Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Ashauer, Roman; O'Connor, Isabel; Hintermeister, Anita; Escher, Beate I. (2015)
Languages: English
Types: Article
Subjects: 1600, 2304
Why do some individuals survive after exposure to chemicals while others die? Either, the tolerance threshold is distributed among the individuals in a population, and its exceedance leads to certain death, or all individuals share the same threshold above which death occurs stochastically. The previously published General Unified Threshold model of Survival (GUTS) established a mathematical relationship between the two assumptions. According to this model stochastic death would result in systematically faster compensation and damage repair mechanisms than individual tolerance. Thus, we face a circular conclusion dilemma because inference about the death mechanism is inherently linked to the speed of damage recovery. We provide empirical evidence that the stochastic death model consistently infers much faster toxicodynamic recovery than the individual tolerance model. Survival data can be explained by either, slower damage recovery and a wider individual tolerance distribution, or faster damage recovery paired with a narrow tolerance distribution. The toxicodynamic model parameters exhibited meaningful patterns in chemical space, which is why we suggest toxicodynamic model parameters as novel phenotypic anchors for in vitro to in vivo toxicity extrapolation. GUTS appears to be a promising refinement of traditional survival curve analysis and dose response models.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • (1) Berkson, J. Why I prefer logits to probits. Biometrics 1951, 7 (4), 327−339.
    • (2) Newman, M. C.; McCloskey, J. T. The individual tolerance concept is not the sole explanation for the probit dose-effect model.
    • Environ. Toxicol. Chem. 2000, 19 (2), 520−526.
    • (3) Jager, T.; Albert, C.; Preuss, T. G.; Ashauer, R. General Unified Threshold Model of Survival - a Toxicokinetic-Toxicodynamic Framework for Ecotoxicology. Environ. Sci. Technol. 2011, 45 (7), 2529−2540.
    • (4) Sprague, J. B. Measurement of pollutant toxicity to fish.I. Bioassay methods for acute toxicity. Water Res. 1969, 3 (11), 793−821.
    • (5) Ashauer, R.; Boxall, A. B. A.; Brown, C. D. Simulating toxicity of carbaryl to Gammarus pulex after sequential pulsed exposure. Environ.
    • Sci. Technol. 2007, 41 (15), 5528−5534.
    • (6) Jager, T.; Kooijman, S. A. L. M. A biology-based approach for quantitative structure-activity relationships (QSARs) in ecotoxicity.
    • Ecotoxicology 2009, 18 (2), 187−196.
    • (7) Ashauer, R.; Hintermeister, A.; O'Connor, I.; Elumelu, M.; Hollender, J.; Escher, B. I. Significance of Xenobiotic Metabolism for Bioaccumulation Kinetics of Organic Chemicals in Gammarus pulex.
    • Environ. Sci. Technol. 2012, 46 (6), 3498−3508.
    • (8) Nyman, A.-M.; Schirmer, K.; Ashauer, R. Toxicokinetictoxicodynamic modelling of survival of Gammarus pulex in multiple pulse exposures to propiconazole: model assumptions, calibration data requirements and predictive power. Ecotoxicology 2012, 21 (7), 1828− 1840.
    • (9) Ashauer, R.; Hintermeister, A.; Caravatti, I.; Kretschmann, A.; Escher, B. I. Toxicokinetic-toxicodynamic modeling explains carry-over toxicity from exposure to diazinon by slow organism recovery. Environ.
    • Sci. Technol. 2010, 44 (10), 3963−3971.
    • (10) Naylor, C.; Maltby, L.; Calow, P. Scope for growth in Gammarus pulex, a fresh-water benthic detritivore. Hydrobiologia 1989, 188−189 (1), 517−523.
    • (11) Ashauer, R.; Hintermeister, A.; Potthoff, E.; Escher, B. I. Acute toxicity of organic chemicals to Gammarus pulex correlates with sensitivity of Daphnia magna across most modes of action. Aquat.
    • Toxicol. 2011, 103, 38−45.
    • (12) Ashauer, R.; Boxall, A. B. A.; Brown, C. D. New ecotoxicological model to simulate survival of aquatic invertebrates after exposure to fluctuating and sequential pulses of pesticides. Environ. Sci. Technol.
    • (13) Pinder, J. E.; Wiener, J. G.; Smith, M. H. WEIBULL DISTRIBUTION - NEW METHOD OF SUMMARIZING SURVIVORSHIP DATA. Ecology 1978, 59 (1), 175−179.
    • (14) Albert, C.; Ashauer, R.; Künsch, H. R.; Reichert, P. Bayesian Experimental Design for a Toxicokinetic-Toxicodynamic Model. J.
    • Stat. Plann. Inference 2012, 142, 263−275.
    • (15) Ashauer, R.; Brown, C. D. Toxicodynamic assumptions in ecotoxicological hazard models. Environ. Toxicol. Chem. 2008, 27 (8), 1817−1821.
    • (16) Matida, Y. A kinetic analysis of the toxicity curve. Bull.
    • Freshwater Fish. Res. Lab. 1960, 9 (2), 1−12.
    • (17) Zitko, V. An equation of lethality curves in tests with aquatic fauna. Chemosphere 1979, 8, 47−51.
    • (18) Kooijman, S. A. L. M. Parametric analysis of mortality rates in bioassays. Water Res. 1981, 15, 107−119.
    • (19) Mackay, D.; Puig, H.; McCarty, L. S. An Equation Describing the Time Course and Variability in Uptake and Toxicity of Narcotic Chemicals to Fish. Environ. Toxicol. Chem. 1992, 11 (7), 941−951.
    • (20) Legierse, K. C. H. M.; Verhaar, H. J. M.; Vaes, W. H. J.; De Bruijn, J. H. M.; Hermens, J. L. M. Analysis of the time-dependent acute aquatic toxicity of organophosphorus pesticides: The critical target occupation model. Environ. Sci. Technol. 1999, 33 (6), 917−925.
    • (21) Lee, J. H.; Landrum, P. F.; Koh, C. H. Prediction of timedependent PAH toxicity in Hyalella azteca using a damage assessment model. Environ. Sci. Technol. 2002, 36 (14), 3131−3138.
    • (22) Kooijman, S. A. L. M.; Bedaux, J. J. M. Analysis of toxicity tests on Daphnia survival and reproduction. Water Res. 1996, 30 (7), 1711− 1723.
    • (23) Ashauer, R.; Boxall, A.; Brown, C. Uptake and elimination of chlorpyrifos and pentachlorophenol into the freshwater amphipod Gammarus pulex. Arch. Environ. Contam. Toxicol. 2006, 51 (4), 542− 548.
    • (24) Ashauer, R.; Escher, B. I. Advantages of toxicokinetic and toxicodynamic modelling in aquatic ecotoxicology and risk assessment.
    • J. Environ. Monit. 2010, 12 (11), 2056−2061.
    • (25) Ashauer, R.; Boxall, A. B. A.; Brown, C. D. Modeling combined effects of pulsed exposure to carbaryl and chlorpyrifos on Gammarus pulex. Environ. Sci. Technol. 2007, 41 (15), 5535−5541.
    • (26) Escher, B. I.; Hermens, J. L. M. Internal exposure: Linking bioavailability to effects. Environ. Sci. Technol. 2004, 38 (23), 455A462A.
    • (27) Altenburger, R.; Scholz, S.; Schmitt-Jansen, M.; Busch, W.; Escher, B. I. Mixture Toxicity Revisited from a Toxicogenomic Perspective. Environ. Sci. Technol. 2012, 46 (5), 2508−2522.
    • (28) Nyman, A.-M.; Schirmer, K.; Ashauer, R. Importance of Toxicokinetics for Interspecies Variation in Sensitivity to Chemicals.
    • Environ. Sci. Technol. 2014, 48 (10), 5946−5954.
    • (29) 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 (20), 4201−4217.
    • (30) McCarty, L. S.; Mackay, D. Enhancing Ecotoxicological Modeling and Assessment. Environ. Sci. Technol. 1993, 27 (9), 1719−1728.
    • (31) Escher, B. I.; Schwarzenbach, R. P. Mechanistic studies on baseline toxicity and uncoupling of organic compounds as a basis for modeling effective membrane concentrations in aquatic organisms.
    • Aquat. Sci. 2002, 64 (1), 20−35.
    • (32) van Wezel, A. P.; Opperhuizen, A. Narcosis due to environmental pollutants in aquatic organisms: residue-based toxicity, mechanisms, and membrane burdens. Crit. Rev. Toxicol. 1995, 25, 255−279.
    • (33) Vaes, W. H. J.; Ramos, E. U.; Verhaar, H. J. M.; Hermens, J. L.
    • M. Acute toxicity of nonpolar versus polar narcosis: Is there a difference? Environ. Toxicol. Chem. 1998, 17 (7), 1380−1384.
    • (34) Verhaar, H. J. M.; Ramos, E. U.; Hermens, J. L. M. Classifying environmental pollutants 0.2. Separation of class 1 (baseline toxicity) and class 2 ('polar narcosis') type compounds based on chemical descriptors. J. Chemom. 1996, 10 (2), 149−162.
    • (35) Maeder, V.; Escher, B. I.; Scheringer, M.; Hungerbühler, K.
    • Technol. 2004, 38 (13), 3659−3666.
    • (36) Ankley, G.; Bennet, R. S.; Erickson, R. J.; Hoff, D. J.; Hornung, M. W.; Johnson, R. D.; Mount, D. R.; Nichols, 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. 2010, 29 (3), 730−741.
    • (37) Ashauer, R.; Thorbek, P.; Warinton, J. S.; Wheeler, J. R.; Maund, S. A method to predict and understand fish survival under dynamic chemical stress using standard ecotoxicity data. Environ. Toxicol. Chem.
    • (38) Tanaka, Y.; Mano, H.; Tatsuta, H. Genetic variance of tolerance and the toxicant threshold model. Environ. Toxicol. Chem. 2012, 31 (4), 813−818.
    • (39) Gerritsen, A.; van der Hoeven, N.; Pielaat, A. The acute toxicity of selected alkylphenols to young and adult Daphnia magna. Ecotoxicol.
    • Environ. Saf. 1998, 39 (3), 227−232.
    • (40) Hendriks, A. J.; Traas, T. P.; Huijbregts, M. A. J. Critical body residues linked to octanol-water partitioning, organism composition, and LC50 QSARs: Meta-analysis and model. Environ. Sci. Technol.
    • (41) Zhao, Y. A.; Newman, M. C. Shortcomings of the laboratoryderived median lethal concentration for predicting mortality in field populations: Exposure duration and latent mortality. Environ. Toxicol.
    • Chem. 2004, 23 (9), 2147−2153.
    • (42) Zhao, Y.; Newman, M. C. Effects of exposure duration and recovery time during pulsed exposures. Environ. Toxicol. Chem. 2006, 25 (5), 1298−1304.
    • (43) Zhao, Y.; Newman, M. C. The theory underlying dose-response models influences predictions for intermittent exposures. Environ.
    • Toxicol. Chem. 2007, 26 (3), 543−547.
    • (44) Groh, K. J.; Carvalho, R. N.; Chipman, J. K.; Denslow, N. D.; Halder, M.; Murphy, C. A.; Roelofs, D.; Rolaki, A.; Schirmer, K.; Watanabe, K. H. Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology. Chemosphere 2015, 120 (0), 764−777.
    • (45) Teh, S. J.; Zhang, G. H.; Kimball, T.; Teh, F. C. Lethal and sublethal effects of esfenvalerate and diazinon on splittail larvae.
    • American Fisheries Society Symposium 2004, 2004 (39), 243−253.
    • (46) Verhaar, H. J. M.; De Wolf, W.; Dyer, S.; Legierse, K. C. H. M.; Seinen, W.; Hermens, J. L. M. An LC50 vs time model for the aquatic toxicity of reactive and receptor-mediated compounds. Consequences for bioconcentration kinetics and risk assessment. Environ. Sci. Technol.
    • (47) Baas, J.; Jager, T.; Kooijman, B. Understanding toxicity as processes in time. Sci. Total Environ. 2010, 408 (18), 3735−3739.
    • (48) Newman, M. C.; McCloskey, J. T. Time-to-event analyses of ecotoxicity data. Ecotoxicology 1996, 5, 187−196.
    • (49) Meyer, J. S.; Gulley, D. D.; Goodrich, M. S.; Szmania, D. C.; Brooks, A. S. Modeling toxicity due to intermittent exposure of Rainbow-Trout and commen Shiners to Monochloramine. Environ.
    • Toxicol. Chem. 1995, 14 (1), 165−175.
    • (50) Ashauer, R.; Brown, C. D. Highly time-variable exposure to chemicals − towards an assessment strategy. Integr. Environ. Assess.
    • Manage. 2013, 9 (3), 27−33.
    • (51) Jager, T.; Heugens, E. H. W.; Kooijman, S. A. L. M. Making sense of ecotoxicological test results: Towards application of processbased models. Ecotoxicology 2006, 15 (3), 305−314.
    • (52) Jager, T. Making Sense of Chemical Stress, Amsterdam, 2013; p 115, http://www.debtox.info/book.php.
    • (53) Bliss, C. I. The method of probits. Science 1934, 79 (2037), 38− 39.
    • (54) Rozman, K. K.; Doull, J. Dose and time as variables of toxicity.
    • Toxicology 2000, 144 (1−3), 169−178.
    • (55) Doull, J.; Rozman, K. K. Using Haber's Law to define the margin of exposure. Toxicology 2000, 149 (1), 1−2.
    • (56) Handy, R. D. Intermittent Exposure to Aquatic Pollutants - Assessment, Toxicity and Sublethal Responses in Fish and Invertebrates. Comp. Biochem. Physiol., Part C: Pharmacol., Toxicol.
    • Endocrinol. 1994, 107 (2), 171−184.
    • (57) Miller, F. J.; Schlosser, P. M.; Janszen, D. B. Haber's rule: a special case in a family of curves relating concentration and duration of exposure to a fixed level of response for a given endpoint. Toxicology 2000, 149 (1), 21−34.
    • (58) Tenberge, W. F.; Zwart, A.; Appelman, L. M. Concentrationtime-mortality response relationship of irritant and systemically acting vapors and gases. J. Hazard. Mater. 1986, 13 (3), 301−309.
    • (59) Peterson, J. L.; Jepson, P. C.; Jenkins, J. J. Effect of varying pesticide exposure duration and concentration on the toxicity of carbaryl to two field-collected stream invertebrates, Calineuria californica (Plecoptera: Perlidae) and Cinygma sp (Ephemeroptera: Heptageniidae). Environ. Toxicol. Chem. 2001, 20 (10), 2215−2223.
    • (60) Detra, R. L.; Collins, W. J. The Relationship of Parathion Concentration, Exposure Time, Cholinesterase Inhibition and Symptoms of Toxicity in Midge Larvae (Chironomidae, Diptera).
    • Environ. Toxicol. Chem. 1991, 10 (8), 1089−1095.
    • (61) Hendriks, A. J. How To Deal with 100,000+ Substances, Sites, and Species: Overarching Principles in Environmental Risk Assessment. Environ. Sci. Technol. 2013, 47 (8), 3546−3547.
    • (62) Hickie, B. E.; McCarty, L. S.; Dixon, D. G. A residue basedtoxicokinetic model for pulse-exposure toxicity in aquatic system.
    • Environ. Toxicol. Chem. 1995, 14 (12), 2187−2197.
    • (63) Ashauer, R.; Wittmer, I.; Stamm, C.; Escher, B. I. Environmental Risk Assessment of Fluctuating Diazinon Concentrations in an Urban and Agricultural Catchment Using Toxicokinetic-Toxicodynamic Modeling. Environ. Sci. Technol. 2011, 45 (22), 9783−9792.
    • (64) 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 (2), 351−361.
    • (65) Jager, T.; Gudmundsdot́tir, E. M.; Cedergreen, N. Dynamic modeling of sublethal mixture toxicity in the nematode Caenorhabditis elegans. Environ. Sci. Technol. 2014, 48 (12), 7026−7033.
    • (66) Kulkarni, D.; Daniels, B.; Preuss, T. G. Life-stage-dependent sensitivity of the cyclopoid copepod Mesocyclops leuckarti to triphenyltin. Chemosphere 2013, 92 (9), 1145−1153.
    • (67) Beaudouin, R.; Zeman, F. A.; Peŕy, A. R. R. Individual sensitivity distribution evaluation from survival data using a mechanistic model: Implications for ecotoxicological risk assessment. Chemosphere 2012, 89 (1), 83−88.
    • (68) Jager, T.; Hansen, B. H. Linking survival and biomarker responses over time. Environ. Toxicol. Chem. 2013, 32 (8), 1842−1845.
    • (69) Gergs, A.; Jager, T. Body size-mediated starvation resistance in an insect predator. J. Anim. Ecol. 2014, 83 (4), 758−768.
    • (70) Nyman, A.-M.; Hintermeister, A.; Schirmer, K.; Ashauer, R. The Insecticide Imidacloprid Causes Mortality of the Freshwater Amphipod Gammarus pulex by Interfering with Feeding Behavior.
    • PLoS One 2013, 8 (5), e62472.
    • (71) Rockström, J.; Steffen, W.; Noone, K.; Persson, A.; Chapin Iii, F.
    • S.; Lambin, E.; Lenton, T. M.; Scheffer, M.; Folke, C.; Schellnhuber, H. J.; Nykvist, B.; de Wit, C. A.; Hughes, T.; van der Leeuw, S.; Rodhe, H.; Sörlin, S.; Snyder, P. K.; Costanza, R.; Svedin, U.; Falkenmark, M.; Karlberg, L.; Corell, R. W.; Fabry, V. J.; Hansen, J.; Walker, B.; Liverman, D.; Richardson, K.; Crutzen, P.; Foley, J., Planetary boundaries: Exploring the safe operating space for humanity. Nature 2009, 14, (2).47210.1038/461472a (72) Vörösmarty, C. J.; McIntyre, P. B.; Gessner, M. O.; Dudgeon, D.; Prusevich, A.; Green, P.; Glidden, S.; Bunn, S. E.; Sullivan, C. A.; Liermann, C. R.; Davies, P. M. Global threats to human water security and river biodiversity. Nature 2010, 468 (7321), 334−334.
    • (73) Hendriks, A. J.; van der Linde, A.; Cornelissen, G.; Sijm, D. T.
    • H. M. The power of size. 1. Rate constants and equilibrium ratios for accumulation of organic substances related to octanol-water partition ratio and species weight. Environ. Toxicol. Chem. 2001, 20 (7), 1399− 1420.
    • (74) Arnot, J. A.; Meylan, W.; Tunkel, J.; Howard, P. H.; Mackay, D.; Bonnell, M.; Boethling, R. S. A quantitative structure-activity relationship for predicting metabolic biotransformation rates for organic chemicals in fish. Environ. Toxicol. Chem. 2009, 28 (6), 1168−1177.
    • (75) Cairns, J. Paradigms flossed - The coming of age of environmental toxicology. Environ. Toxicol. Chem. 1992, 11 (3), 285−287.
  • Inferred research data

    The results below are discovered through our pilot algorithms. Let us know how we are doing!

    Title Trust
  • Discovered through pilot similarity algorithms. Send us your feedback.

Share - Bookmark

Cite this article