1. Nomiracle WP 4.1: Modelling Effects of mixtures of compounds EU Integrated project NoMiracle: http://nomiracle.jrc.it Novel Methods for Integrated Risk assessment of Cumulative Stressors in Europe EU-theme "Global Change and Ecosystems" topic “Development of risk assessment methodologies” Coordination: Dr. Hans Løkke, NERI, DK-8600 Silkeborg, Denmark Interim-report: Modelling effects of binary mixtures on survival in time Jan Baas (2005/10/01 – 2009/10/01) Tjalling Jager & Bas Kooijman (VU-Theor Biol) In collaboration with Mieke Broerse, Kees van Gestel (VU-Ecol, EU-project NoMiracle) Daniel Bontje, Bob Kooi (VU-Theor Biol, EU-project Modelkey) contract No. 003956

2. Biology based methods Effects based on internal concentrations One compartment accumulation-elimination Hazard rate or physiological target parameter is linear in internal concentration (small effects only) Dynamic Energy Budget theory is used to identify potential target parameters translate change in parameter to change in endpoint Interaction of compounds in mixture  product of internal concentrations similar to analysis of variance

3. Suppose that the elimination rate large  internal conc is fast at equilibrium, hazard rate is constant Conclusion : effect on survival  concentration  exposure time well known in pharmacology desinfection of buildings, green houses Hazard model

4. Effect on survival for single compound Effects of Dieldrin on survival of Poecilia NEC 4.49  g l -1 killing rate 0.038 l  g -1 d -1 elimination rate 0.712 d -1

5. Effect on survival for mixture Model for survival in time for a binary mixture: 8 parameters in total using data for all observation times control mortality rate, interaction parameter 2  (NEC, killing rate, elimination rate) Model tested for 6 binary mixtures of metals (Cu, Cd, Pb & Zn) on Folsomia candida (Collembola) Survival measurements daily for 21 days 6  6 concentrations 22  6  6 = 792 data points for each mixture

6. Cd & Cu  survival of Folsomia Data: Bart van Houte Theory: Bas Kooijman Fit: Jan Baas Movie: Jorn Bruggeman Interaction Cu,Cd, Pb, Zn: Cu & Pb: slightly antagonistic Other combinations: nill Folsomia candida

7. Results for NoMiracle RP 3 & 4 New model is available for analysis of data for effects of mixtures of compounds on the survival of organisms This model is shown to be realistic, has few parameters and has attractive statistical properties Software DEBtool is available to make the application of this model feasible http://www.bio.vu.nl/thb/deb/deblab/ Standard deviations are available to judge accuracy Parameters quantify effects in ways that do not depend on exposure time. OECD encourages the development of exposure-time-explicit methods (Braunschweig, 1996) Scaling relationships are available that can help filling gaps in knowledge NECs can be used in risk-assessments to replace NOECs RP 3 RP 4

8. Publication output Kooijman, S. A. L. M., Baas, J., Bontje, D., Broerse, M., Jager, T., Gestel, C. van and Hattum, B. van (2006) Scaling relationships based on partition coefficients and body sizes have similarities and interactions. SAR and QSAR in Environ. Res, to appear Baas, J., Houte, B. P. P. van, Gestel, C. A. M. van and Kooijman, S. A. L. M. (2006) Modelling the effects of binary mixtures on survival in time. Environmental Toxicology & Chemistry, submitted Baas, J. and Kooijman, S. A. L. M. (2006) Statistical properties of NEC estimates if values scatter among individuals. Water Research, in prep Start: 2005/10/01

9. Future plans Research Application of results to (some) NoMiracle data Effects of pH (conc dependent mixtures of molecular & ionic forms) Sublethal effects of mixtures Mixtures of a large number of chemical compounds (frequency distributions of tox parameter values) Effects of metabolic transformations (if time allows) Education DEBtox tele-course 2006 Feb-Mar JRC-ECB workshop on biology-based methods in environmental risk assessment DEB tele-course 2007 Feb-April

10. DEB tele course 2007 http://www.bio.vu.nl/thb/deb/ Free of financial costs; some 200 h effort investment Feb-April 2007; target audience: PhD students We encourage participation in groups that organize local meetings weekly French group of participants of the DEB tele course 2005 wrote special issue of J. Sea Res. 2006 on DEB applications to bivalves Software package DEBtool for Octave/ Matlab freely downloadable Slides of this presentation are downloadable from http://www.bio.vu.nl/thb/users/bas/lectures/ Cambridge Univ Press 2000 Audience : thank you for your attention Organizers : thank you for the invitation