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Pharmaceuticals in the environment

When pharmaceuticals are administered to patients, some of the active pharmaceutical ingredient (API) may not be completely metabolised (biochemically altered and inactivated).  These unmetabolised portions are generally excreted and find their way into sewage systems where they are transported to wastewater treatment systems that remove most of the pharmaceutical residues.  However, extremely low concentrations may pass through the wastewater treatment plant and be discharged to the environment.  Historically, the presence and amount of pharmaceuticals in different parts of the environment have been estimated.  Recently, as a result of advances in analytical techniques, extremely low concentrations of pharmaceuticals are being measured in wastewater, surface water (rivers and streams) and drinking water.  In addition, low level effects on aquatic organisms have been observed for specific APIs such as synthetic hormones

The US Food and Drug Administration (FDA) have regulated pharmaceuticals in the environment in the USA since 1977 under the auspices of the National Environmental Policy act of 1969.  Regulation occurs through the environmental review process for New Drug Applications submitted to the FDA.  In Europe, draft guidelines for Environmental Risk Assessments (ERAs) that accompany Marketing Authorisation Approval Applications have been available for a number of years.  The most recent guidelines were issued in January 2005 and are expected to be approved and implemented in 2006. A key change in these guidelines is the requirement for chronic rather than acute ecotoxicity testing, recognising that most pharmaceutical active ingredients are not acutely toxic but may have longer term chronic effects on aquatic organisms at low levels.  In Canada a requirement for environmental assessment is in place and a specific ERA process for pharmaceuticals is under development.  In Sweden, a classification scheme based on environmental characteristics of APIs is being implemented.

Since the late 1980s GSK has been actively working with various regulatory agencies to ensure that potential environmental impacts of pharmaceuticals are understood and minimised.  Over the last several years, there have been significant industry efforts to develop improved environmental risk assessment models in the United States and Europe.  In the US, the pharmaceutical industry trade association, PhRMA (Pharmaceutical Research and Manufacturers of America) developed a watershed-specific model to predict environmental concentrations from patient use (Anderson et al). The industry task force developed a state-of-the-art geographically explicit model to facilitate a deeper understanding of potential environmental distribution of pharmaceuticals at a local or regional level. The PhATE™ (Pharmaceutical Assessment and Transport Evaluation) model is a watershed-based approach and was developed as a tool to more realistically estimate concentrations of active pharmaceutical ingredients (APIs) discharged to US surface waters through consumption of medicines. 

PhATE™ uses a mass balance approach to model predicted environmental concentrations (PECs) in eleven watersheds that are felt to be representative of most hydrologic regions of the United States. Upon dividing the associated rivers into discrete segments, the model estimates the mass of API that enters a segment from upstream or from sewage treatment works (STWs) and the mass that is subsequently lost from the segment via in‑stream loss mechanisms or flow diversions (i.e., man‑made withdrawals).  STW discharge loads are estimated based on the population served, API use per capita, and the mass of the API removed in the STW.  Monitoring data generated by the United States Geological Survey were used to corroborate the model.  In addition, industry groups working through PhRMA developed human health effects data on the pharmaceutical compounds reported by USGS (Kolpin et al 2002; Tabor and Barber, 1993) and used the PhRMA PhATE™ (Pharmaceutical Assessment and Transport Evaluation) model to carry out human health risk assessments for 26 active pharmaceutical ingredients (APIs). This paper was published in Regulatory Toxicology and Pharmacology (Schwab et al 2005).

Another industry group under PhRMA has been working on potential impact of APIs on aquatic life.  A manuscript on issues connected with these types of assessments was submitted for publication, has been reviewed and is in revision (Cunningham et al 2005).  A literature database on aquatic life impacts and fate and treatability data for APIs has been compiled and is being maintained as new data are published.  The PhRMA Task Force on Pharmaceuticals in the Environment is also preparing two more manuscripts for publication.  One of these details a human and environmental risk assessment for carbamazepine, an anti-epileptic drug that appears to be persistent and is frequently detected in the aquatic environment.  The other focuses on four analgesics, aspirin, acetaminophen (paracetamol), ibuprofen and naproxen, all high volume pharmaceuticals.  These papers are part of a systematic PhRMA programme to develop data and assessments on high profile pharmaceuticals and provide these through publication in the peer-reviewed scientific literature.

This work is part of on-going PhRMA research to provide confidence to the industry, communities and governments that safety of pharmaceuticals in the environment is well understood and provide data needed to prioritize issues requiring further investigation regarding existence and significance of potential impacts.  In addition, through PhRMA and through the Association of the British Pharmaceutical Industry (ABPI), we have actively engaged with the US Interagency Task Force on Pharmaceuticals in the Environment, and with the UK Environment Agency.
 
In 2005, the long-awaited book on Human Pharmaceuticals: Assessing the impacts on aquatic ecosystems was published.  GSK scientists were part of the team of international experts from industry, academia and government that organised and participated in the SETAC Workshop on Science for Assessing the Impacts of Human Pharmaceuticals in Aquatic Systems held in 2003 and co-authored a number of the book chapters.

Independently, GSK has been using these models and methods to identify potential impacts of GSK pharmaceutical products entering the environment through patient use.  A paper on the environmental risk assessment of paroxetine, the API in Paxil/Seroxat, has been published (Cunningham et al 2004).  This paper focuses on potential impacts of paroxetine on aquatic life.  Another paper is in preparation that includes assessment of potential impacts on human health as well as aquatic life in the US for about 35 GSK APIs.  Evaluations for selected European catchments using the GREAT-ER (Geography-referenced Regional Exposure Assessment Tool for European Rivers) Model, similar to PhATEä, are also in progress.  In addition, the assessments and available environmental data for individual APIs are being provided in Safety Data Sheets that are available on the GSK web-site.  The risk assessments that have been carried out to date using these models, combined with currently available human and environmental fate and effects data and methods, indicate that GSK pharmaceuticals in the environment do not appear to present an appreciable risk to humans or the environment. As part of its product stewardship activities, GSK continues to monitor the latest scientific studies and findings to continually improve risk assessments in this area.  GSK is committed to providing leadership with regard to the science needed to assess potential impact, mitigation and management strategies, and to data, assessment and communication transparency.

References

Anderson, P.D., V.J. D’Aco, P. Shanahan, S.C. Chapra, M.E. Buzby, V.L. Cunningham,  B.M. DuPlessie, E.P. Hayes, F. Mastrocco, N.J. Parke, J.C. Rader, J.H. Samuelian, and B.W. Schwab, 2004, Screening analysis of human pharmaceutical compounds in U.S. surface waters, Environmental Science & Technology, 38: 838-849.

Cunningham, V.L., Buzby, M., Hutchinson, T., Mastrocco, F., Parke, N., Roden, N., Pharmaceuticals in the Environment: Implications for Potential Aquatic Life Impacts, 2005, in revision.

Cunningham, V.L., Constable, D.J.C., and Hannah, R.E., 2004, Environmental Risk Assessment of Paroxetine, Environ. Sci. Technol., 38 (12) 3351-3359.

Kolpin, D.W., E.T. Furlong, M.T. Meyer, E.M. Thurman, S.D. Zaugg, L.B. Barber, and H.T. Buxton. 2002. Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000: a national reconnaissance. Environmental Science & Technology, 36: 1202-1211.

Schwab, B.W., Hayes, E.P., Fiori, J.M., Mastrocco, F.J., Roden, N.M., Cragin, D., Meyerhoff, R., D’Aco, V.J., Anderson, P.D., Human pharmaceuticals in U.S. surface water: A human health risk assessment, submitted (12/04) to Regulatory Toxicology and Pharmacology, 42 (2005) 296-312.

Tabor, C.F., and L.B. Barber. 1996. Fate of linear alkylbenzene sulfonate in the Mississippi River: Environmental Science & Technology, 30: 161-171.

Williams, R.T., ed. 2005. Human Pharmaceuticals: Assessing the impacts on aquatic ecosystems,  SETAC PRESS, Pensacola, FL

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