Dingemans ANSWER workshop 1. Bioassays to determine risks of pharmaceuticals and antibiotics

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1 Dingemans ANSWER workshop 1 to determine risks of pharmaceuticals and antibiotics

2 Dingemans ANSWER workshop 2 Chemical water quality complex case of pharmaceuticals and antibiotics Antropogenic chemicals introduced in aquatic ecosystem - environmental risk assessment - human health (via drinking water) different protection goals Antibiotic interventions (clinical use) ánd different substances: - aminoglycosides - macrolides - beta-lactams - quinolones - sulfonamides - tetracyclines chemical water quality microbial water quality (resistance)

3 Dingemans ANSWER workshop 3 Chemical water quality risk assessment Risk = Exposure x Effect Exposure: chemical analysis environmental quality standards (provisional) health-based guidance values Effect of individual chemicals: toxicology effect of unknown mixtures: biomonitoring water quality monitoring treatment processes bioassays! Toxicology in vitro assays cell tests non-animal based methods alternative approaches alternative test methods New Approach Methods Water Quality bioassays in vitro bioassays bioanalytical tools effect-tools effect-based monitoring bioassay sensors

4 Dingemans ANSWER workshop 4 Chemical water quality risk assessment Risk = Exposure x Effect Exposure: chemical analysis environmental quality standards (provisional) health-based guidance values Effect of individual chemicals: toxicology effect of unknown mixtures: biomonitoring water quality monitoring treatment processes bioassays! Advantages chemical monitoring legislation wellknown approach Challenges chemical monitoring many analyses guidance values may be lacking new chemicals Complementary aspects bioassays total effect read-out unknown chemicals only bioactive chemicals

5 Dingemans ANSWER workshop 5 OneHealth ecotoxicology (surface water) human toxicology (drinking water) effects of chemicals in (drinking) water effects that occur at chronic low exposure impact on quality of life

6 Dingemans ANSWER workshop 6 Regulation and legislation knowledge implementation Australian Guidelines for Water Recycling (2008) WHO guidelines for Potable reuse (2017) : promising, innovative methods Common Implementation Strategy Groups (EU WFD) Rizzo et al. (2018): SCHEER opinion on proposed EU minimum quality requirements for water reuse in agricultural irrigation and aquifer recharge. not sufficient to safeguard chemical water quality (e.g. bioassays are not included) Knowledge implementation programs CEC TTW RoutineEDA / EMERCHE Kennisimpuls Waterkwaliteit Effect-gebaseerd monitoring en mengseltoxiciteit Ketenaanpak Medicijnresten uit Water

7 Dingemans ANSWER workshop 7 Selection bioassays applicability and performance *

8 Dingemans ANSWER workshop 8 models and methods 2015

9 Dingemans ANSWER workshop 9 pharmaceuticals 1. endocrine modulators 2. specific therapeutic modes-of-action birth control pills hormone replacement therapy 3. antibiotics aminoglycosides macrolides beta-lactams quinolones sulfonamides tetracyclines beta-blockers (hypertension/hearth treatment) NSAID (anti-inflammatory) effect on specific nuclear receptors effect on specific G-coupled receptor effect on specific enzyme effects on viability or growth (division) of micro-organisms this requires another approach

10 Dingemans ANSWER workshop 10 Hormone receptor CALUX assays 1. miniaturization 2. effect-directed analysis Zwart et al. Environ. Sci. Technol. 52, 2018 early work: 1990 s

11 Dingemans ANSWER workshop 11 Pharmaceuticals with specific modes-of-action therapeutic mode-of-action unwanted side effects in non-target species (evolutionary conservation) Bioassay: mode-of-action modelled in vitro Class (reference chemical) beta-blockers (metoprolol) NSAIDs (diclofenac) Mode-of-action blocking receptor sites of the 1-adrenergic receptor protein (reducing binding of stress hormones) inhibition of cyclooxygenase enzyme activity (reducing production of prostaglandin hormones that play a key role in vasodilation and thus inflammation) Bioassay Chinese hamster ovary (CHO) cells transfected with genes for human 1- adrenergic receptor and FRET sensor (Förster resonance energy transfer) Chinese hamster ovary (CHO) cells transfected with genes for human cox-1 enzyme protein and fluorescent redox sensor Bernhard et al. Water Research 115, 2017

12 Dingemans ANSWER workshop 12 antibiotics 1. Assays for clinical analysis on antibiotic susceptibility to antibiotics 2. Assays to monitor levels of antibiotics in food or water - broth microdilution assay - colorimetric microbial viability assay - bioluminescence-based assay - chemical analyses - Rikilt Water Scan

13 Dingemans ANSWER workshop 13 antibiotics Rikilt Water Scan developed by RIKILT (Food Safety) test for (specific) bacterial growth inhibition antibiotic-group specific identification (5 different types of plates) growth inhibition correlation between inhibition zone and concentration also in 96-wells plates for dilution series Oost et al. Environ Toxicol Chem 36, 2017

14 Dingemans ANSWER workshop 14 application of the RIKILT waterscan Examples: screening the Dutch Meuse river basin (RWS) antibiotics screening Rijn (RIWA) Included in SIMONI (STOWA) emission of antibiotics from households and hospitals

15 Dingemans ANSWER workshop 15 Interpretation using effect-based trigger values expressed as equivalents of the reference compounds Oost et al. Environ Toxicol Chem 36, 2017 Some bioassays respond to a limited amount of chemicals with specific activity Other bioassays may respond to many different chemicals EBT for each different class of antibiotics

16 Dingemans ANSWER workshop 16 Interpretation using effect-based trigger values expressed as equivalents of the reference compounds Brand et al. Environment International 55, 2013 estrogenic (ERα), androgenic (AR), progestagenic (PR), and glucocorticoid (GR) activities ongoing research in BTO acceptable chronic intake levels for antibiotics?

17 17 Dingemans ANSWER workshop Rizzo et al. Proposed EU minimum quality requirements for water reuse in agricultural irrigation and aquifer recharge: SCHEER scientific advice. Current Opinion in Environmental Science & Health Brack et al. Towards the review of the European Union Water Framework Directive: Recommendations for more efficient assessment and management of chemical contamination in European surface water resources. Sci Total Environ Sonneveld et al. Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol Sci Zwart et al. High-Throughput Effect-Directed Analysis Using Downscaled in Vitro Reporter Gene Assays To Identify Endocrine Disruptors in Surface Water. Environ Sci Technol Bernhard et al. Two novel real time cell-based assays quantify beta-blocker and NSAID specific effects in effluents of municipal wastewater treatment plants. Water Res van der Oost et al. SIMONI (smart integrated monitoring) as a novel bioanalytical strategy for water quality assessment: Part i- model design and effect-based trigger values. Environ Toxicol Chem Brand et al. Trigger values for investigation of hormonal activity in drinking water and its sources using CALUX bioassays. Environ Int. 2013