Combined Actions and Interactions of Chemicals in Mixtures

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c TCTFP = 1,1,2-trichloro-3,3,3-trifluoropropene d HCBD = hexachloro-1,3-butadiene e NONEL = No observed nephrotoxic effect level (=LONEL/4) f LONEL = Lowest observed nephrotoxic effect level 5.4 Mixtures of chemicals affecting the same target organ but with different target sites A number of 3-day inhalation studies (6 h/d) were carried out in male rats with formaldehyde, acetaldehyde, and acrolein and mixtures of two or three of these toxicants (Table 5.4.1). They all produce the same type of adverse effect (nasal cytotoxicity) but with different target sites (different regions of the nasal mucosa). Formaldehyde had no effect on the nasal epithelium at 1 ppm, but produced clear changes at 3.2 ppm. Acrolein induced marked nasal changes at 0.67 ppm and less severe changes at 0.25 ppm. Both dose levels of acetaldehyde only produced minor changes. The nasal changes seen after exposure to mixture 1 and mixture 2 were very similar in site, type, degree and incidence to those induced by 0.25 ppm acrolein alone. These changes were therefore considered to be induced by acrolein and not influenced by co-exposure to 1,0 ppm formaldehyde or to 1.0 ppm formaldehyde + 750 ppm acetaldehyde. Mixture 3 induced pronounced changes that were more severe than those found after exposure to the individual compounds at comparable concentrations. The changes indicated that the combined effect of formaldehyde and acrolein on the nasal respiratory epithelium was at least additive and that formaldehyde and/or acrolein probably potentiated the effect of acetaldehyde on the olfactory epithelium. The authors conclude that neither effect addition nor potentiating interactions occur, providing the exposure concentrations of the aldehydes are at NOAELs. They also state that the type of combined action or interaction found at clearly toxic effect levels is not very helpful in predicting what will happen at levels that are not toxic (Feron et al. 1995a, Cassee et al. 1996, 1998). Table 5.4.1. Exposure concentrations (ppm) used in 3-day (6 h/d) inhalation toxicity studies in male rats with nasal toxicants Groups a Formaldehyde Acetaldehyde Acrolein Formaldehyde/low 1.0 Formaldehyde/high 3.2 Acetaldehyde/low 750 Acetaldehyde/high 1500 Acrolein/low 0.25 Acrolein/high 0.67 Mix 1 1.0 0.25 Mix 2 1.0 750 0.25 Mix 3 3.2 1500 0.67 a Each separate study included a control group exposed to clean air only. 5.5 Conclusions of the Dutch studies The overall conclusion that the Dutch group draws from their experiments is that combined exposure to arbitrarily chosen chemicals clearly demonstrated the absence of full additivity, and provided some evidence of partial additivity when all chemicals in the mixture were administrated at their own individual NOAELs. At slightly lower dose levels no clear evidence of toxicity was found. This conclusion was found valid for combinations of chemicals that have either different target organs and or different target sites within the same organ (i.e. differ in the 68
mode of action). Therefore exposure to such mixtures is not associated with a greater hazard than exposure to the individual chemicals, provided that the exposure levels are at or below the individual NOAELs. At exposure levels higher than the NOAELs both synergistic and antagonistic effects may be seen, dependent on the compounds. When the exposure levels are at the ADI/TDI levels no greater hazard is to be expected. The group is of the opinion that the use of the “dose addition” approach to the risk assessment of chemical mixtures is only scientifically justifiable when all the chemicals in the mixture act in the same way, by the same mechanism, and thus differ only in their potencies. Application of the “dose addition” model to mixtures of chemicals that act by mechanisms for which the additivity assumptions are invalid would greatly overestimate the risk (Feron et al. 1995b,c; Cassee et al. 1998). 69
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Combined Actions and Interactions o
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Contents CONTENTS 3 PREFACE 6 SAMME
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7.2.4 Test systems 85 7.2.5 In vitr
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Sammenfatning og konklusioner Indle
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er ingen viden om, hvorledes den ko
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estemt biologisk respons (ED10, ED2
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vivo. The COMET-assay in vivo and g
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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 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 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
Page 90 and 91: Four inhibitors of DNA topoisomeras
Page 92 and 93: cyclophosphamide-metabolising enzym
Page 94 and 95: Nickel compounds are carcinogenic t
Page 96 and 97: 7.2.8 Conclusion As shown in this r
Page 98 and 99: Since no compounds are known to cau
Page 100 and 101: In a more mechanistic sense, promot
Page 102 and 103: Several inhibitors of tumour promot
Page 104 and 105: Table 7.4.1.1 Overview of in vivo t
Page 106 and 107: analysis was used to predict the hi
Page 108 and 109: interaction of TCDD and retinoic ac
Page 110 and 111: and now includes compounds as diver
Page 112 and 113: Furthermore, the estrogenic effects
Page 114 and 115: Dose of A (arbitrary units) 10 8 6
Page 116 and 117: 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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