making sense of sub-lethal mixture effects tjalling jager, tine vandenbrouck, jan baas, wim de coen,...
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Making sense of sub-lethal mixture effects
Tjalling Jager, Tine Vandenbrouck, Jan Baas, Wim De Coen, Bas Kooijman
Challenge of mixture ecotoxicity
Some 100,000 man-made chemicals Large range of natural ‘toxicants’ For animals, 1.25 million species described Complex exposure situations
Typical approach
A B
Typical approach
Typical approach
Typical approach
wait for 21 days …
Dose-response plot
dose-ratio dependent deviation from CA
dose-ratio dependent deviation from CA
concentration A concentratio
n B
tota
l o
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on total Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on Daphnia reproduction after 21 days under standard OECD test conditions?”
dose-ratiodependentdeviation from CA
dose-ratiodependentdeviation from CA
concentration A concentratio
n B
tota
lo
ffsp
rin
g
concentration A concentratio
n B
tota
lo
ffsp
rin
g
What question did we answer?
“What is effect of constant exposure to this mixture on Daphnia reproduction after 21 days under standard OECD test conditions?”
“What is effect of constant exposure to this mixture on Daphnia reproduction after 21 days under standard OECD test conditions?”
Better questions
do we see these time patterns of effects?• can we explain the effects on all endpoints over the life
cycle in one framework?• can we make useful predictions for other mixtures, other
species, and other exposure situations?
externalconcentration
B (in time)
externalconcentration
A (in time)
effectsin time
Process-based
externalconcentration
B (in time)
externalconcentration
A (in time)
toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
Process-based
internalconcentration
A in time
internalconcentration
B in time
survival as achance process
effectsin time
Tolerance distribution• McCarty et al (1992)• Lee & Landrum (2006)Stochastic death• Ashauer et al. (2007)• Baas et al. (2007, 2009)
Tolerance distribution• McCarty et al (1992)• Lee & Landrum (2006)Stochastic death• Ashauer et al. (2007)• Baas et al. (2007, 2009)
Sub-lethal endpoints …
growth
reproduction
feeding
maintenance
maturation
Sub-lethal endpoints …
growth
reproduction
feeding
maintenance
maturationRules for mass and energy flowsDEB (Kooijman, 2000/2001)
Rules for mass and energy flowsDEB (Kooijman, 2000/2001)
Process-based
externalconcentration
A (in time)
externalconcentration
B (in time)
toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
internalconcentration
A in time
internalconcentration
B in time
metabolicprocesses
in timeDEB
model
DEBmodel effects on
all endpointsin time
assimilationmaintenanc
ematuration
….
theory implies interactions …
growth
externalconcentration
A (in time)
toxico-kinetics
toxico-kinetics
externalconcentration
B (in time)
toxico-kinetics
toxico-kinetics
DEBmodel
DEBmodel
internalconcentration
A in time metabolicprocesses
in timeinternalconcentration
B in time effects onall endpoints
in time
Process-based
assimilationmaintenanc
ematuration
….
Simple mixture rules
assimilation
maintenance
…
compound ‘target’ metabolic process
toxicity parameters linked (compare CA)
Simple mixture rules
assimilation
maintenance
…
compound ‘target’ metabolic process
Simple mixture rules
assimilation
maintenance
…
compound ‘target’ metabolic process
toxicity parameters independent (compare IA)
fluoranthene pyrene
PAHs in Daphnia
Based on standard 21-day OECD test• 10 animals per treatment• length, reproduction and survival every 2 days• no body residues (TK inferred from effects)
0 5 10 15 20
0
0.2
0.4
0.6
0.8
1
frac
tio
n s
urv
ivin
g
0 5 10 15 200
0.2
0.4
0.6
0.8
1
frac
tio
n s
urv
ivin
g
0 5 10 15 20
time (days)0 5 10 15 20
time (days)0 5 10 15 200 5 10 15 20
0
10
20
30
40
50
60
70
80
90
cum
ula
tiv
e o
ffsp
rin
g p
er f
ema
le
0
0.5
1
1.5
2
2.5
3b
od
y le
ng
th (
mm
)
00 (solv.)0.08650.1730.346
0
0.5
1
1.5
2
2.5
3b
od
y le
ng
th (
mm
)
00 (solv.)0.08650.1730.346
00 (solv.)0.2130.4260.853
00 (solv.)0.2130.4260.853
0.0865 0.2130.173 0.4260.260 0.6400.0865 0.6400.260 0.2130.346 0.853
0.0865 0.2130.173 0.4260.260 0.6400.0865 0.6400.260 0.2130.346 0.853
pyrene fluoranthene mixtures
Same target:costs reproduction(and costs growth)
Same target:costs reproduction(and costs growth)
Iso-effect lines
0 0.05 0.1 0.15 0.2 0.25 0.30
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
t = 10
t = 10
t = 14
t = 14
t = 14
t = 14
t = 18
t = 18
t = 18
t = 18
t = 21
t = 21
t = 21
t = 21
pyrene (μM)
flu
ora
nth
ene
(μM
)
50% survival
0 0.05 0.1 0.15 0.2 0.25 0.3
t = 10
t = 14
t = 14
t = 21
t = 21
pyrene (μM)
t = 10
t = 18
t = 18t = 10
50% reproduction
for body length <50% effect
Conclusions PAH mixture
Mixture effect consistent with ‘same target’• as expected for these PAHs• explains all three endpoints, over time
Iso-effect lines are functions of time• which differ between endpoints• in this case: little deviation from CA
Few parameters for all data in time• 14 parameters (+4 Daphnia defaults)
(descriptive would require >100 parameters)
Parameter estimates
externalconcentration
A (in time)
externalconcentration
B (in time) toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
internalconcentration
A in time
internalconcentration
B in time
metabolicprocesses
in timeDEB
model
DEBmodel effects on
all endpointsin time
TK pars tox pars DEB pars
Educated extrapolation
externalconcentration
A (in time)
externalconcentration
B (in time) toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
internalconcentration
A in time
internalconcentration
B in time
metabolicprocesses
in timeDEB
model
DEBmodel effects on
all endpointsin time
TK pars tox pars DEB pars
populations
Educated extrapolation
externalconcentration
A (in time)
externalconcentration
B (in time) toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
internalconcentration
A in time
internalconcentration
B in time
metabolicprocesses
in timeDEB
model
DEBmodel effects on
all endpointsin time
TK pars tox pars DEB pars
other endpoints
other, e.g.,repro raterespiration
Educated extrapolation
externalconcentration
A (in time)
externalconcentration
B (in time) toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
internalconcentration
A in time
internalconcentration
B in time
metabolicprocesses
in timeDEB
model
DEBmodel effects on
all endpointsin time
TK pars tox pars DEB pars
time-varying concentrations
Educated extrapolation
externalconcentration
A (in time)
externalconcentration
B (in time) toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
internalconcentration
A in time
internalconcentration
B in time
metabolicprocesses
in timeDEB
model
DEBmodel effects on
all endpointsin time
TK pars tox pars DEB pars
food limitation
Educated extrapolation
externalconcentration
A (in time)
externalconcentration
B (in time) toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
internalconcentration
A in time
internalconcentration
B in time
metabolicprocesses
in timeDEB
model
DEBmodel effects on
all endpointsin time
TK pars tox pars DEB pars
other narcotic compounds
Educated extrapolation
externalconcentration
A (in time)
externalconcentration
B (in time) toxico-kinetics
toxico-kinetics
toxico-kinetics
toxico-kinetics
internalconcentration
A in time
internalconcentration
B in time
metabolicprocesses
in timeDEB
model
DEBmodel effects on
all endpointsin time
TK pars tox pars DEB pars
other (related) species
Final words
A process-based approach is essential …• to progress the science of mixture toxicity• to make useful predictions for RA
Key elements DEB approach• one framework for all endpoints over time• feasible with ‘reasonable’ data sets• certain interactions are unavoidable …
Of course, more work is needed …• validate predicted interactions and extrapolations• ready to tackle more complex mixtures!
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Vacancies• PhD student, Marie Curie training network (CREAM)
Courses• International DEB Tele Course 2011
Symposia• 2nd International DEB Symposium 2011 in Lisbon
More information: http://www.bio.vu.nl/thb