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From molecules to populations On the causality of toxic effects

From molecules to populations On the causality of toxic effects. Tjalling Jager, Bas Kooijman Dept. Theoretical Biology. effects on individual/population. toxicant. Causality. How to link toxicant concentrations to whole-organism and population effects?. NOEC/EC x. molecular.

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From molecules to populations On the causality of toxic effects

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  1. From molecules to populationsOn the causality of toxic effects Tjalling Jager, Bas Kooijman Dept. Theoretical Biology

  2. effects on individual/population toxicant Causality How to link toxicant concentrations to whole-organism and population effects? NOEC/ECx molecular energy budgets Why interesting? • to support chemical risk assessment • to justify research (‘so what’ question)

  3. Precondition 1 Any concept for causality chain should explicitly consider exposure time • Toxicity is a process in time • uptake into organism takes time • biomarker responses can/will change in time • NOEC/ECx values can/will change in time

  4. carbendazim pentachlorobenzene time time EC10 in time Alda Álvarez et al. (2006) body length survival body length cumul. repro cumul. repro

  5. Precondition 2 Causality chain should cover all life-history aspects • Feeding, development, growth and reproduction are linked … • NOEC/ECx differ between endpoints • what about molecular mechanism of action?

  6. A. nanus C. elegans body size body size EC10 reproduction reproduction time time ‘Narcotic’ effects

  7. effects on individual/population Causality of effects toxicant statistics e.g., NOEC/ECx

  8. toxicant target site effects on individual/population molecular mechanism physiological mechanism Causality of effects rest of the organism ENERGY BUDGET

  9. Energy budgets

  10. assimilation reproduction maintenance growth Energy budgets Each ‘MoA’ has specific effects on life cycle (direct/indirect)

  11. Population consequences

  12. Population consequences

  13. assimilation reproduction maintenance growth Population consequences Each ‘MoA’ has specific effects for populations

  14. Biology-based (DEBtox) toxicokinetics external concentration energy-budget parameter assimilation reproduction DEB model maintenance growth Life-cycle effects Kooijman & Bedaux, 1996 (Wat. Res.)

  15. Experiments nematodes Species • Caenorhabditis elegans and Acrobeloides nanus Chemicals • cadmium, pentachlorobenzene and carbendazim Exposure • in agar Endpoints • survival, body size, reproduction over full life cycle • analysed with extended DEBtox Studies published as: Alda Álvarez et al., 2005 (Func. Ecol.), 2006 (ES&T), 2006 (ET&C)

  16. C. elegans and cadmium length eggs Mode of action: assimilation length survival Alda Álvarez et al. (2005) time (days)

  17. A. nanus and cadmium Mode of action: costs for growth Alda Álvarez et al. (2006)

  18. Physiological MoA

  19. Physiological MoA

  20. Physiological MoA

  21. Physiological MoA

  22. Extrapolate to populations • In a constant environment, a population will grow exponentially … • ‘Intrinsic rate of increase’ • calculate from reproduction and survival in time

  23. 1 0.4 0.4 0.4 0.8 0.3 0.3 0.3 0.6 intrinsic rate (d-1) 95% 0.2 0.2 0.2 0.4 90% 0.2 0.1 0.1 0.1 90% 95% 0 0 0 0 0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 0 2 4 6 8 10 12 concentration (mg/L) concentration (mg/L) Extrapolate to populations Mode of action: costs for growth Mode of action: assimilation Cadmium

  24. Pulsed exposure Pieters et al. (2006)

  25. Conclusions Simple summary statistics are useless … • NOEC/ECx change in time and differ between endpoints Molecular mechanism is important, but … • not enough to explain effects on life cycle/population Energy budgets must be considered • ‘physiological MoA’ covers direct and indirect effects • direct link to life-history and population effects Species differ in phys. MoA for the same toxicant

  26. toxicant target site toxicant target site maintenance maintenance reproduction reproduction … … Species differences? Species A Species B

  27. toxicant target site phys. process maintenance effect on life cycle/population reproduction … Outlook Collaboration with CEH Monks Wood • life-cycle experiments with C. elegans • data analysis with DEBtox • microarray work on same animals ?

  28. toxicant target site phys. process maintenance effect on life cycle/population reproduction … Outlook Why useful? • number of chemicals and species is very large … • but number of target sites and processes is limited! ? www.bio.vu.nl/thb Once we know the normal biological processes, all external stressors are merely perturbations of these processes (Yang et al., 2004)

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