sou · GLB3132d2 · 1998-01-01 00:00:00 — Monensin toxicity in a captive white-tailed deer. *OURNAL OF :OO !NIMAL -EDICINE 13-16. 'RANOT ) "ARTOV ) 0LAVNIK ) 7AX % (3 AND 0INES - , 1991. Increased skin tearing in broilers and reduced collagen synthesis in skin IN VIVO and IN in response to the coccidiostats halofuginone. 0OULTRY 3CIENCE 1559-1563. (ALVORSON $ ! 6AN $IJK # AND "ROWN 0 , 1982. Ionophore toxicity in breeders. !VIAN $ISEASES 634-639. (ANRAHAN , ! #ORRIER $ % AND .AOH 3 ! Monensin toxicosis in broiler chickens. 6ETERINARY 0ATHOLOGY 665-671. (ITE - 3KEGGS ( .OVEROSKE * AND 0ECK ( , 1976. Mutagenic evaluation of ronidazole. -UTATION 2ESEARCH 289-304. (OBSON &ROHOCK ! AND *OHNSON ( ! Coccidiostat residues in poultry excreta. *OURNAL OF THE 3CIENCE OF &OOD AND !GRICULTURE 37-44. % , 1984. Salinomycin poisoning in . 6ETERINARY 2ECORD 52. (ORTON 3MITH # AND ,ONG 0 , , 1963. Coccidia and coccidiosis in the domestic fowl and . )N B. Dawes (ed. ), !DVANCES IN 0ARASITOLOGY Vol. (OWELL * (ANSSON * /NDERKA $ AND (ARRIES 7 . , 1980. Monensin toxicity in chickens. !VIAN $ISEASES 1050-1053. *ACOB 4 ! !LVARO 2 & #HAPIN , 2 'REEN - , -ERIWETHER ( 4 /LSON ' 6AN )DERSTINE ! ! AND 7OLF & * , 1982. Tissue residues of arprinocid in Depletion of residues in tissues of chickens fed carbon-14-labelled arprinocid. *OURNAL OF !GRICULTURAL AND &OOD #HEMISTRY 248-253. *EFFERS 4 + , 1989. Anticoccidial drug resistance: a review with emphasis on the polyether ionophores. )N PROCEEDINGS OF TH )NTERNATIONAL #OCCIDIOSIS #ONFERENCE #OCCIDIA AND INTESTINAL COCCIDIOMORPHS INRA, 17-20 October, Tours. *OHNSON , 7 AND %DGAR 3 ! Ea-B and Ea-C cellular antigen genes in Leghorn lines resistant and susceptible to acute cecal coccidiosis. *ONES * % 3OLIS * (UGHES " , #ASTALDO $ * AND 4OLER * % , 1990. responses of broiler-breeders to anticoccidial agents. 0OULTRY 3CIENCE 27-36. +ABELL ' 3AINI 2 + 3OMANI 0 AND 0RESSMAN " # , 1979. Effects of the carboxylic ionophore monensin on regional blood flow in normal and in ischaemic myocardium in normal and anesthetized dogs. *OURNAL OF 0HARMACOLOGY AND %XPERIMENTAL 4HERAPEUTICS 231-237. +AMPHUES * -EYER ( ,IEBLER % - AND *OHANNSEN ! tierärzte - aktuelle fälle klinische störungen bei pferden nach aufnahme ionophore- haltigen mischfutters. $EUTSCHE 4IER¤RZTLICHE 7OCHENSCHRIFT 537-539. ,EEUWEN 7 AND 'END 7 , 1989. Residuen van amprolium in eieren na toediening van amprolium/ethopabaat aan leghennen en opfokleghennen. 4IJDSCHRIFT VOOR $IERGENEESKUNDE 76-82. +ARSAI & AND 0APP , , 1990. Gehäuft auftretende narazin-vergiftung bei hunden. 4IER¤RZTLICHE 5MSCHAU 3116-324. +ONDO & , 1988. )N lecithinase activity and sensitivity to 22 antimicrobial agents of #LOSTRIDIUM PERFRINGENS isolated from necrotic enteritis of broiler chickens. 2ESEARCH IN 6ETERINARY 3CIENCE 337-340. +YRIAKIS 3 # 3ARRIS , +RITAS 3 + 3AOULIDIS , 4SINAS ! # AND 4SILOYIANNIS 6 + , 1995. The effect of salinomycin on the control of #LOSTRIDIUM PERFRINGENS type A infection in growing pigs. *OURNAL OF 6ETERINARY -EDICINE SERIES " 355- ,ANGSTON 6 # 'ALEY & ,OVELL 2 AND "UCK 7 " , 1985. Toxicity and therapeutics of monensin: a review. 6ETERINARY -EDICINE 75-84. ,* 6 AND )NESI ' , 1974. Positive inotrophic effect on isolated human atrial muscle produced by the ionophore X-537A. *OURNAL OF #LINICAL 0HARMACOLOGY 32-34. ,ILLEHOJ ( 3 , 1986. )N assessment of T-cell proliferation response to stage specific parasite antigens. 6ETERINARY )MMUNOLOGY AND )MMUNOPATHOLOGY 321-330. ,ILLEHOJ ( 3 , 1988. Influence of inoculation dose, inoculation schedule, chicken age and host genetics on disease susceptibility and development of resistance to %IMERIA TENELLA infection. !VIAN $ISEASES 437-444. ,ILLEHOJ ( 3 2UFF - $ "ACON , $ ,AMONT 3 * AND *EFFERS 4 + , 1989. Genetic control of immunity to %IMERIA TENELLA Interaction of MHC genes and non-MHC linked genes influences levels of disease susceptibility in chickens. 6ETERINARY )MMUNOLOGY AND )MMUNOPATHOLOGY 135-148. ,INDSAY $ 3 AND "LAGBURN " , , 1995. )N H.R. 6ETERINARY 0HARMACOLOGY AND 4HERAPEUTICS 7th ed., , Ames. ,ONG 0 , ED 1990. #OCCIDIOSIS OF MAN AND DOMESTIC ANIMALS. CRC Press, Boca Raton, , . ,ONG 0 , AND 2EID 7 - , 1982. A guide for the diagnosis of coccidiosis in chickens. ,OYD %VANS , 0 - 1991. 4RENDS IN 6ETERINARY 2ESEARCH AND $EVELOPMENT !NTICOCCIDIALS PJB Publications LTD. ,YNCH - * &RAME ' - %RICSSON * & )LLYES % & AND .OWAKOWSKI - ! Semduramicin in the chicken. Tissue depletion studies, 8ENOBIOTICS AND &OOD PRODUCING !NIMALS Vol. -ACPHERSON ) , 1978. Coccidiosis in broilers and . )N P.L. Long, K.N. Boorman and B.M. ), !VIAN #, -ANCUSO ' 3TAFFA - %RRANI ! "ERDONDINI 2 - AND &ABBRI 0 , 1990. Occupational dermatitis in animal feed mill workers. #ONTACT DERMATITIS 37-41. -ANNING * ' (ARGIS " - (INTON ! *R #ORRIER $ % $E,OACH * 2 AND ## 2 , 1994. Effect of selected antibiotics and anticoccidials on 3ALMONELLA ENTERITIDIS cecal colonization and organ invasion in Leghorn chicks. -C$OUGALD , 2 , 1991. )N B.W. Calnek (ed. ), $ISEASES OF 0OULTRY 9th ed., . pp. -C$OUGALD , 2 &, AND 3OLIS * , 1986. Drug-sensitivity of 99 isolates of coccidia from broiler farms. !VIAN $ISEASES 690-694. -EINGASSNER * ' 3CHMOOK & 0 #ZOK 2 AND ( - , 1978. anticoccidial activity of polyether antibiotics in chickens by tiamulin. 0OULTRY 3CIENCE 308-313. -ILLER $ * 3 / #ONNOR * * AND 2OBERTS . , , 1986. interactions in pigs. 6ETERINARY 2ECORD 73-75. -ILLER $ 3 * , 1990. 0IG 6ETERINARY *OURNAL 9-23. -UYLLE % 6ANDENHENDE # /YAERT 7 4HOONEN ( AND 6LAEMINCK, 1981. monensin sodium toxicity in horses. %QUINE 6ETERINARY *OURNAL 107-108. .AGARAJA 4 ' !VERY 4 " 'ALITZER 3 * AND (ARMON $ , , 1985. Effect of ionophore antibiotics on experimentally induced lactic acidosis in cattle. !MERICAN *OURNAL OF 6ETERINARY 2ESEARCH 2444-2452. .AGARAJA 4 ' AND 4AYLOR - " , 1987. Susceptibility and resistance of ruminal bacteria to antimicrobial feed additives. !PPLIED AND %NVIRONMENTAL -ICROBIOLOGY 1620- #ROWE 3 0 AND 7 . ( , 1982. Clinical signs and pathology of accidental monensin poisoning in sheep. #ANADIAN 6ETERINARY *OURNAL 323-326. .,., 1995. classification, 2nd edition. in association with in , . The veterinary importance of the toxic syndrome induced by ionophores. 6ETERINARY AND (4OXICOLOGY 66-70. /LSEN 0 2 AND (EBJORN - , 1982. Safety of metronidazole? /STROSKY 7EGMAN 0 ,!SSEF ) 3ANTIAGO 0 %LIZONDO ' AND -ONTERO 2 , Metronidazole HPRT mutation induction in sheep and the relationship with its elimination rate. -UTATION 2ESEARCH 253-259. 0EETERS * % $ERIJCKE * 6ERLINDEN - AND 7YFFELS 2 , 1994. to seven chemical and five ionophore anticoccidials in five Belgian integrated broiler operations. !VIAN $ISEASES 483-493. 0ERELMAN " 0IRAK - AND 3MITH " , 1993. Effects of the accidental feeding of lasalocid sodium to broiler breeder chickens. 6ETERINARY 2ECORD 271-273. 0ERL 3 3CHLOSBERG ! (OIDA ' $AVIDSON - 9AKOBSON " AND /RGAD 5 , 1991. Cardiac failure in beef cattle fed dried poultry . 6ETERINARY 2ECORD 35-36. 0INION * , "ILGILI 3 & %CKMAN - + AND (ESS * " , 1995. halofuginone and salinomycin, alone and in combination, on live performance and skin characteristics of broilers. 0OULTRY 3CIENCE 391-397. 0RESCOTT * & AND "AGGOT * $ EDS , 1993. !NTIMICROBIAL THERAPY IN VETERINARY MEDICINE 2nd ed. 1UARLES # , -ATHIS ' & -C$OUGALD , 2 AND #ONWAY $ 0 , 1992. semduramicin, salinomycin and monensin against %IMERIA SPP. in broiler chickens in floor pens. )N PROCEEDINGS OF 8)8 7ORLD S 0ULTRY #ONGRESSAmsterdam. 2ADA 6 2YCHLY ) AND 6ORISEK + , 1994. Susceptibility of chicken intestinal lactobacilli to coccidiostats. !CTA 6ETERINARIA "RNO 9-12. 2EITZ - 2UMPF - AND +NITZA 2 , 1991a. DNA single strand-breaks in lymphocytes after metronidazole therapy. !RZNEIMITTEL &ORSCHUNG 155-156. 2EITZ - 2UMPF - AND +NITZA 2 , 1991b. Metronidazole induces DNA strand-breaks in cultures of human lymphocytes and phytohemagglutinin-stimulated human lymphocytes. !RZNEIMITTEL &ORSCHUNG 65-69. 2UFF - $ , 1989. Interaction of avian coccidiosis with other diseases: a review. )N PROCEEDINGS OF #OCCIDIA AND INTESTINAL COCCIDIOMORPHS TH )NTERNATIONAL #OCCIDIOSIS #ONFERENCE 17-20 October, Tours. !IZENBERG ) AND "ARK ( , 1993. Paralytic syndrome attributed to lasalocid residues in a commercial ration fed to dogs. #LINICAL 2EPORTS 1273-1275. 3AINSBURY $ 7 " , 1991. Disinfection and coccidiosis control. -ARCH 20. AND -ITCHELL - ! The possible roles of Na+ and Ca2+ overload in the mechanism of monensin-induced myotoxicity in isolated avian ('ALLUS DOMESTICUS) skeletal muscle. *OURNAL OF 0HYSIOLOGY 41. 3CHELLING ' 4 , 1984. Monensin mode of action in the rumen. *OURNAL OF !NIMAL 3CIENCE 0ERL 3 0ANO ' $AVIDSON - /RGAD 5 +ALI 5 6AN (AM - (OIDA ' 9AKOBSON " !VIDAR 9 )SRAELI " ! % , 1992. Cardiomyopathy in cattle induced by residues of the coccidiostat maduramicin in poultry given as feedstuff. 6ETERINARY 2ESEARCH #OMMUNICATIONS 45-58. 3EMAN $ ( #ATHERMAN $ 2 -ATSUI 4 (AYEK - ' "ATSON $ " #ANTOR ! ( 4UCKER -UNTIFERING 2 " 7ESTENDORF - , AND -ITCHELL ' % , 1989. Metabolism of decoquinate in chickens and Japanese quail. 3HANE 3 - 'YUIMAH * % (ARRINGTON + 3 AND 3NIDER 4 ' , 1985. Etiology and pathogenesis of necrotic enteritis. 6ETERINARY 2ESEARCH #OMMUNICATIONS 269- 3HIER 7 4 AND $UBOURDIEU $ * , 1992. Sodium- and calcium-dependent steps in the mechanism of neonatal rat cardiac myocyte killing by ionophores: I. The sodium- carrying ionophore, monensin. 4OXICOLOGY AND !PPLIED 0HARMACOLOGY 38-46. AND #ALZONI ' , , 1992. Inhibition of pollen-tube growth and protein secretion by the monovalent ionophore monensin. 3TIPKOVITS , +OBULEJ 4 AND *UH¡SC 3 , 1987. )N testing of the anti-mycoplasma effect of some anticoccidial drugs. 6ETERINARY -ICROBIOLOGY 65-70. 3ZANCER * , 1989. [Toxicity of ionophore-polyether antibiotics. A literature review]. $ANSK 6ETERINAERTIDSSKRIFT 1308-1316. 4HAVEESRI * "OUCNEAU ' AND 6ERSTRAETE 7 , 1994. Effect of monensin on UASB- reactor performance. %NVIRONMENTAL 4ECHNOLOGY 491-496. 5MEMURA 4 .AKAMURA ( 'ORYO - AND )TAKURA # , 1984. monensin-tiamulin myopathy in broiler chicks. !VIAN 0ATHOLOGY 459-468. 7AKELIN $ , 1978. Genetic control of susceptibility and resistance to parasite infection. !DVANCES IN 0ARASITOLOGY 219-308. 7ALDENSTEDT , %LWINGER + ,UNDEN ! 4HEBO 0 AND 5GGLA ! Effects of Paracox© on performance of broilers raised with or without antibiotic in an Eimeria-free environment (report). 6AN &LEET * & !MSTUTZ ( % 7EIRICH 2EBAR ! ( AND &ERRANS 6 * , 1983. Acute monensin toxicosis in swine: effect of graded doses of monensin and protection of swine by pretreatment with selenium-vitamin E. !MERICAN *OURNAL OF 6ETERINARY 2ESEARCH 1460-1468. 7ANG # # , 1975. Studies of the mitochondria from %IMERIA TENELLA and inhibition of the electron transport by quinolone coccidiostats. "IOCHEMICA ET "IOPHYSICA !CTA 7ARMAN 0 2 4HOMAS 2 , #ORKE # 4 AND % 4 - , 1977. Recovery and reactions of amprolium from poultry manure added to soil. 3OIL "IOLOGY AND "IOCHEMISTRY 7ATANABE + 7ATANABE * +URAMITZU 3 AND -AUYAMA ( " , 1981. the activity of ionophores with other antibacterial agents against anaerobes. !NTIMICROBIAL !GENTS AND #HEMOTHERAPY 519-525. 7ATKINS + , 3HRYOCK 4 2 $EARTH 2 . AND 3AIF 9 - , 1997. )N antimicrobial susceptibility of #LOSTRIDIUM PERFRINGENS from commercial and broiler chicken origin. 6ETERINARY -ICROBIOLOGY 195-200. &!33 6%4 1997. 3WEDISH (Drug information service of pharmaceutical companies in ), . 7HEELER 3 * , 1996. Feline neuropathy associated with contaminated food (letter). 6ETERINARY 2ECORD 323. 7IENERNUSZ # * AND 4EETER 2 ' , 1995. Nicarbazin effects on broiler thermobalance during high ambient temperature stress. 0OULTRY 3CIENCE 577-580. 7ILSON * 3 , 1980. Toxic myopathy in a dog associated with the presence of monensin in dry food. #ANADIAN 6ETERINARY *OURNAL 30-31. 8Assessment of the usage of antimicrobial feed additives As mentioned earlier, the authorisation of feed additives is regulated under Council Directive 70/524/EEC. In article 3a of the latest amendment (Concil Directive 96/51/EC) important conditions that must be fulfilled are listed. An assessment of the use of antimicrobial feed additives must consequently include an appraisal of its fulfilment of this article. Such an assessment has been made pre-approval of the products concerned and the conditions have, according to available evidence at that time, been deemed to be met. However, as society and animal production change over time and new scientific and technical knowledge is available, it is natural that the result of re-assessment can be different. $IRECTIVE %%# AS AMENDED IN %# !RTICLE A A WHEN USED IN ANIMAL NUTRITION IT HAS ONE OF THE EFFECTS REFERRED TO IN !RTICLE A B TAKING INTO ACCOUNT THE CONDITIONS OF USE IT DOES NOT ADVERSELY AFFECT HUMAN OR ANIMAL HEALTH OR THE ENVIRONMENT BY ALTERING THE CHARACTERISTICS OF LIVESTOCK PRODUCTS C ITS PRESENCE CAN BE MONITORED AS AN ADDITIVE PER IN FEEDINGSTUFFS OR WHERE APPROPRIATE IN FEED MATERIALS D EXCLUDED THIS CONDITION DOES NOT APPLY TO ADDITIVES BELONGING TO THE GROUP OF COCCIDIOSTATS AND OTHER MEDICINAL SUBSTANCES E FOR SERIOUS REASONS CONCERNING HUMAN OR ANIMAL HEALTH ITS USE MUST NOT BE RESTRICTED TO OR VETERINARY PURPOSES )N ARTICLE OF THIS DIRECTIVE FAVOURABLE EFFECTS OF ADDITIVES ARE SPECIFIED In the following, topics with relevance for the phrases underlined will be discussed. That methods appropriate for the control of the presence of the substances in feedingstuffs are available has been taken for granted. Absence of adverse effects has been interpreted as safety. As there is no such thing as a zero risk, safety is understood as a risk below the acceptable level. The administration of and coccidiostats is typically over a long period and large groups of animals are involved. The assessment of possible risks concerning and coccidiostats must therefore be made with utmost care. Issues of safety are usually dealt with by the tools provided in risk analysis. The question of whether the use of substances should be restricted to or veterinary purposes is linked to the issue of safety, but is rather to be considered as a form of risk management. The question of prophylactic or therapeutic effects of is related to regulatory issues, not to safety. , an assessment of the use of antimicrobial feed additives, based on the background provided in chapters 3-7 and annexes A to G is presented. The substances included are, of course, very different. Notwithstanding, to facilitate the discussion on important general issues, a horizontal approach has been chosen. 8.2Some comments on risk analysis Risk analysis is the science which addresses risk assessments and decisions regarding risks. These processes are part of everyday life, but in complex situations where demands for consistency, flexibility and transparency are constantly increasing, a formal approach to risk analysis and decision-making is warranted. Health risk analysis relies heavily on epidemiology and statistics as well as other sciences, but is not identical to these disciplines. Risk analysis involves predictions or projections into the future based on the historical past and careful analysis of recent events. Predictive science is never perfect, and when a prediction is not upheld, the data on which the judgement was based must be re-examined, and the model reviewed. A careful evaluation of the prediction, and adjustments in the model, may help in producing more precise predictions in the future. Nomenclature in risk analysis is in a state of confusion, partly because it is a new and rapidly developing field, and partly because it involves many scientific disciplines which may use the same words in different ways. There is not yet unanimity with regard to the general field of risk analysis, but attempts have been made to define some terms that are commonly used in risk studies (AhlET AL, 1993). According to these definitions RISK ANALYSIS is the process which includes risk assessment, risk management and risk communication. 2ISK ASSESSMENT is the process of identifying a hazard and evaluating the risk of a specific hazard, in absolute or relative terms, including estimates of uncertainty. 2ISK MANAGEMENT is the pragmatic decision-making process concerned with selecting and implementing procedures to mitigate the risk and RISK COMMUNICATION is an open, two-way exchange of information and opinions about risk, leading to better understanding and better risk management decisions. (AZARDS are events or elements which represent potential harm, i.e. what might go wrong and how this might happen. 2ISK consists of two components; the likelihood and magnitude (of the consequences) of occurrence of an adverse event (i.e. a measure of the probability of harm), and the impact (biological, economical end environmental) of the adverse effects. 3AFETY is the degree to which risks are judged acceptable and is, thus, a subjective measure of the acceptability of risk. There are several specific models of the various steps included in risk analysis. Most risk assessment models begin with hazard identification, i.e. identifying the risk agents and the conditions under which they potentially produce adverse consequences. This is followed by describing and quantifying the potential of a risk source to release the risk agents (e.g. dose- response relationships), the exposure of human and animal populations to risk agents, and the economic and health consequences associated with the exposure to the risk agents. Finally an estimation of the risk, integrating the previous steps, is made, providing a quantitative measure of the likelihood, timing, nature and magnitude of adverse consequences. It has been proposed that risk assessment and risk management should be separated as far as possible, to reduce conflict of interest between the two processes (FAO/WHO, 1997). Interactions between risk assessors and risk managers are essential for practical application and evaluation procedures, but it should be recognised that risk assessment and risk management are separate entities in risk analysis, and must be so in order to avoid confusing the issues. Another important thing to take into account in risk management is the uncertainty in the risk assessment output. The apparent precision of a point estimate gives the misleading impression that the value presented is the one and only answer, although it has been derived from evaluating many possible outcomes and represents only an estimate of one potential outcome among many (MillerET AL, 1993). In view of this, it is of importance that the risk assessment is transparent. The risk estimate should, whenever possible, include a numerical expression of uncertainty. A highly uncertain risk estimate may require a more cautious risk management decision. Risk analytic procedures are not fully objective and quantitative, both because they often have to be based on uncertain assumptions, and because elements of social and moral choice almost always intervene. The assessment of risk is a process that occurs in time and is subject to change simply because of historic and statistical processes (Albanese, 1992). For example, the entire statistical distribution concerning adverse health outcomes can change following a change in detection technologic procedures or, simply, through the accumulation of data and theory. Unless all risk has been linked to a measurable cause with high accuracy, its assessment will have to change with time. The further into the future risks and benefits are projected, the less certain are the predictions. However, long term views are often necessary. In short, risk assessment tries to answer the following questions: 7HAT CAN GO WRONG (THIS TO HAPPEN 7HAT THINGS WENT WRONG If available information is reliable and sufficient enough to at least suggest the answers to these questions, one can go on to the processes of risk management and risk communication. The discussion on financial benefits from belongs in the process of risk management, when trying to determine the reasonable cost for eliminating or diminishing the risk presented in the risk assessment. Risk communication applied to this issue would include communicating the risks to the public so as not to jeopardise consumer confidence in animal products. 8.3Safety for animals and humans The possible adverse effects (hazards) associated with usage of for animals and/or humans can be divided into those related to the antibacterial effects of the substances (microbiological aspects) and those related to the chemical nature of the substance (toxicological aspects). In table 8.I, possible hazards, outcomes and the groups affected by the outcomes have been listed. These possible hazards are reflected in the information required for approval according to the guidelines provided (Commission Directive 94/40/EC). Microbiological risks, specifically those related to bacterial resistance, are more difficult to assess at pre-approval level. Development of resistance in bacterial populations requires two factors to be present; the antibacterial substance and a corresponding resistance determinant. If resistance determinants are not present in the microflora of experimental groups used, most likely no development of resistance will be observed. In such a situation, the experiments do not necessarily provide a basis for accurate projections into the future. Once resistance determinants have gained entry into the microbiota of the animal species in question, the outcome might be different. Unfortunately, the application of post-approval risk assessment to the issue of the microbiological aspects of is frustrated partly by the lack of valid data, partly by the complex interactions of the factors involved. Pre-approval risk assessment of hazards related to chemical aspects of the substances is well established. It is based on results from a variety of toxicological studies in cell cultures, laboratory animals and target species. For residues, the of an acceptable daily intake reflects the acceptable risk level and if risk mitigation is needed, withdrawal times is the management mostly used. Possible hazards of the usage of and their outcomes for animals or humans 4ABELL ) 4¤NKBARA FAROR MED BRUK AV !&4 OCH DESSAS KONSEKVENSER F¶R DJUR ELLER M¤NNISKOR (no)1 toxic reactions, allergic 1 Parenthesis denotes that there may be special circumstances where this hazard is applicable In the following, the elements of a risk assessment based on available data on with special emphasis on microbiological aspects are outlined. The existing background information has been covered in chapters 4-7 and in annexes A-F. Exposure of bacteria to substances selects for resistance to these substances, and sometimes also for resistance against other antimicrobial substances (see Chapter 4). The proportion of the microbiota resistant to the substance will increase. Bacterial resistance is not in itself a problem but associated loss of therapeutic efficiency of the antibacterial substance or group of substances is. , the impact will be dependent on whether the use of a specific additive contributes to resistance in potential pathogens to antibacterials used in therapy of infections caused by these bacteria. If this is the case in target animals, the consequences are direct. Transmission of resistance genes between microbes of the target animal and those of other animals or humans can and does occur. The probability of such transfer and the impact of subsequent indirect effects needs to be evaluated. E N V IR O N M E N T : u ten s ils F O O D p ack in g H U M A N S E N V IR O N M E N T : u ten s ils m anure effluen ts W IL D L IF E W A T E R P L A N T S in cl. C R O P S Some routes by which resistance genes can spread among animal and human microbiota &IGUR ) .¥GRA V¤GAR VIA VILKA RESISTENSGENER KAN SPRIDAS BLAND DJUR OCH M¤NNISKOMIKROBER