J Korean Soc Appl Biol Chem (2012) 55, 701−709 DOI 10.1007/s13765-012-2220-4
REVIEW
Fate, Occurrence, and Toxicity of Veterinary Antibiotics in Environment Ramasamy Rajesh Kumar · Jae Taek Lee · Jae Young Cho
Received: 20 September 2012 / Accepted: 18 October 2012 / Published Online: 31 December 2012 © The Korean Society for Applied Biological Chemistry and Springer 2012
Abstract The increasing worldwide usages of Veterinary Antibiotics (VAs) for therapeutic and nontherapeutic are becoming serious issue due to its adverse effects on all living organisms. Release of VAs into the aquatic and terrestrial environments results in antibiotic resistance in bacteria and toxicity to humans, animals, and plants. This review covers the present scenario on VA usage, occurrence, toxicity, and removal techniques. Keywords antibiotics · antibiotic-resistance · toxicity · veterinary
Antibiotics are chemical therapeutic agents used to kill or inhibit microorganisms, such as bacteria, virus, fungi, or protozoa. Antibiotics that kill bacteria are called “bactericidal” and antibiotics that inhibit the growth of bacteria are called as “bacteriostatic”. In 1928, the antibiotic penicillin was first isolated from the fungus Penicillium by Alexander Fleming. The next discovery was that of streptomycin by Selman Waksman. Streptomycin was isolated from the bacterial genus Streptomyces, which is found naturally in soil, and is an antibiotic cure for many intestinal diseases. The antibiotics penicillin and streptomycin are both relatively effective against certain diseases, but there was a lack of broad-spectrum drugs. Thus, a search ensued for a new panacea; an antibiotic to rule them all. By 1949, various laboratories had discovered a series of antibiotics such as aureomycin, chloromycin, and terramycin all of which had broader effective ranges against bacteria than penicillin and streptomycin. Presently, there are about 250 different chemical
R. R. Kumar · J. T. Lee · J. Y. Cho () Bio-environmental Chemistry, Chonbuk National University, Jeonju 561756, Republic of Korea E-mail:
[email protected]
entities registered and currently being used as human and veterinary antibiotics (VAs) (Kümmerer and Henninger, 2003). Antibiotics are generally classified based on their structure or by their mechanism of action including subgroups such as beta lactums, quinolones, tetracyclines, macrolides, sulfonamides, and others. Under different pH conditions, antibiotics are neutral, cationic, anionic or zwitter-ionic, as they are complex molecules that may possess different functionalities within the same molecule. Due to these different functionalities, their physical, chemical, and biological properties such as log Pow (Cunningham, 2008), sorption behavior, photoreactivity, activity, and toxicity may change with pH (Kümmerer, 2009). The production and use of antibiotics increased rapidly worldwide over the last several decades. Numerous pharmacologically active substances are used as human and animal medicines annually for treating and preventing diseases. Approximately 3,000 compounds are used as medicine (Díaz -Cruz et al., 2003; Sarmah et al., 2006; Calisto and Esteves 2009; Kümmerer, 2009) and 100,000– 200,000 tons year−1 are used globally (Wise, 2002). However, the release of antibiotics into the environment has received attention in recent years. The use of VAs has become necessary due to the growing animal food industry. VAs are used worldwide to protect animal health, prevent economic loss, and help ensure a safe food supply (Boxall et al., 2002; Halling-Sørensen et al., 2002). However, after use, VAs may enter waterways and possibly pose environmental challenges. The presence of antibiotics in the environment was first detected three decades ago in a UK river (Watts et al., 1982). This initiated monitoring for antibiotics in the environment and studies of their environmental impact in many countries (Sarmah et al., 2006). Among the antibiotic release sources, VAs appear to be the most potent source as they are released into the environment through animal manure and by other means (Baguer et al., 2000). In recent years, the occurrence and fate of antibiotics in the environment, including surface water, groundwater, and soil has drawn the attention of researchers all over the world.
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J Korean Soc Appl Biol Chem (2012) 55, 701−709
Use of VAs VAs are most often used for nontherapeutic purpose such as growth promotion, feed efficiency, and weight gain in animals for increasing food production. Growth promotion effect of VAs was first discovered in the late 1940s in chickens and pigs. VAs can be administered to healthy animals in feed at concentrations 14 days as a growth promoter. This high dose is well characterized from therapeutic and prophylactic antibiotic uses, which are generally delivered at a higher minimum dose of about 20 mg L−1 in animals and are generally administered in water (NAAS, 2010). In 1950s the recommended concentration levels in poultry and pig diets were 4 mg L−1 for narrow spectrum and 10 mg L−1 for broad-spectrum antibiotics. However, these levels have currently increased 10–20 fold (NAAS, 2010). The general classes of VAs are listed in Table 1. No clear information is available on the total amount of VAs used worldwide. Based on the amount sold in each country, the amount used is estimated, and the use may vary from country to country based upon the number of livestock. Sales reports indicate that the USA ranks first in the use of antibiotics at about 11,148 tons year−1 (Benbrook, 2002). These antibiotics are utilized largely to promote growth and prevent disease, thereby reducing production costs. Most of the VAs are sold over the counter and do not require a veterinarian’s prescription. The second largest consumer of VAs is China at 6,000 tons year−1 (Zhao et al., 2010). VAs use in both countries is higher than that of other countries not only due to the large numbers of livestock but also due to the common agricultural practice using VAs as growth feed additives. The use
of VAs in Korea, Japan, and France is 1,533 (Kim et al., 2011), 1,059 (Asai et al., 2007), and 1,064 (EMA, 2011) tons year−1, respectively. Of the 20 active ingredients (AIs) in VAs in Korea, five antibiotics such as chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and tylosin are in the top priority group (Seo et al., 2007). Usages of VAs in different countries are listed in Table 2. Consumers in many developed countries have no qualm about consuming meat or livestock products from animals raised on feed containing antibiotics. Thus the use of large quantities of VAs in the USA has caused their trading partners and competitors such as European countries, New Zealand, and South Korea to implement restrictions and prohibitions on the use of certain antibiotics for subtherapeutic or nontherapeutic purposes in animal production. The European Union (EU) has banned growth promoting antibiotics in production animals (Mark et al., 2003). In June 2001, the EU banned the use of almost all growth promoting antibiotics except monensin sodium, salinomycin sodium, avilamycin, and flavophospholipol and these products have also been banned since January 1, 2006. The Korean Ministry for Food, Agriculture, Forestry, and Fisheries banned the use of eight antibiotics such as enramycin, tyrosine, virginiamycin, bacitracin methylene disalicylate, bambermycin, tiamulin, apramycin, avilamycin, and sulfathiazole as feed additives in July 2010 (Renee, 2011). Furthermore, some Southeast Asian countries including Singapore, Japan, Thailand, Taiwan, and Malaysia are also considering banning the use of growth-promoting antibiotics. South American countries such as Argentina, Brazil, and Uruguay are likely to ban the use of many antibiotics in food-producing animals. The USA, Canada, and Australia continuously review and monitor the use of antibiotics
Table 1 Classes of commonly used veterinary antibiotics Class Fluoroqinolones
Acronym CIP ERFX OFL PEF
Compounds
Formula
Ciprofloxacin Enrofloxacin Ofloxacin Pefloxacin
C17H18FN3O3 C19H22FN3O3 C18H20FN3O4 C17H20FN3O3
M.W 331.34 359.40 361.36 333.35
Lincosamides
LIN
Lincomycin
C18H34N2O6S
406.53
Macrolides
TIA
Tiamulin
C28H47NO4S
493.74
Fenicoles
CAP
Chloramphenicol
C11H12Cl2N2O5
323.13
Sulfonamides
SCP SDZ SDM SDO SMT SMX SMZ SQX
Sulfachloropyridazine Sulfadiazine Sulfadimidine Sulfadimethoxine Sulfamethizole Sulfamethoxazole Sulfamethazine Sulfaquinoxaline
C10H9ClN4O2S C10H10N4O2S C12H14N4O4S C12H14N4O4S C9H10N4O2S2 C10H11N3O3S C12H14N4O2S C14H12N4O2S
284.72 250.78 310.33 310.33 270.33 253.27 278.33 300.36
Trimethoprim
TMP
Trimethoprim
C14H18N4O3
290.32
Tetracyclines
CTC DOX OTC TC
Chlortetracycline Doxycycline Oxytetracycline Tetracycline
C22H23ClN2O8 C22H24N2O8 C22H24N2O9 C22H24N2O8
478.88 462.46 460.43 444.43
J Korean Soc Appl Biol Chem (2012) 55, 701−709
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Table 2 Worldwide total usage of veterinary antibiotics Country
Amount sold/used (tonnes)
Africa Australia China Czech Republic Denmark Finland France Japan Korea New Zealand Norway Sweden Switzerland UK USA
14.6 932 6000 82 130 17 1064 1059 1533 93 6 15 73.2 403 11148
Reference Mitema et al. (2001) JETACAR (1999) Zhao et al. (2010) EMA (2011) EMA (2011) EMA (2011) EMA (2011) Asai et al. (2007) Kim et al. (2011) Sarmah et al.(2006) EMA (2011) EMA (2011) EMA (2011) EMA (2011) Benbrook (2002)
in food animals. Worldwide legislation has been created to control the use of antibiotics for other than therapeutic use. Due to the increase in antibiotic-resistant infections in humans, organizations such as World Health Organization, the American Medical Association, and the American Public Health Association have proposed banning the use of antibiotics as growth-promoting additives. Some cautions/actions against the use of antibiotics in animal feed (Source: NAAS, 2010) are shown in Table 3. The US Food and Drug Administration (FDA) issued an order on January 4, 2012 prohibiting certain extra-label uses of cephalosporin drugs (not including cepharin). The prohibited uses of cephalosporin include: 1) unapproved dose levels, frequencies, durations, or routes of administration; 2) cattle, swine, chickens, or turkeys, which are not approved for use (e.g., cephalosporin drugs intended for humans or companion animals; 3) disease prevention. This rule was effective beginning on April 5, 2012. The overall outcome of using antimicrobial growth promoters (AGPs) is the availability of more nutrients for growth and production of livestock and poultry. Improved growth rates and feed conversion ratios (feed:gain) have been reported to be 9–16% in piglets, 5.5–9% in growing pigs, 3–10% in broiler chickens, 1–2% in layers, and 7–10% in veal calves. Antibiotics for therapeutic purposes can be purchased only by prescription from a registered medical practitioner; however, they are freely accessible and sold over the counter as growth promoters. The effects of using AGPs are presented in Table 4 (Source: NAAS, 2010).
Occurrence The occurrence and fate of VAs is a serious environmental threat with the emergence and development of antibiotic-resistant
bacteria (Martinez, 2009; Holzel et al., 2010; Tao et al., 2010). VAs are usually released into the terrestrial environment in the form of organic manure, slurries or other types of biosolids. The activity of VAs in soil is not yet fully understood; however, environmental risk assessments of VAs use persistence and adsorption to estimate their fate and activity in the environment. Tetracyclines (TCs) and sulfonamides (SAs) were the most frequently detected compounds among the VAs used. Ok et al. (2011) studied the occurrence of VAs in water, sediment, and soil samples at a composting facility and reported that the concentration of TCs in a water sample was 2.75 µg L−1, whereas they were 7.02 µg kg−1 in soil, and were below the detection limit in sediments. In contrast, the detected concentrations of SAs in water samples were 14.85 µg L−1, 120.91 µg kg−1 in sediment samples, and 38.82 µg kg−1 in soil samples. Sim et al. (2011) reported that influent from livestock wastewater treatment plants (L-WWTPs) in South Korea contained 319–3630 µg L−1 of pharmaceuticals, and the antibiotic Lincomycin alone contained about 3005 µg L−1 in LWWTPs. These were of higher concentrations than those in 12 other municipal plants, 4 hospitals, and 4 pharmaceutical wastewater treatment plants when they carried out a nationwide study. In China, oxytetracycline (OTC) or chlorotetracycline (CTC) are commonly detected VAs in manure with the highest concentrations of 0.2–134 mg kg−1 OTC and 0.3–121.8 mg kg−1 CTC in the Beijing area (Zhang et al., 2005; Liu et al., 2007; Wei et al., 2008; Zhang et al., 2008). Hu et al. (2008) detected 173.2 mg kg−1 of OTC in swine manure and a similar concentration (172.9 mg kg−1) of OTC was detected by Pan et al. (2011). The residual detected concentration of CTC was >2.6 mg kg−1 and OTC was >0.4 mg kg−1 (Pan et al., 2011). In EU the detected level concentrations of TCs in swine manure ranged from 0.1–46.0 mg kg−1 in Germany (Hamscher et al., 2002), 0.1–24.4 mg kg−1 in Denmark (Jacobsen and Halling-Sørensen, 2006), and
