A review on environmental occurrence, toxicity and microbial degradation of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Graphical abstract
Introduction
Emerging contaminants (ECs) can be defined as newly recognized environmental contaminants causing adverse environmental and/or human health effects (Rasheed et al., 2019). The presence of emerging contaminants in the environment has received more attention over the last few decades. A broad class of these emerging contaminants is pharmaceuticals and personal care products (PPCPs), known to have the ability to stimulate physiological complications in humans at low doses. The widespread use of PPCPs in recent years has led to their accumulation in the ecosystem and their assimilation into living organisms through their involvement in food webs.
The presence of pharmaceuticals in the environment has a direct relation to their increasing global uses reflected from their market size. Among the various classes of pharmaceuticals, analgesics and NSAIDs had the largest market size in 2020, amounting to 46.69 billion US$ and 48.2 billion US$, respectively, while others like antidepressants (28.6 billion US$), antihypertensives (24.17 billion US$), antifungal (13.06 billion US$), and anaesthetics (2.0 billion US$) had significantly smaller market share (IMARC, 2021; Globe Newswire, 2020). NSAIDs are thus regarded as one of the most used pharmaceuticals in human and veterinary medicine and since most of these can be purchased off the counter, NSAIDs constitute one of the most significant groups of pharmacologically active substances from an environmental perspective.
NSAIDs can reach the environment through sewage or hospital wastewater treatment plants, solid waste management plants, leachate from solid waste landfills, or direct dumping by pharmaceutical industries (Paíga et al., 2016). NSAIDs are considered to be persistent and therefore, are found in the range of ng/L to μg/L in various aquatic environments including rivers, lakes as well as drinking waters all around the world (Sibeko et al., 2019; Shanmugam et al., 2014; Lindholm-Lehto et al., 2015; Brozinski et al., 2013; Vulliet and Cren-Olive, 2011; Rabiet et al., 2006). Due to their ubiquitous occurrence in the aquatic environment and chronic ecotoxic effects on the biotic components of the ecosystem, they are considered an emerging contaminant of concern.
NSAIDs have anti-inflammatory, antipyretic, and analgesic properties. The antipyretic effect is majorly attributed to the inhibition of production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus and due to the reorganizing of the thermoregulatory system leading to vasodilation and increased heat loss (Osafo et al., 2017). The analgesic effect is thought to be related to the peripheral inhibition of prostaglandin generation (Cashman, 1996). The anti-inflammatory action of NSAIDs is due to the inhibition of COX or cyclooxygenase enzyme, which are responsible for the conversion of arachidonic acid to prostaglandins (Vane, 1971). Diclofenac, ibuprofen, salicylic acid, naproxen, celecoxib, mefenamic acid, and ketoprofen are some of the major NSAIDs available in the market. Table 1 highlights the major properties of some of the most popular NSAIDs.
Over the last decade, several NSAIDs have attracted extensive research on their occurrence and persistence in the aquatic environment, including rivers, lakes, groundwater as well as wastewater treatment plants. The harmful impacts of NSAIDs on the environment and humans along with the toxicity on many model organisms have also been studied. Although there are few reviews attempting to compile the presence and toxicity of some of the NSAIDs, either these have been limited to specific compound such as diclofenac (Lonappan et al., 2016), or NSAIDs have been given little attention while reviewing emerging contaminants or pharmaceuticals in general (Couto et al., 2019; Tran et al., 2017). Comprehensive reviews focusing on NSAIDs are rare and have been limited to studies like toxicity (Parolini, 2020) and metabolism by non-target wild-living organisms (Mulkiewicz et al., 2021). Reviews on mitigation and removal of NSAIDs are also scarce, as limited focus was given to NSAIDs in wider reviews on removal of pharmaceuticals or trace organic contaminants by conventional or advanced oxidation processes (Caban and Stepnowski, 2021; Tufail et al., 2020; Couto et al., 2019). Even though, the viable microbial degradation of xenobiotics is often regarded as a more sustainable approach for the remediation of such environmental contaminants, and research on microbial degradation of NSAIDs at lab as well as field conditions have received lot of attention in the last decade, no critical review is available on aqueous-phase biodegradation of NSAIDs.
To fill the void, this paper attempted a comprehensive and critical review of microbial degradation potential and pathways of major representative NSAIDs (Diclofenac, Naproxen, Ibuprofen, and Ketoprofen) along with a discussion regarding their environmental occurrence and toxicity. The study also reviewed the status of daughter-products and metabolites of these NSAIDs, and potential mechanism and pathways of the degradation. Special comments regarding the factors impacting scenarios of occurrence and treatment in wastewater treatment plants (WWTPs) has also been made along with an insight in limitations of implementing advanced bioremediation technologies in field scale WWTPs. Overall, the paper aimed at advancing critically reviewed knowledge on the environmental risk and mitigation of major NSAIDs.
Section snippets
Occurrence of NSAIDs in waters around the world
NSAIDs along with other PPCPs can reach the aquatic environment through several routes. NSAIDs are excreted from humans and animals mainly in urine, passing on to the environment directly or via sewage plants. These may be intact or metabolized into some other intermediates (Mulkiewicz et al., 2021). They may also reach the environment unused either via household water or via urban solid garbage handling, mainly through leachate from solid waste landfills with digested sludge (containing
Environmental toxicity and health hazards of NSAIDs and metabolites
NSAIDs are ubiquitously present in our surface waters as well as groundwater. Due to such a widespread presence, the surface water quality and aquatic life are highly affected, which ultimately leads to a decline in the number of aquatic organisms. Bioaccumulation of NSAIDs along the food chain is also a possibility that is rapidly gaining ground since NSAIDs like diclofenac are reported to accumulate in bile or liver of rainbow trout up to a concentration factor of about 2700. (Schwaiger et
Removal of NSAIDs from waters and wastewaters
Due to the pervasive presence of NSAIDs in waters and wastewaters in several parts of the world, and the risk posed with the chronic exposure of such compounds, the treatment or removal of NSAIDs becomes critically vital. At present, highly selective and rapid reactions, such as advanced oxidation processes (AOPs), or adsorbents, such as activated carbon, are seen as efficient ways to remove micropollutants like NSAIDs. AOPs use combinations of reactive oxidants including ozonation,
Microbial degradation of NSAIDs
The microbial degradation of NSAIDs has garnered an incredible interest from the research community all over the world because of their advantages over other treatment methods. While assessing the percentage of biological degradation and sorption in a conventional activated-sludge wastewater treatment plant from Murcia, Spain, Martínez-Alcalá et al. (2017) concluded that microbial degradation was very important for ketoprofen and ibuprofen, since biodegradation contributed 54.3% and 99.7% of
Conclusion
NSAIDs were viewed as a future potential environmental threat due to its ubiquitous occurrence in water bodies around the world and the resultant environmental implications in aquatic ecosystems. Following are the key conclusions drawn through the critical assessment of the state-of-the-art knowledge available on NSAIDs:
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Typical concentrations of individual NSAIDs in surface water bodies is well below 1 μg/L. Only 17.24% of surface water sources of the 29 reports showed a higher concentration of
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
The Ph.D. fellowship to Aishwarya Rastogi, received from Ministry of Human Resources and Development, Government of India, administrated through IIT Kharagpur, India is duly acknowledged.
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