120 and 121:
7.6.5.2 Kindling Kindling is the ph
Page 122 and 123:
Science Institute (RSI) have conven
Page 124 and 125:
eaction with sulfhydryl groups). Th
Page 126 and 127:
7.7.1.3 Mechanisms of immunotoxicit
Page 128 and 129:
tested separately. This is a phenom
Page 130 and 131:
In practical life an allergen may b
Page 132 and 133:
8.3 Conference proceedings Proceedi
Page 134 and 135:
with combinations of environmental
Page 136 and 137:
Boyd MR, Statham CM and Longo NS (1
Page 138 and 139:
De Wall EJ, Schuurman HJ and Van Lo
Page 140 and 141:
theoretical considerations and a su
Page 142 and 143:
Groten JP, Sinkeldam EJ, Muys T, Lu
Page 144 and 145:
Howes D, Guy R, Hadgraft J, Heyling
Page 146 and 147:
cytochrome P450 1A2 expressed in Am
Page 148 and 149:
Lison D, Carbonnelle P, Mollo L, La
Page 150 and 151:
Narotsky MG, Weller EA, Chinchilli
Page 152 and 153:
Ramsey JC and Andersen ME (1984). A
Page 154 and 155:
Silva E, Rajapakse N and Kortenkamp
Page 156 and 157:
Leeuwen FXR, Liem AKD, Nolt C, Pete
Page 158:
Wlodarczyk B, Biernacki B, Minta M,
show all

Combined Actions and Interactions of Chemicals in Mixtures

Create successful ePaper yourself

Delete template?

Save as template?