Combined Actions and Interactions of Chemicals in Mixtures

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0.6% of live births in humans. In somatic cells chromosomal mutations may be involved in processes leading to malignancy. If, for instance, translocations occur at the site of oncogenes their expression can be changed as a consequence of their relocation (Minden 1987). Chromosome deletions and relocations can also lead to elimination of tumour suppressor genes, resulting in malignancy. Figure 7.2.3.1. Most commonly induced chromosomal aberrations including one or two chromosomes. 7.2.3.3 Genome mutations (numerical aberrations) In diploid cells, including mammalian and human cells, interference with normal cell division during meiosis or mitosis may produce genomic mutations, which are the result of changes in the number of chromosomes (aneuploidy). These changes are referred to as “numerical aberrations”. Genomic mutations include monosomy where one of a pair of chromosomes is lost, trisomy where a chromosome is added, and polyploidy where the complete set of chromosomes is increased in number. Agents that induce aneuploidy are called “aneugenes”. Genome mutations in germ cells are detrimental to the health of the individual. In humans, well-known genomic mutations include trisomies such as Down´s (trisomi 21) and Kleinfelter´s (XXY) syndromes. In somatic cells aneuploidy can lead to loss of heterozygosity in e.g. a tumorsuppressor gene, and possibly to development of cancer (Liu etal 1997). The most common cytogenetic aberration in breast tumours is aneuploidy (Devilee & Cornelisse 1994). 7.2.3.4 Recombination Recombination can be defined as exchanges of genetic material between chromosomes. In germ cells high levels of recombination between homologue chromosomes occur and this is a way to increase the diversity of living organisms. However, homologous mitotic recombinations represent one mechanism by which heterozygous tumour suppressor genes become lost. The analyses of various neoplastic cell lines have provided strong evidence for this mechanism. 84 STRUCTURAL CHROMOSO MAL ABERRATIO NS INCLUDING ONE SINGLE CHROMOSOME (“INTRACHANGES”) NORMAL CHROMATIDE GAP CHROMOSOME GAP CHROMOSOME BREAK IN TERSTITIE LL DELETION NORMAL DICENTRIC CHROMOSOME WITH ACE NTRIC FRAGM ENT RING CHROMOSOME ACENTRIC RING STRUCTURAL CHROMOSO MAL ABERRATIO NS INCLUDING TWO CHROMOSOMES (”INTERCHANGES”) PER IC EN TRIC IN VER SION RECIPRO C TRANS LOCATION
7.2.4 Test systems Short-term bioassays for genotoxic effects have been extensively used as screening tools in the toxicological evaluation of complex mixtures, because they are rapid, inexpensive and sensitive indicators of a sample’s potential to induce genetic damage. Since the beginning of the 1970s more than 100 short-term in vitro tests, employing bacteria, yeast, fungi and mammalian cells, and in vivo tests in plants, insects, earthworms and animals have been developed. Table 7.2.4.1. The most commonly used guideline tests for genotoxicity. Assays for measuring primary DNA damage • DNA adduct formation (no guidelines) • DNA damage and repair, unscheduled DNA synthesis (UDS) in vitro and in vivo (OECD guidelines 482 and 486) • Mitotic recombination in Saccharomyces cerevisiae (OECD guideline 481) • COMET assay in vitro and in vivo (no guideline) Assays for measuring the induction of point (gene) mutations • Bacterial reverse mutation assay (OECD guideline 471): Salmonella/mammalian microsome assay Escherichia coli WP2 • Gene mutations in mammalian cells in vitro (OECD guideline 476) • Point mutations in transgenic animals (e.g. MutaMouse and Big Blue mouse/rat) (no guidelines) Assay for measuring the induction of chromosomal aberration • In vitro cytogenetic assay (OECD guideline 473) • In vivo cytogenetic assay in somatic cells (OECD guideline 475), and spermatogonia (OECD guideline 483) • Micronucleus assay in vitro (no guideline) • Micronucleus assay in vivo (OECD guideline 474) • Sister chromatid exchange (SCE) (OECD guideline 479) • Fluorescent in situ hybridisation (FISH) (no guideline) Commonly studied endpoints include DNA damage (e.g. strand breaks, DNA adduct formation, DNA repair and DNA recombinations), gene (point) mutations, chromosomal aberrations (CA), sister-chromatid exchange (SCE), micronuclei (MN) and aneuploidy. However, only a few of these test systems are so well validated that they are routinely used and international guidelines exist. Table 7.2.4.1 shows the most commonly used genotoxicity tests. The OECD guideline number is referred to in parenthesis. A few new non-guideline tests are also mentioned, which might be promising tests for future evaluations of complex mixtures for genotoxic potential. 7.2.5 In vitro assays 7.2.5.1 Assays measuring primary DNA Damage DNA adducts DNA adduct formation is most often measured by direct isolation and identification of the adduct, often using radiolabelled test compound, or by use of the 32 P-postlabelling technique. DNA repair Unscheduled DNA synthesis (UDS) measures the incorporation of DNA precursors such as tritiated thymidine ( 3 HTdR) at times other than the scheduled, S-phase, synthesis of DNA in the cell cycle. UDS indicates that the compound has damaged 85
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Combined Actions and Interactions o
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Contents CONTENTS 3 PREFACE 6 SAMME
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7.2.4 Test systems 85 7.2.5 In vitr
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Sammenfatning og konklusioner Indle
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er ingen viden om, hvorledes den ko
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estemt biologisk respons (ED10, ED2
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vivo. The COMET-assay in vivo and g
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and antagonistic effects may be see
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1 Introduction Prepared by John Chr
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Table 1.3.1: Classification of comb
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Physicochemical interactions will t
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US EPA (1986) applied the concept o
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2.4 Test strategies to assess combi
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Figure 2.4.3.1. Isobologram of two
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CI = d1 /D1 = 1 In this case the is
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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 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
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with combinations of environmental
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Boyd MR, Statham CM and Longo NS (1
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De Wall EJ, Schuurman HJ and Van Lo
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theoretical considerations and a su
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Groten JP, Sinkeldam EJ, Muys T, Lu
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Howes D, Guy R, Hadgraft J, Heyling
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cytochrome P450 1A2 expressed in Am
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Lison D, Carbonnelle P, Mollo L, La
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Narotsky MG, Weller EA, Chinchilli
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Ramsey JC and Andersen ME (1984). A
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Silva E, Rajapakse N and Kortenkamp
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Leeuwen FXR, Liem AKD, Nolt C, Pete
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Wlodarczyk B, Biernacki B, Minta M,
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