Ecopharmacovigilance: an issue urgently to be addressed.

“Every rose has its thorn” and so have the drugs too. Drugs have been a boon for the humanity in curbing the ailments though not fully but to a great extent. Along with beneficial effects they also impart some adverse reactions sooner or later. Owing to this fact, a new branch of science called “Pharmacovigilance” sprouted in 1960 after the incidence of thalidomide disaster.[1] Pharmacovigilance became well accepted and practiced in developed world but developing part of globe consumed decades to it. At present, India has also started a national program to monitor the adverse effects of drugs.[2] Unfortunately, however, despite this achievement worldwide, the effect of drug use on environment remains unaddressed. The exorbitant decline in number of vultures in Indian subcontinent shook the environmental scientists and activists.[3] Prior to this observation, research on the impact of chemical pollution was restricted to persistent organic pollutants.[4] At this verge, attention has been drawn to the environmental impact of chemicals used in small concentration, that is, drugs giving birth to the subject of ecopharmacovigilance. Ecopharmacovigilance can be defined as science and activities concerning detection, assessment, understanding, and prevention of adverse effects or other problems related to the presence of pharmaceuticals in the environment, which affect human and other animal species.[5]

Sources of Entry of Pharmaceuticals into Environment

Drug use in both the human and veterinary population is escalating day by day. According to one estimate 100,000 tons of antimicrobials are consumed every year.[6] More than 30 billion doses of nonsteroidal antiinflammatory drugs (NSAIDs) are consumed annually in the United States only.[7] Consumed drug passes out of the system either as metabolites or unchanged through excretion. Drugs are usually water soluble and therefore find their way into the sewage. Industrial waste of the pharmaceutical companies also contributes toward the entry of drugs into the environment. Though such industries adopt the sewage treatment process before disposal but because of their obsolete processes the contamination of environment by drugs continues. Few drugs are not entirely removed by treatment process leaving their traces to go into water in environment.[8] Cocaine, oral contraceptives, carbamazepine, and iodine contrast media are some of the examples.[9-11] Cocaine has been detected in Po river in Italy.[12] In Niagara river antidepressant drugs, carbamazepine and other antileptics, and lipid-regulating agents (statins) were detected.[13] Apart from these, there are numerous examples of drugs found in aquatic environment. These include antibacterials like flouroquinolones, hormones, paracetamol, diclofenac, etc. Thus water becomes contaminated although with minimum amount of numerous drugs. Supplied as drinking water, it leads to an unwitting re-entry of drugs into humans.

Such pollution of environment by the drugs or their metabolites is creating an alarming situation. According to a report published in Washington Times, treated waste water taken from a plant in an industrial area in south India where about 90 Indian drug factories dump their residues, it was revealed that enough of a single, powerful antibiotic was being spewed into one stream each day to treat every person in a city of 90,000. Waste water downstream from the Indian plants contained 150 times the highest levels detected in the United States of America.[14] Sewage contaminated with traces of drugs may also be used in irrigation. Drugs or their metabolites also find their path to enter the food chain through this route.

Leftover medicines constitute another dominating cause of environmental contamination with drugs. Improper disposal of leftover medication usually contaminates the environment to a great extent. Drug residuals from the formulations like transdermal patches also leave the significant amount of drug in environment.[15] Transdermal patches containing fentanyl are reported to retain 28–84% of the loaded drug after removal from skin.[16]

Consequences of Environmental Pollution by Pharmaceuticals

Exposure of human beings and animals to drugs through environment affects them directly or indirectly. The foremost in discussion is microbial resistance. Continuous exposure to low dose of antimicrobials through drinking water may bring resistance. Decreasing interest of pharmaceutical companies in development of new antimicrobials in favor of developing “lifestyle” drugs may add on to the problem.[17] Although, effect of very low doses from the environmental cycling is not clear, special populations like pregnant women, children, geriatric population, persons with renal or hepatic insufficiencies may remain at a greater risk to such exposure because in these categories the pharmacokinetics gets altered and even minor doses may also prove to be toxic.[18] Similarly, some drugs in these micro doses may also show synergistic actions. Nocebo effect of the drugs even in subtherapeutic concentrations present in environment cannot be ruled out. Moreover, type B adverse reactions may also take place at these doses.[11]

Some examples of impact of drugs through environment on human beings and animals are cited here. The foremost is a substantial decline in number of vultures in Indian subcontinent secondary to their indirect exposure to diclofenac. A study from Pakistan revealed that due to the use of diclofenac in treatment of livestock and consumption of their dead bodies by vultures led to the kidney failures of these vultures.[19] Consequently over a period of time population of vultures declined so drastically that they were declared endangered species. Various Government and nonGovernmental organizations became active to save these most efficient scavengers of nature. Similarly, Government of India also banned diclofenac in India for veterinary use.[20] Sterility in frogs due to traces of oral contraceptive pills in water became the cause of decrease in number of frogs.[21] Ivermectin which is used as anthelmintic in veterinary practice gets excreted through feces and subsequently affects other organisms like dung beetle adversely.[22] Presence of sex hormone in aquatic environment has also feminized the male fishes. Few workers have also tried to correlate the alarming decline in sperm count in men that has decreased by 50% in 50 years.[23] Several persons get unintentionally exposed to an array of drugs through environment. Not only the drugs but also the excipients used in the formulations may pose a threat to the environment.[24]

Remedial Measures

Drug use has become an inevitable part of our lives but it is not imperative to compromise with the balance of ecosystem on any grounds. Solutions need to be suggested to save this only livable planet from ill effects of these chemicals. These may include better sewage treatment plants, education over rational use of drugs, and development of biodegradable products.[25] Biopharmaceuticals may be an alternative but we still lack a scientific evidence to accept them as a complete substitute of drugs in practice.[26]

A mandatory provision may be made in the process of drug development to establish safety in the context of environment and a study of the impact of drug over environment. Environmental Risk Assessment (ERA) has become mandatory before seeking market authorization of drugs in European Union (EU). We should, however, remember that the results of ERA are affected by several factors like dose of the drug used, characteristics of drug, metabolism of drug, biodegradation, measured environmental concentration, and ecotoxicity. It is also difficult to predict the chronic hazard potential of a drug in subacute concentrations on the basis of acute toxicity studies.[2728] Countries like United Kingdom have witnessed the impact of stringent regulations. The American Senate has also passed a legislation to monitor the drugs in environment. As stated above, a number of Governmental and nonGovernmental organizations have also taken initiatives. Few of them are proving to be benchmark for international stakeholders, for example, in Nepal aviaries are being constructed following their success in Pinjore, India. But India with a multifold (almost 150 times) contamination as compared with developed countries is still striving for a robust system to safeguard the environment. Attention is paid to the culprit drugs only after the alarming episodes are reported. It will now be pertinent for regulatory as well as scientific society to work hand in hand to address this vital issue.