Combined Actions and Interactions of Chemicals in Mixtures

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once more exposed and the kinetics of the compounds followed in blood. There seemed to be a systematic decrease (although not statistically significant) in blood concentrations indicative of greater metabolism due to enzyme induction. Chaturvedi et al. (1991) studied the effects of mixtures of parathion, toxaphene and/or 2,4-D on the hepatic mixed-function oxygenase in ICR male mice. They found that a seven days toxaphene pre-treatment enhanced the hepatic biotransformation of parathion and paraoxon both in the presence and in absence of NADP. However, in the absence of NADP the enhancement was minor. The authors suggest that toxaphene induced the metabolic pathways of parathion and paraoxon involving the mixed-function oxygenase and that paraoxonase is not involved in the toxaphene-induced decreases of the two compounds. Toxaphene is enhancing the NADP-dependent metabolism of parathion and paraoxon and thereby decreasing their toxicity. Carboxyl esterase is involved in decreasing the toxicity of parathion and paraoxon by acting as a pool of non-critical enzymes, which compete for the binding of paraoxon thereby preventing an inhibition of cholinesterase. The increase in the level of Carboxyl esterase and cholinesterase has the potential to enhance further the ability of toxaphene to limit the toxicity of parathion. The authors therefore anticipated the toxicity of a mixture of parathion and toxaphene to be lower than that of parathion. Thus the results of the study could indicate an antagonistic effect of toxaphene on parathion and on paraoxon. Chaturvedi (1993) also examined the effect of mixtures of ten pesticides (alachlor, aldrin, atrazine, 2,4-D, DDT, dieldrin, endosulfan, lindane, parathion and toxaphene) administered by oral intubations or by drinking water on the xenobiotic-metabolising enzymes in male mice. He concluded, ”The pesticide mixtures have the capability to induce the xenobiotic-metabolizing enzymes which possibly would not have been observed with individual pesticides at the doses and experimental conditions used in the study.” However, it is not possible to categorise the type of combined action because Chaturvedi (1993) only examined the combined effects of the ten compounds in the mixture and did not consider the effect of the individual pesticides. 6.1.4 Interference with excretion For excretion processes the same reasoning may be used as for absorption. Cases of interaction are only to be expected when active processes are involved. Increased excretion of a chemical following administration of an osmotic diuretic or alteration of the pH of the urine is well known examples of dispositional interaction. 72
7 Combined actions in different toxicological effect areas This chapter describes the major toxicological effect areas that form the basis for most risk assessments of chemicals. When available, examples of combined actions and interactions are given within these areas. 7.1 Local irritation Prepared by Eva Selzer Rasmussen 7.1.1 Introduction Cytotoxic effects of chemicals may cause local tissue irritation to the skin, eyes and respiratory tract. The most severe acute effect is tissue necrosis produced by corrosive chemicals. Less severe effects include impairment of the integrity of cell membranes leading to increase in cell and tissue permeability, which may become manifest as oedema. Local irritative effects may also lead to increase in the blood flow to the tissues causing local erythema or result in capillary leakage producing oedema and blisters. The stratum corneum of the skin and the intact epithelia of the eyes, airways and lungs constitute the main biological barriers against exposure of the underlying tissue cells to xenobiotics. Damage to these barriers may be due to the combined actions or interactions of chemicals. The tissues of the eye and airways are also protected by additional, efficient defence mechanisms such as the blinking reflexes and tear flow of the eyes or the function of the mucociliary escalator of the airways. It has been demonstrated that these defence mechanisms can be impaired following the combined action of chemicals. Finally, it is increasingly being recognised that the cells in the skin, the eyes and the respiratory tract are active in metabolising xenobiotics. Induction or depletion of the enzymatic capacity of these tissues may thus be an additional basis for combined actions of chemicals resulting in local irritative effects. 7.1.2 Skin irritation 7.1.2.1 Composition of the skin The skin is constituted of two major tissue layers: an outer layer of thin stratified epithelium, the epidermis, and an underlying dense connective tissue, the dermis. The main function of the epidermis is to generate the stratum corneum, which functions as the major permeability barrier of the skin, primarily against hydrophilic substances. Epidermis The basal cell layer in the epidermis is the keratinocytes, a layer of fast dividing cylindrical cells. A layer of polygonal cells follows the keratinocytes, along with Langerhans’ cells, melanocytes, and other cells, and a layer of flattened nucleated cells containing keratohyalin granules. The outermost layer, the stratum corneum, consists of several layers of thin, flat anucleated keratinized cells (corneocytes). 73
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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
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1 Introduction Prepared by John Chr
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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 68 and 69: c TCTFP = 1,1,2-trichloro-3,3,3-tri
Page 70 and 71: 6 Interactions in toxicokinetics Pr
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
Page 118 and 119: 7.6.2.3 Receptors A receptor is a b
Page 120 and 121: 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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