Download presentation

Presentation is loading. Please wait.

Published byLillian Patterson Modified over 5 years ago

1
26-27 Jan 2005 Page 1 FOCUS Kinetics training workshop Chapter 7 Recommended Procedures to Derive Endpoints for Parent Compounds Ralph L. Warren, Ph.D. DuPont Crop Protection Delaware, USA

2
26-27 Jan 2005 Page 2 FOCUS Kinetics training workshop Objectives of this part of the training: Description of the procedures to follow for a parent compound to derive endpoints for use as a) trigger values for additional work b) inputs for environmental exposure models (e.g. PECgw) Assessment of kinetic model fits to the observed data using visual and statistical techniques. Selection of the appropriate kinetic model and endpoints for the case of triggers and exposure modelling.

3
26-27 Jan 2005 Page 3 FOCUS Kinetics training workshop Why the distinction between fitting for trigger endpoints versus exposure modelling endpoints? Current regulatory environmental exposure models are based on SFO kinetics. Therefore, an endpoint (i.e. DT 50 ) calculated using a non-SFO kinetic model will not appropriately represent the observed behavior when input into a SFO-based exposure model. A SFO endpoint, if appropriate, or a conservative estimate or a work around must be used. Regulatory triggers are based on DT 50 and DT 90 values which are not constrained to any kinetic model form. The model that most appropriately describes the observed data should be used to generate the endpoint values.

4
26-27 Jan 2005 Page 4 FOCUS Kinetics training workshop The same DT 50 does not mean the same pattern of decline when calculated using different kinetic models

5
26-27 Jan 2005 Page 5 FOCUS Kinetics training workshop Regulatory triggers – examples Annex II to Directive 91/414/EEC 7.1.1.2.2. Field dissipation studies are required when DT 50lab > 60 days at 20 C or 90 days at 10 C Annex III to Directive 91/414/EEC 10.7.1 Testing for effects on soil micro-organisms required when DT 90field > 100 days Draft Guidance Doc. Terrestrial Ecotoxicology (SANCO/10329/2002 rev. 2 final) Sub-lethal earthworm tests required depending on number of applications and DT 90field Guidance Doc. Aquatic Ecotoxicology (SANCO/3268/2001 rev. 4 final) Chronic study on daphnids required when DT 50 in water > 2 days

6
26-27 Jan 2005 Page 6 FOCUS Kinetics training workshop So whats involved in the fitting procedure? Triggers for additional workmodelling endpoints Run SFO and FOMC as a first step Run SFO as a first step Check visual fit and calculate error percentage at which 2 test passed If FOMC better than SFO, test other bi-phasic models Check visual fit and calculate error percentage at which 2 test passed If error % < 15% and visual fit acceptable, use SFO DT 50 If error % > 15% and visual fit not acceptable, run bi-phasic model Use best model fit If 10% of initial reached in study period then calculate DT 50 as FOMC DT 90 /3.32 If 10% of initial not reached in study period then use longer DT 50 from slow phase of HS or DFOP Check optimized parameter uncertainty!

7
26-27 Jan 2005 Page 7 FOCUS Kinetics training workshop Chi-square ( 2 ) test statistic where C = calculated value O = observed value = mean of observed (element of scale) err = measurement error (element of proportionality) If 2 > 2 m, then the model is not appropriate at the chosen sig. level where m = degrees of freedom (No. of obs. used in the fitting – No. of optimized model parameters) = level of significance, typically 5% Remember to use average values where there are replicates!

8
26-27 Jan 2005 Page 8 FOCUS Kinetics training workshop Chi-square ( 2 ) test statistic Since the measurement error is typically unknown (would require numerous replicate measurements) a common error model was proposed. The percent error value is scaled to the mean of the observed values. Therefore, the error term is constant through the measurement period. The relative error is lower for early time points and increases for later time points, which is consistent with the recommendation for unweighted fitting. The minimum error percentage at which the test is passed can be directly calculated. where: C = calculated, O = observed, = mean of observed, and 2 tabulated = lookup value of 2 at the 0.05 significance level for the appropriate degrees of freedom (no. obs. values used in fitting – no. optimized parameters)

9
26-27 Jan 2005 Page 9 FOCUS Kinetics training workshop Chi-square ( 2 ) test statistic Note that field data are inherently more variable than lab data. Therefore the error percentages at which 2 is passed will be larger. The model with the lower 2 error percentage is defined as more appropriate. Further note there is no inherent and definitive error value for any given test system. Choice of an acceptable value is pragmatic and should be considered in light of the visual assessment and parameter uncertainty.

10
26-27 Jan 2005 Page 10 FOCUS Kinetics training workshop Visual Assessment Subjective, yet powerful tool for assessing goodness of fit. Keeps common sense in the assessment process. Two recommended plots > Plot of fitted versus observed over time (typical plot) > Plot of residuals (Predicted – Observed) over time

11
26-27 Jan 2005 Page 11 FOCUS Kinetics training workshop Parameter uncertainty Confidence intervals or t-tests may be used. The t-test is shown below, which assumes normally distributed parameters. where = estimate of parameter i = standard error of parameter i The probability (p-value) for the calculated t-value can be read from statistical tables or calculated with Excel TDIST(t caclulated,df,1) If p is < 0.05 then the parameter is considered significantly different than zero. If p is between 0.05 and 0.1 then weight of evidence should be considered. The t-test is most applicable to degradation rates (k), not necessarily other parameters such as or for FOMC.

12
26-27 Jan 2005 Page 12 FOCUS Kinetics training workshop Parent only flow chart for deriving trigger endpoints (zoom to view) Triggers flowchart

13
26-27 Jan 2005 Page 13 FOCUS Kinetics training workshop Parent only flow chart for deriving exposure modelling endpoints (zoom to view) modelling flowchart

14
26-27 Jan 2005 Page 14 FOCUS Kinetics training workshop Lets look at an example for the triggers flowchart… Time (days) % of applied radioactivity 0 0 3 3 7 7 14 14 30 30 45 45 62 62 90 90 120 120 93.1 99.7 72.9 83.8 60.3 60.3 41.7 37.4 23.3 26.0 20.9 17.1 18.8 18.8 17.9 18.5 16.7 15.9 Laboratory degradation of a compound in aerobic soil

15
26-27 Jan 2005 Page 15 FOCUS Kinetics training workshop

16
26-27 Jan 2005 Page 16 FOCUS Kinetics training workshop

17
26-27 Jan 2005 Page 17 FOCUS Kinetics training workshop Parameter uncertainty ModelParameterOptimized value Standard error Different than zero? (t-test) SFOM0 k 86.98 0.0382 5.399 0.0061 -- Yes FOMCM0 98.20 0.7063 6.372 3.032 0.1038 1.976 -- -- -- DFOPM0 g k 1 k 2 96.79 0.7914 0.09305 0.00149 1.768 0.0326 0.0085 0.00195 -- -- Yes No (P=0.229)

18
26-27 Jan 2005 Page 18 FOCUS Kinetics training workshop Use DFOP with associated endpoints > DT 50 = 10.0 d, DT 90 = 472 d > Relax t-test criteria for k 2 based on visual fit and 2. > Check if other aerobic soil deg and fate studies support this DT 90. Use DFOP. Fix k 2 to a conservative value (e.g. 1000 d) > 2 and visual fits equivalent to above. > DT 50 = 10.1 d, DT 90 = 922 d > Check if other aerobic soil deg and fate studies support this DT 90. Possible conclusions for this data set for the trigger flowchart For comparison with regulatory DT 50 triggers, the result is the same. For comparison with regulatory DT 90 triggers, the result is the same.

19
26-27 Jan 2005 Page 19 FOCUS Kinetics training workshop Continuing with the same data, now lets look at it using the modelling flowchart…

20
26-27 Jan 2005 Page 20 FOCUS Kinetics training workshop

21
26-27 Jan 2005 Page 21 FOCUS Kinetics training workshop Assuming no artifacts, the data is clearly bi-phasic. FOMC fit to the data is superior based on visual assessments and 2 error. If aim of modelling is to link parent with metabolites, then the guidance in Chapter 8 should be followed (covered tomorrow). If the aim is to model parent fate only then check to see if 10% of the initially measured value was reached during the study period. > If yes, then use FOMC DT 90 /3.32 to derive a conservative estimate of SFO DT 50 for modelling (i.e. 160 d/3.32 = 48.2 d). > If no, then use slower k from HS or slower k from DFOP to derive a conservative estimate of DT 50 for modelling.

22
26-27 Jan 2005 Page 22 FOCUS Kinetics training workshop SFODT 50 = 18.1 d DT 90 = 60.2 d FOMCDT 50 = 10.6 d DT 90 = 160 d FOMC DT 90 /3.32 = 48.2 d (SFO) FOMC DT 90 /3.32 is a conservative option where parent only exposure modelling is desired (cant link to metabolites!) FOMC DT 90 /3.32 example (assume last point did reach 10%)

23
26-27 Jan 2005 Page 23 FOCUS Kinetics training workshop

24
26-27 Jan 2005 Page 24 FOCUS Kinetics training workshop Parameter uncertainty ModelParameterOptimized value Standard error Different than zero? (t-test) HSM0 tb k 1 k 2 95.81 21.92 0.06448 0.00397 1.82 1.70 0.00375 0.00162 -- -- Yes Yes DFOPM0 g k 1 k 2 96.79 0.7914 0.09305 0.00149 1.768 0.0326 0.0085 0.00195 -- -- Yes No (P=0.229)

25
26-27 Jan 2005 Page 25 FOCUS Kinetics training workshop Use longest phase of HS to derive conservative value of DT 50 > 10% of initial not reached, so HS and DFOP were assessed. > Longest k from DFOP is not different than zero so it is unreliable. Possible conclusions for this data set for the modelling flowchart Conduct higher-tier modelling using conservative value for DFOP slow phase DT 50 (e.g. 1000 d).

26
26-27 Jan 2005 Page 26 FOCUS Kinetics training workshop Questions?

27
26-27 Jan 2005 Page 27 FOCUS Kinetics training workshop Now its your turn to work through the flowcharts using the observed and fitted data from this morning…

Similar presentations

Presentation is loading. Please wait....

OK

Hypothesis Tests: Two Independent Samples

Hypothesis Tests: Two Independent Samples

© 2019 SlidePlayer.com Inc.

All rights reserved.

To make this website work, we log user data and share it with processors. To use this website, you must agree to our Privacy Policy, including cookie policy.

Ads by Google