Combined Actions and Interactions of Chemicals in Mixtures

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2.2.2 Simple dissimilar action (response or effect additivity, Bliss independence) Simple dissimilar action (simple independent action, independent joint action, Bliss independence and effect addition or response addition) is also a non-interactive process where the toxic effect of each chemical in the mixture is not affected by the other chemicals present. However, the modes of action of the constituents in the mixture will always differ and possibly, but not necessarily, the nature and site of action also differs among the constituents. Response addition is referred to when each individual of a population (e.g. a group of experimental animals or humans) has a certain tolerance to each of the chemicals in a mixture and will only exhibit a response to a toxicant if the concentration exceeds the tolerance dose. In such a case, the number of responders within the group will be recorded rather than the average effect of a mixture on a group of individuals. By definition, response addition is determined by summing the responses of the animals to each toxic chemical in the mixture. Three different concepts have been developed for effect/response additivity depending on the correlation of susceptibility of individuals to the toxic agents: 2.2.2.1 Complete negative correlation There is a complete negative correlation between the effects of two chemicals if the individuals that are most susceptible to one toxicant are least susceptible to the other. This is the simplest form of response additivity. The proportion (P) of individuals responding to the mixture is equal to the sum of the responses to each of the components: Pmixture A,B = PA + PB less than or equal to 1 2.2.2.2 Complete positive correlation There is a complete positive correlation between the effects of two chemicals if the individuals most susceptible to one toxicant are also most susceptible to the other. The proportion (P) of individuals responding to the mixture is equal to the response to the most toxic compound in the mixture: Pmixture A,B = PA if toxicity A ≥ B 2.2.2.3 No correlation, Bliss independence This situation is equal to Bliss independence. There is no correlation if the proportion of individuals responding to the mixture is equal to the sum of proportions of individuals responding to each of the toxicants taking into account that those individuals that respond to constituent A cannot react to B as well: Pmixture A,B = PA + PB ⋅ (1 - PA) Although this type of correlation seems to be similar to complete negative correlation, the difference is that in this case an individual can respond to both compound A and B but not to both at the same time. The approach of response addition can be easily applied to simple problems, such as acute toxicity of pesticides. However, more complex effects are not always easy to summate. Experimental animals are usually obtained from inbred strains, while human populations are more heterogenic. In addition, various effects on different organ systems may occur within different time frames in experimental animals. 22
US EPA (1986) applied the concept of response addition to the determination of cancer risks, assuming a complete negative correlation of tolerance. This assumption is considered to contribute to a conservative estimation of risk, since the correlation of tolerances may not be strictly negative in inbred homogenous experimental animals. There is a major difference between the concepts of response addition and dose addition when the human situation of low exposure levels is assessed. Response addition implies that when doses of chemicals are below the no-effect-levels of the individual compounds (i.e. the response of each chemical equals zero) the combined action of all compounds together will also be zero. In contrast, dose addition can also occur below the no-effect-level and the combined toxicity of a mixture of compounds at individual levels below the noeffect level may lead to a response. For compounds with presumed linear dose-response curves, such as genotoxic and carcinogenic compounds for which it is assumed that a no-effect-level does not exist and for which the mechanism of action may be regarded as similar, response addition and dose addition will provide identical results (Könemann & Pieters 1996). 2.3 Interactions Chemicals may interact with one another and modify the magnitude and sometimes also the nature of the toxic effect. According to Table 1.3.1 the combined action of chemicals that interacts can be divided into two categories: Complex similar action and dependent action (complex dissimilar action). Interactions may take place in the toxicokinetic phase and/or in the toxicodynamic phase. The interactions may result in either a weaker (antagonistic) or stronger (potentiated, synergistic) combined effect than would be expected from knowledge about the toxicity and mode of action of each individual compound. 2.3.1 Antagonism An antagonistic effect occurs when the combined effect of two chemicals is less than the sum of each chemical given alone. Synonyms sometimes used for antagonism are: Interaction, depotentiation, desensitisation, infra-addition, negative synergy, less than additive, subaddition, inhibition, antergism, competitive antagonism, noncompetitive antagonism, uncompetitive antagonism or acompetitive antagonism. 2.3.2 Synergism A synergistic effect occurs when the combined effect of two chemicals is greater than the sum of the effects of each chemical given alone. Synonyms sometimes used to describe synergism are: Coalitivity, interaction, unisynergism, augmentation, sensitisation, supra-addition, independent synergism, dependent synergism, degradative synergism, greater than additive, cosynergism, superaddition, conditional independence or potentiation. 2.3.3 Potentiation Potentiation, being a form of synergism, occurs when the toxicity of a chemical on a certain tissue or organ system is enhanced when given together with another chemical that does not have toxic effects on the same tissue or organ system. This form of interaction is especially well described in mutagenesis and carcinogenesis where a number of compounds have been identified as co-mutagens or cocarcinogens. 23
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: Physicochemical interactions will t
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
Page 68 and 69: c TCTFP = 1,1,2-trichloro-3,3,3-tri
Page 70 and 71: 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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