chemical (and other) stress in deb 3: the ‘target site’ and effects on survival tjalling jager...
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Chemical (and other) stress in DEB3: the ‘target site’ and effects on survival
Tjalling Jager
Dept. Theoretical Biology
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Contents
Toxicodynamics About ‘targets’ and the ‘dose metric’
• how to link internal concentrations to DEB
Effects on survival• in a very simple setup (no growth)
Ageing affects survival
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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
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“Biology-based” modelling
internalconcentration
in time
process modelfor the organism
process modelfor the organism
effects onendpoints
in time
toxicodynamics
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“Mechanism of action”
Toxicants have different ‘molecular targets’:• narcosis or ‘baseline toxicity’ (cell membranes)• uncoupling (mitochondria)• reactivity (macro molecules)• AChE inhibition (nerve transmission)• ...
Start a bit more general ... Effects on life-history traits must be reflected in a change in one or
more DEB parameters
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Targets link to parameters
Assumption• internal toxicant affects a target site• target is linked to one or more DEB parameters
If interaction with target is fast and reversible ...
target sitetoxicant
DEBparameter
organism
DEBparameter
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Targets link to parameters
Model for target site dynamics• ‘damage’ stage (Lee et al, 2002, Ashauer et al, 2007)• receptor kinetics with limited number of receptors (Jager &
Kooijman, 2005)
What if we used the scaled internal concentration??
toxicant
DEBparameter
organism ‘damage’or ‘receptor’
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Receptors: AChE inhibition
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Dose metric options
externalconcentration
(in time)
toxico-kinetics
toxico-kinetics (scaled)
internal conc.in time
DEBparameters
in time
bufferbufferstructurestructure
reservereserve
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Dose metric options
externalconcentration
(in time)
toxico-kinetics
toxico-kinetics (scaled)
internal conc.in time
DEBparameters
in time
receptorkinetics
receptorkinetics
damagekinetics
damagekinetics
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Selecting a dose metric
The appropriate dose metric depends on …• the nature of the target site• species and chemical dependant
What about measured body residues?• always good to have more information ...• whole-body residue may not represent ‘target site’ ...
Advice: • start with a scaled TK model …
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Link dose metric to parameter
Assumptions• low levels of the dose metric have no effect on the DEB
parameter (NEC)
internal concentration
too muchoktoo little
perf
orm
ance
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Link dose metric to parameter
Assumptions• low levels of the dose metric have no effect on the DEB
parameter (NEC)• above the NEC, value of DEB parameter is linearly related to
the dose metric
e.g., scaled internal concentration
e.g.
, m
aint
enan
ce r
ate
NEC
blank value
toler
ance
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Survival
Why does an organism die?• this is a rather complex question ...
Assumption• death can be treated as a chance event in time• chemical exposure increases probability to die
Popular alternative• individuals differ in their threshold for effects• immediate and certain death above threshold
Can we have combinations?• yes, see GUTS (Jager et al, acc. ES&T)
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Chance events in time
0
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12
0 2 4 6 8time (days)
surv
ivin
g c
hic
ken
s
0 cars/hr10 cars/hr20 cars/hr50 cars/hr
Hazard rate is the ‘instantaneous probability’ to die by car encounter
Hazard rate increases with traffic
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Simple survival model
c
on
ce
ntr
ati
on
external
internal
time
external concentrationover timetoxicokinetics
internal concentrationover time
toxic effect
scaled1-comp.
scaled1-comp.
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internal concentrationover time
animal model
Simple survival model
scaled internal concentration
haza
rd r
ate
NEC
blank value
targetparameter
toxicokinetics
toxic effect
killin
g rate
Assumptions• no growth, no reproduction, constant reserve density …
Assumptions• no growth, no reproduction, constant reserve density …
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In equations …
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Hazard modelling
concentration
external
internal
external
internal
NEC
NEC
time
time
hazard rate
time
survival probability
time
time time
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Minnow, hexachloroethane
0 1.33 1.84 3.32 5.81 9.25
0 20 20 20 20 20 20
24 20 20 20 20 20 4
48 20 20 20 20 15 0
72 20 20 19 20 12 0
96 20 20 19 20 10 0
concentration (μmol/L)
time
(h
our
)fathead minnow
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Survival in time
0 20 40 60 80 1000
0.2
0.4
0.6
0.8
1
time (hours)
fra
cti
on
su
rviv
ing
01.331.843.325.819.25
conc. μmol/L
elimination rate 0.141 hr-1
NEC 5.54 (5.26-5.68) μmol/Lkilling rate 0.0408 L/μmol/hrblank hazard 0.000124 hr-1
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Daphnia, nonylphenol
mg/L 0 h 24 h 48 h
0.004 20 20 20
0.032 20 20 20
0.056 20 20 20
0.100 20 20 20
0.180 20 20 16
0.320 20 13 2
0.560 20 2 0
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Daphnia, nonylphenol
elimination rate 0.057 hr-1
NEC 0.14 (0.094-0.17) mg/Lkilling rate 0.66 L/mg/hrblank hazard 0 hr-1
0 10 20 30 40 500
0.2
0.4
0.6
0.8
1
time (hours)
frac
tio
n s
urv
ivin
g
0.0040.0320.0560.10.180.320.56
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Summary survival model
Based on hazard modelling• simple method for chance events in time• linked to simple TK model• DEB-content is very limited!
Resulting parameters are • time-independent• have biological/toxicological meaning
Helps to understand toxicity• e.g., why juveniles often have lower LC50• patterns in parameter values across chemicals …
0 10 20 30 40 500
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1
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frac
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0.0040.0320.0560.10.180.320.56
0 10 20 30 40 500
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time (hours)
frac
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ivin
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0.0040.0320.0560.10.180.320.56
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Fathead minnow database
In the 1980’s ... University of Wisconsin-Superior
• Brooke et al (1984)• Geiger et al (1985, 1986, 1988, 1990)
What’s special?• large number of chemicals• measured exposure• raw data in reports!
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Parameter covariation
10-4
10-2
100
102
10-4
10-2
100
102
104
NEC (mmol/L)
kil
lin
g r
ate
(L
/mm
ol/
h)
narcoticreactivenarcoticreactive
Jager and Kooijman, 2009
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Why slope of -1?
Assumption• hazard rate is determined by occupation of a target site
At this target, there is 1 NEC and 1 killing rate• variation follows from PVd and efficiency of target interaction
narcotic target‘narcotic’
reactive target‘reactive’
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Process-based QSAR
-2 -1 0 1 2 3 4 5 610
-3
10-2
10-1
100
101
102
log Kow
elim
ina
tio
n r
ate
(1/
h)
narcoticreactivenarcoticreactive
Jager and Kooijman, 2009
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Why difference in elimination?
Using the scaled TK model ...• elimination rate is based on effects over time• elimination rate represents slowest process in the chain
narcotic target‘narcotic’
reactive target‘reactive’
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Why so much noise?
Measurements errors of exposure concentration Biological variation in animals Death is assumed to be stochastic … Fish biotransform many compounds …
• metabolites have different targets, elimination rates, …
Assumed mechanism is too simple …
AA
BB
CC
DD
target
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What is ageing?
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Jager et al (2004)
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What is ageing?
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Jager et al (2004)
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Old-age effects
With increasing age ...• survival probability decreases• feeding rates often decrease• reproduction rates decrease• ...
‘DEB3’ offers a model (currently survival only)• observed: caloric restriction increases lifespan• model links ageing to respiration via ROS
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Ageing and ROS
Weindruch R 1996 Caloric restriction and aging. Scientific American 231, 46-52.
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Ageing in DEB3
Treated as a toxicant effect …
damage compoundsdamage compoundsdilution by growth
hazard ratehazard rate
amplification
dilution by growth
reserve mobilisationreserve mobilisation
damage-inducingcompunds
damage-inducingcompunds
free radicals
e.g., affected mitochondria
e.g., “wrong” proteins
There is good news and bad news …There is good news and bad news …
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Example: guppies
caloric restriction
Kooijman, 2010
Implicit assumptions• there is no “repair” of damage (inducing) compounds• there is no threshold for effects on the hazard rate
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Ageing effects on repro?
Still to be investigated in detail! Observations:
• reproduction rate declines with old age• feeding rates decline with old age• body size does not change (much) with old age
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Toxicants influence ageing
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Folsomia candidaand cadmium (fit is not DEB3!)
Jager et al (2004)
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Toxicants influence ageing
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Acrobeloides nanusand carbendazim (not DEB3!)
Alda Álvarez et al (2006)
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Open questions
How to explain increased longevity in e.g., Folsomia?• less growth means decreased production of damage• but, counteracted by decrease in growth dilution …
How to explain changes in reproduction?• should be linked to survival in some way ...• link through decrease in feeding?
Further work is needed!• re-analysis of existing data sets• dedicated testing, e.g., full life cycle at different food levels
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Summarising
Internal concentration affects one (or more) DEB parameter(s) through a ‘target’
Start by using scaled internal concentration• ‘elimination’ rate does not necessarily reflect kinetics of
whole-body residue
One target parameter is the hazard rate• in case of non-growing organisms and short tests, model
becomes extremely simple
Ageing affects hazard rate• ROS as byproduct of metabolism; 2-stage ‘damage’ model