Introduction

The increasing population and increasing standard of living all over the world require an increased demand for the protein of animal origin (Weis 2013). Annual meat consumption at the world level is expected to increase by 70% up to 2050 (Hocquette et al. 2018). New efforts are necessary to produce the required quantities of the protein high quality (Boland et al. 2013). Protecting animals from infectious diseases requires increasing the use of veterinary therapeutics (Mitema 2009). The total global consumption of antibiotics, for example, in animals was estimated to be twice that of humans (Aarestrup 2012) which is expected to be increased 67% by 2030 compared to 2010 (Van Boeckel et al., 2015). A study (Vishnuraj et al., 2016) reported that 80% of all the antibiotics administered in the veterinary field are used as growth promoters. Some drugs are used through a part of animals or birds life and some of them such as growth promoters are often used throughout the entire life, although it has been advised that long-term use of antibiotics as growth promoters, for example, must be avoided to prevent the emergence of resistant strains of microorganisms (Singh and Bhunia 2019). Drugs are used to maintain animals' health; however, healthy food must be guaranteed. Generally, the safety of food has mainly been focused on preventing the transmission of zoonotic diseases, with less attention thus being paid to present chemical pollutants, probably because of the acute nature of the resulting disease. Moreover, drug residues generally may not generate a violation problem on public health. However, adverse effects of residues such as hypersensitivity reaction and occurrence of antibiotic resistance may appear on the human consumer after extensive use of drugs (Singh and Bhunia 2019). Therefore, the appropriate use of veterinary drugs in a manner to prevent feed contamination is necessary.

Drugs and chemicals used for protection against animal and crop diseases represent an important environmental source of residue in food and feed products (Klátyik et al. 2017). There are a large number of approved prescription and over-the-counter (OTC) medications to be used in farm animals. Several products of the approved drugs have significant human health hazards upon intentional or accidental exposure such as clenbuterol, ketamine, tilmicosin (Micotil), testosterone/estradiol, dinoprost, and cloprostenol. The severity of the adverse effects ranges from mild symptoms to life-threatening effects (Lust et al. 2011). Therefore, several documents about drug residues and environmental pollutants have been discussed in the Joint FAO/WHO Expert Committee on Food Additives, and recommended maximum residue limits (MRLs) and acceptable daily intakes (ADIs) for various veterinary products have been established (Joint FAO/WHO 2018). This paper sheds light on the sources of drug and chemical residues in food of animal origin, their risks on human health, and suggested methods of control to minimize or to avoid the existence of drug residues.

Material and Methods

The following databases were searched for scientific literature; the National Library of Medicine’s MEDLINE, the US Department of Agriculture’s National Agricultural Library Catalog (known as AGRICOLA), and the Food and Agriculture Organization (FAO). The US Department of Agriculture’s (USDA), Food Safety Inspection Service (FSIS), The European Food Safety Authority (EFSA), and The Codex Alimentarius Commission website were searched to identify research articles and policy documents about drug residues and food additives in food animals. The following keywords were used: residues, veterinary drug residues, chemical residues, chemical pollutants, antimicrobial residues, residues in meat, milk, eggs, fish, Growth promoters, feed additives, antiparasitic, hormones, steroids, beta 2-agonists, agricultural chemicals, environmental contaminants, insecticides, pesticides, herbicides, fungicides, fertilizers, and organic pollutants. We classified our search results into three main topics: from where chemical and drug residues can come, what are the health risk problems as a result of consuming contaminated food, and finally the suggested method of control to minimize or avoid the existence of residues aiming to produce food of high quality. Our search focused on the period from 2000 to 2019.

Results

From where do drug and chemical residues come?

Intentional use of animal drugs (direct additive)

Animal drugs are used intentionally for therapeutic, prophylactic purposes or as feed additives to improve performance and production. Food contamination by the residue of veterinary drugs is one of the major global issues of special concern (Beyene 2016). The most common drug groups are antimicrobials, antiparasitic, hormones, growth promoters, and feed additives. The diagram (Fig. 1) illustrates the relative use of different veterinary drug groups in the UK market through the year 2019 (https://www.noah.co.uk/about/industry-facts-and-figures/).

Fig. 1
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UK market by product type, 12 months from June 2018 to June 2019

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Antimicrobials

Antimicrobial drugs are used for the treatment or prevention of bacterial diseases in humans, plants, and animals. Although their use for growth promotion of animals and poultry was banned in the European countries since long time ago, they still used in the USA and other countries for this purpose under the pressure of economic causes and its use is expected to continue until satisfactory alternative is provided (Costa et al., 2017). They perform growth promotion by changes in the levels of intestinal biochemical constituents, altering the intestinal metabolome and improving growth and feed efficiency (Gadde et al. 2018). Sometimes antimicrobials such as aminoglycosides and oxytetracyclines are used in the treatment of plant bacterial diseases and consequently enter the food chain either directly or through feeding animals on polluted plants (Wang et al. 2021).

In central Ethiopia for example, the most widely reported contaminants of food of animal origin are the antimicrobial drugs and the steroidal growth promoters (Beyene et al. 2015). In European countries, the prevalence of chemical and drug residues in animal products is less than 1%; however, in some African countries, it reaches up to 94%. The majority of residues confirmed in animals were antibiotic agents such as penicillin, streptomycin, polypeptides, macrolides, tetracyclines, chloramphenicol, sulfonamide, and quinolones (Bacanli and Başaran 2019; Rodrigues et al. 2021). Meat and meat products are still the first sources of antimicrobials drugs used for the treatment of animal diseases (Bacanli and Başaran 2019). Antimicrobials residues are reported, not only in the meat of food animals but also broilers (Gadde et al. 2018; Patel et al. 2018), Milk (Chirollo et al. 2018), eggs (Liu et al. 2021), aquaculture (Liu et al. 2017), beeswax and honey (Mitrowska and Antczak 2017), and even in freshwater and marine environments (Suzuki et al. 2017). It has also been reported that the use of human excretions and animal manures as plant fertilizers, and inappropriate disposal of antibiotics either in the clinics, or direct disposal of the leftover antibiotics are one of the possible main sources of antibiotic pollutants in soil and water as it has been reported in Chinese rural community (Chen et al. 2018a). Although the violation rates of some antibiotics such as chlortetracycline and oxytetracycline decreased, some other antibiotics such as quinolones and penicillin detections increased in some countries such as in Korea (Kim et al. 2013). Recently, higher incidence of ciprofloxacin, enrofloxacin, tetracycline, amoxicillin, and chloramphenicol were reported in chickens and aquaculture food products (Hassan et al. 2021).

Antiparasitic drugs

Antiparasitic drugs include anthelmintics, antiprotozoal, and insecticides (organophosphates, organochlorine) (Patel et al. 2018). Residues of the antiparasitic drugs are reported in several studies probably because of the unregulated and uncontrolled use either due to intentional use or unintentional contamination. However, after the application of a 28-day withdrawal period, moxidectin residues above the MRL were reported in muscle, fat, kidney, and liver of weaned lambs subjected to gastrointestinal parasite control using Moxidectin in Brazil (Fernandes et al. 2017). Albendazole sulfoxide and sulfone metabolites were quantified in eggs 7 days after albendazole single oral administration in Argentina (Moreno et al. 2018). In a study in Spain, albendazole metabolites reached their maximum concentration in goat’s milk one day post-treatment and decreased to a level below the maximum residue limit on day 3 post-treatment (Romero et al. 2017). Similarly, benzimidazole residues were reported in 16% of the samples examined ovine and bovine milk in southern Greece (Tsiboukis et al. 2010). In a study in Brazil, albendazole and its metabolite residues were also reported in fish (Busatto et al. 2018). The ecto-endocidal anthelmintic drug, moxidectin (MOX), was reported with the highest concentrations in the fat as compared to other target tissues (muscle, liver, and kidney) in sheep (Cruz et al. 2018). Ivermectin was also reported in the edible tissues of broilers as reported by Mestorino et al. (2017) who suggested a withdrawal time for ivermectin to stay within the permitted residual levels of 0 days for muscle, 12 days for liver, 8 days for skin/fat, and 10 days for the kidney. Not only the residues of anthelmintics (Patel et al. 2018) but also coccidiostats (Bacila et al. 2017) were reported in meat.

Hormones

Anabolics hormones are used as growth promoters in farm animals to increase meat production in addition to their widespread environmental and water contaminants. This leads to the international debate about the safety of products originating from such anabolics. Zeranol and diethylstilbestrol, for example, were reported in concentrations more than the acceptable limits in a considerable part of samples from food animals in the USA (Nachman and Smith 2015). Several hormonal drugs such as testosterone propionate, estradiol, and estradiol benzoate, and progesterone or hormone-like compounds have been approved by the FDA for use in food animal production. Some of these hormonal products such as trenbolone acetate, zeranol, and melengestrol acetate have a high affinity for natural hormone receptors (Nachman and Smith 2015). Other hormones such as bovine somatotropin are approved for increasing milk production in dairy cattle in the USA (Collier and Bauman 2014). Thyreostatic (Le Bizec et al. 2011) and corticosteroidal hormones are also used alone or in combinations to increase meat production. High concentrations of estradiol are reported in hen's eggs despite the total ban in the EU of all hormonal active growth promoters in livestock production (Stephany 2010). More interesting is that the residue of 17β-estradiol and estrogenic activities was reported in the water of the Hawkesbury River, Australia, in concentrations above the levels that have been linked to the adverse effects in fish and other aquatic organisms (Uraipong et al. 2018).

Growth promoter and Feed Additives

The use of growth promoters and anticoccidials collectively constitutes about 30% of the total veterinary drug consumption. This class is used for long periods and sometimes for the entire lifespan as it occurs in poultry management. The most common growth promoters used in food-producing animals and poultry are the antibacterials, hormones, and β2-agonists (Aroeira et al. 2019). β2-adrenoceptor (β2-AR) agonists such as clenbuterol (Chen et al. 2017), zilpaterol (Loneragan et al. 2014), salbutamol (Zhang et al. 2017), and ractopamine (Aroeira et al. 2019) are used since the 1990s to improve growth and performance. Eighty-first reports of the Joint FAO/WHO Expert Committee on Food additives including β2-adrenoceptor agonists were evaluated (Joint FAO/WHO 2018). Arsenical feed additives are widely used in animal production and elevate arsenic levels in animal tissues (Halford, 2017). Moreover, their release through environmental transformation increases the risk to ecosystems (Hu et al. 2019). Colistin has also been used as a feed additive for a long time ago but recently it has been banned in China as well as in other countries (Walsh and Wu 2016). Diclazuril and nicarbazin feed additives were reported in egg and liver in concentrations above the MRL value in samples from Croatian farms (Bilandžić et al. 2013).

The unintentional residue (environmental pollutants)

Unintentional residue (environmental) pollutants include agrochemicals, dioxins and dioxin-like chemicals, heavy metals, food additives, and natural toxins. The environmental pollutants can be transmitted through animal feed, drinking water, and feedlot manure when used as organic fertilizer and unintentionally contaminates human food (Khan et al. 2008).

Agricultural chemicals‏

Agrochemical products are the main source of toxicities in farm animals (Schediwy et al. 2015). The widely used polychlorinated, polybrominated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), polycyclic aromatic hydrocarbons (PAHs), organophosphorus, and carbamate insecticides do not break down quickly in the environment. Those agrochemicals in addition to those that are released into air or water will end up in soils, and hence, animals feed and accumulate in animal's body and finally to the human consumer (Howard 2017; Chiesa et al. 2018b). Improper use of pesticides appeared to be the principal cause of contamination of food (Szpyrka 2015). High concentrations of the organochlorine pesticides and their metabolites have been found in soil, and water in Southwestern Nigeria, although it has been banned from agricultural and public health use during the past few decades (Adeleye et al. 2019). Moreover, organic honey from different production areas may contain a high concentration of organochlorine pesticides (Chiesa et al. 2018b). Not only animal feed but also surface and groundwater can be an important source of pollution by organochlorine pesticides (Navarrete et al. 2018). This is of particular importance and can account for the fish risk (Chiesa et al. 2019). The organochlorine pesticides, for example, dichlorodiphenyldichloroethylene, were detected in concentrations that exceeded the guidelines in sediments of the river's water in Nigeria (Unyimadu et al. 2019). Hexachlorocyclohexane isomers in freshwater can enter the food chain through worms and carp (Di et al. 2018). Feed and food-packing materials (Wang and Kannan 2018), milk, fish, and pork were reported to contain higher levels of organophosphorus pesticides (OPPs) that are correlated to the diet exposure and can account for risk to population (Liu et al. 2018). The presence of polychlorinated biphenyls, polybrominated diphenyl ether, and polycyclic aromatic hydrocarbons in organic honey was confirmed, not only in proximity to highly urbanized centers, where the concentrations were higher but in all environment contexts, confirming their ubiquity in Italy (Chiesa et al. 2018a). Organophosphorus flame retardants contamination may occur during industrial processing and manipulation of food, e.g., packaging, canning, and drying of food products since organophosphorus pesticides (OPPs) were reported in Belgian foodstuffs (fish, crustaceans, mussels, meat, milk, cheese, dessert, food for infants, fats and oils, grains, eggs, and potatoes) and derived products (Poma et al. 2018). Pyrethroids and chlorpyrifos were reported in animal and chicken origin food in Brazil (Dallegrave et al. 2018). Chlorpyrifos and cypermethrin were reported in high levels in beef and milk from animals fed on treated fruit/vegetable crops in Argentina (Ferré et al. 2018). Furthermore, children living in vineyard rural areas in France seem to be at higher risk of airborne pesticides such as dithiocarbamate, endosulfan, and lindane which were reported in the air, water, and soil and could be a problem of great concern (Raherison et al. 2019).

Herbicides are common soil and groundwater contaminants (Verma et al. 2017). The aquaculture organisms can be contaminated by several herbicides that are used to control aquatic weed growth in fish ponds, lakes, and canals (Tran et al. 2019) which can be of public health concern to human consumers (Chang et al. 2016). Arsenical herbicides were reported in meat, milk, poultry, and eggs (Bencko and Foong 2017). Moreover, pesticide residues in honey and pollen may lead to a negative impact on honeybees' health and hence great economic losses (Muli et al. 2018). Arsenic, cadmium, and iodine were identified as major hazards in the European seaweed chain (Banach et al., 2020).

Fungicides such as Malachite green have been widely used in commercial fish farms and can cause a wide range of toxicological effects on various fish species and mammals (Chang 2017) ‏. Plant protection products and their adjuvants and other co-formulants can have additive, synergistic, or antagonistic side effects with the active ingredients in the final products (Klátyik et al. 2017).‏

Food additives such as antioxidants, coloring agents, preservatives sweeteners, emulsifiers, and stabilizers are all added to human food during processing to improve the quality of the product. These additives may be risky when added in large amounts. A case of poisoning with sodium nitrite occurred recently, in three family members in Serbia after eating homemade sausages (Cvetković et al. 2019).

Other environmental contaminants

Organic pollutants (POPs) such as dioxins and dioxin-like chemicals accumulate up in the animals, an effect is known as biomagnifications, and consequently meat and dairy products, fish, and shellfish are the main source (more than 90%) of human exposure to dioxins (Barone et al. 2019). In France, for example, dioxins, polychlorinated biphenyls, hexabromocyclododecane, etc., were measured at significantly higher levels in organic and conventional meat (Dervilly-Pinel et al. 2017). On the other hand, groundwater, surface water, sediment as well as aquatic flora can be contaminated by pharmaceutical industries, hospitals, sewage, and wastewater (Thai et al. 2018). Consequently, plants treated with wastewater and animal feed are an important sources of organic pollutants (POPs) (Khalid et al. 2018) and have been reported to contain high quantities of antibiotics (Tahrani et al. 2017) and psychoactive substances (Gao et al. 2017).

Animal feed can be contaminated with air-borne metals such as As, Cd, and Pb (Pandey et al. 2012). Plant fertilizers may contain heavy metals that are bioaccumulated in the soil and implicated in animal feed contamination (Dessalew‏‏ et al. 2018). The widespread use of Cu, Zn, and phenyl arsenic compounds in intensive poultry farming is another source of environmental contamination (Hu et al. 2019). Meat and internal organs of broiler birds reared near the roadside/canal and waste disposal site/wastewater drains were reported to contain high concentrations of heavy metals in Pakistan (Abbas et al. 2019). Processed meat products in southeastern Brazil (de Souza Ramos et al. 2019) and seafood in Tianjin, China (Wang et al. 2019), near wastewater drains have also been reported to contain heavy metals and polycyclic aromatic hydrocarbons (PAHs) at levels higher than the MRL. In the EU the accepted MRLs for As, Cd, and Pb in feed materials with some exception are 2, 1, and 10 mg/kg (ppm) relative to a feed with a moisture content of 12% (European Commission 2013). In Vietnam, the USDA foreign agricultural services approved a level range of 0.01–1.0, 0.003–3.0, and 0.02–3.0 mg/kg (ppm) for As, Cd, and Pb in feed, respectively, depending on the type of food (Huong 2013). Nearly similar levels are approved in Australia (0.14–1.4, 0.1–2, and 1–6 mg/kg, respectively, Choi 2011).

Mycotoxins (e.g. aflatoxin, ochratoxins) and plant toxins in particular in food and feed are of growing concern because of their diverse potent pharmacological and toxic effects on human and animal health (Adegbeye et al. 2020). Mycotoxins have been reported in meat and meat products (Elghandour et al. 2019), in eggs and chicken tissues in China (Wang et al., 2018), and muscles and liver of broiler chickens and turkey poults (Tardieu et al. 2019). Representative examples for the unintentional residues in food are listed in Table 1.

Table 1 Examples of the unintentional residue in food of animal origin
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Potential sources of residues in a disaster situation (emergency slaughtered animals)

Emergency slaughtered animals, animals treated before a disaster, meat or milk of unidentified animals, and the slaughter of treating sick and debilitated animals should be suspected as risk points for existing drug residues. In this respect, the anthelmintic drug residues were high in the muscle of emergency slaughtered cattle (Cooper et al. 2012). Similarly, the level of antimicrobial drug residues was high in pork meat of sick animals under treatment and sold preferentially in a local abattoir in Madagascar (Rakotoharinome et al. 2014). Tetracycline or an unidentified microbial inhibitor residue was detected in culled dairy cows in California, USA (Aly et al. 2014). ‏ Moreover, large amounts of anesthetics either administered by inhalation (Lockwood 2010) or intrathecal injection (Aleman et al. 2016) remain in the body for days and their use for euthanasia is potentially harmful and may cause environmental impact and secondary toxicosis (Payne et al. 2015). ‏ A report of a panel meeting concerning euthanasia of animals intended for human or animal food has been published (AVMA, 2020). Figure 2 illustrates the possible hazards from drug residues in food of animal origin.

Fig. 2
figure 2

Possible hazards from drug residues in food of animal origin

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Risk Factors for violative residues in Food-producing Animals

It is supposed that veterinary drug products and agricultural chemicals should not leave any residues at slaughter. However, residues can be found due to possible reasons such as extra-label use of drugs (Cramer et al. 2019), misuse and overuse (Ngumbi and Silayo 2017), failure to follow the recommended dose and or route, failure to apply the recommended withdrawal periods, incorrect mixing, and contamination of animal feed/water (Beyene 2016). Risk factors responsible for the development of residue include also animal factors such as age, species, and diseases of treated animals (Beyene 2016; Yang et al. 2019). However, the failure to observe the appropriate withdrawal time remains the critical risk factor for the development of unacceptable residue especially after using an overdose or the use of long-acting formulations (Riviere et al. 2017). Regulatory agencies (Code of Federal Regulations) prohibited the extra-label use of a list of drugs in food-producing animals including clenbuterol, chloramphenicol, diethylstilbestrol (DES), dimetridazole, ipronidazole, furazolidone, nitrofurazone, sulfonamide drugs in lactating dairy cattle, fluoroquinolones, and glycopeptides (Fajt 2007)‏.

Hazards from drug residues‏

Short-term and long-term hazards can occur due to drug residues in food. The short-term hazards include allergic hypersensitive reactions, mutagenicity, teratogenicity, and direct intoxication. The hazards after long-term use include carcinogenicity, reproductive effects, disruption of normal human intestinal microflora, and development of antibiotic-resistant mutant of bacteria in treated animals (Falowo and Akimoladun 2019). In addition to health hazards, there are important dairy technical problems or condemnation of residues containing carcasses.

Short-term health problems

Drug hypersensitivity reactions

Drug hypersensitivity may occur in humans shortly after the consumption of food containing drug residues. Anaphylaxis, allergic skin reactions, or delayed hypersensitivity response are examples of allergic reactions to drugs (Ortelli et al. 2018; Bacanli and Başaran 2019). Hypersensitivity associated with antibiotics, especially β-lactam (Cardona et al. 2021) and macrolides (Darwish et al. 2013), is very common. ‏ Food additives generate IgE-mediated and non-IgE-mediated immune reactions and act as allergens and pseudo allergens and can generate direct clinical pictures or may exacerbate diseases such as bronchial asthma, dermatitis, chronic urticaria, or anaphylaxis (Andreozzi et al. 2019).

Direct intoxication

Direct intoxication due to consumption of drug residue-containing food is also an important issue of human health concern. Clenbuterol, a beta-agonist growth promoter, was suspected to cause direct intoxication after eating contaminated liver and non-liver beef meat (Zhang and Wu 2002). In Portugal, Barbosa et al. (2005) described four cases of acute food poisoning due to the ingestion of lamb and bovine meat containing residues of clenbuterol.

Hormonal disturbances

There are a large number of pollutants known to be endocrine-disrupting agents such as pesticides, polychlorinated biphenyls, aromatic hydrocarbons, dioxins as well as phytoestrogens (Wilson et al. 2016). Furazolidone induces hormonal disturbances involving the thyroid, ovarian, and adrenal hormones (Ahmed et al. 2008). More recently, the exposure to the fungicide, difenoconazole elicited estrogenic endocrine disruption on the offspring in zebrafish (Teng et al. 2018). The presence of organochlorine pesticides in breast milk is reported to be associated with the exposure of Taiwanese women to OCPs in their diet and is considered a probable cause of infertility (Chen et al. 2018b). Several veterinary drugs have an affinity to the sexual hormone receptors and exhibit endocrine-disrupting effects (Lee et al. 2019).

Disruption of normal intestinal flora

The broad-spectrum antimicrobials may adversely affect a wide range of intestinal flora and consequently cause gastrointestinal disturbances. Antimicrobials residues can reach humans not only through oral administration but may also be present and affect microbiota when administered parenterally (Cresci and Bawden 2016). Antibiotics may reduce the total number or selectively kill some important bacterial species‏ ‏(Mensah et al. 2014; Kim et al. 2017). Some drugs such as flunixin, streptomycin (Russell et al. 2015), and tylosin, vancomycin, nitroimidazole, and metronidazole in humans are known for this effect (Kim et al. 2017‏).

Mutagenic effect

The potential mutagenic activity can be elicited by several chemicals, such as alkalizing agents, phenylurea herbicides, linuron and chlorbromuron (Federico et al. 2016), and the amyloid β-peptide aggregation inhibitor, morin, causing DNA damage (Mori et al. 2019). It has been reported that environmental chemicals may cause a complex gene-environment interaction predisposing to neurodegenerative diseases such as Alzheimer’s and Parkinson's disease (Cicero et al. 2017) or may have an adverse effect on human fertility (Jeng, 2014). Although mutagenicity is usually associated with short-term exposure, an obvious DNA damage and DNA repair gene disorder in male workers engaged in e-waste recycling work for more than 1 year were reported in Tianjin, China (Wang et al., 2019).

Teratogenic effect

Benzimidazole anthelmintics are reported to be embryotoxic and teratogenic when given during the early stage of pregnancy (El-Makawy et al. 2006). Glyphosate, the most widely used pesticide could be toxic at very low concentrations causing teratogenic, carcinogenic, and hepatorenal toxicity probably by GlyBH adjuvants of commercial formulations (Mesnage et al. 2015). ‏ Cytotoxic effects of oxytetracycline residues in the bones of broiler chickens following therapeutic oral administration of a water formulation were reported (Odore et al. 2015), suggesting potential human and animal health risks due to the entry of tetracycline residues contained in the bones of treated livestock into the food-chain.

Hematological disorders

Enzymatic and hematological alterations have been reported in the African catfish, Clarias gariepinus exposed to diclofenac (Ajima et al. 2015), and zebrafish exposed to carbamazepine (da Silva Santos et al. 2018). However, organochlorine pesticides may exert adverse effects on hematopoietic tissue and liver in populations chronically exposed to high levels of these compounds (Freire et al. 2015). Chronic exposure to OTC products causes blood changes such as leucocytosis, toxic granulation of granulocytes and thrombocytopenia, atypical lymphocytes, lung congestion, and brown discoloration of the teeth (Praveena et al. 2019).

Long-term health problems‏

Carcinogenic effect

Several drug residues are reported to be potentially carcinogenic such as metronidazole (Adil et al. 2018‏), steroid hormones, and bovine somatotropin which have been approved for use in food animals by the U.S. Food and Drug Administration (Nachman and Smith 2015). Estrogens have been listed as group 1 carcinogens in human and aquatic organisms by the World Health Organization (Bilal and Iqbal 2019). Some of the thyreostatic compounds are carcinogenic and teratogenic (Yang et al. 2018). Inorganic arsenic (Hu et al. 2019) and malachite green (MG) residues were reported to be toxic to mammals (Chu et al. 2013) causing carcinogenesis, mutagenesis, chromosomal fractures, teratogenicity, and respiratory toxicity (Pierrard et al. 2012). Taiwanese fish consumers have a greater risk of liver cancer due to exposure to leucomalachite green residues from fish products (Chu et al. 2013). Moreover, the illegal use of food additives may increase the formation of carcinogenic compounds during the processing of food containing such additives (Molognoni et al. 2019).

The emergence of resistant strains of pathogens‏

One of the major problems of the existence of drug residues is the emergence of resistant strains of bacteria either affecting the animal itself or transmitted to the human population (Bacanli and Başaran 2019; Singh and Bhunia 2019). Resistant microorganisms can be transmitted to humans, either directly from the environment (Manaia 2017) or indirectly via milk, meat, and/or egg ‏(Lee‏‏ et al. 2018). Despite the recent significant decrease in antibiotic consumption, the resistance rate and distribution of multidrug-resistant bacteria are increasing (Ortelli et al. 2018). More interesting, the emergence of resistant strains of bacteria appears not only in milk-containing antimicrobial residues intended for human consumption (Ondieki et al. 2017) but also in waste milk for feeding calves (Pereira et al. 2018) ‏. Following acute and subchronic exposure to low concentrations of antimicrobial drug residue, the human intestinal microbiome structure and the resistance-gene profile were adversely affected (Jung et al. 2018). It appears that the transfer of resistance is encoded by genes rather than mutation as it was concluded from the results of the European Union surveillance program including the meat-producing animals and the antimicrobial resistance of zoonotic (Salmonella and Campylobacter) and indicator (Escherichia coli and enterococci) bacteria. Plasmids, transposons, and other mobile genetic elements contain resistance genes that can pass from one bacterium to another by horizontal transfer (Florez-Cuadrado et al. 2018). Resistance genes can also be spread and disseminated in the soil and environment from the waste of treated animals (Cheng et al. 2016). Not only is the resistance to the antimicrobial agents that can be transmitted but also the antiparasitic drugs (Liébano-Hernández et al. 2015).

Dairy technical problems

Uncontrolled handling of veterinary drugs in lactating animals, lack of treatment records, use of unapproved drugs, and failure to observe withdrawal period cause release of these drugs into milk leading to major technical problems in the dairy industry. Residual quantities of antimicrobials in milk can interfere with starter culture activity and disruption of the manufacturing of milk products and may inhibit the growth of probiotics micro-organisms during the manufacturing of yoghurt, cheese, acidophilus milk, etc.‏. Antibiotic residues in milk can also cause underestimation of the microbial load in milk through interference with the methylene blue reduction test. Therefore, milk of inferior quality is released that may have to be discarded coupled with the disruption of the production schedule. The possible potential health hazards associated with antibiotic residues in milk are allergic reactions (penicillins and cephalosporins), carcinogenic effects (sulfamethazine and nitrofurazone), and nephrotoxicity and ototoxicity (aminoglycosides) (Patel and Walker 2004)‏.

Economical influences

The awareness about the potential risk of diseases such as cancer and impaired endocrine, nervous, reproductive, cardiovascular, and immune system functions results in a negative impact on individual productivity, the global economy, and international trade (Wilson et al. 2003). The US authorities have opposed restrictions adopted about antimicrobial use in food-producing animals (Maron et al. 2013). However, the EU has prohibited the importation of poultry processed with antimicrobial rinses resulting in a reduction of US poultry exports to the EU from $52 million in 1997 to only $13 million in 2011 (Johnson 2012). On the other hand, antibiotic contaminated milk has been estimated to cost the US dairy industry $50 million annually (Rice et al. 1984). Therefore, evidence strengthens the rationale for restricting antimicrobial use in food animals is mandatory (Ma et al. 2020).

How to control or minimize‏ drug residues

Education

It is difficult to implement a good residue avoidance program without recruitment and retaining specialized scientific staff. The veterinarian must be aware of the pharmacological bases of many drugs such as the elimination half-life (t1/2), the volume of distribution (Vd), total body clearance, rate of absorption of non-intravascularly administered drugs, and their withdrawal period. He must be aware of the factors which affect these estimates. Absorption of the nonparental administered drugs, for example, is influenced by the physiopathological state of the animal, the route of drug administration, and the physical characters of the drug. The maximum concentration and the time to peak concentration are indications of the rate of drug absorption (Sugano and Terada 2015). After reaching blood circulation, the drug has to be distributed through the body compartments. The physicochemical properties of the drug, the percent of binding to plasma protein, the local blood flow, and the drug affinity for the tissue constituents, volume of distribution, and others are the factors that affect the process of distribution (Fan and de Lannoy 2014). A veterinarian must know that most drugs undergo metabolism in the liver, although some drugs are eliminated from the body unchanged. Most drugs are inactivated, but some may be converted in the liver to an activated form. Some drugs can activate liver microsomal enzymes, which can terminate the effect of other drugs rapidly and vice versa (Fu et al. 2016). Moreover, the overall rate of elimination (metabolism and excretion) is very important to the residue of drugs in edible tissue (Busatto et al. 2018). It should be pointed out that there is a great variation among animals in their general ability to handle drugs (Toutain et al. 2010). Special attention should be directed to the depot and sustained-release preparations which are very important to residue avoidance (Chaccour et al. 2018). It should be noted that most of the pharmacokinetic parameters are derived from studies that have been carried out on healthy animals; however, the drugs target animal diseases, which can influence the pharmacokinetic parameters and the potential for residues (Yang et al. 2019). An increased Vd, for example, will reduce drug clearance and prolong the half-life. Decreased blood perfusion of the intestine in diseased animals may prolong the absorption half-life and alter gastrointestinal transit time and could influence the elimination profile than normal animals. On the other hand, ELDU must be taken into consideration since it refers to the use of an approved drug in a manner that is not indicated in the label. Ivermectin, for example, is used in dogs and cats despite its approval for use in cattle. Enrofloxacin solution is only approved for use as an injection, though it is used as a topical ear medication (Bae et al. 2013). Food producing staff must be aware of the restrictions on veterinary drugs prepared by regulatory agencies (Maron et al. 2013). The withdrawal time must be applied strictly to avoid illegal residues (Riviere et al. 2017). The staff must be aware of the prohibited drugs for dairy cattle. The veterinarian should pay attention to the fact that special formulations for dry cow mastitis can have 10 times the amount of drug found in a wet-cow mastitis treatment. Special attention should be paid to the identification of treated animals and avoid mistakes. Animal identification includes using treatment records for withholding periods, a numerical ID: ear tags, neck chains, or "Warning Sign" or leg bands, etc. Finally, treated animals can be segregated into a "hospital pen. Based on this simplified overview, the incidence of violative residues can be reduced‏.

Lab Spot

Analysis of drug residues

Detection of residues must be carried out using sensitive tests with a low quantification level and a low rate of false-negative results. The detection strategy is based on two steps: (1) screening step followed by (2) confirmatory step for the positive results (Mensah et al. 2014). The animal identification and traceability, the lack of resources, and infrastructure for sample collection and transport are all constraints for sampling regimes that must be solved to establish accredited (ISO/IEC 17,025) screening laboratories' food safety. Sampling is conducted to identify possible areas of concern or when a violation has occurred (CFIA 2014). Directed samples are taken from animals or products which are suspected to have residues, or from groups of animals or types of products that are at higher risk. Several methods are developed for both general screenings and more sensitive quantitative measurements of drug residues‏.

Microbial screening method

This method is used for the detection of an inhibitory substance in animal products. It is generally used for antibiotic testing. It is nonspecific and can cover a wide range of antimicrobials. It can be carried out in a test tube containing a growth medium or in a plate containing inoculated nutrient agar. Absence or delay of the color production by the acid produced by the growing bacterial colony in the test tube or the appearance of an inhibitory zone in the plate containing the inoculated nutrient agar indicates growth inhibition and positive antimicrobial drug residues. This method is still used for the rapid screening of antibiotic residues (Wu et al. 2019) ‏.

Immunological technique

This test depends on antigen–antibody interactions and is used for the detection of antimicrobials, hormones, and β-agonists in meat, milk, or eggs. A colorimetric immunoassay, for example, was developed for the detection of amantadine residues in poultry at the ppb level (Yu et al. 2018). An indirect competitive enzyme-linked immunosorbent assay was developed using broad-spectrum monoclonal antibodies for the multi-residue detection of avermectins (Ni et al. 2019) and antibacterial drugs (Han et al. 2019) in animal tissues and milk. The immunoassay was also used for the determination of hormonal residues in food. A method for simultaneous determination of six zeranols by immunoaffinity solid-phase extraction in milk samples (Zhang et al. 2018), eggs (You et al., 2012), in foodstuffs of animal origin (Wang et al. 2014) was developed. A screening method for residues of diethylstilbestrol, dienestrol, hexestrol, and zeranol in bovine urine using immunoaffinity chromatography and gas chromatography/mass spectrometry was also validated (Dickson et al. 2003). The immunoaffinity chromatography was also used for the determination of beta-agonists in animal tissue samples (Mei et al. 2014), animal feed, and feed ingredients (Campbell and Armstrong 2007). A gold immunochromatographic strip is prepared to detect clindamycin, lincomycin, and pirlimycin residues simultaneously with a single monoclonal antibody was prepared (Guo et al., 2020).

Chromatographic method

Liquid chromatography (Fidel and Milagro 2006), and recently the high-performance liquid chromatography (HPLC) and the ultra-performance liquid chromatography–quadrupole electrostatic field orbitrap mass spectrometry has been applied for the detection of multi-residue (Hou et al. 2020) within a short time. Coupling of HPLC with mass spectrometry (MS–MS) has been applied for confirmation in positive samples after initial screening (Chen et al. 2019). Chromatographic methods are used widely for determination a large number of veterinary drug residues in food of animal origin for example in beef (Zhao et al 2018), milk (Yao and Du 2020), eggs (Barreto et al. 2017), propolis (Wen et al., 2018), and aquatic products (Kong et al. 2018). Recently, a simple screening procedure using liquid chromatography–tandem mass spectrometry was developed for the determination of polypeptide antibiotics (Bladek et al., 2020) and anthelmintic residues (Yoo et al., 2021).

Biosensors

This method depends on the recognition of the target antimicrobial residue by a biological element called a bioreceptor, which converts the recognition event into a measurable signal (Velusamy et al. 2010). This method is simple, rapid, highly selective, and inexpensive (Gaudin 2017). A bioreceptor can be an antibody, enzyme, protein, nucleic acid or a living organelle (cells, tissues) or whole organisms (Gaudin 2017). It has been applied successfully for the detection of antimicrobials in animal-derived foods (Majdinasab et al. 2017) ‏. Positive samples of the first screening step should be confirmed in the second step. The positive result of the positive samples should not exceed the MRL limit. The concentration is expressed in mg/kg or mg/L (Beyene 2016).

Rules and Regulations

Every country has an agency that oversees food safety. The safety of animal and poultry products in the USA for example is under the responsibility of the US Department of Agriculture's (USDA) and Food Safety Inspection Service (FSIS). Risk assessment regarding food and animal feed safety in the European Union's (EU) is the responsibility of the European Food Safety Authority (EFSA) (Silano and Silano 2017). The Codex Alimentarius Commission created by the FAO and WHO under the Joint FAO/WHO Food Standards Programme contains the food standards, guidelines, and related texts. For regulating the use of drugs in animal production activities, these organizations have proposed maximum residue levels (MRLs) for livestock products to minimize the risk to human health (Joint FAO/WHO, 2018) (council (EC) No 470/2009 and updated in line with Commission Implementing Regulation (EU) 2017/12)‏. The European Commission (2010) in its current consolidated version: 07/12/2020 shows a list of approved drugs with their MRLs in foodstuffs of animal origin as well as a list of banned drugs. It should be noticed that the registered and approved veterinary uses may vary from country to country because of different efficacious use patterns, especially in regions with great differences in disease distribution, predominant parasites, production methods (e.g. 4 extensive or intensive), predominant animal breeds, climate and water temperature (Joint FAO/ WHO 2008), and consequently differences in their acceptable MRL. The residue limit for albendazole, for example, is 0.05 ppm (50 ug/kg) in meat in the USA and Canada (Canada gov, 2018), while in the EU, it is 100 ug/kg. The limit of doramectin in bovine muscles in Canada is 0.03 ppm (30 ug/kg), while in the EC it is 40 ug/kg (European Commission 2010) and in the Codex Alimentarius, it is 10 ug/kg (Joint FAO/WHO, 2018). The MRL for clenbuterol, for example, is 0.2 in cattle muscle and fat, 0.6 in liver and kidney, and 0.05 ug/kg in milk according to the Codex Alimentarius (Joint FAO/WHO, 2018), while in the EC it is 0.1 in bovine muscle and 0.5 in liver and kidney and 0.05 μg/kg in bovine milk, a fact that necessitates global standardization of the MRL values and harmonization of analytical methodology.

Several drugs such as chloramphenicol, metronidazole, and nitrofurans are prohibited for use in food animals are available (European Commission. 2010). Taking into consideration that antimicrobial residues in edible animal products have increased over the permissible level in developing countries (Odetokun et al. 2019), harmonization on residue definitions, methods of analysis, and evaluation of the MRLs and other issues relating to the use of chemicals both as veterinary drugs and as pesticides is a critical issue (Joint FAO/WHO 2014). In continuation and to achieve this goal, the Codex Alimentarius Commission (Joint FAO/WHO 2014) established a strategic plan through the period 2014–2019. The plan objectives were 1. Establish international food standards that address current and emerging food issues. 2. Ensure the application of risk analysis principles in the development of Codex standards. 3. Facilitate the effective participation of all Codex Members. 4. Implement effective and efficient work management systems and practices. In 2020 the Codex Alimentarius Commission (Joint FAO/WHO 2020) discussed the strategic plan during the period 2020–2025. The Codex Alimentarius Commission commits itself to work towards the achievement of the following five goals: 1. Address current, emerging, and critical issues in a timely manner. 2. Develop standards based on science and Codex risk-analysis principles. 3. Increase impact through the recognition and use of Codex standards. 4. Facilitate the participation of all Codex Members throughout the standard-setting process. 5. Enhance work management systems and practices that support the efficient and effective achievement of all strategic plan goals. The situation in the developing countries still needs more effort to achieve harmonization of MRL, withdrawal periods, and analytical procedure with the industrialized countries although there are some trade development programs in cooperation with the European Commission implemented through twinning projects with the EU.

Residue Avoidance

In general, the strategy is based on preventing the entry of violative residues in animal and poultry products intended for human consumption by proper and rational drug use. A guide developed for use by each veterinarian and food animal (dairy and beef) producer embraces the following:

Herd health management

Vaccination, nutrition, and stress management continues to be the crucial steps of a comprehensive herd health program. Alternatives to current antimicrobials, biosecurity guidelines, and management approaches are essential., Special care should be offered for the pregnant animals during the last third of pregnancy to ensure adequate colostrum both the amount and concentration of antibodies. Special attention should also be paid to avoid residue in aquaculture production systems residue in fish (Reimschuessel 2014).

The use of approved drugs‏

Approved animal drug products only should be used by dairy and beef producers who must follow the guidelines in the Generic Animal Drug and Patent Restoration act regarding animal species, dose, route of administration, withdrawal periods, etc. The list of approved drugs known as the "Green Book" is now updated monthly. To ensure misunderstanding, dairy and beef producers should not keep or store unapproved drugs or products. The herd veterinarian should be sure that ELU involves only the approved products. A good veterinarian–client–patient relationship is critical to the health of animals. A veterinarian should be close with the owner to make judgments regarding the health of the patient by a timely examination, emergency coverage, and continuing care, treatment, and revise medication records. The veterinarian's recommendations and prescription should be accepted by the producer‏. The employees on the farm have to know the drugs approved for each animal species and are familiar with the approved dosage, route of administration, and withdrawal time. As of November 24, 2019, all Green Book reports are updated monthly and are located on the Animal Drugs @ FDA website: https://animaldrugsatfda.fda.gov/adafda/views/#/search. Farmers should keep written/electronic treatment records for all groups of animals. Included in these records are date, ID, the person administering treatment, indication for treatment, a drug used, dosage, route of administration, and withhold information for meat and milk (Vickroy et al. 2014‏). Treated animals should be identified clearly and isolated separately.

The use of alternatives to veterinary drugs

The introduction of ethnoveterinary medicine is recently practiced and proved to be effective in minimizing the use of current drugs for combating animal diseases. Ethno-veterinary therapeutics are obtained mainly from medicinal plants due to their efficacy, availability, and ease of preparation particularly in areas where medical assistance is not available (Eiki et al. 2021). Ethno-veterinary medicine has been used successfully for compacting several animal and poultry diseases (Piluzza et al. 2015). Besides being effective and safe, ethno-veterinary medicines can be a good solution to the problem of antimicrobial resistance and drug residues in animal and poultry products (Ranganathan 2017, WHO 2017).

Identify risks for drug residues

Handling and use of drugs, treatment records, number of treated individuals, culling decisions, identification of treated animals, storage, and accessibility of drugs should be reviewed periodically. Proper drug residue testing capabilities should be available on and off the farm‏. The objective of the residue avoidance program is based upon improving livestock management and keeping healthy animals with emphasis on avoidance of drug residues (Tufa et al. 2018‏). All of these activities can be achieved by implementing an employee training program.

Preslaughter testing of body fluids

Treated animals intended for meat production should not be slaughtered before applying the appropriate withdrawal periods by government authorities or regulatory bodies (Vishnuraj et al. 2016). Preslaughter living monitoring of drug residues is very important not only for the protection of human health but also for the detection of the illegal use and violative residue in food animals. Body fluids such as blood, urine, and milk can be sampled and tested preslaughter for predicting residue levels in edible tissues (Zhang et al. 2017; Chirollo et al. 2018; Aroeira et al. 2019). Urine and hair were excellent for predicting ractopamine residues in tissues of pigs, whereas plasma and urine were satisfactory body fluids for the prediction of ractopamine concentrations in edible tissues of goats (Huang et al. 2016). Chloramphenicol was also reported in the urine of pigs (Trevisani et al. 2014). Hair analysis can be a useful target of sampling for residues testing of some drugs such as sulfamethazine as an alternative to edible tissues in animal farming (Gratacós-Cubarsí et al. 2006). A similar study was carried out for various nitroimidazoles in feathers and shanks in poultry (Církva et al. 2019).‏

Effect of food Thermal treatment on drug residue levels

Previous studies have suggested that chloramphenicol, aminoglycosides, quinolones, clindamycin, novobiocin, trimethoprim, vancomycin, and azlocillin are heat-stable (Rana et al. 2019; Monir et al., 2021). Moreover, quinolones, Lincomycin, tylosin, and oxacillin are degradable by only 10% during thermal treatment (Rozanska and Osek, 2013; Heshmati, 2015). β-lactams, tetracyclines, erythromycin, florfenicol, and thiamphenicol were heat-labile (Hassani et al. 2008; Laszlo et al. 2018; Filazi et al. 2015; Rana et al. 2019; Kellnerova et al. 2015). Although a significant reduction of OTC concentration in meat by cooking was reported (Vivienne et al., 2018), microwaving meat had a limited. However, the food matrix composition and physicochemistry (e.g., pH, fat content), the cooking methods, and the presence of food additives could influence the degradation of antibiotics (Franje et al. 2010, Abou-Raya et al. 2013, Tian et al., 2017). No significant decrease in ampicillin concentration was observed during the first 3 months of storage monitoring at -20 and -75 degrees C. However, after 8 months of storage at -20 degrees C, a significant decrease arose and was never observed at -75 degrees C (Verdon et al. 2000). Sulfadiazine residues were slightly decreased during milk boiling while most sulfonamide residues are stable in animal tissues when frozen (Laszlo et al. 2018). Different cooking procedures have no net effect on clenbuterol residues in incurred tissues (Parr et al. 2016). The sedatives, azaperone, and azaperol residues are stable in pig kidneys and liver under frozen conditions (Aoki et al. 2009). Levamisole residues in fried muscle and rafoxanide in cooked muscle were decreased by only 11% and 17%-18%, respectively (Cooper et al. 2011), while carbadox was stable in muscle (Rana et al. 2019).

Future prospects

International Feed Industry Federation and FAO are looking for new, safe proteins. Among the emerging sources of protein for food are edible insects (Van Huis et al., 2013). Moreover, improving agricultural production and food security are anticipated (FAO, 2017) and the use of natural products can be used as a safe replacement for synthetic agrochemicals (Ogunnupebi et al., 2020). The use of alternative animal therapeutics such as immune modulators, phages against specific bacterial strains, phytochemicals such as oregano and thyme, probiotics such as yeast, fungi, and bacteria, which helps control “bad” bacteria and creates a favorable environment in the gut. Vaccines are among the most promising alternative approaches to control a host of respiratory and digestive diseases, as well as a number of other health problems such as enhancing animal productivity (Hoelzer et al. 2018; Callaway et al. 2021). However, at the present time, prudent use of antibiotics for example and the establishment of scientific monitoring systems are the best and fastest ways to limit the adverse effects of the abuse of antibiotics and to ensure the safety of animal-derived food and the environment (Toutain et al., 2016; More, 2020).

Conclusion and Recommendations

The unregulated use of veterinary products in food-producing animals and poultry is the main cause of the occurrence of drug and chemical residues in food of animal origin leading to a health hazard to the human consumer. The most likely reason for drug residues may result from improper usage, including extra-label or illegal drug use and most importantly is the failure to observe a withdrawal period. Measures to reduce antibiotic residue in livestock products include the following: 1- Farmers should be encouraged to maintain herd health by applying the best hygienic measures to minimize drugs used. 2-Veterinary supervision is critical for the appropriate use of veterinary drugs and for keeping the safety of animals, fish, and chicken products. The veterinarian should use label dispensed drugs and should distinguish the difference between OTC, prescription, and 'extra-label drugs', as well as using alternatives to antibiotics such as vaccination, probiotics, phage therapy, and essential oils and develop a good veterinarian–client–patient relationship. 3- Research projects should be directed to find safe and effective alternatives to veterinary drugs for treating animal diseases. 4-Testing for the presence of residues must be carried on and off the farm using rapid, sensitive, and standardized laboratory tests. 5- Condemnation of meat, milk, or eggs proved to be polluted with drug residues‏‏ is very essential. 6- Regulatory bodies should enforce to apply the appropriate withdrawal periods strictly and to set the harmonized MRLs and analytical methods. 7- Using proper processing techniques to avoid contamination is essential. 8- Researchers should be encouraged to develop new safe methods to inactivate and/or enhance clearance of animals ‘ bodies of residues. 9- Efforts to find out new sources of protein similar to and acceptable as animal protein should be encouraged.