Health effects among refrigeration repair workers exposed to fluorocarbons.

Refrigeration repair workers may be intermittently exposed to fluorocarbons and their thermal decomposition products. An index case of peripheral neuropathy (distal axonopathy) in a commercial refrigeration repairman prompted an epidemiologic investigation of the health of refrigeration repair works. No additional cases of peripheral neuropathy were identified among the 27 refrigeration repair workers studied. A reference group of 14 non-refrigeration repair workers was also studied. No differences were noted between groups for the ulnar (motor and sensory), median (motor and sensory), peroneal, sural, or tribial nerve conduction velocities. Refrigeration repair workers reported palpitation and light-headiness significantly more often than did workers in the reference group. No clinical neurologic or electroneurophysiolocig abnormalities were detected among eight refrigeration repair workers followed for a three-year period during continuous employment.

HEALTH EFFECTS AMONG REFRIGERATION REPAIR WORKERS EXPOSED TO FLUOROCARBONS by David Douglas Campbell A thesis submitted to the faculty of The University of Utah in partial fulfillment of the requirements for the degree of Master of Science Community Medicine Department of Family and Community Medicine The University of Utah December 1983 Copyright @ David Douglas Campbell 1983 All Rights Reserved THE UNIVERSITY OF UTAH GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a thesis submitted by David Douglas Campbell This thesis has been read by each member of the following supervisory committee and by majority vote has been found to be satisfactory. W~ ;(! Rom;U£J Chainnan: William N. Rom, M.D. Oct. ] 2, 1983 Oct. 12, 1983 THE UNIVERSITY OF UTAH GRADUATE SCHOOL FINAL READING APPROVAL To the Graduate Council of The University of Utah: I have read the thesis of David Douglas Campbell 10 Its final form and have found that (l) its format, citations, and bibliographic style are consistent and acceptable; (2) its illustrative materials including figures, tables, and charts are in place; and (3) the final manuscript is satisfactory to the Supervisory Committee and is ready for submission to the Graduate School. Ph.D. Approved for the Major Department C. Hilmon Castle, M.D. Chairman. Dean Approved for the Graduate Council James L. Clayton, ph ¢. Dean (If [he Graduate Schoul ABSTRACT Refrigeration repair workers may be intermittently exposed to fluorocarbons and their thermal decomposition products. An index case of peripheral neuropathy (distal axonopathy) in a commercial refrigeration repairman prompted an epidemiologic investigation of the health of refrigeration repair workers. No additional cases of peripheral neuropathy were identified among the 27 refrigeration repair workers studied. A reference group of 14 non-refrigeration repair workers was also studied. No differences were noted between groups for the ulnar (motor and sensory) I median (motor and sensory) , peroneal, sural, or tibial nerve conduction velocities. Refriger­ation repair workers reported palpitations and light-headedness sig­nificantly more often than did workers in the reference group. No clinical neurologic or electroneurophysiologic abnormalities were detected among eight refrigeration repair workers followed for a three-year period during continuous employment. TABLE OF CONTENTS ABSTRACT. LIST OF TABLES ACKNOWLEDGEMENTS INTRODUCTION . METHODS Study Subjects Medical Laboratory Testing Electroneurophysiologic Testing . RESULTS Case Report . Study Findings DISCUSSION . CONCLUSION . REFERENCES Page iv vi vii 1 3 3 4 5 6 6 7 12 15 16 Table 1. LIST OF TABLES Symptoms Reported by Refrigeration Workers and an Unexposed (Reference) Group of Workers . . 2. Average Maximal Nerve Conduction Velocities of Refriger­ation Repair Workers and a Reference Group of Unexposed Page 8 Workers . • • • . . • • • • . . • • • • . . . • . • . • • 10 3. Average Nerve Conduction Velocities (Meters/Second) Among Eight Refrigeration Repair Workers Followed from 1978 to 1981 • • • • • • • . • • • • • . • • • • • • • • . . . • • 11 ACKNOWLEDGEMENTS I thank Ken Casey, M.D., Michael G. Holthouser, M.D., John W. Gardner, M.D., Dr.P.H., She ran Smith, Sara Shopkow, Virginia Aldrich, and Mary Bishop for their assistance in this project. INTRODUCTION Fluorocarbons are used in industry as refrigerants, solvents and propellants. In the refrigeration industry three widely used fluorocarbons are dichlorodifluoromethane (Fluorocarbon 12, FC 12), monochlorodifluoromethane (Fluorocarbon 22, FC 22) and chloropenta-fluoroethane (Fluorocarbon 115, FC 115). Refrigeration repair workers may be exposed to fluorocarbons during repairs of leaks or while charging a system. The current threshold limit value for each is 1000 ppm. l contact with an open flame or hot metal, which may occur during the repair of leaks, results in thermal decomposition producing hydrogen chloride, hydrogen fluoride, phosgene, carbon dioxide, and chlorine. Cadmium is a component of the solder often used in construction and repair in the refrigeration trade, and it may also represent an occupational hazard. Although several aliphatic hydrocarbons are known to produce peripheral neuropathy,2,3 there are no reported studies to determine the peripheral neurotoxic potential of fluorocarbons and their ther-mal decomposition products. Cadmium chloride has been shown to pro-duce peripheral nerve injury in laboratory animals, but there have not been any human studies reported. 4 The toxicity of fluorocarbons was evaluated in the 1960s because of increased asthmatic deaths associated with the rise in usage of hand-held bronchodilator nebulizers containing fluorocarbons as pro- pellants5. ' 6 In the united States there have been reported sudden 2 unexplained deaths in aerosol "sniffers." Investigators believed this might be due to cardiac arrhythmias induced by the fluorocarbon propellants contained in many commercially available aerosols. 7 Reinhardt et al showed that fluorocarbons could sensitize the canine myocardium to epinephrine, resulting in serious cardiac arrhythmias.8 Speizer et al reported that pathology personnel exposed to FC 22 and FC 12 in the course of preparing frozen sections had a greater preva­lence of palpitations than did an unexposed reference group.9 Levels of FC 22 averaged 300 ppm (0.03%). Continuous electrocardiographic monitoring of several exposed subjects in the course of their work revealed multiple arrhythmias. In 1978 a local refrigeration repairman developed a progressive sensorimotor peripheral neuropathy. After hospitalization and exten­sive evaluation, the etiology could not be determined. A preliminary electroneurophysiologic study on the left median sensory, left ulnar sensory, and left sural nerves of ten of his co-workers revealed mild abnormalities in seven of the subjects. These findings suggested a possible link to workplace exposures. In this study, the potential adverse health effects that could arise as a result of refrigeration repair work were evaluated with particular reference to neurologic, cardiovascular, and respiratory abnormalities. METHODS Study Subjects Exposed subjects were selected from a local refrigeration installation and servicing company for whom the index case had worked. All 24 workers in this company employed at the time of the study in servicing or construction of refrigeration units were included in the study. Of the original group of ten workers studied in 1978, four were still employed at the same company, five were employed as refrigeration repair workers in other local companies, and one had moved from the area. A total of 29 currently employed refrigeration repair workers were invited to participate. TWenty­seven white, male refrigeration repair workers participated, including eight from the initial study. The index case was also examined, and his results are presented separately. A reference group was selected to compare results of the symptom questionnaire and the electroneurophysiologic studies. The reference subjects were selected from one of two local unions of plumbers and pipe fitters or insulation workers. Potential reference subjects were randomly selected from five-year age groups to match the age distribution of the study subjects. Potential reference subjects were excluded if they had prior neurological impairment, had a past history of low-back injury, or if they had been employed in the refrigeration repair trade within the last 12 months. A total of 32 white, male, non-refrigeration repair workers were contacted. Seven 4 declined participation, six had a history of prior back injury, sciatic neuropathy, or other neurological impairment, and three had worked in the refrigeration trade within the last 12 months. This gave 16 potential unexposed subjects, of whom 14 participated. This number of reference subjects resulted in 80% power to detect a differ­ence of 3 meters per second in nerve conduction velocities with alpha set at 5% for a two-tailed student t-test. Medical Laboratory Testing Physical examinations and testing were performed by occupational medicine physicians at the University of Utah Medical Center at least 16 hours after the last work exposure. In addition to physical examination and the medical history, a questionnaire was administered to determine the presence of symptoms related to the neurologic, cardiovascular, and respiratory systems. Chronological occupational histories and information on alcohol consumption were obtained from each study subject. Respiratory function was assessed with the forced vital capacity maneuver. The forced vital capacity (FVC) and forced expiratory volume in one second (FEVl ) were obtained according to the American Thoracic Society standards using an Ohio-Med 822 rolling dry seal spirometer and Spirotech microprocessor. lO The forced expiratory maneuver was repeated until at least two tests were within 5% of each other and within 5% of the best test, i.e., at least three acceptable tests. All results were temperature corrected to standard pressure and body temperature. The best FVC and FEV I were used for interpretation. Results were evaluated in terms of percent of predicted normals as measured by Knudson et al. ll Chest 5 radiographs and standard l2-lead electrocardiograms at rest were obtained. Blood was analyzed for complete blood counts, differential count, albumin, total protein, glucose, calcium, phosphorus, uric acid, urea nitrogen, creatinine, lactic dehydrogenase, alkaline phosphatase, serum aspartate and alanine aminotransferases, bilirubin, triglycerides, cholesterol, electrolytes, and zinc protoporphyrin. Routine urinalysis was done. Reference subjects received identical evaluation and tests except for pulmonary function tests, electro­cardiograms, and chest radiographs. Electroneurophysiologic Testing Nerve conduction speeds were determined at room temperature on a TE42 Electromyograph using surface electrodes on all study and reference subjects. The following nerves were tested bilaterally using supramaximal stimuli: ulnar motor, ulnar sensory, median motor, median sensory, tibial, peroneal, and sural. All nerve conduction velocities were measured orthodromically, except the sural nerve which was measured antidromically. Distal latencies were measured on the median and ulnar motor, peroneal and tibial nerves. Sensory action potentials were measured for the ulnar sensory, median sensory, and sural nerves. Skin temperature was greater than 30°C at the site of recording for all tests. RESULTS Case Report The index case was a 33-year-old Caucasian male who entered the refrigeration repair trade in 1971. In 1976 he began to notice weight loss, difficulty concentrating, depression, and weakness. In the summer of 1978, while he was repairing a leak in a refrigeration sys­tem, the pipe broke releasing fluorocarbons into the work area. He became nauseated, vomited and complained of generalized weakness and abdominal cramps. He left work and remained off work for several weeks. In July 1978, his nerve conduction velocities in his left leg were as follows: peroneal nerve, 40 m/sec (normal >40 m/sec); tibial nerve, 23 m/sec (normal >35 m/sec) i and sural nerve, 21 m/sec (normal >37.5 m/sec). In October 1978 he was hospitalized for further evaluation of his neuropathy. On physical examination decreased vibratory and position senseS in the distal extremities were noted. Touch sensation was intact. His muscle strength, bulk, and tone were all normal. Deep tendon reflexes were mildly decreased in the biceps and triceps bilaterally. The remainder of the examination was normal. Laboratory evaluation showed no abnormalities in albumin, liver enzymes, bili­rubin, glucose tolerance, vitamin B12, serum folate, sedimentation rate, urinalysis, cerebrospinal fluid, chest radiograph, or thyroid function. Serologic tests for rheumatoid arthritis and syphilis were negative. Urine lead and mercury levels were well below the toxic 7 range. The etiology for his distal axonopathy could not be deter­mined, but the history suggested a possible link to workplace expo­sure. He returned to refrigeration repair work for 11 months and was reexamined in 1981 with other refrigeration repair workers in this study. At that time his physical examination was unchanged, with persistent sensory deficits in the feet and hands. The nerve conduc­tion velocities had markedly improved: left peroneal nerve, 46 m/sec; left tibial nerve, 46 m/sec; and left sural nerve, 35 m/sec. Study Findings Among the 27 refrigeration repair workers studied, no additional cases of peripheral neuropathy were identified. Their chest radio­graphs, pulmonary function tests, electrocardiograms, and blood and urine test results were all within normal limits. The mean age of the 27 refrigeration repair workers was 32 years and of the 14 reference subjects, was 35 years. The mean number of symptoms among the exposed was 5.8 versus 4.1 in the reference group, out of 34 symptoms queried. There were similar numbers of drinkers, ex-drinkers, and non-drinkers of alcohol in both groups. Table 1 shows the 11 most common symptoms and the frequency of responses for both the refrigeration repair and reference workers. Lightheadedness was reported by 18 workers (67%); tiring easily was reported by 12 subjects (44%) i trouble breathing, headaches, and pressure in the chest were each reported by 9 workers (33%). Seven workers {26%} reported palpitations, numbness in the fingers, irri­tability or trouble remembering. Perspiring easily and eye irri­tation were each reported by six workers (22%). TWo symptoms were TABLE 1 Symptoms Reported by Refrigeration Workers and an Unexposed (Reference) Group of Workers Refrigeration Workers Reference Workers Symptom (N=27) (N=14) No. % No. % Lightheadedness* 18 67 3 21 Tires Easily 12 44 3 21 Pressure in the Chest 9 33 2 14 Trouble Breathing 9 33 4 28 Headaches 9 33 7 50 Palpitations* 7 26 0 0 Numbness in Fingers 7 26 1 7 Irritability 7 26 1 7 Trouble Remembering 7 26 1 7 Perspiring Easily 6 22 4 28 Eye Irritation 6 22 7 50 *p<0.05 by Fisher's exact test, two-tailed. co 9 reported significantly more often among refrigeration repair workers, i.e., lightheadedness and palpitations. TWelve of the eighteen workers reporting lightheadedness named fluorocarbons as the cause, and four of nine experiencing trouble breathing named soldering or welding as the cause. Other reported symptoms were not as closely associated with particular workplace exposures. Table 2 shows the mean nerve conduction velocities and the lower limits of normal. The mean nerve conduction velocities of the refri­geration repair workers were standardized to the age distribution of the reference group. The refrigeration repair workers had mean nerve conduction velocities essentially the same as the unexposed reference workers for all nerves studied. Sural nerve conduction velocities for both groups of workers were, on the average, at the lower limits of normal. Sensory action potentials of the ulnar and median sensory and the sural nerves were normal, as were distal latencies of the tibial, peroneal, median motor, and ulnar motor nerves. Average nerve conduction velocities of eight workers followed from 1978 to 1981 are shown in Table 3. The average nerve conduction velocities for the ulnar and median sensory nerves increased slightly over this time period. No change in working conditions could account for this increase, and the differences Were not large in comparison to the measurement variability (p>.05). TABLE 2 Average Maximal Nerve Conduction Velocities of Refrigeration Repair Workers and a Reference Group of Unexposed Workers* Refrigeration Workers** Reference Workers Nerve (Lower Limit of Normal) (N=27) (N=l4) Mean SD*** Mean SD*** Ulnar Motor (48) 60 4.0 60 4.1 Unnar Sensory (37) 42 3.6 41 5.2 Median Motor (48) 60 4.8 60 3.6 Median Sensory (37) 42 3.8 42 4.2 Peroneal (40) 49 3.2 47 3.7 Sural (37.5) 37 3.9 37 4.0 Tibial (35) 48 6.3 49 5.3 *All values are in meters per second. **Nerve conduction velocity averages are standardized to the age distribution of the reference group_ ***Standard deviation. p>.05 for all tests of differences between meanS. I-' o TABLE 3 Average Nerve Conduction Velocities (Meters/Second) Among Eight Refrigeration Repair Workers Followed from 1978 to 1981 Nerve Left Ulnar Sensory Left Median Sensory Left Sural 1978 38 36 36 p>.05 for all tests of differences between means. 11 1981 43 40 36 DISCUSSION This cross-sectional study demonstrated a significant increase in lightheadedness and palpitations in refrigeration repair workers intermittently exposed to fluorocarbons compared to a reference group of unexposed workers. No objective evidence of peripheral nerve dysfunction was found in refrigeration repair workers. No decrement in nerve conduction velocities was found in eight refriger-ation workers followed over three years of continuous employment. Lightheadedness and palpitations are difficult symptoms to evaluate, as these symptoms are often found in persons without under-lying pathology. On the other hand, these symptoms are frequently associated with serious cardiac arrhythmias including ventricular tach ycard i a. 12 Lightheadedness may also represent a direct effect on the central nervous system. Speizer et al found arrhythmias among workers who had reported a high frequency of palpitations and who were exposed to fluorocarbons at levels of FC 22 averaging 300 ppm. 9 However, human exposure to fluorocarbons under controlled conditions with electrocardiographic monitoring have failed to show significant abnormalities. Azar et al exposed volunteers to 10,000 ppm FC 12 for 2.5 hours and found no untoward reactl·o ns or card i ac arrh y thmi as. 13 Stewart et al exposed volunteers to 1000 ppm FC 12 for eight hours per day, five days a week, for four weeks. 14 No untoward effects, electroencephalo-graphic abnormalities or cardiac arrhythmias were demonstrated. 13 Personal air samples were obtained from two refrigeration repair workers who participated in the study over the course of a typical work shift. Levels for FC 22 and FC 115 were found to be 1.4 ppm and 2.2 ppm, respectively. These levels are well within the threshold limit value of 1000 ppm. No symptoms were reported during this work shift, which included repairing leaks from pipes containing fluoro­carbons. In light of the very low levels of FC 22 and FC 115 measured, it is difficult to draw a cause and effect relationship between exposure and the symptoms reported in this study. However, these results do suggest that further studies, e.g., continuous ambulatory electro­cardiographic monitoring, may prove useful in evaluating these symp­tom complaints in refrigeration repair workers. No association was found between refrigeration repair work and peripheral neuropathy. There are several explanations for this finding. Fluorocarbons may indeed not be neurotoxic. There are no other studies relevant to the question of a peripheral neurotoxic effect of fluorocarbons, their thermal decomposition products, or cadmium in humans. Nevertheless, this study does not prove that fluorocarbons are not neurotoxic. If it is assumed that fluorocarbons are neurotoxic, there are still other explanations for finding no association. One explanation might be that since refrigeration repair workers seem to be exposed to very low levels of fluorocarbons, the level of exposure is below the threshold level required to produce nerve damage. This possi­bility cannot be excluded based on the results. 14 Another explanation for a false negative study would be the use of an insensitive measuring technique. Clinical examination and nerve conduction velocities may be normal early in the course of dis-tal axonopathy. The most sensitive indicator of early axonopathy is sensory actl.o n potentl. a1 s. 15 However, these were measured and found to be normal. The healthy worker effect may contribute to finding no associa-tion between exposure and disease in cross-sectional studies. In the present study this effect was discounted in three ways. First, early in the course of distal axonopathy an individual may experience few or no symptoms and it would therefore be an unlikely cause for that individual to leave his place of employment. Secondly, a reference group of workers not exposed to fluorocarbons was used to compare results of electroneurophysiologic testing. And finally, eight workers were followed over three years and were found to have no deterioration in their electroneurophysiologic tests. Finally, there may be no association between exposure and dis-ease as a result of a Type II error. The study had a 20% chance of missing a difference in average nerve conduction velocities between exposed and unexposed workers of 3 m/sec at alpha equal to 5%. CONCLUSION Exposure to low levels of fluorocarbons and their thermal degradation products is associated with an increase in the reporting of symptoms of lightheadedness and palpitations. The mechanism of action may be a direct central nervous system effect and/or related to cardiac arrhythmias. Further studies, including ambulatory cardiac monitoring, may help clarify the pathophysiology of these complaints. Long-term exposure to fluorocarbons and their thermal decomposition products in refrigeration repair workers was not found to be associated with any abnormalities in the peripheral nervous system as determined by electroneurophysiologic testing. REFERENCES 1. American Conference of Governmental Industrial Hygienists: Documentation of the Threshold Limit Value for Substances in Workroom Air, ed. 3. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1978. 20 Herskowitz A, Ishii N, Schaumburg H: N-hexane neuropathy. N Engl J Med 285:82-84, 1971. 3. Mendell JR, Saida K, Ganansia MF, et al: Toxic polyneuropathy produced by methyl n-butyl ketone. Science 185:787-789, 1974. 4. Sato K, Iwamasa T, Tsuru T, et a1: An ultra-structural study of chronic cadmium chloride induced neuropathy. Acta Neuropathol 41:185-190, 1978. 5. Speizer FE, Doll R, Heaf P: Observations on recent increase in mortality from asthma. Br Med J 1:335-339, 1968. 6. Inman WHW, Adelstein AM: Rise and fall of asthma mortality in England and Wales in relation to use of pressurized aerosols. Lancet 2:279-285, 1969. 7. Bass M: Sudden sniffing death. JAMA 212:2075-2079, 1970. 8. Reinhardt CF, Azar A, Maxfield ME, et al: Cardiac arrhythmias and aerosol "sniffing". Arch Environ Health 22:265-279, 1971. 9. Speizer FE, Wegman DH, Ramirez A: Palpitation rates associated with fluorocarbon exposure in a hospital setting. N Engl J Med 292:624-626, 1975. 10. Ferris BG: Recommended standardized procedures for pulmonary function testing. Am Rev Respir Dis 118:55-88, 1978. 11. Knudson RJ, Slatin Re, Lebowitz MD, et al: The maximal expira­tory flow-volume curve. Normal standards, variability and effects of age. Am Rev Respir Dis 113:587-600, 1976. 12. Goldberg AD, Raftery EB, Cashman PMM: Ambulatory electro­cardiographic records in patients with transient cerebral attacks or palpitation. Br Med J 4:569-571, 1975. 13. Azar A, Reinhardt CF, Maxfield ME, et al: Experimental human exposure to Fluorocarbon 12 (Dichlorodifluoromethane). Am Ind Hyg Assoc J 33:207-216, 1972. 14. Stewart RO, Newton PE, Baretta ED, et al: Physiological res­ponse to aerosol propellants. Environ Health Perspect 26:275- 285, 1978. 15. Le Quesne PM: Neurophysiological investigation of subclinical and minimal toxic neuropathies. Muscle Nerve 1:392-395, 1978. 17