Combined Actions and Interactions of Chemicals in Mixtures

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7.6.5.2 Kindling Kindling is the phenomenon whereby repeated seizure activity in the brain is accompanied by increased synaptic strength. Experimental kindling is used to study changes in nervous system excitability. Repeated presentations of subthreshold seizure stimuli (electrical, chemical) decrease the threshold for induction of seizures. Certain pesticides (lindane, dieldrin) may change seizure susceptibility. Chlorpyrifos administered to immature rats caused a more rapid occurrence of kindling. The effects were additive with xylene (Wurpel et al., 1993). Exposure to lead, or to trimethyltin rendered rats more susceptible to effects of seizure-inducing stimuli (see Ladefoged et al., 1995). 7.6.5.3 Multiple chemical sensitivity Multiple Chemical Sensitivity (MCS) is often defined by reactivity to common environmental exposures at significantly lower exposure levels than those, which would cause noticeable illness in the general population, and at levels that the majority of individuals tolerate quite well. MCS symptoms include symptoms originating from CNS (concentration and memory difficulties, headache, fatigue, depression, and irritability). Suggested triggers of MCS include odorous and non-odorous volatile organic compounds, solvents, pesticides, industrial chemicals, and metals. An IPCS workshop (IPCS 1996b) on MCS suggested another term for this phenomenon i.e. “Idiopathic Environmental Intolerances” (IEI). A working definition was formulated as follows: Acquired disorder with multiple recurrent symptoms, associated with diverse environmental factors tolerated by the majority of people, cannot be explained by any known medical or psychiatric disorder. Often mixed and multiple chemcial exposure is mentioned in connection with MCS, however it is not known whether the greatest risk for development of MCS is in connection with single chemcial exposure or mixed exposure. A recent review suggests a physical explanation for MCS, that of limbic kindling (Graveling et al. 1999). However, there is not international agreement on the existence of this phenomenon. 7.6.5.4 Gulf war syndrome During the Persian Gulf War, 1990-1991, military personnel were concurrently exposed to biological, chemical, and psychological environments. Some veterans have reported the development of headache, loss of memory, fatigue and different somatic symptoms. Three chemicals used in combination by military Gulf War personnel have been studied in hens with emphasis on peripheral neuropathy. The chemicals were an antinerve gas agent (pyridostigmine bromide), an insect repellent (N,N-diethyl-mtoluamide), and an insecticide (permethrin). The response to individual or simultaneous administration was investigated. The single compounds were administered in doses causing minimal toxicity. Combinations of two agents produced greater neurotoxicity than that caused by individual agents. Neurotoxicity was further enhanced when all three agents were administered concurrently (Abou-Donia & Wilmarth, 1996). A recent Danish survey of Danish Gulf War personnel concludes that the most likely explanation for the symptoms identified in this population is a post-traumatic stress disorder rather than chemical toxicity (Gyntelberg, 2000). 120
7.6.5.5 Conditioning Odour conditioning describes the situation where an agent such as a volatile organic compound with a distinct odour, experienced at a high concentration, evokes illness. On subsequent occasions, lower concentrations of the agent evoke the feeling, but with shorter latencies (Weiss, 1998). Other stimuli may be effective in causing conditioning. Possible stimuli include respiratory irritants, which may induce a neurogenic response at low sub-irritant concentrations after an initial conditioning episode with a higher irritation-producing concentration. 7.6.5.6 Potentiation A chemical without neurotoxic effect may interact with a neurotoxicant and increase the neurotoxic response/effect of the neurotoxicant. Numerous examples of ketoneinduced enhancement of n-hexane- or 2,5-hexanedione-induced neuropathy in animals or man have been reported. This means that hexane or hexanedione is more neurotoxic at the same dose level when a ketone is co-administered. Hexane was 5 times more toxic when methyl isobutyl ketone was co-administered, using a neurotoxicity index (Abou-Donia, 1992). Hexanedione was twice as toxic when acetone was co-administered, based on a behavioural test (Ladefoged et al., 1994). Although the mechanism is not fully elucidated, it is generally believed that the interaction is related to changes in metabolism, distribution, or elimination of the neurotoxic agent. A chemical without neurotoxic effect may open the BBB and thus give access to the brain for a number of neurotoxicants, which otherwise would have been excluded from this tissue. Mannitol is a non-neurotoxic substance, which opens the BBB. An example of a chemical, where enhanced neurotoxicity by mannitol-induced BBBopening is important, is doxorubicin, a cytostatic agent. 7.6.5.7 Promotion In the field of neurotoxicity, the term promotion is used to describe the phenomenon where administration of one chemical, which itself is not neurotoxic, enhances the toxicity of another neurotoxicant. The time interval between exposure to promoter and to neurotoxicant may be long. The initial observation of promotion was made during the study of chlorpyrifosinduced polyneuropathy. Sulfonyl halide, which is not neurotoxic by itself, enhanced the neurotoxic effect of chlorpyrifos when administered after chlorpyrifos (Lotti, 1997). Some organophosphates, which do not induce delayed neuropathy, cause a stronger effect of a subsequently administered true inducer of delayed neuropathy (Lotti, 1992). The mechanism is possibly an interaction by the promoter in the “ageing” process of neuropathy target esterase, NTE, which is believed to be related to the induction of delayed neuropathy. Several NTE inhibitors, such as certain carbamates, phosphinates, and sulfonyl halides protect the animals from neuropathy when they are administered prior to dosing with neurotoxic organophosphorus esters. 7.6.6 Examples of interactions: Agents 7.6.6.1 Organophosphorus insecticides The toxicity of combined exposure to organophosphorus insecticides is generally considered to be additive. The ILSI (International Life Science Institute) Risk 121
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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
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
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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
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Page 112 and 113: Furthermore, the estrogenic effects
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Page 118 and 119: 7.6.2.3 Receptors A receptor is a b
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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Combined Actions and Interactions of Chemicals in Mixtures

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