Roxarsone (3-nitro-4-hydroxyphenylarsonic acid) poisoning in pigs

Roxarsone (3-nitro-4-hydroxyphenylarsonic acid) poisoning in pigs Barry R. Blakley, Edward G. Clark, Rob Fairley Abstract Young pigs, six to ten weeks of age, from two unrelated swine operations were fed a grower ration obtained from a common commercial supplier. Following ingestion of the feed for approximately two weeks, pigs in both groups developed neurological disturbances characterized by blindness, ataxia, incoordination, muscle tremors, posterior paralysis, and quadriplegia. Vocalization described as "screaming" was also observed in several animals. Necropsy findings and tissue arsenic concentrations were consistent with a diagnosis of phenylarsonic acid poisoning. The liver and kidney contained an average arsenic content of 2.9 and 1.8 mg/kg (wet weight), respectively. The feed contained 38 mg of arsenic/kg corresponding to 133 mg roxarsone (3-nitro-4-hydroxyphenylarsonic acid)/kg. This level of roxarsone is approximately three to five times higher than the levels recommended for swine rations. The feed company had placed roxarsone in the ration at levels recommended for the less toxic arsanilic acid. It was assumed that the two organic arsenicals could be added to the rations interchangeably at the same level of formulation. The present investigation indicated that roxarsone is more toxic than arsanilic acid and the margin of safety in swine rations is low. mande dans les dietes de porcs. Le fournisseur de la diete avait ajoute le roxarsone a des taux recommandes pour l'acide arsenilique qui est beaucoup moins toxique. Cette decision fut prise sur la croyance que les deux composes organiques d'arsenic pouvaient etre interchanges dans la diete a des taux identiques. L'enquete indique que le roxarsone est plus toxique que l'acide arsenilique et que la marge de securite dans les diites de porcs est faible. Resume including incoordination, ataxia, paralysis, blindness, and muscle tremors (1-4). Since the toxicosis is usually associated with excessive levels of the arsenical in the feed, high morbidity is generally observed (1, 3). The onset of the clinical syndrome is frequently induced by exercise or mild stress (3,5-7). We describe herein roxarsone (3-nitro-4-hydroxyphenylarsonic acid) poisoning in two groups of pigs consuming feed purchased from a common commercial supplier. Empoisonnement par le roxarsone (acide 3-nitro-4-hydroxyph6nylarsonique) chez le porc De jeunes porcs ages de six a dix semaines, provenant de deux elevages distincts, furent alimentes avec une ration de croissance obtenue d'un fournisseur commercial commun. A la suite de l'ingestion de la diete pour une periode de deux semaines, les deux groupes de porcs ont developpe des desordres neurologiques caracterise's par de la cecite, de l'ataxie, de l'incoordination, des tremblements musculaires, de la paralysie posterieure et de la quadriplegie. Une vocalisation qui se caracterisait par des cris fut aussi observee chez plusieurs animaux. Les observationss a la necropsie ainsi que les concentrations tissulaires d'arsenic furent compatibles avec un empoisonnement par de l'acide phenylarsonique. Le foie et les reins avaient un contenu d'arsenic de 2,9 et 1,8 mg/kg (poids humide) respectivement. La diete contenait 38 mg d'arsenic/kg correspondant a 133 mg de roxarsone (acide 3-nitro4hydroxyphenylarsonique)/kg. Le taux de roxarsone correspond a environ trois a cinq fois le taux recomCan Vet J 1990; 31: 385-387 Department of Veterinary Physiological Sciences (Blakley); Department of Veterinary Pathology (Clark, Fairley), Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N OWO. Can Vet J Volume 31, May 1990 Introduction S everal organic arsenicals, which are derivatives of phenylarsonic acid, have been used as feed additives in the swine industry to control enteric diseases such as swine dysentry or to improve productivity. The most widely used derivatives are arsanilic acid (4-amino-phenylarsonic acid) and roxarsone (3-nitro-4hydroxyphenylarsonic acid) (1). They are fed at levels of 50-100 mg arsanilic acid/kg of feed and 25-37.5 mg roxarsone/kg of feed (1). Both arsenicals produce the same beneficial effects although different concentrations are required for an optimal response. Acute arsenic poisoning caused by phenylarsonic acid derivatives such as arsanilic acid or roxarsone results in a variety of neurological disturbances, History and clinical findings Young pigs, 6 to 10 weeks of age, in two unrelated farrow-to-finish swine farms developed a similar problem. The farms were geographically separated by approximately 150 km, although the disease outbreaks occurred during the same two to three week period. The ration was formulated by the same feed company and was supplied to both producers on a regular basis. The formulations contained an 18Wo wheat ration and a 25W7o protein-base mix containing soya bean, whey, and herring meal. This base mix comprised 15%7o of the total ration. The rations also contained various vitamins, minerals, and medications at recommended levels. In addition, both rations were formulated to contain 150 mg roxarsone/kg of feed as a growth promoting agent. The problem was first identified in the larger operation after the swine had been fed the ration for approx385 imately two weeks. Eleven pigs had died, 15 other pigs were clinically affected, and the remainder of the pigs (2000) appeared normal. The commercial feed was removed one day after the appearance of clinical signs. No additional clinical cases developed after the feed was removed. The affected pigs appeared healthy in many respects. They continued to eat, showed no evidence of depression, but exhibited a variety of neurological disturbances including ataxia, muscle tremors, incoordination, and posterior paralysis. Quadriplegia was apparent in advanced cases prior to death. Several of the pigs appeared blind as evidenced by the lack of a menace reflex, although a detailed ophthalmic examination was not conducted. In pigs from the smaller farm, clinical observations similar to those of the larger farm were made. Yorkshire pigs, 6 to 10 weeks of age, consumed the ration for a comparable period of time (two weeks). In contrast to the previous outbreak of disease, the animals remained on the suspect feed for 8-12 days after the first appearance of the clinical signs. Consequently, 400 of the 600 pigs exhibited clinical signs and five pigs died. The clinical syndrome was similar to that of the larger farm, with minor exceptions. The owner reported that many of the affected pigs "screamed". During the period of time prior to the removal of the feed, a remission of the clinical syndrome was observed in several pigs. Clinical manifestations of poisoning by roxarsone recurred a short time later, however, because the animals continued to consume the toxic feed. Toxicological and pathological evaluations were done on pigs from both farms; live pigs which had consumed the suspect ration during the previous 24 h and were exhibiting moderate to severe neurological disturbances were chosen. Further discussion with the feed company indicated that roxarsone had been added to the ration at levels recommended for arsanilic acid (150 mg/kg). The feed company had assumed that the two organic arsenicals could be used interchangeably at the same level of formulation. Necropsy findings Pigs from both farms were in good body condition. There was no gross abnormality in any pig examined. Histological lesions were confined to the optic nerves and tracts. Lesions were not seen in sections of brain; cervical, thoracic, lumbar, and sacral cord; sciatic or brachial plexus nerves; or lung, liver, spleen, kidney, or heart. Scattered pyknotic nuclei were present in the optic nerves. Lesions which were more prominent in the optic tracts near the chiasma were characterized by variable but generally mild vacuolation of white matter, mild hypertrophy of astrocytes, and pyknosis of scattered nuclei, possibly of oligodendrocytic origin. Laboratory findings Liver and kidney samples collected from both groups of pigs during necropsy were submitted to the Diagnostic Toxicology Laboratory at the Western College of Veterinary Medicine. Increased quantities of arsenic were detected in both tissues [liver, 2.9 mg/kg ± SD 0.4 (n = 8); kidney, 1.8 mg/kg ± SD 0.4 (n = 8), 386 wet weight]. Liver concentrations of arsenic observed in similar outbreaks of roxarsone poisoning range from 2.3-5.4 mg of arsenic/kg (2,3,5). Corresponding kidney concentrations of arsenic are approximately one-third less (5). Normal background arsenic concentrations in pig liver and kidney are usually less than 0.2 mg/kg and 0.1 mg/kg respectively (8). Feed which was available in one instance contained 38 mg/kg arsenic per kg of feed. This concentration of arsenic, which corresponds to 133 mg of roxarsone/kg of feed, is approximately three to five times higher than the levels recommended for swine rations (1). Based upon the detection of excessive levels of arsenic in the tissue and feed and the presence of the classical clinical syndrome, a diagnosis of roxarsone poisoning was made. Discussion In pigs, exposure to excessive amounts of phenylarsonic acid derivatives produces a distinctive clinical syndrome characterized primarily by neurological alterations. A similar syndrome is observed with most derivatives, although minor differences are encountered. Blindness is usually associated with poisoning by arsanilic acid (1,4) but it is rarely observed with other compounds. Vocalization manifested by "screaming" appears to be a consistent feature of roxarsone poisoning (2,5,7), although it is reported that the vocalization may be attributed to anxiety during periods of severe neurological disturbance (5). In this study, vocalization was observed in several pigs exposed to the arsenical for an extended period of time. The onset of the clinical syndrome is related to the level of exposure (1). The clinical syndrome may appear several days or weeks after continual exposure to the toxic feed (3-5). The predominant manifestations of the syndrome gradually transform during the course of the disease. Ataxia, muscle tremors, and clonic convulsive episodes may be observed early, whereas paraparesis and paraplegia develop in the later stages (5). This progression is associated with the development of altered nerve function, however, histological lesions may not be evident for up to 14 days after the onset of clinical disease (4). Lesions in these pigs were mild and were most conspicuous in the optic tracts. It is important to examine these tracts carefully, as the alterations in the optic nerves were minimal and the lesion can be overlooked easily. The -onset of the syndrome and the correlation with pathological damage at a later time are variable. The clinical syndrome may be influenced by such factors as the availability of water, dehydration, diarrhea, or other physiological factors (1). In several instances following exposure to roxarsone, the stress of exercise or animal movement was associated with the onset of neurological signs (2,3,5-7). Since poisoning associated with phenylarsonic acid derivatives produces no distinctive gross abnormalities (1) and few histological lesions suggestive of poisoning, alternative methods for diagnosis must be employed. In the absence of lesions, the diagnosis may be supported by analysis of tissue or feed. InterpretaCan Vet J Volume 31, May 1990 tion of the tissue levels of arsenic must be made with caution. Phenylarsonic acid compounds are excreted rapidly. Approximately 50 to 75Gb of the absorbed phenylarsonic acid derivative may be excreted (1) within 24 hours. An animal which has consumed a sufficient amount to cause the neurological syndrome may eliminate the majority of the compound before death or sample collection if the toxic feed is removed at a much earlier time. In the situation reported here, tissues were removed for analysis within 24 hours of feed removal. In comparable cases (2,3,5), concentrations of arsenic in the liver ranged from approximately 2.3-5.4 mg/kg, which are similar to those observed in the present investigation. Analysis of the feed is not influenced be metabolism and rapid elimination. Therefore, levels of arsenic detected in the feed are more constant with time and indicative of the true level of exposure. Most analytical methods routinely measure only the arsenic content of the feed and do not identify the specific form of arsenic. Since the derivatives of phenylarsonic acid produce poisonings at different levels of exposure, it is critical to identify the form of arsenic contained in the feed. In this investigation, the feed company incorporated roxarsone into the ration. The levels of arsenic detected in the feed, 38 mg/kg arsenic content or 133 mg/kg roxarsone, are comparable to other reports of poisoning associated with this form of arsenic (2,3,7) wherein roxarsone was present in the feed at 105, 106 and 54 mg/kg. The recommended levels in rations for swine are 25 to 37.5 mg/kg (1). The margin of safety for the incorporation of roxarsone into rations for swine is narrow, as indicated by the small difference between the recommended and toxic levels. The addition of moderately excessive levels or the improper mixing of roxarsone may result in poisoning. Reports in the literature indicate that roxarsone is more toxic than arsanilic acid and has a lower margin of safety (5,7). The two forms of organic arsenic cannot be used interchangeably at the same concentration. In this investigation, it was determined that roxarsone was substituted for arsanilic acid without a reduction in the levels in the feed. This error resulted in an outbreak of poisoning. cvi References 1. Osweiler GD, Carson TL, Buck WB, Van Gelder GA. Clinical and Diagnostic Veterinary Toxicology. 3rd ed. Dubuque, Iowa: Kendall/Hunt Publishing Company, 1985: 80-86. 2. Rice DA, McMurray CH, McCracken RM, Bryson DG, Maybin R. A field case of poisoning caused by 3-nitro-4-hydroxyphenylarsonic acid in pigs. Vet Rec 1980; 106: 312-313. 3. Gilbert FR, Wells GAH, Gunning RF. 3-nitro-4-hydroxyphenylarsonic acid toxicity in pigs. Vet Rec 1981; 109: 158-160. 4. Harding JDJ, Lewis G, Done JT. Exerimental arsanilic acid poisoning in pigs. Vet Rec 1968; 83: 560-564. 5. Rice DA, Kennedy S, McMurray CH, Blanchflower WJ. Experimental 3-nitro4-hydroxyphenylarsonic acid toxicosis in pigs. Res Vet Sci 1985; 39: 47-51. 6. Hill BD, Blaney BJ. Poisoning caused by the combined effects of two phenylarsonic acid growth promotants in pigs. Aust Vet J 1984; 61: 241. 7. Wilkinson JD, Wood EN. 3-nitro toxicity in pigs. Vet Rec 1981; 109: 343. 8. Puls R. Veterinary trace mineral deficiency and toxicity information. Agriculture Canada. Publication number 5139, 1982: 15. Need Cages? Save 33 1/3% Clark Cages S"-j$ , "ConurIIl.to U *Quiet & Warm *Sensibly Priced *Durabbl .Attractive Easy to - Assemble Clark Cage Dryer Heavy - duty construction Fuly - assembled Dries aimal qu!cdy and safely *Space - saver design *Vrtually maintenance - free coloibradur. Clark Cages Inc. mai(706)4744 USAT-(214)744-562 IPum.( 2154 /95C --Cd.(l3)8.9z32 Can Vet J Volume 31, May 1990 387