Stereoisomeric profiling of chiral pharmaceutically active compounds in wastewaters and the receiving environment – A catchment-scale and a laboratory study

Dolores Camacho-Muñoz,Bruce Petrie,Luigi Lopardo,Kathryn Proctor,Jack Rice,Jane Youdan,Ruth Barden,Barbara Kasprzyk-Hordern

doi:10.1016/j.envint.2019.03.050

Abstract

Chiral pharmaceutically active compounds (cPACs) are not currently governed by environmental regulation yet are expected to be in the future. As cPACs can exert stereospecific toxicity in the aquatic environment, it is essential to better understand their stereoselective behaviour here. Therefore, this study aims to provide a new perspective towards comprehensive evaluation of cPACs at a river catchment level, including their stereochemistry as a chemical phenomenon driving fate of chiral molecules in the environment. A large spatial and temporal monitoring program was performed in Southwest England. It included 5 sewage treatment works and the receiving waters of the largest river catchment in Southwest England. Simultaneously, lab-scale microcosm studies in simulated activated sludge bioreactors and river water microcosm were performed to evaluate stereoselective degradation of cPACs. A multi-residue enantioselective method allowed the analysis of a total of 18 pairs of enantiomers and 3 single enantiomers in wastewater and river water samples.Our monitoring program revealed: (1) spatial and temporal variations of cPACs in influent wastewaters resulting from different patterns of usage as well as an (2) enantiomeric enrichment of cPACs, likely due to human metabolism, despite their commercialization as racemic mixtures. A similar chiral signature was observed in effluent and receiving waters. Stereoselective degradation was observed in trickling filters (TF) for naproxen, ketoprofen, cetirizine and 10,11-dihydroxy-10-hydroxycarbamazepine, in sequencing batch reactors (SBR) for ifosfamide and in activated sludge (AS) for cetirizine. The extent of enantiomer-specific fate was wastewater treatment dependent in the case of naproxen (TF showed higher stereoselectivity than AS and SBR) and cetirizine (TF and AS showed higher stereoselectivity than SBR) due to differing microbial population. Furthermore, stereoselective degradation of naproxen was highly variable among STWs using similar treatments (TF) and operating in the same region. Microbial stereoselective degradation was also confirmed by both activated and river water simulated microcosm for chloramphenicol, ketoprofen, indoprofen, naproxen and 10,11-dihydroxy-10-hydroxycarbamazepine. Results from our large scale river catchment monitoring study and lab simulated microcosm show wide-ranging implications of enantiomerism of cPACs on environmental risk assessment (ERA). As two enantiomers of the same compound show different biological effects (e.g. toxicity), their non-racemic presence in the environment might lead to inaccurate ERA. This is because current ERA approaches do not require analysis at enantiomeric level.

Highlights

Substantial attention has been given to the presence of pharmaceutically active compounds (PACs) in environmental matrices because of their ubiquity and potential ecological risks (Cizmas et al, 2015; Ebele et al, 2017)
This study aims to provide a new perspective towards comprehensive evaluation of Chiral pharmaceutically active compounds (cPACs) at a river catchment level, including their stereochemistry as a chemical phenomenon driving the fate of chiral molecules in the environment
Considering, the results presented in Section 3.1.1.2, significant differences were observed in the enantiomeric fraction (EF) of some cPACs depending on the wastewater treatment technology used (Figs. 3 and S6)

Summary

Introduction

Substantial attention has been given to the presence of pharmaceutically active compounds (PACs) in environmental matrices because of their ubiquity and potential ecological risks (Cizmas et al, 2015; Ebele et al, 2017). The therapeutic effect of non-steroidal anti-inflammatory drugs resides almost exclusively in the S-enantiomer (S-(+)-ibuprofen is 110 times more active than R-(−)-ibuprofen (Adams et al, 1976; Villaneuva et al, 1993)) whereas the R-enantiomer are partly active, inactive or toxic (naproxen is prescribed as S-(+)-naproxen because the R-enantiomer is suspected to be a liver toxin (Harrington and Lodewijk, 1997)); they can be enantiomer-specific towards aquatic organisms (R-(−)-fluoxetine is 30 times more toxic to the protozoan T. thermophila and more harmful to the algae P. subcapitata than S-(+) fluoxetine whereas S-(+)-fluoxetine is 10 times more toxic to the fish P. promelas than its antipode (AndrésCosta et al, 2017; De Andrés et al, 2009) In spite of this well-established enantiomer-specific toxicity, many cPACs are commercialized as an equal mixture of both enantiomers known as a racemic mixture and indicated by an enantiomeric fraction (EF) of 0.5

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Conclusion