IMPACTS OF HUMAN PHARMACEUTICALS ON FISH HEALTH

IMPACTS OF HUMAN PHARMACEUTICALS ON FISH HEALTH

Bhawna Srivastava and P. B. Reddy *

Government PG College, Ratlam, Madhya Pradesh, India.

ABSTRACT: Human pharmaceuticals and their metabolites affect the endocrine system and physiology of aquatic wildlife, which is an important global ecological concern. The published data from open-source toxicology and worldwide web resources reveal about 175 pharmaceuticals that can affect estrogen pathways to disrupt the endocrine system and metabolism. Such studies demand additional investigations on fish and wildlife. As predicted, the use of therapeutic drugs is expected to progressively increase over the coming years, following increased discharge in a freshwater environment. The widespread use and their incorrect dumping procedures have made these chemicals as contaminants of emerging concern (CEC). Particularly, the active pharmaceutical ingredients (APIs) are universally identified in surface water and soil, where they execute negative effects in living organisms. The associated presence of different drugs may undergo bioaccumulation, which causes potential toxicological effects on behaviour, histopathological alterations, reproductive and immunotoxic responses in fish and wildlife. However, the results of published literature revealed that the intensity of impacts is mostly regulated by the concentration of active pharmaceutical compounds, time of exposure, and some abiotic factors like photoperiod and nutrient availability. The response of species to these active pharmaceutical substances may be noticeably different from species type. Therefore, it is necessary to continue systematic research on active metabolites and drug detection methods, check the great number of active pharmaceuticals in drinking water, surface, and groundwater, and assess the environmental risks arising from their increased presence in the freshwater environment.

Keywords: Freshwater, Fish health, Pharmaceuticals, Surface waters, Toxic responses

INTRODUCTION: All living beings are composed of water, and it is very difficult to imagine life without water. The presence of several cocktails of contaminants, including human pharmaceuticals and their metabolites and other pollutants, are major concerns of the world today ^1-3. A few numbers of these environmental pollutants are omnipresent and cannot be removed from water treatment plants. Indeed, such pollutants can bioaccumulate in the tissues of aquatic organisms and pose a number of health risks.

The majority of pollutants undergo biotic and abiotic degradation in order to safeguard freshwater environments and their organisms. Wastewater usually contains a multifaceted mixture of pharmaceuticals, xenobiotics and microbes of human and animal origin.

In the past, pharmaceuticals pollution was not considered a major issue of the release of drugs into the environment. Nevertheless, the current modern research shows that certain pharmaceutical manufacturing units can cause environmental contamination at levels way above standards ⁴. The living organisms found around such ecosystems may experience adverse effects as reflections. Published literature evidently reveals that certain aquatic plants can absorb these pharmaceuticals and their metabolites and pass these harmful pollutants to all the organisms at various food chain levels ^{5, 6}. Pharmaceutical contamination has become an inevitable global ecological issue. As roughly $800 billion worth of medicines are sold globally, and more and more pharmaceuticals are being discharged into the environment ⁷. Of the 175 potential drugs, around one-third were recognized as estrogen agonists, and two-thirds were acknowledged as estrogen antagonists. The global use of medicines and drug use has continued to elevate, with Americans filling 5.8 billion recommendations in 2018 with an increase of 2.7% over the previous year. In 2018, growth on expenditures on pharmaceuticals in the United States bounced back to 4.5% on a net basis with an estimated $61 billion market. It is expected that in the next five years, the net medicine expenses in the United States alone will enhance from $344 billion in 2018 to $420 billion in 2023 ⁸. The sales growth was witnessed parallel with the advancement in medical technology and enhanced spending on health care.

The Indian sub-continent is the major contributor to generic drugs, bulk drugs, intermediates, drug formulations, and herbal products, and surgical internationally. The country’s pharmaceutical sector provides over 50 percent of worldwide demand for various medicines and 40 percent of generic demand in the US. The Indian pharmaceutical sector is projected to grow up to US$ 100 billion by 2025. The revenue of the nation’s domestic pharmaceutical bazaar reached Rs 1.4 lakh crore (US$ 20.03 billion) in 2019, which is 9.8% raise compared to Rs 129,015 crore (US$ 18.12 billion) in 2018 ⁹.

The commonly found pharmaceuticals and their metabolites in freshwater environments reach water bodies through a variety of pathways. Direct dumping of household leftover drugs, excretion in faeces/urine after medicinal use, incomplete effluent treatment from the manufacturing units ¹⁰ handling and prophylaxis through the water in farms aquaculture farms ¹¹, and livestock treatment and petcare ¹¹ are found to be major pathways to reach the aquatic environment. In general, the detected levels of pharmaceuticals concentrations in the freshwater environment are comparatively low. Usually, they lie between in the ng L−1 to μg L−1 range ¹², but in some nations like India and China, these concentrations are comparatively high due to feeble legislative regulations ¹³. Potential risks associated with the releases of pharmaceuticals into the environment have become an increasingly important issue for environmental regulators and the pharmaceutical industries. This concern has been driven by prevalent exposure of pharmaceuticals in environmental samples due to improved analytical capabilities and the charging of focused field surveys. Pharmaceutical pollutants are biologically active substances intended to interact with a definite physiological pathway in the target organisms. Accordingly, they symbolize a class of emerging pollutants competent enough to affect particular physiological functions like growth, development, defense and reproduction at ecologically pertinent concentrations ¹⁴.

The long-term studies of Grzesiuk et al., ⁵ evidently discovered that the chronic exposure of pharmaceuticals (fluoxetine, ibuprofen, and propranolol) on Acutodesmus obliquus and Nannochloropsis limnetica for 30 generations exhibited decreased in cell number, increased carotenoid to chlorophyll ratio, and affected their consumer feeding. Notably, pharmaceuticals are specifically designed to correct definite physiological functions. This is different from most other pollutants entering the freshwater environment, where biological effects usually happen as an unintentional effect of their principal function ¹⁵. Therefore, many pharmaceuticals designed to provoke a result in humans or livestock have a high possibility of being biologically active in wildlife species. Supporting this statement, the study of Gunnarssan et al., ¹⁶ conclude that zebrafish possesses orthologs to 86% of 1318 tested human gene-drug targets ^{17, 18}.

Besides, the biological target system in wildlife species is somewhat different or is more susceptible to the effects of certain pharmaceuticals than in livestock and humans or livestock animals ¹⁶. For example, the diclofenac, a non-steroidal anti-inflammatory drug, exhibited a severe effect on kidney function in Gyps vulture species and has resulted in their extensive decline and even extinctions ¹⁶. Another example is that the β-blocker drug, which mainly targets the adrenergic function, is believed to be involved in melanophore function in fish ¹⁹ are not, observed in humans.

The most significant adverse effects of pharmaceuticals include their capability to interfere with the endocrine system altering hormone secretion required for fundamental physiological functions. The most effective drugs are synthetic steroid estrogens, for instance, 17β-estradiol (E2), estrone (E1) and 17 α-ethinyl-estradiol (EE2). A number of laboratory investigations offer confirmation that exposure to these compounds can lead to anomalous change or disruption of growth and reproduction in fish and aquatic wildlife. In a study, exposure to the pharmaceutical mixtures of Tb (1, 10, and 50 ng/L) and EE2 (2 and 5 ng/L) on juvenile zebrafish (Danio rerio) for 20 and 60 days caused sexual disruption, masculinization effects, and intersex condition ²⁰. Additionally, a reduction in reproductive function ^{21, 22}, reduced fecundity and/or fertility ^{23, 24,} and alterations to gonadal maturation ²⁵ are among the most frequently observed effects.

Pharmaceuticals are potentially competent to modify homeostasis and critical functions and mechanisms of an organism. In some cases, they may act as endocrine-disrupting chemicals and affect the hormone secretions. Altogether, the measurable effects of pharmaceuticals on physiological, biochemical, or behavioral modifications can be successfully applied as biomarkers in biomonitoring approaches ¹⁴. The current appraisal could offer implications to advance the global pharmaceutical ecological management globally for effective monitoring systems in the release of pharmaceutical compounds in manufacturing units as well as from landfill effluent. Another area with a need for additional research is green chemistry, which could decrease or even remove the probable hazards of pharmaceutical substances that enter the environment. Fish and other aquatic animals are known to be more vulnerable to water pollution. The role of human pharmaceuticals in the endocrine disruption in the fish and the wild is very difficult to assess. In this document, we sincerely evaluate the probable biological impacts of pharmaceuticals discharged into the freshwater environment in fish due to their ecological position and many resemblances with mammalian species in physiological processes. Besides, fish species are perhaps the most credible vertebrate species to be affected by pharmaceuticals in the freshwater environment. Therefore, this document positively assesses the potential for ecological impacts of pharmaceuticals in the freshwater environment on fish health by drawing on comparisons between effects observed in the laboratory and concentrations measured in the field and assessing the scale of the (potential) problem. The Food and Drug Administration (USFDA, 2017) has approved about 10,000 pharmaceuticals and 3,000 ingredients for the treatment and are regular human applications. However, much amount of pharmaceutical waste is generated by improper disposal by patients, veterinary drug additives, and agrarian wastes, which are ultimately released into the freshwater environment. The extensive usage and inappropriate dumping of pharmaceutical drugs cause the spreading of multi-drug-resistant pathogens. As there are no specific guidelines on the antibiotic residue discharge limits, the effluents produced from these industries are treated as per the Central Pollution Control Board (CPCB) guidelines on wastewater, which unfortunately do not include antibiotic residues. As a consequence, they are not monitored in the pharmaceutical industry effluents. Besides, we advocate that pharmaceutical industries should utilize the best available and advanced technology to tackle pharmaceutical contamination in India.

MATERIALS AND METHODOLOGY: The present study is based on a systematic survey of the literature. The literature survey was executed on publications acquired for the data related to the impacts of pharmaceuticals on fish health and ecotoxicity. Web searches began with Google Scholar and Web of Science and using key terms “pharmaceuticals,” “drugs in the water” “aquaculture,” and “fish health.” Supplementary data were obtained from the reference sections of each article. Information was also acquired from news media and periodicals. We reviewed and included the most recent peer-reviewed academic literature for the present study, and 72 key sources are cited in the manuscript to demonstrate key issues and emphasize key research gaps still awaiting attention in future studies.

RESULTS AND DISCUSSION:

Pharmaceuticals in Freshwater Aquatic System: Globally, every year, several tons of pharmaceutical, chemical substances are produced and used. Pharmaceuticals are an important class of emerging environmental micropollutants and their occurrence in the freshwater environment is an increasing environmental concern. Nevertheless, most of these drugs may undergo biotic or abiotic degradation and finally accumulate in the tissues of fish and other aquatic organisms to induce potential toxicological effects like behaviour, histopathology, reproductive disruption, and immunotoxic responses.

Behavioral Responses: Behavioural alterations are the reflections of early toxicity signs, as they offer integrative actions of neurotoxicity ²⁷. Several aquatic organisms in general exposed to various pharmaceutical wastewater. Fish and other organisms potentially exhibit defense behaviour to combat any overall effect. Species may exhibit asymmetrical behavioral effects to pharmaceutical contamination, which vary with the concentration of the drug ²⁸. Many pharmaceuticals and their metabolites can accumulate in aquatic food webs and alter innate and vital behaviors in fish ^29-32. However, the behavioral effects of drugs in freshwater ecosystems depend on species-specific interactions and abiotic interactions ³⁰. For example, in an experiment, the fish Lepomis gibbosus (pumpkin-seed sunfish) was exposed to three anti-anticonvulsant drugs (diazepam, carbamazepine, and phenytoin) exhibited a significant increase in time spent in motion behavior ³³.

Another laboratory study of McCallum et al., ³⁴ demonstrated reduced aggressive behaviour and misplace their nesting site, which is an important behaviour in round goby (Neogobius melanostomus) exposed to wastewater with pharmaceutically active compounds. The study of Lagesson ³⁰ confirmed that the anxiety drug (Oxazepam) has the potential to alter the growth and behaviour in Perca fluviatilis (perch) but not in Esox lucius (pike) in the presence of temperature and predators as additional stressors. The experiment of Melvin ³⁵ evidently confirmed that a mixture of SSRI and SNRI (antidepressant drugs) are capable of altering circadian rhythms (feeding, predation, and competition behaviour) in male mosquitofish (Gambusia holbrooki) at concentrations approaching 1g/L. The study of Saaristo et al., ³¹ had shown altered and abnormal behaviour upon the exposure to psychoactive pharmaceutical drugs with other stressors likes temperature and predation in European perch (Perca fluviatilis). The 35-day experiment of Martin et al., ³⁶ showed that wild male mosquitofish (Gambusia holbrooki) exhibited severe behavioral impacts like boldness, exploration, and mating behaviour upon the exposure of antidepressant fluoxetine at two ecologically relevant concentrations (31 and 374 ng/L). The study of Ziegler et al., ³⁷ have shown that the brown trout (Salmo trutta f. fario) exposed to an antidepressant drug (citalopram) at two different life stages exhibited severe alterations in behaviour (increased swimming behaviour with reduced anxiety), bioaccumulation, and growth. The study also confirms that behavioral changes were stronger in early life stages, which are linked with the chronic exposure time in larvae compared to juvenile fish.

Based on the above literature, it is evident that various pharmaceuticals and their metabolites can induce behavioural alterations in different species. Nevertheless, both drug- and species-specific effects were also obvious. It is clear from the above literature that antidepressants, psychiatric drugs (benzodiazepines), and antihistamines can induce behavioural changes in fish at environmentally relevant concentrations. However, as such, the data is difficult to forecast the direct effects using solitary species and under static laboratory conditions. More investigations should evaluate the adverse effects of pharmaceuticals and their metabolites in freshwater ecosystems under more complex conditions to achieve an enhanced perception.

Even though the existing literature advocates that the environmental effects of pharmaceuticals may occur in freshwater ecosystems dominated by wastewater effluent, and effects of pharmaceuticals were seen only at higher concentrations but not at ecologically relevant concentrations. Therefore, the scarcity of experiments using behavioral endpoints on wildlife makes it tough to depict any universal conclusions on the subject of the ecological impact of pharmaceuticals found in freshwater ecosystems. Further, the behavioural outcomes produce even more complicated data to understand, synthesize, and extrapolate as fish and another aquatic biota living in polluted environments are exposed to a wide range of pharmaceuticals. For that reason, apart from the regular behavioural endpoints, research on the effects of pharmaceutical mixtures is deeply required to acquire a better perception of the biological effects of exposed wildlife.

Impacts of Residual Pharmaceuticals on the Health of Fish and Wildlife: India is the home for more than 10 percent (9.06 million metric tons) of global fish productivity and ranked in the second position at global level ³⁸. The huge productivity is achieved by rigorous farming at elevated mass, which has resulted in an increased vulnerability of fish to infections caused by microorganisms ³⁹. In order to enhance fish productivity, farmers use excessive chemicals and antibiotics to prevent infections and diseases, which enter into the aquatic environment in significant quantities. The introduction of antibiotic drugs in various segments, including aquaculture, threatens the effectiveness of antibiotics ³⁹. The harmful impacts of left-over pharmaceuticals in the freshwater ecosystem and human health are a big concern. Published literature reveals that species and specific substances mainly influence drug circulation and bioaccumulation in the fish ⁴⁰. The laboratory investigations of Triebskorn et al., ⁴¹ have confirmed harmful effects of human pharmaceuticals (carbamazepine, clofibric acid, metoprolol, and diclofenac) in liver, gills, and kidney of the in rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio) at environmentally relevant concentrations.

The study found severe glomerulonephritis with hyaline droplet degeneration of proximal renal tubule as a major pathological effect. The findings of Gürcü et al., ⁴² showed that the accumulation of a common antibiotic, Metronidazole (MTZ), in the fish (Oncorhynchus mykiss) intestine could affect the histopathological organization of the intestine in dose-dependent and time-dependent manner. The alterations include necrosis, edema, inflammation, and small tears in the villi. For instance, when the juvenile fish rainbow trout (Oncorhynchus mykiss) exposed to the common antibiotic oxytetracycline (OTC) had shown the interference of the drug in different biochemical pathways and metabolic processes with increased histological damage like leucocyte infiltrations, hypertrophy, vacuolization, and pyknotic nucleus in the tissues of liver and gills ⁴³. In another experiment, Rodrigues et al., ⁴⁴ exposed the fish rainbow trout (Oncorhynchus mykiss) with a common antibiotic, Erythromycin (ERY), and are frequently prescribed for humans, and livestock medicine is frequently found in the aquatic environment. In an experiment Rodrigues, S., et al., ⁴³ exposed the juveniles of rainbow trout (Oncorhynchus mykiss) exposed to environmentally relevant concentrations of Erythromycin (ERY) exhibited considerable progressive (hypertrophy of mucous cells and hyperplasia) and regressive tissue damage (cytoplasmic vacuolization, pyknotic nucleus and cellular degeneration, hemorrhage, and increase of sinusoidal space) in gills and liver.

The study of Alimba et al., ⁴⁵ found cytogenotoxic, hematological, and histopathological alterations in Clarias gariepinus exposed to pharmaceutical effluents. Pharmaceutical effluent caused a major time-dependent increase in the frequency of micronucleus (MN) and irregular erythrocytes, decline in total erythrocyte counts, hemoglobin and haematocrit values, and increase in total leucocyte number and lymphocytes compared to the control fish. The fish exposed to pharmaceutical effluent also exhibited pathological injuries on gills, liver, and kidneys. Akinpelu et al., ⁴⁶ found histological alterations like infiltration of secondary lamellae, oedema, congestion of the blood vessels, epithelial thickening and lifting, and necrosis in the gill tissues of Clarias gariepinus upon exposure to sub-lethal concentrations of pharmaceutical effluents in dose-dependent manner.

Dos Santos et al., ⁴⁷ found neurotoxic and respiratory effects in a Neotropical fish species, Phalloceros harpagos exposed to two common human used drugs namely paracetamol (analgesic and antipyretic) and propranolol. In a recent study, Santos et al., ⁴⁸ confirmed that chronic environmental concentrations of metham-phetamine could lead to health issues in aquatic organisms. The study found bioaccumulation of methamphetamine (psychostimulant) in various tissues (kidney > liver > brain > muscle > plasma) to induce degenerative symptoms (apoptosis) in liver and heart of the brown trout (Salmo trutta fario) exposed to environmentally relevant concentrations for 35 days. The recent study of Hubená et al., ⁴⁹ showed varied effects of four psychoactive compounds on food intake and brain function in juvenile chub (Squalius cephalus) exposed to environmentally relevant concentrations. From the above literature of review, it is clear that pharmaceuticals in wastewater interfered with histopathological changes in the liver, gill, kidney, and gut tissues of various fish species exposed to wastewater with pharmaceuticals. Results reveal that pharmaceuticals and their metabolites, even at ecologically relevant concentrations, can interfere with exerting harmful effects on the histopathology of important organs like the liver, gills, and kidney and obstruct the proper functioning of these organs. Bioaccumulation of pharmaceuticals via food webs in fish tissues like plasma, brain and muscle samples are slightest or negligible compared to liver, gills and kidney to induce degenerative symptoms like vacuolization, pyknotic nucleus and cellular degeneration, hemorrhage and infiltration of secondary lamellae and lifting in gills and liver while severe glomerulonephritis with hyaline droplet degeneration of proximal renal tubule as a major pathological effect in the kidney. The gut exhibited necrosis, edema, inflammation, and small tears in villi. Results reveal that the interference of the pharmaceuticals in different biochemical pathways and metabolic processes caused increased histological damages in tissues in a dose-dependent and time-dependent manner. These outcomes of the presented worken lightening a prospective for additional studies on metabolic pathways of pharmaceuticals and its metabolomics in fish exposed under natural conditions.

Impacts of Residual Pharmaceuticals on Fish Reproduction: Reproduction is a biological process, which depends on the synchronizing activities of the neuroendocrine system. Several human and veterinary pharmaceuticals are released into urban wastewater, and upon exposure, such contaminants can induce detrimental effects in aquatic organisms and fish. Runnalls et al., ⁵⁰ found a decline in sperm parameters when adult fathead minnow exposed to clofibric acid (human pharmaceutical). The in-situ studies of Sanchez et al., ⁵¹ confirmed the alterations in the enzyme activities, neurotoxicity, intersex, vitellogenin induction in fish exposed to pharmaceutical effluent downstream of the Dore river (France). The study of Galus et al., ⁵² confirmed the incidence of developmental abnormalities like decreased embryo production, atretic oocytes, and altered ovarian and kidney histology in adult zebrafish (Danio rerio) exposed to a pharmaceutical mixture of acetaminophen, carbamazepine, gemfibrozil, and venlafaxine and to diluted wastewater effluent for 6 weeks.

Based on the results of a laboratory study of Margiotta-Casaluci et al., ²¹ addressed the mode of action of human pharmaceuticals in fish species. Their study confirmed that the pharmaceutical drug (dutasteride), which is used to cure benign prostatic hyperplasia in humans, may inhibit the activities of both isoforms of 5α-reductase (5αR). This enzyme converts testosterone into dihydrotestosterone and causes detrimental effects in the fish fathead minnow (Pimephales promelas).

The study of Prasad et al., ⁵³ proven that certain pharmaceutical contaminants present in the natural environment may influence the fish reproductive process by means of the serotonin system. The in-vitro studies of Yokota et al., ⁵⁴ found severe anti-ovulatory activities of non-steroidal anti-inflammatory medicines in comparison with in vivo reproductive studies in medaka (Oryzias latipes). Aguirre-Martínez et al., ⁵⁵ demonstrated significant changes in neurotoxic responses, inflammation, reduced gametogenic activity, and energy status in fish Corbicula fluminea exposed to environmentally relevant concentrations of human drugs for 21 days (caffeine, CAF, ibuprofen, IBU, carbamazepine, CBZ, novobiocin, NOV and tamoxifen, TMX). The laboratory experiments of Martin et al., ³⁶ and Fursdon et al., ²² confirm that the antidepressant drug (fluoxetine) can alter the reproductive behaviour and sperm traits in fish. Fraz et al., ⁵⁶ found transgenerational impacts like reduced reproductive function, courtship, aggressive behaviors, sperm speed, and morphology for four generations in zebrafish exposed to a common drug residue (carbamazepine (CBZ).

Constantine et al., ⁵⁷ found a decline in fecundity and fertility, vitellogenin, and hatching success rate in zebrafish (Danio rerio) exposed to ibuprofen at environmentally relevant concentrations. de Lima et al., ⁵⁸ found that certain diets used to reduce oxidative stress in the human population could interfere with the reproductive process and growth in female Nile tilapia (Oreochromis niloticus). Godoi et al., ⁵⁹ found a significant reduction in reproductive activities by reducing 17β- Estradiol (E₂), and testosterone levels in male fish (Astyanax altiparanae) exposed to common drugs (Diclofenac (DCF) and caffeine (CAF) at normal levels. In contrast, the study of Thoré et al., ⁶⁰ demonstrated increased mating, enhanced fecundity, and alteration in social behaviour in the short-lived kill fish (Nothobranchius furzeri) exposed to antidepressants. The results of a recent laboratory study of Liang et al., ⁶¹ showed reduced plasma 11-ketotestosterone levels in males, increased reproductive toxicity, decreased spermatogenesis, and anti-androgenicity in Japanese medaka (Oryzias latipes) upon the exposure of  3-(4-Methylbenzylidene) camphor (4-MBC) at environmentally relevant concentrations. The above literature survey revealed that pharmaceuticals in the aquatic environment could negatively affect fish reproductive function by affecting sperm parameters, alterations in the enzyme activities, intersex, and vitellogenin induction in fish exposed to pharmaceutical substances. Some reports revealed decreased embryo production, atretic oocytes and altered ovarian histology in exposed fish to even at environmentally relevant concentrations of human drugs. Few studies reported transgenerational impacts like reduced reproductive function, courtship and aggressive behaviors, sperm speed, and morphology in exposed fish species. In contrast, few authors reported better mating, improved fecundity, and alteration in social behaviour in fish exposed to drugs in the laboratory.

Immuno Toxic Effects: The immune system in fish and other organisms possibly affected directly by toxic compounds. The detection of pharmaceutical remains of various drugs in surface waters has provoked concerns about probable adverse effects on freshwater biota. Several ecological pollutants, including pharmaceuticals, are identified as immune modulators in fish and wildlife species 62, making the organism more vulnerable to pathogen infections. The research analysis of Milla et al., ⁶³ had shown the interactions of the immune system with synthetic steroids (estrogenic and androgenic) in fish. The review analysis of Burgos-Aceves et al., ⁶⁴ demonstrated the immunomodulation functions in fish are regulated by both natural and synthetic estrogens, which act through estrogen receptors and regulate definite target genes, and also through microRNAs (miRNAs). The experimental findings of Ribas et al., ⁶⁵ revealed significant immunosuppressive effects by declining in RBC, WBC, haemoglobin, and haema-tocrit values in the fish (Hoplias malabaricus) exposed to common drugs like diclofenac and dexamethasone. Kleinert et al., ⁶⁶ observed a significant reduction in the functional activities of the immune system by decreasing lymphocyte transformation and G₀/G₁ phase of the cell cycle in the harbor seal (Phoca vitulina) exposed to17α-ethinyl estradiol and 25,000 μg/L naproxen as mixtures. Khoei et al., ⁶⁷ observed reduced aggressions, and IgM levels in fish Siamese fighting fish (Betta splendens) exposed to immuno-suppressant drug tacrolimus. The guaranteed immunotoxic effects of pharmaceuticals have been found to be related to the defense mechanism of both host and microbiota ⁶⁸. The laboratory findings of Liang et al., ⁶⁹ demonstrated decreased hatching rate and body length and increased abnormality and mortality in the early life stages of zebrafish (Danio rerio) upon exposure of Norfloxacin nicotinate (an antibacterial fluoroquinolone, NOR-N). The results also confirmed increased antioxidant system (MDA, SOD, CAT, and GPx) and expression of TNFα, IFN, IL-1β, IL-8, CXCL-clc, CC-chemokine, Lzy and C3 genes in exposed fish.

Another recent work of Li et al., ⁷⁰ established immunotoxic effects in association with hepatic damage (hepatic vacuolization and nuclei pyknosis and inflammation) in juvenile zebrafish (Danio rerio) exposed to Benzotriazole ultraviolet stabilizers for 28 days. The experimental findings of Bera et al., ⁷¹ established that triclosan suppressed both cell-mediated and humoral immune responses with a decrease in respiratory burst activity (RBA), myeloperoxidase activity (MPO), phagocytic activity (PA) in triclosan exposed catfish, Pangasianodon hypophthalmus). In an experiment, Rehberger et al., ⁷² demonstrated that the chronic exposure to low ethinylestradiol (EE2) concentrations combined with parasite infection in juvenile rainbow trout (Oncorhynchus mykiss) can induce endocrine disruptive and immunomodulating activities.

In conclusion, it is clear that the majority of pharmaceutical substances and their metabolites mimic hormone structure and interfere in endocrine function to exhibit immunotoxic actions. Accordingly, immunomodulation in affected fish may be a result of such exposure. Several ecological pollutants, including pharmaceuticals are identified as immune modulators in fish and wildlife species. Several authors reported significant immunosuppressive effects like declining in RBC, WBC, haemoglobin, haematocrit values, decreasing lymphocyte transformation and G₀/G₁ phase of the cell cycle in harbor, reduced aggression, and IgM levels in fish exposed to pharmaceutical pollution. Few authors also reported the association of immunotoxic responses with hepatic tissue damage. Therefore, fish immuno-toxicity studies may be used as valuable biomarkers of pharmaceutical contamination. However, to standardize our understanding of these mechanisms, care should be taken when considering the intrinsic and extrinsic factors related to the fish and the contamination model.

CONCLUSION: The presence of persistent drugs in surface waters is a big global concern today. Literature is still scanty regarding how cocktails of pharmaceutical residues in surface water affect the environment or fish health. Until now, the published literature showed bioaccumulation and negative effects on fish and other aquatic organisms. As there is no specific legislation on pharmaceutical waste management, drug contamination in water is increasing globally year by year, effectively forming an epidemiological experiment with the public and freshwater ecosystem. The present study reviewed and analyzed the impacts of pharmaceutical substances on various health aspects of fish. Based on an inclusive assessment of the data and analysis, it is well established that drugs in water can affect fish health by accumulating specific tissues that induce negative effects in histopathology, oxidative stress, haematological indices, reproductive function, gene expression and immunotoxic effects. However, the degree of severity depends on species, sex, and phase of the life cycle, dose, and duration of the substances. The study advocates framing and implementing rigid guidelines for treating and monitoring waste discharged from municipal wastewater and pharmaceutical industries for controlling pharmaceutical pollution in wastewater.

CONFLICTS OF INTEREST: We declare no conflict of interest of any kind with anybody.

Financial Support: None

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    How to cite this article:

    Srivastava B and Reddy PB: Impacts of human pharmaceuticals on fish health. Int J Pharm Sci & Res 2021; 12(10): 5185-94. doi: 10.13040/IJPSR.0975-8232.12(10).5185-94.

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