|Year : 2014 | Volume
| Issue : 1 | Page : 13-17
Ecopharmacovigilance: Current state, challenges, and opportunities in China
Jun Wang, Xiamin Hu
Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan, China
|Date of Web Publication||16-Jan-2014|
Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan
Source of Support: None, Conflict of Interest: None
In a context of severe pharmaceutical pollution, "ecopharmacovigilance" (EPV) has been an area of novel interest. It aims to ensure that significant environmental issues associated with pharmaceuticals in the environment are identified in a timely way, and managed appropriately. EPV has become a research hotspot as a comprehensive and boundary science in Europe and North America, and regulatory requirements governing the comprehensive environmental risk assessment (ERA) of pharmaceuticals exist in these regions. A speedy Chinese pharmaceutical industry development and drug consumption, China should shoulder more international responsibility and contribute to the worldwide EPV. Compared to the west, EPV in China is in its infancy. We analyzed the current state of EPV-related practice in China and found that many efforts have been made by the Chinese government and specialists to control the ever-worsening environmental pharmaceutical pollution problems, including consummating related policies and regulations, revealing the occurrence and behavior of pharmaceutical residues in environment and developing new technologies to improve their removal performance. Besides, we posed some recommendations on appropriate EPV implementation that can be taken with China in future. These include, building perfect laws and regulation system on EPV, defining the evaluation index for EPV, continuing the clinical rational medication and the pharmaceutical take-back programs in China, popularizing the concept of EPV in China, and strengthening the policy-guided and scientific researches of EPV in pharmaceutical firms and academia.
Keywords: China, Ecopharmacovigilance, environment pharmaceutical pollutants
|How to cite this article:|
Wang J, Hu X. Ecopharmacovigilance: Current state, challenges, and opportunities in China. Indian J Pharmacol 2014;46:13-7
| » Introduction|| |
With continuous rapid development of global pharmaceutical industry, environmental issues caused by pharmaceutical pollutants have received increasing attention. These is an increased consumption of pharmaceutical products, their occurrence, and persistence in the environment with their diverse biological effects.  Many pharmaceutical chemicals are nondegradable to resist the acid environment in the stomach or long-lasting, thus present a special risk when they enter, persist, and disseminate in the environment including water supplies and the food chain leading to an unwitting re-entry of drugs into humans. ,, These environmental pharmaceutical pollutants include excretion of pharmaceuticals after human and veterinary therapeutic use. This dominates the global input of pharmaceuticals into the environment and are a much more difficult source to control; adding to the direct release into the wastewater system and terrestrial depositions from manufacturing or hospitals; and disposal of unused drugs.  The long-term exposure to these environmental pharmaceutical pollutants could be responsible for chronic toxicity and subtle effects in animals and plants including microbial resistance, endocrine disruption, growth inhibition, disruption of microbial ecosystems, cytotoxicity, mutagenicity, teratogenicity, and so on. Although there is no systematic study to show the definite hazard or toxicity to humans from environmentally present pharmaceuticals, the potential effects of pharmaceuticals on wildlife species has been demonstrated. Vultures have been poisoned and even critically endangered because they ingested diclofenac through its veterinary application when feeding on the carcasses of livestock.  Similarly, water contamination of ethinylestradiol has been shown to affect the sexual development of male fish.  It is speculated that humans who is on the top of the food chain would be jeopardized through the environmental pharmaceutical pollutants; however, further research is needed to prove this.
Nowadays, pharmaceutical pollution has posed serious threat to the environment worldwide. A study in Spain found that 19 pharmaceuticals of the 27 human pharmaceuticals investigated have been identified in the aquatic environment.  Metabolites of carbamazepine (carbamazepine epoxide), diclofenac (4′- and 5-hydroxy diclofenac), and atorvastatin (o- and p-hydroxy atorvastatin) were detected in flow proportional 24 h composite samples of wastewater effluent collected from the Norwegian cities of Oslo and Tromsø at higher concentrations than the parent pharmaceuticals. Among them, the concentration of 5-hydroxy diclofenac determined in discharged effluent was as high as 3,700 ng/L. And certain metabolites were found in Norwegian coastal environment, marine surface waters, and sediments.  In this alarming situation, the concept of "ecopharmacovigilance" (EPV) has been proposed as an issue of great interest.
| » Meaning of EPV and its Development in the Global Context|| |
Differing from the highly regulated "pharmacovigilance" (PV) in patients, EPV is an emerging science concerning detection, assessment, understanding, and prevention of adverse effects related to the presence of pharmaceuticals in the environment, which affect human and other animal species. , The definition of EPV by Holm et al.,  based on the World Health Organization (WHO) definition of PV is "the science and activities associated with the detection, evaluation, understanding, and prevention of adverse effects of pharmaceuticals in the environment". The approaches of EPV include green drug design, green chemistry in process development, development of biodegradable products, minimization of manufacturing emissions, education over rational use of drugs, improved prescribing practices, the management of unused drugs, etc. ,, And these new EPV approaches have been introduced into the environment monitoring of antidepressants,  antibacterials like flouroquinolones, hormones, paracetamol, and diclofenac. 
Due to the complexity of pharmaceutical environmental exposure and the specific biochemical effect of drugs, more researches including biological monitoring of different species, measurement, prediction, and identification of potential effects of pharmaceutical pollutants are required to improve scientific understanding of pharmaceuticals in the environment. The European Commission (EC)  is currently reviewing data on pharmaceuticals in the environment and the potential impact on the environment and public health, including a review of the current legislation for human and veterinary drugs. And collaborative researches between industry, academia, and government to ensure that EPV guidance is offering adequate levels of environmental protection were encouraged. And some pharmaceutical firms in European Union (EU) such as Astra Zeneca have used Environmental Risk Management Plans (ERMPs) as a centralized resource to assess and manage the environmental risks of a drug throughout its life cycle, which include information such as physicochemistry, human metabolism, pharmacokinetics, preclinical toxicology, and environmental data of the active pharmaceutical ingredient. After launch, the ERMP is updated as necessary if any new or emerging environmental risks are identified as part of EPV process. Besides, related researches in academia are rapidly progressing.  The Society of Environmental Toxicology and Chemistry (SETAC) has recently published the outcomes of a collaborative workshop that identified the top 20 questions related to pharmaceuticals in the environment,  and has identified clear areas where future research is warranted.
Based on these essential theoretical advancements, there have been some mandatory provisions under the guidance of EPV principle in the West. The American Senate has passed a legislation to monitor the drugs in environment. United Kingdom also has witnessed the impact of stringent regulations.  In fact, EC has issued a number of appropriate legislations and regulatory guidance in the area of EPV, which include Knowledge and Need Assessment on Pharmaceutical Products in Environmental Waters (KNAPPE),  environmental risk assessment of pharmaceuticals (ERAPharm),  Pharmas,  and Cytothreat.  These projects have assessed the environmental risks associated with selective serotonin reuptake inhibitors, β-receptor blockers, antibiotics, and cytotoxic drugs. Among all the projects on EPV, pharmaceuticals ERA, which is by definition predictive assessments of potential risks normally based on experimental laboratory studies, is a recognized regulation system as crucial to implement strategies to minimize the possible pharmaceutical environmental impact.  In both Europe and North America, there are regulatory requirements governing the comprehensive ERA prior to launch of any new human pharmaceuticals. , The EU ERA regulations are currently the most demanding and data intensive. In the EU, the ERA must normally be in place prior to approval of a new drug, and if an environmental risk is identified, "specific arrangements to limit it should be envisaged".  As a large number of pharmaceuticals are on sale, it is not feasible to regard all of them as target pollutants. And there is no requirement for ERA to be updated or reviewed once a new drug has been approved.
The ratio of the predicted environmental concentration (PEC) to the predicted no-effect concentration (PNEC) ratio (PEC:PNEC) is a risk quotient used widely to evaluate EPV in the West. ,,, The PEC provides an estimate of the maximum concentration anticipated to occur in the environment based upon their physicochemical properties and annual volume of use (i.e., patient use and subsequent excretion into the wastewater system). The PNEC is derived from ecotoxicological tests normally on algae, daphnids, and fish (representing three trophic levels); together with an assessment factor that accounts for uncertainty in the toxicity quantitative structure-activity relationship prediction resulting from interspecies differences in toxicity. If the PEC:PNEC is less than one the tested drug is considered to have negligible environmental risk and no further information is required. Conversely, if PEC:PNEC is more than one then additional testing is generally needed to refine the PEC or PNEC. If this fails to refine the risk quotient to less than one, this drug becomes a candidate for further EPV risk management.
| » Need for Implementation of EPV in China|| |
In China, the practical application of EPV is an issue that needs to be addressed urgently. More than 19% of the global population (>1.3 billion) is housed in China. The greatest economic development of China is widely recognized. As global pharmaceutical manufacturers relocate their production facilities in China from the west, China has become one of emerging pharmaceutical manufacturing countries in the world and has exported more than 60% of the total active pharmaceutical ingredients including antibiotics, organic acids, and biotech products to the global pharmaceutical industry.  Currently, China has more than 3,500 pharmaceutical companies. Pharmaceutical hubs are scattered around the whole country. It is predicted that China would be ranked in top 10 largest pharmaceutical markets in the world by 2020.  However, this rapid growth in pharmaceutical industry has also posed an elevated risk of environmental contamination with residual pharmaceuticals [Table 1]. Sui et al.  found that, among 39 pharmaceuticals, 17 were considered as priority residual pharmaceuticals in the water environment of China, out of which, erythromycin, diclofenac acid, and ibuprofen had high priority. Although some pharmaceuticals of global concern were included, some pharmaceuticals such as cefalexin, ketoconazole should be also given prior consideration in China. Among them, antibiotics, which were grossly abused in China, contributed the majority of priority pharmaceuticals. In addition, 71 and 100% of the candidate anti-inflammatory and antilipidemic, respectively were identified as the priority pharmaceuticals in China. Other studies ,, revealed the presence of antibiotic residues in the coastal aquatic environment of China, which was due to freshwater inputs or mariculture and could pose high risks to the most sensitive aquatic microorganisms, such as Synechococcus leopoliensis and Pseudokirchneriella subcapitata. Two commonly used antimicrobial agents triclosan and triclocarban also occurred in the surface water and sediments of the Pearl River system in China.  Besides, carbamazepine, an anticonvulsant and analgesic widely used in the treatment of pain and epilepsy, was not completely eliminated after secondary treatment, thus detected in aquatic environment of Yangtze River Delta, East China with the highest concentration of 1,090 ng/L.  And some residues of pesticide such as dichlorodiphenyltrichloroethanes (DDTs),  pentachlorophenol,  hexachlorobenzene,  and dechlorane compounds  were detectable in the aquatic environment of China. These pharmaceutical pollutants pose a health risk in China and around the world, hence the need to implement EPV is emphasized.
|Table 1: Potential environmental pharmaceutical pollutants according to published reports in China|
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| » Current Situation Analysis of EPV-Related Practice in China|| |
Indeed, many efforts have been made by the Chinese government and specialists to control the ever-worsening environmental pharmaceutical pollution, including consummating related policies and regulations, revealing the occurrence and behavior of pharmaceutical residues in environment ,,,,,,,,, and developing new technologies to improve their removal performance.  In 2005, pharmaceutical industry was confirmed as one of highly polluted industries by China's State Environmental Protection Administration (SEPA). Then SEPA enacted the six new discharge standards of pharmaceutical wastewater including Discharge Standards of Water Pollutants for Pharmaceutical Industry. Fermentation Products Category (GB 21903-008), Chemical Synthesis Products Category (GB21904-2008), Extraction Products Category (GB21905-2008), Chinese Traditional Medicine Category (GB21906-2008), Bio-pharmaceutical category (GB21907-2008), and agent of mixed Formulation Category (GB21908-2008) in June 2008 to control pharmaceutical pollutant emission. And the regulations for pharmaceutical residues were strengthened. For example, China's State Food and Drug Administration together with Environmental Protection Administration have jointly issued the announcement to ban the use of chlorofluorocarbons as propellant in pharmaceutical non-inhalation aerosol on March 24, 2013 to reduce damage to the ozone layer. Besides, pharmaceutical take-back programs, including advertising the significance of pharmaceutical take-back, presenting the safe medicine disposal locations and encouraging drug manufacturers to participate in, and pay for the collection and disposal of unused or expired prescription drugs, are also envisaged in China.
These environmental policies and technical standards have provided the foundation for EPV development in China, however, the developed countries of the West seem to be one step ahead.  In China too, the EPV was designed to ensure protection in any region where the drug will be used. Although some western countries have made some attempts for EPV, however, few of them are proving to be a benchmark for international stakeholders in this area of EPV. ,, Due to the speedy development of Chinese pharmaceutical industry and increasing drug consumption, China should shoulder more international responsibility and contribute to the worldwide EPV.
| » Recommendations on EPV Implementation in China|| |
In view of the EPV experience of developed countries of the west, are some recommendations about Chinese EPV. These include [Table 2]:
|Table 2: Key recommendations on ecopharmacovigilance (EPV) implementation in China|
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Building Perfect Laws and Regulation System on EPV
A mandatory provision must be made in the process of drug development to establish safety in the environment.  Referring to ERA in EU, the practice that implements EPV during the approval of new drug, which has been recognized as a feasible and effective means  can be followed by China. In addition, Roos et al.  have prioritized and ranked 582 human drugs based on environmental hazard and risk using nine prioritization schemes, which can also be considered by the Chinese drug and administration authorities. However, because disease prevalence, cultural practices, and climate in China are different from those in the West, the risk profile associated with a pharmaceutical agent may also be different. Therefore, Chinese laws and regulation system on EPV should consider this difference and emphasize the "regional Chinese characteristics".
Defining the Evaluation Index for EPV
Although there are some discharge standards of pharmaceutical wastewater in China, assessment criteria of these standards is mainly related with common index for monitoring pollution of water such as the pH value and heavy metal content. To overall and objectively appraise EPV, it is advisable and feasible to introduce PEC:PNEC prioritization approach used widely to evaluate EPV in the West ,,, into the Chinese EPV management.
Continuing the Clinical Rational Medication and the Pharmaceutical Take-back Programs in China
From EPV point of view, prescribing medication rationally is one of the effective ways to reducing the environmental risk induced by pharmaceutical pollutants. ,,, Although medication utilization in China has gradually changed from improving the accessibility of medications to the rational use of medications, there still are some irrational medication uses of antibiotics, glucocorticoids, and injections prescribed for patients in the rural.  And the quality control of prescription practice and pharmaceutical education to patients could be essential to control drug abuse and then implement EPV.
Besides, disposal of unused or expired drugs is a very specific EPV issue that can be managed effectively if the appropriate preventative methods are put in place. This includes guidance for patients, take-back schemes, and disposal practices.  Pharmaceutical take-back programs are an important part of EPV, and may help prevent leftover pharmaceuticals in the environment from being misused.  In China, these programs have become a routine practice of drug administration, which should be continued and strengthened under the principle of EPV. Especially, the scientific and green management of unused or expired drugs should become one focus of future Chinese pharmaceutical take-back programs.
Popularizing the Concept of EPV in China
Though EPV is a developing science and EPV practice is still in an exploratory stage, the global popularization of scientific understanding of pharmaceuticals in the environment is absolutely crucial because the environmental problems in today's society are becoming increasingly serious. EPV is indispensable for the sustainable development of Chinese pharmaceutical industry. China's pharmaceutical industry should have a solid understanding of EPV and show their commitment to the reduction of the pharmaceutical pollutants' impact on environment. Increasing transparency and availability of environmental data for medicinal products through professional training and the official website may be considered. The effective education of EPV can also create soft environment for the practical implementation of EPV.
Strengthening the Policy-guided and Scientific Researches of EPV in Pharmaceutical Firms and Academia
EPV is a comprehensive research area involving pharmacy, environics, chemistry, and management, and should be further studied by experts from academia, governments, and industry from around the world to bridge the current knowledge gaps. Related researches including administrative supervision and management over pharmaceutical pollutants, the analysis of current distribution levels and fate in different environmental matrices, better sewage treatment plants, development of biodegradable products, the impact of drug over environment, and potential ecotoxicity risks may be further investigated to develop EPV in China. It will be pertinent for regulatory as well as scientific society to work hand in hand to address this vital issue. Pharmaceutical firms, who play a vital role in managing the safety of medicines, should actively involve in the policy-guided and scientific researches of EPV.
To conclude, China is struggling to harmonize economic development and environmental protection. EPV provides useful reference for the disposal of environmental issues associated with pharmaceuticals in the environment in a timely way. Compared to the west, EPV in China is in infancy. We have posed some recommendations on appropriate EPV implementation in China including building perfect laws and regulation system on EPV, defining the evaluation index for EPV, continuing the clinical rational medication, and the pharmaceutical take-back programs popularizing the concept of EPV and strengthening the policy-guided and scientific researches of EPV in pharmaceutical firms and academia.
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[Table 1], [Table 2]