Combined Actions and Interactions of Chemicals in Mixtures

More documents

Recommendations

Info

mixture. These interactions may deviate from additivity (no interactions) and be expressed as synergistic or antagonistic effects due to interactions in either the toxicokinetic and/or toxicodynamic phase. Although the ultimate target molecule for genotoxic agents is the DNA there are a number of different mechanisms by which chemicals can damage DNA. This makes the prediction of the net outcome of the genotoxicity of complex mixtures very difficult. 7.2.2 Types of damages to the hereditary material (DNA) 7.2.2.1 Primary DNA alterations Primary DNA alterations can be caused by radiation (UV or ionising radiation) or by reactive electrophilic agents. Chemicals may be either reactive per se or be metabolically activated to reactive molecules. These reactive agents can react with nucleophilic centres in DNA and cause different primary DNA alterations (figure 7.2.2.1). Chemicals may react with numerous sites in all four bases in DNA. However, not all nucleophilic sites have the same reactivity. Ring oxygen and -nitrogen are nucleophilic centres, and in general ring nitrogen atoms are more nucleophilic than ring oxygen atoms, with N 7 in guanine and N 3 in adenine being the most reactive. Primary DNA lesions include: DNA Adducts A large number of chemicals and/or their metabolites are able to bind covalently to DNA forming DNA adducts. Well known examples are polycyclic aromatic hydrocarbons (PAH) like benzo[a]pyrene, heterocyclic compounds, aromatic amines, and aflatoxins, just to mention a few groups of compounds that produce bulky adducts. A number of small molecular-size compounds, such as nitrogen mustards and N-nitroso compounds, are able to alkylate DNA. The formation of DNA adducts may subsequently result in mutations in daughter cells or in a number of the following other primary DNA damages. DNA strand breaks Single and double stranded DNA breaks may be caused by radiation, reactive chemicals or failure in repair of other DNA damages such as DNA adducts. DNA base modifications Alkylating agents can cause DNA base modifications like deamination. Loss of DNA bases Alkylating agents and agents forming bulky adducts can cause loss of DNA bases (depurimidation/depyrimidation). Such agents can be either mono-functional or bifunctional (with one or two reactive groups). DNA cross-links Inter- or intrastrand cross-links are formed as a result of reaction with bi-functional alkylating agents (with two reactive groups like e.g. mitomycin or nitrogen mustard) with nucleophilic centres in the DNA strands. If the sites of reaction are on opposite polynucleotide strands, interstrand DNA cross-links result. If these sites are situated on the same polynucleotide chain, the reaction product is referred to as an intrastrand cross-link. 82
Some chemicals and radiation can indirectly cause damage to DNA by forming reactive oxygen species (e.g. the OH . radical) that are able to produce modified bases like 8-hydroxyguanine. Interstrand cross link Intrastrand cross link Pyrimidin dimer DNA-protein crosslink 6-4 photoreaction product Figure 7.2.2.1. Different primary DNA damages. 7.2.3 Types of mutations Mutations arise when the primary DNA damages are not repaired or are being misrepaired. Mutations often result in the elimination or alteration of gene functions, and if the damage is not lethal it will lead to inheritable changes. Mutations can vary in character and size and can roughly be divided in: G G G U T A T A C C G C C G G T A T A Strandbreak Base change Base loss Base modification Bulky adduct 7.2.3.1 Point (gene) mutations A gene is the simplest functional unit in the DNA molecule. Gene (or point) mutations are changes in one or a few base pairs in a gene. Base pair, or base substitution, mutations occur when one nucleotide base is replaced with another. Frameshift mutations occur through the addition or deletion of one or a few bases, which alters the reading frame in DNA (and RNA). 7.2.3.2 Chromosomal mutations (structural aberrations) Chromosomal mutations (structural aberrations) are seen as morphological alterations in the structure of eukaryotic chromosomes. The most common chromosomal aberrations are shown in figure 7.2.3.1. Most of the aberrations seen are lethal to the cell because of loss of vital genetic information or, loss of vital cell functions. However, these aberrations are used as indicators for more biological relevant non-lethal aberrations like small deletions, inversions and translocations (for explanation see “test systems” below). These more subtle changes may have important consequences in both germ cells and somatic cells. The presence of structural (or numerical) aberrations in germ cells can lead to spontaneous abortion, congenital malformation, and infertility. It has been estimated that up to 40% of spontaneous abortions have chromosomal defects, and occur in approximately 83
Page 1 and 2:
Combined Actions and Interactions o
Page 3 and 4:
Contents CONTENTS 3 PREFACE 6 SAMME
Page 5 and 6:
7.2.4 Test systems 85 7.2.5 In vitr
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 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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?