Correlations between no observed effect level and selected parameters of the chemical structure for veterinary drugs Grabowski Tomasz a, * , Jaroszewski Jerzy Jan b,1 , Piotrowski Walerian c,2 a Centre of Pharmacokinetics Research FILAB, Ravimed Sp. z o.o., Polna 54, 05-119 Lajski, Poland b Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury, ul. M. Oczapowskiego 13, 10-718 Olsztyn, Poland c Biostatistical Laboratory, Department of Epidemiology, Cardiovascular Disease Prevention and Health Promotion Institute of Cardiology, ul. Alpejska 42 04-628 Warszawa, Poland article info Article history: Received 10 July 2009 Accepted 11 January 2010 Available online 15 January 2010 Keywords: NOEL PSA LogKOW LogSw In silico abstract No observed effect level (NOEL) represents the lowest value among numerous parameters used for the analysis of risk and the safety of a chemical substance and medicinal product. In the present study, the correlation between NOEL and selected topological parameters was determined for a group of 135 veter- inary drugs. Due to the high values of the standard deviation for most of the parameters, the method of NOEL mean values analysis in quintile groups was used. The direct correlations between NOEL and the partition coefficient octanol/water (LogKOW), logarithm of water solubility value (LogSw), polar surface area (PSA), apolar surface area (aPSA), hydrogen bond acceptors and hydrogen bond donors were very low. In quintile groups a significant correlation (P < 0.05) between NOEL and LogKOW, aPSA, PSA, as well as between NOEL and equations based on topological parameters were found. The results obtained indi- cate that, among the analysed parameters, LogSw and PSA play a crucial role in relation to a drug activity, at the NOEL level, in the tested group of compounds. Moreover, the calculation tools, based on the anal- ysis of the molecular structure of topological parameters, can be useful for the prognosis of parameters describing drug safety. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Among others, no observed effect level (NOEL) is a parameter used for veterinary drugs in order to increase their safety for ani- mal and human health (Benford, 2000; US FDA, 2004; WHO, 2004). NOEL represents the lowest value from numerous parame- ters used for the analysis of risk and the safety of a chemical sub- stance and medicinal product safety, such as: no observed adverse effect level (NOAEL); lowest observed effect level (LOEL); lowest observed adverse effect level (LOAEL) and adverse effect level (AEL); NOEL < NOAEL < LOEL < LOAEL < AEL. Depending on a substance, the NOEL value is determined using various biological models and describes: a particular pharmacological or toxicologi- cal effect at the lowest possible level of a dose (subchronic, developmental, reproductive, microbiological NOEL etc.) (Netwig, 2007; Witte et al., 1995). The main purpose of NOEL is to deter- mine the safe quantities of chemical substances consumed by a hu- man. The parameter constitutes an initial value for the calculation of the acceptable daily intake (ADI) using a safety factor (SF), (ADI = NOEL/SF). ADI and NOEL are the initial values for the calcu- lation of the maximum residue level (MRL) EMEA, 2005. NOAEL, identified with NOEL in certain cases, is also used for the calcula- tion of the following values: margin of exposure, reference dose and maximum recommended dose (Contrera et al., 2004; Dourson and Barnes, 1988; Hertzberg and Dourson, 1993; Matthews et al., 2004). The current provisions of the registration authorities require the determination of NOEL for each identified side effect of a drug. The effects of the therapeutic substance on an organism are frequently correlated with particular parameters of the drug’s chemical structure (Farrar et al., 1993; Hollósy et al., 2002; Neighbors et al., 2006). One of the chemical structure parameters related to a drug protein binding ability is lipophilicity. It is usually expressed as an octanol/water partition coefficient. Highly lipo- philic drugs usually bind to plasma proteins better, show a higher 0887-2333/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tiv.2010.01.003 Abbreviations: Å 2 , square ångström; ADI, acceptable daily intake; AEL, adverse effect level; aPSA, apolar surface area; EPMARs, European public MRL assessment reports; F, Fischer test; HBA, hydrogen bond acceptors; HBD, hydrogen bond donors; LOAEL, lowest observed adverse effect level; LOEL, lowest observed effect level; LogKOW, partition coefficient octanol/water (EPI suite algorithm); LogSw, logarithm of water solubility value; MRL, maximum residue level; NOAEL, no observed adverse effect level; NOEC, no observed effect concentration; NOEL, no observed effect level; PSA, polar surface area; R 2 , determination coefficient; SEE, standard estimation error; SF, safety factor; SMILES, simplified molecular input line entry system. * Corresponding author. Tel./fax: +48 (0 22) 78 22 167. E-mail addresses: t.grabowski@filab.com.pl (T. Grabowski), jerzyj@uwm.edu.pl (J.J. Jaroszewski), wpiotrowski@ikard.pl (W. Piotrowski). 1 Tel.: +48 0 89 523 37 58/523 33 63; fax: +48 0 89 523 43 92. 2 Tel.: +48 0 22 343 46 00/815 30 11; fax: +48 0 22 343 45 25. Toxicology in Vitro 24 (2010) 953–959 Contents lists available at ScienceDirect Toxicology in Vitro journal homepage: www.elsevier.com/locate/toxinvit