1. molecular vs. physiological mode of action for sub-lethal effects Tjalling Jager, Bas Kooijman Olga Alda Álvarez, Jan Kammenga

2. ‘Classic’ mode of action …  Based on molecular target, e.g.: narcosis (cell membranes) uncoupling (mitochondria) AChE inhibition target sitetoxicant Questions  Predictive for life-cycle and population?  To what extent species-specific? Questions  Predictive for life-cycle and population?  To what extent species-specific?  Popular for predicting acute LC50

3. sub-lethal QSARs? ECx log descriptor log concentration

4. What is sub-lethal ‘toxicity’?  ECx is a poor measure of ‘the toxicity’  Species respond differently to PeCB  ECx is a poor measure of ‘the toxicity’  Species respond differently to PeCB EC10 time body size reproduction A. nanus C. elegans

5. What causes effects? effect on life cycle/population ENERGY BUDGET toxicodynamicstoxicokinetics rest of the organismtarget sitetoxicant molecular MoA physiological MoA

6. Energy budgets

7. growth reproductionassimilation Each phys. MoA has specific effects on life cycle maintenance

8. Population consequences

10. growth reproduction maintenance assimilation Each phys. MoA has specific effects for populations

11. 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)

12. reproduction DEB model Biology-based (DEBtox) target parameter toxicokinetics growth maintenance assimilation Life-cycle effects Kooijman & Bedaux, 1996 (Wat. Res.)

13. PeCB in A. nanus Effects on assimilation A. nanus

14. PeCB in C. elegans Costs for growth and reproduction C. elegans

15. Physiological MoA nematodes C. elegansA. nanus PeCB (narcotic) Cadmium (heavy metal) Carbendazim (inhibits mitosis)

16. Physiological MoA nematodes C. elegansA. nanus PeCB (narcotic) costs for growth and reproduction assimilation Cadmium (heavy metal) Carbendazim (inhibits mitosis)

17. Physiological MoA nematodes C. elegansA. nanus PeCB (narcotic) costs for growth and reproduction assimilation Cadmium (heavy metal) assimilationcosts for growth (+ ageing) Carbendazim (inhibits mitosis)

18. Physiological MoA nematodes C. elegansA. nanus PeCB (narcotic) costs for growth and reproduction assimilation Cadmium (heavy metal) assimilationcosts for growth (+ ageing) Carbendazim (inhibits mitosis) assimilation (- ageing)

19. Conclusions ‘Molecular’ MoA is important, but … not enough to predict effects life cycle/population does not consider toxicodynamics ‘Physiological’ MoA gives extra information includes toxicodynamics direct link to population effects Clearly, species differ in phys. MoA …

20. Species differences? Species ASpecies B target sitetoxicanttarget sitetoxicant maintenance reproduction … maintenance reproduction …

21. target sitetoxicantphys. process effect on life cycle/population maintenance 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)