In silico prediction of persistent, mobile, and toxic pharmaceuticals (PMT): A case study in São Paulo Metropolitan Region, Brazil

Abstract

Computational modelling (in silico) methods based on quantitative structure-activity relationship ((Q)SAR) models, are powerful tools for the assessment of the potential “persistency, mobility, and toxicity” (PMT) of pharmaceuticals compounds. Moreover, the use of (Q)SAR models, is recommended by European Union’s REACH Regulation. In this context, the aims of this research were estimating, for the first time and based by REACH guidelines, the PMT potentials of 115 most sold pharmaceuticals in São Paulo Metropolitan Region (a megacity with 21 million of Brazilian), through five (Q)SAR updated models, namely: the OPERA QSAR; the VEGA QSAR (Version 1.1.5); the EPI Suite (Version 4.11); the ECOSAR (Version, 2.0); and the QSAR Toolbox (Version 4.5). This study prioritized the in-silico predictions from the OPERA and the VEGA, because both QSARs can generate reliable predictions, i.e., they have detailed information about the applicability domains. In silico predictions were performed considering ten endpoints: (i) Molecular weight (MW); (ii) “STP total removal”: Sewage Treatment Plant; (iii) Octanol-water partition coefficient (KOW); (iv) Predicted ready biodegradability; (v) Soil organic adsorption coefficient (KOC); (vi) “Short-term and long-term ecological assessments”; (vii) “Carcinogenicity”; (viii) “Mutagenicity”; (ix) “Estrogen receptor binding”; (x) “Cramer decision tree”. The main results showed that: (a) These 115 pharmaceuticals cover a wide range of so-called small molecules (range from 100 to 600 MW); (b) In STP, a predicted removal lower than 10 % was found for 76 pharmaceuticals; (c) Additionally, 101 chemicals has low (Log KOW <2.5), or medium sorption potential (2.5< log KOW <4.0); (d) Ultimately, 36 PPCPs were considered “persistent” after a weight-of-evidence assessment. In addiction, 17 among these 36 persistent chemicals, were classified as “very mobile” in water (log KOC <3). Finally, only three among 17 PPCPs, namely ciprofibrate, fluconazole and metoclopramide, exhibited one or more toxic characteristics (described in items vi – x). These results it will be possible to alert about the potential risks arising from the indiscriminate disposal of these PPCPs along the water sources of this Brazilian mega metropolis.