Free QSARs in Regulatory Eco/Toxicology: Feedback from Users

B. Frayssea, M.L. Teisseirea, S. Moulina, C. Reteunaa, M.C. Lienhartb, C. Perazzoloc, E. Saouterc

aEquiTox,

Lyon, France Chasse-sur-Rhone, France cScience & Environnement, Geneva, Switzerland

bBiomatech,

15th International Workshop on Quantitative Structure-Activity Relationships in Environmental and Health Sciences

Tallinn June, 18th-22d, 2012

How are we?

We are not - Chemists, - QSAR makers, - R&D scientists. We are Regulatory Eco/Toxicologists compiling dossiers in regulatory frameworks (REACh, Biocide, Cosmetic, Detergency). We are the scientists delivering the "Expert judgment"!

Constraints for an expert judgment

The basic equation is EffortQSAR
Prediction + Discussions with Authorities + Testing ?=0

<<<

EffortTesting
Testing

For using QSARs in regulatory frameworks such as REACh, we must:

Trust the prediction (sensitivity, specificity, precision), Be able to very well document the prediction (QPRF).

The Playground
Focus on diversity:
o of QSARs models and endpoints.
Episuite (v4.1) LC50 Fish (96h) LD50-Oral Rat Ames (Salmonella) Skin Sensitisation X X X CAESAR (VEGA, v1.0.4) T.E.S.T. (v4.0.1) X X X (X) (X) OECD Toolbox (v2.3) (X)

o of chemical structures.
Mono-constituent, registered under REACh (full-dossier, disseminated). Main functional group Alcool Phenol/Diphenol Nitrile Amino N# 23 8 2 14 Main functional group Phosphite/phosphate Fluorated Chlorinated N# compounds
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N# 9 4 7 67

Differences between assessors

Influence of "Expert judgment": Ability to make a prediction
93%

Ames test (N=15).

87% 80% 87% %Prediction %Not Determined 20% Consensus: at least two similar decisions

CAESAR

13% 7%

13% Consensus

Asses. 1 Asses. 2 Asses. 3

Consensus makes the prediction more robust, OECD Toolbox: variability for making a prediction AND concluding on the prediction (discrepancies between assessors).

Endpoint predictibility
Two QSARs instead of one.
Ability to make a Prediction vs Not Determined (96h-LC50 fish)

38% 68% 60% 77% %Prediction %Not Determined 62% 32% 40% 23%

Episuite N=60

TEST N=60

OECD TB N=15

Combined N=60

Complementarity of QSARs (different applicability domains)

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QSAR's capabilities (combined) [1/2]

Fish (96h-LC50) N=46
Observed No Hazard 10-100 mg/L 1-10 mg/L < 1 mg/L Predicted 10-100 1-10 No Hazard mg/L mg/L 15 4 0 8 0 1 5 1 0 2 4 2 < 1 mg/L 0 0 3 1

o Accuracy: 0.54 "No Hazard": 0.79 o Overestimation: 0.19 (false positive) o Underestimation: 0.26 (false negative)

Rat (Oral-LD50) N=36

No Hazard Observed 300-2000 mg/kg 50-300 mg/kg 5-50 mg/kg < 5 mg/kg

Predicted No Hazard 19 3 1 0 0 300-2000 50-300 5-50 mg/kg mg/kg mg/kg 4 7 1 0 0 0 1 0 0 0 0 0 0 0 0 <5 mg/kg 0 0 0 0 0

o Accuracy: 0.72 "No Hazard": 0.83 o Overestimation: 0.14 (false positive) o Underestimation: 0.14 (false negative)

QSAR's capabilities (combined) [2/2]

AMES N=59
Observed Negative Positive Predicted Negative Positive 53 1 1 4

o Accuracy: 0.97 o False positive: 0.02 o False negative: 0.02

Skin Sens. N=15

Observed Negative Positive

Predicted Negative Positive 8 0 4 3

o Accuracy: 0.73 o False positive: 0.33 o False negative: 0

Good accuracy for all endpoints, Accuracy improved for "No Effects" cases (LC50-Fish, LD50-Rat), Poor specificity for skin sensitisation.
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Any chemical specificities?

Ability to make a Prediction by chemical groups (Ames, combined, N=66)
0 Alcool (N=21) Phenol/Diphenol (N=7) Nitrile (N=3) Amino (N=14) Phosphite/phosphate (N=8) Fluorated (N=5) Chlorinated (N=8) %Prediction %Not Determined 50% 100%

Prediction can be made for any tested chemical groups.

In-house guidance for Reg. Dossiers

Key message: Trust your prediction, be ready to convince! Reject a prediction instead of keeping a weak value, Use two or more QSARs for one endpoint, Ask at least to two assessors, Confidence in prediction increases with decrease of toxicity, Make a range-band transformation for continuous data, Use QSARs extensively for surrounding issues (C&L, testing strategy, test plan optimisation).
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Special thanks to: Chiarra Perazzolo, alias Assessor 2, Christine Reteuna, alias Assessor 3.

And thank you for your attention.