Document N2DB8O8bppa9DpG7Bw4eyZBng

3. Perry, K.; Bowler, R. G.; Buckell, H. M.; Druett, H. A.; and Shilling, R, S. F. 1948. Studies in the incidence of cancer in a factory handling inorganic compounds of arsenic. II. Chemical and environmental investigations. BrJIndMed 5: 6*15. 4. Lee, A. M., and Fraumeni, J. F., Jr. 1969. Arsenic and respira tory cancer in man: An occupational study. J Natl Cancer Inst 42: 1045-52. 5. Ott, M. G.; Holden, B. B,; and Gordon, H. L. 1974. Respiratory cancer and occupational exposure to arsenicals. Arch Environ Health 29: 250-55. 6. Snegireff, L. S., and Lombard, O. M. 1951. Arsenic and cancer. ' Observations in the metallurgical industry. Arch Ind Hyg Occup Med A: 199-205. 7. Pinto, S. S., and Bennett, B. M. 1963. Effect of arsenic trioxide exposure on mortality. Arch Environ Health 7: 583*91. 8. Nelson, W, C.; Lykens, M. H.; Mackey, J,; Newill, V. A.; Finkles, J. F.; and Hammer, D. 1.1973. Mortality among orchard workers exposed to lead arsenate spray: A cohort study. J Chron Dis 26: 105-18. 9. Pinto,S. S.; Warner, M. O.; Nelson, K. W.; Labbe, A. L.; and White, L. D. 1976. Arsenic trioxide absorption and excretion in industry. J Occup Med 18: 633*35. 10. World Health Organization. 1957. International Classification ofDiseases, 1955 Revision. Geneva: World Health Organization Publishers. 11. Henderson, V. Estimating the risk of respiratory cancer due to occupational exposure in smokers vs. non-smokers: a method for adjustment. Unpublished observations. 12. Jones, H. B., and Grendon, A. 1975. Environmental factors in the origin of cancer and estimation of the possible hazard to man. Food Cosmet Toxicol 18: 251-68. 13. Enterline, P. E. 1974. Respiratory cancer among chromate workers. J Occup Med 16: 523-26. 14. World Health Organization. 197A. Assessment of the Carcino genicity and Mutagenicity of Chemicals. Technical Report Series, No. 546. Geneva: World Health Organization Publishers. 15. Druckery, H. 1967. Quantitative aspects of chemical carcino genesis. In Potential Carcinogenic Hazards from Drugs (Evalua tion ofRisks), Ed. Truhart, R. UICC Monograph Series, Vol. 7, pp. 60-78. New York: Springer-Verlag. Health of Workers Exposed to 1,1, 1,Trichloroethane: A Matched-Pair Study C G. KRAMER, M.D. M. GERALD OTT, M.S. J. E. FULKERSON, B.S. N. HICKS, R.N., M.S. The Dow Chemical Company Midland, Michigan H. R. IMBUS, M.D. Burlington Industries Greensboro, North Carolina An epidemiologic study of 151 matched pairs of employees was conducted in two adjacent textile plants, one of which used inhib ited 1,1,1-trichloroethane as a general cleaning solvent. Employees in the study population had exposures to the solvent for 6 yrs or less at varying concentrations which were measured by breathing zone sampling and personal monitoring. While cardiovascular and hepatic observations were of primary interest, other health parameters were also studied. Application of sensitive statistical techniques and careful examination of all data did not reveal any clinically pertinent findings that were associated with exposure to 1,1,1-trichloroethane. The statistically significant associations that were observed between health measures and nonexposure factors emphasize the need to consider age, sex, race, and other variables in designing epidemiologic studies. TWO LITERATURE REVIEWS of 1,1,1 -trichloro ethane toxicity have recently been published.1 '2 Although extensive toxicological studies in animals were reported, less information was available on potential effects in humans, especially in employee populations chronically exposed to the solvent. The existing data indicate that 1,1,1 -trichloroethane is a central nervous system depres sant with low hepatotoxicity.3 _1 The chemical is capable of causing a temporary increase of heart sensitivity to epi nephrine and similar substances that could result in severe or fatal arrhythmias, but only at levels well above those acceptable as an occupational exposure.11 _14 The recom mended 1976 Threshold limit Value (TLV) published by the American Conference of Governmental Industrial Hygienists is 350 ppm (1.9 mg/1) as a daily time-weighted average (TWA). The main purpose of this study was to investigate pos sible health effects of 1, 1, 1 -trichloroethane exposure in an industrial population. Particular attention was given to the issue of whether or not chronic exposure resulted in any effect on the heart that would be detectable by electrocar diography. It was also desirable to search for hepatotoxic and central nervous system effects. Study Design The manufacture of 1, 1,1 -trichloroethane has involved a limited employee population exposed to relatively low concentrations of the solvent. Therefore, to investigate potential health effects associated with chronic exposure at levels approaching the TLV, it became necessary to design an inter-industry study. This investigation was undertaken by the manufacturer (The Dow Chemical Company), as November/December 1978 SL 036647 331 and control population, with respect to demographic vari ables. Health Examination Procedures The members of the on-site examining team worked closely with nurses and a physician from Burlington Indus tries in scheduling examinations and in review and follow up of individual findings. Extensive orientation and train ing prior to the study included a 1 wk pretest period during which only nonstudy persons were seen. The subset of individuals in the paired study was exam ined within a defined 7-wk period. Upon entering the examination area (a mobile unit especially equipped for the project), the employee's height, weight, blood pressure, and pulse were first obtained. To maximize consistency in the responses, a nurse assisted each person in completing the questionnaire, patterned after the Coronary Drug Project and using similar criteria for interpretation.16 Emphasis was placed on questions related to possible cardiac prob lems, with a check list for other body systems. A venipuncture was performed after the questionnaire had been completed. Laboratory determinations on whole blood and serum included hematocrit, hemoglobin, red blood cells (RBC), white blood cells (WBC), mean corposcular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and mean corpuscular volume (MCV). These tests were performed by a local commercial labor atory. The clinical chemistries, alkaline phosphatase serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), Gamma glutamyl trans peptidase (GGT), total bilirubin, urea nitrogen (BUN), lactic dehydrogenase (LDH), uric acid, total protein, albu min/globulin (A/G) ratio, albumin, calcium and phosphorus, were sent to Bio-Science Laboratories in Van Nuys. Calif ornia. Split samples were mailed separately on Fridays and Mondays to check for variability in clinical chemistries due to potential delays in shipment. The coefficients of varia bility for the seven sets of samples were comparable, although somewhat higher than internal coefficients pub lished by the laboratory.17 Following spirometric evaluation, participants proceeded to the industrial hygiene area where instructions were given for procuring an expired air sample. Samples were immed iately analyzed quantitatively for 1,1,1 -trichloroethane content by gas chromatography.10 The last procedure performed was the electrocardio gram (ECG). A computer-interpreted program was chosen because of the objectivity and consistency it would provide. The Smith-Mayo Program, in the version current at the be ginning of the study was selected as the best available, given the situation, due to its relative immunity from lead placement variation.18 The ECG equipment was connected by landlines to a reading computer in Birmingham, Ala bama, which immediately responded to any abnormal Findings by notifying the nurse examiners. The ECGs were overread clinically by a cardiologist and this reading was utilized in reviewing results for individual patients. The computer readings expressed by the program algorithms were used in the statistical analysis. All persons were informed of the examination results. Those with abnormal test results were either recalled for repeat studies or referred to a physician. Environmental Considerations Operations at the study plant began in 1969 and consisted of producing a dyed yarn suitable for knitting or weaving. During processing, fabric dust and trimer dust (a three-molecule polyester polymer) scattered through the area, contaminating machinery and building structures. These materials were treated as nuisance dusts not known to have any adverse effects on health. The solvent, 1,1, 1trichloroethane, was used in many operations to remove dust, oil, and other contaminants either from machinery, floors, or building structures. For approximately one yr Table 2.-Sutmnaiy of Estimated TWA Concentrations of 1,1,1-Tnchloroethane by Job Description, April 1973 Through March 1975 (in ppm and number of (ample*) Job Description or Work Area April 1973 Halide Meter* July-Aug 1973 Charcoar Date and Sampling technique Oct 1973 Charcoal ^ Nov 1973 Jan 4, 1974 Charcoal + Jan 15. 1974 -Feb 14. 1974 Charcoal 1 March 1975 8 hr personal sampling Machine cleaning Packer Conorspjd operators Sweiier operators Other operators Service and yarn loading Winding superintendent Laboratorj Office Other uork areas At air conditioner 245 (1) 194 (3) 838 (5) 485 (5) 648 (3) 439 (5) 347 (13) 435 (S) 50(1) 476 (7) 157 (3) 113(3) 131 (3) 191 (31 109 (7> 97 (3) 0(1) 182(16) 168 (5) 136 (9) 205 (10) 170 (10) 120 (12) 162 (10 49 (10) 4 (4) 153 (32) 188 (4) 287(4) 175 (3) 199(4) 150(4) 84 (4) 180 (32) 217(5) 125 (8) 183(3) 201 (5) 163(1) 34(1) 57 (4) 11 (1) 12 (1) list (31) Sampled for up to 45 min, numbe) of samples in parentheses indicates number of locations. ^Samples collected on charcoal rube at 1/min. for 10 min and analyzed on portable gas chromatograph. iSamples collected on charcoal rube at 1/mm. for 5 min. November/December 1978 SIj 036648 333 Table 4.-Distribution of Exposure Measures for 151 Workmen Exposed to 1, 1, 1 Trichloroethane (determined from Industrial Hygiene Surveys and Personnel Work Histories) Exposure Measures Duration of exposure Total <12 months 12-35 months 36-59 months 60 + months Number of Employees 151 2 87 41 21 Current TWA level of exposure Total <15 ppm 15-49 ppm 50-99 ppm 100-149 ppm 150-249 ppm 151 11 5 19 48 68 Estimated career dosage (TWA X months of exposure) Total < 2000 ppm months 2000-3999 ppm months 4000-5999 ppm months 6000 + ppm months 151 18 35 57 41 assigned to one of five concentration categories so that exposure measures for individuals could be estimated in conjunction with work history data. The categorizaion was based upon the following class intervals: Exposure Index 1,1,1 -Trichloroethane Concentration (ppm) 1 1 - 14 2 15 - 49 3 50 - 99 4 100 -149 5 150 -249 Each job was assigned an exposure index which changed in a few instances where the job itself was relocated or re structured. The levels assigned are considered to be conser vative since previous work practices, higher consumption of the solvent, and limited hygiene data suggest higher expos ure levels during the earlier years. Peak concentrations had exceeded 1000 ppm on occasion. The control plant did not use 1,1,1-trichloroethane. This was verified by an industrial hygiene survey and the negative results of expired air analysis for control employ ees. Results Selected demographic characteristics and smoking his tory of the exposed and matched control populations are shown in Table 3. A majority of the people were black and there were many more women than men in the populations. The populations also included many individuals under age 35. The Table does not reflect the additional matching for shift, socioeconomic status, or job description. Smoking patterns did not differ between exposed and control groups. Environmental measures for the 151 exposed employees are summarized in Table 4. Only two employees had been exposed less than one yr; maximum exposure was for 6 yr. Current TWA levels of exposure were skewed to the upper end of the intensity categories, reflecting the selection pro cedure which favored including individuals with higher exposure. Highest TWA exposure levels for one or more months, although not shown in the Table, were skewed even more with many individuals exceeding exposures of 250 ppm TWA prior to the study period. Estimated career dose was calculated by multiplying months of exposure by the mean TWA concentration in ppm for the appropriate class interval, summed over the individual's work experience. The expired air samples in Table 5 are in reasonable agree ment with the estimated dose on day of examination (ppm November/December 1978 SL 036649 335 Table 6.-Comparison of Dichotomous Health Exam Responses between 1, 1, 1-Trichloroethane Exposed and Matched Controls Health Exam Items Positive Responses Exposed Controls HISTORY Cardiac pain, aching, tightness, or pressure in the chest Difficulty in breathing Obvious stroke Weakness or paralysis of any part of the body Fainting spells or blacking out Dizziness spells Sudden pain or coldness of a foot or leg Pains or cramps in legs when walking Pain relieved when walking is terminated Abnormality in the following systems: Circulatory Gastrointestinal Genitourinary Nervous Musculoskeletal Dermal Respiratory OBSERVATIONS Irregular rhythm Positive romberg URINALYSIS FINDINGS Glucose Ketones Protein Blood 1 7 0 3 12 31 3 4 3 31 28 45 31 17 26 22 16 0 0 1 2 9 5 8 0 5 13 29 0 5 1 24 21 45 32 29 25 31 26 0 0 0 1 4 the exposed population that would account for the observed associations. However, they directed out attention to apparently chance trends in the control population in regard to four health parameters and to several individuals for whom further clinical review was needed. Table 9 compares positive findings between 121 matched pairs for whom computerized ECGs were obtained. The data were incomplete for the remaining 30 pairs due to transmission problems and delays in equipment servicing. No statistically significant differences were observed in regard to numbers of positive findings for any algorithm. A rank sum test was used to determine if the positive find ings on ECGs for the exposed persons were correlated with either estimated cumulative dose or level of 1,1,1 -trichloroethane in expired air. When the ECG findings were rank ordered, approximately five statistically significant differ ences were expected at the .05 level, whereas eight were found. Two of the associations were negative. The remaining positive correlations were due to ECG findings from one or more of four exposed individuals. One of these four indi viduals was functioning well in a high-exposure area although he was one of two persons in the study who had recent silent myocardial infarctions. Based on known his tory of these individuals, the infarcts were considered to be unrelated to work exposure. A review of deaths among active employees during the 6 yr of plant operations revealed two accidental deaths unrelated to exposure. During the year since the examina tion, there have been two nonfatal myocardial infarctions: one was a paired control individual and the other was a non-study employee from the control plant. Comment Many technical and social difficulties are encountered when organizing and executing studies where surveying a broad spectrum of potentially exposed individuals is November/December 1978 SL 036650 337 mize the direct effect of age, sex, race, and job description on comparisons of potential health effects associated with 1,1,1 -trichloroethane. In view of the need for controlling demographic variables, multiple regression analyses were run separately for men and women to explore associations among the health variables and selected nonexposure fac tors. The many statistically significant associations that were observed point out the importance of careful]}' design ing studies to minimize confounding effects of work expos ure with other factors. Animal studies and reports of human fatalities indicate that 1,1,1 -trichloroethane in massive acute exposures may cause apneic deaths or fatal cardiac arrhythmias.11 "14 20 At this site, no deaths attributable to the solvent have occurred during the 6 yr of plant operation. No statistically significant differences in rhythm were found between the exposed and control populations by either computer-read ECG or nurse observation (60 sec pulse rate). The brief monitoring period of the ECG allowed, at best, a very lim ited assessment of potential short duration arrhythmias and Table 8.-Summary of Statistically Significant Associations Based on the Regression of Thirty-One Quantitative Health Measures on Five Environmental Measures Pius Height of individuals (Matched-Pair Differences)* Quantitative Health Measure Cardiovascular measures A P - duration Hepatic measures AGGT A Alkaline phosphatase Blood Measures AWBC A Hematocrit Miscellaneous A BUN Independent Variable, Direction of Association and Level of Significance! Cumulative dose t fP < -05) Current level of exposure t if < .025) Breath analysis 1,(/><C.05) estimated dose on day of exam ^(P<.05) Cumulative dose f(P<.05) Duration t (F< .05) Duration |V'P<.05) NOTE: 4refers to a positive association and4to a negative association. * Environmental measures were: 1) estimated cumulative dose; 2) estimated current TWA exposure category; 3) duration of exposure; 4) body burden at time of exam (breath analysis [ppm]); and 5) day dose (estimated from hours on job and envir onmental surveys). t -05 significance level employed in Table, at slightly above the .05 level A SGP-T was associated with cumulative dose ^ (P ".05) and A Hemoglobin was associated with duration t (P -- .05). $ Two health measures were associated with A height alone: 1) A weight f (f < -001) and A R-Durauon T (f < .01). certain short duration S-T segment changes in the study. The limitations of 12-lead resting ECGs in comparison with ambulatory ECG monitoring have been reported.211 22 Use of ambulatory electrocardiography could provide addi tional information for evaluating abnormalities associated with cardiac sensitizing agents. No evidence of differences in chronic ECG changes were discovered between the ex posed and control groups. The absence of observed central nervous system effects is consistent with reports of minimal impairment of coor dination, and lightheadedness occurring with brief expos ure of 900 to 950 ppm. but not occurring with exposures of less than 500 ppm.3 '4 Finally, no association between increased exposure and hepatic dysfunction, as measured by enzyme studies, was detected in the present population. Medical results were reviewed in detail by the field phy sician and the Dow physician who directed the study partic ularly where trends were thought to show increased res ponse with increased career dose. No recognizable clinical pattern nor other evidence of adverse effects from exposures to 1,1,1 -trichloroethane were found in this study. November/December 1978 SL 036651 339 Table 9 (Continued) Program Algorithm Exposed/Control Average Rank Breath Levelf Average Rank Career Dose E. Axis deviation Left ventricular hypertrophy with marked ST-T abnormalities of left ventricular strain Left axis deviation marked degree minimal degree Vertical axis of QRS complex Horizontal axis of QRS complex Right ventricular hypertrophy (possible) Low anterior forces F. Other findings Unusual late depolarization Abnormal depolarization probably from inferior infarct from inferior infarct Inferior infarct no other qualification (high likelihood) possible Pericarditis Repolarization abnormality (hypokalemia) 37 14 13 01 15 10 01 01 01 20 10 10 33 22 10 01 10 01 32.2 no sample no sample 33 68 47.8 33 62.5 66.7 57 106 81 35.7 61.5 61.5 75.5 50 83.3 75.5 91 91.3 76-5 121 120t * Excludes 25 pairs for whom transmission of an ECG was either not sent or not received over telephone lines and five pairs where an ECG was judged to be of poor technical quality. t Breath samples were not available for four persons. Expected mean rank for breath level analysis is 59.0 and for cumulative dose analysis is 61.0. Higher rank scores correspond to higher exposures. ZP<.QS. P<.01. ********** Among those who provided technical and field assistance are: Maxine Coin, Roger Lee, Miriam McCormack, R.N., David R. Spen cer, and Theodore R. Torkelson. Submitted for publication September 9,1976; revised; accepted June 6,1977. Requests for reprints of this article should be addressed to: M. Gerald Ott, Dow Giemical USA, Bio Medical Res., 1603 Bldg., Mid land, Michigan 48640. ********** REFERENCES 1. Aviado, D. M.; Zakhari, S.; Simaan, J. A.; and Ulsamer, A. G. 1976. Methyl Chloroform end Trichloroethylene in the Environ ment. Cleveland, Ohio: CRC Press. 2. Department of Health. Education and Welfare. 1976. Criteria for a Recommended Standard: Occupational Exposure to 1, 1,1trichloroethane. HEW Publication No. (NIOSH) 76-184. Wash ington, D. C.: United States Department of Health, Education and Welfare. 3. Torkelson. T. R.; Oyen, F.; McCollister, D. D.;and Rowe, V. K, 1958. Toxicity of 1, 1, 1-trichloroethane as determined on lab oratory animals and human subjects. Am Ind Hyg Assoc J 19: 353-62. 4. Stewart, R. D.; Gay, H. H.;Erley, D. S.; Hake, C. L.;and Schaf fer, A. W. 1961. Human exposure to 1,1.1-tnchloroethane vapor: Relationship of expired air and blood concentrations to exposure and toxicity. Am Ind Hyg Assoc J 22: 252-62. 5. Rowe, V. K.; Wujkowski, T.; Wolf, M. A.; Sadek, S. E.; and Stewart, R. D. 1963. Toxicity of a solvent mixture of 1, 1,1trichloroethane and tetrachloroethylene as determined by exper iments on laboratory animals and human subjects. Am Ind Hyg Assoc J 24: 541-54. 6. Prendergast, J. A.; Jones, R. A.; Jenkins, L. J. Jr.; and Siegel, J. 1967. Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1, 1-trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethylene. Toxicol ApplPharmacol 10: 270-89. 7. Stewart, R. D.; Gay, H. H.; Schaffer, A. W'.; Erley, D. S.; and Rowe, V. K. 1969. Experimental human exposure to methylchloroform vapor. Arch Environ Health 19: 467-72. 8. Salvini, M.; Binaschi, S.; and Riva, M. 1971, Evaluation of the psychophysiological functions in humans exposed to the "thresh old limit value" of 1, 1, 1-trichloroethane. BrJlndMed 28: 28692. 9. Gamberale. F., and Hultengren, M. 1973. Methyl chloroform November/December 1978 SL 036652 341