Combined Actions and Interactions of Chemicals in Mixtures

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7.6.2.3 Receptors A receptor is a binding site for endogenous and exogenous chemical substances. Receptor binding elicits a specific biological reaction. The nervous system is unique compared to other organs because of its large number of different types of receptors and receptor agonists (neurotransmitters). A single neuron can possess different receptors even for the same agonist, and these receptors may transduce receptor binding to different/opposing signals. It is the integrated sum of transduced signals that determines the overall effect on the neuron and its output. Furthermore, nervous system receptor interactions can exert their effect for a long time period in that receptors can ´remember´ binding and it is possible to make specific circuits among neurons more effective by potentiation and ´learning´. Many nervous system receptors are composed of more than one subunit and allosteric effects are common i.e. binding to one subunit affects (increase/decrease) binding characteristics of others. 7.6.2.4 CNS In the CNS two main functional barriers protect the brain from entry of toxic chemicals present in the blood. The blood-brain barrier (BBB) is formed by close contact between the endothelial cells of brain capillaries and supported by astrocytes, which are found in close proximity to the endothelial cells. These cells cover more than 99% of the capillary surface in the brain. The brain-cerebrospinal fluid barrier is situated in defined small circumventricular regions, and covers approximately 0.5% of the capillary surface. These barriers inhibit influx of hydrophilic substances along electrochemical gradients. They contain different transport systems each of selective affinity to physiological substances. The barriers also allow access of many unphysiological hydrophilic substances with carrier affinity (Pardridge, 1988). Lipophilic substances can penetrate the barriers by unspecific mechanisms due to their lipophilicity. In spite of this protection, the brain is very susceptible to toxic compounds. This is mainly due to the structural, functional, and integral complexity, the specific metabolic characteristics, and the limited capacity for compensation and repair. 7.6.2.5 PNS In the PNS, nerve axons are surrounded by myelin, high in lipid content, which protects and insulates the axon membrane. Further, axons are bundled together in fascicles that are protected by connective tissue, thus creating a blood nerve barrier. A special feature of the PNS is the long distance between cell body and axon terminal. Common modes of action for peripheral nerve toxicity are affection of bi-directional axonal transport mechanisms and of myelin integrity. Substances and other factors (physical stimuli, infections) interfering with BBB and myelin sheet integrity may give access to chemicals normally not penetrating these protective barriers and thereby indirectly induce neurotoxicity. 7.6.3 Developmental neurotoxicity It is generally agreed that the brain is highly susceptible to effects of exposure to xenobiotics during development. During development, there is extensive mutual interaction between the developing brain and other organs, especially the thyroid gland and sex organs. Disturbance of this intimate interconnection may affect structure and function of brain and peripheral organs. Therefore, chemicals that affect sex organs or thyroid may affect the developing nervous system, and interaction between such chemicals is possible. 118
Apoptosis, programmed cell death, plays a significant role during brain development. Interference by neurotoxicants on apoptotic processes during development may be important. An example of toxic interaction in relation to developmental neurotoxicity is the interaction between dimethoate and lead. Predosing of rats with low doses of dimethoate (a pesticide) accentuates the developmental neurotoxicity of lead as measured by electrophysiological parameters. Predosing with lead has the same effect on dimethoate neurotoxicity, but not as pronounced (Nagymajtényi et al., 1998). 7.6.4 Consequences of adverse effects on the nervous system The nervous system is central in the physical and psychological performance of man. It is one of the most complex organ systems in terms of both structure and function. The risk of permanent damage to the nervous system after toxic injury is greater than for many other target organs, as mature neurons are not capable of regeneration. The nervous system possesses great plasticity, which means that injuries do not necessarily become apparent immediately after the insult. Proper function of the nervous system depends on a delicate electrochemical balance for uncompromized communication of information throughout the body. Large energy supply and unaffected neuron function maintain this. Chemicals affecting these elements may cause neurotoxicity. Theoretically, there are many possibilities for interaction between chemicals on the above-mentioned targets (membranes, intracellular transport, energy supply). 7.6.4.1 Mechanism of interaction The mechanism of action is unknown for the majority of neurotoxicants, especially in the CNS. In the PNS, a well-known mode of action for peripheral neuropathy is the inhibition of the anterograde transport of cellular components. Interaction is possible between chemicals which both affect this transport system, even if the target is not identical. 7.6.4.2 Most important test systems Animal studies performed according to present guideline methods give information about nervous system effects. Investigation of potential interaction with other chemicals is normally not a part of such studies. The complexity of research on mixtures and dose-response relations is obvious, considering the possible number of binary combinations for a single mixture. It is difficult to study interactions in epidemiological investigations because of uncertainties regarding exposure levels and duration and because the effects of individual factors normally cannot be isolated. 7.6.5 Examples of interactions: Mechanisms 7.6.5.1 Reactive oxygen species Generation of reactive oxygen species (ROS) is a mechanism whereby similar action by chemicals can occur. ROS generation may initiate cellular injury leading to neurotoxicity and/or neurodegeneration. Several chemicals may lead to increased ROS generation. Various ROS types may be generated, depending on the chemical. Although the neurotoxic effect of the various ROS types may vary, at least an additive effect is expected. 119
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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
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 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 120 and 121: 7.6.5.2 Kindling Kindling is the ph
Page 122 and 123: Science Institute (RSI) have conven
Page 124 and 125: eaction with sulfhydryl groups). Th
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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