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I I. IV- Vx ( Itlhl Acute Effects of Aroclor 1254 on the Feline Cardiovascular System 11 I'. Rh.iiiik, N H. Bonin,1 ,v\n K. H. It ski I >n iunit <>l Yrlrtittttrv Mrtin til Hr\rtitclt. I utul ti/nl thui; AJinmiMi tiinni I ' S /> iHiniiwm iit /It tilih. t t/iii iiiimi. tmj Wrlhiu\ Hrllwillr. M<tr\lttiui 'U7u`` Received July (>, 1975 Anu'loi I ?M w;t>, tiiliiiinisfi-u'd mi rnvc non sly ill Ml-minute inlet vuls to anesthetized mis ,m .1 dosage ot 1011 rnc.'kj: body woi^hc Arterial and venous blood samples uru1 taken .it 10 tumult' intervals lot dclciimnulion ol oxygen tension (pO.). c'nibon dioxide tension <p( (M. and pll l-.leiDoeiiidiagrams. bloml prcssuie. ami icspirntion weie recorded as wi ll I lie pi) of the Mi>i ul was reduced rapidly and markedly with concurrent changes in pi <> and pH i Maine In i/mj: a icspuaU'i v acidosis. Respiratory rate increased to a m/able depiee wul development ol eiiidiae atihythmias. All animals died within Ml minutes followmr initial ilosinj;. Sovciely lieinouhanie limns m conjunction with edema wcie observed m all cal s nl m i i u|'\\ The Aroelors are members of a group of compounds called polychlorinated biphenyls (PCHs). The Aroelors. which have many industrial uses, arc utilized as components in heal exchange units of fishmeal processing plants. In 1971. a leak ing heat exchange unit resulted in the contamination of poultry fishmeal hy A roc lor 1242. This incident and others focused attention on the potential toxicily ol the K'Hs. since they persist as environmental contaminants. The vat ions Aroelors are reported to be onc-quartcr to one-fifth as toxic as DDT (IVakall and I .inter, 1970). Some of Die major toxic effects of PC Us in fowl (I lick rf nI.. 1905; 11arris, 1971; MeC'une <( al.. 1902; Vos and Kocman. 1970) and nils (I bod and Drug Administration. 1971; Grant cl til.. 1971) have been described and include the development ol edema, lowered hemoglobin levels, enlarged kidneys, and liver damage. Vosct al. (1970) have suggested that a toxic factor ot imputity may be present in PCUs and may cause the toxic effects. In preliminary studies in our laboratory, we observed that a high degree ol hypoxia and maikeilly darkened arterial blood occurred in dogs administered ml ravenously Aroclor 1254 in dimethyl sulfoxide (DMSO) carrier at dose levels of 100 250 mg/kg. This observation and the lack of information on the toxic effects (if PCHs in the cat emphasized the need to initiate this study. Consequents. the primary purpose of this study was to evaluate the action of Aroclor 1254 on selected parameters of the feline cardiovascular system. MATERIALS AND METHODS Aroclor 1254 lI DA sample 370 71-698) was warmed in a beaker ol hoi waici to reduce viscosity. A 25-ml glass-stoppered graduate was lined on a top-loading balance, and 5.0 g (3.25 ml) of A roc lot was pipetted into the gi admit e ami diluiol ' Ibvscnl aildtrss l)i|'iii imciii ul I'liy su'lugy .md Pharmad'lo^ . College i>l Velum,it) MuIkiik University ol (icur^i.i, Alliens, (.eiut:ia *UM)I. ^4 KJ(. II I I K. |'l M > to a volume of 11) ml with 99.9*.^ DMSO. A clear solution w as pioduccd w 11h agitation. ami there was no evidence of separation of the tuo pluses through.an the study. All ulensils containing Aroelor 1254 were rinsed with hexane and eiln I aloohol and the rinses were plaeed in a plastie jug for proper disposal l.aeh of seven mongrel eats (three males and four females), weighing between 2.A and 4.1 kg. was anesthetized with sodium pentobarbital i 25 30 mg-kgi \ in die seplulic vein. The right and left fcmoial veins and the lell c.tiolnl anciv uiu cal betel i/cd. following .i pioccduie of blunt dissection, with inii.uncilu polyethylene tubing (0.034 in. i.d.; 0.0A0 in. o.d.i. file catheter i/ed vcsm.1-. kept patent by flushing them with hcparini/ed saline solution lie foie and alte administration of (he compound and blood sampling. Anesthesia uas numiamed hv administering sodium pentobarbital into the right femoral vein as required | In1 Aroclor-DM.SO solution was administered into the left femoral vein al a dosage id 100 mg Arocfor/kg at 30*minute intervals to six of the seven eats; the fluid \ ohmic averaged 0.6 ml. The remaining eat received three doses of 0.A ml o! 1 )MSO alone at 30-minutc intervals followed by two doses of Aroelor'-DMSU. also at 30-minute intervals. The catheter' used for administration of Aroelor 1254 was rinsed with hexane and ethyl alcohol and was used in all cals lor Aiocloi administration onl\ Blood samples were taken with bint glass syringes coaled with Vaseline t<< reduce gas loss ami purged with sodium hepaunale (1000 umi-hmli lo pie\eui coagulation. Approximately 0.5 nil of blood was taken at cash sampling time Arterial and venous samples were taken from the carotid aitcry ami nglii lemoi.il vein, respectively, just prior to the first dose and at 10 ami 20 minutes alter cm. h dose. All samples were analyzed for pH. oxygen tension (p(>). and CO lension (p( ().) by using the blood microsystem and digital acid base analwci * Arterial pressure was monitored through a physiological pressure tiansdwvo and recorded along with respiration and an electrocardiogram by using an eight channel recording system.1 Respiration w\is recorded with a bellows tvpe pneumograph, ami a lead 1 or 11 electrocardiogram was obtained In using a stand ard live-wire patient cable. Recordings of the above physiological parameters w;cre obtained at two intervals prior to the initial dose and just preceding and following each dose thereafter. Tracings were also taken at various mien aK dm mg the dosing period when a change was observed in the clecirocaidrogiaphie tracing. Record tracings were taken at a chart speed ol 25 nim/secoml RESULTS I'hc most noticeable and immediate effects of Aroeloi 1254 ucie an iik leased respiratory rate, a reduction in the pO., of the blood ( I able 11. and the production of cardiac arrhythmia. Respiratory rates increased from a predose rate of I s m between 40 and A0 vespnations/minute over an approximate I -hour dosing period The effect w-as immediate in that a tw'O- to three-fold increase in respiratory rate usually occurred within about 2 minutes after the initial administration of Aiocloi 1254. The pOv was reduced by SOA; in both arterial and venous blood (table 1). ' K minimi1 in ( i |h: ullage n, 1 lie I iunion (v. ( li vi I,in. I I )lm> 1 llewlell I'm kard. Sanlnnn Uivicum. Wnilham. Miismh Ihim-Hs. MONS 035845 lAHi.l- I i.ini is ui Isinwtsnts Aomisin i ka i ims mi Akiii mu 12.`'I ns Hmh.i. A< imJUm ( mm nisi s i s is <m C,i 1 iiiK' Ailcnal hlootl Vcmms hlond (mini pH p(). |*C(>, pH p(). p(<) 0 7.40 i)(Him kk, i 1 1<H 14 0 2 K<(.) 7 11 * (I 02(7) .14.(1 2 7|7| 4| X 2 2i7i 10 7.2H u HUM 7(1 ( - S ||7j 45 <> 7.?<7j 7.20 II 0f((>) .1) t 2 VO) si (. t mi.. 20 7.2l 0 OM'-I M) I 4.7(0) 44 5 .1 1(7) 7 21 (I 02(s) 2(.,5 1.7(5) ss.2 . ? 40 40 7 11 (I (IMS) S'?.4 S.S(<J u.,2 2 H((>| 7.20 (UUi'i 21.0 o y((>i s: i \ r< 11 '0 7 II 0.01(1) 42 1 4.H(4) IS. j . S 1(4) 7.17 7 0.11.7(1) IKS 4 1(4) S4 H (, M il 7(1 7.?(, (I) SO 0 (1/ 41.1 (I) 7.21 (I) 21. K III '41 (li '* A i in lei 12 s 4 ,ts ,i<lnimisU'u'il ,il Jnsvs (0 I (HI mg-kg ,i( (1. K). and (HI minings V nines .uc pivrn ,i means SI . Nunihus in p.iiTiitliescs .uc I he numlH'i ol animals in each gump. M)';; of that reduction occurred in the first 10 minutes following the initial ad ministration. Acid-huso changes were reflected by an increased pC02 with a con current reduction in pH: I his effeel wns more noticeable in venous blood than m aitonal blood. Hie most predominant feature of the electrocardiograms taken after Aroclor 1254 administration was the development of premature ventricular contractions (l-ig. I. A ami M). These arrhythmias occurred generally as multiple unifocal conliacliotis with or without coupling. Occasionally, ventricular extrasystoles occuncd singly with compensatory pause followed by a normal sinus rhythm. Multifocal prcmainic veuiiiculat contractions were evident to a lesser degree. VeiitiKiilar tachycardia usually preceded expiration in association with rapidly declining blood pressure and loss of respiration. T wave flattening was observed m all cats immediately after the initial dosing with Aroclor 1254. S-T segment deviations wcie observed at various times throughout the dosing period. Wood pressure remained relatively constant throughout the study with the av erage piessure tor all cals over the J-hour dosing period ranging between 91 and In. I ( null.it an In iJunias in cals .ulinimslcrcd Aioclor 1254 (A) Lead 1 clccliocaidiogiam s minim s lolluwiiiiMidmmiMialion ol 1'0 mu Ann. Ini I?'4 Urals 17 II atul 21 aif um local vri.li i. i.u nt ptfmaUUf n>li atturns. Alttt * 5. 25 turn/sec (Hi Lead l ctccirocardtugiam 2.5 minutes lolloss ng .nlmiilisMalum <il MX) 114: Aunlor 1254. dvmonsUaling miilrilni at vi-miiculai 01 piiinatnic imiiIi.h lions. Heals 1. 7. 4. | | | s. and IV ate ahci lanl coin pic sc s. Heals l. 5. 1.1. and 17 aic also aimoiiii.il heats ausing li cm .1 dillcrcnl locus. Attn. -2. 25 mm/scc \M> I 105 mm Hg. Body temperature was difficult to maintain within Oh- mu nial i .min i <\ this study in ail cats ami, I ho re lore, this parameter could not he .uein.iU-k evaluated; however, there diet not appear to he any increased loss ol hoik he.a throughout the experimental period thal could he attributed to admmiMiaiion ot Aroclor 1254. Loss of body heat was ostensibly associated with eerie ml .me si he mu and appeareil to be a slow continuous process from the beginning of pivp.nation for the experiment to expiration of the animal. Application ol he.it liuhi> ami drapes did assist in stabilizing the body temperature. Postmortem examination of all cals revealed grossly hemon hagie anil monied lungs with severe congestion of the dorsal lobes. Incision of the trachea, hi mw In and lung parenchyma revealed the presence of ptilmonarv edema I he cpn.niih.il and endocardial surfaces of the heart were all grossly noimal. as wcic the liu i and kidneys. The control cat given DMSO alone developed an increase m i c'-pu.ii>u \ t,uc from 10 to 25 respirations per minute during the dosing legimen Hlood picssme was essentially unchanged. The p(), of at let ial and venous blood was not creased foliowing administration of DMSO alone at 30-minute intera ah (I able 2). in fact, it increased over control levels by 7 and IOO in arterial and \cmnis blood, respectively, over the dosing period. In general, (he pCO. ami pll lei conversely affected compared with values lor the test animals, as shown h\ iIk decreased pCO. and increased pH. The electrocardiogram from the cat receiving DMSO alone pnoi to AioJoi 1254 show'eil a short senes of synchronous ventnculai piem.itnic contiuetions alter the (ivst and second doses of DMSO. Hat toning of the \ wave was obsei \ed in both cases prior to initiation of the arrhythmias. The administration of Aroclor 1254 after the DMSO injections resulted m a p< > reduction of 55-40'T in arterial and venous blood; pt'O. was mueased and pll was decreased, demonstrating a response similar to that of the ic^t annuals Vi/muis Maml < \KI III l\ \ S( I J M( III] Changes u\ 1 lie electrocardiogram were also similar to those of the test animals following administration of Aroclor 1254: i.e.. T wave flattening. reduced heart rale, ami ventricular cxlra.xysloles occurred. DISCUSSION A roe In r 1254 is a viscous ami highly irritating material ami. although it appear* lo he miscible m the Hood when administered in DMSO. the possibility of ns sepaialion or pieeipitation must he considered. If separation docs lake place, physical blockage of semipcrmcahle membranes aiul/or tissue irritation may o. cur. The development of pulmonary edema would also produce a physical block age to an interchange of oxygen and carbon dioxide at the alveolar level I he mai ked and immediate reduction in oxygen tension (hypoxia) and t lie clas sical lespitatnry acidosis syndrome (low pH and elevated CO.-), as well as the apparently compensating and marked increase in respiration rate, would seem to indicate a physical impairment of gaseous exchange. I'he increased respiratory rale appeared lo have no effect in improving p0_. levels nor did it affect to any great degree the ttcid-ba.se balance (Tabic I). I he mark ed hernon hagic condition of the lungs of all cats observed at postmoi tern examinations would indicate that the primary blockage or impairment may occur at this site. To examine the possibility of interference with the hemoglobin mechanism by A roc lor 1254. a sample of arterial blood from one of the test animals was aerated in a flask containing glass heads. After the blood had been shaken vigoinusiy. il changed from a dark brownish color to bright red. Nubsei|iienl analysis of this sample revealed a marked increase in p():. levels. This demonstrated dial the hemoglobin mechanism was functional i/i wrro and that oxygen uptake by the blood was not impaired. I lectrocardiographic patterns were remarkably similar in all cats. A very defin ile ventricular arrhythmia predominated, ami was always preceded by flatten ing of the T wave and in some eases S T segment dev ialton. T wave changes arc know n io occur undei conditions of hypoxia (Lamb, I9(>5). The ability to produce cardiac arrhythmia with DMSO alone, even for short periods, implies that the more sevue and lasting arrhythmias which developed following administration of the Aroclor DMSO mixture were not totally due lo Aroclor 1254 alone. That the arrhythmias which did develop were prompted by an inability of the ventricle to tepolut i/e must he considered since T wave changes usually preceded development of the arrhythmias. Ilus study suggests that a blockage or interference of the pulmonary al veolar capillary interface hail occurred in (he cats anti resulted in a general hypoxemia. A gradual physiological deterioration, including cardiac impairment, eventually ocemred. leading lo death of the animal. All of these effects would appear to he ditcctly related to those produced by Aroclor 1254 am) not to the vehicle or solvent (i.e., DMSO) for Aroclor 1254. The elfeets of DMSO m the control animal of this study are similar to those previously reported in the dog (IVletson and Koherlson. I%7). lor example, intravenous aihumisliairon of graded doses of DMSO from 5 to 10.000 mg/kg produced few alterations m ear liiopuhnonary dynamies and in arterial pH. p(T. and pC(T. only at the high dose levels of DMSO were physiological alterations detected. 1* Q858S0 HONS It should he emphasized that the effects dcmonstiated in this study icmiIiciI from an Aroclor dosage of a sizable magnitude (KM) ppm) chosen to produce an acutely toxic effect. Such levels do not normally occur in the environment. REFERENCES I'lick. D. t .. O'Dell. K. (j.. and C hitils. V A. (I 9651. Si udics id I lie c hie k ede m.i Jimmm 1 Sumi.mi, of symptoms produced by feeding chlorinated biphenyl Sii 4a. ijmi MiA I ood ami Unig Administration. (197(1). Status report on llic chemisiiv ami luvinilup , f |.oiw I,,,.,, nalcd biphenyls (PC'B) or Aroclors as of June I. 1970 Bureau of I oods. 1-ood and Ding Admmo (ration. Washington. D. C. Gram. D. I... Phillips. W. li. J., and Viltcncu'e. C. I). (19711 Mcinlndism ot a polMldonn.ii.tl biphenyl (Aroclor 1254) mix lute in ibe i al. Hull, i.m in-n ( .ninm I n. i, , ,l t,, |(P I I ' Harrts. J R. (1971). Toxicity of polychlorinated biphenyl and chlor inaicd liy.li oc:o bon pc-I Mile- m broiler chickens. Pood and Drug Administialion. Kockvdlc. Maitland Lamb, L. K. (t%5). "lilectrocardrography and Vector Cardiography. ' pp 414 416 w II Saunders Co., Philadelphia. McCone, li. I... Savage. J H.. and O'Dell. B I. (I%?) Hydropei itaulmm and asc ties m s Iik tel chlorinated hydrocarbon, /'uuhrv \a. 41, 295 299 Penkidt. 1>. B.. amt t.mcer. J l.. 09711) Polychlorinated biphenyls Anoihci lonelily \ndcspic.nl chemical m (be environment. Ihu.Si inn < 20. 9Sg >m,4 Peletson. C. G , amt Robert son. R. I) (1907). A phann.icodvnanm siudy ol duncibvl sulloxidc t<or \' ) Ai Si i. 141, 271 27(i. Vos. J C i.. ami Koetnan, J. H. (1970). Comparative toxicological stiiih wnli pain 'ilomi.iii d biphenyls in chickens w ith special reference lo porphyrins. edema lonnai lissiie residues, hniiul A/'pl. I'liunmu "I. 17. 6V. (><>s Vos. .1. Ci . Koemon. J. H.. Van Der Maas. U. I... Ten Nnevci de Biaow M < .,nd,l. \os U II (1970). Idcnliticalion and toxicologic evalnalion ot i him in.lied dibcn/olm.m ami chloi mated naphthalene in two commercial polychloi ninicd biphenyls. I i !>< i.H r>'' f. I i