Combined Actions and Interactions of Chemicals in Mixtures

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eaction with sulfhydryl groups). Therefore, the possibility for interactions is potentially great (Cassarett & Doull, 1986). Lead, mercury and manganese exhibit interaction with other neurotoxicants, possibly via kinetic mechanisms. Ethanol may increase the absorption of lead from the gastrointestinal tract (Barton & Conrad, 1978). Cadmium and lead absorption is increased in individuals with low iron status (Flanagan et al., 1978, Berglund et al., 1994, Watson et al., 1980). The neurotoxicity of toxic metals may be reduced by chelation with chelators as EDTA, n-acetyl-D-penicillamine, dimercaptosuccinic acid, and 2,3dimercaptopropane (Goyer et al., 1995). 7.6.6.4 Pesticides and manganese Many epidemiological investigations demonstrate a relation between exposure to pesticides and increased incidence for the development of Parkinson’s disease (Ho et al., 1989; Koller et al., 1990, Semchuk et al., 1992, Gorell et al., 1997, Golbe, 1998, Gorell et al., 1998, Tüchsen & Jensen, 2000, Engel et al., 2001). Inhalation exposure to manganese is known to induce symptoms of Parkinson’s disease (Parkinsonism, manganism) (Zayed et al., 1990, Calne et al., 1994, Gorell et al., 1997). The underlying mechanisms are not known in details (Veldman, 1998), but are proposed to include elements different from those supposed to be related to Parkinson’s disease (Arlien-Søborg, 2001). Because of the similarity in effect, a potential for interaction between pesticides and manganese in the development of symptoms of Parkinson’s disease exists. However, this potential has not been investigated. 7.6.6.5 PCB Polychlorinated biphenyl (PCB) is a mixture of compounds, which may possess individual effects on the nervous system as well as exhibit interaction phenomena. Developmental neurotoxicity involving cognitive and behavioural disturbances has been implicated following perinatal exposure to environmental pollutants through fish. Mainly PCBs have been implicated (Jacobson & Jacobson, 1996). There are several studies, which show that PCBs produce a wide spectrum of neurochemical and neuroendocrine effects in animals. Ortho-substituted PCB congeners affect brain neurochemistry, while non-ortho-substituted PCBs having dioxin-like activity may have little or no activity in the nervous system (Tilson & Kodavanti, 1997). However, the fish contains a mixture of methylmercury, arsenic, lead, PCBs, DDT and DDE, and effects may be the end result of additive or synergistic interaction between these components (Mergler et al., 1997). 7.6.6.6 γ-diketones When γ-diketone precursors are co-administered, the neurotoxic effect observed equals the sum of effects caused by the individual substances. 7.6.6.7 Glutamate agonists Injection of the glutamate agonist NMDA prior to injection of the causative agent for shellfish poisoning, domoic acid, which is also a glutamate agonist, potentiates the acute neurotoxicity of domoic acid in mice by a factor less than two (Tasker & Strain, 1998). This is an example of toxicodynamic interaction at the level of the glutamate receptor. 7.6.6.8 Physical stimuli Physical stimuli may interact with the neurotoxicity of chemicals. One example is the increased hearing loss caused by interaction between organic solvents and noise (Morata et al., 1993). 124
7.6.6.9 Stress Stress may increase the brain’s vulnerability to chemical substances by making the protective shield, the BBB, more permeable to neurotoxicants. This may be a possible mechanism for the entry of pyridostigmine into the brain of soldiers (Friedman et al., 1996). 7.6.7 Conclusion There are many possibilities for interaction between neurotoxicants because of the complex hierarchical structure of the nervous system. A number of examples have been described of which the most well-known are the additive effects of organic solvents with respect to narcotic effects, and organophosphorus insecticides and acetylcholinesterase inhibition. It is therefore evident that interaction is a real phenomenon and not just a theoretical possibility. The strongest interaction found in the literature was a 5-fold increase in the neurotoxicity of hexane when methyl isobutyl ketone was co-administered. However, very few quantitative studies have been performed. Interaction has not been studied systematically, and the present state of knowledge does not allow general conclusions. Potential neurotoxic interaction of chemicals by additive and synergistic effects and promotion should always be considered in the risk assessment procedure. 7.7 Immunotoxicity Prepared by Charlotte Madsen 7.7.1 Direct toxic effect on the immune system 7.7.1.1 Introduction The immune system is comprised of a number of organs and cells throughout the body. The cells are lymphoid cells of different lines and stromal cells in the lymphoid organs e.g. epithelial cells in thymus important for T-cell differentiation. A successful immune response is dependent on co-operation between different cell types. For example the production of antibodies against a foreign antigen requires macrophages presenting the antigen to T-cells, which as a consequence produces cytokines necessary for B-cells to differentiate into immunoglobulin producing plasma cells. The reactions of lymphoid cells are associated with gene amplification, transcription, and translation, and compounds that can affect these processes of cell proliferation and differentiation may exert immunotoxicity, in particular by affecting the rapidly dividing thymocytes and haematopoietic cells of the bone marrow (IPCS 1996a). 7.7.1.2 Measuring immunotoxic response Toxic responses to the immune system can be measured experimentally in vivo using classical haematology and pathology, total and differential white blood cell counts, and weight and histology of lymphoid organs. Additional immunological methods include measurement of serum immunoglobulins, lymphocyte subsets, and unspecific lymphocyte reactivity to mitogens, specific lymphocyte reactivity to allogenic cells, Natural Killer cell activity and antibody production after immunisation with sheep red blood cells. 125
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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
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Physicochemical interactions will t
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US EPA (1986) applied the concept o
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2.4 Test strategies to assess combi
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Figure 2.4.3.1. Isobologram of two
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CI = d1 /D1 = 1 In this case the is
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2.5 Toxicological test methods When
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3 General concepts in the risk asse
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NOAEL, this indicates that the subs
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of uncertainty i.e. differences in
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describe toxicities that appears to
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should be estimated for all endpoin
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1,2,3,6,7,8-HxCDF 0.1 1,2,3,7,8,9-H
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shows the pronounced influence of t
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Table 4.3.1 Estimates of carcinogen
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Figure 4.4.1.1. Scheme for safety e
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obvious ranking of individual const
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4.5 Approach for assessment of join
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4.6 Approaches currently used by re
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no internationally accepted procedu
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Figure 4.6.3.1 Flow chart of the ri
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octyltin dichloride). A number of a
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stannous chloride and cadmium chlor
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seen in the animals from the 1000x
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c TCTFP = 1,1,2-trichloro-3,3,3-tri
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6 Interactions in toxicokinetics Pr
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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
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
Page 126 and 127: 7.7.1.3 Mechanisms of immunotoxicit
Page 128 and 129: tested separately. This is a phenom
Page 130 and 131: In practical life an allergen may b
Page 132 and 133: 8.3 Conference proceedings Proceedi
Page 134 and 135: with combinations of environmental
Page 136 and 137: Boyd MR, Statham CM and Longo NS (1
Page 138 and 139: De Wall EJ, Schuurman HJ and Van Lo
Page 140 and 141: theoretical considerations and a su
Page 142 and 143: Groten JP, Sinkeldam EJ, Muys T, Lu
Page 144 and 145: Howes D, Guy R, Hadgraft J, Heyling
Page 146 and 147: cytochrome P450 1A2 expressed in Am
Page 148 and 149: Lison D, Carbonnelle P, Mollo L, La
Page 150 and 151: Narotsky MG, Weller EA, Chinchilli
Page 152 and 153: Ramsey JC and Andersen ME (1984). A
Page 154 and 155: Silva E, Rajapakse N and Kortenkamp
Page 156 and 157: Leeuwen FXR, Liem AKD, Nolt C, Pete
Page 158: Wlodarczyk B, Biernacki B, Minta M,
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