TY - JOUR
T1 - Pharmacology beyond the patient – The environmental risks of human drugs
AU - Gunnarsson, Lina
AU - Snape, Jason R.
AU - Verbruggen, Bas
AU - Owen, Stewart F.
AU - Kristiansson, Erik
AU - Margiotta-Casaluci, Luigi
AU - Österlund, Tobias
AU - Hutchinson, Kathryn
AU - Leverett, Dean
AU - Marks, Becky
AU - Tyler, Charles R.
N1 - Funding Information:
The work of the authors is supported by the following institutes, organisations and grants: (1) AstraZeneca Global SHE Research Programme grant to C.R.T.; (2) the research leading to these results has received support from the Innovative Medicines Initiative (IMI) Joint Undertaking under ‘Intelligence-led Assessment of Pharmaceuticals in the Environment’ (iPiE) grant agreement n° 115735, resources of which are composed of financial contribution from the EU's Seventh Framework Programme (FP7/2007-2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in kind contribution. (3) J.R.S. and S.F.O. effort represents part of the AstraZeneca contribution to the Innovate UK, ‘National Centre for the Replacement, Refinement & Reduction of Animals in Research’ (NC3Rs) funded project number 102519 ‘Virtual Fish EcoToxicology Laboratory’; (4) Per capita use for 22 European markets is calculated from kg sales data provided by IMS Health, MIDAS International Data 2015 (www.imshealth.com); (5) the research based pharmaceutical trade organisation of Sweden (LIF) provided a list of drugs with environmental data (www.fass.se); (6) The authors thank their collaborators for discussions and valuable input, particularly members of the iPiE consortium.
Funding Information:
The work of the authors is supported by the following institutes, organisations and grants: (1) AstraZeneca Global SHE Research Programme grant to C.R.T.; (2) the research leading to these results has received support from the Innovative Medicines Initiative (IMI) Joint Undertaking under ‘Intelligence-led Assessment of Pharmaceuticals in the Environment’ (iPiE) grant agreement n° 115735 , resources of which are composed of financial contribution from the EU's Seventh Framework Programme ( FP7/2007-2013 ) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in kind contribution. (3) J.R.S. and S.F.O. effort represents part of the AstraZeneca contribution to the Innovate UK, ‘National Centre for the Replacement, Refinement & Reduction of Animals in Research’ (NC3Rs) funded project number 102519 ‘Virtual Fish EcoToxicology Laboratory’; (4) Per capita use for 22 European markets is calculated from kg sales data provided by IMS Health, MIDAS International Data 2015 ( www.imshealth.com ); (5) the research based pharmaceutical trade organisation of Sweden (LIF) provided a list of drugs with environmental data ( www.fass.se ); (6) The authors thank their collaborators for discussions and valuable input, particularly members of the iPiE consortium.
Publisher Copyright:
© 2019
PY - 2019/8
Y1 - 2019/8
N2 - Background: The presence of pharmaceuticals in the environment is a growing global concern and although environmental risk assessment is required for approval of new drugs in Europe and the USA, the adequacy of the current triggers and the effects-based assessments has been questioned. Objective: To provide a comprehensive analysis of all regulatory compliant aquatic ecotoxicity data and evaluate the current triggers and effects-based environmental assessments to facilitate the development of more efficient approaches for pharmaceuticals toxicity testing. Methods: Publicly-available regulatory compliant ecotoxicity data for drugs targeting human proteins was compiled together with pharmacological information including drug targets, Cmax and lipophilicity. Possible links between these factors and the ecotoxicity data for effects on, growth, mortality and/or reproduction, were evaluated. The environmental risks were then assessed based on a combined analysis of drug toxicity and predicted environmental concentrations based on European patient consumption data. Results: For most (88%) of the of 975 approved small molecule drugs targeting human proteins a complete set of regulatory compliant ecotoxicity data in the public domain was lacking, highlighting the need for both intelligent approaches to prioritize legacy human drugs for a tailored environmental risk assessment and a transparent database that captures environmental data. We show that presence/absence of drug-target orthologues are predictive of susceptible species for the more potent drugs. Drugs that target the endocrine system represent the highest potency and greatest risk. However, for most drugs (>80%) with a full set of ecotoxicity data, risk quotients assuming worst-case exposure assessments were below one in all European countries indicating low environmental risks for the endpoints assessed. Conclusion: We believe that the presented analysis can guide improvements to current testing procedures, and provide valuable approaches for prioritising legacy drugs (i.e. those registered before 2006) for further ecotoxicity testing. For drugs where effects of possible concern (e.g. behaviour) are not captured in regulatory tests, additional mechanistic testing may be required to provide the highest confidence for avoiding environmental impacts.
AB - Background: The presence of pharmaceuticals in the environment is a growing global concern and although environmental risk assessment is required for approval of new drugs in Europe and the USA, the adequacy of the current triggers and the effects-based assessments has been questioned. Objective: To provide a comprehensive analysis of all regulatory compliant aquatic ecotoxicity data and evaluate the current triggers and effects-based environmental assessments to facilitate the development of more efficient approaches for pharmaceuticals toxicity testing. Methods: Publicly-available regulatory compliant ecotoxicity data for drugs targeting human proteins was compiled together with pharmacological information including drug targets, Cmax and lipophilicity. Possible links between these factors and the ecotoxicity data for effects on, growth, mortality and/or reproduction, were evaluated. The environmental risks were then assessed based on a combined analysis of drug toxicity and predicted environmental concentrations based on European patient consumption data. Results: For most (88%) of the of 975 approved small molecule drugs targeting human proteins a complete set of regulatory compliant ecotoxicity data in the public domain was lacking, highlighting the need for both intelligent approaches to prioritize legacy human drugs for a tailored environmental risk assessment and a transparent database that captures environmental data. We show that presence/absence of drug-target orthologues are predictive of susceptible species for the more potent drugs. Drugs that target the endocrine system represent the highest potency and greatest risk. However, for most drugs (>80%) with a full set of ecotoxicity data, risk quotients assuming worst-case exposure assessments were below one in all European countries indicating low environmental risks for the endpoints assessed. Conclusion: We believe that the presented analysis can guide improvements to current testing procedures, and provide valuable approaches for prioritising legacy drugs (i.e. those registered before 2006) for further ecotoxicity testing. For drugs where effects of possible concern (e.g. behaviour) are not captured in regulatory tests, additional mechanistic testing may be required to provide the highest confidence for avoiding environmental impacts.
UR - http://www.scopus.com/inward/record.url?scp=85066274014&partnerID=8YFLogxK
U2 - 10.1016/j.envint.2019.04.075
DO - 10.1016/j.envint.2019.04.075
M3 - Article
C2 - 31150974
AN - SCOPUS:85066274014
SN - 0160-4120
VL - 129
SP - 320
EP - 332
JO - Environment International
JF - Environment International
ER -