Combined Actions and Interactions of Chemicals in Mixtures

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octyltin dichloride). A number of adverse effects seen at the LOAEL, such as decreased prothrombin time, increased liver enzyme activity (ALAT and ASAT) in plasma, increased kidney weights, reduced number of corpora lutea in ovaries, and increased numbers of multinucleated giant cells in the epididymides had not been seen at all or had been found at doses higher than the LOAEL of the individual compounds. Although some of these changes may be related to the severe growth retardation, they suggested some kind of interaction resulting in a slightly more severe and maybe broader range of toxic response. On the other hand the changes in the thymus were less pronounced on combined exposure than after exposure to di-n-octyltin dichloride alone, suggesting interaction leading to less severe toxicity. Table 5.2.1. Toxicological studies of chemicals with different target organs and/or modes of action. Compound Potassium nitrate Stannous chloride Sodium metabisulphiteMetalde- hyde 62 NOAEL/10 NOAEL/3 NOAEL LOAEL Mg/kg bw/day Target organ 10 33 100 300 Adrenals 100 330 1000 3000 Body weight, blood, liver 500 1670 5000 20000 Blood, stomach, liver 20 70 200 1000 Liver Loperamide 0.5 1.7 5 25 Body weight Mirex 0.5 1.7 5 80 Body weight, liver blood Lysino- 3 10 30 100 Kidneys alanine Di-n-octyltin dichloride 0.6 2 6 30 Thymus, liver The authors concluded that the study demonstrates absence of a simple additive effect and synergism, and provides some, but no convincing evidence for an increased risk from exposure to a combination of chemicals when each chemical is administered at its own individual NOAEL. At lower dose levels no increased risk appeared to exist. The other experiment (Feron et al. 1995a, Groten et al. 1997) was a 4-week oral/inhalatory study in male Wistar rats in which the toxicity of combinations of nine compounds was examined (Table 5.2.2). In this study a combination was used of compounds highly relevant to the general population in terms of use patterns and levels and frequency of exposure. The study included 20 experimental groups, four groups of eight rats in the main study and 16 groups of five rats in a satellite study. In the main study, the rats were simultaneously exposed to mixtures of all nine chemicals. Dichloromethane and formaldehyde were administered by inhalation and aspirin, di(2- ethylhexyl)phthalate (DEHP), cadmium chloride, stannous chloride, butyl hydroxyanisol (BHA), loperamide, and spermine were given in the diet at concentrations equal to the "minimum-observed-adverse-effect level" (LOAEL), the NOAEL, or one third the NOAEL. The satellite study was designed as a fractionated two-level factorial study in which the rats were simultaneously exposed to combinations of maximally five compounds at their LOAEL. These 16
combinations of nine factors (9 chemicals) jointly comprise a 1/32 fraction of a complete study. Table 5.2.2. Toxicological studies of chemicals with different target organs and/or modes of action. Compound NOAEL/3 NOAEL LOAEL Mg/kg bw/day Target organ Aspirin 330 1000 5000 Liver, stomach Cadmium 3 10 50 Red blood chloride cell, liver Stannous 260 800 3000 Red blood chloride cell Spermine 130 400 2000 Hearth, liver Loperamide 2 6 30 Liver BHA 330 1000 3000 Stomach DEHP 65 200 1000 Liver Dichloromethane 30 100 500 Blood Formaldehyde 0.3 1 3 Nose A number of effects were observed at the LOAEL. Growth retardation and reduced food intake were signs of general toxicity. In haematology, a decrease in mean corpuscular volume, MCV (cadmium) and thrombocyte count (aspirin) and an increase in mean corpuscular haemoglobin, MCH (DEHP/aspirin) and carboxyhaemoglobin (dichloromethane) was seen. A number of biochemical/clinical chemistry parameters were also affected, notably decreased alkaline phosphatase, glucose, triglycerides, and cholesterol concentrations, and an increase in ALAT, ASAT and palmityl CoA activities, albumin, bilirubin, and total protein concentrations. The absolute weights of the liver and kidney were increased while spleen and hearth weights were decreased and the relative weights of all organs except spleen and hearth were significantly higher in all animals. Treatment related histopathological changes were observed in the liver and nasal cavity of all rats of the LOAEL group. The lesions consisted of hepatocellular hyperthropy and hyperplasia of the transitional epithelium and/or squamous metaplasia of the respiratory epithelium in the nose. Based on the toxicity data of the individual compounds most of these effects were expected. A few effects seen in the toxicity studies with the individual compounds had disappeared in the combination, whereas some effects not seen in the rangefinding studies with the individual compounds appeared in the combination. For most of the end points studied in the satellite groups, the factorial analysis revealed main effects of the individual compounds and interactions (cases of nonadditivity) between the compounds. As an example, the factorial analysis revealed that two compounds, aspirin and DEHP were able to induce palmityl CoA activity, whereas BHA slightly reduced the activity. In addition, there was a slight and unexpected interaction between BHA and DEHP, which resulted in a decreased palmityl CoA activity. As another example, it was found that cadmium chloride, aspirin, and loperamide were able to increase the ASAT activity whereas stannous chloride was able to decrease it. In addition, two cases of interactions were identified, namely the interaction between cadmium chloride and loperamide resulting in a higher ASAT activity than would be expected on the basis of summation of the effects of the two compounds and the interaction between 63
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Combined Actions and Interactions o
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Contents CONTENTS 3 PREFACE 6 SAMME
Page 5 and 6:
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
Page 11 and 12: estemt biologisk respons (ED10, ED2
Page 13 and 14: vivo. The COMET-assay in vivo and g
Page 15 and 16: and antagonistic effects may be see
Page 17 and 18: 1 Introduction Prepared by John Chr
Page 19 and 20: 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 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 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
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Dose of A (arbitrary units) 10 8 6
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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 124 and 125:
eaction with sulfhydryl groups). Th
Page 126 and 127:
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
Page 136 and 137:
Boyd MR, Statham CM and Longo NS (1
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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
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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
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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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