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Environmental Assessment of Veterinary Medicinal Products in Denmark

3. Environmental fate and occurrence of Veterinary Medicinal Products

Information about fate and occurrence of veterinary medical substance in the environment is found in a relatively small number of scientific papers. Far more information is available when it comes to the pharmacological fate of the veterinary medicine in the animals prior to excretion. All identified data concerning environmental fate and occurrence is presented in Tables F1 and F2 in Appendix F. Residues of veterinary medical substances have primarily been found in sediments as a result of the use of feed additives in fish farms or in cow dung as a result of treatment of grazing cattle with antiparasitics. In the following a few papers are reviewed in more details.

3.1 Pharmacological fate of veterinary medicines

Medicinal substances may be metabolised in the animal before entering the environment. This may have major importance for the risk assessment procedure. If the medical substance is metabolised to one or few major metabolites the environmental risk assessment has to be conducted on these major metabolites rather than on the parent substance.

Most medicines are metabolised to phase I or phase II metabolites before being eliminated in the urine and/or faeces. Phase I reactions usually consist of oxidation, reduction or hydrolysis Phase II reactions involve conjugation, which normally results in inactive compounds. Both phase I and phase II reactions changes the physical chemical behaviour of the substance because metabolisation always renders the metabolites more water soluble than the parent compounds. For a comprehensive introduction of drug metabolisation see Gibson and Skett (1986).

3.2 Fate in the environment

In the environment veterinary medicinal substances may be absorbed, transported, bioaccumulated or undergo transformations such as biotic and abiotic degradation or reactivation.

Reactivation

There are examples of breakdown products of veterinary medicinal products being converted back to their parent compounds in nature. Berger et al. (1986) showed that chloramphenicol glucoronide and N-4-acetylated sulphadimidine, both phase II metabolites, were converted to the parent compounds chloramphenicol and sulphadimidine in samples of liquid manure. Often metabolites are less toxic than the parent substance. However, if metabolites is reactivated in the environment it complicates the estimation of the environmental exposure and hence the risk assessment.

Abiotic degradation in water

Veterinary medicinal substances may undergo abiotic degradation in water by photolysis or hydrolysis. The importance of these degradation processes is relatively unknown. It is well known that dissolved furazolidone is photosensitive, e.g. Paul and Paul (1964). Aqueous solutions of oxytetracycline kept in dark for a period of two months seem very stable. If oxytetracycline solutions are illuminated, the situation dramatically changed. A half-life of 30 days in fresh water (pH = 7) and only 30 hours in sea water (pH = 8) was observed. Similar findings have been reported by Samuelsen (1989) and Lunestad and Goksøyr (1990). Oka et al. (1989) found seven metabolites of tetracycline after photodecomposition under conditions similar to natural waters in a fish culture pond. However, more field experiments should be carried out to evaluate the significance of photo-degradation under natural conditions.

Biodegradation in sediments

Whereas abiotic degradation dominate in the water, microbial degradation is the main degradation pathway in sediment. Antibiotics or their breakdown products may accumulate in the sediment of fish farms. The fate of drug residues in fish farm sediments is not completely clear. Factors like temperature, water flow, distance between cage and sediment, bacterial activity, chemical composition and depth of the sediment, will affect the decomposition and / or leaching of the drug.

The persistence of oxytetracycline (OTC), in bottom deposits from fish farms has been investigated by Jacobsen and Berglind (1988). It was found to be relatively persistent in anoxic sediments. OTC was found in concentrations varying from 0.1 to 4.9 mg/kg dry matter. A conservative estimation of a half-life of approximately 10 weeks was estimated through a pilot study. Coyne et al. (1994) investigated the concentration of OTC in the sediment of two cages at a fish farm site, and found half-lives of 16 and 13 days. Oxytetracycline, oxolinic acid, flumequine and sarafloxacine were all found to be very persistent in sediments (Hektonen et al. 1995). In the deeper layer of the sediment hardly any degradation had occurred after 180 days and a calculated half-life of more than 300 days was estimated. The residues in the top layer of the sediment disappeared more rapidly. The removal of these substances from the sediment is most probably due to leaching and redistribution rather than degradation. Quinolones were found to adsorb to the sediment. Sulfadiazine and Trimetroprim were less persistent than the quinolones. The concentration of Florfenicol decreased rapidly in the sediment with a calculated half-life of 4.5 days, and a metabolite, florfenicol amine, was identified in the sediment.

Samuelsen et al. (1994) showed that the toxicity of OTC to bacteria declined rapidly in sediments, although no degradation occurred. Binding to ions (Ca²⁺, Mg²⁺) and other substances were mentioned as possible explanation for the inactivation of oxytetracycline., The same study found that both oxolinic acid and flumequine sustained their antimicrobial activity over a six month period in sediment material.

Biodegradation in soils and manure

The degradation of ceftiofur sodium, a wide-spectrum cephalosporin antibiotic, was studied by Gilbertson et al. (1990) in different soils. Fortification of cattle faeces with [¹⁴C]-ceftiofur showed that it was quickly degraded to non-degradable metabolites. Sterilisation of the cattle faeces inhibited the degradation of the substance which suggests that microorganisms may be responsible for the degradation. Halv-lifes of aerobic degradation of ceftiofur sodium in different soils were found in the range of 22.2 to 49.0. Gilbertson et al. also showed that the hydrolysis of ceftiofur was accelerated by increasing pH. The half-lives at pH 5, 7 and 9 was approximately 100, 8 and 4 days, respectively. Donoho (1984) found that monencin, an antibiotic applied as growth promoter for pigs, is degradable in manure and soil. The persistence of medicines from liquid manure throughout the food chains is outlined by Berger et al. (1986).

The antiparasitic compound ivermectin has been shown to be persistent in dung voided from treated cattle (Sommer et al 1992). It was not possible to detect any decrease in the ivermectin concentration in dung pats during the entire experiment (45 days) in the field under temperate conditions. Ivermectin is also persistent under tropical condition (Sommer and Nielsen 1992). These findings are in agreement with the insecticidal properties observed for aged dung (Madsen et al. 1990).

Binding properties to sediments and soils

Hektoen et al. (1995) reports that quinolones such as oxolinic acid, flumequine and sarafloxacin were found to adsorb to sediment of marine origin, and oxolinic acid retained its antibacterial activity throughout the experiment of 180 days. The latter is in accordance with Hansen et al. (1992). Björklund et al. (1991), however, found no antibacterial activity in sediment from fish farms 10 days after the addition of oxolinic acid.

The sorption of efromycin, an antibiotic, developed as a growth promoter for pigs, was investigated by Yeager and Halley (1990) in five soils of various properties. Sorption occurred within 7 hours. Sorption distribution constants ranged from 8 to 290. Classifying efromycin as immobile in most soils (Koc = 580 to 11000). Avermectin was also determined immobile in three different soils by Gruber et al. (1990).

3.2.1 Bioaccumulation

No information about bioaccumulation of veterinary medicinal substances has been found in the literature. However, based on the distribution coefficient of chemicals between n-octanol and water (Kow), which is commonly used as a good estimate of the potential for bioaccumulation in aquatic animals like fish, only a few veterinary medicinal products have high potential for bioaccumulation. Empirical calculations using the software ACD log P^â , showed that only a few of the antibiotic substances covered in this report have log Kow values higher than 2 and hence are likely to bioaccumulate significantly in the environment if available as parent compounds. Antiparasitic substances are often more hydrophobic making them more bioaccumulative. Avermectins for example have log Kow values higher than 5. Antibiotics, being mono- or poly protic substances, are not always fitting the normal relationship between K_ow and the biocentration factor (BCF), which may complicate the estimation of bioaccumulation.

3.3 Occurrence in the environment

3.3.1 Measured environmental concentrations

Aquatic environment

Antibacterial agents have been detected near fish farms (Bjørklund et al. (1990; 1991); Lunestad, (1992); Ervik et al. (1994a,b); Coyne et al. (1994); Kerry et al. (1995b); Weston et al. (1994); Samuelsen et al. (1992). Cravedi et al. (1987) have shown that more than 90 % of orally administered oxytetracycline was excreted into the surrounding waters (without any biotransformation). Bjørklund et al. (1990) have shown that oxytetracycline may reach concentrations of zero to 16 mg/g sediment and that the compound conditions may be very stable in fish farm sediments at low temperatures and stagnant, anoxic conditions. Jacobsen and Berglind (1988) found also oxytretracycline in concentrations varying between 0.1 and 4.9 mg / kg dry matter in natural sediment samples.

Terrestrial environment

Warman and Thomas (1981) found chlortetracyclines in soil amended with chicken manure and Shore et al. (1988) found testosterone and estrogen in manure from American chickens. In the US it is, in contrariety to the EU, legal to treat chickens hormones as growth promoters.

Ivermetic

Ivermectin, an antiparasitic drug used for cattle, pigs, horses and sheep, is excreted almost entirely in faeces. Chiu et al. (1990) showed that 60-80% of an injection dose on 0.3 mg kg^-1 was excreted in the faces over the first week and that more than 60% was excreted during the first three days. Less than 1% was excreted through the urine. Halley et al. (1989) found by using radio-labelled ivermectin that parent compounds consisted of approximately 40-45% of the total radioactivity in dung from steers, 60-70% and 40% in dung from sheep and pigs, respectively. Although not directly comparable, as the application form was not identical, this correspond to approximately 0.27, 0.67 and 0.22 mg parent ivermectin pr. kg dung. The remaining components were primarily polar metabolites. Sommer & Nielsen (1992c) found two days after injection with 0.2 mg kg^-1 body weight a maximum concentration in dung from cattle of 3.8 mg kg^-1 d.w. After 7 and 17 days the concentration dropped to 1.6 and 0.3 mg kg^-1, respectively. Sommer et al. (1992) detected from 0.4 to 9.0 mg kg^-1 (d.w.) of ivermectin in cow dung. On the basis of the above studies it is concluded that the concentration of ivermectin in cow dung may occasionally reach 10 mg kg^-1 (d.w.) shortly after application, but do not generally exceed 2 mg kg^-1.

Ivermectin and other antiparasitic drugs may be given to cattle and sheep by a so-called sustained release boli. These release the drug over an extended period of time, which most often encompasses the entire grazing season. This is of particular concern as it will prolong the time of exposure for dung and soil living organisms.

3.3.2 Predicted Environmental Concentrations (PECs)

For the environmental release scenarios described in Box 2.1, e.g. animals in stables, on grassland or in fish farms, it is possible to estimate the environmental concentrations (Predicted Environmental Concentrations - PECs) as a result of the release pathway in question. Important measures in this context is for an example, as described in Box 2.1, the use and consumption, interval of medical treatment, the metabolic rate, the excretion pathways and rate, the agricultural practise when collecting, storing and applying manure/slurry on the field etc. Not all of these issues are equally important for all release scenarios, e.g. is information on the excretion pathways and excretion rates of less importance for animals in stables, where the urine and faeces are collected and stored together in a period prior to application on the field. Information on excretion pathways and excretion rates is on the other hand very important if estimating the concentration of medicinal residues in dung or urine excreted directly on the soil by field going animals medicated with e.g. antiparasitics.

For the majority of veterinary medicines, including the antibiotics, the major environmental release is from animals in stables. Therefore, PEC calculations for a number of drugs used either for medical treatment or as growth promoters for animals in stables are presented in the following sections. The regulations controlling the application rate of manure and slurry are presented in Box 3.1. Relatively much information is available on the measured concentration of antiparasitics in dung from field going animals (see section above). Hence no attempt to calculate PEC values for this group of substances have been made.

Box 3.1.
Regulations on the use of manure as fertiliser on arable land

On the basis of the information available about the use of prescribed drugs, the recommended dose of veterinary medicinal products and normal application of manure in Denmark, an attempt is here made to calculate the environmental concentration of veterinary medicinal products . The estimation is based on the recommendation on PEC calculations presented in a paper by Spaepen et al. (1997). It has only been attempted to calculate the PEC for soil, as the major environmental release of most veterinary medicines is associated to the terrestrial environment. Some relevant characteristics of the various livestock useful for PEC calculations are presented in Table 3.1. As an example of a worst case PEC calculation, the environmental concentration of the antibiotic tylosin is shown in Box 3.2. A soil concentration of approximately 1.5 mg kg^-1 is predicted as a result of a single amendment with manure from animals receiving the recommended treatment of tylosin (Box 3.2).

Box 3.2.
Predicted Environmental Concentration (PEC) scenario estimating tylosin and tylosin residues in soil after amendment with manure.

Table 3.1
Some relevant characteristics of the various types of husbandry. Data used to perform the exposure scenarios (PEC calculations). Source: Spaepen et. al. (1997).

Table 3.1
Relevante data for forskellige husdyr i landbruget. Data anvendt til eksponeringsscenarier (PEC beregninger). Kilde Spaepen et al. (1997).

Similar calculations have been made for different types of veterinary medicinal products applied by different dosage form, e.g. premix, injection and growth promoter, to both pigs and diary cows. Detailed calculations are showed in Appendix E. For pigs and cows it was calculated, on basis of data received from the Danish Environmental Protection Agency, that pig and cow manure/slurry was dispersed on an average of 150 kg N /ha and 265 kg N / ha annually, respectively. A ploughing depth of 10 cm was used in the calculations. Results are presented in Figure 3.1 and 3.2 and show that hormones (oxytocin and vasopressin) amended with pig or cow manure may be found in the range of 0.01-0.05 µg kg^-1 soil. PECs for antibiotics used therapeutically were found in a range of 1 to 9 mg / kg soil. If the substance is given by injection it seems that the PEC value is slightly higher than when the same substance is given with the food. For antibacterial growth promoters used for pigs, PEC values are found at a much lower level, i.e. in the range of 0.2 to 1.3 mg / kg soil. For substances used in connection with the alimentary tract and metabolism, PECs were found in the range of 0.04 mg / kg soil (dexamethasoniconitat) to 5.7 mg / kg soil (menbuton). For CNS substances used to cows, PECs are found between 0.09 mg / kg soil (xylasin) and 28 mg / kg soil (metamizolnatrium).
  

Figure 3.1
Estimated PEC values (mg kg^-1 soil) for soil fertilised with pig manure containing various veterinary medicines. The substances may be ordinated in the feed as premix (P) or growth promoter (G) or it may given as injections (I).

Figure 3.1
Estimerede PEC-værdier (mg kg^-1 ) for jord gødet med svinegylle.Stofferne kan ordineres i foderet som præmix (P) eller som vækstfremmer (G) eller det kan gives ved injektion (I).

Due to higher N content in cow manure than in pig manure, PECs are generally somewhat higher when soil is amended with cow manure than with pig manure. All these PEC estimations are considered worst case situations and are submitted to a range of uncertainties. There is very little information available to confirm or resolve the calculations.

A paper published by Goll van (1993) estimates that if the total amount of growth promoters used in the Netherlands were spread over all the 2 million hectares of Dutch arable land, an annual average of 130 mg antibiotics and antibiotic metabolites per m² of arable land would be found. If this amount were located in the top ten cm of the field, a concentration of 0.87 mg/ kg of soil should be expected. These results falls in line with the estimated worst case PEC estimations presented above and in Appendix E of this report. None of the studies do, however, take fully or partly degradation into account. This may off course lead to major overestimation of the environmental concentrations. On the other hand it may be justified by the fact that very little is known about degradation during storage of manure and slurry and that some drug metabolites (e.g. glucuronides) excreted by medicated livestock are decomposed by bacterial action in the liquid manure and subsequently reconverted into the active drugs (Berger et al. 1986).
 

Figure 3.2
Estimated PEC values (mg kg^-1) for soil fertilised with cattle manure containing various veterinary medicines. The substances may be ordinated in the feed as præmix (P) or growth promoter (G) or it may given as injections (I).

Figur 3.2
Estimerede PEC værdier (mg kg^-1) for forskellige veterinære lægemidler i jord gødet med kvæggylle. Stofferne kan ordineres i foderet som præmix (P) eller som vækstfremmer (G) eller det kan gives ved injektion (I).

3.4 Summary and conclusions on fate and occurrence of veterinary medicines

The environment may be exposed to residues of veterinary drugs in excreta, i.e. manure or slurry, from treated animals.

Manure and slurry are normally substrates with a high biological activity. The fauna and microflora that help in the decomposition of organic matter and mineralisation of nutrients may be exposed to residues of veterinary medicines.

Degradation data were only available for antibiotics and antiparasitic agents. Biodegradation data are found for 18 different antibiotics both applied therapeutically and non-therapeutically. Half-lives vary from a few days to years depending on characteristics of the substance and on environmental conditions such as temperature, humidity and pH.

The antiparasitic drug ivermectin is only slowly degradable under normal storage conditions, and may hence maintain its antiparasitic properties in the dung for months.

Data is scarce regarding fate of veterinary substances during storage of manure/slurry. It has, however, been shown that certain excretion metabolites can be reactivated and converted into the parent compounds in samples of liquid manure. This complicates the estimation of environmental release and exposure.

Very few field measurements of veterinary medicines are found. The best information concerns antibacterial agents in the vicinity of fish farms and avermectines in dung dropped directly on the soil by animals on the field.

The environmental release of veterinary medicines that are associated with fish farms is special, as the drugs are released directly and deliberately to the environment. Sediment concentration up to 11 mg oxytetracycline kg -1 have been observed in the vicinity of fish farms.

Data on the environmental fate of the antiparasitic compound Ivermectin is well represented in the scientific literature. For cattle, dung concentrations of 1.6 mg / kg ivermectin was measured one week after injection with 0.2 mg ivermectin/kg body weight. After 17 days a reduction in dung concentration to 0.3 mg / kg dung was found.

Although submitted to a number of uncertainties, PEC_soil calculations was made for a number of substances used for medication of animals in stables. Worst case PEC estimations were made for hormones (0.01-0.05 µg kg^-1), antibiotics (0.2 to 9 mg kg^-1) and substances used for treatment of diseases associated with the alimentary tract and the metabolism, (0.04 - 5.7 mg kg ^-1). PECs is generally somewhat higher when soil is amended with cow manure than with pig manure, as the higher nitrogen content in pig prescribes a lower load of manure/slurry according the regulations governing a maximum load of nitrogen pr hectare. In cases of direct deposition on the soil with no subsequent tilling, the concentration may locally be higher. For the estimation of PEC_dung/PEC_soil for animals in the field it is important to take into account the excretion rate and the pathway of excretion. If the drug is excreted primarily via the urine it may be very difficult to estimate the PEC_soil/PEC_groundwater.

 

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