Biodegradability and transformation of human pharm

Authors: Silvia Berkner Claudia Thierbach

Publish Date: 2013/06/14

Volume: 21, Issue: 16, Pages: 9461-9467

PDF Link

Abstract

Human pharmaceutical active ingredients that are orally or parenterally administered may be metabolised in the body and after excretion may be further transformed in the receiving environmental compartments The optimal outcome from an environmental point of view—complete mineralisation—is rarely observed Small molecule pharmaceuticals are commonly not readily biodegradable according to Organisation for Economic Cooperation and Development OECD 301 tests However primary transformation is often observed To gain information on the transformation of active ingredients in the environment longterm studies like transformation in aquatic water/sediment systems according to OECD guideline 308 are required for the environmental risk assessment for human active pharmaceutical ingredients Studies received until mid 2010 as part of the dossiers for marketing authorisation applications were evaluated concerning transformation products The evaluation revealed that in 70  of the studies at least one transformation product TP is formed above 10  of the originally applied dose but in only 26  of the studies are all TP identified The evaluation also revealed that some TP of pharmaceutical active ingredients show a considerably longer DT50 compared to the parent compound An example is the TP valsartan acid that is formed from an antihypertensive compoundHuman pharmaceutical active ingredients AI are being consumed in increasing amounts worldwide The high amounts consumed combined with the desired stability and resulting persistency of the compounds have led to their ubiquitous presence in water bodies Hughes et al 2013 This has triggered concerns about the ecotoxicological effects and the potential for the contamination of groundwater and raw drinking water Therefore since 2001 an assessment of environmental fate and effects is a mandatory part of the procedure for the marketing authorisation for human pharmaceuticals EC 2001 The assessment is based on estimating the exposure of the environment and on experimental studies to characterise the fate and effects of pharmaceutical AI in the environment EMA 2006The most common pathway into the environment for human pharmaceutical AI after usage by patients is via excretion subsequent transport to a wastewater treatment plant WWTP and entry into the environment via the WWTP effluent or via spreading of sewage sludge on agricultural areas or its use in other open applications Additionally AI from topical formulations eg gels crèmes etc and AI emitted from production and formulation facilities also contribute to the pharmaceutical compounds introduced into the environment Fick et al 2009 Phillips et al 2010 Sanchez et al 2011 During their use and their subsequent entry into the aquatic or terrestrial environment AI are subject to metabolism and transformation In the patient the parent compound may be metabolised into phase I or phase II metabolites ME For many AI a high fraction of the administered dose is excreted as mineralisation is rarely observed and accumulation of AI or its ME in the patient is in most cases not desired During sewage treatment further transformation may take place The resulting mixture of the parent compound ME and transformation products TP reaches different environmental compartments eg rivers lakes sediment soil with either the sewage plant effluent or the spreading of sewage sludge onto land where further transformation occurs including biotransformation and abiotic transformations like eg phototransformationDepending on their sorption and biodegradation properties and the amount that is consumed many pharmaceutical AI are not or only partly removed by conventional wastewater treatment technologies Joss et al 2006 Pharmaceuticals are just now starting to be incorporated into routine monitoring programmes for surface waters EC 2012 but despite this lack of consistent monitoring efforts it becomes clear from many studies that pharmaceutical AI and their ME and TP are widely detected in surface water and in some cases also in groundwater or raw water for drinking water production Ternes 1998 Heberer 2002 Kolpin et al 2002 Bergmann et al 2011 Hughes et al 2013ME and transformation products are covered in the environmental risk assessment by the socalled total residue approach EMA 2006 This approach assumes that the parent compound ME and TP show the same behaviour and effects in the environment In many cases this approach might be valid but in some cases the ME or TP actually might be of higher concern than the parent compound and therefore further information is required to comprehensively conduct an environmental risk assessment ME or TP might be of higher ecotoxicological concern than the parent Strategies to deal with this concern have been described Escher et al 2006 Escher and Fenner 2011 However if TP are of concern because they are more persistent and/or more mobile than the parent compounds cannot be covered by the proposed testing scheme Information on the persistence of a TP should be available from simulation type studies conducted as part of the environmental risk assessment eg studies on transformation in water/sediment systems according to Organisation for Economic Cooperation and Development OECD guideline 308 Additionally information on the mobility of the TP eg their adsorption/desorption behaviour in relevant matrices is required to estimate their risk for groundwater or raw drinking water contamination It is important to know the identity of the respective ME or TP to be able to include it into monitoring programmes Currently for human pharmaceutical AI that are not readily biodegradable according to tests following OECD guideline 301 more detailed studies on transformation in water/sediment systems according to OECD guideline 308 have to be conducted EMA 2006 OECD 2002 The guideline requires screening for TP to quantify their amount to determine the DT50 time required until 50  of the substance has dissipated and to identify the TP that are formed at more than 10  of the applied doseThe aim of this study was to evaluate information from the environmental risk assessment for human pharmaceutical AI concerning biodegradability and transformation in water/sediment systems Studies conducted according to OECD guideline 301 on ready biodegradability OECD 1992 and OECD 308 on transformation in water/sediment systems OECD 2002 were analysedFirst an overview was gained on how often TP are observed in these studies Furthermore the quality of studies concerning detection quantification identification and determination of DT50 for TP was evaluated Additionally it was studied whether TP are just transient phenomena or if there are indications of a longer persistence in the environment compared to the parent compounds Emphasis was put on identifying specific problems that complicate the interpretation of results from OECD 308 studies from pharmaceutical AI A comparison of results from OECD 301 tests on determining ready biodegradability and results from OECD 308 water/sediment systems was also conducted

Keywords: