1. Dose Extrapolation Models
Fish Physiologically Based Toxicokinetic Models

2. Acknowledgements Gill sub-model pivotal to PBTK for fish
James McKim
Russell Erickson
John Nichols
Melvin Andersen
Michael Gargas
Harvey Clewell III
Alex Hoffman
Doug Kuehl
Correne Jenson
Sharon Bertelsen
Partrick Fitzsimmons
Frank Whiteman
Gill sub-model pivotal to PBTK for fish
1st PBTK model about 1990

3. Jim’s Question:
“Can fish PBTK models be used to accurately predict uptake, disposition, and elimination of organic chemicals, across routes of uptake and across species? ”

4. Rainbow trout
Channel Catfish
Lake Trout
Brook Trout
Fathead Minnow
Japanese Medaka

5. Started with gill exchange

6. Lake trout – note lower oxygen consumption
-lower cardiac output
Greater fat volume
Lower B/W partition coefficient

7. Tetra – Penta – Hexa-chloroethane TCE = 2.6 PCE = 3.6 HCE = 4.6 21C
Concentration of three chlorinated ethanes in arterial blood of channel catfish
Tetra – Penta – Hexa-chloroethane
TCE = 2.6
PCE = 3.6
HCE = 4.6
21C

8. Concentration of three chlorinated ethanes in arterial blood of rainbow trout

9. Concentration of three chlorinated ethanes in liver of lake trout
Confidence interval for simulation
13 individual simulations
SE of the Mean

10. Gill uptake in small fish

11. FHM ~150mg

12. Bioconcentration model for small fish

13. TCB logP = 6.0
FHM B/W =
Med B/W =

14. A = functional gill area – Randall 36% at rest 70% active
Rate constants (L/h) used to predict branchial and cutaneous uptake of TCB
Subscript
A = functional gill area – Randall
36% at rest
70% active
B= total gill area

15. Observed and predicted clearance of TCB by Fathead Minnow
Upper limit = total gill area
Lower limit = functional

16. Red = diffusion in skin
Green = blood from skin

17. Red – exchange capacity of water to gill
Blue – diffusion in gill
Green – blood from gill

18. Skin exchange as percent of total vs logP

19. Saarikoski 1986
80 mg guppies

20. PBTK model for small fish
Carcass – poorly perfused
Viscera – richly perfused
Balance perfusion – affinity for chemical – shear volume

22. Blood binding determining factor

24. Large fish skin model
Same three compounds

25. RBT 1-2%
Catfish 3-4%

27. Concentration of TCB in contents of stomach ( ) upper intestine ( ) and lower intestine ( )

28. Conclusions:
PBTK models can be used to accurately predict uptake, elimination, and disposition of organic chemicals in fish.
PBTK models can be used to accurately predict dose in fish via branchial, cutaneous and gut uptake.
PBTK models can be used to accurately extrapolate dose across fish species.