Tools and perspectives for assessing chemical mixtures and multiple stressors

Toxicology

Volumn 313, Issue 2-3, 2013, Pages 73-82

  Løkke, Hans ^a   Ragas, Ad M J ^b,c   Holmstrup, Martin ^a,d  

^a AARHUS UNIVERSITY   (Denmark)

^b RADBOUD UNIVERSITY NIJMEGEN   (Netherlands)

^c OPEN UNIVERSITY OF THE NETHERLANDS   (Netherlands)

^d Arctic Research Centre   (Denmark)

Author keywords

Chemical mixtures; Cumulative risk assessment; Dynamic energy budget; Natural stressors; NoMiracle; Toxicity

Indexed keywords

AQUATIC ENVIRONMENT; ARTICLE; BUDGET; CLIMATE CHANGE; COMPUTER SYSTEM; DATA BASE; DRUG MIXTURE; ECOTOXICOLOGY; ENVIRONMENTAL FACTOR; HUMAN; MICROCLIMATE; NOMIRACLE; PREDICTION; PRIORITY JOURNAL; RISK ASSESSMENT; TOXICOKINETICS; ANIMAL; BIOASSAY; BIOLOGICAL MODEL; CHEMICAL MIXTURES; CHEMISTRY; CUMULATIVE RISK ASSESSMENT; DYNAMIC ENERGY BUDGET; ENVIRONMENTAL EXPOSURE; EUROPE; GOVERNMENT REGULATION; LEGAL ASPECT; METHODOLOGY; NATURAL STRESSORS; POLLUTANT; PREDICTIVE VALUE; REVIEW; TOXICITY; TOXICITY TESTING; UNITED STATES; ANALYSIS; LEGISLATION AND JURISPRUDENCE; PROCEDURES;

CHEMICAL MIXTURES; CUMULATIVE RISK ASSESSMENT; DYNAMIC ENERGY BUDGET; NATURAL STRESSORS; NOMIRACLE; TOXICITY;

ANIMALS; COMPLEX MIXTURES; ENDPOINT DETERMINATION; ENVIRONMENTAL EXPOSURE; ENVIRONMENTAL POLLUTANTS; EUROPE; GOVERNMENT REGULATION; HUMANS; MODELS, BIOLOGICAL; PREDICTIVE VALUE OF TESTS; RISK ASSESSMENT; TOXICITY TESTS; UNITED STATES;

DRUG MIXTURE; POLLUTANT;

EID: 84886746045     PISSN: 0300483X     EISSN: 18793185     Source Type: Journal    
DOI: 10.1016/j.tox.2012.11.009     Document Type: Article

References (106)

1. Andersson T., Förlin L. Regulation of the cytochrome P450 enzyme system in fish. Aquat. Toxicol. 1992, 24:1-19.
2. Altenburger R., Backhaus T., Boedeker W., Faust M., Scholze M., Grimme L.H. Predictability of the toxicity of multiple chemical mixtures to Vibrio fischeri: mixtures composed of similarly acting chemicals. Environ. Toxicol. Chem. 2000, 19:2341-2347.
3. ATSDR (Agency for Toxic Substances and Disease Registry) Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures 2004, US Department of Health and Human Services, Atlanta.
4. Baas J., Jager T., Kooijman S. A model to analyze effects of complex mixtures on survival. Ecotoxicol. Environ. Saf. 2009, 72:669-676.
5. Baas J., Jager T., Kooijman S. A review of DEB theory in assessing toxic effects of mixtures. Sci. Total Environ. 2010, 408:3740-3745.
6. Baas J., Jager T., Kooijman S. Understanding toxicity as processes in time. Sci. Total Environ. 2010, 408:3735-3739.
7. Baas J., Stefanowicz A.M., Klimek B., Laskowski R., Kooijman S. Model-based experimental design for assessing effects of mixtures of chemicals. Environ. Pollut. 2010, 158:115-120.
8. Baas J., Van Houte B.P.P., Van Gestel C.A.M., Kooijman S. Modeling the effects of binary mixtures on survival in time. Environ. Toxicol. Chem. 2007, 26:1320-1327.
9. Baas J., Willems J., Jager T., Kraak M.H.S., Vandenbrouck T., Kooijman S.A.L.M. Prediction of daphnid survival after in situ exposure to complex mixtures. Environ. Sci. Technol. 2009, 43:6064-6069.
10. Backhaus T., Altenburger R., Boedeker W., Faust M., Scholze M., Grimme L.H. Predictability of the toxicity of a multiple mixture of dissimilarly acting chemicals to Vibrio fischeri. Environ. Toxicol. Chem. 2000, 19:2348-2356.
11. Bindesbøl A.M., Bayley M., Damgaard C., Hedlund K., Holmstrup M. Changes in membrane phospholipids as a mechanistic explanation for decreased freeze tolerance in earthworms exposed to sublethal copper concentrations. Environ. Sci. Technol. 2009, 43:5495-5500.
12. Bindesbøl A.M., Holmstrup M., Damgaard C., Bayley M. Stress synergy between environmentally realistic levels of copper and frost in the earthworm Dendrobaena octaedra. Environ. Toxicol. Chem. 2005, 24:1462-1467.
13. Boobis A., Budinsky R., Collie S., Crofton K., Embry M., Felter S., Hertzberg R., Kopp D., Mihlan G., Mumtaz M., Price P., Solomon K., Teuschler L., Yang R., Zaleski R. Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment. Crit. Rev. Toxicol. 2011, 41:369-383.
14. Brent R.L. Environmental causes of human congenital malformations: the pediatrician's role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. Pediatrics 2004, 113:957-968.
15. Callahan M., Sexton K. If cumulative risk assessment is the answer, what is the question?. Environ. Health Perspect. 2007, 115:799-806.
16. Cedergreen N., Christensen A.M., Kamper A., Kudsk P., Mathiassen S.K., Streibig J.C., Sorensen H. A review of independent action compared to concentration addition as reference models for mixtures of compounds with different molecular target sites. Environ. Toxicol. Chem. 2008, 27:1621-1632.
17. Chandra A., Martinez G.M., Mosher W.D., Abma J.C., Jones J. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. National Center for Health Statistics. Vital Health Stat. 2005, 23:175.
18. Deneer J.W., Sinnige T.L., Seinen W., Hermens J.L.M. The joint acute toxicity to Daphnia magna of industrial organic-chemicals at low concentrations. Aquat. Toxicol. 1988, 12:33-38.
19. Deneer J.W., Seinen W., Hermens J.L.M. Growth of Daphnia magna exposed to mixtures of chemicals with diverse modes of action. Ecotoxicol. Environ. Saf. 1988, 15:72-77.
20. Dimitrov S., Dimitrova N., Parkerton T., Comber M., Bonnell M., Mekenyan O. Baseline model for identifying the bioaccumulation potential of chemicals. SAR QSAR Environ. Res. 2005, 16:531-554.
21. Dimitrova N., Dimitrov S., Georgieva D., Van Gestel C.A.M., Hankard P., Spurgeon D., Li H., Mekenyan O. Elimination kinetic model for organic chemicals in earthworms. Sci. Total Environ. 2010, 408:3787-3793.
22. Dondero F., Negri A., Boatti L., Marsano F., Mignone F., Viarengo A. Transcriptomic and proteomic effects of a neonicotinoid insecticide mixture in the marine mussel (Mytilus galloprovincialis, Lam.). Sci. Total Environ. 2010, 408:3775-3786.
23. Dorne J.L.C.M. Human variability in hepatic and renal elimination: implications for risk assessment. J. Appl. Toxicol. 2007, 27:411-420.
24. Dorne J.L.C.M. Metabolism, variability and risk assessment. Toxicology 2010, 268:156-164.
25. Drost W., Backhaus T., Vassilakaki M., Grimme L.H. Mixture toxicity of s-triazines to Lemna minor under conditions of simultaneous and sequential exposure. Fresen. Environ. Bull. 2003, 12:601-607.
26. European Scientific Committees, 2011. Toxicity and Assessment of Chemical Mixtures - (Preliminary Opinion Approved for Public Consultation. Scientific Committee on Consumer Safety (SCCS), Scientific Committee on Health and Environmental Risks (SCHER), Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR)), DG Health & Consumers, Directorate D: Health Systems and Products, Unit D5 - Risk Assessment, Brussels (accessed 07.01.12). http://ec.europa.eu/health/scientific_committees/consultations/public_consultations/scher_consultation_06_en.htm.
27. Faust M., Altenburger R., Backhaus T., Blanck H., Boedeker W., Gramatica P., Hamer V., Scholze M., Vighi M., Grimme L.H. Predicting the joint algal toxicity of multi-component s-triazine mixtures at low-effect concentrations of individual toxicants. Aquat. Toxicol. 2001, 56:13-32.
28. Faust M., Altenburger R., Backhaus T., Blanck H., Boedeker W., Gramatica P., Hamer V., Scholze M., Vighi M., Grimme L.H. Joint algal toxicity of 16 dissimilarly acting chemicals is predictable by the concept of independent action. Aquat. Toxicol. 2003, 63:43-63.
29. Fisker K.V., Sørensen J.G., Holmstrup M. No costs on freeze tolerance in genetically copper adapted earthworm populations (Dendrobaena octaedra). Comp. Biochem. Physiol. C: Pharmacol. Toxicol. Endocrinol. 2011, 154:204-207.
30. Gohlke J.M., Thomas R., Zhang Y., Rosenstein M.C., Davis A.P., Murphy C., Becker K.G., Mattingly C.J., Portier C.J. Genetic and environmental pathways to complex diseases. BMC Syst. Biol. 2009, 3:46. 10.1186/1752-0509-3-46.
31. Gomezeyles J., Svendsen C., Lister L.J., Spurgeon D.J. The measurement and modelling of mixture toxicity of imidacloprid and thiacloprid on the soil dwelling nematode Caenorhabditis elegans and the earthworm Eisenia fetida. Ecotoxicol. Environ. Saf. 2009, 72:71-79.
32. Gordon C.J. Role of environmental stress in the physiological response to chemical toxicants. Environ. Res. 2001, 92:1-7.
33. Hering D., Borja A., Carstensen J., Carvallo L., Elliott M., Feld C.K., Heiskanen A.-S., Johnson R.K., Moe J., Pont D., Solheim A.L., Van den Bund W. The European Water Framework Directive at the age of 10: a critical review of the achievements with recommendations for the future. Sci. Total Environ. 2010, 408:4007-4019.
34. Hermens J., Konemann H., Leeuwangh P., Musch A. Quantitative structure activity relationships in aquatic toxicity studies of chemicals and complex-mixtures of chemicals. Environ. Toxicol. Chem. 1985, 4:273-279.
35. Heugens E.H.W., Hendriks A.J., Dekker T., Van Straalen N.M., Admiraal W. A review of the effects of multiple stressors on aquatic organisms and analysis of uncertainty factors for use in risk assessment. Crit. Rev. Toxicol. 2001, 31:247-284.
36. Hoegh-Guldberg O., Mumby P.J., Hooten A.J., Steneck R.S., Greenfield P., Gomez E., Harvell C.D., Sale P.F., Edwards A.J., Caldeira K., Knowlton N., Eakin C.M., Iglesias-Prieto R., Muthiga N., Bradbury R.H., Dubi A., Hatziolos M.E. Coral reefs under rapid climate change and ocean acidification. Science 2007, 318:1737-1742.
37. Højer R., Bayley M., Damgaard C.F., Holmstrup M. Stress synergy between drought and a common environmental contaminant: studies with the collembolan Folsomia candida. Global Change Biol. 2001, 7:485-494.
38. Holmstrup M. Drought tolerance in Folsomia candida (Collembola) after exposure to sublethal concentrations of three soil-polluting chemicals. Pedobiologia 1997, 41:354-361.
39. Holmstrup M., Bindesbol A.-M., Oostingh G.J., Duschl A., Scheil V., Koehler H.R., Loureiro S., Soares A.M.V.M., Ferreira A.L.G., Kienle C., ' Gerhardt A., Laskowski R., Kramarz P., Bayley M., Svendsen C., Spurgeon D. Interactions between effects of environmental chemicals and natural stressors: a review. Sci. Total Environ. 2010, 408:3746-3762.
40. Howard G.J., Schlezinger J.J., Hahn M.E., Webster T.F. Generalized concentration addition predicts joint effects of aryl hydrocarbon receptor agonists with partial agonists and competitive antagonists. Environ. Health Perspect. 2010, 118:666-672.
41. Hope B.K. Performing spatially and temporally explicit ecological exposure assessments involving multiple stressors. Hum. Ecol. Risk Assess. 2005, 11:539-565.
42. Houben J. Oehoe jaagt in centrum: populatie stadsduiven daalt. Dagblad De Limburger 2011, (in Dutch).
43. Jager T., Vandenbrouck T., Baas J., De Coen W.M., Kooijman S.A.L.M. A biology-based approach for mixture toxicity of multiple endpoints over the life cycle. Ecotoxicology 2010, 19:351-361.
44. ILSI (International Life Sciences Institute), 2008. Cumulative and Aggregate Risk Evaluation System (CARES) V3.0. Downloaded from (accessed 24.07.08). http://cares.ilsi.org/.
45. IPCC Climate Change 2007: Synthesis Report. Contribution of Working Groups I-III to the Fourth Assessment. Report of the Intergovernmental Panel on Climate Change 2007, 104. IPCC, Geneva. R.K. Pachauri, A. Reisinger (Eds.).
46. Jahnke G.D., Iannucci A.R., Scialli A.R., Shelby M.D. Center for the evaluation of risks to human reproduction - the first five years. Birth Defects Res. B Dev. Reprod. Toxicol. 2005, 74:1-8.
47. Johnson A.C., Nylén P., Borg E., Höglund G. Sequence of exposure to noise and toluene can determine loss of auditory sensitivity in the rat. Acta Otolaryngol. 1990, 109:34-40.
48. Jonker M.J., Svendsen C., Bedaux J.J.M., Bongers M., Kammenga J.E. Significance testing of synergistic/antagonistic, dose level-dependent, or dose ratiodependent effects in mixture dose-response analysis. Environ. Toxicol. Chem. 2005, 24:2701-2713.
49. Jørgensen K., Ipsen J.H., Mouritsen O.G., Bennett D., Zuckermann M.J. The effects of density-fluctuations on the partitioning of foreign molecules into lipid bilayers - application to anesthetics and insecticides. Biochim. Biophys. Acta 1991, 1067:241-253.
50. Kimizuka G., Ohwada H., Hayashi Y. Co-carcinogenic effect of asbestos and benzo(a)pyrene. Acta Pathol. Jpn. 1987, 37:465-474.
51. Kimizuka G., Hayashi Y. Combined effects of asbestos and smoking on hamster lung. Health Risks from Exposure to Mineral Fibres: An International Perspective 1993, 254-263. Captus University Publications, Ontario, Canada. G.W. Gibbs, J. Dunnigan, M. Kido, T. Higashi (Eds.).
52. Kooijman S.A.L.M. Dynamic Energy Budget theory for metabolic organization 2009, Cambridge University Press, UK. 3rd edition.
53. Kozlov M., Zvereva E. Industrial barrens: extreme habitats created by non-ferrous metallurgy. Rev. Environ. Sci. Biotechnol. 2007, 6:231-259.
54. Kortenkamp, A., Backhaus, T., Faust, M., 2009. State of the Art on Mixture Toxicity. Report. Available at: (accessed 06.01.12). http://ec.europa.eu/environment/chemicals/pdf/report_Mixture%20toxicity.pdf.
55. Laskowski R., Bednarska A.J., Kramarz P.E., Loureiro S., Scheil V., Kudlek J., Holmstrup M. Interactions between toxic chemicals and natural environmental factors - a meta-analysis and case studies. Sci. Total Environ. 2010, 408:3763-3774.
56. Leitte A.M., Petrescu C., Franck U., Richter M., Suciu O., Ionovici R., Herbarth O., Schlink U. Respiratory health, effects of ambient air pollution and its modification by air humidity in Drobeta-Turnu Severin, Romania. Sci. Total Environ. 2009, 407:4004-4011.
57. Cumulative stressors - risk assessment of mixtures of chemicals and combinations of chemicals and natural stressors. Sci. Total Environ. 2010, 408:3719-3963.
58. Loos M., Ragas A.M.J., Plasmeijer R., Schipper A.M., Hendriks A.J. Eco-SpaCE: an object-oriented, spatially explicit model to assess the risk of multiple environmental stressors on terrestrial vertebrate populations. Sci. Total Environ. 2010, 408:3908-3917.
59. Loos M., Schipper A.M., Schlink U., Strebel K., Ragas A.M.J. Receptor-oriented approaches in wildlife and human exposure modelling: a comparative study. Environ. Modell. Softw. 2010, 25:369-382.
60. Loureiro S., Svendsen C., Ferreira A.L.G., Pinheiro C., Ribeiro F., Soares A.M.V.M. Toxicity of chemical mixtures to Daphnia magna: chemical modes of action and deviations from conceptual models. Environ. Toxicol. Chem. 2010, 29:1716-1726.
61. Martin H.L., Svendsen C., Spurgeon D.J., Lister L.J., Gomezeyles J. Measurement and modelling the combined toxicity of binary mixtures in the nematode Caenorhabditis elegans - a test of independent action. Environ. Toxicol. Chem. 2009, 28:97-104.
62. Meek M.E., Boobis A.R., Crofton K.M., Heinemeyer G., Van Raaij M., Vichers C. Risk assessment of combined exposure to multiple chemicals: a WHO/IPCS framework. Regul. Toxicol. Pharmacol. 2011, 60:S1-S14. 10.1016/j.yrtph.2011.03.010.
63. A framework for cumulative risk assessment. International Life Sciences Institute 1999, ILSI Press, Washington, DC, USA. B. Mileson, E. Faustman, S. Olin, P.B. Ryan, S. Ferenc, T. Burke (Eds.).
64. MSFD, 2008. Directive 2008/56/EC of the European Parliament and of the Council of 17 June 2008 establishing a framework for community action in the field of marine environmental policy. (Marine Strategy Framework Directive).
65. Munns W.R. Assessing risks to wildlife populations from multiple stressors: overview of the problem and research needs. Ecol. Soc. 2006, 11(1). (article no. 23) http://www.ecologyandsociety.org/vol11/iss21/art23/.
66. NRC (National Research Council) Science and Judgment in Risk Assessment. Committee on Risk Assessment of Hazardous Air Pollutants, Board on Environmental Studies and Toxicology, Commission on Life Sciences 1994, National Academy Press, Washington, DC, USA.
67. Ogunbayo O.A., Jensen K.T., Michelangeli F. The interaction of the brominated flame retardant: tetrabromobisphenol A with phospholipid membranes. Biochim. Biophys. Acta 2007, 1768:1559-1566.
68. Oostingh G.J., Schmittner M., Ehart A.K., Tischler U., Duschl A. A high-throughput screening method based on stably transformed human cells was used to determine the immunotoxic effects of fluoranthene and other PAHs. Toxicol. In Vitro 2008, 22:1301-1310.
69. Oostingh G.J., Wichmann G., Schmittner M., Lehmann I., Duschl A. The cytotoxic effects of the organophosphates chlorpyrifos and diazinon differ from their immunomodulating effects. J. Immunotoxicol. 2009, 6:136-145.
70. PCCRARM (Presidential/Congressional Commission on Risk Assessment and Risk Management), 1997. Framework for Environmental Health Risk Management. Washington, DC, USA.
71. Price P.S., Hollnagel H.M., Zabik J.M. Characterizing the noncancer toxicity of mixtures using concepts from the TTC and quantitative models of uncertainty in mixture toxicity. Risk Anal. 2009, 29:1534-1548.
72. Ragas A.M.J., Teuschler L.K., Posthuma L., Cowan C. Human and ecological risk assessment of chemical mixtures. Mixture Toxicity - Linking Approaches from Ecological and Human Toxicology 2011, 157-215. SETAC, CRC Press, New York. C.A.M. Van Gestel, M.J. Jonker, J.E. Kammenga, R. Laskowski, C. Svendsen (Eds.).
73. Ragas A.M.J., Oldenkamp R., Preeker N.L., Wernicke J., Schlink U. Cumulative risk assessment of chemical exposures in urban environments. Environ. Int. 2011, 37:872-881.
74. Rappaport S.M. Implications of the exposome for exposure science. J. Expo. Anal. Environ. Epidemiol. 2011, 21:5-9.
75. Ross, H.L.B., 1996. The interaction of chemical mixtures and their implications on water quality guidelines. Hons Thesis, University of Technology, Sydney, NSW, Australia. p. 167.
76. Ross H.L.B., Warne M.St.J. Most chemical mixtures have additive aquatic toxicity. Proceedings of the Third Annual Conference of the Australasian Society for Ecotoxicology 1997, 30.
77. Röder-Stolinski C., Fischäder G., Oostingh G.J., Feltens R., Kohse F., von Bergen M., Mörbt N., Eder K., Duschl A., Lehmann I. Styrene induces an inflammatory response in human lung epithelial cells via oxidative stress and NF-κB activation. Toxicol. Appl. Pharmacol. 2008, 23:241-247.
78. Röder-Stolinski C., Fischäder G., Oostingh G.J., Eder K., Duschl A., Lehmann I. Chlorobenzene induces the NF-κB and p38 MAP kinase pathways in lung epithelial cells. Inhal. Toxicol. 2008, 20:813-820.
79. Santore R.C., Mathew R., Paquin P.R., Ditoro D. Application of the biotic ligand model to predicting zinc toxicity to rainbow trout, fathead minnow, and Daphnia magna. Comp. Biochem. Physiol. C: Toxicol. Pharmacol. 2002, 133:271-285.
80. Schlink U., Fritz G.J., Herbarth O., Richter M. Longitudinal modelling of respiratory symptoms in children. Int. J. Biometeorol. 2002, 47:35-48.
81. Schlink U., Ragas A.M.J. Truncated Lévy flights and agenda-based mobility are useful for the assessment of personal human exposure. Environ. Pollut. 2011, 159:2061-2070.
82. Skovlund G., Damgaard C., Bayley M., Holmstrup M. Does lipophilicity of toxic compounds determine effects on drought tolerance of the soil collembolan Folsomia candida?. Environ. Pollut. 2006, 144:808-815.
83. Spurgeon D.J., Jones O.A.H., Dorne J.L.C.M., Svendsen C., Swain S., Sturzenbaum S.R. Systems toxicology approaches for understanding the joint effects of environmental chemical mixtures. Sci. Total Environ. 2010, 408:3725-3734.
84. Spurgeon D.J., Pohl H.R., Loureiro S., Løkke H., Van Gestel C.A.M. Mixture Toxicity - Linking Approaches from Ecological and Human Toxicology 2011, 1-45. SETAC, CRC Press, New York. C.A.M. Van Gestel, M.J. Jonker, J.E. Kammenga, R. Laskowski, C. Svendsen (Eds.).
85. Svendsen C., Jager T., Haddad S., Yang R.S.H., Dorne J.L.C.M., Broerse M., Kramarz P. Mixture Toxicity - Linking Approaches from Ecological and Human Toxicology 2011, 47-93. SETAC, CRC Press, New York. C.A.M. Van Gestel, M.J. Jonker, J.E. Kammenga, R. Laskowski, C. Svendsen (Eds.).
86. Talent L.G. Effect of temperature on toxicity of a natural pyrethrin pesticide to green anole lizards (Anolis carolinensis). Environ. Toxicol. Chem. 2005, 24:3113-3116.
87. The Lifeline Group Inc. User's Manual. LifeLine™ Version 4.4 2007, The LifeLine Group, Annandale, VA, USA, p. 117.
88. Thomas R., Gohlke J.M., Stopper G.F., Parham F.M., Portier C.J. Choosing the right path: enhancement of biologically relevant sets of genes or proteins using pathway structure. Genome Biol. 2009, 10:R44. 10.1186/gb-2009-10-4-r44.
89. Topping C.J., Hansen T.S., Jensen T.S., Jepsen J.U., Nikolajsen F., Odderskær P. ALMaSS, an agent-based model for animals in temperate European landscapes. Ecol. Modell. 2003, 167:65-82.
90. Trasande L., Landrigan P.J. The National Children's Study: a critical national investment. Environ. Health Perspect. 2004, 112:A789-A790.
91. US EPA (U.S. Environmental Protection Agency), 2000. Supplementary guidance for conducting health risk assessment of chemical mixtures. EPA/630/R-00/002. ORD/NCEA. Cincinnati, Ohio.
92. US EPA (U.S.Environmental Protection Agency) Framework for Cumulative Risk Assessment 2003, United States Environmental Protection Agency, Risk Assessment Forum, Washington, DC, USA.
93. US EPA (U.S.Environmental Protection Agency) Total Risk Integrated Methodology (TRIM) Air Pollutants Exposure Model Documentation (TRIM. Expo/APEX, Version 4) Volume I: User's Guide 2006, Office of Air Quality Planning and Standards, Durham, NC, USA, p. 86.
94. US EPA (U.S.Environmental Protection Agency) Total Risk Integrated Methodology (TRIM) Air Pollutants Exposure Model Documentation (TRIM. Expo/APEX, Version 4) Volume II: Technical Support Document 2006, Office of Air Quality Planning and Standards, Durham, NC, USA, p. 92.
95. US EPA (U.S.Environmental Protection Agency) Concepts, methods and data sources for cumulative health risk assessment of multiple chemicals, exposures and effects: a resource document (EPA/600/R-06/014F). National Center for Environmental Assessment, Office of Research and Development 2007, US Environmental Protection Agency, Cincinnati, Ohio.
96. Vallotton N., Eggen R.I.L., Chèvre N. Effect of sequential isoproturon pulse exposure on Scenedesmus vacuolatus. Arch. Environ. Contam. Toxicol. 2009, 56:442-449.
97. Mixture Toxicity: Linking Approaches from Ecological and Human Toxicology 2010, 280. SETAC, CRC Press, Boca Raton. C.A.M. Van Gestel, M.J. Jonker, J.E. Kammenga, R. Laskowski, C. Svendsen (Eds.).
98. Van Wezel A.P., Cornelissen G., Van Miltenburg J.K., Opperhuizen A. Membrane burdens of chlorinated benzenes lower the main phase transition temperature in dipalmitoyl-phosphatidylcholine vesicles: implications for toxicity by narcotic chemicals. Environ. Toxicol. Chem. 1996, 15:203-212.
99. Vandenbrouck T., Soetaert A., Van der Ven K., Blust R., De Coen W. Nickel and binary metal mixture responses in Daphnia magna: Molecular fingerprints and (sub)organismal effects. Aquat. Toxicol. 2009, 92:18-29.
100. Warne M.S., Hawker D.W. The number of components in a mixture determines whether synergistic and antagonistic or additive toxicity predominate: the funnel hypothesis. Ecotoxicol. Environ. Saf. 1995, 31:23-28.
101. Warne M.S.J. A review of the ecotoxicity of mixtures, approaches to, and recommendations for, their management. Proceedings of the Fifth National Workshop on the Assessment of Site Contamination 2003, National Environment Protection Council Service Corporation, Adelaide, SA. A. Langley, M. Gilbey, B. Kennedy (Eds.).
102. Weber R.E., De Zwaan A., Bang A. Interactive effects of ambient copper and anoxic, temperature and salinity stress on survival and hemolymph and muscle tissue osmotic effectors in Mytilus edulis. J. Exp. Mar. Biol. Ecol. 1992, 159:135-156.
103. Wharton D.A. Life at the Limits 2002, Cambridge University Press, Cambridge, p. 307.
104. WHO (World Health Organization) Assessment of Combined Exposures to Multiple Chemicals: Report of a WHO/IPCS International Workshop 2009, International Programme on Chemical Safety (IPCS), Inter-Organization Programme for the Sound Management of Chemicals (IOMC), Geneva.
105. Zartarian V.G., Xue J., Ozkaynak H.A., Dang W., Glen G., Smith L., Stallings C. A probabilistic arsenic exposure assessment for children who contact Chromated Copper Arsenate (CCA)-treated playsets and decks, part 1: model methodology, variability results, and model evaluation. Risk Anal. 2006, 26:515-531.
106. Zartarian, V.G., Glen, G., Smith, L., Xue, J., 2007. Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway Chemicals. SHEDS-Multimedia Model version 3. Technical Manual, United States Environmental Protection Agency, Presented to the USEPA Office of Pesticide Program's FIFRA Scientific Advisory Panel, August 14-15, 2007. Available at:. http://www.epa.gov/scipoly/sap/meetings/2007/august/sheds_techmanual_06_14.pdf.