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From molecules to populations On the causality of toxic effects. Tjalling Jager, Bas Kooijman Dept. Theoretical Biology. effects on individual/population. toxicant. Causality. How to link toxicant concentrations to whole-organism and population effects?. NOEC/EC x. molecular. - PowerPoint PPT Presentation
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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