Chemical (and other) stress in DEB2: toxicokinetics

Tjalling Jager

Dept. Theoretical Biology

Contents

Toxicokinetics The one-compartment model and diffusion Effects of composition and reproduction

Complications: toxicants in soil and feeding

externalconcentration

(in time)

toxico-kineticmodel

toxico-kineticmodel

“Biology-based” modelling

internalconcentration

in time

process modelfor the organism

process modelfor the organism

effects onendpoints

in timetoxicokinetics

toxicodynamics

externalconcentration

(in time)

toxico-kineticmodel

toxico-kineticmodel

“Biology-based” modelling

internalconcentration

in time

toxicokinetics

Toxicokinetic modelling Quite popular in

(eco)toxicology and pharmacology

Models differ in complexity

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

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

Start from diffusion

Let the cube grow …• without changing the shape• leads to dilution and change in surface:volume ratio

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 …

One-compartment model

Model is a classic, and often fits well …

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

co

nce

ntr

atio

n

external

scaled internal

time

Adding some realism

Organisms may grow ...• dilution of concentration• change of surface:volume ratio

externalconcentration

(in time)

toxico-kineticmodel

toxico-kineticmodel

“Biology-based” modelling

internalconcentration

in time

process modelfor the organism

effects onendpoints

in time

body sizegrowth

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

More realism

eggseggsbufferbufferstructurestructure

reservereserve

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

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

eggseggsbufferbufferstructurestructure

reservereserve

water

More realism

eggseggsbufferbufferstructurestructure

reservereserve

water

Reproduction buffer

Assumptions• chemical follows reserves associated with eggs• rest remains in buffer

bufferbuffer eggseggs

overheadoverhead

remainderremainderreservereservechemicalchemical

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Reproduction buffer

Assumptions• chemical follows reserves associated with eggs• rest remains in buffer

bufferbuffer eggseggs

overheadoverhead

remainderremainder

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What happens in an egg?

During the embryonic phase …• mass is lost so concentration increases

• if PEV > 1, conversion reserve to structure increases concentration structure even more

• how does egg exchange toxicants with surroundings?

reservereserve

structurestructure

reservereserve

structurestructure

overheadsmaintenancewater

??

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

externalconcentration

(in time)

toxico-kineticmodel

toxico-kineticmodel

“Biology-based” modelling

internalconcentration

in time

process modelfor the organism

effects onendpoints

in time

body sizegrowth

reservesreproduction ratebuffer handling

(and toxicant effects on them)

externalconcentration

(in time)

toxico-kineticmodel

toxico-kineticmodel

“Biology-based” modelling

internalconcentration

in time

process modelfor the organism

effects onendpoints

in time

More extensions?

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

Summarising

TK models range from simple to complex• simplest is scaled one-compartment model with constant

composition (1 parameter: ke)

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 …