After conducting appropriate animal tests to ascertain safe levels, human subjects were exposed to concentrations of from 1.25% to 16.9% V/V of FE 1301. Assessment of judgement, alertness and neuromuscular skill indicated minimal but discernible effects at the lowest concentration in some individuals. At 10% V/V all subjects were effected. Stage I anesthesia occurred at 15% and Stage II would probably have occurred at 20%. A marked cardiac arrhythmia resulted in one subject exposed to 14%. There was complete recovery in all subjects within 20 minutes after exposure. No liver dysfunction occurred. The critical level for effective fire control is near 6%. This level would be acceptable on clinical toxicologic criteria

Elliott, H. W.

Hine, C. H.

Kaufman, J. W.

Leung, S.

English

Embry-Riddle Aeronautical University

The Space Congress® Proceedings 1969 (6th) Vol. 2 - Space, Technology, and Society Apr 1st, 8:00 AM Clinical Toxicologic Studies on Freon R FE 1301 C. H. Hine University of California, San Francisco; School of Medicine H. W. Elliott University of California, San Francisco; School of Medicine J. W. Kaufman University of California, San Francisco; School of Medicine S. Leung University of California, San Francisco; School of Medicine Follow this and additional works at: https://commons.erau.edu/space-congress-proceedings Scholarly Commons Citation Hine, C. H.; Elliott, H. W.; Kaufman, J. W.; and Leung, S., "Clinical Toxicologic Studies on Freon R FE 1301" (1969). The Space Congress® Proceedings. 4. https://commons.erau.edu/space-congress-proceedings/proceedings-1969-6th-v2/session-8/4 This Event is brought to you for free and open access by the Conferences at Scholarly Commons. It has been accepted for inclusion in The Space Congress® Proceedings by an authorized administrator of Scholarly Commons. For more information, please contact commons@erau.edu. CLINICAL TOXICOLOGIC STUDIES ON FREON ® FE 1301The Hine Laboratories, Inc.301 Seventh Street San Francisco, California 94103andToxicological Group, Department of Pharmacology,School of Medicine University of California at San Francisco, California 94122 aC. H. Hine, M.D., Ph.D. H. W. Elliott, M.D., Ph.D. J. W. Kaufman, M.D. S. Leung, B.A.aSponsored jointly by The Boeing Company and I. E. du Pont de Nemours and CompanySummaryAfter conducting appropriate animal tests to ascertain safe levels, human subjects were exposed to concentrations of from 1.25% to 16.9% V/V of FE 1301. Assessment of judgement, alertness and neuromuscular skill indicated minimal but discernible effects at the lowest concentration in some individuals. At 10% V/V all subjects were effected. Stage I anesthesia occurred at 15% and Stage II would probably have occurred at 20%. A marked cardiac arrhythmia re­ sulted in one subject exposed to 14%. There was complete recovery in all sub­ jects within 20 minutes after exposure. No liver dysfunction occurred. The crit­ ical level for effective fire control is near 6%. This level would be acceptable on clinical toxicologic criteria.IntroductionThis study of the pharmacology and toxicology of the fluorocarbon fire ex­ tinguishing agent, Freon © FE 1301, has special reference to possible myocardial sensitizing properties of the compound, and effects on the central nervous sys­ tem.It was conducted for the purpose of evaluating the medical aspects of toxi- cological hazards inherent in the release of FE 1301 into closed spaces such as aircraft cockpits or cabins. Although no adverse effects have been encountered in the use of portable extinguishers con­ taining FE 1301 , it is known that some halogenated hydrocarbons, as well as simple hydrocarbons, can cause abnormal­ ities in cardiac rhythm when inhaled by persons with high blood levels of adren­ alin.The investigation was done in two parts. The first part involved exposure of dogs to various levels of FE 1301 under fright-producing situations in order to ascertain whether endogenously released epinephrine would cause myocar­ dial arrhythmias. The second part wasconcerned with exposure of human subjects to varying concentrations with measuremert of mental alertness and acuity and moni­ toring of the electrical activity of the myocardium. Extensive animal studies had been conducted by the toxicology group at the du Pont Company, the Hazelton Lab­ oratories and Dr. Back, Wright-Patterson Air Force Base, Dayton, Ohio.Stoppes of the Haskell Laboratories exposed three volunteers to concentra­ tions up to 10% for 3-1/2 minutes. No other studies had previously been con­ ducted on man. The intent of this study was to obtain data which might help de­ fine those levels which could be consid­ ered as safe for passengers and operative personnel in those situations where there might be need for exposure to FE 1301.Experimental ApproachMaterialThe test material FE 1301 is identi­ fied chemically as bromotrifluoromethane (chemical symbol: CBrF3). The material was furnished through the courtesy of Freon Products Division of E. I. du Pont de Nemours and Company. The material was described as typical of commercial pro­ duction and free from impurities. Fluoro­ carbon 22B1 (CHBrF2) and fluorocarbon 12B2 (CBr2F2) were stated to be present at concentrations of less than 1 ppm though specifications on the product would allow up to 50 ppm of either com­ pound. Free halogen or acids were stated to be absent.Exposure FacilitiesAll exposures took place in a cubi­ cle exposure chamber of 8064 liter capa­ city. The chamber was lighted and equip­ ped with circulating fans. All exposures were made in a static environment. Ex­ posure in man lasted up to 25 minutes.Determination of FE 1301An appropriate method was developed for the determination of air concentra­ tions of FE 1301 utilizing an Aerograph 600 gas-liquid chromatograph. For this purpose we used a hydrogen flame ioniza- tion detector and a stainless steel tube column, i.d. 4 mm. and 15 cm. in length, packed with 80-100 mesh Polapak "A". A volume of one ml. of gas under these con­ ditions gave a full scale deflection at 16 volumes percent with X4 attenuation.Production of Desired ConcentrationFE 1301 gas was allowed to flow from the cylinder at a metered rate into the chamber to give the desired nominal con­ centrations. The air and FE 1301 input were adjusted to achieve the desired con­ centration which was then monitored and maintained at this level (or within 1.4% of this level) for the remainder of the exposure.8-1Exposure of Human Subjects Test SubjectsFifteen test subjects were used in assessment of the effects of FE 1301 on behavior and 10 on myocardial irritabil­ ity. They were drawn from the population of research personnel, medical and dental students from the professional schools at the University of California at San Fran­ cisco. The nature of the test and the risks involved were explained to each sub­ ject emphasizing that the clinical pharm­ acology of the substance had not been fully ascertained and that this was part of the purpose of the experiment.General ProcedureSubsequent to acceptance into the program we questioned them concerning their previous experience with anesthe­ tics, allergies and sensitivities, and current drug ingestion. A physical ex­ amination was performed and their mood and affect appraised. Where high concen­ trations were to be used an electrocardi­ ogram was taken. Prior to exposure all subjects were trained to acceptable Ieve3s of performance on tests measuring mental alertness and neuromuscular coordination. The FE 1301 was administered to four sub­ jects at 1.25%, six subjects at 2.5%, four subjects at 5% and six at 10%. While in the chamber, subjects made observations as to sensory stimulation and carried out tests for mental alertness and neuromus­ cular coordination. All exposures were for 22 minutes or until the subjects com­ pleted the schedule given below:Time (Minutes) Test0 Record Sensory Experience1 Record Sensory Experience2 Record Sensory Experience5 Record Sensory Experience6 Perform Romberg7 Perform Finger-to-Finger8 Perform Maze10 Record Sensory Experience11 Perform Pursuit Rotor15 Record Sensory Experience16 Perform Simple Reaction20 Record Sensory Experience21 Perform MazeLeave chamber and narrate descriptionof exposure experience.Experiments Monitoring Vital SignsTen subjects were administered FE 1301 in concentrations of 5-16% by mask. During this time pulse, respirations, blood pressure and electrical activity -of the heart were monitored. Carbon dioxide at 5-10% was administered intermittently to six subjects.Control of BiasThe experiment was carried out on a single blind basis but without placebo control, subjects being unaware of the concentrations that were being administered.Final interpretation of the electrocardi­ ograms was made without the reader's knowledge of the concentration to which the subjects had been exposed.Results Characteristics of the SubjectsThe age span was 22 to 33 years of age. Only one of the subjects was re­ ceiving chronic medication. Seven had a past history of allergies and sensitivi­ ties. Two of these were currently clini­ cally active. One subject had a systolic murmur accentuated by exercise and had a history of a congenital heart problem.Levels of ExposureThe concentrations determined by GLC were close to nominal concentrations in all runs.Unusual EventsThe experiment proceded satisfactor­ ily according to experimental design and it was not necessary to significantly al­ ter any of the procedures during the course of the investigation. No subject asked to terminate his chamber exposure; however, three subjects breathing mask- concentrations of 12% or greater had a feeling of impending unconsciousness. Subject 5 developed an unusual myocardial activity and dissociation of the pace maker after reaching a level of 16.1%, so his exposure was discontinued. Return to normal rhythm occurred within 3 minutes. It was not necessary to use any resusci- tative devices at any time. All subjects recovered from their central nervous sys­ tem depression within 20 minutes after exposure. Two subjects reported headache during or following exposure; one of these persisted for 12 hours.Mental Alertness and Neuromuscular Coor­ dinationThere was a deterioration in perfor­ mance in one or more tests at all of the four levels of exposure. Test in which the fingers were brought into proximation was the most sensitive and showed de­ creased performance at the lowest level tested. The maze test was second in sen­ sitivity and decreased performance and was correlated with increasing FE 1301 concentration. The Romberg test was the least sensitive showing no effect until the 10% level was reached when 3 of 6 sub­ jects failed the test. Scores obtained in the rotor and simple reaction time tests did not correlate with concentration; in a number of instances in both tests there was improvement following exposure. At the 1.25% concentration there was con­ vincing evidence of decrement in the finger-to-finger test and decrement in 4 of the 8 maze tests. At 2.5% finger-to- finger test again was more poorly per­ formed by all subjects and there was a de­ crease in coordination as measured by the rotor test. There was no significant change at the 5% level of exposure. At8-2the 10% level there was a marked decre­ ment in performance of the maze test as well as the finger-to-finger coordination test and failure of Romberg test. Im­ provement in skill test scores when the is exposed to central nervous system de­ pressants is not the expected event but is sometimes observed in tests of the type used here. Two explanations are 1) an increase in the learning curve which continues during the testing session and 2) relaxation of tensions with a decrease in tendency to over-correct. At the 10% level there were 6 tests in which there were improvements , 7 in which there was no change and 23 in which there was a de­ crement performance.Descriptive WordsThe results of this test indicated a clear pattern of change in self apprai­ sal of mood and mental clarity. There was a decrease in words with positive values such as alert, careful, clear­ headed, forceful, industrious, resource­ ful and increase in words with negative values such as detached, drowsy, dull, elated, groggy, irritable, lackadaisical, lightheaded, sluggish and talkative. Fifty percent of the subjects at the low­ est level and all of the subjects at the highest.level indicated a feeling of lightheadedness . This generally was noted after 3 to 5 minutes of exposure.Sensory AppraisalThe majority of subjects did not ex­ perience eye irritation, nose irritation or pulmonary discomfort during most of the period of testing. No eye irritation was noted at the two lower levels. Two subjects noted a slight irritation at both the 5 and 10% levels while one re­ sponded with moderate irritation at the 10% level. Only slight nasal irritation was noted by any subjects at the three lower levels; however, one subject classi­ fied nasal irritation at the 10% level as severe. This was identified as a bromine- like odor. Pulmonary discomfort descri­ bed as either a feeling of coolness in the respiratory tract or nasal stuffiness was rated as no more than slight at any level. Olefactory recognition was rated as moderate in intensity by one or more subjects at all levels. Generally there was a decreased olefactory cognition with time. Lightheadedness just detected at the lower levels of exposure increased to a moderate disturbance in alertness and mental acuity in one of the four subjects at the 5% level, while three of the six subjects at the 10% level described marked sensation of giddiness and loss of normal alertness. Judging from all fac­ tors, it can be concluded that at concen­ trations at 10% a state of inebriation was beginning to appear.The narrative descriptions defined varying degrees of central nervous system depression with paresthesias, alteration in auditory perception, euphoria, and silliness occurring at levels of 5%. There was numbness about the lips andbeginning inebriation at the 10% level. A feeling of pending unconsciousness was related by three subjects at concentra­ tions of 14.4 to 16.9%. Only one subject who reached 15% did not feel markedly confused.Electrocardiographic ChangesThere were no significant and unex­ pected findings at the baseline electro­ cardiograms. No changes occurred in seven of the EKG's during exposure even when concentrations of as high as 16.9% were reached. One subject had lowering of the T-wave 5 minutes after exposure to 8.2% of FE 1301 and 26 minutes later at a concentration of 12.1% when carbon dioxide had been added to the inhalant mixture. A second subject had flattening of the T- waves after 10 minutes of exposure at 12.5% FE 1301 >and increased sinus arrhy­ thmia at a later time. The most marked changes were noted in a 24-year old, 165 pound, Caucasian male of athletic build, hypertonic in mood and affect. Five min­ utes after exposure to 12.8% of FE 1301, he developed a flattening of the T-wave. This was followed in two minutes by pre­ mature ventricular contractions and one minute later when the concentration had reached 14% by auricular-ventricular dis­ sociation. Rhythm was restored two min­ utes after cessation of the exposure.DiscussionStudy of the toxicity and biology of the fluorocarbons indicates that FE 1301 is one of the least toxic members of this class. The majority of overt pharmaco- logic signs refer to the central nervous system, the principal effect being narco­ sis, and anesthesia. However, there have been reported tremors and convulsive re­ actions in dogs exposed at high concen­ trations. Based on our experiments the only effect on the central nervous system of man which would be expected at concen­ trations short of those producing uncon­ sciousness would be decreased awareness and alertness and slight confusion. A large number of halogenated hydrocarbons may cause cardiac sensitization to epine- phrine; according to the evidence devel­ oped in animals and now in man FE 1301 would have to be classified among these compounds. The occurrence of cardiac ar­ rhythmias is dose related, based on exten­ sive experience with the anesthetics cy­ clopropane and chloroform. Arrhythmias produced by these compounds and presumably FE 1301 include a wandering pacemaker, atrial extrasystoles, atrial fibrillations, sporadic ventricular extrasystoles, mild focal and multifocal ventricular tachy­ cardias and bigeminal rhythm. Given a large enough series of exposed persons at high enough concentrations and under se­ vere conditions of epinephrine release, the probability exists that FE 1301 could produce myocardial sensitization and sig­ nificant cardiac arrhythmia. The question therefore evolves about the relative de­ gree of risk. The number of subjects in our study in whom the electrical activity was monitored is small, however we observed8-3no arrhythmias at concentrations below 10%. We did not establish an anesthetic level for our human subjects. However, the majority approached Stage I (anal­ gesia) at concentrations of about 14%. The stage of delerium would probably have been achieved when an additional 2-3% was present. Loss of consciousness would oc­ cur, in our opinion, in most people at about 20 volumes %. At concentrations of 10% of FE 1301 or greater all subjects ex­ perienced some degree of confusion, mis­ interpretation of the surroundings or un­ steadiness and giddiness. Clearly, one would have difficulty in sustaining com­ plex operations at such concentrations. Tasks requiring precise timing and high degree of coordination would undoubtedly deteriorate. At the 5% level while ef­ fected to some degree by lightheadedness and change in mood, skilled tasks could be performed and even balance and locomo­ tion were unimpaired. In the sitting po­ sition the sensation was not at all un­ pleasant nor was there any distress. In­ halation of the FE 1301 produces a sen­ sation which in the inexperienced is slightly disturbing; however, those who previously had received anesthetics or consumed moderate quantities of alcoholic beverages were familiar with the sensa­ tion produced and were not disturbed by the exposure at concentrations of 10% or below.There is no reason, based on our study, to believe that passengers would have any significant degree of confusion or be incapable of leaving their seats were rapid evacuation of the cabin area necessary at a FE 1301 level of 6%.8-4

Clinical Toxicologic Studies on Freon R FE 1301

https://commons.erau.edu/cgi/viewcontent.cgi?article=3041&amp;context=space-congress-proceedings

Clinical Toxicologic Studies on Freon R FE 1301

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