Document VjGy0am0MvZpjo9om5ndJDkOo

R&S 135897 is ^ 2to'b'i-~(! oo\ > [197/j / ' ' .> 1 upon tho -* | studies.- , :rnnLi from .'ouncil for p <-t- 0|VTX'^/` 1 265 U <">t 4 I College of 7. J. d 4. K of Educa- flnd Home erm motion nlion with in Lab //:- Cardiac Arrhythmias and Aerosol "Sniffing" Charles F. Reinhardt, MD; Alex Azar, MD; Mary E.^taxfield, PhD; Paul E. Smith, Jr., MA; and Linda S. Mullin, Wilmington, Del olorimotric m 66:375- A clinical 'd endogef 32.-65-79, oved and trie deleri 35:1961- hydroxyW, 1965. ' /or (A Hill Book axial and i caloaB 196^H tho ilson JT, ew York, to. losphorua 8:76-79, -steoporo- ile oateo- t et al: '/re Joint (Aerosol "sniffing," a variant of glue "sniffing," the "sniffing" of aerosol products or aerosol involves the deliberate inhalation of aerosol product propellants for the same purpose. j products and propellants. Approximately 65 deaths "Sniffing," incidentally, is a misnomer, since 1 have been attributed to this practice. They have the practice involves the deliberate, deep Ibeen predominantly sudden and generally lack conclusive autopsy findings. The cause of death Iras not been defined in most cases; however, various mechanisms have been postulated. The evidence suggests acute cardiac arrest as a fre- inhalation of highly concentrated vapors, but the term has received popular usage. . Occasional fatalities have resulted from, tho various forms of solvent sniffing. That (quenl cause. It could result from the sudden onset fatalities could also occur from tho sniffing ol ventricular fibrillation due to sensitization of of aerosol products and aerosol product pro I the heart to epinephrine by inhalation of high pellants was somewhat of a surprise, since concentrations of aerosol contents. Experimental these have been noted for their low toxicity. investigation revealed that the commonly used Thus far, approximately 65 deaths have * aerosol propellants, in high concentrations, are been attributed to this fad. The first were capable of sensitizing the heart to epinephrine reported in early 1967. In that year seven resulting in serious cardiac arrhythmias. There- deaths occurred and all followed the sniffing tare, it is concluded that cardiac sensitization is of a product used to chill cocktail glasses. In a likely mechanism of death In many of the , eerosol-sniffing fatalities. 1968 and 1969 there were 31 and 27 deaths, respectively. During these two years, the practice encompassed numerous aerosol PLE, and especially teen-agers, have been "snifnng" glue, paint thinner, gasoline,' products including fry pan lubricant, hair spray, deodorant, antiseptic, and others. j I and other volatile solvents for years in an attempt to get "high" or for "kicks." More The principal technique used in sniffing aerosols is to spray an aerosol product into recently the practice has been extended to a balloon or bag and then deeply inhale the contents. This procedure results in the inha Submitted for publication Feb 23, 1970; accepted lation of a high concentration of gas and March 25. vaporized liquid from the aerosol. The From the Haskell Laboratory for Toxicology and Industrial Medicine, E. 1. du Pont de Nemours & "gas," in most cases, would consist of a high Co.. Wilmington, Del. proportion of aerosol propellant Propellants J Read before the 22nd annual meeting of the American Academy of Occupational Medicine, Cin- used widely in aerosol products include such dnnati. Feb 11, 1970. halocarbons and hydrocarbons as fluorocar Reprint requests to E. L du Pont de Nemours & Co, Haskell Laboratory for Toxicology and Indus trial Medicine, Elkton Road, Newark, Del 19711 (Dr. Reinhardt), bon 12, fluorocarbon 11, fluorocarbon 114, isobutane, propane, and vinyl chloride. The aerosol sniffing deaths have been pre- Arch Environ Health--Vol 22, Feb 1971 R&S 135898 i i i l f 4 f I { \ l f Ir t f I i pr<S=ons Table 1.--Compounds Tested tor Cardiac Sensitization Properties A.thos* Considered Most Active ^/Benzene Potent sensitizer in animals and Is even active without epinephrine'.*; cases of sudden death In industry where mechanism could be ventricular fibrillation**" S*Hep(ana Similar to benzene In potency in animals9; no deaths reported in industry but industrial use is limited ^ Chloroform ^ ^ , ^~Z " t * . t CT i- o // * Similar to benzene in potency in animals'.**"; known to be a cause of sudden death In map due to ventricular fibrillation; this experience comes from its use as an anesthetic; acute mortality is reported to be about 1:3,500 when the agent is used as the sole anesthetic agent in a concentration of 1.0%*l.65&" / Trichloroethylene -2. SVO Little animal data are available but sensitization has been shown to occur".*4; sudden deaths have occurred in industry following exposure to high concentrations of this agent and these deaths are compatible with ventricular fibrillation"-"; perhaps because of its wider use, more deaths are recorded for this agent than any of the others i/a. Those Considered Intermediate in Potency Carbon tetrachloride K>- "/1 *\ v. Because of a sparsity of animal data it is difficult to classify this compound"; it has caused sudden death in man"; but considering its earlier wide use* experience would suggest that it is not as active as trichloroethylene Halothang "" (or ftuothane) ^ Shown to cause sensitization in animals*1 *** and in humans in the 0,5%*1*05? range1*; not used In industry; should perhaps be classified in group A but because of dose supervision during anesthesia untoward results are rare .'e in t the ccurs In and 3SOC1- aths, tizagen- 11 S3 e of 5Dtn- C, Those Considered Weak Sensitizing Agent| or Where D*ta Make Classification Difficult diethyl chloride" ^ isopropyl chloride" 7' 'Lflfethyl bromide" K ?J l/Methylene chloride" y/tthy! chloride" < iia Z. ^ V Ethylene chloride" \Jbppyt chloride" C' V1 ethane" <3 V WH f n/ propylene"* /'C j. -*c? / :' ^ ^Butane1** ATJ<?72.j\ - ^fctylene4* fC* SVJ V Spiropentane4* Trifluorochlor-ethylene*** ^ ^primary butyl chloride" fOO'7 j^pthyt bromide" AC f *7 -^r' \ '^^Secondary butyl chloride" Isobutyl chloride" j^ethyl iodide" s . i_*fhyl iodide" Jfc; xT? 31 Tertiary butyl chloride" L/f^obutane11* j> 1> \^8t - ^Cydopentane" 7." cis-or trans-butene*2M* J) 3 2. *7^ ^>4opentane* 3 3 5* ^ Cydobutene"* 2,2-dlmethyl-butane11* 3 Cydobutane"* u^inyl chloride4* ^ Methyl cyclobutane1* -< Isopropenyl chloride4* THchloromonofluoroethyfene*'*^,/^^ri^a_na-dichloroethylene1,* T P *7 Monochforodifluaroethylene*?* ^, ,-t,crCici~sd^tdcihciholrooreotehtyhf<ylene*7" ^ 0* Compounds Which Old Mot Cause Sensitization LfHjylene S' O.So'ht p. /C47<f7 7 K (jfrfjrafluaroethylene^ AT 7 17-Tt- ' DLhuoroethylenc'' ^.--Ethy,l-e--n--e---o---x--id--e" - - *'w *- 'J'Vtooqpylene oxide4* fc i lol _ Alcohol (very ws.k)" 4[^tetona (very wtaky* ^ V * Compound given In high concentration (15% to 90%) and arrhythmias produced In 1C0% of dogi teated. Arch Environ Health--Vol 22, Feb 1371 4*UU oivin'iivu -- /i.><*41444 4 44Ml*l>kf / U 1 Lj t\. * l \\JLt tiftii'tumuj i r, i u > dominantly sudden and only in two cases of death. This could bo caused by sensitiza- ( has an explanation for the deaths been dem tion of the heart to epinephrine with the (' onstrated at autopsy. Although the cause of sudden onset of cardiac arrhythmias result- death has not been defined in most eases, ing from the inhalation of high conccntm- [ various mechanisms have been postulated. tions of propellant compounds in the pres- > These include anoxia, narcosis, oxygen dis encc of elevated levels of epinephrine. This I placement from the lungs, freezing injury to phenomenon is referred to ns cardiac sensiti- [ the respiratory epithelium, laryngeal spasm zntion. ' 'i or edema, and acute cardiac arrest (ventric The phenomenon of cardiac soasitizatioa I ular fibrillation). The latter four are listed is not new. It has been known from some ? among possible mechanisms of death in the time that the inhalation of certain hydrocar- ( National Clearinghouse for Poison Control bons, for example cyclopropane and chloro- j Centers Bulletin,l form among inhalation anesthetics, can ) Under the conditions in which these aero make the mammalian heart abnormally rc- [ sols arc inhaled, ie, taking several deep active or sensitive to epinephrine, resulting f breaths of a highly concentrated compound in cardiac arrhythmias. These arrhythmias \ from a bag or balloon, it is easy to see that are usually ventricular in origin and may I anoxia and narcosis with their accompany result in sudden death. r ing symptoms could occur. However, should Cardiac sensitization was first demon these conditions progress to the point that strated by Levy-1-* in the early years of this the individual would become incapacitated, century when he showed that in cats the the bag or balloon should fall free from the intravenous injection of an amount of epi- | breathing zone and the person would resume nephrine that alone was nonhazardous breathing fresh air and regain complete con would, during chloroform inhalation, cause . sciousness. In addition, the fact that some of ventricular fibrillation. Since then, a grow- these subjects were walking or running im Ing number of unsubstituted and halogenat* mediately before death occurred is evidence ed hydrocarbons have been found which sen that anoxia or narcosis were not causes of sitize the heart to epinephrine, resulting in ? death in these instances. For both reasons, it the production of ventricular arrhythmias. I seems that anoxia or narcosis could not A list of chemicals (not all inclusive) ( account for more than a small percentage of which have been reported in the literature these deaths. as being capable, experimentally, of produc Since previous animal experiments2 with ing cardiac sensitization is found in Table 1. sulfur hexafluoride did not demonstrate that The majority of these compounds have l this heavy gas displaced air from the lungs, merely been rated as causing or not causing it is doubtful that the gases inhaled in the sensitization. A few studies have been more * aerosol-sniffing cases would have had this quantitative and where a judgment has been y effect. In regard to damage of the re made as to whether a compound is a strong f spiratory epithelium by freezing, there has or weak sensitizer, this has been noted. If j been no evidence that this was a causal there is relevant information on human ex- I factor in the aerosol-sniffing deaths. perience with the test compound, this is also j Laryngeal spasm or edema could result noted. t from aspiration of yet unvaporized droplets As indicated in Table 1, experience in f of the aerosol product or propellant causing medicine and industry has shown that the shock to or freezing of the larynx sufficient phenomenon of cardiac sensitization occurs to produce laryngeal edema or spasm and, in man as well as laboratory animals. In thus, cause death by blocking the flow of air view of this plus the clinical picture and in and out of the lungs. This has reportedly nondiagnostic pathological findings associ been shown to have occurred in two cases os ated with most of the norosoI-sniiTing deaths, / indicated by the autopsy findings. it was decided to study Lhc cardiac sensitiza- The clinical picture plus the general lack tion potential of the aerosol propellants gen- f of autopsy findings suggests that an acute erally involved in these deaths as well as cardiac arrest such as would occur in ven other aerosol propellants. The purpose of | tricular fibrillation may be a frequent cause this study was to determine if these com- r A* Thote Beni* HepUn Chlorofc TrtehlO'C 6. Those Corbon t Hafothor (or F C, Thot MethyEthyl c Ethyl*Propyl Ethant Proper Pr opy* n-ButJ AcetyU Spirop Trifluo Mpnoc D, Comp Ethyl*' Tctraf; Ethyl** AlcohO * Com; Arch Environ Health--Vat 22, Feb 1971 f r &S 135901 Table 2.--Materials Used lor the Screening Experiment and Their Sources Dcsipnation fiaorocarbon 1 1 fluorocarbon 12 Fluorocarbon 22 ^joroearbon 114 pPLorocarbon 1 ] 5 Fluorocarbon C*3218 , fluorocarbon 152a Fluorocarbon 142b Fluorocarbon 502 laobutane Propone Dimethyl ether Vinyl chloride Chemical Name Trichlorofhioromcthane Dichlorodiiluoromcthane Chioroditluofomelhane 1.2-d<chiorotetfatluoroethane ChlpropcntoHuorocthane Octafluorocyctobutane 1.1 *dfluoroetha ne 1 -chloro-1.1 ddluoroethane Azeotrope; 48.5% Chioroditluofomelhane/ 51.5% ehloropentailuoroethane by weight 2*methyl propone Oimcthylmcthane Methoxymethane Chloroethene Source e. 1. <lu Pont dc Nemours A Co. e. 1, du Pont do Nemours A Co. E. 1. du Pont de Nemours A Co. E. 1. du Pont do Nemours A Co. . 1. du Pont dc Nemours A Co. e. 1. du Pont de Nemours A Co. E. 1. du Pont de Nemours A Co. E. i. du Pont de Nemours A Co. E. 1. du Pont dc Nemours A Co. Phillips Petroleum Co. Phillips Petroleum Co* Matheson Scientific Matheson Scientific Table 3.--General Protocol Standard Exposure TTTt 0 min: Start O*- *o0 Air =2 o a- 2 min; Administer epinephrine intravenously; the total dose (0.0C8 mg/kg) is contained In 1 mi of normal saline and is Injected in 9 sec by an automatic infusion pump t. '*1 7 min: Administer compound c o K < -c _ Air and -- Compound - 4- - 17 min: Stop compound administration; end experiment Short*Term Exposure 0 min: Start 2 min: Administer epinephrine intravenously; the total dose (0.008 mg/kg} ~ is contained in 1 ml of normal saline and is injected In 9 sec - by an automatic infusion pump O Air c Oo H VAPc--------------._______________-: { Alr jn I 12 min: 12*5 min; Administer compound: administer epinephrine (challenge injection) Discontinue vapor exposure CL-. ------------ :________--3 15 min: End experiment * Vapor administration period* air and compound. Arch Environ Health--Vol 22. Feb 1971 J 4 *4 *4 4 J 4 iii usiKj /mi/ f\,nv&vL, owirritvi* --lihlNUAtiU'L' hT AL ai:i> R&S 135902 pounds possess this property and thus at- a metered volume of the gas from the cylinder tcinpt, experimentally, to verify the hypoth and diluting it with a known volume of air (Fig Dc sifn*ton esis that cardiac sensitization is a probable 3 f gases]). The diluting airflow was fi-fl fluorocarbon 1 l cause of death in aerosol-sniffing fatalities. through a flowmeter fitted with a feedback fluorocarhon ! 2 differential pressure regulator so that the flow FluOrnd Materials and Methods downstream from the regulator remained con stant despite changes in the upstream pressure. f luorocarbon 1 I * ! .1 Two types of experiments were performed. The first, a series of screening experiments, involved exposure of doss to various unsulvstltuted and halogenatod hvdroearhons at several The diluting flow was maintained at a level of 10 to 20 lifer/min except in the ensc of expo sure to 50.0% fluorocarbon C-318 where the flow was 8 liter/min. Where necessary, a heating tape was Fluorocarbon C-."' Fluorocarbon 1 5 fluorocarbon Fluorocarbon 50^ concentrations for a duration of five minutes. wrapped around the copper tubing leading di This was followed by administration of a chal rectly from the cylinder to ensure complete Isobutane lenge injection of epinephrine and the record vaporization of the material. Propane ing of an electrocardiogram to determine the effect of this procedure on the cardiac rhythm. In the case of dichlorodifiuoromethanc. the duration of exposure was varied to examine the effect of (his factor upon cardiac sensitization. The flowmeters used for monitoring the vol ume of test material were calibrated with each compound using a dry test meter. The flowmeter used for monitoring the diluting air was calibrated in a similar- manner. Dimethyl ether Vinyl chloride Following the initial screening experiments, The final compound-air mixture then passed it was decided to carry out an experiment into a 1-inch bore copper tube about 3 feet in which might closely simulate what actually length and was carried to the dog mask. happens in aerosol sniffing. It dealt primarily Since the concentrated and diluting flows with those compounds most frequently used as entered this tubing within a few centimeters of aerosol propellants and involved the adminis each other, mixing of the two flows occurred tration of a high concentration of compound for rapidly. The compound-air mixture was ex- a duration of 30 seconds, accompanied by a hausted to the outside atmosphere by means of I ' stimulus intended to frighten the animals and an exhaust fan. A 20.5-gal drum with an open thereby cause the endogenous release of epi ing to the laboratory atmosphere was placed in nephrine. Screening Experiment the exhaust line to absorb changes in flow rates due to the dog's respiration. The relatively high rate of the combined vapor (gas) and airflow, oo f?i coupled with a slight negative pressure applied Materials.--The materials studied and their to the exhaust tube from the mask, assured an source are listed in Table 2. AH of the com pounds studied were commercial materials which were analyzed and found to meet speci fications required for aerosol use.' adequate air supply to the dog and rapid re moval of the expired air. The vapor of fluorocarbon 11 was generated by passing air through the compound which toO-. 2Vrt X"o3 Epinephrine (adrenaline) hydrochloride, was contained in a gas-washing bottle (Fig 3 1:1,000, was obtained from a commercial phar [liquids]). The bottle was partially immersed maceutical company. in a water bath maintained at the optimum Experimental Animals.--Healthy, male, bea temperature for generation of the desired con gle dog3, 13 to 26 months old, weighing 7 to 14 centration. The water bath was heated by an kg (15.4 to 30.9 lb) were used in this study. electric heater for immersion, agitated by an EZ The dogs were kept in a laboratory kennel electric stirrer, and the temperature was main environment for several weeks prior to their tained by a temperature controller. Once the use. They were trained to maintain a standing optimum bath temperature was established, the position while lightly supported by a cloth concentration of vapor being generated was sling, to wear a mask over their nose and controlled by varying the airflow through the mouth, and to accept a venipuncture (Fig 1 test compound. A heating tape wa3 wrapped and 2). Generation and Administration of Com pound.--Except for fluorocarbon 11. all of the around the stainless steel tubing just beyond the vaporizer to overcome evaporative cooling and, thus, prevent condensation of the vapor. compounds studied exist in the vapor or gase A short distance beyond the vaporizer, a tube ous phase at normal ambient temperature and fitted with a toggle valve led to the exhaust pressure and, therefore, were stored in pressure reservoir. This enabled the airflow from the cylinders. The desired concentrations (calculat vaporizer to bypass the dog and thus permitted ed concentrations) were achieved by delivering only fresh air to pass through the dog mask at ' Vapor admin.; Arch Environ Health--Vol 22, Feb 1971 from a standard size 7 sur geon's glove. All parts of the mask wore coated with a heavy layer of epoxy resin, and the mask, although held in place by an external rloth cover, was supixirtcd by hand. Measurement of Vapor Concentration.--A small por tion of the compound-air mixture was withdrawn con tinuously for analysis at a point just before the mixture entered the mask. For all compounds except fluorocar bon 11, the concentration was calculated from the gas and airflows and monitored hy a Haskell Laboratory thermal conductivity gas analyzer so that any significant changes in concentration could be de tected. For fluorocarbon 11 and for the one-half- and one- hour fluorocarbon 12 expo sures, a gas chromatograph, incorporating a hydrogen flame ionization detector with nitrogen serving as the carrier gas, was used to mea sure the vapor concentration. The column used was stain less steel, 5 feet in length with an outside diameter of -one eighth-inch. The column material was 5% SE-30 on a celite base chromatograph Fig 3.--Diagrams of apparatus used for administration of com pounds. Dog mask. 1; exhaust reservoir, 2; flowmeter, 3; toggle valve, 4; pressure reducing valve, 5; cylinder, 6; vaporizer and water bath, 7; differential pressure regulator, a. column packing material (Chromasorb W). The column temperature was 110 to 115 C; the hydrogen flow rate, 20 ml/min: and a 0.5-ml sample loop was attached to the chromatograph and used to those times when it was necessary for the mask introduce samples for analysis every 1*4 to 2 to remain in place without the animal being minutes during the exposure. A 10-inch, linear, exposed to the vapor. This arrangement also 1-mv range, strip chart recorder was coupled provided a means of uninterrupted vaporization to the gas chromatograph. and thus ensured that the desired vapor con Administration of Epinephrine.--The epi centration could be immediately supplied to the nephrine was administered intravenously into animal by moving the toggle valves. the cephalic vein of the foreleg of the dog. The The diluting airflow and the rest'of the injection was made by an automatic infusion- delivery and exhaust system were the same as withdrawal pump set to deliver the total epi those described above. nephrine dosage of 0.008 mg/kg in a volume of Dog Mask.--The dog mask (Fig 4) was con 1 mi of normal saline in nine seconds. structed from a standard 8-oz paper cup, fitted Electrocardiograms.--An ECG was recorded with intake and exhaust ports without valves, continuously during each experimental run us and a rubber sleeve for a tight fit over the dog's ing a standard electrocardiograph in association nose and mouth. The rubber sleeve was the cuff with an oscilloscope having a low-level type Arch Environ Health--Vol 22, Feb 1971 270 ARRHYTHMIAS AND AEROSOL "SNIFFING"--REINHARDT ET AL I1 -I !r ` it! *. \: iI 1/ ;n i> ** f ,l I i ! ! i t 33 CO !! I! !i Arch Enuiron Health--Vol 22, Feb 1971 Hg pound 4; ptt 7; did those t to retr expose provid and th centra animaJ The deliver those c Dog struct* with i: and a nose a 135904 .fc '" > Ml i ta a * a ah i /to /1<Vu nanusuL "SNIFFING"--REINHARDT ET AL 4 273 Normal beats (showing initial increase in heart rate followed by rede slowing) I. : J 1 "f I :i ,i 1 < \ \ > B i i' I rrrrrrrt c I- I { 1 ` f ' i I 1 i 1 I it;; ..ii i i . ,i. i . ' I f Isolated abnormal beats . .: -i i- J , [ i ' ' |li il, jli'*e [Vi l, ,1; -ft. |l1 '* il,` \\ A, |l \ i-r --*J-,i J(i\jyyyyyyy y yyV*.--a i I I : : i : ! I I , ,.1 i! , Multiple ventricular beats . i 't , ` .I'll i.iV ' ' .. . ,w D Multiple ventricular beats preceding ventricular fibrillation Fig 5,--Examples of electrocardiographic patterns recorded following challenge injection of epinephrine. that occurred after the second injection of sponses as the indicator, the results show epinephrine as compared to the first There that all of the compounds studied are capa fore, in order to evaluate the effect on car ble of sensitizing the mammalian heart to diac rhythm of the second injection of epi epinephrine. Of this group of compounds, nephrine alone, an experiment was done in fluorocarbon 11 has the greatest cardiac sen which the usual protocol was followed ex sitization potential since it produced this cept that the animals breathed only fresh air phenomenon in 8.3% and 41.7% of the dogs the entire time. The results of 13 dog expo at concentrations of 0.5% and 1.0% while sures show that although no marked re fluorocarbon C-318 which produced this sponses occurred, a significant number of effect in 16.7% and 83.3% of the animals at mild responses (6[46.2%j) resulted from concentrations of 25.0% and 50.0% was at the second injection of epinephrine in an ex the opposite end of the spectrum. Most of posure to air alone. In view of this, only the remaining compounds caused sensitiza marked responses were considered to repre tion to epinephrine at concentrations in the sent a significant cardiac sensitization effect range of 5.0% to 20.0%. in the screening experiments. There is little The results obtained with fluorocarbon doubt that the marked responses which fol 502, an azeotrope of fluorocarbon 22 and lowed the challenge injection of epinephrine fluorocarbon 15 (Table 2), suggest that resulted from exposure to the test material there may be a potentiating effect when since no serious arrhythmias followed any sensitizing compounds are administered si control injection of epinephrine and none multaneously. occurred following the challenge injection in Tlie sensitization potential of a compound the control experiment with air alone. apparently depends partly on the degreo The results for the various compounds and type of lvalogcnation. Those compounds studied in the screening experiments were containing chlorine atoms produced the tabulated as shown in Table 4 and those for greatest degree of sensitization while those the variable exposure durations using fluoro containing only fluorine atoms were among carbon 12 in Table 5. Using marked re compound in the presence of a relatively Arch Environ Health--Vol 22, Feb 1971 444 04* 41'i" i i\<_T --1A4>4 4 V 4 4 4n4 A4F 4 4j 1 n LJ differential amplifier input for base-line stabili zation. The electrodes were held in place on the dog by a rubber strap extending around the body and were positioned over shaved areas as follows: (1) two active electrodes--one on each side of the chest just behind the foreleg; and (2) one indifferent eleglrode--over the ster num. General Protocol.--A so-enllcd standard ex posure whieh was similar to those done in the past by other investigators in this field was given for each compound (Table 3). For fluoro carbon 12 only, additional exposures of 30 sec onds (Table 3) and one-half and one hour were carried out to determine what efTect duration of exposure might have on the cardiac sensitiza tion potential of a compound. Since the experimental procedure required relatively quiet and cooperative animals, the maximum concontration'of each agent used in these studies was that which the animals would tolerate for about ten minutes without undue struggling or incoordination. The lower test levels studied were chosen to determine a con centration at or near which no significant car diac arrhythmias develoi>ed. Endogenous Epinephrine Experiment The compounds studied in this experiment included fluorocarbon 11, fluorocarbon 12, and fluorocarbon 114 which are commonly used aer osol propellants. Fluorocarbon 142b was also tested for comparison purposes since it, in the presence of epinephrine, produced a high per centage of serious cardiac arrhythmias in the screening experiment Generation and adminis tration of the desired vapor or gas concentra tions was carried out in essentially the same manner as described above. However, in the case of fluorocarbon 11, the vapor was gener ated from a 1-liter, high-pressure cylinder which was fitted with a pressure relief valve (60 pounds per square inch [psi]) and wrapped with a heating tape maintained at a temperature sufficient to produce adequate va porization of the material. The dogs were ex posed to a mixture of 80% compound and 20% oxygen for 30 seconds while simultaneously being frightened by a loud noise provided by an amplified sound-effects tape recording having sounds of sirens, gongs, jet takeoffs, etc. Moni toring of the compound concentration was car ried out indirectly by maintaining the oxygen concentration at 20% using an oxygen analyz er. Since llio fright was intended to slimulalo the release of endogenous epinephrine, no epi nephrine was administered exogenously. Elec trocardiograms were obtained in the same man ner aa described above. Fig 4.--Dog mask showing Intake and exhaust ports. Results The first step in assessing and tabulating the results in the screening experiments was to establish response criteria. Based upon the ECG recorded during each experimental run, a "mild response" was recorded when there was an increase in the number of isolated, abnormal beats (abnormal com plexes) following the second or challenge injection of epinephrine as compared to the control injection (Fig 5rB). A "marked re sponse" was recorded when an arrhythmia developed which was considered to pose a serious threat to life (multiple consecutive ventricular beats) or which ended in cardiac arrest (ventricular fibrillation) (Fig 5,C and D). The ECG shown in Fig 5,A, illustrates a frequent pattern observed after the chal lenge injection of epinephrine and would. not constitute a response. No serious ar rhythmias were observed to follow any of the control injections of epinephrine. In the screening experiments, many of the responses were mild, consisting of only a slight increase in the number of isolated abnormal beats (frequently by one or two) Arch Environ Health--Vol 22. Feb 1971 AI. 1 .t>------- I Ml -- A i i y J! B iii y C D Fig 5.-- tlvat occurn epinephrine- fore, in ore diac rhythn nephrinc ai whicl^fcp - cept Wwth the entire t sures show l9 sponses oct mild respc: ( the second : posure to : marked re; sent a sicni in the scree doubt that lowed the c, resulted fre since no se control inj-. occurred fo! the control K / The resc f studied in t tabulated a. the variable carbon 12 [ 7.7 33.3 8.3 16-7 83.3 83.3 0,0 25.0 0.0 41.7 100.0 0.0 41.7 100.0 0.0 33.3 00,0 0.0 16.758.3 0.0 50.0 00.0 0. 16.7 33.3 lduded in . On the of expolot pro stration i fluorohe oxylevcl of lypoxia npound tive to to the Table 5.--Cardiac Sensitization: Results ot Variable Duration ot Exposure to Fluorocarbon 12 Quration of Exposure Concentration. % v/v No. of dog exposures No. of marked responses Percent marked responses 0.5 Min 5 Min 0,5 Nr 7.0* 7.0 13.5 2.5 5.0 (2.48-2.58)t 67 i0 7 12 2<m 0 12 5(1)1 6 0 16.7 0.0 28.6 0.0 41.7 0.0 1 Hr (2.48-2.50)t 6 0 0.0 * Oxygen concentration reduced to approximately 8.0%. t Analytic concentration. j Numbera in parentheses indicate number of cases of ventricular fibrillation and cardiac arrest included in marked responses. Table 6.--Cardiac Sensitization: Results of Endogenous Epinephrine Experiment 80% Compound/20% Oxygen lor 30 Seconds V/ith Noise Compound No. of Dog Exposures fluorocarbon 11 12 fluorocarbon 114 12 fluorocarbon 12 12 fluorocarbon 142b Compound & noise Compound alone Noise alone 12 12 6 No. of Mild Responses 9 i 2 4 3 1 No. of Marked Responses 2* 1* 0 5 1 0 Percent Responses Mild 75.0 8.3 16.7 Marked 16.7 8.3 0.0 33.3 25.0 16.7 41.7 8.3 0.0 Bigeminal rhythm with areas suggestive of multiple ventricular beats. No. of Convulsions 0 5 9 9 5 0 Percent Convulsion* 0.0 41.7 75.0 ' 75.0 41.7 0.0 normal oxygen concentration. The results, 11 and fluorocarbon 114 were not the classi which are included in Table 5, suggest that cal multiple consecutive ventricular beats the combination of hypoxia and exposure to seen in the screening experiments but consist the compound makes the heart more sensi ed mainly of a bigeminal rhythm with some tive to epinephrine. areas highly suggestive of multiple ventricu An autopsy was performed in all cases lar beats. A marked tachycardia (300 to 350 which ended in sudden death. The heart was beats per minute) was frequently observed examined grossly and microscopically and in with exposure to fluorocarbon 12 and fluoro each instance appeared to be normal, thus carbon 114. giving no indication that a pathological con The effect of the noise was studied using dition existed which might have made these fluorocarbon 142b, It was apparent that noise animals more susceptible to cardiac arrhyth was a contributing factor since in combina mias. tion with fluorocarbon 142b it resulted in The results of the fright experiment are 41.7% marked responses as compared to presented in Table 6. In this experiment, the 8.3% with compound alone and none with severity of the response was categorized in the noise alone (Table 6). the same manner as in the screening experi The convulsions observed with fluorocar ments. Fluorocarbon 142b was the most po bon 142b and fluorocarbon 12 were severe, tent compound tested, resulting in 41.7% generalized clonic, tonic seizures, occasional marked responses. Of the three compounds ly associated with fecal and urinary incon most frequently used as aerosol propellants, tinence. Those seen with fluorocartxm 114 fluorocarbon 11 resulted in two cases of were mild and characterized by spasticity of questionable marked responses and fluoro the extremities. Although fluorocarbon 11 carbon 114 in one. No marked responses were did not result in convulsions, the dogs did seen with fluorocarbon 12. The questionable not tolerate the compound and struggled vio marked responses observed with fluorocarbon lently. Arch Environ Health--Vol 22, Feb 1971 I i f ( 1 v fr i. r I i\ 1 i f i i t { R&S 135907 274 ARRHYTHMIAS AND AEROSOL "SNIFFING"--REINHARDT ET AL Table A.--Cardiac Sensitization: Results ot Screening Experiments* Test Compound Concentration, % V/V Oufation of No. of Oog Exposure (min) Exposures No, of Marked Percent Marked Responses Responses Fluorocarbon 11 (0.09-0.13)t (0.35-0.61) (0.96-I.21) 5 12 0 0,0 5 12 i an 8.3 5 12 5 (3) 41.7 Fluorocarbon 12 2.5 5.0 5 12 0 0.0 5 12 5(1) 41.7 Fluorocarbon 22 2.5 5:0 5 12 0 5 12 2 0.0 16.7 Fluorocarbon 114 2.5 5.0 5 12 i 8.3 5 12 7(2) 58.3 Fluorocarbon 115 15.0 25.0 5 13 1 5 12 4 7.7 33.3 Fluorocarbon C-318 10.0 25.0 50.01 50.01 5 12 i 8.3 5 12 2 16.7 5 6 5(1) 83.3 5 65 83.3 Fluorocarbon 152a 5.0 15.0 5 12 0 5 12 3 0.0 25.0 Fluorocarbon 142b 2.5 5.0 10.0 5 60 5 12 5 5 12 12 0.0 41.7 100.0 Fluorocarbon 502 5.07 10.0 20.0 5 6 0. 0.0 5' 12 5 . 41.7 5 12 12 100.0 laobutane 2.5 5.0 10.0-20.0 5 12 0 0.0 5 12 4(1) 33.3 5 6 6(3) 100.0 Propane 5.0 10.0 20.0 5 60 0.0 5 12 2 16.7 5 12 7(1) 58.3 Vinyl chloride 2.5 5.0 10.0 5 12 0 0.0 5 12 6 50.0 5 6 6(1) 100.0 Dimethyl ether 10.0 20.0 30.0 5 60 5 12 2 5 2 0.0 16.7 . 33.3 * The duration of ait exposures prior to challenge injection of epinephrine is five minutes, t Concentrations in parentheses are analytical, Z Numbers in parentheses indicate number of cases of ventricular fibrillation and cardiac arrest included in marked responses. fOxygen concentration reduced to approximately 10%. | Oxygen concentration enriched to 20%. * Represents concentration of azeotropic mixture. the weaker sensitizers. However, halogenation is not necessary for the production of cardiac sensitization since propane and iso butane produced a similar measure of sensit ization as compared to many of the halogenated compounds. Using fluorocarbon 12, it was demonstrat ed that an exposure of only 30 seconds was sufficient to produce cardiac sensitization; however, the concentration of the compound had to be somewhat higher to produce the same effect as that observed after the stan dard five-minute exposure (Table 5). On the other hand, increasing the duration of expo sure to one-half and one hour did not pro duce a sensitization effect at a concentration of 2.5%. A series of 30-second exposures to fluoro carbon 12 was conducted in which the oxy gen concentration was reduced to a level of about 8% to determine whether hypoxia combined with exposure to the compound would make the heart more sensitive to epinephrine than would exposure to the Arch Environ Health--Vol 22, Feb 1971 c c ?r i >. 7 7 \ r( Y Compo. fluorocarbt F luorocari: Fluo/'Pc*fpc Fluorocarsc Compoufl Compout Noise * Bigemin normal c which an the comb thecomp (ep au which er.; examinee each ins: giving r.o dition ex: animals r mias. The re \ presentee ` s severity i the same ments. FI tent com marked : most free fV fiuorocar: questions carbon 11 i seen with marked r l l - ( si dosage Jtnc and csults to oni^fcdrin^Pt inilar to ccrotion. hnicallv ecurring ns boon measure occur in JI I 1 i V.14 u nn /ir.nu-.'HJLi v>rv/r/'/iVC,'"--REINHARDT ET AL Epinephrine Dose 0.03 m^/kg 0.01 mj/kg *0,01*0.04 mg/kg 0.01*0.04 mg/kg 0.0J mg/kg 0.004-0.017 mg/kg 0.01-0.05 mg/kg Table 7.--Epinephrine Dosage Vehicle Not stated 5 cc normal Saline Oilute HCI Not stated Not stated 5 cc normal saline 5 cc normal saline Rate of infection Rapidly 1 ee/10 see 'Made as rapidly as possible" Sot stated Made during 25~ 40 sec" 1 ce/10 sec l 1 cc/10 sec Author Hermann & Vial*1* Meek et al" Chenoweth* Philips et al" Kranii et al** Raventos'* Bamforth et ai* 277 . Printi lled that rom the reach a 'annon3of epi- X)5 mg/ dose of riinents 50 mg/ of epimber of ecretion 'C, similcnts in be the inically orimenive n c isitizers iu!d be is there human tr. S4 i ti i probaunephuggest, iay not nes re 's with- b I A 'itional Sect of n 12, it cari very its obcrpo- . j , i sures suggest that there is a threshold con- lar arrhythmias, thus demonstrating the ne- centration independent of the duration of cessity for the concurrent presence of epi- . exposure which must be reached before an nephrine or norepinephrine to achieve this effect will be produced. phenomenon. Limitations of Protocol.---The protocol .adopted is considered to provide a sensitive and rigorous screening test for determining the cardiac sensitization potential of a com Price1* states, the term cardiac "sensitization" (to the actions of catecholamines! is unfortunate because there is no aspect of the intrinsic cardiac response to pound and as such is intended mainly to s^catecliolamincs which is actually increased by identify compounds which are capable of the administration of a "sensitizing" anaesthet producing cardiac sensitization. Even ic. Instead, the functional parameters thus far though it does permit a rank order of the sensitization potential of the compounds tested, its limitations should be considered in attempting to establish significant effect measured have been found to be depressed. He bases his conclusion upon the work of Smith et al33 which demonstrates that in the myocardium the threshold to electrical stim levels on the basis of the results obtained. The demonstration of cardiac sensitization without the use of injected epinephrine in the fright experiment lends support to the ulation is increased, conduction velocity re duced, and latency increased by most anes thetics, and the reports of Hiker et al-18 and Vick.31 These reports indicate that the im validity of the standard exposure as a portant feature of the action of the sensitiz screening tool. ing agents is that they somehow suppress Mechanism of Cardiac Sensitization.-- the ability of the sinus and atrioventricular Even though a precise explanation cannot nodes and the ventricular conducting system be given for cardiac sensitization, it seems to respond to a primary increase in cardiac apparent that the underlying mechanism in rate and automaticity, thus permitting the volves a disturbance in the normal conduc emergence of other ectopic foci of pacemak tion of the electrical impulse through the er activity. heart, probably due to a local disturbance in Significance of Cardiac Sensitization.--As the electrical potential across the cell mem indicated in Table 1, there is ample evidence brane. which indicates that cardiac sensitization is As suggested by Garb and Chenoweth,33 not simply an interesting laboratory finding, during the inhalation of hydrocarbons, but that it can and has occurred in humans which markedly reduce myocardial irritabil during periods of stress while being exposed ity, some portions of the myocardium are to certain unsubstituted and halogenated hy less irritable than others, and, therefore, drocarbons. Many unexpected deaths due to small, temporary blocks may be produced the sudden onset of ventricular fibrillation which could result in a conduction disturb have occurred in humans during the admin ance giving rise, to cardiac arrhythmia. istration of certain volatile, hydrocarbon Their work showed no evidence that the anesthetic agents such as chloroform. There hydrocarbons themselves induced ventricu- are also case histories of sudden deaths in Arch Environ Health--Vol 22, Feb 1971 R&S 135910 .1 1 I f II i iI : i ![ : ti Aiu /uwti; i i f\&HU&KSL/ - oistr t n\L, '--n,it\UAUUT AT AL a a. Whether the loud noise by itself resulted in sufficient endogenous epinephrine to pro duce cardiac sensitization is questionable. It is probable that the convulsions and strug "Materials and Methods," the total dosage was contained in 1 ml of normal saline and was injected in nine seconds. In extending these experimental results to r Epirvf 0,03 gling which occurred at these high concen human exposures, there would be some ad trations also .resulted in an increase in the vantage in using dosages of epinephrine that level of endogenous epinephrine. Unis, it is would yield blood concentrations similar to felt that most likely a combination of these those resulting from adrenal gland secretion. factors was involved and that the noise in In practice, however, it has been technically 0,01. 0.01 * creased the severity of the struggling and very difficult to assay naturally occurring 0.00^ convulsions. This reasoning is supported by epinephrine, and this difficulty has been the finding that the number and severity of compounded when attempting to measure o,o:-. the convulsions seen with fluorocarbon 142b peaks of epinephrine output such as occur in and noise together were greater than those emotional states. with either noise or compound alone. In Starling and Evans' textbook. Princi sures supscs; Comment ples of Human Physiology,31 it is stated that the rate of epinephrine secretion from the 7> ccntration ir exposure wh adrenal gland in time of stress may reach a Design of Protocol.--In considering the level of 0.004 mg/kg/min. Also, Cannon3? effect will be Limitation experimental investigation of cardiac sensiti estimated that the reflex secretion of epi adopted is cc zation, a number of somewhat arbitrary de nephrine might reach the level of 0.003 mg/ and rigorous cisions must be made in designing a suitable kg/min. The rate at which the dose of the cardiac s protocol. Three of these which are of some 0.008 mg/kg was given in our experiments pound and : importance are (1) the animals used; (2) would provide a dose of about 0.050 mg/ identify coir, the dosage of epinephrine used; and (3) the duration of exposure. Animals.--For a variety of practical and kg/min. Even though this dosage of epi nephrine probably exceeds by a number of times the maximum rate of human secretion t- V < I producing though it do sensitization pharmacological reasons, large animals are under stress, it is, as mentioned above, simi > tested, its Hr preferred for this type of experiment and traditionally two species have been used al most exclusively. Earlier work was done with cats, but recent work utilized the dog. Meek et aln state that "all the evidence with which we are familiar indicates that conclusions from experiments with anesthet lar to dosages used in other experiments in which those compounds proven to be the most potent cardiac sensitizers clinically have also been identified as such experimen tally. Similarly, compounds which have pro duced little or no cardiac sensitization clini cally have been found to be weak sensitizers k in attemptin: levels on the tI The demonst withoi^tehe i ti / i. the fn^P ex validity of . screening too ics on the dog may be applied to man with in the laboratory. However, it should be );much more certainty than those from the pointed out that for many compounds there cat" is still no relevant information on human MechanisTT Even though be given for Dose of Epinephrine.--Since epinephrine experience. apparent that can cause ventricular fibrillation when in Furthermore, too much emphasis proba volves a disU jected alone in sufficient quantity, it is nec bly need not be placed on the exact epineph tion of the essary to use a smaller dose when looking rine dosage since, as Price et al33 suggest, heart, probab for possible synergistic efTects. Representa the circulating level of epinephrine may not the electrical tive amounts of epinephrine used by other be as important as the catecholamines re brane. investigators studying cardiac sensitization leased from sympathetic nerve endings with As suggest- . are given in Table 7. As can be seen, the in the myocardium. during the majority of investigators have used an intra Duration of Exposure.--An additional rvenous dose of 0.01 mg/kg or greater given variable that was examined was the effect of over a period ranging from "as rapidly as duration of exposure. Using fluorocarbon 12, which market ity, some po: less irritable possible" to about one minute. The dosage of epinephrine used in the screening experiments reported herein was 0.008 mg/kg which is similar to that used by it was demonstrated that the length of expo sure is an important variable and that car diac sensitization can occur even with very brief exposures (Table 5). The results ob >t r i ( small, tempo: which could r ance giving Their work ; other investigators. As mentioned under served in the one-half- and one-hour expo- t) hydrocarbons Arch Environ Health--Vol 22, Feb 1971 l ': 7 dprod.. <& References '3g or olwnt oforo. 1. Fluorocarbon inhalation deaths, in National Clearinghouse lor poison Control Center* tinHetin. US Dept of Health, Education, and Welfare, 1969, p 20. Vclry VH: Tlie dnngers of (he dry shampoo, Lancet 2:116,2-1163. 1909. 21. Hall KD. Norris FH Jr: Fluolhane scnsltizA- L* 5. tion of dog heart to action of epinephrine. Anesthe 2, Lester D, Greenberg LA: TJie (oxirity of sulfur siology 19:631-641, 1953. iionfs, .drop-. ' may <m or hr<nllnori<ie. Arch 1ndinstr live 2:348.349, 19.70. .1. Levy AG, Lewis T: Henrt irregularities, re sulting from the inhalation of low percentages of chloroform vapour, and their relationship to ventricu lar fibrillation. Heart 3:90-111, 1911-1912. 22. ILaventos J: The action of (luothane: A new volatile nnacsllielic. Brit J Pharmacol 11:334-410, 1956, 23. Millar RA, Gillicrt RGB, Rrindle CF: Ven tricular tachycardia during halotliane anaesthesia. 4. levy AG: The exciting causes of ventricular Anaesthesia 13:161-172. 1958, ipnifperty the tihriltation in animals under chloroform anesthesia. Heart 4:319-373. 1913. 5. Chcnowolh MU: Ventricular fibrillation in duced by hydrocarbons anti epinephrine. J Industr 24. Hermann H, Vial J: Syncope ndrennlino-monochlorocthaniquc. C R Soc Biol 117:439-440, 1934. 25. Krantz JC Jr. Carr CJ. Vitcha JF: Anesthe sia: XXXI. A study of cyclic and noneyclic hydro Hyg Toxicol 23:151-153,194G. carbons on cardiac automaticity. J Pharmacol Exp nans. liolopro- 6. Nahum LH. Hog HE: The mechanism of sudden death in experimental acute benzol poison ing. J Pharmacol Exp Thcr 50:336-345, 1934. 7. Fell A: Le benzolismo professional. Press* Ther 94:315-318. 1948. 26. Carr CJ. Burgison RM: Vitcha JF, et al: Anesthesia: XXXIV. Chemical constitution of hy drocarbons and cardiac automaticity. J Pharmacol pro- Med 41:129-130. 1933. -- Exp Ther 97:1-3. 19-19. 8. Hamilton A: Industrial Poisons in the United 27. Burgison M. O'Malley WE, Heisse CK. et al: Stoles. New York, Macmillan Co Publishers, 1925, Anesthesia: XT.VI. Fluorinated clhylencs and car- pp 457-4GI, disc arrhythmias induced by epinephrine. J Plusr- 9. McCord CP: Benzol fBenzene) Poisoning. Cin macnl Exp Ther 114:470-(72. 1955. comnd a cinnati. Industrial Health Conservancy Laboratory, 1932. 10. Final Report of the Committee on Benzol, 28. Garb S. Chenowcth MB: Studies on hydrocar bon-epinephrine induced ventricular fibrillation. J Pharmacol Exp Ther 94:12-18. 1948. 3nif- National Safety Council. Chemical and Rubber Sec 29. Philips FS, Gilman A, Crescitelli FN: Studies tions. New York, National Bureau of Casualty and on the pharmacology of DDT (2.2,bi3-para-chlort>- ding is a rom ling Surety Underwriters, 1926, pp 10-18. 11. Meek WJ, Hathaway HR, Orth OS: The effects of ether, chloroform and cyclopropane on cardiac automaticity. J Pharmacol Exp Ther 61:240-252, 1937. phenyl-l.l.l-trichloroethane): II. The sensitization of the myocardium to sympathetic stimulation dur ing acute DDT intoxication. J Pharmacol Exp Ther 86222-228, 1946. 30. Bamforth BJ, Siebecker KL, Kraetner R, et fely can^^ > 1 as 12. Sollmann T: A Manual of Pharmacology and fit Application to Therapeutics and Toxicology, ed 8. Philadelphia, WB Saundera Co, 1957, pp 897, 902. 13. Morris LE. Noltensmeyer MH, White JM Jr: Epinephrine induced cardiac irregularities m tho al: Effect of epinephrine on the dog heart during methoxyflunme anesthesia. Anesthesiology 22:169173. 19GL 31. Starling EH, Evans L: Principles of Human Physiology, ed 13. H Davson, MG Egglcton feds). ices dog during: anesthesia with trichloroethylene, cyclo Philadelphia, Lee it Febiger Publishers, 1962. p 1413. nay ph- propane, ethyt chloride and chloroform. Anesthesiol ogy 14:153-158. 1953. 14. Waters RM. Orth OS, Gillespie NA; Trichlor- 22, Cannon WB: Studies in the conditions of activity in endocrine glands. Amer J Physiol 50:399-432, 1919. ethylene anesthesia and cardiac rhythm. Anesthe 33. Price HL, Lurie AA, Jones RE, et al: Cyclo be siology 4:1-5. 1943. propane anesthesia: II. Epinephrine in initiation of illy 15. Bell AP: Death from trichlorethylene in a ventricular arrhythmias by carbon dioxide inhala >ci- dry-cleaning establishment New Zeal Med J tion. Anesthesiology 19:619-630, 1958. is 50:119-126, 195L 34. Price HL: The significance of catecholamine 16. Hoschek R: Cases of delayed sudden death release during anaesthesia. Brit J Anaesth 38:705- are after slight exposure to trichloroethylene, lnt Arch 711,1966. nil Gewerbepatk 19:319-328, 1962. 35. Smith SI* Webb WR, Fabian LW, et al: u-d 17. Kleinfetd M, Tabershaw IR; Trichloro Cardiac excitability in ether, cyclopropane, and cts ethylene toxicity. Arch Industr Hyg Occup Med halothana anesthesia. Anesthesiology 23:766-775, 10:134-141, 1954. 1962. aa 18. Schotlmeyer W: Sudden death due to trichlor 36. Riker WF, Depierre F, Roberts J, et al: The oethylene poisoning after prolonged exposure to the epinephrine and hydrocarbon-epinephrine riisturb- tin poison. Arch Toxilt 18:229-235, 19641. nm-on in the cat J Pharmacol Exp Ther 114:1-9, 19. lfonuann H, Vinl J: NouvelluH nynroj k-n curri- 195.7. on im]ucs par association loxiquo do I'ikJrvnnlino et ilo 37. Vick KL: Effects of altered heart rate on o- `divers produita organiquea volatile. C R Soe Biol chloroform-epinephrine cardiac arrhythmia. Circ Res or 119:1316-1317, 1935. 18:316-322, 1966, R&S 135911 Arch Environ Health--Vol 22, Feb 1971 R&S 135912 Iffl ! iI: 27S ARRHYTHMIAS AND AEROSOL "SNIFFING"--REINHARDT ET AL tn.i * industry following exposure to such com pounds ns benzene and trichloroethylene in which ventricular fibrillation was suspected as the mechanism of death. The results of the screening and fright experiments indicate that all of the aerosol propellants studied are capable of sensitiz ing the mammalian heart to epinephrine, resulting in serious cardiac arrhythmias. The fright experiment is particularly signif icant in that the cardiac arrhythmias de veloped without the administration of exo genous epinephrine: On the basis of (1) the positive experi mental results; (2) the historical evidence cited above; (3) the presence of the neces sary requisites for cardiac sensitization, (a) exposure to high concentration of compound and (b) presence of a high circulating level of epinephrine; and (4) the lack of clinical and pathological findings associated with many of the aerosol-sniffing deaths, it is concluded that cardiac sensitization to epi nephrine is a likely mechanism of death in many of the aerosol-sniffing fatalities. It is quite probable that such factors as hypoxia and hypercarbia could be contribut ing elements in cardiac sensitization. Stand ard exposures to a 50.0% concentration of fluorocarbon C-318 foxygen reduced to about 10%) produced 83.3% marked re sponses (one death included!, while a simi lar exposure with the oxygen enriched to 20% also yielded 83.3% marked responses but no deaths (Table 4). In the case of fluorocarbon 12, a 30-second exposure to a 7.0% concentration of the compound in the presence of a normal oxygen concentration resulted in no marked responses, while a similar exposure to the same concentration with oxygen concentration reduced to about 8% resulted in 16.7% marked responses. The results of these experiments, although not conclusive, suggest that hypoxia en hances to a slight degree the cardiac sensitization potential of a compound. Some de gree of hypercarbia would be expected in aerosol sniffing because of breath holding and rebreathing from a bag or balloon. Price ct al33 believe that hypercarbia is a key factor in the production of cardiac sensitiza tion. The question of whether components of the aerosol, other than the propellant, play a role in these deaths should be considered. When the aerosol is sprayed into a bag or balloon for sniffing, much of any solvent present would be vaporized and, therefore, would be inhaled with the propellant and, thus, might produce a toxic effect. This fac tor was not explored in these experiments. However, where unvaporized liquids (drop lets) from the aerosol are inhaled, they may be a factor in producing laryngeal spasm or edema. In making a judgment about the signif icance of the cardiac sensitization property of a compound as it relates to humans, the following factors should be considered: 1. Translation of animal data to humans. Past experience in the field of anesthesiolo gy indicates that compounds found to pro duce cardiac sensitization in dogs also pro duce it in humans. 2. Individual susceptibility. 3. Variations in individual health. 4. Effect of combination of these com pounds with caffeine, drugs, exercise, and a stress such as acute or chronic anxiety. Overcoming the Problem of Aerosol Snif fing.--There is a special danger attending the sniffing of aerosol propellants. It is a false sense of security which is derived from the fact that numerous episodes of inhaling these materials may be carried out safely and then suddenly a fatality occurs. It can be likened to playing Russian roulette. This factor may be attributed to such things as individual susceptibility and circumstances surrounding the sniffing which may or may not give rise to increased levels of epineph rine. The answer to this problem seems to be one of education of the public, especially teen-agers, of the potential danger associ ated with misuse of these materials. It is hoped that an understanding of the nature of this problem on the part of the public will lead to a better appreciation of the hazard of deliberate inhalation of aerosol products or propellants which in turn might lead to a decrease in the practice. The experimental results reported herein in no way indicate that cardiac sensitization poses a risk when aerosol products and pro pellants are handled properly and used for the purposes and in the manner intended. r 1. Fluorocarbon Cleoringhoute hr US Dept ririfcalth 2. C* hexafluoride. Arch 3. lovy AC. J> suiting from the chloroform vapour, lar fihrillation. He 4. Levy AC: T: fibrillation in nnir Heart 4:319-373, 1; 5. Chenowelh ? duced by hydroca: Hys Toxicol 2S:15 6. Nahum I.H. sudden death in ( ingp J Pharmacol i 7. Feit A: Le Mtd 41:129-130. 1 8. Hamilton A: Staid. New York pp 457*461, 9. McCord CP: cinnati. Industrial 1932, 10. Final Rrpo National Safety C tions. New York, Surety Underwriti 11.'Meek WJ. efteeta of ether, cardiac automat 61:240-252. 1937. 12. SoIImnnn T If> Apptic^tt t' , 8. rhilnde^^B V 13. Mor^^^E. Epinephrine inn: dog during anes:. propane, ethyl cr. ogy 14:153-153. If 14. Waters RN ethylene anesthe tiology 4:1-5. 19-t- 15. Bell AP: dry-cleaning tst 50:119-126. 195 L 16. Hoschek F alter alight expo Ccwerbcpath 19-2 17. Kleinleld ethylene toxicity 10:134-141. 1954. 18. Schollmevt oethylene poi,<on poison. Arch Tor 19. Hermann i iaquca par assoc divers ptoduits 119:1316-1317, U Arch Environ Health--Vol 22, Feb 1971 m