thiomolybdate-Cu complexes (19). Sulphate and t hiosulfate inhibited the uptake of selenate (55 ) , and the possible involvement of s ulphate in an increased.
SCIENTIFIC REVIEWS Neurotoxicity and Secondary Metabolic Problems Associated with low to Moderate levels of Exposure to Excess Dietary Sulphur in Ruminants: A Review Andr e w A Olkowski PhD, DVM, MSc, BSc Department of Animal and Poultry Sc i ence , Un iv ers i ty of Saskatchewan , Canada, S?N 585
Saskatoon, SK ,
ABSTRACT . Prob l ems assoc i ated wit h a low to moderate excess in d i etary sulphur (S) intake in ruminants are being incr eas i ngly recogn i zed. Comparing more recent reports with older data, there is an evident decrease i n tolerance of cat tle and sheep for even moderately elevated levels of dietary S, and an apparen t drastic change in the clinical picture of chronic d i etary S toxicoses. Ou tbreaks of polioencephalomalacia (PEM) in ruminants i n assoc i ation with excess dietary S nave been reported in recent years throughout the world . Excessive levels of S- containing compounds in domestic ruminant animals' ration s , and clinical prob l ems associated with low to moderate levels of exposure to d i etary S may be more common than previously thought. Thi s rev i ew presents a comprehensive eval uation of the p r oblems associated w i th excessive levels of S in ruminants' rat i ons . Emphas i s i s placed on the recent_ly i nc r easi n g i nc i dence of S- induced PEM . Secondary metabolic d i sorders associated with excessive intake of S are also discussed .
In recen t years there has been an increasing number of reports f r om many parts of the wo rld, both from field cases a nd research, describing an assoc iation between excess dietary s ulphur (S ) a nd outbreaks of po l ioencephalomalacia (PEM) in ruminants (1- 13) . Although nutritional toxicity of S compounds h as been well documented, more problems associ a ted with low to moderate excess in dietary S intake are increasingly r ecognized . Interestingly, comparing older literature with more recent r eports , it becomes apparent that there is a decrease in to l erance of cattle and s heep for excess dietary S. It also becomes evident that ther e is an apparent drastic ch ange in the clinical pi c tur e of chronic di e tar y S toxicoses . Indeed , S- induced PEM a ppears to be quite a r ecent p henomenon. This pr oblem deserves more atten tion be cau se t h e l osses associated with outbreaks of this di sease are very h igh and excess of S- cont a ining compou nds in domestic ruminant animals' ration may be more common than prev i o u sly thought . The aims of th i s r e vi ew a r e to . present a comprehensive evaluation of t he problem of excessive levels of S in ruminan ts ' ration, to compile and critically discuss reports describing S-induced PEM, to discuss poss ible pathogenesis of S-induced PEM, and to discuss other metabolic problems associated with excessive intake of S .
SOURCES CONTRIBUTING TO EXCESS S IN RUMINANT RATIONS Sulphur intake b y a ruminant animal depends on numerou s dietary and e n vironmental variab l es. It is important to st r ess that the factors contributing to dietary sulphur may be extremely variable , and frequently difficult to control .
Sulphu r in the drinkin g water has often been i gnored in t he calcu lation of th e total d i etary i ntake of S in ruminants, yet water is likely the major cont ributor to t he overall load of dietary S. For instan ce, the co nsumption of wate r conta i ning the moderate l y hig h level of 1000 ppm of su lphate can contribute 0.1 to 0. 27% of the dietary S . Considering that the S content in common ruminants' ra tions is in a ran ge 0 . 15 to 0 . 20% of DM, this example illustrates that even wit h moderately e l evated S content in water , the practi cal ration for ruminants ' 1 total d i etary S may easily exceed 0 . 4%. 1 Dietary S at a level above 0.3 - 0 . 4% may cause toxic effects ( 14, 1 5) . High S content in the d r inking water i s prevalent in many areas of the wo rl d . High to excessive S concentrations in some plants occur naturally and can increase under a variety of soil management condit ion s ( 1 6, 17) . Hig h concentrations of S are inherently present in a number of commonl y used feedstuffs ( 14), and s ub sequently excessive S content can be expected in the rations b ased on these ingredients . Tab le 1 shows several examples of feedstuffs commonly used in ruminant rations con taining high l evels of S . A s u bstantial contribu tion to the overall dietary S may also originate from indust r ial sou rces (eg power plants, factories, smelters) and intensive farmi ng practices (eg fertili zers, waste produc ts of an i mal industry) . I n areas where S content of soi l and/or water is high, t h e uptake of S by p l ants may b e significant (16) . Further, constantly increasing emi ssion s of S products from industrial sour ces make, no doubt, a signi ficant a dditiona l contribution .
Reprinted from Veterinary and Human Toxicology, Vol. 39, No. 6, December 1997, pp. 355-360
Table 1. Fe-xlstuffs commonly used in ruminant livestock diets containing high concentrations of sulphur (14).
Feed
Sulfur content % (DM)
alfalfa extracted cotton seeds mangel beets sugar beets and their byproducts soybean meal molasses rape seeds mechanically extracted sweetclover hay turnip yeasts wheatgrass dehydrate whey brewers dried grains
0.40 0.34-0.56 0.63 0.22-0.54 0.49 0.40-0.61 0.50 0.47 0.43 0.45-0.62 0.47 1.12-.1.15 0.32
Pollution by airborne S compounds presen ts perhaps a more discrete, but neve r the l ess important, problem . Under no rmal diet a r y conditions th e con tribution of S from mi neral supple ments is relatively s mal l; however, if the dietary S obtained from feeds and water is a l ready e x cessive, the contribution of mine ral supplements may be significant . Sulphate salts of mine r als typ i cally contain 10 to 24% S ( 14). Some mi neral s are commonly s u pplemented in the form of s u l fate s alts . Nutritional Errors Ac ute S toxicity r esul ting from nutritional e rrors is r e lativel y r are. Interestingly, howe ver, t he number of reports f r om the f i eld on S-i nduced PEM associated with nutritional e r rors is in creas ing (10-13). Nutritional errors a l so o u gh t to be consid ered in the context of the proper balance of micronutrie nt s . Mar gi nally adequate level s of s ele nium ( 1 8) or c opper ( 19) are likely to exacerbat e th e detrimental e ffect of even moderat e l y high dietary S . The ef f ect of d i etary S on copper may be more pronounced when t he content of other divalent metals in th e rat i on is excessive (20) . Environme ntal S
AVAILABILITY OF S IN RUMINANTS IN THE CONTEXT OF S TOXICITY In ruminants, nu tritional S toxicity mu st be considered in the co n text of the b iotransfo r mation of S, since common S compounds (e l emen tal S, sulphates, methionine, cystei ne), although relatively nontoxic per se , are metabolized by the rumen micr oo r ganisms to toxic sulph ites and / or su l phides. When co n sidering the toxic i ty of dietary S to ruminants, it is important to recognize that almost all ingested su lph ate passes through t he sequ ential reduction to sulphite an d s u l phide, and a bsorbed sulph ide i s oxidized sequen tially to s ulphi te and su l phate in t i ssues while s ulphate is recycled to the rumen via saliva. Excess dietary S may cause proliferation of S-r e duci ng bacteria i n the rumen (21,22), wh i c h may furt h er incr ease the systemi c poo l o f toxic S metabol it es of di etar y origin . I t i s not ewo r t h y that in rum i nants, relative to monogastric species, su lphides and s ulphi t es are generated in considerable quantities , and the ir inadequate eliminatio n due to overload may be of primary toxico logical importance in the pathogenesis o f the necrot i c lesions observed i n the brains of cattle or sheep fed e xcess dietary
s.
HISTORY OF PEM AND ASSOCIATION OF S AS AN ETIOLOGIC FACTOR IN PEM Polioence phalomalac ia (PEM), also known as cerebrocorti cal necrosi s (CCN) , was fi r st identifie d a s a distinct pathological entity i n ruminant s i n the US ( 23) and in England ( 24) . Morphologically, PEM i s char acterized by a focal necrosis of g ray matter i n t he brain. The term po l ioenceph alomalaci a applies to softening of the cerebrocortical gray matter [ ( Gr) polio gray, e ncephala = b rai n , malacia= softening] . Polioen cephalomalacia has bee n re cognized for more than 3 d ecad es ; howeve r , its et iology is st ill not completely understood . The disease i s one of t h e most prevalent di sea ses of the central nervous system in catt l e and sheep. It occur s in may parts of t h e world and i s of co ns ide rable economic importance in areas of intensive product i on . Historicall y , PEM or CCN has been regarded as an effect of t hiamine d e ficiency (25,26), but th i s has been di s pute d ( 27). A var i ety of other factors, such as cobalt d ef i cien cy (28), se l e nium toxicity (29), lead po i soning ( 30), and molasses toxici ty ( 31) , have been implicate d in the pat hogenesis o f malac i c lesions . In r ecen t years, PEM has been observed in c at t l e and sheep exposed to excess di e tary S ( 1-13 ) .
Environmental pollut i on is a proble m of i nc reasi ng importance in agricu l tural centers located i n th e vic i nity of indus trial a r eas , natural gas factories , s melte rs, or power plants or factories using coal as an ene r gy sour ce . Sulphur i s o ne of the most common pollutants in man y industrialized countries . The industria l pollution fallout i s likely to cau se an i ncrease in soil and water S con te t an d t he accumulatio n of S in plants, t h ere or~ contribu ting to th e already exist n g burde n.
Clinical signs of PEM have been observed cattle a nd sheep exposed to a excess d 1etary concentration of S in feed (1 2 8 1013) a?d in water (3,5,6,9) . Polio en~e~h~lo ~alac la was also ident ifi ed i n systems of 1ntens1ve beef production u si ng molasses a s a prin cipal sour ce of e n ergy ( 31 , 32) . The
356
(6) December 1997
Vet Human Toxicol 39
Field Observations i~
involvement of S in the pathogenesis of molasses-induced PEM was not considered in the past, but in view of the high S content in molasses, there is a possibility that S may be a contributing factor. Experimental Evidence The neurotoxic effect of excess dietary S in ruminants i s evident from alterations of brain electrophysiology (33). Clinical signs of PEM have been experimentally induced by feedi ng excess dietary S to sheep ( 34 36) and catt l e (2,4 ,7, 22). The occurrence of mal acic lesions was attributed to excess dietary S (37). In addition, clin i cal signs of PEM were observed incidental ly during experiments involving excess dietary S ( 38, 39). Clinical Features The clinical signs usually occur between the 3rd and 8th week of exposure ( 81 3,34,35) . In the initial stage the animals exhibit transient attacks of mild excitat i on, loss of appetite and restlessness. The affected animals tended to gather in t he darkest corner of the pen ( 8) , and it appeared as though they were exper i encing sensitivity to light. Similar behavior was described as "standing in the corner" (7) . Some of the initially affected animals recovered spontaneously (untreated), but growth of these i ndi v ictua l s was stunted. In more severely affected animals the c lin ical signs progressed to aimless wandering, head pressing, hyperexcitability, rigidity, opisthotonos, recumbency, v i o l ent convul sions, coma and death. Clinical Biochemistry of S-Induced PEM Little is known of the mechanisms or the biochemical changes associ ated with S-induced PEM in ruminants. Generally, the biochemical parameters observed in high S-r elated PEM in catt l e appear s i mil ar to those observed in other spontaneously occurr ing and amprolium-induced PEM in ruminants. Se rum creat in ine and urea levels may be moderately elevated in some animals . Aspartate aminotransferase activity and creat inine phosphokinase activity are incr eased s ubstantiall y in severely affected a nimals . Serum gamma- glutamyltransferase levels do not appear changed . Overall, the changes in serum e l ectrolytes and enzymes appear only marginal and do not occur cons i stently. The significant alterations of blood biochemistry parameters (usually occurring i n advanced cases) can be attribu t ed to the cli ni cal status (recumbency) rather than to other etiologic factors . No pathognomonic diagnostic markers enab ling early recognition of S-induced PEM were iden t if i ed among the most commonly used c linical chemi stry parameters (8,34) . HYPOTHETICAL MECHANISM S-INDUCED NECROTIC LESIONS IN THE BRAIN The toxicity of S, and more so its metabolites such as s ulphides and sulphi tes, may cause the development of necrotic brain lesions. Hydrogen s ulphide gas in high Vet Human Toxicol 39
concentratio n can produce necrotic lesions in the brain (40), but there is the lingering question whether the amount of hydrogen sulfide gas produced in the rumen of animals exposed to a madera te excess of dietary S is sufficient to cause such injury or if a more complex metabo l ic process is involved. The disposal mechanisms for sul p hides a nd sulphites in ruminants may be relevant to the pathogenesis of necrotic lesions in the brain. In ruminants, the process of e limination of sulfide via oxidative processes may be important, since in this pathway s u lphite is an intermediary metabolite. Sul phite is a relatively strong nu cleophi l ic anion that can react with a variety of cellular structures and cause toxicity. Severe brai n abnormalities, including progressive destruction of brain tissue, were observed in a patient with sulphite oxidase deficiency ( 41, 42) . Brain tissue, because of its high lipid content, is vulnerab l e to oxidative damage. Brain h as a high rate of oxidative metabolism and a relatively low antioxidant system. Su lphite -derived radicals can be formed through a catalytic react i o n of peroxidases and ar e postulated to cause lipid peroxidation and damage to biological membranes (43). Insufficient rates of s ulphite oxidation due to overl oad and subsequent accumulation of this metabolite in the brain may be important in the pathogenesis of dietary S- i nduced necrotic lesions in the brain. THE ROLE OF THIAMI NE STATUS IN S-INDUCED PEM The existing studies on S- induced PEM (7 9,34) indicate that overt thiamine deficiency is not the primary cause of the disease. Nevert heless, it is worthwhile to briefly discuss this subject because of the possible role of thiamine in the prevention and treatment of S-induced PEM. The r epo rt s on thiamine deficiency in animals affected with PEM are con flicting, and thus far numerous studies on the pathogenesis of PEM have not produced conclusive evidence that ove rt thiamine deficiency is indeed involved ( 27) . The increased metabol i c demand for thiamine was initially postulated as a possible etiologic factor for PEM (44). Paradoxically, blood thiamine concentrations were elevated during the appearance of early neurologic signs of S-induced PEM in sheep ( 34) . Hence, it is a rea s onable assumption that animal s fed excess S may h ave a greater demand for t hi amine due to the toxic effect of excessive dietary S. Animals exposed to excess dietary S and supplemented with thiamine are at considerably l ower risk of develop ing fulmi nant PEM ( 35), but thiamine treatment of S-associated PEM is not always effective. Animals affected with PEM associated with excess i ve intake of S appear to respond to thiamine treatment in some cases (3,5,8,20,38). Some an i mals responded after prolonged treatment ( 12), whereas others did not appea r res ponsive to th i ami ne treatment (10,11). However, the (6) December 1997
357
lack of r esponse may b e due to the f ac t that t he brain l es ion s we re advanced b eyond clinical r ecove r y . No tabl y, i n most cases of PEM treatme nt with mass i ve doses of t hi amine i s effect ive only in the early stages of disease . Tbe dose of t hiamine indi cat es that th e effect of r e quire d thiamine is pharmaco l ogical rat her tha n biochemical . Although the S -induced PEM cannot be explained sol ey by metabo li c changes originating from depletion of t h iamine, a hi gher availabl e l e vel o f thi ami ne may have a protecti ve effect . The thiamine molecule has natural f eatures e nablin g a protective f unc tion against s ulphur's tox i c me t a bolite s, ie s ulphit e and s ulphide, whi c h are continuous l y produced in the rumen . Free t hi ami ne may offer protection by scavenging free radical s (45) . A def i cit of t hi ami ne can inc r ease t he intensity of lipid peroxidation (46) . Further, the r eadiness of thiamine to r eact with s ulphit e ions (4 7 ,48) may i tself be c on s idered a These processes o ccu r detoxifying process . at the expense of destroying th e thiamine mo l ecule, with t he poss ibl e con sequen c es of a secondar y metabol ic defi c i t. The con formational form of the thiamine mol ecu le i n its t hiazo l e open ring with the e xposed -SH group could ser ve as a con jug a te to detoxify sulphide derivatives . He nce, the hypothes i s of a n incre a sed r e quir ement for f re e thiami ne ( independent f r om the requirement of thiamine pyrophosph a t e dependent e nzymes) in S toxic it y seems plausib l e .
METABOLIC PROBLEMS ASSOCIATED WITH EXCESS DIETARY S INTAKE IN RUMINANTS Excess diet ary S interferes wi t h several essent i a l nutrients . These effects represent a ve r y discr ete class of nutrit ional S toxicity linke d to spec ific features of S metaboli s m in rumi na n t species . The to xi c effects are no n - specific secon dary metabol ic dis turban ces . The destructive mechanism of t he s ulph ite i on on the thi amine molecul e has been estab lishe d ( 47,48). Practi cal validit y of t h is can b e inf e rred fr om the clinical reports of thiamine defi c i e n cy in cats and dogs ( 49) a nd in pigs (50) i n associ a tio n with f eeding meat preserved wit h s ulphur diox i de . In normal c i rcumstances an outright thiamine deficien cy in ruminants i s not l i k e l y to occur, but the det rimental e f fect of S on thiamine in the GI tract of ruminants is s u ppo r te d by expe rimental data (5 1, 52) . Field s tudies (6,20) indi cate that cons umpt ion of h igh s ulphate water by c attle affects b l ood th iamine concentrat ion. With increased me t abol i c dema nd , t hiami ne deficits can occur in ruminants exposed to exc ess dietar y S . The det rime ntal eff ect o f d ietary S on Cu bioavailability is we ll docume n ted from both exper imental (53) a nd f i eld studies (20,54) . I t i s common l y accepte d that t h e decreas e d bioavailabili t y of copp e r with S is due to t he formation of insolub l e Cu S a nd/or 358
thiomol ybdate - Cu comp l exes (19). Sulphate and t hiosulfate inhib ited the uptake of selenate (55 ) , and the possible involvement of s ulphate in an increased inc ide nce of muscu lar dyst r oph y was reported (58 ). The effect of dietary S may b e reversed by an inc r e a sed s upplement a tion of selenium ( 1 8) . Hence, the ef f ect of S may be of more import a nce in c a ses where se l enium is marginal ly adequate. The r etention of both cal c ium and phosphorus was r e duced by the addi tion of s ulphate to diets (57,58). Mor e recent re search indi cates that S, e i tber a l one or in a syner gistic effect with mol ybdenum , can affect gastrointestinal metaboli sm of zinc, manganese, magnes ium and phosphorus (59). Acid-Base Balance The i nfluence of dietary S on cation-anion balance bas not b een studied ext e ns ively in ruminant r esearch, and thus far research h as mai nly f ocused on dairy cattle . However, t he contributi on of dietar y S t o overal l di etary ions and its influence o n ac id-base b alance cannot be i gnored. This p r oblem dese r ves more c onsideration, s ince dietar y S may h ave a s imil a r acid-ge nerating pot e ntial as c hlorine (58) .
TOXICITY OF HYDROGEN SULPHIDE GENERATED IN THE RUMEN Hydr ogen s ul p hide gas generated in the rume n a nd inhaled during regurgitat ion, if in s uff ici e n t amou nts, can cause an acut e systemic r esponse . However, in situat i ons of moderate excess dietary S the gas accumu lated in the rumen is like l y to b e in a n insuffi cient concentratio n to e x e rt a toxic effect p e r se . Further, s ince the respiratory motion i s consisten t l y altered at t he onset of e ructa tion, with a momentary cessation of act i v i ty bei ng the ru l e, an d eructation occurs in conjunction wi th r umination at whi c h time due to c hewing motions the mou th is p oorly sealed (60) . Th e probabi lit y of inhalation of hydrogen s u lph i de l eve l s causing acute toxic it y appear s quit e r emote. However, some of the e ructa t ed h ydro gen s ulphide gas is i nha l ed and can contribu te to chronic aspects o f S toxicos is pat hogen es i s .
EXTENT OF THE PROBLEM OF EXCESS DIETARY S IN RUMINANTS The excess ive intake of S i s prima rily r e l a t e d to the concentration of S in f eeds a nd /or wat e r s . The problem of pollution may be prominent in some areas. Drinking water is probably the most c ommon source of excessive intake of S for livestock. A comprehensive study assess ing the dist ribution of S content in fee ds o r in waters has not been done . -::ase s t;udy report s ( 1, 3, 5 , 6, 20, 6 1 ) indicate that t h is probl em i s widel y Limited s urveys in Canada (6,62,63 ) s pread . indi cat e that some 20 to 40% of farms on the Canadian pra~r~ es use dri nki ng water containing more than 1 000 ppm of s ulphate.
Vet Human Toxicol 39 (6) December 1997
IMPACT ON THE LIVESTOCK INDUSTRY
Considering the increased number of report s of neurotoxicity from di etary S, it would appear that S toxicoses in ruminants is increasing. The economi c losses associated with high morbidity/mortality of S-induced PEM (1,5,9- 13) ar e sign ifi cant . The economic impact associated with non-specific effects of dietary S may be more diffi cult to ass ess . The severi ty of nutr itional S toxicity may depend on nume rous nutritional and management factors. Decreased performance is a common problem in animal s fed e x cess S (64) or b ei ng exposed to drinking waters containing hi gh Daily milk yield l eve l s of S (20,54,65) . and fat and protein cont e nt of mi lk we re decreased b y dietary S suppl eme ntation (58). Additional subcl inica l problems associated with excess dietary S also occur, but there is no data available about their significance. Subcl inical toxic}ty from excessive S intake an d associated with secondary nutritional deficiencies (20,54,59) may represent a plethora of non-specific metabolic disorders . Howeve r , the nonspecific s i gns of marginal dietary S to xicoses has never been studie d , and without an in depth investigation these marginal problems can not be eas il y associated with the excessive S intake. TREATMENT/PREVENTION
Preventative measures to be considered inc lude balanc ing the ration to decrease excess i ve intake of S and the s upplementat i on of nutri e nt s like l y affected by S. Controlling the total intake of S may be difficult, particularly in areas wi t h specific soil conditio ns high l eve l s of pollution or where the drinki ng water cont ains a high S concent ratio n . In problem areas, an attempt should b e made to d ecr ease the load of di etary S by blending feedstuff contai ning high levels of S with feed and mineral suppl ements with low S content . The cost of water purification for livestock at present is prohibitive, but may be applicable in the f u ture. Dietary supplementation of copper (20,66) a nd thiamine (36) in quanti ties exceedi ng the normal dietary r equirement may decrease the ri sk of PEM occurrence. Early adm inist ration of thiamine to affected individu als may prevent f urther devel opment of t he di sease ( 12) . CONCLUSIONS From t he publish e d reports there i s little doubt that the problem of S-induced PEM is i ncreasing. Howeve r, the docume nted reports originate from diagnostic labo r atories or r esear c h centers and may represent only a fra ct i o n of the over a ll problem. Considering that high levels of S in feed and /or drinking water are common, many of the fie ld cases of PEM may be associate d with excessive i ntake o f S. The lack of apparent clinical signs in s h eep which had malacic lesion s in the brain (38) indi cates a subclinical form of th i s condition and opens the possibilit y that t he di sease may be more prevalent . Be tt e r e pidemiological recognition of the problem of excess di e tary S is necessary.
Based on the pub l ished reports, the morbidity and mortali ty assoc i ated with Sinduced PEM is high. It is also remarkable that the problem i s often not recognized until an ou tbreak of f u lminant disease occurs, which indi cates the di agnostic difficulty of pre- cli nical stages. More r esearch i s needed to improve diagnostic methods, and the development of approp riate diagnostic procedures for the early assessme nt of dietary S toxic it y would be des i rab le. Early recognition may also be important for successful t r eatment . safeguards of preventing SNut ritional induced PEM a nd other metabolic problems s hould be developed .
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