Pharmaceuticals and Personal Care Products in the Environment: What are the Key Research Questions? Alistair BA Boxall, Murray A Rudd, Bryan W Brooks, Daniel J Caldwell, Kyungho Choi, Silke Hickmann, Elizabeth Innes, Kim Ostapyk, Jane P Staveley, Tim Verslycke

Why a prioritisation exercise?

Key Questions Approach Horizon scanning method Systematic way to identify major research and policy directions Previous exercises on ecology, conservation, biodiversity and agriculture Int. J. Agric. Sust. 8(4): 2010

20 Question Exercise Run by the SETAC Pharmaceuticals Advisory Group (PAG) Effects and risks of PPCPs Global exercise Approach Web-based survey Expert workshop (April 2011) Out of scope: analysis, occurrence, treatment etc Future dissemination to policy makers and research funders

An ideal question Address important gaps in knowledge Be answerable through a realistic research design Have a factual answer that does not depend on value judgments Cover a spatial and temporal scale that could realistically be addressed by a research team($10M over 5 years) Not be answerable by it all depends or yes or no If related to impact and interventions, should contain a subject, an intervention, and a measurable outcome

Input Geographical inputSector input 403 Questions

SETAC PAG 20 Question Exercise

General categories of questions prioritisation of substances for assessment routes of exposure bioavailability and uptake effects assessment risk antibiotic resistance risk management

Prioritisation What parameters should be used to prioritize PPCPs for research on environmental and human health exposure and effects? >4000 PPCPs properties usage mode of action side effects QSAR predictions therapeutic dose etc. Compounds of most concern

Routes of exposure What are the environmental exposure pathways for organisms (including humans) to PPCPs in the environment and are any of these missed in current risk assessment approaches? ?

Bioavailability and uptake How can the uptake of ionizable PPCPs into aquatic and terrestrial organisms and through food chains be assessed? What is the bioavailability of non-extractable residues of PPCPs?

Effects characterisation How can pharmaceutical preclinical and clinical information be used to assess the potential for adverse environmental impacts of pharmaceuticals? What can be learned about the evolutionary conservation of PPCP targets across species and life stages in the context of potential adverse outcomes and effects? How can non-standard ecotoxicological responses (e.g., biomarkers), observed for PPCPs, be translated to traditional ecologically important endpoints such as survival, growth and reproduction of a species?

Non standard vs traditional endpoints SETAC 20Q Exercise 2011

Effects characterisation How can ecotoxicity test methods, which reflect the different modes of actions of active PPCPs, be developed and implemented in customized risk assessment strategies? How can effects from long-term exposure to low concentrations of PPCP mixtures on non-target organisms be assessed? Can non-animal testing methods be developed that will provide equivalent or better hazard data compared to current in vivo methods?

Risk and relative risks How can regions where PPCPs pose the greatest risk to environmental and human health, either now or in the future, be identified? How important are PPCPs relative to other chemicals and non-chemical stressors in terms of biological impacts on the natural environment? Do PPCPs pose a risk to wildlife such as mammals, birds, reptiles and amphibians?

Risk and relative risks How can the environmental risks of metabolites and environmental transformation products of PPCPs be assessed? How can retrospective analyses be used to validate prospective risk assessments?

Antibiotic resistance Does environmental exposure to PPCP residues result in the selection of antimicrobial resistant micro-organisms and is this important in terms of human health outcomes? How can the risks to human health, arising from antibiotic resistance selection by PPCPs in the natural environment, be assessed?

Risk management If a PPCP has an adverse environmental risk profile what can be done to manage and mitigate the risks? What effluent treatment methods are effective in reducing the effects of PPCPs in the environment while at the same time not increasing the toxicity of whole effluents? How can the efficacy of risk management approaches be assessed?

Ranking of questions Niagara workshop participants only Web-based Participants asked to select top ranked and lowest ranked questions from sets of four to generate a top 20 list identify challenges/barriers to addressing a question

Ranked order of 20 Important PPCP Questions: Means calculated with Hierarchical Bayesian (HB) 95% CI now calculated with sample mean (vs HB)

How important are PPCPs relative to other chemicals and non-chemical stressors in terms of biological impacts on the natural environment?

What parameters should be used to prioritize PPCPs for research on environmental and human health exposure and effects?

How can pharmaceutical preclinical and clinical information be used to assess the potential for adverse environmental impacts of pharmaceuticals?

How can effects from long-term exposure to low concentrations of PPCP mixtures on non-target organisms be assessed?

What is the bioavailability of non-extractable residues of PPCPs?

Can non-animal testing methods be developed that will provide equivalent or better hazard data compared to current in vivo methods?

Follow-up workshops: E. Asia; Australia/NZ Niagara workshop

Additional questions Global How can we better communicate risk issues to the public? Local What are the risks of natural medicines to the environment? Should cultural considerations be incorporated into the environmental risk assessment process?

Next steps Manuscript submitted to EHP - under revision Dissemination to policy makers etc. Pellston style workshops on selected questions Web-based survey to rank questions Local workshops Special symposium at SETAC world meeting in Berlin

Acknowledgements Astrazeneca Americal Cleaning Institute Health Canada Janssen Pharmaceutical Companies of Johnson and Johnson Workshop delegates and those who submitted questions

Contact details: Pharmaceuticals Advisory Group open to everyone