sou · GLB3132d2 · 1998-01-01 00:00:00 — No traces of monensin were found in soil 33 days after the deposition and the monensin concentrations declined in manure piles during natural weather conditions (Donoho, 1984). However, in manure piles under relatively anaerobic conditions monensin levels declined slowly (Donoho, 1984). It is, however, reasonable to presume that the microbiological activity in the soil may be altered initially, which may influence the release of nutrients. As ionophores are against anaerobic bacteria, interference with anaerobic microbial processes, such as in biogas production or wastewater treatment might be expected. A reduction in the biogas conversion efficiency of UASB-(Upflow Anaerobic Sludge Blanket) reactors by when monensin was added has been reported (Thaveesri ET AL , 1994). Additionally, the acclimatisation period was twice as long and total volatile acid concentrations were twice as high compared to the control. Direct effects on plants, fruits and vegetables are generally not expected, but an inhibitory effect of monensin on apple pollen has been reported (Speranza and Calzoni, 1992; Ciampolini ET AL , 1993). No published information about persistence or effects of ionophores in aquatic environment have been found. 7.4.2Environmental aspects on other coccidiostats It has been shown that some non-ionophore coccidiostats, e.g. decoquinate and amprolium, are excreted in form in poultry manure (Warman ET AL , 1977; Hobson-Frohock and , 1983). During simulated field conditions it was found that amprolium was adsorbed in the upper layers of the soil and amprolium could be recovered from the soil up to 80 days post deposition (Warman ET AL , 1977). No effect on soil respiration or soil microflora was shown. Halofuginone is known to be acutely toxic to fish at low doses (acute toxicity to carp at 0.7 ppm) (, 1995). The possible impact of this on the aquatic environment is not known. Available data indicate that ionophores are degradable under aerobic conditions. Ionophores may interfere with anaerobic systems such as biogas production Some non-ionophoric coccidiostats may persist longer in the environment. During the last fifteen to twenty years concern has been expressed regarding the future long-term for chemical control of coccidiosis. The rapid and continuous development of coccidial drug resistance and the slow and expensive development of new anticoccidial drugs will probably limit the usefulness of chemical control in the future. Awareness of potential hazards for feed mill workers, farmers, target and non target animals and the environment will probably also increase the interest in alternative means of control. Finally, consumers have become increasingly concerned about feed additives, food safety, food quality and welfare problems in meat producing animals and egg laying hens. On the other hand, new housing systems, such as the of layers in deep production systems, are being introduced, and larger economical demands increase the need for efficient and safe coccidiosis control. Several possibilities for non-chemical coccidiosis control are being investigated. These include improved hygienic conditions, genetic selection of more resistant animals and further development of immunological control. One of the motives for birds on wire floor is to separate the birds from their faeces and thereby avoiding contact with oocysts. It is, however, very difficult to eradicate avian coccidia by means of strict hygienic measures during commercial farming conditions with birds maintained on the floor. Once the coccidia have been introduced into the poultry house the residual oocyst contamination spreads to the following flock of birds (Loyd- , 1991). Good hygiene and dry reduce the number of oocysts, but do not eliminate the risk of rapid spread of the parasites. Recently, a new oocidal disinfectant has become commercially available (, 1991). 7.5.2Genetic resistance to coccidiosis Infection with coccidia in chickens induces immunity to the parasite as demonstrated by a reduction of parasite replication in the birds (Horton- and Long, 1963). The immune response depends on several factors linked to the parasites as well as to the host. Two important host factors are the age and breed of the birds. It has been known for some time that the breed of chickens influence immunity to infection by coccidia (Wakelin, 1978; Lillehoj, 1986; Lillehoj, 1988). Differences are seen both in humoral and cell mediated immunity. Studies in inbred chickens have confirmed that this is a genetically heritable trait linked to the MHC genes and modulated by other genes (, 1985; and , 1986; Lillehoj ET AL , 1989). Although it has been shown in experimental systems that genetically determined resistance to chicken coccidiosis represents a possible alternative to chemical prevention, this finding still awaits commercial application. Commercial broiler and layer hybrids are primarily selected and bred for high productivity by a limited number of multi-national breeding companies. The efficacy and low cost of the anticoccidials, and the priority of production qualities in the breeding programmes of commercial hybrids have impeded the progress of development of genetic immunity to diseases in the birds. During recent years live vaccines against coccidiosis in chickens have become commercially available. Vaccines based on infectious and pathogenic oocysts given at carefully controlled doses followed by post- exposure chemical prevention with coccidiostats are used in breeders in some countries. The need for continuous chemical prevention is thereby avoided. This kind of vaccination programme is not used in broiler chickens. Live, attenuated vaccines based on oocysts of so-called precocious strains of the chicken coccidial species are sometimes used in litter-based production systems, e.g. in breeders and some layer chickens. These vaccines provide adequate immunity to coccidiosis. Such an attenuated vaccine has been used with good results in breeders in . The major drawback of live vaccines is their relatively high cost which limits their use in broiler chickens and replacement layers. In broilers, however, the results of vaccination trials with precocious strains in a coccidia-free environment have shown that vaccinated chickens reared without coccidiostats and antibacterial feed additives show significantly lower live weight at 13, 28 and 36 days of age compared to animals receiving narasin (/kg feed) or virginiamycin (/kg feed). Both vaccinated birds and unvaccinated controls showed higher numbers of # PERFRINGENS than birds given either narasin or virginiamycin (Waldenstedt ET AL , 1997). Suppression of subclinical necrotic enteritis (NE) by narasin and virginiamycin is the most likely explanation for the differences in performance. This indicates that unless subclinical NE can also be properly controlled, vaccination against coccidiosis may not be economically feasible in broiler chickens. Further research in the field of non-chemotherapeutic prevention of coccidiosis and NE will be needed if broilers are to be raised without coccidiostats. No non-live vaccines are commercially available at the moment. Subunit vaccines based on immunogenic polypeptides possibly carried by live vectors may be a possibility in the future. Long term for chemical control of coccidiosis are uncertain. Improved hygiene will reduce coccidiosis. research efforts are needed on the development of suitable vaccines and other preventive methods for the control of coccidiosis and necrotic enteritis. 7.6Summary comments on coccidiostats Coccidiostats are used specifically for the control of coccidiosis, but may also suppress subclinical necrotic enteritis. At the moment it does not appear feasible to rear broilers without coccidiostats. Breaches in good manufacturing procedures may result in toxic effects of coccidiostats in both target and non-target species. In order to achieve an effective coccidiosis control and proper prevention of NE, anticoccidials must be used carefully and their effectiveness should be monitored continuously. While alternative measures for the control of coccidiosis and NE are developed, coccidiostats should be available on veterinary prescription and used under veterinary supervision. In spite of the wide use of anticoccidial substances, is known about resistance mechanisms. Further research into this area is needed in order to effectively combat the increasing problem of resistance. 7.7Addendum: dimetridazole, ipronidazole and ronidazole Dimetridazole, ipronidazole and ronidazole all belong to the 5-nitroimidazole group, which also includes metronidazole. These substances are against obligate anaerobic and microaerophilic bacteria, amoebas and flagellated protozoa (Breccia, 1980). In animals, the 5-nitroimidazoles are used for treatment of infections with anaerobic bacteria and protozoa (Prescott and Baggot, 1993). Metronidazole was introduced for the treatment of anaerobic bacteria and 4RICHOMONAS VAGINALIS in human medicine. It is mainly used against anaerobic infections in humans (Prescott and Baggot, 1993). In some countries, metronidazole is also used in food-producing animals. The main veterinary use for 5-nitroimidazoles is for the treatment of histomoniasis, a disease for which few alternative drugs are available. 7.7.2Histomoniasis - the parasite and the disease Blackhead, also known as histomoniasis, is a disease of gallinaceous birds which is caused by unicellular protozoa called (ISTOMONAS MELEAGRIDIS (McDougald, 1991). The organism may infect various bird species, e.g. , peafowl, pheasant, quail, grouse, fowl and chickens. The is, however, the most susceptible species. The birds develop inflammations of the caeca and liver, and mortality rates may be high. The parasite is often carried by clinically healthy birds such as chickens, by earthworms, various arthropods and by the caecal nematode (ETERAKIS GALLINARUM (McDougald, 1991). The control of histomoniasis is based on appropriate management. should not be reared on ground where chickens have been farmed. Several years must elapse before can be kept on land where chickens have been reared. Confinement rearing of reduces the incidence of the disease. Histomonads are extremely delicate organisms and they do not survive outside their host, earthworms or heterakid eggs for more than a few minutes (McDougald, 1991). Preventive chemotherapy is practised in many countries in growing but not in chickens, except on problem farms. Chemoprophylactic medication in the feed with arsenicals, nitrofuran or 5-nitroimidazoles is often used. Efficient therapeutic and preventive alternative drugs are at present lacking. Histomoniasis has not been a problem in Swedish commercial farming during the last decade. The disease is sometimes diagnosed in small flocks reared outside, and occasionally in other bird species such as peafowl and pheasant. Chemoprevention is not applied in . 7.7.3Toxicological aspects on 5-nitroimidazoles Nitroimidazoles are well absorbed after oral administration to monogastric animals (Prescott and Baggot, 1993). Dimetridazole is rapidly absorbed from the gastrointestinal tract in the target species. In approximately is eliminated within three days and in swine approximately of the dose is eliminated within seven days (FAO/WHO, 1989). The metabolism of dimetronidazole leads to reduction of the 5-nitro group, fragmentation of the imidazole ring, and formation of covalently bound residues (FAO/WHO, 1989). At the 34th JECFA meeting (FAO/WHO, 1990) it was found that the use of dimetridazole at permitted concentrations to poultry and swine gives rise to residues that deplete below detectable levels at 2-3 days postdosing. However, due to the possibility of bound residues, it was stated that the total residue in tissues of poultry and swine had not been characterised. After oral administration of radiolabelled ipronidazole to rats, approximately of the total radioactivity was excreted in urine, bile and faeces (FAO/WHO, 1989). Two hydroxylated metabolites still containing the 5-nitro group have been identified in the faeces of and rats after oral administration of ipronidazole (FAO/WHO, 1989). The total residues have not been characterised (FAO/WHO, 1989). Ronidazole is absorbed from the gastrointestinal tract in both laboratory and target animals (FAO/WHO, 1990). In studies using radiolabelled ronidazole, the radioactivity was found to be widely distributed in tissues and eliminated via the urine, faeces and expired air of the animals (FAO/WHO, 1989). The exact nature of ronidazole metabolites has not been determined, but there appears to be a certain amount of bound residue (FAO/WHO, 1990). The antibacterial and antiprotozoal properties of 5-nitroimidazoles involves the reduction of the 5-nitro group which results in short-lived hydroxylamine derivatives that bind covalently to proteins and DNA, as a result of which DNA strands may also break (, 1977). Following therapeutic treatment with metronidazole, single strand-breaks have been demonstrated in the DNA of peripheral human lymphocytes (, 1991a). For dimetridazole, short-term toxicity in the form of clinical effects on the nervous system and testicular atrophy has been demonstrated in rats fed high doses of the substance (FAO/WHO, 1989). Maternal toxicity has been demonstrated in rabbits fed high doses of dimetridazole (FAO/WHO, 1989). Dimetridazole and its urinary metabolites gave positive results in mutagenicity tests on strains of 3ALMONELLA Typhimurium with nitroreductase activity, but negative results in a variety of other mutagenicity tests (FAO/WHO, 1989). In a study evaluating the mutagenic and genotoxic potential of 48 nitroimidazoles and related imidazole derivatives, dimetridazole was found to have both mutagenic and genotoxic potential (De , 1992). In this study it was also found that the presence of a nitro substituent at the 5-position is essential for the genotoxic activity of the imidazole derivatives. Increased incidence of benign mammary tumours in rats fed dimetridazole, as compared to nonmedicated control rats, has been reported, as well as a dose-dependent increase in the incidence of benign mammary tumours (FAO/WHO, 1989). In the absence of results from carcinogenicity studies in a second animal species, JECFA could not establish an (Acceptable ) in 1989 (FAO/WHO, 1989) The 34th JECFA meeting also stated that ipronidazole showed mutagenic properties in bacterial test systems, but because of inadequate study design of studies in mammalian test systems the genotoxic potential could not be properly evaluated (FAO/WHO, 1989). Studies on chronic toxicity and carcinogenicity indicate an effect of ipronidazole on mammary tumour formation in female rats given high doses of the substance, and a decrease in body weight along with other signs of toxicity in rats and dogs fed high doses (FAO/WHO, 1989). In 1989, JECFA could not establish an , because the rat carcinogenicity study was inadequate for determining a no-effect level for ipronidazole. Ronidazole has been found to have mutagenic potential in various bacterial assays (Hite ET AL , 1976; FAO/WHO, 1989). The results of several IN VIVO tests were variable, with both positive and negative results (Hite ET AL , 1976; FAO/WHO, 1989). However, a range of metabolites gave negative results in the Ames test (FAO/WHO, 1989). Ronidazole has been found to increase the incidence of benign mammary tumours in rats and lung adenomas and carcinomas in mice (FAO/WHO, 1989). A temporary was established at the 34th JECFA meeting (FAO/WHO, 1989), but this was not extended at the 42nd JECFA meeting, since requested additional data were not made available (FAO/WHO, 1995). Metronidazole has been shown to cause DNA strand breaks in human lymphocytes in both IN studies (, 1991b; AL , 1991a; Elizondo ET AL , 1996). Similar genotoxic effects have been demonstrated in lymphocytes from metronidazole-treated sheep (Ostrosky- Wegman ET AL , 1994). The study in sheep also showed that increased susceptibility to the genotoxicity of metronidazole may be associated with individual variations in pharmacokinetics. In earlier publications it has sometimes been stated that there was no evidence of any genotoxic effects of metronidazole in mammalian cells (and Hebjorn, 1982), but this has now been disproven in the more recent studies. This may be explained by the fact that most tests for mutagenicity demonstrate lesions due to a defective DNA repair, while DNA single strand-breaks partly demonstrate DNA damage before DNA repair (, 1991a). Therefore, detection of DNA single strand-breaks can be a more sensitive indicator. Such studies on the other 5-nitroimidazoles have not been found, but there is no evidence that they would be any different in this aspect, as they all share the reactive 5- nitro group. 7.7.4Summary comments on nitroimidazoles The strong indications of genotoxic and carcinogenic potential of 5- nitroimidazoles, combined with the lack of appropriate studies needed to fully evaluate the risk, have been regarded as enough motive for a ban on their therapeutic use in animals within the EU. Withdrawal times are supposed to ensure that no residues will be present in meat. However, when the risk cannot be fully evaluated, neither nor Maximum Residue Limits (MRL) can be established. Consequently it is not been possible to determine withdrawal times necessary to mitigate the risk for the 5-nitroimidazoles. When 5-nitroimidazoles are used as feed additives, the potential hazards to human health are not restricted to the consumers. Farmers and feedmill workers will be exposed on a regular basis to these substances. Considering the strong indications of genotoxicity and carcinogenicity of the 5- nitroimidazoles, this must be regarded as totally unacceptable. !NGEL 3 7EINBERG : ' 0OLISHUK / 0LAVNIK ) AND "ARTOV ) , 1985. between a dietary coccidiostat and skin tears in female broiler chickens. 0OULTRY 3CIENCE 294-296. !TEF - 2AMADAN ! ( AND !BO %L 3OOUD + , 1993. disposition, systemic bioavailability and tissue distribution of salinomycin in chickens. 2ESERACH IN 6ETERINARY 3CIENCE 179-183. !TEF - 3HALABY ! ! AND !BO .ORAGE - ! Fetotoxicity of some anticoccidial drugs in chickens. "ABA % 9AUDA 4 &UKATA 4 AND !RAKAWA ! Effect of %IMERIA TENELLA infection on the caecal population of lincomycin-resistans #LOSTRIDIUM PERFRINGENS introduced into chickens. 2ESEARCH IN 6ETERINARY 3CIENCE 219-221. "AIRD ' * #ALDOW ' , 0EEK ) 3 'RANT ! Monensin toxicity in a flock of ostriches. 6ETERINARY 2ECORD 624-626. "ECK " % AND (ARRIES 7 . , 1979. The diagnosis of monensin toxicosis: A report on outbreaks in horses, cattle and chickens. )N PROCEEDINGS OF !NNUAL MEETING OF !SSOCIATION OF 6ETERINARY ,ABORATORY $IAGNOSIS , . "+ 0 ,UKERS ( AND %RHORN ) , 1988. Anticoccidia Vertraeglichkeit des Wassergefluegels. $EUTSCHE 'EFLUEGELWIRTSCHAFT UND 3CHWEINEPRODUKTION 511- "9 %NDO + 3HIRAGAMI . AND -ITSOUKA 4 , 1988. anaerobic bacteria from pigs and chicken to five polyether antibiotics for growth promotion. *APANESE *OURNAL OF 6ETERINARY 3CIENCE 783-790. "RAUNIUS 7 7 , 1989. [Poisoning of poultry by ionophore anticoccidials]. 4IJDSCHRIFT VOOR $IERGENEESKUNDE 933-938. Chemical properties and reaction mechanisms of nitroimidazoles. )N PROCEEDINGS OF .ITROIMIDAZOLES #HEMISTRY 0HARMACOLOGY AND #LINICAL !PPLICATION Plenum Press, . #ATHERMAN $ 2 3ZABO * "ATSON $ " #ANTOR ! ( 4UCKER AND -ITCHELL ' % , 1991. Metabolism of narasin in chickens and Japanese quail. #HALMERS ' ! Monensin toxicity in dogs. #ANADIAN 6ETERINARY *OURNAL 459. #HAPMAN ( $ , 1993. Resistance to anticoccidial drugs in fowl. + ', ,UNT $ + "AKER * & AND +NUTSON , 1988. and ruminal fluid characteristics of beef cows grazing oat pastures and supplemented with or without lasalocid. *OURNAL OF !NIMAL 3CIENCE 1746-1754. #HRISTENSEN + $ :IMMERMANN . ' 7YATT # , AND 'OODMAN 4 . , 1994. Dietary and environmental factors affecting skin strength in broiler chickens. 0OULTRY 3CIENCE 224-235. #IAMPOLINI & ,I 9 1 #RESTI - #ALZONI ' , AND 3PERANZA ! Disorganization of dictyosomes by monensin treatment of IN germinated pollen of -ALUS DOMESTICA Borkh. !CTA "OTANICA .EERLANDICA 349-355. #LARE 2 ! 3TROUT 2 ' 4AYLOR 2 , #OLLIND 7 - AND "RILES , 1985. histocompatibility (B) complex effects on acquired immunity to caecal coccidiosis. )MMUNOGENETICS 593-599. 7 2EAVIS $ 5 AND 0ANCIERA 2 * , 1983. Light and electron microscopic changes in cardiac and skeletal muscle of sheep with experimental monensin toxicosis. 6ETERINARY 0ATHOLOGY 590-602. $AVIS # , 1983. Narasin toxicity in . 6ETERINARY 2ECORD 627. $AVISON + , , 1984. Monensin absorption and metabolism in calves and chickens. *OURNAL OF !GRICULTURAL AND &OOD #HEMISTRY 1273-1277. $E -EO - 6ANELLE 0 "ERNADINI % ,AGET - -ALDONADO * *ENTZER / #ROZET - 0 AND $UMENIL ' , 1992. Evaluation of the mutagenic and genotoxic activities of 48 nitroimidazoles and related imidazole derivatives by the Ames test and the SOS chromotest. %NVIRONMENTAL AND -OLECULAR -UTAGENESIS 167-181. , , 1984. Biochemical studies on the fate of monensin in animals and the environment. *OURNAL OF !NIMAL 3CIENCE 1528-1539. $OWLING , , 1992. Ionophore toxicity in chickens: a review of pathology and diagnosis. !VIAN 0ATHOLOGY 355-368. AND 6AN !SSCHE 0 & , 1983. from farm animals to 21 antimicrobial agents including some used for growth promotion. *OURNAL OF !NTIMICROBIAL #HEMOTHERAPY 347-356. $YKSTRA $ $ , 1978. Relationship of anaerobic bacteria to coccidiosis in the chicken. $ISSERTATION !BSTRACTS )NTERNATIONAL " 7. %DWARDS $ ) , 1977. The action of metronidazole in DNA. *OURNAL OF !NTIMICROBIAL #HEMOTHERAPY 43-48. %KSTR¶M , ' 3LANINA 0 AND $AHLSTR¶M +ING , , 1984. Tissue residues of clopidol (3,4-dichloro-2,6-dimethyl-4-pyridinol) in chickens in relation to withdrawal times. &OOD !DDITIVES AND #ONTAMINANTS 17-22. %LIZONDO ' 'ONSEBATT - % 3ALAZAR ! - ,) 3ANTIAGO 0 (ERRERA * (ONG % AND /STROSKY 7EGMAN 0 , 1996. Genotoxic effects of metronidazole. -UTATION 2ESEARCH 75-80. %LWINGER + %NGSTR¶M " "ERNDTSON % &OSSUM / AND 7ALDENSTEDT , , 1996. Effect of growth promoters and coccidiostats on performance and growth of #LOSTRIDIUM PERFRINGENS in the caeca of broilers. )N PROCEEDINGS OF 88 7ORLD S 0OULTRY #ONGRESS 2-5 September, . %LWINGER + %NGSTR¶M " &OSSUM / (3 AND 4EGL¶F " , 1994. coccidiostats on necrotic enteritis and performance in broiler chickens. 3WEDISH *OURNAL OF !GRIULTURAL 2ESEARCH 39-44. %LWINGER + 3CHNEITZ # "ERNDTSON % &OSSUM / 4EGL¶F " AND %NGSR¶M " , Factors affecting the incidence of necrotic enteritis, caecal carriage of #LOSTRIDIUM PERFRINGENS and bird performance in broiler chickens. !CTA 6ETERINARIA 3CANDINAVICA 361-370. &AHIM - AND 0RESSMAN " # , 1981. Cardiovascular effect and pharmacokinetics of the carboxylic ionophore monensin in dogs and rabbits. ,IFE 3CIENCES 1959-1966. &!/ 7(/, 1989. 34th report of the Joint FAO/. 4ECHNICAL REPORT SERIES .O 20-32. &!/ 7(/, 1990. Monographs prepared by the 34th meeting of the Joint FAO/WHO Residues of some veterinary drugs in animals and foods. &!/ &OOD AND NUTRITION PAPER 41/2 pp. &!/ 7(/, 1995. Forty-second report of the joint FAO/on Evaluation of certain veterinary drug residues in food. 7(/ 4ECHNICAL 2EPORT 3ERIES .O pp. &OWLER . ' !NTICOCCIDIAL COMPENDIUM Health. &RIGG - "* AND 7EBER ' , 1983. Compatibility studies of ionophore anticoccidials with various antibiotics and chemotherapeutics in broiler chicks. !RCHIV FUR 'EFLUGELKUNDE 213-220. 'ALITZER 3 * +RUCKENBERG 3 - AND +IDD * 2 , 1986. Pathologic changes associated with experimental lasalocid and monensin toxicosis in cattle. !MERICAN *OURNAL OF 6ETERINARY 2ESEARCH 2624-2626. 'ALITZER 3 * AND 7 / & , 1984. A literature review on the toxicity of lasalocid, a polyether antibiotic. 6ETERINARY AND (4OXICOLOGY 322-326. 'LOVER ' * AND 7OBESER ' , 1983.