Download presentation

Presentation is loading. Please wait.

Published byCarlos O'Neill Modified over 3 years ago

1
Claude Beigel, PhD. Exposure Assessment Senior Scientist Research Triangle Park, USA Practical session metabolites Part III: plenary discussion of results

2
1 Results Example 1 Visual Evaluation of Goodness of fit (Parent + Metabolite1)

3
2 Hands-on Example 1 Visual Assessment (Parent + Metabolite1) GraphAssessment / Remarks Parent Overall fit Good, initial scattering ResidualsRandom distribution Metabolite1 Overall fitExcellent ResidualsRandom distribution

4
3 Hands-on Example 1 Statistical Indices (Parent + Metabolite1) 2 -test Relevant Parameters Estimated (y/n) Number of Parameters Minimum 2 Error Percentage Parent Pini kP yyyy 29.2 Metabolite1 ffM1 kM1 yyyy 24.9 t-test Estimated Value Standard Error Number of Data Points Number of Estimated Parameters P-valueConclusion kP0.05080.0033384<0.001Significant kM10.10180.0320384<0.001Significant

5
4 Hands-on Example 1 Conclusion and Endpoints (Parent + Metabolite1) SFO model is considered appropriate for both parent and metabolite Trigger endpoints for Metabolite 1: DT50 = 6.8 d and DT90 = 22.6 d Modeling endpoints: kP = 0.0508 d -1 (equivalent to half-life of 13.7 d), ffM1= 0.5881 and kM1= 0.1018 d -1 (equivalent to half-life of 6.8 d) kP_M = 0.0299 d -1 (equivalent to half-life of 23.2 d), kP_S = 0.0209 d -1 (equivalent to half-life of 33.1 d), and kM1= 0.1018 d -1 (equivalent to half-life of 6.8 d) or

6
5 Hands-on Example 1 Parent + Metabolite1+ Metabolite2 Initial fit with flow from Metabolite 1 to sink results in formation fraction ffM2 of 0.98 (stepwise fit, parent and M1 parameters fixed) or >1 (simultaneous fit, all parameters free) The question is: should we remove or keep this flow (does Metabolite 1 degrade exclusively to Metabolite 2, or does it form other metabolites and/or bound residues too)? Lets assume that additional information, e.g. a degradation study conducted with Metabolite 1 also suggests 100% formation of Metabolite 2, ffM2 is fixed to 1, i.e. the flow from Metabolite 1 to sink is removed

7
6 Results Example 1 Visual Evaluation of Goodness of fit (Parent + Met1 +Met2)

8
7 Hands-on Example 1 Visual Assessment (Parent + Met1 +Met2) GraphAssessment / Remarks Parent Overall fit Good, initial scattering ResidualsRandom distribution Metabolite1 Overall fitExcellent ResidualsRandom distribution Metabolite2 Overall fitExcellent ResidualsRandom distribution

9
8 Hands-on Example 1 Statistical Indices (Parent + Met1 +Met2) 2 -test Relevant Parameters Estimated (y/n) Number of Parameters Minimum 2 Error Percentage Parent Pini kP yyyy 29.2 Metabolite1 ffM1 kM1 yyyy 25.0 Metabolite2 ffM2 kM2 n (fixed to 1) Y 13.9 t-test Estimated Value Standard Error Number of Data Points Number of Estimated Parameters P-valueConclusion kP0.05070.0021565<0.001Significant kM10.09990.0091565<0.001Significant kM20.01140.0014565<0.001Significant

10
9 Hands-on Example 1 Conclusion and Endpoints (Parent + Met1 +Met2) SFO model is considered appropriate for parent and both metabolites Trigger endpoints Metabolite1 DT50 = 6.9 d and DT90 = 23.1 d Metabolite2 DT50 = 61.0 d and DT90 = 203 d Modeling endpoints: kP = 0.0507 d -1 (equivalent to half-life of 13.7 d), ffM1= 0.5813 and kM1= 0.0999 d -1 (equivalent to half-life of 6.9 d), kM2= 0.0114 d -1 (equivalent to half-life of 61.0 d), kP_S = 0.0212 d -1 (equivalent to half-life of 32.7 d), kP_M = 0.0295 d -1 (equivalent to half-life of 23.5 d), kM1_M2 = 0.0999 d -1 (equivalent to half-life of 6.9 d), and kM2_S = 0.0114 d -1 ( equivalent to half-life of 61.0 d) or

11
10 Results Example 2 Visual Evaluation of Goodness of fit (Parent FOMC)

12
11 Hands-on Example 2, parent FOMC Visual Assessment GraphAssessment / Remarks Parent Overall fitExcellent ResidualsRandom distribution Metabolite Overall fitExcellent ResidualsRandom distribution

13
12 Hands-on Example 2, parent FOMC Statistical Indices 2 -test Relevant Parameters Estimated (y/n) Number of Parameters Minimum 2 Error Percentage Parent Pini P yyyyyy 35.5 Metabolite ffM kM yyyy 24.1 t-test Estimated Value Standard Error Number of Data Points Number of Estimated Parameters P-valueConclusion kM0.02000.0019385<0.001Significant

14
13 Hands-on Example 2 Conclusion and Trigger Endpoints (Parent FOMC) SFO model is considered appropriate for metabolite in combination with FOMC model for parent Trigger endpoints for Metabolite: DT50 = 34.7 d and DT90 = 115 d Endpoints for PEC soil calculations: P = 0.9425, P = 4.436, ffM= 0.8018 and kM= 0.0200 d -1

15
14 Results Example 2 Visual Evaluation of Goodness of fit (Parent DFOP)

16
15 Hands-on Example 2, Parent DFOP Visual Assessment GraphAssessment / Remarks Parent Overall fit Excellent up to DT90, slight overestimation afterward Residuals Random distribution up to DT90 Metabolite Overall fitExcellent ResidualsRandom distribution

17
16 Hands-on Example 2, Parent DFOP Statistical Indices 2 -test Relevant Parameters Estimated (y/n) Number of Parameters Minimum 2 Error Percentage Parent Pini g k1 k2 yyyyyyyy 46.5 Metabolite ffM kM yyyy 23.6 t-test Estimated Value Standard Error Number of Data Points Number of Estimated Parameters P-valueConclusion k10.32270.0613386<0.001Significant k20.03400.0064386<0.001Significant kM0.02160.0021386<0.001Significant

18
17 Hands-on Example 2 Conclusion and Modeling Endpoints (Parent DFOP) SFO model is considered appropriate for metabolite in combination with DFOP model for parent Modeling endpoints (higher Tier approach based on parent DFOP): g = 0.5509, k1 = 0.3227 d -1 (equivalent to half-life of 2.15 d), k2 = 0.0340 d -1 (equivalent to half-life of 20.4 d), ffM= 0.8332 and kM= 0.0216 d -1 (equivalent to half-life of 32.0 d)

19
18 Results Example 2 Visual Evaluation of Goodness of Fit (Metabolite Decline)

20
19 Hands-on Example 2, Metabolite Decline Visual Assessment GraphAssessment / Remarks Metabolite decline Overall fit Good, slight underestimation at last time points ResidualsNo distinct pattern

21
20 Hands-on Example 2, Metabolite Decline Statistical Indices 2 -test Relevant Parameters Estimated (y/n) Number of Parameters Minimum 2 Error Percentage Metabolite Mmax kM yyyy 25.7 t-test Estimated Value Standard Error Number of Data Points Number of Estimated Parameters P-valueConclusion kM0.02160.0021122<0.001Significant

22
21 Hands-on Example 2 Conclusion and Endpoints (Metabolite Decline) SFO model is considered appropriate for metabolite decline Metabolite decline rate may be used as worst-case estimate for trigger endpoints Trigger endpoints: DT50 = 49.7 d and DT90 = 165 d (compared to DT50 = 34.7 d and DT90 = 115 d from actual degradation rate) Decline rate may also be used as modeling endpoint for metabolite, if calculated from maximum observed Modeling endpoint: kM= 0.0139 d -1 (equivalent to half-life of 49.7 d)

Similar presentations

OK

Parent Session #1 Thursday, March 5th, 2015. Parent Session #1 Thursday, March 5, 2015.

Parent Session #1 Thursday, March 5th, 2015. Parent Session #1 Thursday, March 5, 2015.

© 2017 SlidePlayer.com Inc.

All rights reserved.

Ads by Google

Ppt on cattle farming for class 9 Ppt on magnetic field lines Ppt on south america continent Ppt on regular expression library Free download ppt on area related to circles Ppt on waves tides and ocean currents and weather Ad mad show ppt on tv Jit ppt on manufacturing overhead Ppt on road accidents Ppt on seven segment display decoder