Veterinary drugs in the environment and their toxicity to plants

Chemosphere Volume 144, February 2016, Pages 2290-2301 Chemosphere Review Author links open overlay panelHanaBártíkováaRadkaPodlipnábLenkaSkálováa a Department of Biochemical Sciences, Charles University in Prague, Faculty of Pharmacy, Heyrovského 1203, Hradec Králové, CZ-500 05, Czech Republic b Laboratory of Plant Biotechnologies, Institute of Experimental Botany, Czech Academy of Sciences, Rozvojová 263, Praha 6, CZ-165 02, Czech Republic Received 12 August 2015, Accepted 31 October 2015, Available online 21 November 2015. Handling editor: Shane A. Snyder crossmark-logo https://doi.org/10.1016/j.chemosphere.2015.10.137 Get rights and content Highlights • Wide scale of veterinary pharmaceuticals enter the environment. • Veterinary drugs may affect non-target organisms, including plants. • Many veterinary antibiotics and hormones are phytotoxic. • Phytotoxicity data on the other veterinary drugs are insufficient. • Impact of veterinary drugs on plants needs to be investigated more thoroughly. Abstract Veterinary drugs used for treatment and prevention of diseases in animals represent important source of environmental pollution due to intensive agri- and aquaculture production. The drugs can reach environment through the treatment processes, inappropriate disposal of used containers, unused medicine or livestock feed, and manufacturing processes. Wide scale of veterinary pharmaceuticals e.g. antibiotics, antiparasitic and antifungal drugs, hormones, anti-inflammatory drugs, anaesthetics, sedatives etc. enter the environment and may affect non-target organisms including plants. This review characterizes the commonly used drugs in veterinary practice, outlines their behaviour in the environment and summarizes available information about their toxic effect on plants. Significant influence of many antibiotics and hormones on plant developmental and physiological processes have been proved. However, potential phytotoxicity of other veterinary drugs has been studied rarely, although knowledge of phytotoxicity of veterinary drugs may help predict their influence on biodiversity and improve phytoremediation strategies. Moreover, additional topics such as long term effect of low doses of drugs and their metabolites, behaviour of mixture of veterinary drugs and other chemicals in ecosystems should be more thoroughly investigated to obtain complex information on the impact of veterinary drugs in the environment. Graphical abstract Download high-res image (379KB)Download full-size image Previous article Next article Keywords Veterinary antibiotics Growth promoters Phytotoxicity Environmental impact 1. Introduction Pharmacologically active substances which are part of veterinary drugs represent important mean how to treat and prevent diseases in animals. Although the health benefits of medication on target species are particularly important, the pharmaceuticals enter the environment where they can act negatively on many non-target species. These environmental risks have become higher because more and more drugs are applied to animals due to increasing intensive agriculture and aquaculture (Kummerer, 2010; Arnold et al., 2013). This issue began to receive more attention by scientists in the late 1990s and has become recent research topic (Santos et al., 2010). Veterinary drugs are potential group of chemical contaminants, because they are designed, as other drugs, to have biological effects at low concentration (Arnold et al., 2013). They include not just parent form of chemical, i.e. active compound or prodrug (inactive precursor that is converted into active form by normal metabolic processes), but also their bioactive metabolites and transformation products (Daughton, 2007). Veterinary pharmaceuticals belong to several pharmacological categories: antiparasitics (ectoparasiticides, endectocides, endoparasiticides including antiprotozoals and anthelmintics), antimicrobials (antibiotics including growth promoters and antiseptics), hormones, antifungals, anti-inflammatory (steroidal and non-steroidal) drugs, anaesthetics, euthanasia products, tranquilizers, sedatives, bronchodilators, antacids, diuretics, emetics, emulsifiers. Except substances for disease treatment and protecting animal health, animals may be exposed to other chemicals as feed additives, e.g. growth promoters, which are incorporated into the feed of animals reared for food in order to improve their growth rates (Boxall et al., 2003; Sarmah et al., 2006). Although there is a wide spectrum of therapeutic classes, veterinary practice tends to use mostly antibiotics, antiparasitic drugs and steroidal hormones. These veterinary compounds are followed by substances employed for treatment of alimentary tract and metabolism, compounds used on the central nervous system and other pharmaceuticals. Hormones are banned as growth promoters in EU, but they still have other application as oestrus inductors or suppression agents. Although they are not utilized in large quantities, they are substances with very high biological activity. Therefore, the monitoring of hormones behaviour in the environment is important. In 25 EU countries, the use is estimated to 5393 tons antibiotics, 194 tons antiparasitics and 4.6 tons hormones (Kools et al., 2008). Drug consumption does not arise only from approved usages, but also from unapproved (e. g. extra-label) and illegal use. So called off label prescribing for non-approved conditions is quite widespread. Thus, illicit drugs account for an unknown but potentially significant fraction of total drug use and contribute to overall environmental contamination by veterinary drugs. Relative usage rates can differ not only between countries, whose list of approved drugs is not necessarily the same, but also among geographic localities within the country reflecting prescribing practices and preferences (Daughton, 2007). Veterinary drugs can be introduced to environment via different pathways. The most significant sources of environmental pollution are comprised of treatment processes (livestock, aquaculture, companion animals), inappropriate disposal of used containers and unused medicine or livestock feed, and manufacturing processes. Intensive livestock and aquaculture treatments are considered more relevant than treating companion animals. Application of drugs in intensively reared livestock represents the main route of entry in terrestrial environment, while aquaculture therapy has a high potential to reach aquatic environment, because the drugs are added to the environment directly. The excretion of drugs and/or their metabolites in urine and faeces of livestock, wash-off of topical treatments from livestock animals and direct discharge of aquaculture products are probably the most important entry into the environment. Unused veterinary drugs, their containers and leftover livestock feed entering the environment enhance the amount of veterinary drugs contaminating soil and water. Emissions from manufacturing processes and formulation are assumed to be not seriously threatening EU and USA due to tight regulatory controls (Halling-Sorensen et al., 1998; Jjemba, 2002; Boxall et al., 2003; Kummerer, 2010). Whether a drug is disposed or excreted by animals as parent drug, bioactive metabolite responsible for therapeutic or side effect, and inactive metabolites, which can be subsequently hydrolysed after excretion to release parent drug, e.g. via microbial activity, it passes to the environment directly or indirectly. Direct way is through the drug disposal and the use of veterinary drugs in pasture-reared animals which excrete drug residues straight to the environment. Indirect route consist of the application of manure and slurry originating from treated animals to land. In this case, drug metabolites do not arise only in animals, but the compounds may degrade further during the storage period of manure. The persistence period of veterinary drugs in manure may vary from days to months and is dependent also on manure type. Eventually, drug and/or their biotransformation products find their way into the soil and groundwater if they are not bound to soil constituents or they may reach surface water from runoff during the rainfall episodes (Boxall et al., 2002; Daughton, 2007; Kummerer, 2010). From water and soil, the veterinary drugs are capable to affect living organisms, including plants. The concentrations getting into the organisms are translated into effects, which can be classified into three groups. The first group includes normal toxic effects typical for all xenobiotics. They can occur on any level of biological hierarchy: cells – organs – organisms – population – ecosystem. Effects of second group, ascribed to antibiotics, are connected with resistance development and selection of more harmful bacteria. The caused changes are long-term, high extent irreversible and exerted at even very low concentrations. Third group effects comprise so called endocrine disrupters, i. e. chemicals which can disturb the normal function of hormones, again at very low doses (Jorgensen and Halling-Sorensen, 2000). Plants may take up the tainted groundwater to meet the evapotranspiration and photosynthetic requirements. Leakage from landfill can expose vegetation to these agents if tainted water is used for irrigation (Jjemba, 2002). Xenobiotic effects in plants involve not only biochemical and physiological disruption based on interaction with macromolecular or cellular targets, but also the disruption of signalling pathways. Xenobiotics have capability to induce changes at the levels of gene expression, regulation, and signal transduction. Moreover, some specific xenobiotics interact with plant hormone receptors and plant hormone signalling pathways. Modifications of gene expression, revealed thanks to development of transcriptomics and proteomics analysis, have shown to be important mechanisms of plant responses to xenobiotics (Ramel et al., 2012). Evidence of toxicity of common veterinary drugs is available for various aquatic and terrestrial organisms. A number of studies have investigated the toxic effects on aquatic species, such as marine bacteria, phytoplankton, algae, plants, crustaceans, fish (e. g. (Wollenberger et al., 2000; Yoshimura and Endoh, 2005; Tisler and Erzen, 2006; Kolodziejska et al., 2013; Wagil et al., 2015). Other studies focused on soil environment examined microorganisms, insects, earthworms, springtails (Baguer et al., 2000; Halling-Sorensen, 2001) and plants (e.g. reviewed in (Jjemba, 2002)). Although the veterinary drugs can affect different species once they get into the environment, this review focuses on the toxicity exerted on plants as they have not received as much attention as other organisms in the studies dealing with environmental impacts of drugs. The present review brings overall characteristic of the most used veterinary drugs, which is followed by their potential to negatively affect the environment, and these findings are supplemented with information on toxic actions in plants. 2. Veterinary drugs in the environment and their toxicity to plants 2.1. Antibiotics 2.1.1. General characteristic Antibiotics are drugs that can kill microorganisms or inhibit their growth or metabolic activity via biochemical actions. Now they are extensively used in the treatment and prevention of bacterial diseases. To treat or prevent infections of veterinary animals, they are applied as drugs or feed additives. Except the treating purposes, veterinary antibiotics can be used as growth promoters to improve feed efficiency and weight gain for increased food production (Sarmah et al., 2006; Du and Liu, 2012). Although the inclusion of antibiotics in feed for growth promotion in livestock production was banned in EU in 1998, large scale of use of antibiotics in animal production is being widely adopted worldwide (Du and Liu, 2012). The use of veterinary antibiotics (VA) reflects the growing animal food industry as they serve for protecting animal health, prevention of economic loss and help ensure a safe food supply. These nontherapeutic purposes represent the most often reason of VA use. Sales report indicates that the USA ranks first in the consumption of VA (over 11,000 tons per year) followed by China (6000 tons per year). Thus, the consumption in both countries is high not only due to the large numbers of livestock but also due to the common practice employing VA as growth feed additives. The usage of VA in USA is facilitated by selling over the counter without a veterinarian's prescription (Kumar et al., 2012). Leading countries in VA consumption in Europe based on sales of active ingredients in 2009 are France (1064 tonnes), Netherlands (514 tonnes) and United Kingdom (403 tonnes) (EMA, 2011). The most frequently used antibiotics are tetracyclines, sulphonamides, β-lactams and macrolides (Kools et al., 2008; Grave et al., 2010; Du and Liu, 2012). 2.1.2. Behaviour in the environment The occurrence and fate of VA is a serious environmental threat comprising development of antibiotic resistant bacteria, human health impacts of VA ingestion via animal or plant-based food products and drinking water with antibiotic residues, ecotoxic effects on non-target animals (e. g. environmental microorganisms) and ecological impacts on agro-ecosystems (Du and Liu, 2012; Kumar et al., 2012). The major concern of extended VA use is promotion of bacterial resistance, when VA released into the environment can enhance the formation of single, cross- and multiple resistance in pathogens, commensal and environmental bacteria (Kemper, 2008). Many of VA are poorly absorbed in the animal gut, so the most of administered dose is excreted by faeces. VA are often released into the environment only slightly transformed, conjugated to the polar molecules or even unchanged. As a result, VA have been detected in manure and natural environment, including soil, surface and groundwaters (Kemper, 2008; Furtula et al., 2012). Major source of VA in environment is the fertilization by contaminated manure and biosolids. Once in the environment, VA are transported and distributed among major environmental compartments. They can be taken up by plants where they exert toxic effects and/or are accumulated in the plant tissues which potentially lead to subsequent exposure of humans through the vegetable consumption (Jjemba, 2002; Boxall et al., 2003; Kemper, 2008; Du and Liu, 2012). 2.1.3. Plant toxicity The phytotoxicity of VA on plants in soil varies between plant species and antibiotic compound. A majority of VA that has been found phytotoxic has been assayed in vitro rather than under soil conditions. Moreover, in most cases the in vitro experiments seem to have been performed at concentrations that are unlikely to occur in soil (Jjemba, 2002). The most frequent effects of VA on plants comprise impacts on germination, plant growth and development. The earlier results are reviewed by Jjemba (2002) and Sarmah et al. (2006). For later studies dealing with toxicity of VA, reader is referred to reviews written by Du and Liu (2012) and Kumar et al. (2012). The overview of commonly used VA, accessible data on toxicity to plant species including later studies, but excluding algal toxicity with corresponding references are given in Table 1. 2.2. Antiparasitic drugs 2.2.1. Ectoparasiticides and endectocides 2.2.1.1. General characteristic Ectoparasiticides are antiparasitic veterinary drugs used to control external parasites. Endectocides are antiparasitic drugs which serve for treatment of diseases caused by both internal and external parasites. Ectoparasticides and endectocides are applicable to a wide range of animals including livestock and companion animals. Animals are infected by a number of insects and arachnids, such as various flies, lice mites, ticks, keds. Infections on livestock can cause intense irritation leading to poor condition, weight loss, and reduced milk yield. Altogether it results in major economic losses in production livestock. Moreover, many parasitic species are responsible for transmission of disease to animals themselves or are vectors of diseases to humans. Thus, the effective control of ectoparasites is necessary. It still relies on the chemicals which work as neurotoxins and attack ectoparasites' nervous system. Ectoparasiticides may act systematically, following uptake from the host's tissues, or by direct contact with external parasite after external application (Taylor, 2001; Boxall et al., 2002). Based on chemical structure, ectoparasiticides can be grouped into several classes. Amidines acting at octopamine receptor in ectoparasites are represented by amitraz. Carbamate insecticides inhibit acetylcholinesterase. Two main carbamate compounds are carbaryl and propoxur. Imidacloprid from nitroguanidines binds specifically to nicotinic acetylcholine receptor in insect. The use of organochlorines is nowadays prohibited in most countries due to environmental impacts, their persistence and resistance development. This group comprises of various compounds, e. g. DDT (dichlorodiphenyltrichloroethane), aldrin, dieldrin, and benzene hexachloride. Organophosphates act by inhibiting acetylcholinesterase and they can be extremely toxic in animals and humans. In some countries, chlorpyrifos is available. Diazinon and propetamphos have been available in dip formulations for the control of sheep scab. Other compounds include phosmet, fampur and fenthion. Fipronil, a phenylpyrazole compound, is used worldwide for the treatment of flea and tick infestation on dogs and cats. Synthetic pyrethroids are derived from pyrethrin, naturally occurring alkaloid. Common pyrethroids used in veterinary medicine are cypermethrin, deltamethrin, fenvalerate, flumethrin, lambda-cyhalothrin, phenothrin and permethrin. Other ectoparasiticide groups benzoylphenyl ureas (diflubenzuron, flufenoxuron) and triazine/pyrimidine derivatives (cyromazine) represent a relatively new category of insect control agents. They do not kill target parasite, but interfere with its growth and development. Juvenile hormone analogues (methoprene, pyriproxyfen) prevent metamorphosis of larvae to the adult stage because they mimic juvenile hormones. A number of macrocyclic lactones include the avermectins (abamectin, doramectin, eprinomectin, ivermectin, selamectin) and milbemycins (moxidectin, milbemycin oxime). As these drugs are active not only against ectoparasites, but also wide range of nematodes, they are termed as endectocides (Taylor, 2001). 2.2.1.2. Behaviour in the environment Generally, insecticidal and acaricidal compounds possess lot of drawbacks, like development of resistance and concerns over environmental safety. In the environment, aquatic organisms are more susceptible to ectoparasiticides than terrestrial forms. However, ectoparasiticides properly administered to livestock are used in relatively small quantities, and therefore represent the minor source of environmental pollution compared to application in agronomic crop production. Most of drug remains on animal, while very little is dispersed for potential soil and water contamination. There might be concerns of dip vats for pest control in certain countries, e. g. in sheep. Compromised vats can be a source for soil contamination from where compounds can leak into ground water. The disposal of large amounts of waste from vats might also be a problem (Kunz and Kemp, 1994). 2.2.1.3. Plant toxicity In general, ectoparasiticidal substances are not considered to be toxic for plants (EMA, 2004). Accordingly, the study dealing with effect of diazinon, fipronil and lambda-cyhalothrin has not shown the toxicity in rice (Oryza sativa) (Moore and Kroger, 2010). No phytotoxicity has been observed in the study performed with avermectines (Halley et al., 1993; Kolodziejska et al., 2013). 2.2.2. Endoparasiticides Endoparasiticides are antiparasitic agents that are used to control internal parasites. They comprise anthelmintics for the control of gastrointestinal worms, lungworms and flukes as well as antiprotozoals and coccidiostats which can be found in feeding stuffs mainly for therapeutic or prophylactic purposes (Boxall et al., 2002). 2.2.2.1. Anthelmintics 2.2.2.1.1. General characteristic Anthelmintic drugs serve for treatment of infections caused by parasitic worms - helminths. Parasitic worms include flat worms (flukes and tapeworms) and round worms, i.e. nematodes. Helminthoses of livestock result in considerable morbidity and mortality, leading to substantial socioeconomic losses (Johnston et al., 2009). Anthelmintics are administered to wide range of animals in agriculture and aquaculture and they form a large part of the animal pharmaceutical industry (Horvat et al., 2012). Table 1. Overview of veterinary antibiotic classes, their representatives and reported toxicity to plants. Class Compound Plant species Impacts on plants Reference Tetracyclines Chlortetracycline Phaseolus vulgaris Root growth and development Batchelder (1981), (1982) Cichaorium endivia (sweet oat) Seed germination Liu et al. (2009) Cucumis sativus (cucumber) Oryza sativa (rice) Lactuca sativa (lettuce) Root length Hillis et al. (2011) Medicago sativa Daucus carota (carrot) Doxycycline Triticum aestivum Photosynthesis and chlorophyll content Opriş et al. (2013) Oxytetracycline Phaseolus vulgaris Root growth and development Batchelder (1981), (1982) Cichaorium endivia (sweet oat) Seed germination Liu et al. (2009) Cucumis sativus (cucumber) Oryza sativa (rice) Phragmites australis Root activity and chlorophyll content Liu et al. (2013) Medicago sativa Plant growth Kong et al. (2007) Lemna minor Kolodziejska et al. (2013), Pro et al. (2003), Zounkova et al. (2011) Daucus carota (carrot) Root length, plant growth Boxall et al. (2006), Hillis et al. (2011) Lactuca sativa (lettuce) Tetracycline Lolium perenne Root biomass and phosphorus assimilation reduction Wei et al. (2009) Euphorbia pulcherrima Supression of free branching Bradel et al. (2000) Triticum aestivum Photosynthesis and chlorophyll content Opriş et al. (2013) Daucus carota (carrot) Root length Hillis et al. (2011) Sulfonamides Sulfadiazine Triticum aestivum Root and shoot elongation Jin et al. (2009) Brassica campestris Cyphomandra betacea Salix fragilis Plant growth, root alterations Michelini et al. (2012) Sulfadiazine Zea mays Plant growth, root alterations Michelini et al. (2012) Sulfadimidine Sulfamethoxazole Cichaorium endivia (sweet oat) Seed germination Liu et al. (2009) Cucumis sativus (cucumber) Oryza sativa (rice) Seed germination, plant growth Lemna gibba Plant growth and development Brain et al. (2004) Myriophyllum sibiricum Daucus carota (carrot) Plant growth Hillis et al. (2011) Sulfamethizole Sulfadimethoxine Panicum miliaceum Plant growth and development Migliore et al. (1995) Pisum sativum Zea mays Migliore et al. (1995), (1998) Hordeum disthicum Migliore et al. (1998) Amaranthus retroflexus Plantago major Rumex acetosella Barley (Hordeum distichum) Migliore et al. (1996) Lythrum salicaria Migliore et al. (2010) Sulfamethazine Cichaorium endivia (sweet oat) Seed germination Liu et al. (2009) Oryza sativa (rice) Cucumis sativus (cucumber) Seed germination, plant growth Phragmites australis Root activity and chlorophyll content Liu et al. (2013) Daucus carota (carrot) Plant growth Hillis et al. (2011) Sulfachloropyridazine Lemna minor Plant growth Pro et al. (2003) Sulfaquinoxaline Lemna gibba Plant growth De Liguoro et al. (2010) Macrolides Tylosin Cichaorium endivia (sweet oat) Seed germination Liu et al. (2009) Cucumis sativus (cucumber) Oryza sativa (rice) Daucus carota (carrot) Root length Hillis et al. (2011) Azithromycin Clarithromycin Clindamycin Erythromycin Triticum aestivum Chlorophyll content Opriş et al. (2013) Lemna minor Plant growth Pomati et al. (2004) Roxithromycin Spiramycin Vancomycin Tilmicosin Fluoroquinolones Ciprofloxacin Triticum aestivum Photosynthesis and chlorophyll content Opriş et al. (2013) Lemna minor Reproduction rate, chlorosis Robinson et al. (2005) Daucus carrota Plant growth and development Eggen et al. (2011) Phragmites australis Root activity and chlorophyll content Liu et al. (2013) Enrofloxacin Lactuca sativa Plant growth and development Migliore et al. (2003), Boxall et al. (2006) Daucus carota Cucumis sativus Phaseolus vulgaris Migliore et al. (2003) Raphanus sativus Triticum aestivum Root and shoot elongation Jin et al. (2009) Brassica campestris Cyphomandra betacea Lupinus angustifolius Seed germination, plant growth Adomas et al. (2013) Lemna minor Reproduction rate, chlorosis Robinson et al. (2005) Ofloxacin Lemna minor Reproduction rate, chlorosis Robinson et al. (2005) Perfloxacin Levofloxacin Lemna minor Reproduction rate, chlorosis Robinson et al. (2005) Lemna gibba Plant growth and development Brain et al. (2004) Myriophyllum sibiricum Lactuca sativa Root length Hillis et al. (2011) Levofloxacin Medicago sativa Root length Hillis et al. (2011) Daucus carota Clinafloxacin Lemna minor Reproduction rate, chlorosis Robinson et al. (2005) Lomefloxacin Lemna minor Reproduction rate, chlorosis Robinson et al. (2005) Flumequine Lythrum salicaria Plant growth Migliore et al. (2000) Lemna minor Plant growth, chlorophyll content, reproduction rate Cascone et al. (2004), Robinson et al. (2005), Zounkova et al. (2011) β-lactams Amoxicillin Triticum aestivum Photosynthesis Opriş et al. (2013) Daucus carota (carrot) Plant growth Hillis et al. (2011) Ampicilin Triticum aestivum Photosynthesis Opriş et al. (2013) Procaine penicillin Procaine benzylpeniciline Benzylpenicillin Triticum aestivum Photosynthesis Opriş et al. (2013) Benzatine penicillin Cephotaxim Antirrhinum majus Plant growth Holford and Newbury (1992) Cloxacilin Cephalexin Ceftiofur Aminoglycosides Dihydrostreptomycin Neomycin Apramycin Paromomycin Lincosamides Lincomycin Daucus carota (carrot) Root length Hillis et al. (2011) Clyndamycin Polyether ionophores Salinomycin Brassica rapa Plant growth and development Furtula et al. (2012) Monensin Gossypium hirsutum Plant growth and development Hoagland (1996) Hibiscus esculentus Monensin Sesbania exaltata Plant growth and development Hoagland (1996) Cassia obtusifolia Datura stramonium Sorghum halapense Abutilon theophrasti Anoda cristata Sida spinosa Maduramycin Amaranthus hypochondriacus Plant growth and development Gutierrez-Lugo et al. (1999) Echinochloa crus galli Trifolium alexandrinum Triticum vulgare Phaseolus aureus Lasalocid Phenicols Chloramphenicol Florfenicol Lemna minor Plant growth Kolodziejska et al. (2013) Thiamphenicol Other antibiotics Trimethoprim Cichaorium endivia (sweet oat) Seed germination Liu et al. (2009) Cucumis sativus (cucumber) Oryza sativa (rice) Novobiocin Bacitracin Virginiamycin Tiamulin Anthelmintics are categorized into classes according to their similar chemical structure and mode of action. Macrocyclic lactones also belonging to anthelmintic drugs are already mentioned in Ectoparasiticides and endectocides (chapter 2.2.1). Benzimidazoles, broad spectrum anthelmintics, work through a selective interaction with β-tubulin leading to cytoskeleton impairment. Representatives of this group are thiabendazole, albendazole, mebendazole, flubendazole, fenbendazole and triclabendazole. Benzimidazoles pro-drugs, so called pro-benzimidazoles (febantel, netobimin) have better solubility. Imidazothiazoles (levamisole, tetramisole) and tetrahydropyrimidines (morantel, pyrantel) act as nicotinic agonists receptors. The most important drug of pyrazinoisoquinolines is praziquantel. First used anthelmintic, piperazine, belongs together with diethylcarbamazine to heterocyclic compounds. Salicylanilides include niclosamide, which is effective against tapeworms, and closantel with rafoxanide acting against flukes. Other groups are nitrophenolic compounds (nitroxynil, nitroscanate), organophospates (haloxon, dichlorvos, naphthalophos), benzoenedisulfonamides (clorsulon) and diphenylsulfides (bithionol) (Dayan, 2003; McKellar and Jackson, 2004; Holden-Dye and Walker, 2007; Horvat et al., 2012). The use of anthelmintics frequently leads to drug resistance development. Thus, there is an urgent need for new drug candidates with different mode of action. The amino-acetonitrile derivatives, with monepantel being the most important drug, have filled this gap as they are effective to resistant nematodes of cattle and sheep (Kaminsky et al., 2008). 2.2.2.1.2. Behaviour in the environment Although the anthelmintic action against parasites in therapeutic concentrations has been evaluated, the effects in general terms relevant to environmental pollution are still not well known. There is very limited information on anthelmintics concentration in the environment. Due to their wide use, anthelmintics are supposed to impact the terrestrial and aquatic environment. These compounds can occur in the environment by excretion, either unchanged or as metabolites, which may retain antiparasitic activity. The amount entering the environment depends on husbandry system and the stocking densities. Exposure to low concentrations of antiparasitic agents in the environment may facilitate the formation of resistant parasitic strains (Horvat et al., 2012). 2.2.2.1.3. Plant toxicity There are not many studies dealing with phytotoxicity of anthelmintics. Wagil et al. (2015) have observed no adverse effect of flubendazole and fenbendazole on growth of duckweed Lemna minor (Wagil et al., 2015). To the best of our knowledge, the studies documenting the toxicity of anthelmintics to plants are not available. 2.2.2.2. Antiprotozoals and anticoccidial drugs 2.2.2.2.1. General characteristic Antiprotozoals and anticoccidial drugs belonging to antiprotozoals are often incorporated into feed stuff for medicinal purposes. They are used in prophylactic way to prevent diseases and for therapeutic purposes to treat diseases (Boxall et al., 2002). The protozoan infections of domestic animals cause heavy economic losses to farmers by affecting growth, production and high mortality (Kant et al., 2013). Protozoan parasites often lead to abortion and infertility in domestic ruminants (Kaltungo and Musa, 2013). Many antiprotozoals are represented by antibiotics which except antibacterial effect exert also the activity towards protozoa. The most frequent protozoal infections of farm livestock are babesiosis treated with diminazene aceturate, phenemidine diisethionate, imidocarb dipropionate and amicarbalide diisethionate, theileriosis treated with buparvaquone, sarcocystosis controlled by salinomycin and amprolium. Cryptosporidiosis can be dealt with paromomycin, halofuginone, decoquinate and nitazoxanide; giardiasis is handled with antibiotics (paromomycin, trimethoprim + sulfodoxine) and anthelmintic drug fenbendazole. Combination of sulfamethazine and pyrimethaminecan proved to be effective during toxoplasmosis. The most common drugs for treatment of trypanosomosis are diminazene aceturate, homidium bromide/chloride and isometamidium. For besnoitiosis and neosporosis there are currently no effective drugs (Sahinduran, 2012; Shahiduzzaman and Daugschies, 2012). Coccidiosis affect not only farm livestock, but it is also major cause of poor performance and lost productivity in poultry (Chapman et al., 2010). Anticoccidial drugs include several antibiotic groups, which are presented in Table 1: ionophores (salinomycin, lasalocid, monensin, maduramycin, narasin and semduramycin), sulfonamides (sulphadimidine, sulphaquinoxaline). Other anticoccidial drugs belong to pyrimidine derivatives (amprolium, nicarbazine), quinolones (buquinolate, decoquinate), quanidines derivatives (robenidine), quinazoline derivatives (halofuginone), pyridinols (clopidol) (Kant et al., 2013). Diclazuril and toltrazuril with triazine structure are also anticoccidiocidal drugs (Boxall et al., 2002; Shahiduzzaman and Daugschies, 2012). 2.2.2.2.2. Behaviour in the environment In spite of extensive application of antiprotozoals and anticoccidial drugs, the data regarding their environmental impact are scarce. Among authorized anticoccidial feed additives, ionophore antibiotics are used most frequently. Their widespread application can promote resistant strains of protozoa, leading to the diminished prophylactic efficiency (Olejnik et al., 2013). 2.2.2.2.3. Plant toxicity Phytotoxicity of antiprotozoals (including anticoccidial drugs), which also exert antibiotic effect (ionophores and sulfonamides), are given in Table 1. The influence of other compounds on plants has not been well documented. There have been no serious symptoms of phytotoxicity for halofuginone hydrobromide when the drug is properly used (FDA, 1991). 2.3. Hormones 2.3.1. General characteristic Hormones are extensively used agents in veterinary medicine. There are three main purposes for their administration to animals. In the treatment of sick animals, glucocorticoids play the most important role. Reproductive disorders, control and synchronization of oestrus are dealt with sex hormones. Third area of hormones application is to improve growth rate of animals, they serve as growth promoters. Hormones are generally highly active substances which influence physiology of animals in small doses. Therapeutic use of hormones means that sick animals are treated and the physiological functions of normal ones are not altered. Glucocorticoids are anti-inflammatory and immunosupresant agents possessing steroidal structure. Their main therapeutic use is to suppress the clinical manifestation in wide range of disorders, such as rheumatoid disease, asthma, gastrointestinal, renal, cardiac and skin disorders. The major part is represented by application of glucocorticoids due to ketosis in cows. Examples of natural corticosteroids are cortisol and cortisone. Dexamethasone, prednisolone, methylprednisone, betamethasone represent synthetic corticosteroids (Miller, 1999; Courtheyn et al., 2002; Sivertsen, 2006). Therapeutic use of hormones also include treatment of companion animals suffering from endocrine dysfunction, such as diabetes and hypothyroidism. Except cortisol-analogues, insulin, thyroxine, adrenalin and its analogues are utilized. Reproduction hormones are used to treat reproduction disorders, e.g. lack of oestrus, ovarian cysts, and endometrial infections. Except disorders, hormones serve for oestrus synchronization and abort induction. These agents comprise gonadotropin-releasing hormone and analogues (buserelin), gonadotropins, oxytocin, progesterone with its derivatives and analogues (medroxyprogesterone acetate), somatostatin analogues, prostaglandin F2α analogues (cloprostenol and dinoprost). In EU, the synthetic steroidal compounds have only been approved for therapy in non-food producing animals. Hormones in the form of feed additives have also been employed to enhance growth, production and meat quality. They have arisen by modification of natural estrogens and androgens. Anabolic steroids diethylstilbestrol and stilbene estrogens are generally prohibited because of adverse effect on human consumers. All growth promotion with hormones and related substances is prohibited in EU and Norway, but legal and widespread in USA. Growth promoting purposes accomplish estrogens, growth hormones, zeranol, trenbolone acetate, progesterone and testosterone derivatives (Refsdal, 2000; Sivertsen, 2006; Lozano and Trujillo, 2012). 2.3.2. Behaviour in the environment Environment has been polluted both by endogenous hormones and exogenous steroids administered to livestock. Hormones and their metabolites enter the environment directly from livestock or through application of biosolids to agricultural land. The environmental behaviour of steroids from livestock excretion depends on storage and condition and soil type of the fields where the dung is spread. The origin of hormones also plays a role, as synthetic hormones possess higher stability and possibly longer persistence in the environment. Residual hormones that reach soil and water via livestock excrements may cause problems to animal and human health. The reports on the occurrence and distribution of hormone steroids in the environment have been limited. Moreover, most of studies have been conducted on estrogens, little attention has been paid to androgens (Lange et al., 2002; Ying et al., 2002) 2.3.3. Plant toxicity The influence of exogenous mammalian sex hormones, such as 17β-estradiol, estrone, progesterone, and testosterone, on plant growth and generative development has been investigated in various studies whose results are summarized in review written by Janeczko and Skoczowski (2005). Briefly, many experiments showed stimulation of growth and induced flowering. However, when the steroids were applied to plants at higher concentrations, the plant growth was rather negatively affected. The effect of sex hormones in plants is assumed to be connected with the presence of receptors which may be involved in steroid action. But the exact molecular mechanisms still requires explanation (Janeczko and Skoczowski, 2005). In addition, developmental and physiological processes in plants, including regulation of gene expression, cell division, differentiation, apoptosis and homoeostasis, are controlled by plant-specific steroid hormones called brassinosteroids (Thummel and Chory, 2002). Due to many similarities of animal and plant steroids in biosynthesis and function, the interference of animal hormones with brassinosteroid signalling cascade might be anticipated. Nevertheless, distinct steroid perception and signal transduction in plant and animals make this hypothesis rather improbable. Brassinosteroids are perceived by cell surface receptor kinase BRI1, while steroid responses in animals depend mostly on nuclear receptor family of transcription factors which are not known in plants. Although some of the animal steroid responses rely on cell surface receptors too, their cloning did not reveal resemblance with those for brassinosteroids (Li et al., 1997; Bishop and Yokota, 2001; Wang and He, 2004; Wehling and Losel, 2006). However, negative effects of hormones on brassinosteroid-regulated processes originating from altered concentration of brassinosteroids cannot be excluded. These interactions might occur on biotransformation enzymes level. There is evidence that hormones have the ability to modify activity of animal biotransformation enzymes, e.g. cytochromes P450 (CYP) (Coecke et al., 2000; Guillette and Gunderson, 2001; Vaccaro et al., 2005) and it raises question if hormones cannot perform the same potential on plant enzymes involved in synthesis or metabolism of brassinosteroids, comprising among others CYP (Bajguz, 2007). Yet, this hypothesis remained to be confirmed by experimental data. 2.4. Growth promoters 2.4.1. General characteristic Growth promoters are substances which improve the growth rate and feed efficiency of domestic animals when added to animal feed in sub-therapeutic doses over an extended period of time (Niewold, 2007; Lozano and Trujillo, 2012). Except hormones mentioned above, antibiotics represent another important group which serves for growth promoting purposes. However, in Europe, both classes of drugs have been banned for growth promotion and are restricted for therapeutic purposes (Dibner and Richards, 2005). The exact mechanism of antimicrobial growth promoters has not been established yet. But it is assumed that they can increase weight gain and product output by following mechanisms: the drugs a) inhibit endemic subclinical infection, b) reduce growth-depressing metabolites produced by microbes (ammonia, bile degradation products), c) lower microbial consumption of nutrients and d) enhance the uptake and use of nutrients, because the intestinal wall in antibiotics-fed animals is thinner. Antibiotic groups comprise ionophores (monensin, salinomycin, macrolides (tylosin, spiramycin), peptide antibiotics (ardacin, avoparcin, bacitracin, efrotomycin) and quinoxalines (olaquindox, carbadox). Examples of other antibiotics are virginiamycin, bambermycin and avilamycin (Butaye et al., 2003; Callaway et al., 2003; Niewold, 2007). Various compounds with growth promoting action can be found in different classes of veterinary drugs. They are registered as growth promoters in some countries outside Europe, or they are used illegally. Typical examples are β-adrenergic agonists (ractopamine, clenbuterol, zilpaterol) intended especially to increase growth efficiency and meat percentage in carcasses by promotion of protein synthesis and reduction of fat content, antithyroid agents (thiouracils, 1-methyl-2-mercaptoimidazole) and corticosteroids (cortisone, dexamethasone/prednisolone, flumethasone, methylprednisolone, clobetasolpropionate and beclomethasone dipropionate) which can be applied alone to elevate food intake, weight gain, fat content and water retention, or are combined with β-agonists to increase water content in meat or with anabolic steroids. Some veterinary drugs are misused in the field of breeding animals for their secondary pharmacological effects, e. g. non-steroidal anti-inflammatory drugs (NSAIDs) as pale meat-making agent and short acting benzodiazepines (brotizolam) as feed intake enhancers (Courtheyn et al., 2002; Serratosa et al., 2006; Sivertsen, 2006; Lozano and Trujillo, 2012). 2.4.2. Behaviour in the environment A major part of the growth promoters are spread in environment by the manure used as a fertilizer (Jorgensen et al., 1998). Environmental fate has been studied especially in endocrine disrupting growth promoters (hormones), such as trenbolone acetate and melengestrol acetate, mainly due to high concerns about the safety of these agents raised in scientific community. As mentioned before, synthetic hormones show greater stability and resistance to microbial degradation. These properties ensure accumulation and persistence in the environment where they can exert adverse effects on aquatic and terrestrial life (Schiffer et al., 2001; Qu et al., 2012; Biswas et al., 2013). 2.4.3. Phytotoxicity Phytotoxicity of antimicrobials agents used as growth promoters can be found in Table 1, if accessible. Although there are studies aimed at toxicological impacts of hormonal growth promoters, they focus on animals, not plants (e. g. (Ankley et al., 2003). 2.5. Antifungals 2.5.1. General characteristic The drugs from this therapeutic group are applied to manage mycotic infections, both superficial and life threating. As the majority of antifungal drugs are approved for humans, the number of therapeutics applicable to animals is limited. The antifungal drugs routinely used for the treatment of deep mycoses include the polyenes (amphotericin B, nystatin), azoles (miconazole, ketoconazole, itraconazole, fluconazole, voriconazole), and the newer class called echinocandins (caspofungin). Life threatening infections can be cured with flucytosine. Superficial mycoses, especially ones caused by dermatophytes, are targets of the azoles (clotrimazole, miconazole, itraconazole, enilconazole, econazole, oxiconazole, sulconazole, thioconazole), allylamines (terbinafine, naftifine) and griseofulvin (Moriello, 2004; Hector, 2005). 2.5.2. Behaviour in the environment Generally, topically applied antifungals lead to higher emission of active substance due to relatively small absorption (5–10%) via skin, which means that majority (90–95%) of the drug is subject to enter the environment from treated skin by washing. Therefore, massive usage and higher emission of antifungals may result in substantial amount of antifungals in the environment (Peng et al., 2012). Moreover, greater amount of antifungals gets into the environment as they are widely applied on plants because of their protection against fungal infections (Hof, 2001). 2.5.3. Phytotoxicity So far, only few studies have focused on the effect of antifungal residues in environment on living organisms. Unfortunately, no data regarding phytotoxicity are accessible. 2.6. Others 2.6.1. General characteristics Several other therapeutic groups used in veterinary medicine have been mentioned in the chapter 2.4 concerning growth promoters. NSAID, non-steroidal anti-inflammatory drugs, have gained great importance in practical therapy. They function through their interference with the synthesis of prostaglandins and leukotrienes. The pain, inflammatory conditions, fever, osteoarthritis and rheumatoid arthritis represent the main indications for their use in domestic animals. They are often combined with antibiotics. Salicylates belonging to NSAID are routinely used to condition animals just after transport to reduce stress (Courtheyn et al., 2002; Sivertsen, 2006). The NSAID drugs used in veterinary medicine are e.g. acetylsalicylic acid, paracetamol, phenylbutazone, flunixin meglumine, ketoprofen, meloxicam, tolfenamic acid, carprofen, etodolac, meloxicam, deracoxib and firocoxib (Bergh and Budsberg, 2005; Smith et al., 2008). Diclofenac, another NSAID, is known for its controversial use as it is linked to rapid decline of vulture populations in Southeast Asia. In EU, diclofenac has been authorised in animals since 1993. Currently, the drug is approved for use in cattle, pigs and horses in five EU states and continues to be used illegally for veterinary purposes in Indian subcontinent (EMA, 2014). Unlike NSAID, corticosteroids are anti-inflammatory and immunosupresant agents with steroidal structure and are mentioned in chapter 2.3. Benzodiazepines are anxiolytic and sedative drugs, which can be applied in companion animals for wide range of conditions, from treatment of insomnia, behaviour problems to pre-anaesthetic medication. In veterinary medicine, benzodiazepines often induce anaesthesia. Some of them, e. g. diazepam, serve as anxiolytic and sedative in sheep transport to prevent stress. Whereas diazepam is probably best known in the veterinary field, alprazolam, chlordiazepoxide, clonazepam, lorazepam, oxazepam, and triazolam are all commonly prescribed medications, especially to dogs and cats (Crowell-Davis 2008). Benzodiazepines are often used with β-agonists in order to reverse reduced feed intake and/or tremors of animals caused by β-agonists. However, in the prolonged dosage up to 10 times higher the therapeutic one, β-agonists support weight gain and are used as illegal growth promoters (Courtheyn et al., 2002). The only β-agonists registered for veterinary use in cattle, horses and pets in almost all European countries is clenbuterol intended as bronchospasmolytic and tocolytic agent (Kuiper et al., 1998). Another β-agonist, ractopamine is approved for use in swine in USA (Courtheyn et al., 2002). Other pharmaceuticals used in veterinary practice comprise anaesthetics (e.g. ketamine, xylazine, guaifenesin), euthanasia products (e. g. pentobarbitone sodium), tranquilizers (e. g. pentobarbitone), enteric bloat preparations (e. g. dimethicones, ploxalene), antacids, diuretics and emetics (Boxall et al., 2003; Mama et al., 2005; Sarmah et al., 2006). 2.6.2. Behaviour in the environment Among the veterinary drugs, the therapeutic groups mentioned here are used less frequently than the previously described groups. Of all mentioned drugs, two examples illustrate the serious ecological consequences caused by drugs classified here as Others (chapter 2.6). One is connected with improper discarding of carcasses from animals euthanized or heavily medicated by tranquilizer pentobarbitone, which led to poisoning of wildlife, especially eagles, in at least 14 states since mid- 1980s. A second example involves massive poisoning of vultures in Southeast Asia by their feeding on carcasses of cattle that had been treated with NSAID diclofenac (Daughton, 2007). The impact of other drugs from this group cannot be excluded, but results of relevant research are not available. 2.6.3. Phytotoxicity The studies dealing with phytotoxicity are very scarce. The growth of carrot and lettuce exposed to phenylbutazone was significantly impaired (Boxall et al., 2006) as well as the growth of hydroponic willow clone SP3 (Salix alba) (Iori et al., 2013) and common duckweed (Lemna minor) (Pomati et al., 2004) exposed to ibuprofen. 3. Conclusions and future directions From the overview of veterinary drugs, it is obvious that there are various pharmaceuticals in use. It is expected that consumption of veterinary drugs will increase due to growing agriculture and aquaculture production which will have to meet demands of expanding human population for food. Thus, the amount of veterinary drugs reaching the environment will further rise. With exception of a few groups of compounds, especially antibiotics, available information on potential environmental impact including toxicity in plants is scarce. However, the fact that the toxicity of drugs has not been studied does not go hand in hand with the absence of toxic and adverse impact on the environment. Toxicity on non-target organisms can be evaluated using tests which determine acute effects or chronic effects (after exposure to different concentrations of chemicals over a prolonged period of time). Unfortunately, the potential chronic effects from long-term and low-level exposures to veterinary medicine have not been sufficiently determined because the standard laboratory studies oriented on acute toxicity prevail (Santos et al., 2010). As the concentrations of veterinary medicines in the environment, available from monitoring studies in water, soil and dung samples, are usually much lower than concentrations exerting toxic effect on standard organisms, it may be assumed that acute toxicity of veterinary drugs for non-target species is mostly low. Thus, acute toxicity data is only valuable when accidental discharge of drugs occurs (e. g. abovementioned cases of diclofenac and pentobarbitone poisoning). Exceptions include ivermectin and doramectin in dung and monensin in soil, whose environmental concentrations have been found higher than effective concentration for selected species. Omitting these exceptions, longer-term and subtle effects are more likely to occur than acute environmental impacts (Boxall et al., 2003). Regarding the behaviour of veterinary drugs in the environment, it is important to have in mind that a drug does not occur in the environment as single contaminant, but rather as complex mixture of various veterinary, human drugs and other contaminants. These compounds interact and it may affect their total impact on the environment (Kummerer, 2010; Horvat et al., 2012). Knowledge regarding the environmental occurrence of veterinary products is increasing, but information in the literature on the fate and effects of most veterinary pharmaceuticals is limited. Therefore, numerous research topics need to be implemented in further research, such as gathering together data on quantity and use of veterinary drugs in different countries, systematic monitoring of veterinary drugs and their biotransformation products in environmental matrices and analysis of drugs concentration entering the living organisms including plants. Moreover, there is urgent need for studies addressing long-term effects of low doses of veterinary medicines and/or their degradation products in the environment, behaviour of mixture of veterinary drugs or interaction of veterinary drugs with other pharmaceuticals or chemicals in the ecosystem. Concerns over the environmental safety of veterinary drugs do not exclude plants. Toxicity studies performed on plants have been even scarcer than studies dealing with other organisms. Knowledge of phytotoxicity is important because some plant species might be sensitive to xenobiotic action and occurrence of drug in certain areas may lead to reduced biodiversity. On the other hand, the appropriate plant species can withstand the presence of veterinary drugs due to the ability to uptake and transform these xenobiotics. This plant-mediated detoxification represent the principle of phytoremediation strategy to decrease xenobiotic pollution in the environment (Sharma and Pandey, 2014). Accordingly, it is desirable to understand better the impact of veterinary drugs on plants. Acknowledgement This project is supported by Czech Science Foundation, grant No. 15-05325S. References Adomas et al., 2013 B. Adomas, J. Antczak-Marecka, G. Nalecz-Jawecki, A.I. Piotrowicz-Cieslak Phytotoxicity of enrofloxacin soil pollutant to narrow-leaved lupin plant Pol. J. Environ. 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