sou · GLB3132d2 · 1998-01-01 00:00:00 — The example above illustrates that even a seemingly marginal increase of the prevalence of enteric pathogens in animal products can have a significant impact on human health. A further quantification of the risk cannot be performed as hitherto published studies on the possible effects of on enteric pathogens have not addressed the issue of consumer exposure (see also 4.8). Most are not absorbed from the gut and/or are given at comparatively low dosages. Toxic reactions in the target species would therefore normally not be expected. Exceptions are the quinoxalines (see chapter 5), halofuginone, nicarbacin and the ionophores (see chapter 7). The quinoxalines cause adrenal damage in pigs leading to hypoaldosteronism at doses and exposure times well within the range of those permitted for growth promotion. This has been clearly documented in experimental settings but no field reports have been found. Symptoms of intoxication may be overlooked as they typically consist of dry faeces and increased thirst. Halofuginone interferes with collagen synthesis resulting in loss of skin tensile strength. This leads to skin scratches and sores in live birds and skin tears during slaughter and processing, leading to reduced carcass quality. Unpublished Swedish observations when this product was used in the middle of the 80s are consistent with these findings. to problems with carcass quality that were put in connection with the use of halofuginone, the product was abandoned by the industry (, B. 2 personal communication 1997) Nicarbacin interferes with the thermoregulatory balance at high ambient temperatures. The effect is dose dependent. In regions where climatological conditions are such that critical temperatures are seldom reached, this problem is not likely to occur. The ionophores have a narrow safety , often in the range of 2-3 times the recommended dose. Toxic effects are directed mainly against skeletal muscle and/or cardiac muscle. Numerous reports on intoxication of poultry due to accidental overdose with ionophores have been published. The prevalence of this condition may be underestimated due to diagnostic difficulties. 2 , , () Exposure of non-target species, e.g. by accidental intake, may have serious consequences but is not likely to present a substantial risk under good manufacturing practices. As mentioned above, most are not absorbed from the gut and/or are given at comparatively low dosages. Residues at levels potentially harmful for the consumer would therefore normally not be expected. Exceptions to this are the quinoxalines and the nitroimidazoles. Quinoxalines and their metabolites are mutagenic IN and are potentially genotoxic (FAO/WHO, 1995). Genotoxic substances cause chromosomal aberrations in eukaryotic cells. to the additive effects of such aberrations, even a very low dose may pose a risk. Acceptable daily intakes () have not been set. Nitroimidazoles have shown mutagenic and genotoxic potential in several tests and their carcinogenic potential cannot be ruled out. Neither JECFA, not CVMP could establish an . Low, or very low concentrations of residues in food might elicit allergic reactions in sensitised individuals. Such low concentrations might be present in or on animal products due to absorption from the gut or to faecal contamination. The population at risk for such allergic reaction is likely to be very small and the cause of the reaction would be difficult to determine. No reports of food related allergy implicating approved in EU have been found. Several (macrolides, quinoxalines, bacitracin) are antigens and occupational exposure on a daily basis can lead to sensibilisation. Occupational contact dermatitis and/or asthma seem to be rather frequent as judged by reports in the literature. Allergic reactions have also been reported for amprolium, meticlorpindol, robenidine and halofuginone. Airborne antigen or direct contact is thought to be the main cause for these reactions. As the handling of feed and inevitably involves formation of airborne particles, the exposure of the population at risk must be regarded as high. Usage of special galenic formulations of premixes may reduce the exposure. As for the remaining and coccidiostats, no reports on allergic reactions have been found. However, the causal diagnosis of such reactions can be extremely difficult. At least in , there is no report system for side-effects in humans caused by substances used in animals. Thus, the absence of reports does not exclude the possibility of such hazards. Concerning the potential genotoxicity of nitroimidazoles and quinoxalines, not only the safety for the consumer should be considered. When these substances are used on the farm, humans are exposed to low doses on a daily basis. The exposure by inhalation or other routes during the handling of feed and manure is not known. The possibility of additive effects has to be borne in mind, as farmers are often exposed not only to these but to many, potentially offensive chemicals. 8.4Safety for the environment are typically administered over a long period. Large groups of animals are involved and many additives are poorly absorbed and therefore excreted to a considerable extent. The effects will depend on the length of time that the substance in question persists in the environment. Persistence may lead to increase in concentrations over time, due to bioaccumulation. In order to assess the exposure in various environmental compartments, the fate of the in the ecosystem has to be known. A model for antibiotic release from feedlots was presented by (1984) in which volatilisation, degradation, diffusion, adsorption to sediment, losses to ground water and streams etc. is calculated. This model clearly illustrates the complexity of the matter. Table 8.VI shows some hazards for the environment related to usage that can be envisaged. Potential hazards and consequences of usage for the environment 4ABELL 6) 0OTENTIELLA FAROR OCH KONSEKVENSER F¶R MILJ¶N ORSAKADE AV !&4 ANV¤NDNING Toxic effect on terrestrial Toxic effect on aquatic fauna reduction of fish numbers Toxic effect on plants Toxic effect on microflora increased virulence of plant Most are likely to be degraded by soil microbes, as they are antibiotics, produced by microorganisms. According to available literature, most antibiotic substances appear to have a half life in soil of about 2-3 weeks at , while lower temperatures generally cause a slower As light and temperature are important variables regarding degradation times, separate risk assessments may be necessary for different geographic areas. Synthetic substances such as quinoxalines are more likely to persist in the environment. Concentrations in manure would be expected to be too low for any toxic effects on either terrestrial or aquatic fauna, provided that no bioaccumulation occurs. If the slurry concentration of the substance is 50 ppm, the concentration in soil would be roughly 1 ppm with an application of manure of 25 /hectare and a ploughing depth of (table 8.VII). This is in most situations unlikely to have an effect on eukaryotic cells. However, as the minimum inhibitory concentration for naturally susceptible soil microbes is in the same magnitude, a temporary disruption of the microflora would be expected. This effect has been demonstrated as a transient reduction in nitrification when a low concentration of tylosin was added to soil (Bewick, 1978). Predicted environmental concentration (ppm) in soil at various concentrations of in slurry1 4ABELL 6)) 5PPSKATTADE !&4 KONCENTRATIONER I JORD PPM EFTER G¶DSLING MED G¶DSEL MED OLIKA !&4 KONCENTRATIONER PPM AT PLOUGH DEPTH OF 1Application of 25 slurry per ha, soil density 1.5g/cm3 !PPLIKATION AV TON FLYTG¶DSEL PER HA JORDDENSITET G CM As discussed in chapter 4 and 6, the environment will also serve as a reservoir for resistance genes and bacteria carrying these genes. Resistance in itself is not a problem for the environment, as the consequence of resistance is impairment of therapy. If the resistance genes are located on DNA segments harbouring virulence genes, transfer between microorganisms present in soil or water could theoretically lead to an increase in virulence of plant or wildlife pathogens. This could ultimately increase the prevalence or severity of diseases. No information is available on the occurrence of such events. Accurate risk-assessment of environmental effects of is hampered by the circumstance that the most extensive data bearing on the effects of are those gathered by commercial organisations when seeking regulatory approval, and that these data are dealt with confidentially between the organisations and the regulatory agencies. It would be in the public interest, and would help to strengthen confidence in regulatory decisions, if these data were made publicly available under arrangements that protect the legitimate commercial interests of the companies concerned. Many authors have discussed increased animal health problems due to infectious diseases when antibacterial feed additives are withheld (e.g. McOrist, 1997; Viaene, 1997). This poses questions as to what degree antibacterials at their permitted dosages for growth promotion also have therapeutic and/or prophylactic effects. Permitted dosages are usually around 20 ppm (range 1-100 ppm) which for most substances is substantially lower than therapeutic doses, but there is an overlap between dosages permitted for growth promotion and recommended doses for prophylaxis and therapy. Even at a low dosage they will have antimicrobial effects in the intestine, since minimum inhibitory concentrations for normally sensitive bacteria are around 1-5 ppm (see 3.2 and 4.2) The Swedish experience from banning antibacterial growth promoters in 1986 was the emergence of clinical problems and disturbances of the health status of piglets and broilers which initially created an increased demand for medicated feed with antibiotics at therapeutic dosages. By changing feed composition, improvements in hygiene, changing rearing strategies etc. this is now largely corrected for (Wierup, 1996). Important animal diseases for which preventive effects of at the dosages given for performance enhancement have been described include necrotic enteritis in poultry, swine dysentery, bacterial enteritis and porcine proliferative enteritis (see chapter 3.2). Several antibacterial feed additives also have indications as therapeutic drugs for these animal diseases. According to the available literature there are no indications that the basic mode of action of is different from that of antibacterials when used for prevention or therapy. The growth promoting effect can be ascribed to a reduction of pathogen load and the animals response to this. This prophylactic effect is applicable whether the manifestastion of the pathogen is clinical or subclinical. Documentation on prophylactic and/or therapeutic effects of is not included in the application for approval and such effects are therefore not evaluated in the approval process. 8.6The risks and the benefits The major beneficial effect of is their prophylactic and therapeutic effects in relation to some bacterial diseases. However, according to article 7 in directive 70/524/EEC such properties are only allowed for coccidiostats and other medicinal substances. It is questionable whether this lack of coherence between regulations and the actual situation caters for consumer confidence built on transparency. Usage of improves feed utilisation and growth rate. This will generate an economic profit and, depending on its distribution, producers, consumers or others may benefit. Other sequels to usage are reductions in manure and nitrogen output. This may be seen as beneficial from an environmental point of view. However, all these positive effects can also be achieved by other means. 8.6.2Indirect long-term losses and animal welfare aspects have been used for over 4 decades and this has undoubtedly contributed to the development of the current systems for animal production. Use of caters for high stocking rates which from an economic point of view is favourable but from a disease point of view raises serious questions about disease control. Examples of situations where animal density create problems are the control of outbreaks of epizootic diseases (e.g. swine fever), zoonotic diseases (e.g. salmonella) and production diseases (e.g. swine dysentery). Only certain diseases in the latter group are prevented by usage. These high density production systems have also been questioned from the point of view of animal ethics and animal welfare. Neither animal welfare nor animal health are created through administration of antibacterials. A sound approach from an animal welfare point of view is to rear animals employing management strategies and animal care of high standard. A modern is also an Animal Health Act. are considered to be part of a production model in which productivity is over-emphasised. Clearly, a development towards more health-orientated production systems is needed. Agriculture must, as all other sectors, aim towards a sustainable development. This means the development of production systems that meet the need of the present without compromising the ability of future generations to meet their own needs. In essence, sustainable development is a process of change in which the exploitation of resources, the direction of investments, the orientation of technological development, and institutional change are all in and enhance both current and future potential to meet human needs and aspirations. In view of the above, it is questionable whether continued reliance on usage of favours a sustainable development of animal production systems. Non-usage of in a region or a country would contribute to an innovative and dynamic climate for finding measures to raise healthy animals in the absence of without compromising the efficiency of the production. The future of the Common Agricultural Politics was addressed by Mr. , President of Commission, in a speech to Parliament on February 18, 1997. He made the following statement: 4HE STARTING POINT FOR THE REFORM MUST BE A GREATER FOCUS IN %UROPEAN AGRICULTURE ON QUALITY PROTECTION OF THE ENVIRONMENT ANIMAL WELFARE A RETURN TO METHODS AND A SIMPLIFICATION OF #OMMUNITY The main hazard associated with use of is increased resistance of commensals and pathogens. The consequence of this might be impairment of therapy in both animals and man. Transmission of resistance genes between animal and man can and does occur. The risk for loss of effectiveness of therapeutical drugs has been estimated to be far from negligible. The estimate is uncertain due to the complexity of the problem and to lack of pertinent data. Consequently, the magnitude of the risk can presently not be fully established. In order to reduce some of the uncertainties, the following information needs to be on hand: ·exposure of animals to ·exposure of animals to therapeutic antimicrobials ·exposure of man to therapeutic antimicrobials ·prevalence of relevant resistance genes in animals ·prevalence of relevant resistance genes in animal products ·prevalence of relevant resistance genes in the environment ·prevalence of relevant resistance genes in man ·dose response relationship between antimicrobial use and prevalence of resistant genes ·identification of relevant resistance genes ·identification of transfer mechanisms of relevant resistance genes ·transfer rates of relevant resistance genes between animal and human bacteria in realistic settings ·transfer rates of relevant resistance genes between animal and environmental bacteria in realistic settings ·transfer rates of relevant resistance genes between human and environmental bacteria in realistic settings ·persistence of relevant resistant genes in human or animal hosts in the absence and presence of a selective pressure ·incidence of co-transfer of resistance and other relevant genes ·probability of acquiring an infection caused by a bacterium carrying the relevant resistance gene ·probability of the infection above requiring therapy with the relevant substance Needless to say the above information is required for each resistance gene and for each antimicrobial substance. The minimum time required to undertake this research would be 5-10 years. Whenever the conditions change or new information or techniques become available parts of the above given studies will have to be repeated and the risk assessment updated. The economic benefits of in livestock production in EU has been estimated to 2 billion ECU annually. In view of this it is surprising that the data necessary for a risk assessment of the most controversial hazard are still lacking as information on the level of risk is essential for the consumer. A search through scientific databases shows that the number of publications available on performance enhancing effects of is more than 10-fold the sum of publications on microbiological effects. At the present stage it is impossible to fully quantify the risk. Risk-assessment of environmental effects of is hampered by the fact that the information necessary is not publicly accessible. Based on available information, the usage of most does not appear to be associated with major risk for the environment. Other hazards that can be identified for some and medicinal feed additives (MFA) are toxic effects. Halofuginone and the quinoxalines have toxic effects on the respective target species. In addition, many and MFA are allergens and thereby present an occupational hazard and possibly a consumer hazard. The risk for the latter is assumed to be very small. Quinoxalines and nitroimidazoles are potentially genotoxic. The use of such substances in animal production is highly questionable. risk group is persons handling the substances including feedingstuffs. The nitroimidazoles have been banned as veterinary drugs for food-producing animals through listing in annex IV of Council Directive 2377/90/EEC. This lack of coherence between regulations is also associated with a risk of losing public credibility. It is the overall opinion of this commission that the benefits of antibacterial feed additives do not outweigh the risks. With regard to coccidiostats and other medicinal substances, they are specifically used to prevent disease and therefore they should be treated as pharmaceutical specialities, i.e. as medicated feed. Our opinion can be summarised as follows: ·Antibacterial feed additives have favourable economic effects on livestock production, but from a long term perspective these are questionable, especially regarding animal welfare and animal health. can, at levels permitted in feedingstuffs, be used for treatment or prevention of animal diseases, which is in violation of Council Directive 70/524EEC. ·Further, the quinoxalines and the nitroimidazoles are potentially genotoxic thereby posing an occupational hazard. ·Halofuginone and the quinoxalines are toxic for target species. This is deleterious for the well being of the animals. ·The risk for increased resistance associated with the general use of antibacterials as feed additives is far from negligible and the potential consequences are serious for both animal and human health. Antibacterials that are not yet used as therapeuticals in human or veterinary medicine are valuable templates for future drugs. As emergence of resistance is considered to be a threat to animal and human health, all should be restricted to and veterinary purposes only. 8.6.5Considerations for risk management decisions Although it is somewhat beyond the scope of this assignment, some preliminary ideas relating to possible actions to mitigate the risks involved have been noted for consideration. As the risks involved are of uncertain magnitude, the decisions on risk management are particularly difficult. The risk can obviously not be excluded with certainty, nor can it be determined as acceptable. Scientists may declare that the information is inadequate for decision making, but for the policymakers, failure to take action is not a neutral position but represents a positive decision to do nothing. In a climate of uncertainty it is preferable to show caution. The determination of what level of risk is acceptable is established by the public, not by scientists. Communication on the subject of risk, in form of a two-way exchange of information between scientists, decision-makers and consumers, is essential in order to establish the level of acceptance. In general, the risk acceptance tends to increase considerably if there is a possibility of control (i.e. choice) involved compared to a situation were one can not actively avoid the risk. Another important aspect on risk management is to decide on who is to bear the cost - the risk maker or the risk taker. In the event of an over- cautious decision, the risk maker may suffer a cost through reduced benefits. On the other hand, inadequate risk management may lead to a cost for the risk taker. In terms of risk management, a range of measures involving various degrees of intervention are available. Since , like coccidiostats, are products they should be approved and used as pharmaceutical specialities and not as feed additives. Dual authorisations are not acceptable. A single system would reduce the administrative burdens. Further, the transparency of the system would increase. It is understood that animal production would need time to adjust to the situation, allowing for knowledge on appropriate changes in management and feeding practices to expand and to be implemented. Countries which today have restrictions in the use of should be allowed to maintain these until the regulatory system can be fully harmonised. !DDISON * " , 1984. Antibiotics in sediments and run-off waters from feedlots. 2ESIDUE 2EVIEWS 1-28. 3 !CREE * ! 'IPSON 0 3 -C$OWELL 2 - -ILLER , AND -C%LVAINE - $ , 1993. Standardization of nomenclature for animal health risk analysis. 2EVUE 3CIENTIFIQUE ET 4ECHNIQUE /FFICE )NTERNATIONAL DES %PIZOOTIES 1045-1053. Risk analysis and food safety. *OURNAL OF !MERICAN 6ETERINARY -EDICAL !SSOCIATION 245-249. 3VENSK ,¤KEMEDELSSTATISTIK , . "AQUERO & , 1996. )N DISCUSSION FOLLOWING , W., Impact of antibiotic use in animal feeding on resistance of bacterial pathogens in humans. )N PROCEEDINGS OF !NTIBIOTIC RESISTANCE ORIGINS EVOLUTION SELECTION AND SPREAD Whiley, Chichester (Symposium 207), 16-18, . "ARROW 0 ! Further observations on the effect of feeding diets containing avoparcin on the excretion of salmonellas by experimentally infected chickens. %PIDEMIOLOGY AND )NFECTION 239-252. "EWICK - 7 - , 1978. Effect of tylosin and tylosin fermentation waste on microbial activity of soil. 3OIL "IOLOGY AND "IOCHEMISTRY 403-407. ", AND $OYLE - 0 , 1995. Health risks and consequences of 3ALMONELLA and #AMPYLOBACTER JEJUNI in raw poultry. *OURNAL OF &OOD 0ROTECTION 326-344. #ALDWELL * $ 5NDERDAHL . 2 AND 9OUNG ' ! Performance of primary SPF pigs on farms. *OURNAL OF !MERICAN 6ETERINARY !SSOCIATION 141-145. $!.-!0, 1997. Consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark.No. %DMOND - " /BER * & 7EINBAUM * , 0FALLER - ! (4 AND 3ANFORD - $ , 1995. Vancomycin-resistant %NTEROCOCCUS FAECIUM bacteriemia: risk factors for infection. #LINICAL )NFECTIOUS $ISEASES 1126-1133. AND #, 1994. The economics of the Swedish Salmonella control. A cost/benefit analysis. )N PROCEEDINGS OF .6) 7(/ )NTERNATIONAL COURSE ON 3ALMONELLA CONTROL IN ANIMAL PRODUCTION AND PRODUCTS 21- 27 1993, . &!/ 7(/, 1995. Forty-second report of the joint FAO/on Evaluation of certain veterinary drug residues in food.7(/ 4ECHNICAL 2EPORT 3ERIES .O pp. &!/ 7(/, 1997. Risk management and food safety. Joint FAO/WHO consultation, .