Document 0JY8dqEX79aE7EOMeELrvBpJV

I UIKDSMI \1 M IllSf \Hl II 1 J . 353 35g ( I 97(0 Acute Effects of Aroclor 1254 on the Feline Cardiovascular System Jl. ]'. Rich iih, N. H. Boo rn,1 ,\.\'i> R. H, Ti ski f)i\i\imi of Veterinary MeJital Re\etnvh. final ami Petty: Administration. I'. ,S, I>i f>urnni`nt of Health, f ilm ufion. tmd Welfare, fiellsviffe. Maryland 2()7Ue` Received July 6. 1975 Amcloi 1254 was aihninisteied iniravcnously at 30-minute intervals U> anesthetized eats at a dosage o! 1(H) mn/kjt body weight. Arterial and venous Mood samples were taken at UMmmiie intervals tor dcleunination of oxygen tension (p(),). eaibon dioxide tension (p('();). and pit. hlei. Mocardiogranis. blood pressure, and respiration were recorded as well. The p< >v of I lie blood was reduced rapidly and markedly with concurrent changes in p('(). and pH chaiacleri/ing a respuatory acidosis. Respiratory rate increased to a sizable dcgiee with development of cardiac arrhythmias. Alt animals died within 60 minutes following initial dosing. Severely hemorrhagic lungs in conjunction with edema were observed in all cals at necropsy. The Aroclors are members of a group of compounds called polychlorinaied biphenyls (RCBs). The Aroclors. which have many industrial uses, arc utilized as components in heat exchange units of fishmeal processing plants. In 1971. a leak ing heat exchange unit resulted in the contamination of poultry fishmeal by Aroc lor 1242. This incident and others focused attention on the potential toxicity of the RCBs. since they persist as environmental contaminants. The various Aroclors are reported to be one-quarter to one-fifth as toxic as DDT (lVakall and l.inccr, 1970). Some of the major toxic effects of RCBs in fowl (l-'lick cl nl.. 1965; Harris. 1971: McCune cl al.. 1962; Vos and Kocman. 1970) and rats (Rood and Drug Administration, 1971; Grant cl at., 1971) have been described and include the development ol edema, lowered hemoglobin levels, enlarged kidneys, and liver damage. Vos cl nl. (1970) have suggested that a toxic factor or impurity may be present m RCBs and may cause the toxic effects. In preliminary studies in our laboratory, we observed that a high degree of hypoxia and markedly darkened arterial blood occurred in dogs administered intravenously 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 of RCBs in the cat emphasized the need to initiate this study. Consequently, the primary purpose of this study svas to evaluate the action of Aroclor 1254 on selected parameters of the feline cardiovascular system. MATERIALS AND METHODS Aroclor 1254 (i 'I)A sample 370 71-698) was warmed in a beaker of hot water to reduce viscosity. A 25-ml glass-stoppered graduate was tared on a top-loading balance, and 5.0 g (3.25 ml) of Aroclor was pipetted into the giaduate and diluted 1 Present .hMicss Depaiimeni nl Physiology anti Pharmacology. College ol Vetcrm.u) Medicine. University ol (ieoigi.i. Alliens. Ccotgia 30601. < >>ps ll7r, B, Ac ,,dei Russ liu 353 b;,;: - 3^4 KI(;H 1 IK, DIKMII \M) IINKI in ;i volume of 10 ml with 99.99? DM SO. A clear solution was produced with agitation. anil (here was no evidence of separation of the two phases throughout the study. All utensils containing Aroclor 1254 were rinsed with hexane and etlnl alcohol and the rinses were placed in a plastic jug for proper disposal. bach of seven mongrel cats (three males and lour females).'weighing between 2.6 and 4.1 kg. was anesthetized with sodium pentobarbital (25- 30 mg-'kg) via the cephalic vein. The right and left femoral veins and the left carotid artery weie cathcleri/cd. following a procedure of blunt dissection, with intramedic polyethylene tubing (0.034 in. i.d.; 0.060 in. o.d.). The cathetcri/cd vessels weie kepi palenl by flushing them with heparinized saline solution before and al'ie. administration of the compound and blood sampling. Anesthesia was maintained by administering sodium pentobarbital into the tight femoral vein as required. 1 he Aroclor-DMSO solution was administered into the left femoral v ein at a dosage of 100 mg Aroclor/kg at 30-minute intervals to six of the seven eats; the fluid volume averaged 0.6 ml. The remaining cat received three doses of 0.6 ml of I)MS() alone at 30-minulc intervals followed by two doses of Aroelor-DMSO. also at 30-mimiic intervals. The catheter used for administration of Aroclor 1254 was rinsed with hexane and ethyl alcohol and was used in all cats for Aroclor administration onl\ blood samples were taken with 1-ml glass syringes coated with Vaceline to reduce gas loss and purged with sodium heparinate (1000 unils.hnll to pi event coagulation. Approximately 0.5 ml of blood was taken at each sampling time Arterial and venous samples were taken from the carotid artery and t ight femoral vein, respectively, just prior to the first dose and at 10 and 20 minutes after each dose. All samples were analyzed for pH. oxygen tension (p(and ('()_ icnsiou (pCO.) by using the blood microsystem and digital acid base analyzer.- Arterial pressure was monitored through a physiological pressure transduce! and recorded along with respiration and an electrocardiogram by using an eight channel recording system.n Respiration was recorded w ith a bellows t \ pc pneumograph, and a lead 1 or 11 electrocardiogram was obtained by using a stand ard live-wire patient cable. Recordings of the above physiological parameters were obtained at two intervals prior to the initial dose and just preceding and following each dose thereafter. Tracings w'ere also taken at various intervals din ing the dosing period when a change was observed in the electrocardiographic tracing. Record tracings were taken at a chart speed of 25 mm/second. RESULTS The most noticeable and immediate effects of Aroclor 1254 were an increased respiratory rate, a reduction in the pOv of the blood (Table 1). and the production of cardiac arrhythmia. Respiratory rates increased from a predose rate of 15 to between 40 and 60 respirations/minute over an approximate 1-hour dosing period. The effect was immediate in that a two- to three-fold increase in respiratory rate usually occurred within about 2 minutes after the initial administration of Aroclor 1254. The pO_, was reduced by 50'/? in both arterial and venous blood (Table I). 7 RadionK`k*i-( npenluncn, I lie 1 .ondon ('nutpuny , ( Ic vclatnl. ( Hmt '* 1 U'wJell-Rackatd. Sanhorn Division, Waltham. MassacItuscMs. DSW 031519 STLCOPCB4015481 < .A U! > l > V,\S< ! I A K I I I I ( : I S J N IS i. I \ |- .S 3 55 tami.l i I'.IIU is 1)1 [\ I K.w I MH S AlM IMS J kA J IMS' Of A HOC1 OK 1 254 OS Ml ooi) Ar n>-B\sl ('omi'iimms is nil C\v d' Time Ark-rial blood Venous blood (mm) I'll pO pro,. pH P<>. pCO 0 7.40 o.ooo) 100.1 - 7.7(0) 74.0 2.8(0) 7.77 - 0.02(7) 79.0 2.7(7) 41.8 - 2 2i7i It) 7.28 ' 0 0110) 70 I 7.1(7) 47.0 - .7.2(7) 7.20 - 0.01(01 .71.7 2.9(7) 71.0 7 11(01 20 7.20 o (0(0) 00.1 : 4.7(0) 44.7 - .7.1(7) 7.27 .-. 0.02(7) 20.7 ' 1.7(7) .77.2 - 2 9(7) 40 7 71 (I (17(7) 72.4 5.7(0) .70.2 2.8(0) 7.20 0.01(7) 27.0 0.9(0) 72.1 - 7. 1(1) 70 7 .11 0.01(7) 42.7 < 4.8(4) 77.1 - 7.7(4) 7.17 2: 0.07(7) 18.7 ? 4.1(4) 74.8 0 1(1) 70 7.20 (1) 70.0 (1) 41.7 0) 7.21 (I) 27.8 (1) 74,1 (1) " Amcloi 1254 was .idnimislcicd al Joses of KM) mg/kg at 0. 30. and (>() minutes. Values ;ue given as means ` SI . Numbers in parentheses are Ihe number of animals m each group. of that reduction occurred in the first 10 minutes following the initial ad ministration. Acid-base changes were reflected by an increased pC02 with a eoncurrent reduction in pH: this effect was more noticeable in venous blood than in arterial blood. The most predominant feature of the electrocardiograms taken after A roc lor 1254 administration was the development of premature ventricular contractions (l;ig. I. A and H). These arrhythmias occurred generally as multiple unifocal contractions with or without coupling. Occasionally, ventricular extrasystoles occurred singly with compensatory pause followed by a normal sinus rhythm. Multifocal premature vcntiicular contractions were evident to a lesser degree. Ventricular tachycardia usually preceded expiration in association with rapidly declining blood pressure anil loss of respiration. T wave flattening was observed in all cats immediately alter the initial dosing with Aroclor 1254. S-T segment rle vial ions were observed at vat ions times throughout the dosing period. Illood pressure remained relatively constant throughout the study with the av erage pressure for all cats over the 1-hour dosing period ranging between 91 and In.. I. ('aidinc ;u r hs ihmias in cals administered Aroclor 1254. (A) Lead 1 clccirocardiogram 5 minutes following admimstlalion id 350 mg Aroclor l?*>4 Meats 3. 7.11. and 21 arc unifocal venlricnlai ot ptcmaliuc coniiactions. Ann. *5, 25 inm/sec. (M) Lead 1 electrocardiogram 2.5 minutes following administration ot 3tM> nig Aioclor 1254. demonstialmg multifocal ventricular or premature contrac tions. Heal s L 7. d. ) |. | and |9 are abet rani complexes. Heals L 5. 13. and 17 arc also a boot mal beats arising Mom a diMcrcnl focus. Alin. *2. 25 mm/see. 35(> K II M II K. Ill II) III AMI II SM 105 mm 1 Ig. Body temperature was difficult in in;iinl.iin wit!>in the normal r.inttc nl this sluily in nil cuts and. therefore, ihis parameter could not he accmaiili evaluated; however, there did not appear to be tiny increased loss of hodv he,it throughout the experiment;!] period that could be attributed to administration ol Aroclor 1254. Loss of body heat was ostensibly assoeiated with general anesthesia and appeared to be a slim continuous process from the beginning of preparation lor the experiment to expiration of the animal. Application of heat Indus and drapes did assist in stabilizing the body temperature. Postmortem examination ol' all cats revealed grossly hemorrhagic and mottled lungs with severe congestion of the dorsal lobes. Incision of the trachea, bronchi, and lung parenchyma revealed the presence of pulmonary edema. The epic.ii dial and endocardial surfaces of the heart were all grossly normal, as were the li\ci and kidneys. The control eat given DM SC.) alone developed an increase in respirators tale from 10 to 25 respirations pet minute during the dosing regimen. Blood piesstue was essentially unchanged. The p(), of arterial and venous blood was not de creased following administration of DMSO alone at 30-minute inlcr\als ( I able 2i: in fact, it increased over control levels by 7 and I0D in arterial and venous blood, respectively, over the dosing period. In general, the pC'O. and pi I levels were conversely affected compared with values lor the test animals, as shown by tliedec leased pC(L and increased pH. The electrocardiogram from the cal receiving DMSO alone piior to Aroeloi 1254 showed a short series of synchronous ventricular premature contractions after the first and second doses of DMSO. flattening of the T wave v\ as iTsct \ cd in both cases pi ior to initiation of the arrhythmias. The administration of Aroclor 1254 after the DMSO injections resulted in a p( > redaction of 35-400 in arterial and venous blood; pCO, was ineieased and pH was decreased, demonstrating a response similar to that of the lest animals TlU t a n i .!: ? ['. Mil ()> l\IRUI\l>l s Ahmimsih \ I 1( IN ( >| ] )l Ml nm Si ii> i\ini (PMS( )i \j \ i A Id X U >K 1254- DMSO Mini nti M's Ml OOl) A< 111-H\m C'* > m i IS tut <1. i" \ Time (min) 0 10 20 40 .Ml 70 Wl 1(H) 1 10 Oil pH 7.-tv 7.44 7.4-1 7.4 V 7.47 7. MX 7..V4 7.44 7.4? 7.40 Arlcrial Mood pt>.. 00.0 S4.V 01. V 90.0 07.0 102..S 111.5 67. V V7.0 6V 0 pot), 77.5 70.0 2^.9 27.5 27.2 21. K 20.0 ?K.O 2v.li pit 7.10 7 VI 7.42 7.41 7.41 7.42 7.4.1 7 12 7.27 7 2? Vcnius hJoiul pO.. 20.1 Vl 5 41.1 40 0 ,1V 0 17 7 W> 5 21 7 72 o 7' ^ P< 1 1 41 0 Vs 1? 7 s IS K 7' 0 Vi. 1 in ; ' IS s " DMSO alone (0.6 ml) was ailministeieil al t). .10, anil 60 minutes: Aiocloi 12.V4 (inn DMSO was ailnilnistcreil at 00 ami 120 minutes. mi Ss$! itiLu. DSW 031521 ,v, Jka ftVJi STLCOPCB4015483 ( \KUIU\ AM I 1 All I I I 1 l IS IN 1,1 IMA IS 7 Changes in (Ik- electrocardiogram were also similar lu those of (lie lesl animals following administration of Aroelor 1254; i.e.. T wave flattening. reduced head rale, and ventricular cxtrasysloles occurred. DISCUSSION Aroelor 1254 is a viscous and highly irritating material anil, although it appears to he miscible in (lie blood when administered in DMSO. the possibility of its separation or precipitation must be considered. IT separation does take place, physical blockage of semipei mcahle membranes and/or tissue irritation may oc cur. The development of pulmonary edema would also produce a physical block age to an interchange ol oxygen and carbon dioxide at the alveolar level. The marked and immediate reduction in oxygen tension (hypoxia) and the clas sical respiratory acidosis syndrome (low pJ I and elevated C(b). ax well as the apparently compensating and marked increase in respiration rate, would seem to indicate a physical impairment of gaseous exchange. The increased respiratory rate appeared to have no effect in improving p().. levels nor did it affect to any great degree the acid-base balance (fable I). The marked hemorrhagic condition of (he lungs of all cats observed at postmor tem examinations would indicate that the primary blockage or impairment may oeem at this site. To examine the possibility of interference with the hemoglobin mec hanism by Aroelor 1254, a sample of arterial blood from one of the lest animals was aerated in a flask containing glass heads. Aflcr the blood had been shaken vigomusly. it changed from a dark brownish color to blight red. Sub sequent analysis of this sample revealed a marked increase in p().. levels. This demonstrated that the hemoglobin mechanism was functional in vino and that oxygen uptake by the blood was not impaired. Idcciiocardiographic patterns were remarkably similar in all cats. A very definite ventricular arrhythmia predominated, and was always preceded by flatten ing ol the T w'avc and in some eases S- I segment deviation. T wave changes arcknown to occur under conditions of hypoxia (Lamb, I9(>5). The ability to produce cardiac arrhythmia with DMSO alone, even lor short periods, implies that the more severe and lasting arrhythmias which developed following administration of the Aroelor-DMSO mixture were not totally clue to Aroelor 1254 alone. That the arrhythmias which did develop were prompted by an inability of the ventricle to repolai Dc must be considered since T wave changes usually preceded development of the- arrhythmias. This study suggests that a blockage or interference of the pulmonary al veolar capillary interlace had occurred in the cats and resulted in a general hypoxemia. A gradual physiological deterioration, including cardiac impaiimcnt. eventually oceuiic-d, leading to death of the animal. All of these effects would appear to he directly related to those produced hy Aroelor 1254 and not to the vehicle or solvent (i.e.. DMSO) tor Aroelor 1254. The effects of DMSO in the control animal of this study arc similar to those previously reported in the dog (IVleison and Kohc-rison, l%7). Tor example, intravenous administration of graded doses of DMSO from 5 to H).(KK) mg/kg produced lew alterations in car diopulmonary dynamics and in arterial pH. p()L.. and pC(T; only at the high dose levels of DMSO were physiological alterations detected. K]<:11 i l it, imiim ami i i ski ll should he emphasized that the effects demonstrated in this study resulted from an Aroclor dosage of a sizable magnitude (100 ppm) chosen to produce an acutely toxic effect. Such levels do not normally occur in the environment. REFERENCES I 'lick. I). I ., O'Dell, K. G., and Childs. V. A. (1965). .Studies of the chick cdcm.i disease ' Similar iu of symptoms produced by feeding chlorinated biphenyl, f'oultrv Sn. 44. 1460 I46< food nnd Drug Administration. (1970). Stains report on the chemistry and to\icnlog\ >f pols x him i nalcd biphenyls (PCD) or Aroclors as of June I, 1970. Bureau ofloods, hood and Ding Admmis (ration, Washington. 1). C. Grant, D. I,.. Phillips, W. T. J., and Vilfcncuve. C. I). (1971). Metabolism of a polxchlounatcd biphenyl (Aroeior 1254) mixture in the rat. linlf. l-.n\-in>n. ('wi/mu fn.xuni u. 10? ) I ? Harris, J. R. (1971). Toxicity of polychlorinated biphenyl and chlorinated hydrocarbon peMisido" m broiler chickens. Pood and Drug Administration, Rockville. Maiyland. Lamb. L. P. (l%5). "hlcctrocardiography and Vector Catdiography." pp. 434 - 436 W. B. S.tumlers Co., Philadelphia. McCune. L. L.. Savage. J. H., and O'Dell. B. I., (1962) Hvdropei icauhum and ascites in chk k^ led a chlorinated hydrocarbon. /`aulfrv Sri. 41, 295 -299. Pcakall, D. M.. and lancer, J. L. (J970). Polychlorinated biphenyls; Anothei long-lilv uidcsptc.ul chemical in the environment. Hia.Srtrm r 20, 95K 964. Petei son, C. (>, and Robertson. R. D. (1967). A pharmacodynamic study of dimethyl sultovide Wm A'. Y Arad. Sri. 141, 273 276. Vos. J. G., and Koeman, J. II. (1970). Comparative toxicological study with polychlorinated biphenyls in chickens with special reference to porphyrias, edema formation, hvei ihmusix and tissue residues. lo.xiitd. AppL Iduirnitn id. 17, 656 66K. Vos. J. G , Koeman, .1. H.. Van I)er Maas. II. L.. Ion Noever tie Hiaii'A. M C . and de Vns R II (1970). Identification and toxicologic evaluation of chlorinated ilibcn/ohnan and vhiomi.tted naphthalene in two commercial polychlorinated biphenyls. iiKut Co.wm r ./ H. (05 6^' STLCOPCB4015485