Mixture toxicity revisited from a toxicogenomic perspective

Environmental Science and Technology

Volumn 46, Issue 5, 2012, Pages 2508-2522

  Altenburger, Rolf ^a,b   Scholz, Stefan ^a   Schmitt Jansen, Mechthild ^a   Busch, Wibke ^a   Escher, Beate I ^b  

^a HELMHOLTZ CENTRE FOR ENVIRONMENTAL RESEARCH UFZ   (Germany)

^b UNIVERSITY OF QUEENSLAND   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ANECDOTAL EVIDENCES; BIOINFORMATIC ANALYSIS; BIOINFORMATIC TOOLS; BIOLOGICAL RESPONSE; CHEMICAL MIXTURES; COMBINED EFFECT; CONCEPTUAL FRAMEWORKS; CURRENT LIMITATION; DATA TRANSFORMATION; DESIGN STUDIES; DOSE RESPONSE; EXPERIMENTAL STUDIES; GENE TRANSCRIPTS; INDIVIDUAL COMPONENTS; LOW DOSE; METABOLOMICS; METHODOLOGICAL PROBLEMS; MIXTURE EFFECTS; MIXTURE TOXICITY; MULTIPLE RESPONSE; PROTEOMIC ANALYSIS; STATISTICAL TREATMENT; STRESS RESPONSE; TIME DEPENDENCY; TOXICOKINETICS;

BIOINFORMATICS; GENES; MIXTURES;

TOXICITY;

11 OXOTESTOSTERONE; 2,2,4,4, TETRABROMODIPHENYL ETHER; 4 NITROQUINOLINE 1 OXIDE; 4,4' ISOPROPYLIDENEDIPHENOL; ANTIESTROGEN; BENZO[RST]PENTAPHENE; BENZOPHENONE; CHEMICAL COMPOUND; CHLORPHENOTANE; CHLORPYRIFOS; DIBENZ[A,H]ANTHRACENE; ESTRADIOL; ETHINYLESTRADIOL; FLUORANTHENE; FLUVESTRANT; GLYPHOSATE; HEXABROMOCYCLODODECANE; HEXACHLOROBENZENE; HEXAVALENT CHROMIUM; MESTRANOL; MESYLIC ACID METHYL ESTER; METHYLMERCURY; METHYLNITRONITROSOGUANIDINE; MITOMYCIN C; NAPHTHENIC ACID; NONYLPHENOL; NONYLPHENOL MONOETHOXYLATE CARBOXYLATE; ORGANOCHLORINE PESTICIDE; POLYBROMINATED DIBENZO 4 DIOXIN; POLYCHLORINATED BIPHENYL; UNCLASSIFIED DRUG; UNINDEXED DRUG;

BIOASSAY; BIOINFORMATICS; CONCEPTUAL FRAMEWORK; DECADAL VARIATION; EXPERIMENTAL STUDY; GENOMICS; HYPOTHESIS TESTING; LITERATURE REVIEW; QUANTITATIVE ANALYSIS; TOXICITY; TOXICITY TEST;

BIOINFORMATICS; BIOLOGICAL ACTIVITY; CHEMICAL INTERACTION; CONCENTRATION (PARAMETERS); CONCEPTUAL FRAMEWORK; DOSE RESPONSE; EXPERIMENTAL MODEL; GENOMICS; HUMAN; METABOLOMICS; MIXTURE TOXICITY; NONHUMAN; PROTEOMICS; QUANTITATIVE ASSAY; REVIEW; SIGNAL TRANSDUCTION; TOXICITY; TOXICOGENETICS; TRANSCRIPTOMICS;

ANIMALS; COMPLEX MIXTURES; HUMANS; MODELS, BIOLOGICAL; TOXICOGENETICS;

EID: 84857846864     PISSN: 0013936X     EISSN: 15205851     Source Type: Journal    
DOI: 10.1021/es2038036     Document Type: Review

References (96)

1. Berenbaum, M. C. Criteria for analysing interactions between biologically active agents Adv. Cancer Res. 1981, 35, 269-335
2. Bödeker, W.; Altenburger, R.; Faust, M.; Grimme, L. H. Methods for the assessment of mixtures of pesticides: Mathematical analysis of combination effects in phytopharmacology and ecotoxicology Nachrichtenbl. Dtsch. Pflanzenschutzdienstes (Braunschweig, Ger.) 1990, 42 (5) 70-78
3. Greco, W. R.; Bravo, G.; Parsons, J. C. The search for synergy: A critical review from a response surface perspective Pharmacol. Rev. 1995, 47, 331-385
4. Schwarzenbach, R. P.; Escher, B. I.; Fenner, K.; Hofstetter, T. B.; Johnson, C. A.; con Guntern, U.; Wehrli, B. The challenge of micropollutants in aquatic systems Science 2006, 313, 1072-1077
5. EU Council of Ministers. Combination effects of chemicals-Council conclusion 17820/09. 2009.
6. Teuschler, L.; Klaunig, J.; Carney, E.; Chambers, J.; Conolly, R.; Gennings, C.; Giesy, J.; Hertzberg, R.; Klaassen, C.; Kodell, R.; Paustenbach, D.; Yang, R. Support of science-based decisons concerning the evaluation of the toxicology of mixtures: a new beginning Regul. Toxicol. Pharmacol. 2002, 36, 34-39
7. Yang, R. S. H.; El-Masri, H. A.; Thomas, R. S.; Dobrev, I. D.; Dennison, J. D.; Bae, D.-S.; Campain, J. A.; Liao, K. H.; Reisfeld, B.; Andersen, M. E.; Mumatz, M. Chemical mixture toxicology: from descriptive to mechanistic, and going on to in silico toxicology Environ. Toxicol. Pharmacol. 2004, 18, 65-81
8. Kortenkamp, A. Ten years of mixing cocktails: A review of combination effects of endocrine-disrupting chemicals Environ. Health Perspect. 2007, 115 (S-1) 98-105
9. Posthuma, L.; Richards, S. M.; De Zwart, D.; Dyer, S. D.; Sibley, P. K.; Hickey, C. H.; Altenburger, R. Mixture Extrapolation Approaches. In Extrapolation practice for ecotoxicological effect characterization of chemicals; Solomon, K. R.; Brock, T. C. M.; de Zwart, D.; Dyer, S. D.; Posthuma, L.; Richards, S. M.; Sanderson, H.; Sibley, P. K.; van den Brink, P. J., Eds.; SETAC, CRC Press: Boca Raton, London, NewYork, 2008; p 135.
10. Kortenkamp, A.; Altenburger, R. Toxicity from combined exposure to chemicals. In Mixture toxicity: Linking approaches from ecotoxicology and human toxicology; Van Gestel, C. A. M.; Jonker, M. J.; Kammenga, J. E.; Laskowski, R.; Svendsen, C., Eds.; CRC Press: Boca Raton, 2010; p 95.
11. Mumatz, M. M.; Hugh, H.; Pohl, H. R. Mixtures and their risk assessment in toxicology Met. Ions Life Sci. 2011, 8, 61-80
12. Kortenkamp., A.; Backhaus, T.; Faust, F. State of the art report on mixture toxicity. Report to the European Commission. 2009. Web site: http://ec.europa.eu/environment/chemicals/pdf/report-Mixture%20toxicity.pdf (accessed February 11, 2010).
13. EU SC-Health (European Union Scientific Committees on Health). Toxicity and Assessmentof Chemical Mixtures (Preliminary Opinion for Public Consultation).By Scientific Committees on Consumer Safety (SCCS), Health and EnvironmentalRisks (SCHER), Emerging and Newly Identified Health Risks (SCENIHR). (2011. Web site: http://ec.europa.eu/health/scientific-committees/ consultations/public-consultations/scher-consultation-06-en.htm (accessed July 21, 2011).
14. Berenbaum, M. C. What is synergy? Pharmacol. Rev. 1989) 41, 93-141
15. Brack, W.; Klamer, H.; de Alda, M.; Barcelo, D. Effect-directed analysis of key toxicants in European river basins. A review Environ. Sci. Poll. Res. Int. 2007, 14, 30-38
16. Ankley, G. T.; Daston, G. P.; Degitz, S. J.; Denslow, N. D.; Hoke, R. A.; Kennedy, S. W.; Miracle, A. L.; Perkins, E. J.; Snape, J.; Tillitt, D. E.; Tyler, C. R.; Versteeg, D. Toxicogenomics in regulatory ecotoxicology Environ. Sci. Technol. 2006, 40, 4055-4065
17. Yang, L.; Kemadjou, J. R.; Zinsmeister, C.; Bauer, M.; Legradi, J.; Müller, F.; Pankratz, M.; Jäkel, J.; Strähle, U. Transcriptional profiling reveals barcode-like toxicogenomic responses in the zebrafish embryo Genome Biol. 2007, 8 (10) R227
18. Hook, S. E.; Lampi, M. A.; Febbo, E. J.; Ward, J. A.; Pakerton, T. F. Heaptic gene expression in rainbow trout (Onchryhynchus mykiss) exposed to different hydrocarbon mixtures Environ. Toxicol. Chem. 2010, 29, 2034-2043
19. Spurgeon., D. J.; Jones, O. A. H.; Dorne, J. L. C. M.; Svendsen, C.; Swain, A.; Stürzenbaum, S. R. System toxicology approaches for understanding the joint effects of environmental chemical mixtures Sci. Total Environ. 2010, 408, 3725-3734
20. Bae, D.-S.; Hanneman, W. H.; Yang, R. S. H.; Campain, J. A. Characterization of gene expression changes associated with MNNG, arsenic, or metal mixture treatment in human keratinocytes: application of cDNA microarray technology Environ. Health Perspect. 2002, 110 (suppl 6) 931-941
21. Mumtaz, M. M.; Tully, D. B.; El-Masri, H. A.; De Rosa, C. T. Gene induction studies and toxicity of chemical mixtures Environ. Health Perspect. 2002, 110 (suppl 6) 947-956
22. Garcia-Reyero, N.; Perkins, E. J. Systems biology: Leading the revolution in ecotoxicology Environ. Toxicol. Chem. 2011, 30, 265-273
23. Sen, B.; Mahadevan, B.; DeMarini, D. M. Transcriptational responses to complex mixtures - A review Mutat. Res. 2007, 636, 144-177
24. Paules, R. Phenotypic anchoring: Linking cause and effect Environ. Health Perspect. 2003, 111, 6
25. Lettieri, T. Recent applications of DNA microarray technology to toxicology and ecotoxicology Environ, Health Perspect. 2006, 114, 4-9
26. Nesatyy, V. J.; Suter, M. J.-F. Proteomics for the analysis of environmental stress responses in organisms Environ. Sci. Technol. 2007, 41, 6891-6900
27. Bundy, J. G.; Davey, M. P.; Viant, M. R. Environmental metabolomics: a critical review and future perspectives Metabolomics 2009, 5, A3-21
28. Vandegehuchte, M. B.; Janssen, C. R. Epigenetics and its implications for ecotoxicology Ecotoxicology 2011, 607-624
29. Hendriks, B. S. Functional pathway pharmacology: chemical tools, pathway knowledge and mechanistic model-based interpretation of experimental data Curr. Opin. Chem. Biol. 2010, 14, 489-497
30. Schirmer, K.; Fischer, B.; Madureira, D.; Pillai, S. Transcriptomics in ecotoxicology Anal. Bioanal. Chem. 2010, 397, 917-923
31. Costa, F. F. Non coding RNAs: Meet thy masters BioEssays 2010, 32, 599-608
32. Fiehn, O.; Kopka, J.; Dormann, P.; Altmann, T.; Trethewey, R. N.; Willmitzer, L. Metabolite profiling for plant functional genomics Nat. Biotechnol. 2000, 18 (11) 1157-1161
33. Simpson, A. J.; McNally, D. J.; Simpson, M. J. NMR Spectroscopy in environmental research: From molecular interactions to global processes Prog. Nucl. Magn. Reson. Spectrosc. 2011, 58, 97-175
34. Theodoridis, G.; Gika, H. G.; Wilson, I. D. (2011): Mass spectrometry-based holistic analytical approaches for metabolite profiling in systems biology studies Mass Spectrom. Rev. 2011, 30 (5) 884-904
35. Roessner, U. The chemical challenge of the metabolome. In Metabolme analysis; Villas-Boas, S. G.; Roessner, U.; Hansen, M. A. E.; Smedsgaard, J.; Nielsen, J., Eds.; Wiley: Canada, 2007; p 15.
36. Ankley, G. T.; Bennett, R. S.; Erickson, R. J.; Dale, J. H.; Hornung, M. W.; Johnson, R. D.; Mount, D. R.; Nicols, J. W.; Russom, C. L.; Schmieder, P. K.; Serrano, J. A.; Tietge, J. E.; Villeneuve, D. L. Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment Environ. Toxicol. Chem. 2009, 29, 730-741
37. Escher, B. I.; Hermens, J. L. M. Modes of action in ecotoxicology: their role in body burdens, species sensitivity, QSARs, and mixture effects Environ. Sci. Technol. 2002, 36, 4201-4217
38. Altenburger, R.; Schmitt, H.; Schüürmann, G. Algal Toxicity of Nitrobenzenes: Combined Effect Analysis as a Pharmacological Probe for Similar Modes of Interaction Environ. Toxicol. Chem. 2005, 24, 324-333
39. Altenburger, R.; Nendza, M.; Schüürmann, G. Mixture toxicity and its modeling by quantitative structure-activity relationships Environ. Toxicol. Chem. 2003, 22, 1900-1915
40. Williams, T. D.; Gensberg, K.; Minchin, S. D.; Chipman, J. K. A DNA expression array to detect toxic stress response in European flounder (Platichthys flesus) Aquat. Toxicol. 2003, 65, 141-157
41. Garcia-Reyero, N.; Escalon, B. L; Loh, P.-R.; Laird, J. G.; Kennedy, A. J.; Berger, B.; Perkins, E. J. Assessment of chemical mixtures and groundwater effectson Daphnia magna transcriptomics. Environ. Sci. Technol. 2012, 46, 42 - 50.
42. Mortensen, A. S.; Tolfsen, C. C.; Arukwe, A. Gene expression patterns in estrogen (nonylphenol) and aryl hydrocarbon receptor agonists (PCB-77) interaction using rainbow trout (Oncorhynchus mykiss) primary hepatocyte culture J. Toxicol. Environ. Health, Part A 2006, 69, 1-19
43. Pinto, P. I. S.; Singh, P. B.; Condeça, J. B.; Teodósio, H. R.; Power, D. M.; Canário, A. V. M. ICI 182,780 has agonistic effects and synergizes with estradiol-17 beta in fish liver, but not in testis Reprod. Biol. Endocrinol. 2006, 4) 67
44. Garcia-Reyero, N.; Kroll, K. J.; Liu, L.; Orlando, E. F.; Watanabe, K. H.; Sepúveda, M. S.; Villeneuve, D. L.; Perkins, E. J.; Ankley, G. T.; Denslow, N. D. Gene expression responses in male fathead minnows exposed to binary mixtures of an estrogen and antiestrogen BMC Genomics 2009, 10, 308
45. Pomati, F.; Castiglioni, S.; Zuccato, E.; Fanelli, R.; Vigetti, D.; Rossetti, C.; Calamari., D. Effects of a complex mixture of therapeutic drugs on human embryonic cells Environ. Sci. Technol. 2006, 40, 2442-2447
46. Krasnov, A.; Afanasyev, S.; Oikari, A. Hepatic responses of gene expression in juvenile brown trout (Salmo trutta lacustris) exposed to three model contaminants applied singly or in combination Environ. Toxicol. Chem. 2007, 26, 100-109
47. Dardenne, F.; Nobels, I.; De Coen, W.; Blust, R. Mixture toxicity and gene induction: Can we predict the outcome? Environ. Toxicol. Chem. 2008, 27, 509-518
48. Staal, Y. C. M.; Pushparajah, D. S.; von Herwijnen, M. H. M.; Gottschalk, R. W. H.; Maas, L. M.; Ioannides, C.; van Schooten, F. J.; van Delft, J. H. M. Interactions between polycyclic aromatic hydrocarbons in binary mixtures: Effects on gene expression and DNA adduct formation in precision-cut rat liver slices Mutagenesis 2008, 23, 491-499
49. Mortensen, A. K.; Arukwe, A. Targeted salmon gene array (SalArray): a toxicogenomic tool for gene expression profiling of interactions between estrogen and aryl hydrocarbon receptor signalling pathways Chem. Res. Toxicol. 2007, 20, 474-488
50. Vandenbruck, 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
51. Collette, T. W.; Teng, Q.; Jensen, K. M.; Kahl, M. D.; Makynen, E. A.; Durhan, E. J.; Villeneuve, D. L.; Martinović-Weigelt, D.; Ankley, G. T.; Ekman, D. R. Impacts of an anti-androgen and an androgen/anti-androgen mixture on the metabolite profile of male fathead minnow urine Environ. Sci. Technol. 2010, 44, 6881-6886
52. Costa, P. M.; Chicano-Gálvez, E.; López Barea, J.; DelValls, T. À.; Costa, M. H. Altertions to the proteome and tissue recovery responses in fish liver caused by a short-term combination treatment with cadmium and benzo[a]pyrene Environ. Pollut. 2010, 158, 3338-3346
53. Dondero, F.; Negri, A.; Boatti, L.; Marsano, F.; Migone, F.; Viarengo, A. Transcriptomic and proteomic effects of a neonicotinoid insecticide mixture in the marine mussel (Mytilus galloprovinciales Lam.) Sci. Total Environ. 2010, 408, 3775-86
54. Hutchins, C. M.; Simon, D. F.; Zerges, W.; Wilkinson, K. J. Transcriptomic signatures in Chlamydomonas reinhardtii as Cd biomarkers in metal mixtures Aquat. Toxicol. 2010, 100, 120-127
55. Vandenbrouck, T.; Jones, O. A. H.; Dom, N.; Griffin, J. L.; De Coen, W. Mixtures of similarly acting compounds in Daphnia magna: From gene to metabolite and beyond Environ. Int. 2010, 36, 254-268
56. Vinuela, A. L. B.; Snoek, L. B.; Riksen, J. A. G.; Kammenga, J. E. Genome-wide gene expression analysis in response to organophosphorus pesticide chlorpyrifos and diazinon in C. elegans PLoS One 2010, 5 (8) 8
57. Wu, H.; Wang, W.-X. NMR-based metabolomic studies on the toxicological effects of cadmium and copper on green mussels Perna viridis Aquat. Toxicol. 2010, 100, 339-345
58. Dondero, F.; Banni, M.; Negri, A.; Boatti, L.; Dagnino, A.; Viarengo, A. Interactions of a pesticide/heavy metal mixture in marine bivalves: a transcriptomic assessment BMC Genomics 2011, 12, 195
59. Johns, S. M.; Denslow, N. D.; Kane, M. D.; Watanabe, K. H.; Orlando, E. F.; Sepúlveda, M. S. Effects of estrogens and antiestrogens on gene expression of fathead minnow (Pimephales promelas) early life stages Environ. Toxicol. 2011, 26, 195-206
60. Kim, S.; Ji, K.; Lee, S.; Lee, J.; Kimm, J.; Kim, S.; Kho, Y.; Choi, K. Perfluorooctane sulfonic acid exposure increases cadmium toxicity in early life stage of zebrafish Danio rerio Environ. Toxicol. Chem. 2011, 30, 870-877
61. Tilton, F. A.; Tilton, S. C.; Bammler, T. K.; Beyer, R. P.; Stapleton, P. L.; Scholz, N. L.; Gallagher, E. P. Transcriptional impact of organophosphate and metal mixtures on olfaction: Copper dominates the chlorpyrifos-induced response in adult zebrafish Aquat. Toxicol. 2011, 102, 205-215
62. Finne, E. F.; Cooper, G. A.; Koop, B. F.; Hylland, K.; Tollefsen, K. E. Toxicogenomic responses in rainbow trout (Oncorhynchus mykiss) hepatocytes exposed to model chemicals and a synthetic mixture Aquat. Toxicol. 2007, 81, 293-303
63. Hendriksen, P. J. M.; Freidig, A. P.; Jonker, D.; Thissen, U.; Bogaards, J. J. P.; Mumtaz, M. M.; Groten, J. P.; Stierum, R. H. Transcriptomics analysis of interactive effects of benzene, trichloroethylene and methyl mercury within binary and ternary mixtures on the liver and kidney following subchronic exposure in rat Toxicol. Appl. Pharmacol. 2007, 225, 171-188
64. Pomati, F.; Cotsapas, C. J.; Castiglioni, S.; Zuccato, E.; Calamari, D. Gene expression profiles in zebrafish (Danio rerio) liver cells exposed to a mixture of pharmaceuticals at environmentally relevant concentrations Chemosphere 2007, 70, 65-73
65. Canesi, L. C.; Borghi, C.; Ciacci, C.; Fabbri, R.; Lorusso, L. C.; Vergani, L.; Marcomini, A.; Poiana, G. Short-term effects of environmentally relevant concentrations of EDC mixtures on Mytilus galloprovincialis digestive gland Aquat. Toxicol. 2008, 87, 272-279
66. Hook, S. E.; Skillman, A. D.; Gopalan, B.; Small, J. A.; Schultz, I. R. Gene expression profiles in rainbow trout, Onchorynchus mykiss, exposed to a simple chemical mixture Toxicol. Sci. 2008, 102, 42-60
67. Pelletier, G.; Masson, S.; Wade, M. J.; Nakai, J.; Alwis, R.; Mohottalage, S.; Kumarathasan, P.; Black, P.; Bowers, W. J.; Chu, I.; Vincent, R. Contribution of methylmercury, polychlorinated biphenyls and organochlorine pesticides to the toxicity of a contaminant mixture based on Canadian Arctic population blood profiles Toxicol. Lett. 2009, 184, 176-185
68. Wei, Y.; Shi, X.; Shi, X.; Zhang, H.; Wang, J.; Zhou, B.; Dai, J. Combined effects of polyfluorinated and perfluorinated compounds on primary cultured hepatocytes from rare minnow (Gobiocypris rarus) using toxicogenomic analysis Aquat. Toxicol. 2009, 95, 27-36
69. Evrard, E.; Marchand, J.; Theron, M.; Pichavant-Rafini, K.; Durand, G.; Quiniou, L.; Laroche, J. Impacts of mixtures of herbicides on molecular and physiological responses of the European flounder Platichthys flesus Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol. 2010, 152, 321-331
70. Jin., Y.; Chen, R.; Liu, W.; Fu, Z. Effect of endocrine disrupting chemicals on the transcription of genes related to the innate immune system in the early developmental stage of zebrafish (Danio rerio) Fish Shellfish Immunol. 2010, 28, 854-861
71. Merhi., M.; Demur, C.; Racaud-Sultan, C.; Bertrand, J.; Canlet, C.; Blas y Estada, F.; Gamet-Payrastre, L. Gender-linked haematopoietic and metabolic disturbances induced by a pesticide mitxture administered at low dose to mice Toxicology 2010, 267, 80-90
72. Norman Haldén, A.; Arnoldsson, K.; Haglund, P.; Mattson, A.; Ullerås, E.; Struve, J.; Norrgren, L. Retention and maternal transfer of brominated dioxins in zebrafish (Danio rerio) and effects on reproduction, aryl hydrocarbon receptor-regulated genes, and ethoxyresorufin-O-deethylase (EROD) activity Aquat. Toxicol. 2011, 102, 150-161
73. Filby, A. L.; Neuparth, T.; Thorpe, K. L.; Owen, R.; Galloway, T. S.; Tyler, C. R. Health impacts of estrogens in the environment considering complex mixture effects Environ. Health Perspect. 2007, 115, 1704-1709
74. Menzel, R.; Swain, S. C.; Hoess, S.; Claus, E.; Menzel, S.; Steinberg, E. W.; Reifferscheid, G.; Stürzenbaum, S. R. Gene expression profiling to characterize sediment toxicity - a pilot study using Caenorhabditis elegans whole genome microarrays BMC Genomics 2009, 10
75. Lyche, J. L; Nourizadeh-Lillabadi, R.; Almaas, C.; Stavik, B.; Berg, V.; Skåre, J. U.; Alestrøm, P.; Ropstad, E. Natural mixtures of persistent organic pollutants (POP) increase weight gain, advance puberty, and induce changes in gene expression J. Toxicol. Environ. Health, Part A 2010, 73, 1032-1057
76. Garcia-Reyero, N.; Lavelle, C. M.; Escalon, B. L.; Martinović, D.; Kroll, K. J.; Sorensen, P. W.; Denslow, N. D. Behavioural and genomic impacts of a wastewater effluent on the fathead minnow Aquat. Toxicol. 2011, 101, 38-48
77. Zhang, X.; Wiseman, S.; Hu, H.; Liu, H.; Giesy, J. P.; Hecker, M. Assessing the toxicity of naphthenic acids using a microbial genome wide live cell reporter array system Environ. Sci. Toxicol. 2011, 45, 1984-1991
78. OECD (Organisation of economic cooperation and development). Current approaches in the statistical analysis of ecotoxicity data: A guidance to application. In OECD Series on testing and assessment. Number 54, Paris, France, 2006.
79. Hertzberg, R. C.; MacDonell, M. M. Synergy and other ineffective mixture risk definitions Sci. Total Environ. 2002, 288, 31-42
80. Belden, J. B.; Gilliom, R. J.; Lydy, M. J. How well can we predict the toxicity of pesticide mixtures to aquatic life? Integr. Environ. Assess. Manage. 2007, 3 (3) 364-372
81. Altenburger, R. Understanding combined effects for metal co-exposure in ecotoxicology Met. Ions Life Sci. 2011, 8, 1-26
82. Judson, R. S.; Houck, K. A.; Kavlock, R. J.; Knudsen, T. B.; Martin, M. T.; Mortensen, H. M.; Reif, D. M.; Rotroff, A. M.; Shah, I.; Richard, A. M.; Dix, D. J. In vitro screening of environmental chemicals for targeted testing prioritization: The ToxCast project Environ. Health Perspect. 2010, 118, 485-492
83. Causton, H. C.; Ren, B.; Koh, S. S.; Harbison, C. T.; Kanin, E.; Jennings, E. G.; Lee, T. I.; True, H. L.; Lander, E. S.; Young, R. A. Remodeling of yeast genome expression in response to environmental changes Mol. Biol. Cell 2001, 12, 323-337
84. Svendsen, C.; Owen, J.; Kille, P.; Wren, J.; Jonker, M. J.; Headley, B. A.; Morgan, A. J.; Blaxter, M.; Sturzenbaum, S. R.; Hankard, P. K.; Lister, L. J.; Spurgeon, D. J. Comparative transcriptomic responses to chronic cadmium, fluoranthene, and atrazine exposure in Lumbricus rubellus Environ. Sci. Technol. 2008, 42, 4208-4214
85. Gündel, U.; Kalkhof, S.; Zitzkat, D.; von Bergen, M.; Altenburger, R.; Küster, E. Concentration-response concept in ecotoxicoproteomics: Effects of different phenanthren concentrations to the zebrafish embryonic proteome. Ecotoxicol. Environ. Saf. 2012, 76, 11 - 22.
86. Sans Piché, F.; Kluender, C.; Altenburger, R.; Schmitt-Jansen, M. Anchoring metabolic changes to phenotypic effects in the chlorophyte Scenedesmus vacuolatus under chemical exposure Mar. Environ. Res. 2010, 69, S28-30
87. Gou, N.; Gu, A. Z. A new transcriptional effect level index (TELI) for toxicogenomics-based toxicity assessment Environ. Sci. Technol. 2011, 45, 5410-5417
88. Kluender, C.; Sans-Piché, F.; Riedl, J.; Altenburger, R.; Härtig, C.; Laue, G.; Schmitt-Jansen., M. A metabolomics approach to assessing phytotoxic effects on the green alga Scenedesmus vacuolatus Metabolomics 2009, 5, 59-71
89. Broderius, S.; Kahl, M.; Hoglund, M. Use of joint toxic response to define the primary mode of toxic action for diverse industrial organic chemicals Environ. Toxicol. Chem. 1995, 14, 1591-1605
90. Rotroff, D. M.; Wetmore, B. A.; Dix, D. J.; Ferguson, S. S.; Clewell, H. J.; Houck, K. A.; LeCluyse, E. L.; Andersen, M. E.; Judson, R. S.; Smith, C. M.; Sochski, M. A.; Kavlock, R. J.; Boellmann, F.; Martin, M. T.; Reif, D. M.; Wambaugh, J. F.; Thomas, R. S. Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening Toxicol. Sci. 2010, 117, 348-358
91. Jusko, W. J.; Jin, J. Y.; DuBois, D. C.; Almon, R. R. Pharmacodynamics and pharmacogenomics of corticosteroids: microarray studies. In Advanced methods of pharmacokinetic and pharmacodynamic systems analysis; D'Argenio, D. Z., Ed.; Kluwer Academic Publ.: Norwell, MA, 2004; p 85.
92. Jager, T.; Albert, C.; Preuss, T. G.; Ashauer, R. General unified threshold model of survival - a toxicokinetic-toxicodynamic framework for ecotoxicolgy Environ. Sci. Technol. 2011, 45, 2529-2540
93. Jager, T.; Vandenbrouck, T.; Baas, J.; De Coen, W. M.; Kooijman, S. A. L. M. A biology-based approach for mixture toxicology of multiple endpoints over life cycle Ecotoxicology 2010, 19, 351-361
94. Williams, T. D.; Turan, N.; Diab, A. M.; Wu, H.; Mackenzie, C.; Bartie, K. L.; Hrydziuszko, O.; Lyons, B. P.; Stentiford, G. D.; Herbert, J. M.; Abraham, J. K.; Katsiadaki, I.; Leaver, M. J.; Taggart, J. B.; George, S. G.; Viant, M. R.; Chipman, K. J.; Falciani, F. Towards a system level understanding of non-model organisms sampled from the environment: a network biology approach. PLoS Comput. Biol. 2011, Aug., 7 (8): e1002126.
95. Judson, R. S.; Kavlock, R. J.; Setzer, R. W.; Cohen Hubal, E. A.; Martin, M. T.; Knudsen, T. B.; Houck, K. A.; Thomas, R. S.; Wetmore, B. A.; Dix, D. J. Estimating toxicity-related biological pathway alterating doses for high-throughput chemical risk assessment Chem. Res. Toxicol. 2011, 24, 451-462
96. Simmons, S. O.; Fan, C.-Y.; Ramabhadran, R. Cellular stress response pathway system as a sentinel ensemble on toxicological screening Toxicol. Sci. 2009, 111, 202-225