Document 3Jyp3eZQejKOb9zm025XjoQbx

- ex 3.6 23 3.9 25 4.2 29 4.9 26 4.4 23 3.9 23 3.9 to a 24- r%. The for e.xto 180 >Hb is iverage Ition, it els well ! resulticed by :hloride aid pro as 50 y Public W309-15. uman exfrA En '.v uiard h* Ilonojruit. Occupy* : Con?itlthat incontra' D, 1965, Cardiovascular Effects of 1,1,1-Trichloroethane Paul A- Herd, PhD; Milton Lipsky; Horace F. Martin, PhD, Providence, hi Acute exposure of anesthetized dogs to 1,1,1-trlchloroethane (TCE) results in a dose-dependent, biphasic decline In arte rial pressure similar to that observed fol lowing exposure to a commercial solvent containing TCE. The initial phase of pres sure decline is associated with peripheral vasodilation whose magnitude exceeds concomitant, reflex, positive chronotropic snd inotropic effects on myocardial func directly attributed to intoxication by TCE-3 and, further, this compound has been shown to have arrhythmigenic properties.8 " The resultant car diac malfunction is thought to be due to spontaneous10 adrenergic-mediated arrhythmias' " or both during exposure to TCE, and possibly subse quent to exposure, during an adrener tion. The peripheral dilation could be re gic crisis.5"' Compounds containing versed by injection of the a-agonist, phenylephrine hydrochloride. The second phase of pressure decline is primarily as sociated with a depression of myocardial function; heart rate, stroke output, and myocardial contractility declined. Injec- uwts toi wet ameiiwiuwy sitw I wh`inuuvb3 alteration of myocardial contractility and blood pressure was protected. The data suggest that comprehension of the mech TCE and sold on the retail market, eg, spot removers and, more recently, nasal decongestants,' have proved dangerous and fatal in the hands of "glue sniffing" youngsters.* Partic ularly alarming in this regard has been a recent report from the Food and Drug Administration that at least 18 deaths have occurred due to anism^) by which TCE induces cardio the use (one death) and abuse (17 vascular depression may lead to more ef fective clinical management of the toxic effects of this compound. deaths) of an over-the-counter nasal decongestant spray which contained TCE as a carrier solvent,3 During development of a clinical Ahalogenated hydrocarbon that was introduced in 1954 as an in procedure for detection of organic sol vents in the breath,13 profound cardi dustrial solvent,' 1,1,1-trichloroethaneovascular depression was noted after (TCE) is sold on the retail market in acute exposure of anesthetized dogs various spot remover preparations to TCE. Although central nervous and so on. Its potentially toxic effects system depression is described as the have been recognized for several usual mechanism for TCE-induced years.3-3 However, since TCE is less toxicity,'3 the above experimental ob toxic than several other halogenated servation, as well as the fact that compounds of comparable function (it TCE sensitized the heart to the devel is reported to be replacing carbon tet opment of arrhythmias.'-1" suggested rachloride under numerous circum that TCE may exert additional direct stances'3 4), its commercial use is in effects on the cardiovascular system. creasing greatly. In 1971, 169.6 In view of the growing commercial million kilograms of TCE were pro importance of this compound and the duced, an increase of 50% over the increased frequency of reported in previous five years.* toxication,* the cardiovascular effects At least 30 deaths have been of TCE were explored. Evidence is Submitted for publication Aug 8, 1973; ac cepted Sept 14. From the Department of Biochemistry, Rhode Island Hospital. Providence, KI. Reprint requests to Department of Biochem'Ury, Rhode Island Hospital, 593 Eddy St, Provi dence, R1 02902 (Dr. Herd). presented that a sequence of specific cardiovascular events is associated with inhalation of TCE in the anesthetized dog and, in addition, that the toxic properties of this com pound, particularly during acute in halation, cannot be adequately ex plained as a manifestation of generalized CNS depression. Methods Dog Experiments.--Nine mongrel dogs (25 to 35 kg) were anesthetized with pento barbital sodium (35 mg/kg), or chloralose (50 mg/kg) and 10% pentobarbital sodium. Arterial pressure was measured by a transducer connected to a femoral arterial cannula, and left ventricular pressure (LVP) was obtained from a manometer catheter inserted (fluroscopically) into the left ventricle. Cardiac stroke output was measured with an electromagnetic flowmeter chronically implanted at the base of the aorta, and blood flow was inte grated electronically and defined by arbi trary units, as noted in "Results" (Fig 1). These various monitors, as well as electro cardiogram leads, were connected to an eight-channel recorder. In order to measure myocardial contrac tility (in vivo), ie, the force-generating ca pacity of the heart, the first derivative of the LVP trace, dP/dt, derived electron ically, was used during our initial experi ments. '*** However, these values are re ported to be suspect because of their sensitivity to alterations in cardiac afterload."-" Subsequently, in order to obviate this potential difficulty, (see "Results" and Fig 3 for comparison) the maximum con tractile element, velocity (V,,,,), was calcu lated according to the method described by Grossman et al.`` These values are pur ported to be less susceptible to alterations in cardiovascular loading than dP/dt. A positive pressure ventilation appa ratus was connected in parallel with a bubble-type vaporizer. Each animal re ceived mechanical ventilation for a 3D-min ute contra) period, and then a designated fraction of the inspired air was bubbled through a solution of TCE at 20 C. Follow ing exposure (lasting no more than five minutes), the animals were allowed to re cover. The criteria for recovery were the return to initial values of both blood pres sure and heart rate, approximately 10 to 45 minutes, respectively, for most doses of TCE tested. A second dose of TCE was then adminis tered, approximately one hour after the first exposure, and this procedure was car ried out during the course of each experi mental day. In experiments in which drug effects were studied (Table, Fig 5 through 7), care was taken to insure that subse quent exposures to TCE were independent of possible long-term effects of these com pounds. in addition to the monitoring of cardiovascular dynamics, control (ic, with Arch Environ Hpalth/Vol ?B Aoril 1974 er SL 036627 Cardiovascular Effects of 1,1.1-Tiichloroethane'Herd et al 227 ECG LVP, mm Hg dP/dt, mm Hg/sec Integral of Flow Blood Flow Arterial Blood Pressure, mm Hg Control 90 sec After 1.5% TCE Fig 1 .--Cardiovascular response to TCE. Typical data obtained from 24-kg dog anesthetized with chioraloee pentobarbital and exposed to 1.5% TCE. out added drug) exposures of TCE were generally interspersed between drug inter ventions to insure the reproducibility cf the data. In several experiments pH and arterial blood gas levels were measured throughout the course of a day's experiment Only dur ing severe exposure to TCE, ie, greater than 2.5%, were these hematological mea surements altered (specifically, pH de clined from 7.42 to 7.30 during an exposure to 2.8% TCE), and these data are not re ported here. Under our experimental con ditions, blood pH remained between pH 7.44 to 7.38 and blood gas levels were unal tered from initial conditions. Data.-The data presented in this report represent typical experiments which were repeated at least three times on at least two different animals (see "Results" for additional experimental details and num ber, N, of experiments). Papillary Muscle Expertments.-Papillary muscles (weighing 2 to 3 mg) obtained from 200 to 250-gm female albino rats were prepared and isometric contractions were studied according to the technique of Henderson et al.,s The muscles were stimu lated at 12 beats per minute (at 5 to 10 v, 0.5 msec in duration). After an initial equil ibration period of two hours in KrebsRinger solution (pH 7.4) supplemented with 0.5% bovine serum albumin, during 228 Arch Environ Health/Vol 28. April 1974 Cardiovascular Effects of 1,1,1-Trichloroethane/Herd et si SL 036628 f mm CORRECTION Base Line Erroneously Elevated.-In the article "Cardiovascular Effects of 1,1,1-Trichloroethane," published in the April Archives (23:227-233,1974), the base line in Fig ure, 1, page 228, for the left ventricular pressure (LVP, mm Hg) was elevated errone ously. Compared with that for the control (column 1), the left ventricular end diastolic pressure (base line) was unchanged after exposure to TCE (column 2). Coincidentally, the left ventricular end systolic pressure declined when compared with that for the con trol. Figure 1 has been corrected and is published below. ECG x<5 ca a X T0J o m rn < LVP, mm Hg Integral of Flow Blood Flow Arterial Blood Pressure, mm Hg Control 90 sec After 1.5% TCE Fig 1 .--Cardiovascular response to TCE. Typical data obtained from 24-kg dog anesthetized with chloralose pentobarbital and exposed to 1.5% TCE. SL 036629 he 10! as mi i wl ta P ad tii id dt in si S' 1, IT 1b IT U SI n 9 ti t I r ni < t ( WUM9 0.8% TCE I 0 ' --- i i i------------- - 200' 2.5% TCE Time, sec Fig 2.--Effects of commercial spot remover on blood pressure, heart rate, and TPR on 24-kg dog anesthetized with chloraiose/pentobarbital. Various fractions of inspired air (designated as solvent) bubbled (at 20 C) through chamber containing com mercial spot remover reported to contain 10% TCE. 200 300 400 Time, sec Fig 3.--Effects of varying doses of TCE on blood pressure of 25-kg dog anesthetized with pentobarbital and sequentially ex posed to increasing doses of TCE. which maximal resting tension was ob tained, the muscles were divided into groups (usually two per group) and were administered TCE by saturating the aera tion mixture (95% oxygen/5% carbon diox ide) with the drug (at 20 C). In addition to developed tension and the rate of tension generation (dT/dt), the total tension time interval, the time to peak developed ten sion, and the time to peak rate of tension generation were measured.1* Reagents---Preliminary evaluation of 1,1,1-triehloroethane indicated approxi mately 3 to 3.5 vol% contamination as seen by vapor phase chromatography. The pri mary contaminant (2 to 2.5 vol%) had a re tention time identical with that of dioxane, and it was extracted with water, hydrogen sulfate, and then additional water to re move acid. This procedure resulted in prep arations of TCE yielding a minimum of 99.5 vol% parity by vapor phase chroma tography, and this reagent was used throughout the course of the investigation. Results Exposure of anesthetized dogs to a commercial spot remover containing TCE results in a dose-dependent de cline in blood pressure (Fig 2). Ini tially, total peripheral resistance (TPR) declines and then stabilizes. The heart rate increases following ex posure to the spot remover and in creases further with increased dose of solvent, but then begins to decline. Stroke output (not shown in Fig 2) began to fall slowly approximately 50 seconds after exposure to the solvent, and the rate of fall increased with in creasing dose of solvent. Essentially identical data were obtained in two additional experiments in which the fraction of inspired solvent was varied. The decline in blood pressure seen during exposure to a commercial spot remover (Fig 2) is similar to that observed when anesthetized dogs (N = 9) are exposed to TCE (Fig 1 and 3). The decline in blood pressure be gins within 10 to 15 seconds after in troduction of TCE into the ventilator, and the magnitude and pattern of pressure decline were found to be de pendent on the dose of TCE inspired (Fig 3). Under these conditions, two distinct phases of pressure decline were observed (Fig 2). The initial phase (Fig 3, 0.8% and 1.5% TCE, and Fig 4) is characterized by a parallel decline in systolic and diastolic pres sures, while both myocardial contraotility and cardiac output (both heart rate and, to a lesser extent, stroke volume) increase. Thus, the decline in blood pressure during this initial phase results from a marked decrease in TPR (Fig 4). The positive chronotropic (and inotropic) response seen during the initial phase of pressure decline (Fig 3) could be abolished by pretreatment with the ^-receptor antagonist, pro pranolol hydrochloride (Inderal), as seen in the Table. These data suggest a neurohumoral-mediated stimulation of myocardial function during this phase. The second phase of blood pressure decline is characterized by a reduction in cardiac output, marked by de creases in both stroke volume and heart rate (Fig 4). In addition, myo cardial contractility also declines, as evidenced by the decline in Vm,, as well as dP/dt. The TPR is not markedly altered during this second phase of blood pressure decline, an in dication that maximum peripheral vasodilation is obtained during the initial phase and that peripheral vas- Arch Environ Health/Vol 28, April 1974 Cardiovascular Effects of 1,1,1-Trichloroethane/Herd et al 229 SL 036630  o o> 3.000 Fig 4.--Alterations in cardiovascular measurements following exposure to TCE. Typical data (N-9) obtained from 30-kg dog anesthetized with chloralose/pentobarbital and exposed to 1.5% TCE. Fig 5.--Effect of phenylephrine (PE) on TCE-induced alteration in blood pressure and dP/dt in 28-kg dog anesthetized with chloralose/pentobarbital and exposed to control exposure (x) ol TCE, followed by second exposure in which phenylephrine was injected intravenously (solid circles). culature plays a minor role in the sub sequent cardiovascular depression. The decline in arterial pressure could be terminated by removal of TCE from the inspired air. However, at pressures below 50 mm Hg (sys tolic), most animals died. At autopsy, no unusual changes were noted in the lungs, liver, brain, and so on upon ei ther gross or histologic examination (H. Martin, PhD, unpublished data). These results agree with earlier re ports.: During the course of these experi ments (a total of 60 exposures ob tained during 12 trials on nine dogs), we did not observe the development of spontaneous, TCE-dependent ar rhythmias. It is also noteworthy that the type of anesthetic used in the experiments contributed in part to the cardio vascular response to TCE. Pento barbital sodium, as one of its central effects, inhibits myocardial parasym pathetic tone,17 and, thus, sympa thetic tone is enhanced. In general, these animals (N-3) had higher ini tial heart rates (and Vm.,,) than the chloralose anesthetized dogs, and there was little or no attendant posi tive chronotropic (or inotropic) re sponse immediately following expo sure to TCE. However the TCEinduced alterations in TPR and myo cardial function were unaltered. Effect of Phenylephrine Hydrochloride.-In lieu of epinephrine or nor epinephrine administration to coun teract TCE-induced cardiovascular depression with associated risk of in duction of arrhythmias,'"11 most clini cal methods for resuscitation suggest supportive, rather than active, treat ment following exposure.17 The pure a-agonist, phenylephrine, is reported to have minimal direct effects on the myocardium.1' It appears to act pri marily on the peripheral vasculature to produce vasoconstriction. Injection of phenylephrine, 1.2 mg, as demon strated in Fig 5, reverses the course of blood pressure decline in anesthe tized dogs exposed to TCE, although no marked alterations were noted in dP/dt. Heart rate fell transiently, but returned to preinjection levels within 20 seconds after injection of the drug and was unaltered, with respect to the control, during subsequent altera Effect of Propranolol Hydrochloride on Positive Chronotropic Response Following Inhalation of 2.0% TCE Heart Rate* Beats/Min Time After TCE and Propranolol Exposure, see TCE Hydrochloride 0 150 130 20 150 140 40 ISO 145 60 190 140 80 200 130 100 192 118 120 190 110 * Data obtained from single dog anesthe tized with chloralose and pentobarbital. Con trol (TCE) repeated twice and animal then given propranolol hydrochloride (250yug/kgl and exposed to TCE five minutes later. Simi lar results were obtained in second animal, similarly prepared. tions in blood pressure. The slight alteration in dP/dt that, was observed may be ascribed to the increase in arterial pressure1"4 rather than to a direct effect on myo cardial contractility. No alteration in left ventricular end diastolic pressure was observed, and the rate of return of dP/dt to initial values was similar 230 Arch Environ Health/Vol 28. April 1974 Cardiovascular Effects of 1,1,1-Trichloroethane/Herd et a1 SL 036631 t I--* t-* 1.5% TCE Blood Ca1" Levels. mQ/Liter * k nr ,, ++ +Ca 0 ration i with > (*> of ie was ise ;e Ain ioIoI e esthe. ConI then ibAg) , Slminimal. that, a the jgii.ii myoin in 1 et a' Fig 6.--Effect of exogenous Ca*` injection (x) and infusion (open circles) on mean blood pressure and myocardial contractil ity during exposure to 2.0% TCE in 35-kg dog (N - 4) anesthe tized with chloralose/pentobarbital. Data similar to those ob tained from four additional experiments in which levels of Ca*injected were varied. Following return of blood Ca-- levels to control values (4.8 mEq/liter), fourth exposure to TCE resulted in essentially identical cardiovascular alterations as seen in initial control (solid circles). Fig 7.--fcriect of raising exogenous Ca (2.54 irtM tu 5.03 mH) on recovery of isolated rat papillary muscles from exposure to TCE. in both cases. Upon cessation of expo sure to TCE, the phenylephrine-in jected preparation returned to or, as seen in this case (Fig 5), exceeded the initial blood pressure values at a much faster pace than in the prepara tion without phenylephrine. Ninety minutes after exposure to TCE and phenylephrine, the dog was again exposed to TCE, and blood pressure declined in a manner identi cal to that seen in the initial control experiment (Fig 5). Essentially similar results were ob tained in eight additional exposures on three animals. The response to phenylephrine appeared to be depen dent on the dose used and the initial level of mean blood pressure. It is also noteworthy that, in the presence of phenylephrine (injection or prein fusion), no evidence of arrhythmigenic activity was observed that could be ascribed to an interaction between phenylephrine and the TCE-altered myocardium. Myocardial Effects.--In addition to peripheral vascular effects, our data (Fig 1 through 3) indicate that signif icant alterations in myocardial func tion also occur during exposure to TCE. During the course of these ex periments it was noted that blood pressure returned to initial values within 15 minutes after cessation of exposure to TCE, but that the myo cardial factors, eg, heart rate, stroke volume, and Vm,,, recovered much more slowly, requiring at least 45 minutes to return to initial values. Since extracellular Ca*- levels are known to affect myocardial contrac tility dramatically,1* -1 alteration of exogenous Ca' * was studied to deter mine its effect on the TCE-dependent decline in myocardial function. In Fig 4, the effects of Ca** injec tion (9.4 mEq gluconate calcium) and Ca* * infusion (9.4 mEq gluconate cal cium followed by infusion of 0,48 mEq Ca**/min) on the TCE-dependent al teration of myocardial contractility and mean blood pressure are pre sented. The initial phase of blood pressure decline is similar in each case and was associated with a sim ilar decrease in TPR (not shown). However, myocardial contractility differed in the calcium-injected prep aration: contractility increased to a much greater extent than in the ini tial control, and in the Ca* -infused preparation the initial level of myo cardial contractility was markedly greater than that of the control and did not change appreciably during ex posure to TCE. With continued expo sure to TCE, mean blood pressure falls precipitously in the control prep aration, but not in the Ca*'-treated preparations, and this maintenance of mean pressure was paralleled by Arch Environ Health /Vol 28, April 1374 Cardiovascular Effects of 1,1,1-Trtchloroethane/Herd et al 231 SL 036632 higher levels of Vmu*' That exogenous Ca" is acting directly on the contractile mechanism and thereby enhancing the force-gen erating capacity, ie, contractility, of the myocardium is also seen in Fig 7. Pairs of rat heart papillary musdes (\=4) were simultaneously exposed to TCE. After exposure, the Ca* con centration was raised in one muscle group and the return of developed tension and the rate of tension gener ation (dT/dt) were followed. The TCE had no effect on the time taken to de velop peak tension or on the duration of a contraction cycle. However, in agreement with similar results ob tained with halothane," the time taken to develop peak dT/dt de creased approximately 10% during the exposure period, independent of dosage of TCE used in these experi ments. Addition of Ca-* following ex posure to TCE produced a marked en hancement of the rate of return of developed tension and dT/dt toward initial values. The final values for de veloped tension and dT/dt were gen erally slightly greater (at least 10%, four experiments) than those ob tained in control experiments, ie, when Ca*-was added in the absence of TCE (not shown). Comment The demonstration of a dose-de pendent, biphasic depression of blood pressure associated with the inhala tion of TCE (Fig 3 and 4) is consis tent with the suggestion of Bass* that an adequate explanation for the tox icological effects of acutely inhaled organic solvents, cannot be ascribed solely to generalized CNS depression. Thus, during the initial phase of pres sure decline, positive chronotropic and inotropic effects were observed (Fig 3 and 5). since these effects were abolished by ^-blockade (Table), the findings suggest reflex stimulation of the heart. The decline in TPR associated with this initial phase of inhalation (Fig 3) is analogous to the reflex, peripheral vasodilation which occurs following chemical irritation of the respiratory stretch receptors2'; alternatively, pas sive vasodilation resulting from ganglionic blockade-4 may also serve to explain this observation. In prelim inary studies designed to identify which mechanism is responsible for the peripheral vasodilation, the ef fects of vagotomy and n-receptor blockade were studied. Although pre liminary evidence suggested that va gotomy abolished the TCEl-induced peripheral vasodilation, the data were complicated by concomitant reflex al terations in sympathetic tone which prevented a clear-cut analysis of the results (P. Herd, PhD, M. Lipsky, un published data). Further clarification must await additional studies, such as cross-perfusion experiments (eg, that of Van Stee and Back"), in order to elucidate the actual mechanisms in volved in the TCE-induced peripheral vasodilation. With respect to the myocardial ef fects of TCE, our data suggest that the drug acts by inhibiting myocar dial contractility. The active state of muscle contraction has been divided into extensive and intensive compo nents." The extensive component, ie, the duration of the active state, is de fined as the time required for peak tension development and is a func tion of two events: intracellular Ca** release and its sequestration.10-21 This time interal was unaffected by TCE in the papillary muscle experiments, as reported above. In contrast, the in tensive component, ie, the rate of force generation defined by (Fig 4 and 6) and dT/dt (Fig 7), is markedly affected by TCE. The extracellular Ca-- concentra tion has been shown to control the rate of force generation because it, in part, determines the level of bound intracellular Ca** which is available for contractile function, thereby con trolling the magnitude and rate at which Ca" binds the troponin-acti- nomycin complex"51 Ca**-troponin formation releases actinomycin for adenosine triphosphate (ATP)-depen- dent cross-linkage formation, ie, myo cardial contractility, as seen in Fig 6. In addition, increase is extracellular Ca* * concentration protected against the TCE-induced decrease in myocar dial contractility (Fig 6) and en hanced the rate of return of myocar dial function to preexposure levels (Fig 7). At the present time, the precise site(s) at which TCE affects myocar dial contractility remain(s) to be de termined. Perhaps, because it is highly lipophilic, TCE affects mem brane-dependent functions. In this regard, Krantz and co-workers-'' have shown that TCE inhibits the respira tion of tissue slices obtained from the rat heart, and we have recently ob served that TCE depresses mitochon drial respiration associated with ATP synthesis as well as low-level Ca* - up take.21 Whether these findings reflect the in vivo situation remains to be de termined. However these data1*-27 are consistent with a possible explanation that TCE-induced depression of myo cardial contractility results from a decrease in the capacity of the cardiac mitochondria to supply sufficient ATP to mediate the contractile process. Elevation of the extracellular Ca-concentration (Fig and 7) would then increase the contractile effi ciency of the available supply of ATP by increasing the intracellular Ca*concentration available for contraction."**". Thus, in acute intoxication with TCE, eg, during exposure in confined spaces1* or as a result of "giue sniff ing," one may expect profound altera tions in cardiovascular function to oc cur independent of, but perhaps in addition to, CNS depression.1 It is suggested that the extent to which these cardiovascular effects may be altered by exogenous Ca", or phenyl ephrine, or both may, following more detailed study, provide a basis for more active and safe resuscitation of exposed individuals. Previous studies*-11 1*-S1 of the toxic effects of TCE have, in general, used exposure levels lower than those in the present study, especially in hu man toxicity experiments.1*-51 Stew art and Andrews have pointed out that the effective dose of TCE is a function of several variables of which not only the inspired concentration and duration of exposure are impor tant, but also the lipophilicity of the exposed areas contribute signifi cantly to the net effective accumula tion of this compound in the body. In deed, in human trials,5"51 TCE can be detected in the breath more than 24 232 Arch Environ Health/Vol 28, April 1974 SL 036633 Cardiovascular Effects of 1,1,1-Trichloroethane/Herd et al hours af sure and ods after Routine function out dun: of dym vascular sued. Ui not kno in myot low-levt themsei on sub: vascula gic crisi logical1 of card trial wc vapors, ent tim nicatioi we beli need ft myocat close tc cumula those i workin This ir per Four Hnmitel 1. Ste :ion wit 1966. 2. Oli Arch f Drecise ar* deit is memi this have sspiraim the ly ob>ehoni ATP ** up'effect be de21 are lation myo t>m a irdiac ATP >cess. Ca* rould efffATP Ca trac- miffierad ocs in It is hich ' be nyllore for i of xic sed in huwout 5a ich ion or:he iff* la in- hours after a single, low-dose expo sure and is detectable for longer peri ods after chronic, low-dose exposures. Routine blood, urine, and hepatic function studies are generally carried out during these trials,2*-11 but studies of dynamic alterations in cardio vascular function have not been pur sued. Under these circumstances, it is not known whether slight alterations in myocardial function occur during low-level exposure which may lend themselves to more dramatic sequelae on subsequent insult to the cardio vascular system, eg, during adrener gic crisis.*10 Unfortunately, epidemio logical evidence such as the incidence of cardiovascular accidents in indus trial workers who are exposed to TCE vapors, are not available at the pres ent time (G. Hickey, MS, oral commu nication, February 1973). However, we believe that our data suggest a need for further investigation of the myocardial effects of low-level (ie, close to the threshold limit value) and cumulative exposures to TCE, such as those that may occur under normal worlwiag conditions This investigation was supported by the Tap per Foundation, New York, and the Rhode Island Hospital. References 1. Stewart RD, Andrews JT-. Acute intoxica tion with methylchloroform. JAMA 195:501-906, 1966. 2. Olishifski J, McElroy F: Fundamental* of Industrial Hygiene. Chicago, National Safety Council, 1971, pp 65-66. 3. Adams EM, et ai: Vapor toxicity of 1,1,1-trichloroethane determined by experimenta on lab oratory animals. Arch Ini Hyg Occup Med 1:225236, 1950. 4. Synthetic Organic Chemicals: United States Production and Sales of MisrtUannm* Chem icals. US Tariff Commission, 1970. 5. Mote to Correspondents. Food and Drug Ad ministration, 1973. 5. Stahl CJ, Fatleh AV, Domininguez AM: Trichloroethane poisoning: Observations on the pa thology and toxicology in six fatal cases. J Fo rensic Sei Soc 14393-397,1969. 7. Hatfield TR, Maykoski R: A fatal methyl chloroform (trichloroethane) poisoning. Arch Environ Health 20279-281, 1970. 8. Baas M: Sudden sniffing death. JAMA 212:2075-2079, 1970. 9. Rennick RB, et al: Induction of idioven tricular rhythms by 1,1,1-trichloroethane and epi nephrine, abstracted J Pharmacol Exp Ther 94327.1949. 10. Reinhardt C, Mullin L, Mayfield M: Halocarbon-epinephrine induces cardiac arrhythmic potential of some industrial solvents, abstracted. Toxicol Appl Pharmacol 22305,1972. 1L Strosberg AM, Johnson L. Miller L: Methylchloroform-induced fibrillation in the mouse, abstracted Fed Proc 323178,1973. 12. Griffiths WC, et al: Rapid identification of and assessment of damage by inhaled volatile substances in the clinical laboratory. Clin Biochem 5:222-231, 1972. 13. Mason DT; Usefulness and limitations of the rate of rise of intraventricular pressure (dP/dt) in the evaluation of myocardial contrac tility in man. ,4m J Cardiol 23316-527,1909. 14. Grossman W, et al: Alterations in preload and myocardial mechanics in the dog and in man. Circ Res 31:83-94, 1972. 15. Henderson A, et al; Depression of myocar dial contractility in rats by free fatty acids dur ing hypoxia. Circ Res 26:439-449, 1970. 16. Buckley NM, Penefsky 2J, Litwack RS: Comparative force-frequency relationships in human and other mammalian ventricular myo cardium. Ffluegers Arch 332:259-270, 1972. 17. Greiaheimer E; The circulatory effects of anesthetics, in Hamilton WF (ed): Handbook of Physiology, Baltimore, Williams & Wilkens Co, 1965, vol 3, pp 2477-2510. 18. Innes IR, Nickerson M: Drugs acting on postganglionic adrenergic nerve endings and structures innervated by them, in Goodman LS, Gilman A (eds): The Pharmacological Basts of Experimental Therapeutics. New York, Macmil lan Co, 1971, pp 510-511. 13. Winegrad S, Shanes A: Calcium flux and contractility in guinea pig atria. J Gen Physiol 45371-394,1962. 20. Nayler W: Cellular exchange of calcium, in Harris P, Opie L (eds): Calcium and the Heart, New York, Academic Press Inc, 1971, pp 24-65. 21. Linger GA: Heart: Excitation-contraction coupling. Ann Rev Physiol 3555-86, 1973, 22. Goldberg A, Ullrich W: Effects of halothane on isometric contractions of isolated heart muscle. Anesthesiology 28:838-845, 1967. 23. Paintal AS: Vagal sensory receptors and their reflex effects. Physiol Rev 53:159-227,1973. 24. VanStee EW, Back KC: The mechanism of the peripheral vascular resistance change during exposure of dogs to bromotrifluoromethane. Tox icol Appl fharmacol 23:423-442,1972 25. Kata AM: Contractile proteins of the heart Physiol Rev 50:63-89, 1970. 26. Kranti J Jr, Park CS, Ling J: The anes thetic properties of 1,1,1-trichloroethane. Anes thesiology 00335-640,1959. 27. Herd PA, et al: Alterations in mitochon drial respiratory control characteristics induced by 1,1,1-trichloroethane. Fed Proc, to be pub lished. 28. Kleinfeld M, Feiner B: Health hazards as sociated with work in confined spaces. J Occup Med 8:358-364, 1966. 23. Tixheiaon T, et ai: Toxicity of 1,1,1-trichloroethane as determined on laboratory ani mals and human subjects. Am Ind Hyg Assoc J 19353-361,1958. 30. Stewart RD, et al: Human exposure to 1,1,1-tridrkmethane vapor Relationship of ex pired air aud blood concentrations to exposure and toxicity. Am Ind Hyg Assoc J 22252-262, 1961: 3L Stewart RD, et al: Experimental human exposure to methyl chloroform vapor. Arch En viron Health 19:467-472 1969. MYTHOLOGY FOR ECOLOGY Herakles' Reducing Salon A girdle was no easy thing to find In the ancient Attic time, And when Eurystes' chubby daughter Heard about Omphale's, she thought she'd orter Have one, too. It's no proper labor for a hero To find a girdle labeled forty--zero. So Herakles most gaily Brought his problem to Omphale, Who with fast and exercise reductive Contrived to make herself seductive Without the use of belt or stay. She promptly gave away Her girdle, on condition That Herakles would stay And help in her attrition. --Rusticatus. Arch Environ Health/Vol 2B, April 1974 SL 036634 Cardiovascular Effects of 1,1,1-Trichloroethane/Herd et al 233