title: Evaluation and comparison of benchmark QSAR models to predict a relevant REACH endpoint: The bioconcentration factor (BCF).
abstract: The bioconcentration factor (BCF) is an important bioaccumulation hazard assessment metric in many regulatory contexts. Its assessment is required by the REACH regulation (Registration, Evaluation, Authorization and Restriction of Chemicals) and by CLP (Classification, Labeling and Packaging). We challenged nine well-known and widely used BCF QSAR models against 851 compounds stored in an ad-hoc created database. The goodness of the regression analysis was assessed by considering the determination coefficient (R(2)) and the Root Mean Square Error (RMSE); Cooper's statistics and Matthew's Correlation Coefficient (MCC) were calculated for all the thresholds relevant for regulatory purposes (i.e. 100L/kg for Chemical Safety Assessment; 500L/kg for Classification and Labeling; 2000 and 5000L/kg for Persistent, Bioaccumulative and Toxic (PBT) and very Persistent, very Bioaccumulative (vPvB) assessment) to assess the classification, with particular attention to the models' ability to control the occurrence of false negatives. As a first step, statistical analysis was performed for the predictions of the entire dataset; R(2)>0.70 was obtained using CORAL, T.E.S.T. and EPISuite Arnot-Gobas models. As classifiers, ACD and logP-based equations were the best in terms of sensitivity, ranging from 0.75 to 0.94. External compound predictions were carried out for the models that had their own training sets. CORAL model returned the best performance (R(2)ext=0.59), followed by the EPISuite Meylan model (R(2)ext=0.58). The latter gave also the highest sensitivity on external compounds with values from 0.55 to 0.85, depending on the thresholds. Statistics were also compiled for compounds falling into the models Applicability Domain (AD), giving better performances. In this respect, VEGA CAESAR was the best model in terms of regression (R(2)=0.94) and classification (average sensitivity>0.80). This model also showed the best regression (R(2)=0.85) and sensitivity (average>0.70) for new compounds in the AD but not present in the training set. However, no single optimal model exists and, thus, it would be wise a case-by-case assessment. Yet, integrating the wealth of information from multiple models remains the winner approach.
authors.affiliation: Laboratory of Environmental Chemistry and Toxicology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy; Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gissi
authors.affiliation: Laboratory of Environmental Chemistry and Toxicology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Lombardo
authors.affiliation: Laboratory of Environmental Chemistry and Toxicology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Roncaglioni
authors.affiliation: Laboratory of Environmental Chemistry and Toxicology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy; Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Gadaleta
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Giuseppe Felice
authors.initials: GF
authors.lastname: Mangiatordi
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.affiliation: Laboratory of Environmental Chemistry and Toxicology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milano, Italy. Electronic address: emilio.benfenati@marionegri.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Benfenati
mesh_terms: D000818:Animals; D016208:Databases, Factual; D004785:Environmental Pollutants / Q000378:metabolism*; D005399:Fishes / Q000378:metabolism; D008954:Models, Biological; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis
chemical_list: D004785:Environmental Pollutants
keywords: Applicability domain; Bioconcentration factor; QSAR; REACH