Combined Actions and Interactions of Chemicals in Mixtures

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4 Approaches used in the assessment and regulation of chemical mixtures Prepared by John Chr. Larsen 4.1 Introduction Various approaches have been suggested in the scientific literature for use in the evaluation of the health risks from exposure to mixtures of chemicals. These are briefly discussed in this chapter. Most attention and effort has been devoted in the literature to procedures to assess cumulative effects of exposure to chemicals that act by a similar mechanism of action. However, the Dutch group around Victor Feron (Groten et al. 2001) as well as ATSDR (2002) have suggested more general approaches that cover also chemicals that differ in their modes of action (see sections 4.4 and 4.5). Following this discussion an overview is given on approaches so far used in Denmark in the regulation of certain types of chemical mixtures (section 4.6). 4.2 Procedures used to assess cumulative effects of chemicals that act by a common mechanism of action A number of approaches have been suggested to combine the exposure to chemicals that act by a similar mechanism of action but have different potencies and exposure characteristics (US EPA 1999, 2000). Wilkinson et al. (2000) have critically evaluated these approaches due to the renewed interest triggered by the US Food Quality Protection Act (FQPA) that requires the US EPA to consider the cumulative effects of pesticides and other substances that have a “common mechanism of toxicity”. The approaches discussed are the hazard index (HI), toxicity equivalency factor (TEF), and combined margin of exposure (MOE) procedures and the point of departure index (PODI) and cumulative risk index (CRI) methods. An ILSI Working Group (Mileson et al. 1998) has also recently addressed the “common mechanism” issue. The ILSI Working Group concluded that a common mechanism might exist if two compounds: • Cause the same critical effect • Act on the same molecular target at the same target tissue, and • Act by the same pharmacological mechanism of action and may share a common toxic intermediate It should be realised that with the exception of a few groups of chemicals, such as some organophosphorous and carbamate pesticides and some polychlorinated dibenzo(p)dioxins, – dibenzofurans and - biphenyls, precise mechanistic information on their toxic effects are scarce. In realising that the exact molecular mechanism is not known for most chemicals the term “mode of action” is used to 38
describe toxicities that appears to be similar albeit the mechanism is not known in details. For several groups of endocrine disrupters this terminology seems appropriate. Another critical issue is the question of concurrent exposure. This refers to coexposure to more than one chemical able to interact with a defined target in a specific target tissue during a particular time frame of interest (Wilkinson et al. 2000). It is important to distinguish between concurrent or simultaneously “external” exposure, referring to the timing of oral, dermal or inhalation exposure, from concurrent “internal” exposure that relates to the dose actually attained at a given biological target in a given time frame. For the risk assessment it is the “internal” exposure that is of toxicological significance, however, it is seldom known. The factors that determine whether a cumulative effect is likely from exposure to several different common mechanism compounds are the timing and duration of external exposure, the persistence (biological half-life) of the chemicals in the body, and the duration of the effect. The effect of any chemical at a biological target depends of its ability to attain a target site concentration that exceeds the threshold required to elicit the response. The intensity and duration of the response depends on the toxicokinetic properties of the compound (absorption, distribution, metabolism and excretion) and the nature of the target site interaction (reversible, irreversible). If recovery is complete between successive exposures no cumulative toxicity is to be expected. However, a short-term acute exposure could potentially add to the long-term burden of a persistent chemical and be relevant for the magnitude of the chronic effect. For acute and short-term exposures difference in the toxicokinetic properties, which will result in different times to maximum effect for the individual compounds, are critical in determining concurrency at the target site. Therefore, exposure intervals and the sequence of exposures to different chemicals may have significant impact on the potential cumulative effect. The risk assessment of exposure to mixtures of defined chemicals should make optimal use of the toxicological databases. Ideally, in the opinion of Wilkinson et al. (2000) the point of departure (POD) for the assessment should be a dose associated with a particular biological response (ED10, ED20) since this takes into account all of the dose-response data available. A POD based on doses causing a particular response should always take preference over the NOAEL. This is because the NOAEL is a single point value and not a measure of a biological response and is largely an artefact of experimental design. The POD should also ideally be based on studies with the same animal species using the same route of administration. However, the data available for most chemicals will not permit an estimation of for instance ED10 and relative potencies may have to be based on NOAELs as PODs. In describing the various procedures proposed to evaluate the risk associated with combined exposure to a group of chemicals with a common mechanism of action Wilkinson et al. (2000) emphasise that the biggest problem associated with all methods of cumulative risk assessment is how to accommodate the different uncertainty factors (UF) that are applied to derive regulatory values such as ADIs or RfDs. If the uncertainty factors applied are the same for all the chemicals, all the methods will give the same result. However, this is most often not the case and the different uncertainty factors applied to the various chemicals will dominate the result of the risk assessment. In order to illustrate this, exposure to a hypothetical group of four common mechanism chemicals, differing in potency by 100-fold and having exposures ranging from 0.01 to 0.5 mg/kg bw/day, was assessed assuming 39
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: of uncertainty i.e. differences in
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 84 and 85: 0.6% of live births in humans. In s
Page 86 and 87: DNA, and that the cell was capable
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(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
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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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