Combined Actions and Interactions of Chemicals in Mixtures

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One especially successful method of testing complex mixtures is bioassay-directed fractionation followed by chemical identification of active compounds. Until now this method has mainly been used for the testing and identification of genotoxic compounds in environmental mixtures such as air particulates, exhaust condensates and cooked foods. In this approach, each fraction is bioassayed until the major class of specific chemical(s) responsible for the activity can be isolated and chemically characterised, which make a risk assessment of the mixture possible. The advantage of fractionation includes the separation of active constituents from inactive or otherwise toxic components. Disadvantages include the limited amount of sample available for testing following processing, the likelihood of “spillover” of chemical classes between fractions, and the possible loss or modification of components with fractionation. Alternatively (or initially) the mixture is treated as a whole and tested in its crude state. The advantage of this strategy includes the relevancy of the tested sample to its environmental counterpart, decreased potential for artefact formation, and inclusion of combined effects of chemicals in the mixture. Moreover if the mixture is representative of others in its class (e.g. diesel emissions from different sources would share certain characteristics), it may be possible to extrapolate results across samples. This method also circumvents the labour-intensive process of individually testing of multiple chemicals. But sometimes a complex mixture is to cytotoxic to be tested directly in a bioassay. Furthermore, it may be incompatible with the test system because of the physical matrix. Other disadvantages include the inability to specify the constituent of the mixture responsible for the toxicity, as well as potential masking effect (e.g. the masking of mutagenicity by cytotoxicity). 32
3 General concepts in the risk assessment of single chemicals Prepared by John Chr. Larsen 3.1 Introduction It is often stated that the current practice of establishing acceptable or tolerable exposure levels of single chemicals do not provide adequate health protection of the population because humans are always exposed to cocktails of chemicals. In order to examine and bring into perspective the potential health risks from exposure to complex mixtures of chemicals in the food, air, water, environment and workplace it is essential to relate the outcome of potential combined actions of chemicals to the current protection levels based on single chemical assessments. Therefore the principles of risk evaluations are briefly outlined below. There is worldwide agreement that the measures taken to protect human health from exposure to chemicals in food, air, water, and the environment at large should be based on sound scientific assessments and various international organisations have proposed that the risk analysis be divided into three distinct and separate steps: • Risk assessment, • Risk evaluation (including risk management) • Risk communication (to consumers, industry, stakeholders, etc.). Principles for the risk assessment of new and existing chemicals have been laid down by the European Union in the Commission Directive 93/67/EEC (EC 1993) and the Commission Regulation (EC) 1488/94 (EC 1994) supported by Technical Guidance Documents (EC 1996). The international Programme on Chemical Safety (IPCS) also provided guidance on the assessment of human health risks of chemicals (IPCS 1994). There is also international agreement within the World Trade Organization (WTO) on the principles used in the safety evaluation of food additives, pesticides, veterinary drugs and other chemicals in foods such as food contaminants. These principles were agreed upon at the Uruguay Round and are laid down in “Agreement on the Application of Sanitary and Phytosanitary Measures” (the SPS Agreement). This agreement requires health and safety measures to be based on sound scientific risk assessment and WTO recognises FAO/WHO Codex Alimentarius Commission (CAC or “Codex”) standards as a reference point for the safety of foodstuffs traded internationally. These standards are established in the Codex Committee on Food Additives and Contaminants (CCFAC), which uses the Joint FAO/WHO Expert Committee on Food Additives (JECFA) as an advisory committee with regard to the safety evaluation of food additives and contaminants. 3.2 Steps in the risk assessment In the human risk assessment of chemicals an attempt is made to identify the hazards of the substances and relate them to exposure. According to WHO the risk assessment can be divided into four steps: 33
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: 2.5 Toxicological test methods When
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
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
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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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