1. Chemical (and other) stress in DEB 2: toxicokinetics Tjalling Jager Dept. Theoretical Biology TexPoint fonts used in EMF. Read the TexPoint manual before you delete this box.: AAAAA A A A A

2. Contents Toxicokinetics  The one-compartment model and diffusion  Effects of composition and reproduction  Complications: toxicants in soil and feeding

3. external concentration (in time) toxico-kinetic model toxico-kinetic model “Biology-based” modelling internal concentration in time process model for the organism process model for the organism effects on endpoints in time toxicokinetics toxicodynamics

4. external concentration (in time) toxico-kinetic model toxico-kinetic model “Biology-based” modelling internal concentration in time toxicokinetics Toxicokinetic modelling  Quite popular in (eco)toxicology and pharmacology  Models differ in complexity

5. Start from diffusion Let’s assume … well-mixed homogeneous cube with water, in a solution cube has a semi-permeable membrane exchange proportional to area and concentration difference

6. Start from diffusion Let’s change the cube … the same cube, now filled with oil... correct one concentration with partition coefficient between oil and water

7. Start from diffusion Let the cube grow … without changing the shape leads to dilution and change in surface:volume ratio

8. Diffusion in organisms Let’s move to an organism … can we talk about internal ‘concentration’? can we assume it is ‘well-mixed’? what is the surface area for exchange? when size and composition is constant …

9. One-compartment model  Model is a classic, and often fits well …

10. Scaled concentration Problem often, internal concentrations are not measured … or not relevant for effects  Effects data contain information... effects over time provides info on build up of body residue but, no information about absolute levels concentration external scaled internal time

11. Adding some realism Organisms may grow... dilution of concentration change of surface:volume ratio

12. external concentration (in time) toxico-kinetic model toxico-kinetic model “Biology-based” modelling internal concentration in time process model for the organism effects on endpoints in time body size growth

13. Active uptake  Uptake/elimination of chemicals may be active ions such as metals, nutrients chemicals may be metabolised, or bound  No difference as long as: uptake flux  external concentration elimination flux  internal concentration  But... active processes can saturate possible link to metabolic processes

14. More realism eggs buffer structure reserve water Body composition may change reserve density changes with food level and toxicants females build up a reproduction buffer Females may reproduce chemicals can be transferred to eggs

15. More realism Assumptions distribution chemical over internal compartments is fast reserve, buffer and egg have same composition only structure exchanges with environment chemicals from buffer are transferred to egg eggs buffer structure reserve water

16. More realism eggs buffer structure reserve water

17. Reproduction buffer Assumptions chemical follows reserves associated with eggs rest remains in buffer buffer eggs overhead remainder reserve chemical

18. Simulations

22. Reproduction buffer Assumptions chemical follows reserves associated with eggs rest remains in buffer buffer eggs overhead remainder

23. Simulations

26. What happens in an egg? During the embryonic phase … mass is lost so concentration increases if P EV > 1, conversion reserve to structure increases concentration structure even more how does egg exchange toxicants with surroundings? reserve structure reserve structure overheads maintenance water ??

27. Assumptions realistic? Difficult to say...  Most test setups avoid growth, reproduction and changes in feeding status...  Some support: Russell et al 1999: lipid-normalised concentrations in fish and eggs are similar Daley et al 2009: fish eggs increase in fugacity of PCBs over incubation  This extension takes the DEB assumptions to their logical consequences with a minimum of additional parameters

28. external concentration (in time) toxico-kinetic model toxico-kinetic model “Biology-based” modelling internal concentration in time process model for the organism effects on endpoints in time body size growth reserves reproduction rate buffer handling (and toxicant effects on them)

29. external concentration (in time) toxico-kinetic model toxico-kinetic model “Biology-based” modelling internal concentration in time process model for the organism effects on endpoints in time

30. More extensions? Plenty of options to make it more complex … uptake from food/inhalation saturating uptake or elimination biotransformation more compartments (as in PBPK)...

31. Summarising  TK models range from simple to complex simplest is scaled one-compartment model with constant composition (1 parameter: k e )  DEB offers logical links to include effects of growth, reserve and reproduction one-compartment model with varying parameters TK becomes closely integrated with the DEB organism toxicants can affect their own TK …