Combined Actions and Interactions of Chemicals in Mixtures

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Dermis The dermis consists of a supportive connective tissue composed mainly of collagen fibres together with elastic fibres in a matrix of glycosaminoglycan, salt and water. The dominant structural elements are synthesised by the dermal fibroblasts. The dermis also contains blood vessels, nerves, hair sacs, sebaceous glands and sweat glands. The three latter structures may act as an alternative "shunt" in the percutaneous absorption of chemicals. The dermis is stretching up papillae in epidermis, providing the viable epidermis with essential nutrients and draining it for waste products and penetrants. The viable epidermis and the dermis also constitute a permeability barrier, primarily against lipophilic substances. 7.1.2.2 Percutaneous absorption Absorption of chemicals through the skin involves several individual transport processes, including adsorption to the surface of the stratum corneum, passive diffusion through this barrier, desorption into the viable epidermis, diffusion through this part of the epidermis and the papillary dermis, and ultimately transfer into the blood circulation. It has been demonstrated that the rate-limiting event for dermal absorption of xenobiotics in undamaged skin in most cases is the passive diffusion through the stratum corneum. The stratum corneum can be considered morphologically and functionally to represent a two-compartment system consisting of corneocytes largely composed of fibrous protein networks in an intercellular matrix, predominantly composed of neutral lipid. Although not considered totally impermeable to neither water nor lipid soluble compounds, the intact stratum corneum layer is in practice impermeable for large molecules (MW>500). Among compounds of lower molecular weight, the best skin penetrants are soluble in both lipid and water. The major pathway for penetration appears to be through regions with a high lipid content (the intercellular matrix), and within series of similar substances the rate of penetration often correlates with their water/lipid partition coefficients. Hydrophilic substances may penetrate through the protein-rich, hydrated intracellular regions. Some absorption may occur through "shunts" (hair follicles and sweat ducts), but the transdermal flux through this pathway is considered to be minimal. However, for very lipophilic and large molecules together with electrolytes, the alternative shunt seems to be important for penetration. Highly lipophilic substances may penetrate the stratum corneum easily, and for such compounds the viable epidermis and dermis may be the rate-limiting barrier. 7.1.2.3 Test systems Skin irritancy is most often studied in animal experiments or in studies with human volunteers. Skin organ cultures with human or animal skin have been used to model effects of chemical irritants (van de Sandt and Rutten, 1995). Preliminary results obtained with reconstructed human epidermal tissue cultures hold promise as future test systems (Coquette et al., 1999; De Burgerolle de Fraisinette, A. et al. 1999). Compounds or factors that can modulate the barrier function of the stratum corneum may dramatically affect the effects of dermal irritants. Hydration and delipidization are known to decrease the barrier function of the stratum corneum. Hydration plays an extremely important role in the rate of absorption of materials through the skin. In normal skin, a gradient in water concentration exists through the tissue corresponding to an average concentration of 0.9 g of water per gram of dry tissue. In vitro studies have demonstrated that this amount of water increases the rate of absorption of various materials approximately 5-10 fold compared to dry skin. The stratum corneum can ultimately absorb three to five times its own weight of water, and this further hydration may results in an additional 2-3 fold increase in the rate of absorption of water and other polar molecules (Wester & Maibach 1985). Extraction of lipids from the skin by delipidization with organic solvents appears to decrease the barrier effect 74
for rather short time periods, since the barrier is restored through dynamic intrinsic lipogenesis (Menczel, 1985). 7.1.2.4 Examples of combined action Local toxic effects to the skin include irritation and corrosion (tissue necrosis). Examples of dermal irritants are strong bases and acids, oxidising or reducing substances, organic solvents and surfactants. When the skin is mildly irritated the dermal blood flow will increase and a local erythema may be produced. More severe irritants can induce capillary leakage to produce manifestations as local oedema or blisters. Very severe intoxications may result in cell and tissue necrosis, and the formation of scars. Substances and preparations (mixtures) may be classified as corrosive due to their physical-chemical properties on the basis of the pH value and the acidic or alkaline capacity. Changes in transepidermal water loss may be the cause of combined effects of dermal irritants. Tandem application of topical retinoic acid and sodium lauryl sulphate has been shown to cause synergistic effects concerning non-specific skin irritation. Transepidermal water loss increases dramatically shortly after application of sodium lauryl sulphate, but the increase is delayed after application of retinoic acid (Ale et al., 1997). Various chemicals have been used in dermatologic preparations in order to enhance the percutaneous absorption of drugs, and additive or synergistic effects by combined exposure to such substances and dermal irritants may be expected. The literature contains many references to skin penetration enhancers that produce minimal irritation and are of low toxicity. Among the most popular and regularly used penetration enhancers are dimethyl sulfoxide (DMSO) and propylene glycol. DMSO appear to enhance skin penetration by either solubilizing the drug in the vehicle or by preceding the drug in penetration and altering the biochemical and structural integrity of the skin, whereas propylene glycol appear to more strictly function as a solubilizer (Gummer, 1985). The addition of lipids to the skin may prevent loss of skin lipids due to e.g. exposure to organic solvents or replace skin lipids extrinsically. Lipid ingredients of cream bases have been demonstrated to protect industrial workers against the effects of exposure to organic solvents (Menczel, 1985). Other skin-protective materials include different types of waxes, e.g. paraffin wax and bees wax. Application of the waxes to the skin of human volunteers before treatment with irritants or allergens has significantly suppressed the dermal irritancy of sodium lauryl sulphate and combined ammonium hydroxide/urea treatment and moreover appeared to protect against the induction of allergic contact dermatitis (Zhai et al., 1998). Several investigations have shown a pronounced dermal capacity for metabolism of xenobiotics, and induction or inhibition of dermal enzyme activities by one compound may affect the dermal effect of another compound. The viable epidermis is the most metabolically active part of the skin. For several enzyme activities, e.g. aromatic hydrocarbon hydroxylase, 7-ethoxycoumarin deethylase, aniline hydroxylase, and NADP-cytochrome c reductase, the specific activities in the epidermis and in the liver are comparable (Noonan & Wester, 1985). 75
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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
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Table 1.3.1: Classification of comb
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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 72 and 73: once more exposed and the kinetics
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
Page 122 and 123: 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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