Combined Actions and Interactions of Chemicals in Mixtures

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8.3 Conference proceedings Proceedings of a symposium sponsored by the Health Effect Research Laboratory of the U.S. Environmental Protection Agency, November 7-10, 1994 entitled Chemical mixtures and quantitative risk assessment has been published as a special issue of Toxicology (vol. 105 (2-3), 1995). It contains 8 session summaries and a total of 29 scientific papers presenting updated knowledge on combination toxicology. Proceedings of The European Conference on Combination Toxicology, held in Veldhoven, The Netherlands, October 11-13, 1995 was published in Food and Chemical Toxicology (34 (11/12), 1996). Nineteen fairly brief articles present the European state of the art in combination toxicology. 8.4 Reports Combination Effects. A survey of biological responses to mixtures of industrial chemicals and pesticides was prepared by Steen Clemmensen in 1986 for the Nordic Council of Ministers. This report was the first Danish effort to highlight the importance of evaluating the possible combined effects of chemical mixtures. The report deals with the fundamental concepts, biological mechanisms of interaction, combined actions after acute or prolonged exposure to chemical mixtures, including reproductive, mutagenic and carcinogenic efects, as well as how to extrapolate from high dose exposure to low dose exposure. The report: Sundhedsmæssig vurdering af luftforurening fra vejtrafik (“Health Evaluation of Air-Pollution from Road Traffic”) by Larsen PB, Larsen JC, Fenger J and Jensen SS (1997) published in Danish by the Danish Environment Protection Agency contains an extensive Summary and Conclusions in English. The report contains evaluations of health effects from combined exposures to traffic related air pollutants especially in the areas of airway irritation, allergy and hypersensitivity, and cancer. Combined actions of pesticides in food was prepared by Trine Klein Reffstrup in 2002, Institute of Food Safety and Nutrition at the Danish Veterinary and Food Administration (FødevareRapport 2002:19). The report summarises and evaluates the current knowledge on combined toxic effects of mixtures of pesticides. The most important models for risk assessment of pesticide residues in food are discussed and recommendations for future approaches in risk assessments in Denmark are presented. Guidance manual for the assessment of joint toxic action of chemical mixtures was prepared by the Agency of Toxic Substances and Disease Registry (ATSDR) under the U.S. Department of Health and Human Services (ATSDR 2002). This report summarises terminology and basic concepts of toxicological interactions among chemicals and gives an overview of the approaches used for risk assessments by various North American agencies. It also provides its own strategies for exposurebased assessments for noncarcinogenic and carcinogenic effects, respectively. 132
9 References Abou-Donia MB (1992). Neurotoxicology. CRC Press, Boca Raton, Ann Arbor, London, Tokyo. Abou-Donia MB and Wilmarth KR (1996). Neurotoxicity resulting from coexposure to pyridostigmine bromide, DEET, and permethrin: Implications of Gulf War chemical exposures. J Toxicol Environ Health, 48, 35-56. Ahmed FE and Setlow RB (1981). DNA repair in human fibroblasts treated with a combination of chemicals. J Biophys, 35, 17-22. Akay MT, Ozmen G and Elcüman EA (1999). Effects of combinations of endosulfan, dimethoate and carbaryl on immune and hematological parameters of rats. Vet Hum Toxicol, 41(5), 296-299. Ale SI, Laugier JP and Maibach HI (1997). Differential irritant skin responses to tandem application of topical retinoic acid and sodium lauryl sulphate: II. Effect of time between first and second exposure. Br J Dermatol, 137, 226-233. Allen N, Mendell JR, Billmaier D, Fontaine RE and Oeill J (1975). Toxic polyneuropathy due to methyl-n-butylketone. Arch Neurol, 32, 209-218. Altenburger R, Bödeker W, Faust M and Grimme LH (1993). In: Corn M (Editor) Handbook of hazardous materials. Academic Press, 15-27. Anard D, Kirsch-Volders M, Elhajouji A, Belpaeme K and Lison D (1997). In vitro genotoxic effects of hard metal particles assessed by alkaline single gel and elution assays. Carcinogenesis, 18, 177-184. Andersen ME, Clewell III HJ and Fredrick CG (1995). Applying simulation modeling to problems in toxicology and risk assessment – a short perspective. Toxicol Appl Pharmacol, 133, 181-187. Andrews JE, Ebron-McCoy M, Schmid JE and Svendsgaard D (1998). Effects of Combinations of Methanol and Formic Acid on Rat Embryos in Culture. Teratology, 58, 54-61. Arlien-Søborg P (2001). Chronic Toxic Encephalopathy Following Occupational Manganese Exposure. Proceedings of 8th Meeting of the International Neurotoxicology Association, 87. Arnold SF and McLachlan JA (1996). Synergistic signals in the environment. Environ Health Perspect, 104(10) 1020-1023. Arnold SF, Klotz DM, Collins M, Vonier PM, Guilette LJ Jr and McLachlan JA (1996). Synergistic activation of estrogen receptor with combinations of environmental chemicals. Science, 272, 1489-1492. Arnold SF, Vonier PM, Colllins BM, Klotz DM, Guillette LJ Jr and McLachlan JA (1997). In vitro synergistic interaction of alligator and human estrogen receptors 133
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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
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Dermis The dermis consists of a sup
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7.1.3 Ocular irritancy 7.1.3.1 Comp
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Another in vitro test for ocular ir
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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 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 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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