Combined Actions and Interactions of Chemicals in Mixtures

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they had either the same UF of 100 (Table 4.2.1a) or UF ranging from 10 to 1000 (Table 4.2.1b). Table 4.2.1. Hypothetical example for cumulative risk assessment (adapted from Wilkinson et al (2000)) Compound ED10 (mg/kg/d) 40 Uncertainty factor (UF) RfD (mg/kg/d) a. Chemicals with the same UF I 100 100 1 0.5 II 500 100 5 0.5 III 25 100 0.25 0.01 IV 5 100 0.05 0.01 b. Chemicals with different UF I 100 10 10 0.5 II 500 100 5 0.5 III 25 1000 0.025 0.01 IV 5 100 0.05 0.01 4.2.1 Hazard index (HI) Exposure (mg/kg/d) The hazard index is the sum of the hazard quotients (HQ) of the individual chemicals, i.e. the sum of exposure to each chemical expressed as a fraction of its RfD/ADI/TDI. The HI should not exceed 1 since this indicates that the FQPA (US Food Quality Protection Act) “risk cup”, a kind of combined RfD for the common mechanism group, is full. HI = HQI + HQII + HQIII + HQIV or HI = ExpI/RfD1 + ExpII/RfDII + ExpIII/RfDIII + ExpIV/RfDIV Although the HI method is transparent, easily understandable and directly relates to the RfD, the major disadvantage is that the RfD is not an appropriate metric to use as a POD for cumulative risk assessment, since the RfD is normally derived by using NOAELs and uncertainty factors, which are not data based, but may incorporate significant policy-driven assumptions. Use of the information in Table 4.2.1a where the UF values for each compound is the same gives the following result: HI = 0.5 + 0.1 +0.04 + 0.2 = 0.84 Risk units Whereas use of the information in Table 4.2.1b where the UF values differ gives: HI = 0.05 + 0.1 + 0.4 + 0.2 = 0.75 Risk units Although the overall HI is quite similar, this example illustrates that the contribution of each chemical is highly dependent on the UF. Moreover, the method do not reflects that the components of the mixture do not all have the same critical effect. The hazard index method has been refined by the introduction of the target-organ toxicity dose (TTD) method. This method suggests that separate hazard indexes
should be estimated for all endpoints of concern. This implies that a TTD should be established for all relevant endpoints for each chemical using the same principles as used in the “normal” derivation of the RfD/ADI/TDI and that “hazard quotients” be calculated for the relevant effects of each chemical (for details see ATSDR 2002). 4.2.1.1 Weight-of-Evidence (WOE) modification to the hazard index The hazard index method does not incorporate information on interactions among components of the mixture (ATSDR 2002). Mumtaz and Durkin (1992) proposed a weight-of-evidence (WOE) method to systematically address this need. The method was designed to modify the hazard index to account for interactions, using the weight of evidence for interactions among pairs of mixture components. Thus, the basic assumption is that pair wise interactions will dominate in the mixture and adequately represent all the interactions. For example, if chemicals A and B interact in a certain way, the presence of chemical C will not cause the interaction to be substantially different. It should be noted that experience with the method has revealed that it is mainly useful for a qualitative prediction as to whether the hazard may be greater or less than indicated by the hazard index (ATSDR 2002). The method evaluates the data relevant to joint actions for each possible pair of chemicals in the mixture in order to make qualitative binary weight-of-evidence (BINWOE) determinations for the effect of each chemical on the toxicity of every other chemical. Two BINWOEs are needed for each pair: one for the effect of chemical A on the toxicity of chemical B, and another for the effect of chemical B on the toxicity of chemical A. The BINWOE determination indicates the expected direction of the interaction, such as greater than additive, less than additive, additive, or intermediate. It scores the data qualitatively by using an alphanumeric scheme that takes into account mechanistic understanding, toxicological significance, and relevance of the exposure duration, sequence, bioassay, and route of exposure. The alphanumeric terms are finally converted into a single numeric score. The BINWOE evaluations should be target organ specific. A more detailed description and discussion has been provided by ATSDR (2002). 4.2.2 Point of Departure Index (PODI) A scientifically more appropriate method of addition is summing the exposures of each compound expressed as a fraction of their respective PODs instead of the ADI or RfDs. These POD fractions (PODF) are reciprocals of the individual margin of exposures (MOE) of each compound. This approach sums the exposures to the compounds in terms of their relative potencies. In this example the ED10 (Table 4.2.1) are used as PODs: PODI = 0.005 + 0.001 + 0.0004 + 0.002 = 0.0084 Risk units The PODI can be converted into a “risk cup” unit by multiplying by an appropriate group UF. For example, a group UF of 100 would result in a combined risk of 0.84 risk units. 4.2.3 Toxicity equivalency factors (TEF) The TEF approach normalises exposures to common mechanism chemicals with different potencies to yield a total equivalent exposure (TEQ) to one of the chemicals, the “index compound”. TEFs are derived as the ratio of the POD of the index compound to that of each member in the group. The exposure to each 41
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: describe toxicities that appears to
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
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Four inhibitors of DNA topoisomeras
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cyclophosphamide-metabolising enzym
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Nickel compounds are carcinogenic t
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7.2.8 Conclusion As shown in this r
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Since no compounds are known to cau
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In a more mechanistic sense, promot
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Several inhibitors of tumour promot
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Table 7.4.1.1 Overview of in vivo t
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analysis was used to predict the hi
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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
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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
Page 142 and 143:
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
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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