Biology-Based Modelling Tjalling Jager Bas Kooijman Dept. Theoretical Biology Contents Current procedures in (eco)tox Biology-based methods A glimpse into the future? Workshop announcement RISK Risk assessment EXPOSURE EFFECTS Available dataAssessment factor Three LC50s1000 One NOEC100 Two NOECs50 Three NOECs10 Integrated model for system Integrated model for system Process parameters at env. conditions Process parameters at env. conditions PEC Lab. experiments Exposure assessment Extrapolation to e.g.: different compartment sizes different temperature time-varying emissions Effects assessment PNEC Lab. experiments Contr. Analysing test data NOEC Response log concentration * 1. Statistical testing Analysing test data EC50 Response log concentration 1. Statistical testing 2. Regression Limitations Practical problems as summary statistic NOEC has received serious criticism ECx and NOEC change with exposure time EC10 changes in time survival body length cumul. reproduction body length cumul. reproduction carbendazim time (days) pentachlorobenzene time (days) Alda Alvarez et al., 2006 (ES&T) Limitations Practical problems as summary statistic NOEC has received serious criticism ECx and NOEC change with exposure time Not all data are used only data at last time point test protocols prescribe more time points in some cases, more endpoints available Survival dichlorobutene concentration (mM/L) survival 1-3 days 4 days Data from Geiger et al., 1985 Reproduction phenol 9-20 days 21 days concentration (mg/L) total eggs/female Further available - survival data - possibly body weight Data from OECD ring test Limitations Practical problems as summary statistic NOEC has received serious criticism ECx and NOEC change with exposure time Not all data are used only data at last time point test protocols prescribe more time points in some cases, more endpoints available No biological mechanism selected curve for ECx is descriptive limits analysis of non-standard data (e.g. degradation) limits extrapolation to other scenarios process parameters? integrated model? Effects assessment Assessment factor Regression or statistical test Regression or statistical test Lab. experiments Available data Assessment factor Three LC50s1000 One NOEC100 Two NOECs50 Three NOECs10 Extrapolation to e.g.: different body sizes? different temperature? time-varying exposure? populations? PNEC Biology-based modelling Biology based methods OECD recommendations (1996) NOEC is inappropriate and should be phased out incorporate exposure time in data analysis favour mechanistic models if they fit the data ISO and OECD guidances (2006) statistical analysis of ecotoxicity data biology-based methods included next to standard methods Biology based methods exposure concentration effects in time toxicokinetics internal concentration toxicodynamics calculated by fate models e.g. one-comp. model or PBPK e.g. DEB model Dynamic Energy Budgets (DEB) growth reproduction assimilation maintenance DEB provides simple rules for resource acquisition and allocation Effect of toxicants in DEB blank value internal concentration DEB parameter NEC Potential targets probability to die maintenance costs assimilation costs for growth costs for reproduction death of embryos DEBtox Currently only method with general applicability combines toxicokinetics and -dynamics analysis of all regular ecotox endpoints data from standard OECD protocols Large body of literature over last 10+ years Windows software version 1.0 in 1996, version in 2004 freely downloadable Windows version Only for standard tests acute survival Daphnia reproduction fish growth algal population growth Example: Hexachlorobutadiene Fitting 4 parameters for entire data set No-effect concentration: NEC = 0.13 ( ) Data from Geiger et al., 1985 Example: Hexachlorobutadiene external concentration (mol/L) time (hours) LC0 LC10 LC25 LC50 NEC iso-effect lines Example: Phenol Fitting 4 parameters for entire data set MoA: costs for growth NEC = 0.82 ( ) Data from OECD ring test Example: Phenol time (days) external concentration (mg/L) EC0 EC10 EC25 EC50 NEC iso-effect lines Advantages Make efficient use of all data points in time more accurate parameter estimates reduce number of test animals Extract more information from same data kinetic information on toxicity (e.g., ECx at any time point) physiological mode of action (for population response) Yield a more robust summary statistic time-independent NEC may replace NOEC and ECx Using standard test data Advantages Fit non-standard data loss of compound from test system limited tests (single dose, no control, one indiv. per dose) no need to discard existing test data Simultaneous fit on multiple data sets more endpoints (life-cycle toxicity) different compounds: mixture toxicity Educated extrapolations intermittent exposure, food limitation, population etc. between compounds (QSARs), between species Furthermore A glimpse into the future? Characterisation of impacts? PEC/PNEC EXPOSURE EFFECTS EXPOSURE EFFECTS IMPACTS Example Daphnia magna exposed to Cd Test based on OECD repro test 15 days survival and offspring daily body weight at end of test Data from Heugens et al., 2006 (ET&C) Analysis in Jager et al., 2006 (Ecotox) survival reproduction body size Mode of action Cd decreases assimilation Mode of action Cd decreases assimilation Simultaneous fits Extrapolations concentration population growth rate (1/day) PEC impact NEC ecologically relevant time independent integrates endpoints Extrapolations concentration population growth rate (1/day) NEC impact PEC impact ecologically relevant time independent integrates endpoints compare chemicals PEC Extrapolations concentration population growth rate (1/day) 90% food 80% food Matching release scenario time exposure time survival time emission Announcing a workshop There is potential for improvement of RA with biology-based methods Biology-based methods are available and described by ISO and OECDWorkshop organised by ECB introduce these methods to regulatory community discuss potential for implementation planned for 2 days in week of 4-8 June 2007