Combined Actions and Interactions of Chemicals in Mixtures

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suggested, and for compounds that interact, use of interaction hazard index have been suggested. Several reports have suggested that since the pesticides are found in food at levels well below their respective no observed adverse effect levels (NOAEL), the approaches based on toxicologically similar mechanism (same mechanism of action) and toxicological independence (different mechanism of action) should be used for risk assessment of pesticide residues. In fact, it has been suggested that methods for toxicologically similar compounds could be used in most cases, even when the compounds are not toxicologically similar. The present knowledge about combined toxic effects of mixtures of pesticides (the active substances of pesticide formulations) that have been published in the scientific literature were summarised and evaluated in the report in order to test the hypothesis behind the risk assessment models presented. The in vivo studies on pesticide mixtures were performed at high doses (ten times NOAEL or higher) compared to the expected pesticide residues in food. Studies employing high doses have shown both additivity and interactions such as synergism or coalism as well as antagonism. None of the studies reported in the literature used low pesticide doses, in the range normally found for residues in food. Furthermore, the number of theoretical possible pesticide mixtures is enormous compared to the number of mixtures studied and published in the scientific literature and the overall quality of the data in the studies is not good enough to reach a clear conclusion. Therefore it was concluded that there is no scientific background for establishing a general standard formula for risk assessment of pesticide mixtures in food. However, studies on other chemical mixtures at low doses have been found not to demonstrate a risk different from that of the single compounds in the mixture. The authors of these studies have concluded that combined exposure to arbitrarily chosen chemicals did not demonstrate more than an additive action when all chemicals in the mixture were administrated at their own individual NOAELs (see chapter 5). In the report it is suggested to use the flow chart shown in figure 4.6.3.1 for risk assessment of pesticide mixtures in crops. The risk assessment of pesticide mixtures in crops should be done by a case-by-case evaluation in which the available chemical and toxicological data on the pesticides are evaluated in a weight of evidence process. Then the hazard index with the ADI (where the individual safety factors are included) and not the NOAEL’s (where the safety factors are not included) as the acceptable level in the denominator is recommended for use. However, in cases where the weight of evidence process points out that the compounds in the mixture share a common mechanism (e.g. for the organophosphorus pesticides), the toxicity equivalency factor (TEF) approach should be used, if possible (Reffstrup 2002). 58
Figure 4.6.3.1 Flow chart of the risk assessment approach for pesticide mixtures found in food. Yes Do the compounds act by the same mode of action? Yes Are the available data adequate for the toxic equivalency factor approach? Yes Use the toxic equivalency factor approach for the risk assessment Do the compounds in the mixture have the same target organ? No No No The compounds are toxicologically independent Use the hazard index approach for the risk assessment 59
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Combined Actions and Interactions o
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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: no internationally accepted procedu
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
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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
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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
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tested separately. This is a phenom
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In practical life an allergen may b
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8.3 Conference proceedings Proceedi
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with combinations of environmental
Page 136 and 137:
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
Page 146 and 147:
cytochrome P450 1A2 expressed in Am
Page 148 and 149:
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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