molecular vs. physiological mode of action for sub-lethal effects

molecular vs. physiological mode of action

for sub-lethal effects

Tjalling Jager, Bas Kooijman

Olga Alda Álvarez, Jan Kammenga

‘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

sub-lethal QSARs?

ECx

log descriptor

log

co

nce

ntr

atio

n

Cl

Cl

Cl Cl

Cl

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

EC

10

time time

body sizebody size

reproduction reproduction

A. nanus

C. elegans

Cl

Cl

Cl Cl

Cl

What causes effects?

effect onlife cycle/population

ENERGYBUDGET

toxicodynamicstoxicokinetics

rest of the organismtarget sitetoxicant

molecular MoA

physiological MoA

Energy budgets

Energy budgets

growth

reproduction

assimilation

Each phys. MoA has

specific effects on life cycle

Each phys. MoA has

specific effects on life cycle

maintenance

Population consequences

Population consequences

Population consequences

growth

reproduction

maintenance

assimilation

Each phys. MoA has

specific effects for populations

Each phys. MoA has

specific effects for populations

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)

reproduction

DEB model

Biology-based (DEBtox)

targetparameter

toxicokinetics

growthmaintenance

assimilation

Life-cycle effectsKooijman & Bedaux, 1996 (Wat. Res.)

PeCB in A. nanus

0 5 10 15 20 25 3015

20

25

30

35

40

45

50

55

60

65

time (days)

bo

dy

len

gth

020406080

0 5 10 15 20 25 30 35 400

50

100

150

200

250

300

350

400

450

time (days)

cum

ula

tive

off

sp

rin

g

020406080

Effects on assimilation

A. nanus

PeCB in C. elegans

0 2 4 6 8 10 120

20

40

60

80

100

120

140

time (days)

bo

dy

len

gth

0507090110130

0 2 4 6 8 10 12 14 160

50

100

150

200

250

300

350

400

450

500

time (days)

cum

ula

tive

off

sp

rin

g

0507090110130

Costs for growth and reproduction

C. elegans

Physiological MoA nematodes

C. elegans A. nanus

PeCB(narcotic)

Cadmium(heavy metal)

Carbendazim(inhibits mitosis)

Physiological MoA nematodes

C. elegans A. nanus

PeCB(narcotic)

costs for growth and reproduction

assimilation

Cadmium(heavy metal)

Carbendazim(inhibits mitosis)

Physiological MoA nematodes

C. elegans A. nanus

PeCB(narcotic)

costs for growth and reproduction

assimilation

Cadmium(heavy metal)

assimilation costs for growth

(+ ageing)

Carbendazim(inhibits mitosis)

Physiological MoA nematodes

C. elegans A. nanus

PeCB(narcotic)

costs for growth and reproduction

assimilation

Cadmium(heavy metal)

assimilation costs for growth

(+ ageing)

Carbendazim(inhibits mitosis)

assimilation assimilation

(- ageing)

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 …

Species differences?

Species A Species B

target sitetoxicanttarget sitetoxicant

maintenance

reproduction

…

maintenance

reproduction

…

target sitetoxicant phys. process

effect onlife 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/thbwww.bio.vu.nl/thb

Once we know the normal biological processes, all external stressors are merely perturbations of these processes (Yang et al., 2004)

Once we know the normal biological processes, all external stressors are merely perturbations of these processes (Yang et al., 2004)