DEMETRA

Another aspect is that multiple QSAR models can exist, and indeed this is likely. The consequences of such a complex picture, with many endpoints and models based on different approaches, are that it is not realistic to have a single approach, but the models have to be modulated considering these issues. Different approaches can be used for the same target and they improve the reliability of the prediction. In some cases, they have been combined into a unified system to improve overall results. This is the case of the models for regulatory purposes developed within the project DEMETRA (see below). 

Publicly available models may be open source or not. Another difference is that some models require calculation of the chemical descriptors as a separate task, while others simply need the chemical structure. Examples are the EPA [11] and DEMETRA models [20],... 

Another difference in the models is that some are fixed, focused for a certain target, and optimized for that. It is the case of many of the commercial programs and of the public models from EPA and DEMETRA. 

European Projects on QSAR and Regulations 8.6.1 The DEMETRA Project... 

The DEMETRA project [20, 26] represents the first important case of a European project to develop QSAR models for regulatory purposes. DEMETRA developed five free models to determine the ecotoxicity of pesticides using endpoints that include trout, daphnia, bees, and quails (oral and dietary exposure). Since the target was to develop models for the user, these five endpoints were decided by them, not by the developers. 

We notice that in practically all cases, a QSAR model was developed having only considered the data availability, without the other assessment evaluation carried out for the DEMETRA project. 

DEMETRA clearly stated the requirements for the data to be used because the models were based on the Pesticide Directive, and only the data produced according to the protocols defined in the directive were used. 

Regulators and stakeholders within DEMETRA project defined that an accepted uncertainty of the toxicity experimental data was a factor of 4. If the data uncertainty for the same chemical was higher, the chemical was not used for the model in the training set. Here, we notice that QSAR studies do not involve looking at the uncertainty of the property/toxicity value, thereby highlighting the difference between typical and regulatory models. 

Different partners within DEMETRA checked all chemical structures independently, at least twice, to be sure that they were correct, and limited numbers of errors were found. Such quality control processes are typically not carried out in depth, owing to the time and other resources required. 

The full details of the DEMETRA project are available, with full description and explanation [26] and the models and structures are also available [20]. 

The DEMETRA models have been optimized to minimize the number of false negatives in order to achieve a safer regulatory application. Conversely, evaluation using only squared statistical parameters (such as R2), which deal with false positives and negatives in the same manner, is typical in QSAR modeling. 

DEMETRA optimized the algorithms coefficients fixing them in the freely-available software to produce the same result in all European countries. 

The approach of CAESAR is quite similar to that of DEMETRA. So far good results have been obtained for the bioconcentration factor (BCF) in fish, superior to those of other models. Models have been tested with an external validation set. The model gives as prediction the BCF as continuous value, but it has been optimized to reduce false negatives. In the specific case of the REACH legislation, which is the target of the project, bioaccumulative chemicals are defined if the BCF value is above 3.3 in logarithmic unit. This shows another example of the specificity of the models, because different threshold may apply in other countries. 

The EC funded project CHEMOMENTUM will also implement QSAR models for pesticides and industrial chemicals, taken from the DEMETRA and CAESAR projects, and presented in a more user-friendly form [29]. 

CHEMOMENTUM is working with the XML standard. XML has been identified as the preferable standard within the information technology community for QSAR (see for instance the US EPA DSSTox database and the EC projects CHEMOMENTUM, DEMETRA, and OpenMolGRID). 

E. Benfenati, The specificity of the QSAR models for regulatory purposes the example of the DEMETRA project. SAR QSAR Environ. Res. 18, 209-220 (2007)... 

C. Porcelli et al., Regulatory perspectives in the use and validation of QSAR. A case study DEMETRA model for daphnia toxicity. Environ. Sci. Technol. 42, 491 196 (2008)... 

Very recently the EC funded project DEMETRA (http //www.demetra-tox. net) developed a series of QSAR models for the prediction of toxicity of pesticides toward five endpoints trout, daphnia, quail (oral and dietary exposure), and bee [80]. This project introduced a number of innovative issues, compared to previous QSAR models. The target of the project was to develop models for pesticides to be used for regulatory purposes in accord with European legislation. A questionnaire was distributed to a great many end-user to identify their needs. The endpoints to be modeled were chosen from among those defined in writing by the end-user, and not by the modeler, in order to make the models as useful as possible. This attention to the needs of the end-users is unique in the use of QSAR for ecotoxicity prediction. Other novel... 

DEMETRA includes specific confidence restrictions capable of identifying outliers. The regulator can chose the confidence level for a factor of 50 or 10 and then can apply, or not, some restriction rules [80]. This way models with... 

DEMETRA models are based on hybrid techniques. Each model for trout, daphnia, quail, or bee is composed of a number of submodels. A hybrid model integrates, in an intelligent way, the results of the submodels to achieve better prediction values capable of reducing false negatives. The regulator can see the minimal and maximal values of the individual models, should the regulator decide to use the lowest predicted value. Another innovative feature of DEMETRA is that its models are freely available (http //www.demetra-tox. net) for wide use, and the user has only to calculate 2D descriptors. 

We acknowledge the EC funded projects DEMETRA (QLRT-2001-00691), HAIR (SSPE-CT-2003-501997), EUFRAM (QLRT-2001-01346) and CHEMOMENTUM (1ST-2005-033437). 

Fisher, B., Joffre, S., Kukkonen, J., Piringer, M., Rotach, M., and Schatzmann, M. (Eds.) (2005) Meteorology applied to urban air pollution problems. Final Report of COST Action 715. Demetra Ltd Publishers, ISBN 954-9526-30-5... 

Physiology and Clinical Uses of Pentoses and Pentitols, B, L, Horecker et al, Eds. (Springer-Verlag New York, 1969) 408 pp Sugars in Nutrition, H, L, Sipple, K, W. McNutt, Eds. (Academic Press, New York, 1974) passim G, E, Demetra-kopoulos. H. Amos. World Rev Nutr Diet 32, 96-122 (1978) R, Ylikahri Adv, Food Res. 25, 159-180 (1979). Book XylitoL 3 N. Counsel, Ed. (Applied Science London 1978) 191 pp. 

Sfendoni-Mentzou, Demetra, et al., eds. Aristotle and Contemporary Science. 2 vols. New York P. Lang, 2000-2001. 

Plummer EL, Cardis AB, Martinez AJ, Van Saun WA, Palmere RM, Pincus DS, Stewart RR (1983) Pyrethroid insecticides derived from substituted biphenyl-3-methods. Pestic Sci 14 560-570 Porcelli C, Roncaglioni A, Ghana A, Boriani E, Benfenati A (2007) A protocol for quantitative structure, activity relationship (QSAR) for regulatory purposes the example of DEMETRA. In Environmental fate and ecological effects of pesticides, symposium pesticide chemistry, 13th, Piacenza, Italy, Sept 3-6, 2007, pp 669-674. 

Cinotti, L., Smith, C., Sekimoto, H.,Mansani, L., Reale, M., Sienicki, J., August31,2011. Lead-cooled system design and challenges in the frame of Generation IV International Forum-Proceedings of the International DEMETRA Workshop on Development and Assessment of Structural Materials and Heavy Liquid Metal Technologies for Transmutation Systems. Journal of Nuclear Materials 415 (3), 245—253. 

C. Fazio, et al.. Development and assessment of structural materials and heavy liquid metal technologies for transmutation systems (DEMETRA) highlights on major results, in Technology and Components of Accelerator Driven Systems, Workshop Proceedings, Karlsruhe, Germany, 15—17 March 2010, OECD-NEA, June 2011, ISBN 9789264117297. 

---