Pharmaceuticals

UNCERTAINTY AND VARIABILITY IN RISK ASSESSMENT OF HUMAN PHARMACEUTICALS - Uncertainty risk assessment of human pharmaceuticals and variability in environmental RIK OLDENKAMP Rik Oldenkamp Uncertainty and variability in environmental risk assessment of human pharmaceuticals Rik Oldenkamp Colofon Author: Rik Oldenkamp Cover design en lay-out: Miranda Dood, Mirakels Ontwerp Photography cover: Nils van Rooijen Printing: Gildeprint - The Netherlands ISBN: 9789492380012 Uncertainty and variability in environmental risk assessment of human pharmaceuticals. PhD thesis, Radboud University, Nijmegen, the Netherlands. © Oldenkamp, R., 2016 All rights reserved. No part of this publication may be reproduced or transmitted in any form by any means, without permission of the author. Uncertainty and variability in environmental risk assessment of human pharmaceuticals Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus, volgens besluit van het college van decanen in het openbaar te verdedigen op dinsdag 14 juni, om 14:30 uur precies door Rik Oldenkamp geboren op 4 oktober 1984 te Wageningen Promotoren Prof. dr. A.M.J. Ragas Prof. dr. M.A.J. Huijbregts Manuscriptcommissie Prof. dr. ir. A.J. Hendriks Prof. dr. F.G.M. Russel Prof. dr. A.B.A. Boxall Paranimfen Daan Huizer Marloes Oldenkamp Don’t be like the ingrate who got a castle as a present and worried about the mildew in the bathroom – remember that you are a Black Swan. | Nassim Nicholas Taleb Uncertainty and variability in environmental risk assessment of human pharmaceuticals TABLE OF CONTENTS Chapter 1 General introduction p.12 Chapter 2 Spatially explicit prioritisation of human antibiotics and p.22 antineoplastics in Europe Environment International, 51: 13-26. Chapter 3 Environmental impact assessment of pharmaceutical p.48 prescriptions: does location matter? Chemosphere, 115: 88-94. Chapter 4 The influence of uncertainty and location-specific p.66 conditions on the environmental prioritisation of human pharmaceuticals in Europe Environment International, 91: 301-311. Chapter 5 Predicting concentrations of the cytostatic drugs p.90 cyclophosphamide, carboplatin, 5-fluorouracil, and capecitabine throughout the sewage effluents and surface waters of Europe Environmental Toxicology and Chemistry, 32(9): 1954-1961. Chapter 6 Uncertainty and variability in human exposure limits p.110 – a chemical-specific approach for ciprofloxacin and methotrexate Critical Reviews in Toxicology, 46(3): 261-278. 8 Table of Contents Chapter 7 Hierarchical Bayesian approach to reduce uncertainty in the p.140 aquatic effect assessment of realistic chemical mixtures Environmental Science and Technology, 49(17): 10457-10465. Chapter 8 General discussion p.160 Literature cited p.178 Summary p.206 Samenvatting p.210 Rik assessment p.219 Acknowledgments p.222 9 1 CHAPTER 1 General introduction Uncertainty and variability in environmental risk assessment of human pharmaceuticals 1.1 PHARMACEUTICALS IN THE ENVIRONMENT 1 Since ancient times humans have used natural resources for the treatment of disease. Indeed, archaeological evidence suggests that natural antibiotics and laxatives were already used in prehistorical times [1], and the first structural documentations of traditional Chinese medicine date back more than 3000 years [2]. However, it took until halfway through the nineteenth century for modern day medicine to arise. Facilitated by the emergence of the sciences of pharmacology and synthetic organic chemistry, the already present apothecaries began their transition into pharmaceutical companies [3, 4]. Since then, pharmaceutical companies have grown into the global enterprises with yearly billion-dollar revenues that they are today [5], contributing significantly to the worldwide increase in life expectancy and quality [6]. Along the way, the originally empirical chemistry-driven search for new pharmaceuticals shifted towards a target- based biology-driven approach in which new pharmaceuticals are designed rather than discovered [4]. Consequently, newly developed pharmaceuticals have become increasingly effective through designing for increased potency, bioavailability and degradation resistance [8]. Due to these characteristics and their large consumption volumes [9], human pharmaceuticals can be transported into the environment via the effluent of sewage treatment plants or bound to sewage sludge dispersed on agricultural soils (Fig. 1.1). Indeed, several decades ago the first observations of pharmaceuticals detected in the aquatic environment arose in scientific literature[10-12] . However, only after the publication of influential reviews from Halling-Sørensen et al. [7], Ternes [13] and Daughton and Ternes [14] did the topic catch broader interest, resulting in a considerable increase in the amount of peer-reviewed publications related to pharmaceuticals in the environment [15, 16]. The majority of these studies focused on the documentation of the presence of pharmaceuticals in media such as wastewaters, surface waters and ground waters [17-19]. As a result of improvements in analytical sensitivity and selectivity, pharmaceuticals were even detected in drinking waters [e.g., 20, 21], proving that they can eventually make their way back to humans. Additionally, human exposure routes other than drinking water have been identified in the form of the consumption of fish[22-24] and agricultural crops, as pharmaceuticals bound to agriculturally dispersed sewage sludge can be taken up from soils into plants [25]. 12 General introduction Human pharmaceuticals 1 Excretion parent Disposal of leftover compound pharmaceuticals to sewerage Sewage treatment plant Sludge dispersed on Sewage effluent agricultural soils Runoff Aquatic environment FIGURE 1.1 Pathways of human pharmaceuticals into the aquatic environment (modified from Halling- Sørensen et al. [7]). Although concentrations reported are generally low, i.e. in the ng/L to µg/L range [18,19,26], adverse effects caused by pharmaceuticals are not unlikely considering their specific modes of action and high potency. This has become apparent in the feminising effect of (semi-)synthetic steroidal hormones on fish downstream of sewage treatment plants [27], and the catastrophic decline of vulture populations in the Indian subcontinent due to diclofenac poisoning [28]. Contrary to ecological risks, human health risks resulting from environmental exposure to pharmaceuticals have been considered negligible in a number of risk assessment studies [29-32]. However, since these studies tend to lack differentiation (e.g., spatially or interindividually), completeness (e.g., only exposure via drinking water), and/or specificity (e.g., the use of general dilution factors or general intake rates), a more sophisticated analysis is required before solid conclusions can be drawn. 13 Uncertainty and variability in environmental risk assessment of human pharmaceuticals 1.2 REGULATION AND PRIORITISATION OF PHARMACEUTICALS 1 In the wake of the increasing scientific and public awareness on the issue of human pharmaceuticals in the environment, a formal European guideline has been installed for the registration of new pharmaceuticals [33]. This guideline requires new pharmaceuticals to be subjected to an environmental risk assessment (ERA) for their registration (see Box 1.1 for a description of chemical risk assessment in general and Box 1.2 for a description of the ERA required for pharmaceuticals). However, any potential risks to the environment identified through this procedure are not grounds to block their marketing approval. Furthermore, existing pharmaceuticals are not part of the guideline and are thus not explicitly addressed in current legislation. Exceptions to this are three pharmaceutical compounds that have been proposed for inclusion on the list of priority substances as formulated in the Water Framework Directive, i.e. the abovementioned diclofenac and the two steroidal hormones 17α-ethinylestradiol and 17β-estradiol [34]. However, there are currently thousands of different pharmaceuticals in use, a far too large number to assess experimentally within a reasonable timeframe. Therefore, their prioritisation for further study has been identified as one of the key outstanding issues concerning pharmaceuticals in the environment [35]. A logical first step is to focus on the group, or groups, of pharmaceuticals considered most likely to be a threat to the environment and/or human health. Cunningham et al. [29] identified anticancer agents and antibiotics as two such groups (see Box 1.3). Subsequently, several methods can be used for further prioritisation of the individual pharmaceuticals, a number of which have been discussed and compared by Roos et al. [36]. More recently, Caldwell et al. [37] have proposed a combined prioritisation approach integrating multiple earlier developed methods. Many of these methods are either based on simple chemical- specific characteristics and hazard estimations[38, 39], basic exposure and toxicological predictions [40], or information on pharmaceutical potency [41]. While such relatively simple and straightforward approaches enable the assessment of a large number of pharmaceuticals, their lack of spatial differentiation limits their application potential [35]. Indeed, prioritisations are likely to vary between geographical regions due to differences in for example pharmaceutical consumption, demographics, sewage treatment plant 14 General introduction design,

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