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Making sense of sub-lethal mixture effects

Making sense of sub-lethal mixture effects. Tjalling Jager, Tine Vandenbrouck, Jan Baas, Wim De Coen, Bas Kooijman. Challenge of mixture ecotoxicity. Some 100,000 man-made chemicals Large range of natural ‘toxicants’ For animals, 1.25 million species described Complex exposure situations.

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Making sense of sub-lethal mixture effects

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  1. Making sense of sub-lethal mixture effects Tjalling Jager, Tine Vandenbrouck, Jan Baas, Wim De Coen, Bas Kooijman

  2. Challenge of mixture ecotoxicity • Some 100,000 man-made chemicals • Large range of natural ‘toxicants’ • For animals, 1.25 million species described • Complex exposure situations

  3. Typical approach A B

  4. Typical approach

  5. Typical approach

  6. Typical approach wait for 21 days …

  7. total offspring concentration B concentration A Dose-response plot dose-ratio dependent deviation from CA

  8. What question did we answer? “What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”

  9. What question did we answer? “What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”

  10. What question did we answer? “What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”

  11. What question did we answer? “What is effect of constant exposure to this mixture on totalDaphnia reproduction after 21 days under standard OECD test conditions?”

  12. What question did we answer? “What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”

  13. What question did we answer? “What is effect of constant exposure to this mixture on total Daphniareproduction after 21 days under standard OECD test conditions?”

  14. What question did we answer? “What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”

  15. What question did we answer? “What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”

  16. What question did we answer? “What is effect of constant exposure to this mixture on Daphnia reproduction after 21 days under standard OECD test conditions?”

  17. What question did we answer? “What is effect of constant exposure to this mixture on Daphnia reproduction after 21 days under standard OECD test conditions?” Why!

  18. Better questions do we see these time patterns of effects? • can we explain the effects on all endpoints over the life cycle in one framework? • can we make useful predictions for other mixtures, other species, and other exposure situations? Why

  19. external concentration B (in time) external concentration A (in time) effects in time Process-based

  20. toxico- kinetics internal concentration A in time internal concentration B in time external concentration B (in time) external concentration A (in time) effects in time toxico- kinetics Process-based • Tolerance distribution • McCarty et al (1992) • Lee & Landrum (2006) • Stochastic death • Ashauer et al. (2007) • Baas et al. (2007, 2009) survival as a chance process

  21. feeding reproduction maturation maintenance growth Sub-lethal endpoints …

  22. feeding reproduction maturation maintenance growth Sub-lethal endpoints … Rules for mass and energy flows DEB (Kooijman, 2000/2001)

  23. toxico- kinetics internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) toxico- kinetics Process-based assimilation maintenance maturation …. growth DEB model effects on all endpoints in time theory implies interactions …

  24. internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) Process-based ?? assimilation maintenance maturation …. toxico- kinetics DEB model toxico- kinetics effects on all endpoints in time

  25. compound ‘target’ metabolic process assimilation maintenance … Simple mixture rules toxicity parameters linked (compare CA)

  26. Simple mixture rules compound ‘target’ metabolic process assimilation maintenance …

  27. Simple mixture rules compound ‘target’ metabolic process assimilation maintenance … toxicity parameters independent (compare IA)

  28. fluoranthene pyrene PAHs in Daphnia • Based on standard 21-day OECD test • 10 animals per treatment • length, reproduction and survival every 2 days • no body residues (TK inferred from effects)

  29. Same target: costs reproduction (and costs growth)

  30. Iso-effect lines for body length <50% effect

  31. Conclusions PAH mixture • Mixture effect consistent with ‘same target’ • as expected for these PAHs • explains all three endpoints, over time • Iso-effect lines are functions of time • which differ between endpoints • in this case: little deviation from CA • Few parameters for all data in time • 14 parameters (+4 Daphnia defaults) (descriptive would require >100 parameters)

  32. internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) Parameter estimates TK pars tox pars DEB pars toxico- kinetics DEB model toxico- kinetics effects on all endpoints in time

  33. internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) Educated extrapolation TK pars tox pars DEB pars toxico- kinetics DEB model toxico- kinetics effects on all endpoints in time populations

  34. internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) Educated extrapolation TK pars tox pars DEB pars toxico- kinetics other, e.g., repro rate respiration DEB model toxico- kinetics effects on all endpoints in time other endpoints

  35. internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) Educated extrapolation TK pars tox pars DEB pars toxico- kinetics DEB model toxico- kinetics effects on all endpoints in time time-varying concentrations

  36. internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) Educated extrapolation TK pars tox pars DEB pars toxico- kinetics DEB model toxico- kinetics effects on all endpoints in time food limitation

  37. internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) Educated extrapolation TK pars tox pars DEB pars toxico- kinetics DEB model toxico- kinetics effects on all endpoints in time other narcotic compounds

  38. internal concentration A in time internal concentration B in time metabolic processes in time external concentration A (in time) external concentration B (in time) Educated extrapolation TK pars tox pars DEB pars toxico- kinetics DEB model toxico- kinetics effects on all endpoints in time other (related) species

  39. Final words • A process-based approach is essential … • to progress the science of mixture toxicity • to make useful predictions for RA • Key elements DEB approach • one framework for all endpoints over time • feasible with ‘reasonable’ data sets • certain interactions are unavoidable … • Of course, more work is needed … • validate predicted interactions and extrapolations • ready to tackle more complex mixtures!

  40. Advertisement Vacancies • PhD student, Marie Curie training network (CREAM) Courses • International DEB Tele Course 2011 Symposia • 2nd International DEB Symposium 2011 in Lisbon More information: http://www.bio.vu.nl/thb

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