From molecules to populations

energy budgets in the causality of toxic effects

Tjalling JagerDept. Theoretical Biology

Dept. Theoretical Biology

Aim: ‘Quantitative bioenergetics’

Dept. Theoretical Biology

Aim: ‘Quantitative bioenergetics’

Head of dept.: Prof. Bas Kooijman Permanent staff: Dr. Bob Kooi and Dr. Tjalling Jager PhD students in Amsterdam:

• Jan Baas : NoMiracle, mixture toxicity• Daniel Bontje : ModelKey, food-chain toxicity• Anne Willem Omta : organic carbon pump• Jorn Bruggeman : organic carbon pump• George van Voorn : bifurcation analysis

Causality

How to link toxicant concentrations to whole-organism and population effects?

toxicant

effects onindividual/population

NOEC/ECx

MoA

energy budgets

CBR

Precondition 1

All concepts in 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/CBR 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

con

cen

trat

ion

Precondition 2

Causality chain should cover all life-history aspects

Feeding, development, growth and reproduction are linked …

• NOEC/ECx/CBR 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

target sitetoxicant

molecular mechanism

effects onindividual/population

CBRs etc.

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

reproduction

DEB theory

growthmaintenance

assimilation

Kooijman (2000)

(first edition 1993)

DEB theory

Kooijman (2000)

(first edition 1993)

Quantitative theory; ‘first principles’• time, energy and mass balance

Life-cycle of the individual• links levels of organisation: molecule

ecosystems

Fundamental, but practical applications• bioproduction, biodegradation, (eco)toxicity,

sewage treatment, climate change, …

DEB allocation rules

food faeces

reserves

assimilation

structure

somatic maintenance

1-

maturityoffspring

maturity maintenance

DEB model

Toxicants: DEBtox

energy-budgetparameter

toxicokinetics

Life-cycle effectsKooijman & Bedaux, 1996 (Wat. Res.)Jager et al., 2006 (Ecotoxicology)

food faecesfood faeces

reservesreserves

assimilationassimilation

structure

somatic maintenance

structure

somatic maintenance

1- 1-

maturityoffspring

maturity maintenance

maturityoffspring

maturity maintenance

Target: maintenance

time

cum

ula

tive

off

spri

ng

time

bo

dy

len

gth

triphenyltin

Crommentuijn et al. (1997), Jager et al. (2004)

Target: costs for growth

time

bo

dy

len

gth

time

cum

ula

tive

off

spri

ng pentachlorobenzene

Alda Álvarez et al. (2006)

Target: hazard to embryo

time

cum

ula

tive

off

spri

ng

time

bo

dy

len

gth

Chlorpyrifos

Crommentuijn et al. (1997), Jager et al. (2007)

‘Non-toxicant’ effects

food faeces

reserves

structure maturityoffspring

maturity maintenancesomatic maintenance

assimilation

1-

‘Gigantism’• parasites in snails and Daphnia

Decreased size at maturity• parasites and kairomones in Daphnia

Gorbushin and Levakin (1999)

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

Alda Álvarez et al., 2005 (Func. Ecol.), 2006 (ES&T), 2006 (ET&C)

0 2 4 6 8 10 12 14 160

100

200

300

400

500

600

0 5 10 15 20 250

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 160

100

200

300

400

500

600

0 2 4 6 8 10 12 14 160

100

200

300

400

500

600

0 5 10 15 20 250

0.2

0.4

0.6

0.8

1

0 5 10 15 20 250

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 120

20

40

60

80

100

120

140

0 2 4 6 8 10 120

20

40

60

80

100

120

140

0 2 4 6 8 10 120

20

40

60

80

100

120

140

0 2 4 6 8 10 120

20

40

60

80

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

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1fr

actio

n su

rviv

ing

0 10 20 30 40 50 60 700

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1fr

actio

n su

rviv

ing

0 5 10 15 20 25 30 3515

20

25

30

35

40

45

50

55

60

65

bod

y le

ngth

(µ

m)

0 5 10 15 20 25 30 3515

20

25

30

35

40

45

50

55

60

65

bod

y le

ngth

(µ

m)

0 10 20 30 40 50 600

50

100

150

200

250

300

350

400

450

time (days)

cum

ulat

ive

offs

prin

g pe

r fe

mal

e 02681012

0 10 20 30 40 50 600

50

100

150

200

250

300

350

400

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)

Population consequences

growth

reproduction

assimilation

maintenance

Population consequences

Population consequences

Population consequences

Each ‘MoA’ has specific effects for populations

Each ‘MoA’ has specific effects for populations

assimilation

reproduction

growthmaintenance

Extrapolate to populations

Constant environment: populations grow exponentially

• ‘intrinsic rate of increase’• calculate from reproduction and survival in time

2 4 6 8 10 120

0

0.2

0.4

0.6

0.8

1

concentration (mg/L)2 4 6 8 10 12

concentration (mg/L)0

0

0.1

0.2

0.3

0.4

2 4 6 8 10 1200

0.1

0.2

0.3

0.4

00

0.1

0.2

0.3

0.4

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

Conclusions

Simple summary statistics are quite useless …• NOEC/ECx change in time and differ between endpoints• not helpful to derive CBRs on basis of ECx

Molecular mechanism is important, but …• not enough to explain effects on life cycle/population

Energy budgets must be considered• direct link to life-history and population effects• cover direct and indirect effects

target sitetoxicant phys. process

effect onlife cycle/population

maintenance

reproduction

…

Outlook

?

Collaboration with CEH Monks Wood life-cycle experiments with C. elegans DEBtox analysis and micro-array work

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