From molecules to populations

On the causality of toxic effects

Tjalling Jager, Bas KooijmanDept. Theoretical Biology

CausalityHow to link toxicant concentrations to whole-organism and population effects?Why interesting?to support chemical risk assessmentto justify research (so what question)NOEC/ECxmolecularenergy budgets

Precondition 1

Any concept for causality chain should explicitly consider exposure time

Toxicity is a process in timeuptake into organism takes timebiomarker responses can/will change in timeNOEC/ECx values can/will change in time

EC10 in timeAlda lvarez et al. (2006)survivalbody lengthcumul. reprobody lengthcumul. repro

Precondition 2

Causality chain should cover all life-history aspects

Feeding, development, growth and reproduction are linked NOEC/ECx differ between endpointswhat about molecular mechanism of action?

Narcotic effects

Causality of effectstoxicantstatistics e.g., NOEC/ECx

Causality of effectsENERGYBUDGETrest of the organism

Energy budgets

Energy budgetsEach MoA has specific effects on life cycle(direct/indirect)

Population consequences

Population consequences

Population consequencesEach MoA has specific effects for populations

Biology-based (DEBtox)externalconcentrationreproductionDEB modelenergy-budgetparametertoxicokineticsgrowthmaintenanceassimilationLife-cycle effectsKooijman & Bedaux, 1996 (Wat. Res.)

Experiments nematodesSpeciesCaenorhabditis elegans and Acrobeloides nanusChemicalscadmium, pentachlorobenzene and carbendazimExposurein agarEndpointssurvival, body size, reproduction over full life cycleanalysed with extended DEBtox

Studies published as: Alda lvarez et al., 2005 (Func. Ecol.), 2006 (ES&T), 2006 (ET&C)

C. elegans and cadmiumlengthlengtheggssurvivalMode of action: assimilationAlda lvarez et al. (2005)time (days)

A. nanus and cadmiumMode of action: costs for growthAlda lvarez et al. (2006)

Physiological MoA

Physiological MoA

Physiological MoA

Physiological MoA

Extrapolate to populationsIn a constant environment, a population will grow exponentially Intrinsic rate of increasecalculate from reproduction and survival in time

Extrapolate to populationsMode of action: assimilationMode of action: costs for growthCadmium

Pulsed exposurePieters et al. (2006)

ConclusionsSimple 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 consideredphysiological MoA covers direct and indirect effectsdirect link to life-history and population effects

Species differ in phys. MoA for the same toxicant

Species differences?Species ASpecies B

OutlookCollaboration with CEH Monks Woodlife-cycle experiments with C. elegansdata analysis with DEBtoxmicroarray work on same animals?

OutlookWhy 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)www.bio.vu.nl/thb