Combined Actions and Interactions of Chemicals in Mixtures

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Figure 4.4.2.2 Scheme for safety evaluation of complex chemical mixtures Complex mixtures Mixtures readily available for testing in their enterity Mixture unavailable for testing in its entirety "Top-ten" classes of chemicals readily identifiable "Top-ten" chemicals readily identifiable Testing in their entirety indicated Identification of the "top-ten" chemicals Lump "top-ten" classes of chemicals to "pseudo top-ten" chemicals Consider "top-ten" chemicals as a simple mixture Adverse effects found in adequate and relevant studies No adverse effects found in adequate and relevant studies Consider "top-ten" chemicals as a simple mixture Consider "pseudo top-ten" chemicals as a simple mixture Data should be useful for risk assessment Toxicity profile indicates fractionation according to toxicity Toxicity profile satisfactorily characterized Data should be useful for risk assessment Data should be useful for risk assessment Data should be useful for risk assessment Identification of the chemical, group of chemicals or fraction responsible for toxicity Data should be useful for risk assessment Data should be useful for risk assessment 52
4.5 Approach for assessment of joint toxic action of chemical mixtures suggested by ATSDR The American Agency for Toxic Substances and Disease Registry (ATSDR) in 2002 issued a “Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures” (ATSDR 2002) in which strategies for exposure-based assessments are proposed for noncarcinogenic and carcinogenic effects, respectively. The strategies are based on a number of sequential questions asked and are outlined in the following: 4.5.1 ATSDR strategy for noncarcinogenic effects Step 1 and step 2 ask questions as to whether the mixture has already been either regulated or scientifically evaluated in which case this information should be used. If this is not the case further steps are proposed: Step 3 Are the hazard quotients (HQs, see 4.2.1) equal to or greater than 0.1 for at least 2 of the mixture components? If no, additivity and interactions are unlikely to result in health hazard. If yes, further evaluation of additivity and interactions is necessary for the components of concern (HQ equal to or greater than 0.1). Step 4 Is a relevant PBPK/PD model or studies on joint toxic action available for mixture of components of concern? If yes, use model or study to evaluate potential health hazard. If no, go to step 5. Step 5 Do components of concern have the same critical effects? If yes, go to step 6a. If no go to step 6b. Step 6a Apply the hazard index (HI) method (see 4.2.1). Step 6b Apply target-organ toxicity dose (TTD, see 4.2.1) modification of HI method for overlapping targets of toxicity or access any unique critical effect with separate HQ. If HI or separate HQ are equal to or less than 1 go to step 7a, if greater than 1 go to step 7b (HI > 1: potential health hazard due to additivity; separate HQ >1: potential health hazard due to unique critical effect. Step 7a Apply qualitative WOE (see 4.2.1.1, and ATSDR 2002): is combined score positive? If no, health hazard is unlikely 53
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: obvious ranking of individual const
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
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analysis was used to predict the hi
Page 108 and 109:
interaction of TCDD and retinoic ac
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and now includes compounds as diver
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Furthermore, the estrogenic effects
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Dose of A (arbitrary units) 10 8 6
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chance or experimental error. One w
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7.6.2.3 Receptors A receptor is a b
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7.6.5.2 Kindling Kindling is the ph
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Science Institute (RSI) have conven
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eaction with sulfhydryl groups). Th
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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
Page 140 and 141:
theoretical considerations and a su
Page 142 and 143:
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
Page 158:
Wlodarczyk B, Biernacki B, Minta M,
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Combined Actions and Interactions of Chemicals in Mixtures

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