Combined Actions and Interactions of Chemicals in Mixtures

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implications for hazard identification, hazard characterisation and risk assessment of chemicals are highlighted. In this context, special attention is paid to the low levels of exposures normally encountered from the unintended, indirect exposure to chemical mixtures through food and environment. A better understanding of the combined effects between different chemicals is anticipated to improve the safety evaluations of such mixtures performed by the Danish Environmental Protection Agency and the Danish Veterinary and Food Administration and provide a more rational basis for making risk assessments on combined exposure to chemicals. It has to be recognised that it is not possible for this report to cover all possible combined exposures to chemicals. In order to focus on the mutual needs of the Danish Environmental Protection Agency and the Danish Veterinary and Food Administration, the main emphasis is paid on the identification of the basic principles for combined actions and interactions of chemicals and on the current knowledge on effects of exposures to mixtures of industrial chemicals, including pesticides and environmental contaminants. Thus, interactions between natural components in food, such as inherent plant constituents, as well as their interactions with industrial chemicals and contaminants are not the topic of this report. In addition, influences of dietary habits are not dealt with. However, when studies on interactions between natural components of food provide significant understanding of the modes of action of chemical mixtures such information is included. These basic principles on combined actions and interactions of chemicals in mixtures are summarised and discussed in chapters 2-6. Chapter 7 contains a comprehensive review of different relevant effect areas, including examples of combined effects and interactions. 1.3 Key historical developments Interactions between chemicals administered to humans at high doses have been known for many years in the field of pharmacology. However, these experiences are not directly useful for predicting toxic effects of mixtures of environmental chemicals because the exposure levels of the general human population are relatively low and interactions occurring at high doses may not be representative for low-dose exposures (Könemann & Peters 1996). Toxicity studies with mixtures have been performed for several decades. Initially, most studies were done with binary mixtures. Later, studies with defined mixtures of more than two compounds have been reported. Studies have also been performed with complex mixtures of environmental chemicals, such as exhaust condensates, in order to gain insight into the toxic effects of such a particular mixture. However, the interpretation of the toxicity seen in these latter studies is complicated because the exact composition of such mixtures is normally not known, and the “real life” mixtures may vary considerably in composition. Therefore extrapolation to other situations may be difficult. This fact is often ignored for the sake of simplicity. A major issue in the assessment of the combined toxicological effect of chemicals in a mixture is the type of combined action to be expected. What kind of toxicity may be expected, given the toxicity profiles of the individual components? Bliss (1939) was the first to provide a conceptional framework for the combined action of chemicals and later contributions were made by Finney (1942), Hewlett and Placket (1959 and 1964), Placket and Hewlett (1952, 1963 and 1967), Ashford and Cobby (1974) and Ashford (1981). Placket and Hewlett (1952) provided a scheme of possibilities of combined (joint) actions (Table 1.3.1). 18
Table 1.3.1: Classification of combined (joint) toxic actions of two compounds in mixture Interaction Similar action Combined action Dissimilar action Absent Simple similar action Independent action, (No interaction) (Dose addition) Response addition Present Complex similar action Dependent action or (Interaction) (Antagonism or complex dissimilar synergism) action (Antagonism or synergism Modified after Placket and Hewlett (1952) A major clue that can be taken from this scheme is that in the initial assessment it is important to evaluate whether interactions are actually occurring (present) or not (absent). Interaction was defined as the influence of one chemical on the biological action of another (either qualitatively or quantitatively). The scheme represents the extremes of combined actions. In many cases there are not adequate information about the underlying mechanisms of combined actions. This led Berenbaum (1985 and 1989) to propose three classes of combined action: zero interaction, synergism and antagonism. In more recent years several reference books, review articles and reports have been published on the issue of toxicological effects from combined exposure to chemicals. The more important are outlined in chapter 8. 19
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: 1 Introduction Prepared by John Chr
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 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
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c TCTFP = 1,1,2-trichloro-3,3,3-tri
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6 Interactions in toxicokinetics Pr
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once more exposed and the kinetics
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Dermis The dermis consists of a sup
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7.1.3 Ocular irritancy 7.1.3.1 Comp
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Another in vitro test for ocular ir
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lipid peroxidation was observed, wh
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mixture. These interactions may dev
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0.6% of live births in humans. In s
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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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Combined Actions and Interactions of Chemicals in Mixtures

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