from molecules to populations on the causality of toxic effects tjalling jager, bas kooijman dept....
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From molecules to populations
On the causality of toxic effects
Tjalling Jager, Bas KooijmanDept. Theoretical Biology
Causality
How to link toxicant concentrations to whole-organism and population effects?
toxicant
effects onindividual/population
Why interesting? to support chemical risk assessment to justify research (‘so what’ question)
NOEC/ECx
molecular
energy budgets
Precondition 1
Any concept for causality chain should explicitly consider exposure time
Toxicity is a process in time• uptake into organism takes time
• biomarker responses can/will change in time
• NOEC/ECx values can/will change in time
Cl
Cl
Cl Cl
Cl
EC10 in time
Alda Álvarez et al. (2006)
carbendazim
time
pentachlorobenzene
time
survival
body length
cumul. repro
body length
cumul. repro
Precondition 2
Causality chain should cover all life-history aspects
Feeding, development, growth and reproduction are linked …• NOEC/ECx differ between
endpoints• what about molecular
mechanism of action?
Cl
Cl
Cl Cl
Cl
‘Narcotic’ effects
time
EC
10
time
body sizebody size
reproductionreproduction
A. nanus
C. elegans
Cl
Cl
Cl Cl
Cl
Causality of effects
toxicantstatistics e.g., NOEC/ECx
effects onindividual/population
Causality of effects
ENERGYBUDGET
rest of the organismtarget sitetoxicant
molecular mechanism
physiological mechanism
effects onindividual/population
Energy budgets
Energy budgets
growth
reproduction
assimilation
Each ‘MoA’ has specific effects
on life cycle(direct/indirect)
Each ‘MoA’ has specific effects
on life cycle(direct/indirect)
maintenance
Population consequences
Population consequences
Population consequences
Each ‘MoA’ has specific effects for populations
Each ‘MoA’ has specific effects for populations
assimilation
reproduction
growthmaintenance
externalconcentration
reproduction
DEB model
Biology-based (DEBtox)
energy-budgetparameter
toxicokinetics
growthmaintenance
assimilation
Life-cycle effectsKooijman & Bedaux, 1996 (Wat. Res.)
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)
0 2 4 6 8 10 12 14 160
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600
0 5 10 15 20 250
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0 2 4 6 8 10 12 14 160
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0 2 4 6 8 10 12 14 160
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600
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0 2 4 6 8 10 120
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0 2 4 6 8 10 120
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0 2 4 6 8 10 120
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40
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0 2 4 6 8 10 120
20
40
60
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100
120
140
length
length
eggs
survival
C. elegans and cadmium
Mode of action: assimilation
Alda Álvarez et al. (2005)time (days)
0 10 20 30 40 50 60 70
0
0.1
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1fr
actio
n su
rviv
ing
0 10 20 30 40 50 60 700
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1fr
actio
n su
rviv
ing
0 5 10 15 20 25 30 3515
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bod
y le
ngth
(µ
m)
0 5 10 15 20 25 30 3515
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bod
y le
ngth
(µ
m)
0 10 20 30 40 50 600
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time (days)
cum
ulat
ive
offs
prin
g pe
r fe
mal
e 02681012
0 10 20 30 40 50 600
50
100
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450
time (days)
cum
ulat
ive
offs
prin
g pe
r fe
mal
e 02681012
02681012
A. nanus and cadmium
Mode of action: costs for growth
Alda Álvarez et al. (2006)
Physiological MoA
C. elegans A. nanus
PeCB(narcotic)
Cadmium(heavy metal)
Carbendazim(inhibits mitosis)
Physiological MoA
C. elegans A. nanus
PeCB(narcotic)
costs for growth and reproduction
assimilation
Cadmium(heavy metal)
Carbendazim(inhibits mitosis)
Physiological MoA
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
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)
Extrapolate to populations
In a constant environment, a population will grow exponentially …
‘Intrinsic rate of increase’• calculate from reproduction and survival in time
2 4 6 8 10 120
0
0.2
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1
concentration (mg/L)2 4 6 8 10 12
concentration (mg/L)0
0
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2 4 6 8 10 1200
0.1
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00
0.1
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intr
ins
ic r
ate
(d-1)
Extrapolate to populations
95%
90%
95%90%Mode of action:
assimilation
Mode of action: assimilation
Mode of action: costs for growth
Mode of action: costs for growth
Cadmium
Pulsed exposure
Pieters et al. (2006)
Conclusions
Simple summary statistics are useless …• NOEC/ECx change in time and differ between endpoints
Molecular mechanism is important, but …• not enough to explain effects on life cycle/population
Energy budgets must be considered• ‘physiological MoA’ covers direct and indirect effects• direct link to life-history and population effects
Species differ in phys. MoA for the same toxicant
Species differences?
Species A Species B
target sitetoxicanttarget sitetoxicant
maintenance
reproduction
…
maintenance
reproduction
…
target sitetoxicant phys. process
effect onlife cycle/population
maintenance
reproduction
…
Outlook
?
Collaboration with CEH Monks Wood life-cycle experiments with C. elegans data analysis with DEBtox microarray work on same animals
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!
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)
www.bio.vu.nl/thbwww.bio.vu.nl/thb