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

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

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

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

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

Cd & Cu survival of Folsomia

Data: Bart van HouteTheory: Bas KooijmanFit: Jan BaasMovie: Jorn Bruggeman

Interaction Cu,Cd, Pb, Zn: Cu & Pb: slightly antagonistic Other combinations: nill

Folsomia candida

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

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

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

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