Abstract

An environmental risk assessment is presented for mycophenolic acid (MPA), an immunosuppressive pharmaceutical used for prevention of organ rejection, and its prodrug mycophenolate mofetil (MPM). Mycophenolic acid will not significantly adsorb to activated sludge. In activated sludge, 14C‐MPA attained >80% degradation, supporting an older environmental fate test with the same compound. Based on n‐octanol/water distribution coefficient (log DOW) values of 2.28, 0.48, and ≤–1.54 at pH 5, 7, and 9, respectively, MPA is not expected to bioaccumulate. Sales amounts of MPA+MPM in Europe were used to derive predicted environmental concentrations (PECs) in surface waters; PECs were refined by including expected biodegradation in sewage treatment, average drinking water use, and average dilution of the effluents in the receiving waters per country. In addition, the exposure to pharmaceuticals in the environment (ePiE) model was run for 4 European catchments. The PECs were complemented with 110 measured environmental concentrations (MECs), ranging from below the limit of quantitation (<0.001 µg/L) to 0.656 µg/L. Predicted no‐effect concentrations (PNECs) were derived from chronic tests with cyanobacteria, green algae, daphnids, and fish. The comparison of PECs and MECs with the PNECs resulted in a differentiated environmental risk assessment in which the risk ratio of PEC/PNEC or MEC/PNEC was <1 in most cases (mostly >90%), meaning no significant risk, but a potential risk to aquatic organisms in generally <10% of instances. Because this assessment reveals a partial risk, the following questions must be asked: How much risk is acceptable? and Through which measures can this risk be reduced? These questions are all the more important in view of limited alternatives for MPM and MPA and the serious consequences of not using them. Environ Toxicol Chem 2019;38:2259–2278. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Highlights

  • Pharmaceuticals in the environment have gained increasing scientific and regulatory attention over the past 30+ yr (Straub and Hutchinson 2014; Kümmerer 2016)

  • Because mycophenolate mofetil (MPM) is fully cleft to mycophenolic acid (MPA) and the excreted metabolites are 7‐O‐MPA glucuronide (MPAG) and MPA, all new tests were performed with the active moiety MPA

  • Gao et al (2014) exposed D. rerio embryos at 72 hpf in an acute toxicity assay over 24 h; this test resulted in an LC50 of 55.4 μmol MPA/L (17.75 mg/L), which is clearly lower than the results reported for juvenile carp over 96 h in an OECD test guideline 203 (Organisation for Economic Co‐operation and Development 1993) test of >100 mg/L (European Chemicals Agency 2018) and may evidence increased sensitivity of embryonic stages

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Summary

Introduction

Pharmaceuticals in the environment have gained increasing scientific and regulatory attention over the past 30+ yr (Straub and Hutchinson 2014; Kümmerer 2016). Regulatory requirements for environmental risk assessments for APIs have been introduced and developed further in the United. One particular issue regarding pharmaceuticals in the environment concerns those APIs that have carcinogenic, mutagenic, or reprotoxic properties in laboratory mammals, due to the suspicion of comparable adverse effects in environmental organisms (Committee for Medicinal Products for Human Use 2015). The present study is an environmental risk assessment for an API with such carcinogenic, mutagenic, or reprotoxic properties, mycophenolic acid (MPA), which has gathered attention in various prioritization lists for pharmaceuticals in the environment (Roos et al 2012; Daouk et al 2015; Guo et al 2015; Aubakirova et al 2017; Santos et al 2017a)

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