Final Report Summary - CVME (Chiral veterinary medicines in the environment)
Veterinary pharmaceuticals are potent environmental contaminants. Research has been undertaken to understand their environmental fate and toxicity. However, one very important phenomenon has been overlooked and it is that more than half of the drugs currently in use are chiral compounds.
Chiral compounds exist in the form of enantiomers, which have similar physicochemical properties but they differ in their biological properties and, therefore, in their potency, toxicity and environmental fate. Because most studies on chiral pharmaceuticals do not explicitly account for individual stereoisomers, they implicitly and incorrectly assume that enantiomers have identical environmental behaviour. Furthermore, there is also a lack of information concerning enantioselective toxicity of chiral pharmaceuticals in the environment. This might lead to a significant under- or overestimation of their toxicity, as well as, an incorrect environmental risk assessment.
Trace analysis of pharmaceuticals in environmental samples is always challenging due to the complexity and diversity of sample matrices, and until today, only a few chiral analytical methods for environmental trace-level determinations have been developed. Most of them focused on a few pharmaceuticals, and none of them targeted veterinary pharmaceuticals of environmental relevance.
The aim of this project was:
Objective 1: To develop and validate reliable multi-residue analytical methods for the quantification of chiral veterinary medicines in environmental matrices using microextraction techniques and determination by LC-MS/MS
Objective 2: To analyse enantiomers of chiral veterinary medicines and their metabolites in the aqueous environment to study their environmental fate and their toxicity effects towards different organisms from different tropic levels
Objective 3: To evaluate the environmental risk posed by these compounds
The project achieved all planned objectives. In addition, it delivered outputs that were additional to planned deliverables. Three multi-residue analytical methods for the quantification of chiral veterinary medicines and their metabolites in surface water using solid phase extraction and liquid chromatography tandem mass spectrometry detection were developed for several groups of chiral veterinary medicines and chiral medicines for human use. Three additional multi-residue analytical methods using ultraperformance convergence chromatography tandem mass spectrometry were also developed in collaboration with Norwegian Water Research Institute. This innovative methodology proved to have a strong potential application in environmental chiral analysis. During the design of the experiments the initial list of analytes for the study (amoxicillin, ampicillin, carprofen, ceftiofur, cephalexin, chlortetracycline, dexamethasone, doxycycline, erythromycin, florfenicol, griseofulvin, imazalil, ivermectin, ketoprofen, lasalocid, levamisole, lincomycin, methylprednisolone, monensin, moxidectin, neomycin, oxytetracycline, penicillin G, progesterone, salinomycin, spiramycin, tilmicosin and tylosin) was increased and modified (racemic mixtures were not commercially available) to include also chiral medicines for human use (aminorex, amoxicillin, ampicillin, carboxyibuprofen, carprofen, ceftiofur, cephalexin, chloramphenicol, chloramphenicol base, danofloxacin, 3-N-dechloroethylifosfamide, O-desmethylnaproxen, 10,11-dihydro-10-hydroxycarbamazepine, dihydroketoprofen, doxycycline, erythromycin, fenoprofen, fexofenadine, florfenicol, flurbiprofen, griseofulvin, 2-hydroxyibuprofen, ibuprofen, ifosfamide, imazalil, indoprofen, ketoconazole, ketoprofen, mandelic acid, methylprednisolone, minocycline, naproxen, ofloxacin, omeprazole, oxytetracycline, penicillin G, penicillin V, 2-phenylpropionic acid, praziquantel, tetracycline and tetramisole). Furthermore, complex environmental matrices such as influent, effluent wastewater and activated sludge were also included to obtain a more comprehensive understanding of environmental fate and effects of drugs. Laboratory microcosm experiments have been also carried out in two different environmental matrices (30 days surface water simulating microcosms and 48h activated sludge simulating microcosms) to study the related toxicological effects and to evaluate their persistence in their environment under controlled conditions. Finally, an extensive 6 months long sampling campaign was carried out in Southwest of England to verify the occurrence of chiral drugs, their environmental fate and to identify environmental pollution hotspots.
The results of the study proved the widespread occurrence of several targeted chiral drugs in the environment. Furthermore, some identified chiral drugs were found to be present in the environment in non-racemic compositions, which could be directly linked with changes in ecotoxicity of chiral drugs and their environmental impacts. Further research on chiral drugs, their fate and effects is needed to fully understand their environmental impacts.
Chiral compounds exist in the form of enantiomers, which have similar physicochemical properties but they differ in their biological properties and, therefore, in their potency, toxicity and environmental fate. Because most studies on chiral pharmaceuticals do not explicitly account for individual stereoisomers, they implicitly and incorrectly assume that enantiomers have identical environmental behaviour. Furthermore, there is also a lack of information concerning enantioselective toxicity of chiral pharmaceuticals in the environment. This might lead to a significant under- or overestimation of their toxicity, as well as, an incorrect environmental risk assessment.
Trace analysis of pharmaceuticals in environmental samples is always challenging due to the complexity and diversity of sample matrices, and until today, only a few chiral analytical methods for environmental trace-level determinations have been developed. Most of them focused on a few pharmaceuticals, and none of them targeted veterinary pharmaceuticals of environmental relevance.
The aim of this project was:
Objective 1: To develop and validate reliable multi-residue analytical methods for the quantification of chiral veterinary medicines in environmental matrices using microextraction techniques and determination by LC-MS/MS
Objective 2: To analyse enantiomers of chiral veterinary medicines and their metabolites in the aqueous environment to study their environmental fate and their toxicity effects towards different organisms from different tropic levels
Objective 3: To evaluate the environmental risk posed by these compounds
The project achieved all planned objectives. In addition, it delivered outputs that were additional to planned deliverables. Three multi-residue analytical methods for the quantification of chiral veterinary medicines and their metabolites in surface water using solid phase extraction and liquid chromatography tandem mass spectrometry detection were developed for several groups of chiral veterinary medicines and chiral medicines for human use. Three additional multi-residue analytical methods using ultraperformance convergence chromatography tandem mass spectrometry were also developed in collaboration with Norwegian Water Research Institute. This innovative methodology proved to have a strong potential application in environmental chiral analysis. During the design of the experiments the initial list of analytes for the study (amoxicillin, ampicillin, carprofen, ceftiofur, cephalexin, chlortetracycline, dexamethasone, doxycycline, erythromycin, florfenicol, griseofulvin, imazalil, ivermectin, ketoprofen, lasalocid, levamisole, lincomycin, methylprednisolone, monensin, moxidectin, neomycin, oxytetracycline, penicillin G, progesterone, salinomycin, spiramycin, tilmicosin and tylosin) was increased and modified (racemic mixtures were not commercially available) to include also chiral medicines for human use (aminorex, amoxicillin, ampicillin, carboxyibuprofen, carprofen, ceftiofur, cephalexin, chloramphenicol, chloramphenicol base, danofloxacin, 3-N-dechloroethylifosfamide, O-desmethylnaproxen, 10,11-dihydro-10-hydroxycarbamazepine, dihydroketoprofen, doxycycline, erythromycin, fenoprofen, fexofenadine, florfenicol, flurbiprofen, griseofulvin, 2-hydroxyibuprofen, ibuprofen, ifosfamide, imazalil, indoprofen, ketoconazole, ketoprofen, mandelic acid, methylprednisolone, minocycline, naproxen, ofloxacin, omeprazole, oxytetracycline, penicillin G, penicillin V, 2-phenylpropionic acid, praziquantel, tetracycline and tetramisole). Furthermore, complex environmental matrices such as influent, effluent wastewater and activated sludge were also included to obtain a more comprehensive understanding of environmental fate and effects of drugs. Laboratory microcosm experiments have been also carried out in two different environmental matrices (30 days surface water simulating microcosms and 48h activated sludge simulating microcosms) to study the related toxicological effects and to evaluate their persistence in their environment under controlled conditions. Finally, an extensive 6 months long sampling campaign was carried out in Southwest of England to verify the occurrence of chiral drugs, their environmental fate and to identify environmental pollution hotspots.
The results of the study proved the widespread occurrence of several targeted chiral drugs in the environment. Furthermore, some identified chiral drugs were found to be present in the environment in non-racemic compositions, which could be directly linked with changes in ecotoxicity of chiral drugs and their environmental impacts. Further research on chiral drugs, their fate and effects is needed to fully understand their environmental impacts.