Progress in regulatory degradation kinetics - SETAC Europe 24th … · 13-05-2014 · SETAC Europe...

Progress inregulatory

kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

1/22 jrwb.de

Progress in regulatory degradation kineticsSETAC Europe 24th Annual Meeting

PD Dr. Johannes RankeScientific consultant

Basel, 13 May 2014

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

2/22 jrwb.de

How do you define progress?

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

3/22 jrwb.de

Outline

1 The tasks of regulatory degradation kinetics

2 Parameter confidence intervals

3 Biphasic models for metabolites

4 Conclusions

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

4/22 jrwb.de

The tasks of regulatory degradation kinetics

Derive endpoints for fate modelling

Provide endpoints for comparison with trigger values

Triggers for further data requirements(EU pesticides: FOCUS kinetics “persistence endpoints”)Triggers for persistence, P and vP(Regulation 1107/2009, REACH)

Reflect endpoint uncertainty

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

4/22 jrwb.de




Triggers for further data requirements(EU pesticides: FOCUS kinetics “persistence endpoints”)

Triggers for persistence, P and vP(Regulation 1107/2009, REACH)


http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

4/22 jrwb.de




Triggers for further data requirements(EU pesticides: FOCUS kinetics “persistence endpoints”)Triggers for persistence, P and vP(Regulation 1107/2009, REACH)


http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

5/22 jrwb.de

Motivation to improve regulatory degradationkinetics

Provide the best possible foundation

Transparency

X

Scientific quality

?

Technical quality

Collaboration

!

www.r-project.org - focus.jrc.ec.europa.eu/dkR CMD check mkin 0.9-27.tar.gz - github.com/jranke/mkin

http://www.jrwb.de

http://r-project.org

http://focus.jrc.ec.europa.eu/dk

http://github.com/jranke/mkin


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

5/22 jrwb.de



Transparency X

Scientific quality

?

Technical quality

Collaboration

!

www.r-project.org

- focus.jrc.ec.europa.eu/dkR CMD check mkin 0.9-27.tar.gz - github.com/jranke/mkin

http://www.jrwb.de





kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

5/22 jrwb.de



Transparency X

Scientific quality ?

Technical quality

Collaboration

!

www.r-project.org - focus.jrc.ec.europa.eu/dk

R CMD check mkin 0.9-27.tar.gz - github.com/jranke/mkin

http://www.jrwb.de





kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

5/22 jrwb.de



Transparency X


Technical quality

Collaboration

!

www.r-project.org - focus.jrc.ec.europa.eu/dkR CMD check mkin 0.9-27.tar.gz

- github.com/jranke/mkin

http://www.jrwb.de





kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

5/22 jrwb.de



Transparency X


Technical quality

Collaboration !

www.r-project.org - focus.jrc.ec.europa.eu/dkR CMD check mkin 0.9-27.tar.gz - github.com/jranke/mkin

http://www.jrwb.de





kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

6/22 jrwb.de

Critical areas

t-test for parameter significance (assumes normaldistribution for estimator)

Confidence intervals for fitted parameters

Modelling biphasic behaviour of metabolites

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

7/22 jrwb.de

Elements of success

mkin was first published in May 2010, including biphasic models formetabolites since May 18. It was then used to develop

KinGUII (Bayer Crop Science)

CAKE (Syngenta)

by adding a graphical user interface (GUI), iteratively reweightedleast squares (IRLS) and Markov Chain Monte Carlo (MCMC)

Isometric logratio transformation (ILR) for fitting formation fractionstogether with Rene Lehmann (UBA) in 2012

Parameter confidence intervals based on transformed parameters(2013)

mkin (≥ 0.9-27) allows for fitting models with or without formationfractions, with or without parameter transformations.

Ranke and Lehmann, SETAC World 20-24 May 2012, Berlinmkin 0.9-27 published on CRAN 10 May 2014

http://www.jrwb.de

http://cran.r-project.org/package=mkin


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

7/22 jrwb.de

Elements of success



CAKE (Syngenta)





Ranke and Lehmann, SETAC World 20-24 May 2012, Berlin

mkin 0.9-27 published on CRAN 10 May 2014

http://www.jrwb.de



kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

7/22 jrwb.de

Elements of success



CAKE (Syngenta)





Ranke and Lehmann, SETAC World 20-24 May 2012, Berlinmkin 0.9-27 published on CRAN 10 May 2014

http://www.jrwb.de



kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

8/22 jrwb.de

Soil metabolism of 2,4,5-T in the labCl

Cl

Cl

O O

O

0 50 100 150 200

020

4060

80Commerce

Time

Obs

erve

d

●

●

●

●

● ●● ●

0 50 100 150 200

020

4060

80

Catlin

Time

Obs

erve

d

●

●

●

●● ● ● ●

0 50 100 150

020

4060

80

Fargo

Time

Obs

erve

d

●●●

●

●

●

●

●

0 50 100 150

020

4060

80

Keith

Time

Obs

erve

d

●●●

●

●

● ● ●

0 50 100 150

020

4060

80

Walla Walla

Time

Obs

erve

d

●

●

●

●

●● ●

0 50 100 150

020

4060

80

Cecil

Time

Obs

erve

d

●

●

●

●

●●

●

● T245phenolanisole

McCall et al. (1981) J Agric Food Chem 29 100-107

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

9/22 jrwb.de

2,4,5-T in Commerce soil in gmkin

gmkin user interface

http://www.jrwb.de

http://github.com/jranke/gmkin


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

10/22 jrwb.de

Pathway from 2,4,5-T-phenol to sink?Cl

Cl Cl

OH

k phenol sink negligible - fix to zero

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

11/22 jrwb.de

2,4,5-T in Commerce soil, no path to sink

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

12/22 jrwb.de

Rate parameters log transformed during fit

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

13/22 jrwb.de

Proposal regarding t-test

Instead of testing rate constants for significant difference fromzero:

Use best available estimate

Consider if it is neglibly small

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

14/22 jrwb.de

2,4,5-T in Fargo soil

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

15/22 jrwb.de

2,4,5-T in Fargo soilModel with formation fractions

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

16/22 jrwb.de

2,4,5-T in Fargo soilModel with transformed formation fractions

We get a plausible confidence interval without doing an MCMC

simulation

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

17/22 jrwb.de

Parallel formation of metabolites

Confidence intervals only for single formation fractions(slide corrected after the meeting)

Data from Schafer et al. (2007) Proc. XIII SymposiumPesticide Chemistry, Piacenza, 2007, p. 916-923

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

18/22 jrwb.de

Conceptual comparison of DFOP and SFORB

Both possible for metabolites, but with two extra parameters.

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

19/22 jrwb.de

Alternative with one extra parameter

We could also use an Indeterminate Order Rate Equation(IORE) for metabolites

dm

dt= ...− kmm

n...

This is used in North America for parent compounds as anequivalent alternative to the FOMC model, with the possibilityto test if n is different from unity.

NAFTA Technical Working Group on Pesticides, Guidance forEvaluating and Calculating Degradation Kinetics inEnvironmental Media (7 p)

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

20/22 jrwb.de

Challenges for the future

Better collaboration

Improve error model

Evaluate related datasets in one step (mixed effect models)

Improve model comparisons (ANOVA, AIC)

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

21/22 jrwb.de

Conclusions

With gmkin + mkin, we now have a completely opensourced software toolset

Biphasic models for metabolites can conveniently be fitted

The use of t-tests for parameter significance is questioned

Plausible confidence intervals for rate constants and singleformation fractions are easily available

(slide corrected after the meeting)

http://www.jrwb.de


kinetics

PD Dr.Johannes

Ranke

Tasks andmotivation

Confidenceintervals

Metabolitemodels

Conclusions

22/22 jrwb.de

Documentation

kinfit.r-forge.r-project.org/mkin static

http://www.jrwb.de

http://kinfit.r-forge.r-project.org/mkin_static

Progress in regulatory degradation kinetics - SETAC Europe 24th … · 13-05-2014 · SETAC Europe...

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Transcript of Progress in regulatory degradation kinetics - SETAC Europe 24th … · 13-05-2014 · SETAC Europe...