Document 0jmVJygoaX204MJmXN3r2RXM

R&S 140841 THE CORRELATION OF CLINICAL AND ENVIRONMENTAL MEASUREMENTS FOR WORKERS EXPOSED TO VINYL CHLORIDE By J. E. Mutchler, M-S.E. and C. G. Kramer, M.D. Biochemical Research Laboratory and Medical Department The Dow Chemical Company Midland, Michigan / For Presentation At The 1968 Gordon Research Conference On Industrial Hygiene Tilton, New Hampshire August 1968 INTRODUCTION A careful and comprehensive study of the exposed workmen should be /crucial in validating an industrial hygiene standard. In practice, howbver, the number of substances for which such studies have been reported have been very few. A number of factors operate against such long-term comprehensive investigation. Certainly, the cost of an adequate clinical program is a prohibitive aspect -- especially when carried on over many years with essentially negative results. The development of environmental measurements for correlation with the clinical findings entails considerable cost and requires a high degree of cooperation and planning between Medical and Industrial Hygiene functions. Although toxicologists have become quite proficient in predicting what exposures are likely to be safe for people, there is always some doubt until enough human experience has been gained to prove that their predictions are correct. This "proof of the pudding" should result from the correlation of good environmental measurements with the results of a well planned medical surveillance program. This feed back from human experience likely will differ from the animal experimental data in that it will not define a level of exposure which will actually cause injury, at least frank injury. It could be expected, however, to describe a level of exposure which has been shown to be either acceptable or marginally R&S 140842 R&S 140843 2 unacceptable. This information would be valuable in assisting the toxicologists in strengthening their skills in predicting effects on humans from r experimental animal data, and in a broader sense, this information would be useful in substantiatin criteria to be used for industrial hygiene standards. The Dow Chemical Company's medical and environmental health groups have for several years been conducting concurrent medical and environmental surveillance for a large worker population exposed to many different chemicals. Among the most; carefully observed workers have been those exposed to vinyl chloride. For nearly two decades, industrial hygienists at Dow have been estimating chronic exposures to vinyl chloride. With increasing sophistication and accuracy, including the more recent use of continuous monitoring, we have been able to estimate exposures to enough men for enough time to provide the basis for a unified industrial hygiene-medical study of worker exposures to vinyl chloride. ' ....................... This paper describes a method for the statistical consolidation and correlation of environmental measurements and clinical findings using as an example a group of 98 healthy male workers t 3 exposed routinely to vinyl chloride for periods up to 25 years. Retrospective in nature, the study reveals several statistical!y significant effects from chronic exposures to vinyl chloride, anc by medical interpretation of these apparent effects we suggest appropriate revision of the Threshold Limit Value. II. VINYL CHLORIDE Vinyl chloride (CH^CHCl) is a chemical of increasing industrial importance. It is a monomer used both in the polymerization of polyvinyl chloride resin, Saran and other copolymers, as a chemica intermediate, and as a solvent. Animal Toxicity The toxicity of vinyl chloride has been reviewed by von Oettingen, Mastromatteo, et. al., 2 and more recently by Torkelson, et al., 2 and Lester, et al.^ The gas is anesthetic and narcosis is the only reported effect of acute overexposure. a h Torkelson, Lester, and their co-workers studied the chronic toxicity of vinyl chloride on-rats. -Torkelson and a-s-sociafce-s-- included rabbits, guinea pigs and dogs in a study of effects from repeated exposure. Using controlled concentrations of 50-500 ppm, Torkelson found that repeated seven-hour exposure to 200 ppm caused liver pathology in rabbits, and at 100 ppm R&S 140844 R&S 140845 4 he noted slight but statistically .significant increases in ;the average weight of rat livers. Other animals were unaffected by 100 ppm. Using concentrations of 20,000 and 50,000 ppm Lester found no evidence of lung or other vital organ effects upon repeated daily exposures lasting 92 days at the lower concentration^ and 19 days at the higher level. However, he also detected some increase in relative weights of the rat liver n well as the spleen. The Committee on Threshold Limit Values (American Conference of Governmental Industrial Hygienists), weighing both studies, concluded that "although the experimental data are conflicting, / the preponderance indicates a compound of relatively low toxicity with which a threshold limit of 500 ppm is consistent."-^ Human Toxicity There are few reported human exposure effects from vinyl chloride except for narcosis upon acute exposure. At least two industrial deaths are reported from overexposure to vinyl chloride.^ In a 4 controlled study, Lester, et al., exposed six.vol.unjte.ers fpr_____ five-minute/ periods to 4,000, 8,000, 12,000, 16,000 and 20,000 op of vinyl chloride. They found the first signs of intoxication appearing at 8,000-12,000 ppm. No other effects were reported. Baretta, et al.,' exposed human volunteers to 50, 250 and 500 porn R&S 140846 for 7 1/2 hours. The primary purpose of their investigation concerned expired air studies, but no clinical changes nor neurological responses were measured in the thirteen volunteers upon thorough physical examination. Filatova and Gronsberg^ reported angioneurosis of a spastic character in workers exposed to the monomer in a polyvinyl chloride polymerization process. Air samples usually varied between 20 ppm and 315 ppm. Wilson, et al, report several cases of acroosteolysis in the hands of workmen working on vinyl chloride polymerization processes. No vinyl chloride exposure estimates are cited, but the nature of the disorder and the circumstances of its appearance suggest that the effect may have resulted from a "combination of physical insult, chemical insult, and personal idiosyncrasy. " Suciu, _et al. studied the clinical manifestations of a group of 186 employees working in polyvinyl chloride, plants. Without, quantifying the exposures to vinyl chloride and other substances in the work environment of these men, the authors report the presence of the "narcotic syndrome, " asthenic nervous symptoms, Raynaud's syndrome and hepatomeglia. R&S 140847 III. ENVIRONMENTAL ASPECTS The Work Environment Subjects included in this investigation have worked in one or both of two manufacturing facilities which use vinyl chloride in polymerization processes. In both plants the environmental stresses of the work area have been essentially equivalent. There are two airborne materials present in the work environment vinyl chloride and vinylidene chloride, the vinyl chloride being present in much higher concentrations than vinylidene chloride. The overriding presence of vinyl chloride can be attributed to its relative use and relatively volatility of the two materiaI ls. i During the first of two decades covered in this study the worker exposures to vinyl chloride and vinylidene chloride 11 12 were estimated solely by nonspecific combustion techniques. ' The concentrations were expressed as vinyl chloride, although the presence of both materials was known. In more recent measurements, infrared and gas chromatographic techniques ~ have established that the ratio of vinyl chloride to vinylidene chloride concentrations is usually around 10, with virtually all vinylidene chloride concentrations less than 5 ppm, and usually detectable only in trace amounts. For this reason, all exposure estimates used in this study haVe been Indexed as "vinyl chloride." Our conclusions, however, must R&S 140848 be viewed in the proper context: a work environment with two airborne materials -- vinylidene chloride in nearly trace amounts and vinyl chloride in substantial amounts. Environmental Surveillance Industrial hygiene surveys of the operations in which the workers under study have been exposed, started in 1950* Since then and until 1959, environmental surveillance was conducted on a regular basis, but with the traditional techniques of grab sampling and portable analyzers. 11 ' 12 Since 1959, permanent multipoint continuous monitors have been used to estimate the exposures to the workers in the study population. The application of data processing and computer technology to environmental control has allowed us to document exposures more thoroughly and validate our continuous monitoring technique by breath sampling surveys. 7 13 The environmental sampling related to this investigation has focused on the exposure levels of men working In eight critical Job classifications. Sampling was performed in this regal'd for one or more of these classifications' in" 1950, 1952, 1953, 195^, 1955, 1958, 1959, and each year thereafter. Before continuous monitors were installed in 1959, the periodic R&S 140849 9 exposure estimates were based on a few discrete samples gathered over a few days. In later surveys, the exposure estimates were based on hundreds of thousands of samples gathered over long time periods -- on a continuous basis. Therefore, the quality and quantity of environmental sampling has increased over the years In a manner that parallels the medical surveillance program. As a result of the environmental sampling conducted since 1950 yearly TV/A estimates were tabulated for each of the 98 individuals in the study population by following the work history for each man as he stayed within or moved among the critical job classifications during his employment. The result was a table of yearly exposure levels for each individual. V.'ith such a table, a man's previous exposure history was available -- both on a cumulative dosage basis (ppm - years) and as a career time-weighte< average exposure (TWA). Suitable Air Quality Parameters Obviously, a study of the possible effects of repeated inhalation of changing concentrations of an airborne material like vinyl chloride requires the use of a quantitative expression of air quality. We base our choice, the "time-weighted average concentration" on consideration of both the problem under study R&S 140850 and on availability. We recognize the desirability of including an expression of air quality that would help characterize the tremendous concentration variation that may exist, as well as a measure of central tendency such as the weighted average. From a practical viewpoint the heterogeneity of the environmental sampling limits the choice of an air quality parameter for this study to the time-weighted average. A Furthermore, Bartlett and Carroll " note that for agents passing through the respiratory membranes, as vinyl chloride apparently does, we know very little of how repeated or continuous exposure leads to chronic effects. However, since the process is presumably cumulative and progressive, a suitable parameter of air quality would be the mean concentration; e^g., the time-weighted average concentration. IV. MEDICAL ASPECTS It has been customary for. many years to perform-periodic----- ---- examinations on those employees exposed to potentially hazardous environments while we have often neglected the employee who we feel is not exposed to a significant hazard. R&S 140851 The periodic examination has consisted of a history, physical, chest X-ray, timed vital capacity, urinalysis and minimum hematology. To this basic exam we have added those particular laboratory tests which appeared justified by the particular hazard which was suspected. The tests have varied from year to year as the state of medical knowledge changed. As a result, it is difficult to provide a good control population for comparative studies. Control groups are particularly difficult to acquire with studies such as the BSP where a possible risk to the individual exists. Recently, we have instituted a program in which all employees are given the same basic, but far more complete battery We now include all individuals in our plant, regardless of their degree or type of exposure, thus hoping in the future, to acquire more easily comparable data. The experience discussed in this paper is based on our previous methods of acquiring data and at this point we are seeking to establish a method with which we can study the accumulated data of the past. Over the years, our exams have served their basic purpose of protecting the health of the individual employees and have resulted in the discovery of some obvious abnormalities. However, the more subtle effects may have been missed. Those who have worked in the industrial setting appreciate the difficulties encountered in studying a population which is subject to continuing change and often to mixed exposures. It is rare in actual practice to encounter a stable population with exposure to a single environmental contaminant. By the traditional method of comparing populations, we can only use 66 of these "exposed" individiuals who had examinations during 1965 and 1966, and compare them with a group of 605 employees from other departments, subject to varying exposures who had their examinations during the same period. However, in the strictest sense, this larger group of employees would not qualify as an ideal control group. R&S 140852 Many of the individuals in this "control group" were given laboratory tests similar to those given to the "exposed" group only when their exposure was such that we would expect an effect similar to that which might result in excessive exposures to vinyl chloride. The document used to record the physical exam data is reproduced I in the Appendix. By asterisk we indicate all those 'responses and measurements which were processed for computer retrieval. All of these factors were compared with the control group by a test for difference between means using a normal approximation, and the significant differences are noted in Table One. It should be noted that there were no group differences in the EKG's or chest X-rays. Hand X-rays on the individuals in the "exposed" group showed no significant abnormalities and no case of acroosteolysis. In comparing the mean BSP of the study group with the control group, only 116 measurements were available in the control population. The mean BSP for the study group was 2. 73 (50 observations) and the mean for the control group was 2. 89 (116 observations). In addition, all records were individually reviewed for data which were not processed for computer retrieval, but no significant additional findings were noted. R&S 140853 Table One: FACTORS IN WHICH VC1 GROUP DIFFERED SIGNIFICANTLY FROM THE CONTROL GROUP BY A TEST FOR DIFFERENCE BETWEEN M^ANS USING A NORMAL APPROXIMATION (P < 0. 05) Number of exams History: Asthma Stomach, Liver, Intestinal trouble Kidney Stone, Bloody Urine Nervous Trouble of any Sort Have you ever worked with Radioactive Substances Physical: Anus - Rectum Identifying Body Marks Disease Category: Category IX (Diseases of Digestive System) VCl Group 66 10. 8% 6. 2% 9. 2% 4. 6% 1. 5% 13. 8% 7, 7% 3. 0% Control Group 605 2.6% 18. 0% 3. 0% 13. 4% 15. 5% 6. 1% 18. 7% 13. 2% < * ! i tS80tL S9U R&S 140855 Considering the many factors studied, some differences would be expected. However, this conventional comparison of the two groups does not suggest that there is any basic difference between the two populations and it appears that no significant disease has occurred as a result of exposure to vinyl chloride and trace amounts of vinylidene chloride. V. STATISTICAL CONSOLIDATION OF DATA WITHIN THE EXPOSED GROUP Dependent Variables Upon compiling the accumulated clinical data from the 98 men in this study we found 21 clinical parameters for which sufficient data existed to warrant inclusion in further statistical analysis. The criterion for inclusion was "at least one observation per man for 25 men for any given test. " The 21 clinical parameters are listed in Table 2. Independent Variables In identifying factors which could explain some or all of the variation in the observed clinical variables we recognize the, need_________ to include age and obesity, important nonenvironmental variables, and level of exposure and duration of exposure, essential environmental variables. Age was recorded to the nearest whole year. Obesity R&S 140856 Table 2 TWENTY-ONE CLINICAL PARAMETERS SCREENED FOR CORRELATION WITH EXPOSURE TEST PHYSICAL SYSTOLIC BLOOD PRESSURE DIASTOLIC BLOOD PRESSURE TIMED VITAL CAPACITY CHEMICAL BROMSULPHALEIN (BSP) ICTERUS INDEX ALKALINE PHOSPHATASE SERUM GLUT OXAL TRAN (SGOT) THYMOL TURBIDITY PROTEIN, SERUM TOTAL ALBUMIN GLOBULIN ALPHA 1 ALPHA 2 BETA GAMMA AG RATIO HEMATOLOGICAL HEMOGLOBIN HEMATOCRIT RED BLOOD CELLS WHITE BLOOD CELLS PROTHROMBIN TIME URINE SPECIFIC GRAVITY was defined as the ratio of actual weight to "standard weight. " The level of exposure was expressed as the cumulative time-weighted', average concentration (TWA). The product of TWA and time-on-job (TOJ) gave a measure of the cumulative dosage. Data Format At this point we had prepared two concurrent sets of data for each man: his medical information and environmental information. All that remained was the individual matching process and collective analysis. At the time of each clinical observation, both types of data for each man were registered in the following format: / R&S 140857 13 MAN NO, DATE, AGE, TOJ, TWA, HT, WT, STD WT, Y] . . . y21 , where TOJ - time-on-job (time of exposure), yrs TWA = career time-weighted average exposure STD WT = standard (desired) weight as tabulated by the Metropolitan Life Insurance Company. 15 Yi = clinical observation i, i = 1, 2, . . . 21. VI. STATISTICAL ANALYSIS The technique used for extracting relationships hidden in the available data was "step-wise multiple linear regression analysis," This procedure, made powerful by the advent of digital computers, systematically builds a mathematical model from a choice of independent variable terms based on the fundamental Independent variables. In the step-wise regression procedure the independent variable (X^) most highly correlated with the response is entered into the model, and the coefficients are determined by the method of least squares. Using partial correlation coefficients, the next variable (Xg) to enter the regression is that whose partial correlation with the response is highest. Given the regression equation Y = f{X^,.,,,Xg), ..tj}e_ method now examines the contribution X^ would have made if Xg had been entered first. Repeatedly, the step-wise method selects as the next variable in the regression the one most highly partially correlated with the response. At each R&S 140858 14 stage, the "best" regression equation Y = X2, . . . X) is determined by the method of least squares, after checking the partial F criterion for each variable to verify the 16 significance of each term included. The object of this technique is to express a relationship by some relatively simple mathematical function such as polynominal which contains appropriate variables and which approximates the true response of the dependent variable over some limited ranges of all the variables involved. Since this is an empirical approach, the resulting equation could be physically meaningless, but it may nevertheless be extremely valuable for predicting the values of-some dependent variable from knowledge of other variables, at least under certain stated restrictions. However, just because a particular functional relationship has been developed and a specific computational procedure followed, we cannot conclude that a causal relationship exists among the variables. R&S 140859 At this point we had accumulated the data and selected a strategy for analysis of the information. The remaining stc could be broadly classified as screening, and refinement. R&S 140860 Correlation Matrix The first step in analyzing the consolidated inf ormation was to examine the linear correlation matrix for all the independent and dependent variables available. This screening technique revealed several clinical variables that appeared related to exposure. The correlation matrix is shown in Table 3. Six clinical parameters of the twenty-one under study showed significant (P0.05) correlations with the exposure variables? cumulative TWA and cumulative dose. These were: systolic and diastolic blood pressure, bromsulphalein, icterus index, hemoglobin and beta-protein. Of these, three showed correlation with age and four with obesity. Three other clinical parameters were significantly associated with age. The correlation-screening procedure pointed out the fact that the "independent" and "dependent" variables are interrelated, in addition to identifying a series of clinical tests which could be examined critically. Table 4 shows the correlation matrix (P<0.05) between all of the crucial variables, dependent and independent. The general consistency of the relationships among the variables justifies more rigorous analysis. Table 3 CORRELATION OF ALL DEPENDENT VARIABLES WITH ALL INDEPENDENTVARIABLES (P<0. 05) TEST Physical Systolic blood pressure Diastolic blood pressure Vital capacity Chemical Bromsulphalein (BSP) Icterus Index Alkaline phosphatase Serum glut oxal tran (SGOT) Thymol turbidity Protein, serum total albumin globulin / alpha 1 alpha 2 beta gamma ag ratio Hematological Hemoglobin Hematocrit Red blood cells White blood cells Prothrombin time Urine Specific gravity AGE OB TWA DOSE +++ +++ -oo + 4* 0 G> + + + oO +. + Ooo o Ooo o Ooo o ooo o + oo ooo o+ + - oo ooo o o + o o -o oo oo oo oo -. - - oo - o o o o o - o o o o -- o R&S 140861 1, ) 'flVftU "S## T'vJ`; CoRRELAVpt/ Cosrncieisr caAt^ik- crucial VARIABLES , Age ^& oO & ++ 4- /y v o -- o 08 0 0+ Xi -P f o o+ TV/) 0 0 f" + + X< f ME + 'b + f T f --+ --+ Ws + ++ + i" X o 0 o r f f h I- K 0 o o %? TT 0+ 00 + + -P 0 o 4*- 3flo7 o o0 0o --u4 og> til --0- -- 0 00 c O S ?RmtJ 0 H + + 0 e> + 0 D .... ------------- + POSITIVE CORRELATIONS P ^ o.oS 0 No CfiRfiCLATiOA/ f>* O'OS NCGHTU/e CoftneMTlofi/ 1P0.0& 18 R&S 140863 Development of Regression Models In the development of a linear regression equation for each clinical test Y in terms of independent variables, age, obesity, TWA, and dose, we took the view that the complete set of terms from which the model is chosen should include the independent variables themselves, together with interaction or cross-product terms which may be helpful in explaining variation in the observed variables. For example, we allow for the possibility of age and exposure operating together (interacting) in a manner differently than ^ age and exposure acting independently. However, we faced two opposing criteria for selecting a predictive equation: (1) For utility and accuracy we wish our model to include as many significant independent variable terms as possible so that reliable values can be predicted. (2) For simplicity and ease of communication we wish to fciave the equation includa as few. significant _______ independent variable terms as possible. Operating largely from an empirical viewpoint, we drew up a list of 30 independent variable terms including transformations of the four basic independent factors. Since for any given test we had unequal numbers of observations for each individual, it was necessary to choose randomly one observation per individual for ' each test in order to weight each man equally. This random selection reduced the number of observations for each test as indicated in Table 5. R&S 140864 VII. STATISTICAL RESULTS The results of the regression analyses for each of the six crucial clinical variables are given below: Systolic Blood Pressure BPg = A1 + B1(AGE)3 + (TWAMAGE) (OB) -D^] Diastolic Blood Pressure 7 BPd = A2 + B2 (AGE)1/2 (OB)1/2 + C2 (TWA)(OB) B rom s ulphalein BSP = A3 + B3 (AGE) (DOSE) Icterus Index II = A4 + B4 (TWA)4 Hemoglobin Hb = A5 B5 (AGE)1/2 -Cg(TWA)3 Beta-Protein Beta-protein = A,, + Bc (DOSE)3 bb Table 5 TEST TOTAL NUMBER OF OBSERVATIONS Systolic Blood Pressure 323 Diastolic Blood Pressure 323 Bromsulphalein 92 Icterus Index 29 Hemoglobin 145 Beta-Protein 58 NUMBER OF SUBJECTS AND NUMBER OF RANDOMLY SELECTED OBSERVATIONS 98 98 65 25 83 58 R&S 140865 R&S 140866 Statistical Significance of Models An appropriate question is: What measures of precision can be attached to the regression models? Three useful indices are: the Standard Error of the Regression, Se, the overall F-Statistic, and the coefficient of multiple determination, ft2. These measures of the "goodness of fit" for each model of the clinical variables are listed in Table 6. Utility of the Models The regression models must be used with discretion. The least squares regression coefficients are adjusted for other variables in the regression procedure and, therefore, attempting to predict the response by changing only one variable arbitraril; may be misleading; therefore, we must specify the prediction range for each variable under investigation. Such prediction ranges are shown in Table 7. To relate the statistical results to the practical question of an industrial hygiene standard requires careful consideration. First, an acceptable workroom air quality concentration must allow for men working in that environment for an entire career, up to 45 years; our data are useful only over a 20 year span. For effects which are cumulative, such as most of those isolated in this study apparently are, the last part of a man's career is the limiting consideration. For these MODEL Systolic Blood Pressure Diastolic Blood Pressure Bromsulphalein Icterus Index Hemoglobin Beta Protein 'p 4 0. oo I fz o.o3 * ^980H. S^y I Table (g N 98 98 65 25 83 58 Se 12.9 7.6 1.5 1.6 0.83 2.6 p(dfi; df,,) 24.53 (3; 94) * 0.180 39-46 (2; 95)"* 43.85 (1; 63) * 0.193 0.407 5.66 (1; 23)^^ 0.191 8.95 (2; 80) *" 0.162 12.65 (1; 56) * 0.170 Page 22 able 7* * ystolic Blood Pressure iastolic Blood Pressure romsulphalein cterus Index emoglobin ata-Protein Mean SB Limit 128 14 188 AGE Mean SB Limit 40 10 65 TO J Mean SD Limit 10 5*0 25 TWA Mean ~3B Limit 80 75 375 81 8 109 40 10 65 10 5.0 25 80 75 375 3.3 1.9 9-4 41 11 65 11 5.3 25 75 70 340 7.0 1.8 11.1 40 7.1 52 14 5.7 25 55 45 200 14.5 0.9 16.4 10 64 9.4 4.8 20 70 70 315 14.7 2.9 22.6 42 10 65 12 5.0 23 60 50 200 j 8980H S9hf R&S 140869 reasons, and in view of our data and the predictive ranges thereof, we wish to examine the clinical variables at TOJ = 20, and AGE = 60. In the case of blood pressure, obesity must be fixed also, if we are to predict the effect of the level of exposure, TWA. For this purpose we hold "OB" constant at 1.06, the overall mean for the blood pressure data. The following functions result: Systolic Blood Pressure = 136.83 + 0.034035 (TWA) Diastolic Blood Pressure = 84.74 + 0.018845 (TWA) Bromsulphalein Icterus Index 2.12 + 0.034599 (TWA) = 6.82 + 0.000000002309522 (TWA)1* Hemoglobin 13.97 -0.0000000457339 (TWA)3 Beta-Protein 14.15 + 0.000001371545 (TWA)3 These functions are evaluated and presented in Table 8 as a function of TWA. -* 'able 8. EXPECTED RESPONSE OP CRUCIAL TESTS VERSUS CAREER TWA (AGE = 60, OBES = 1.06, TOJ = 20) Test ystolic Blood Pressure 0 136.8 50 138.5 100 140.2 TWA, ppm 150 200 141.9 143.6 250 145.3 300 147.0 'iastolic Blood Pressure - tC j OticzS. ~l.06) romsulphalein (toT-^o ,A&E-yC>) cterus Index :emoglobin (r v>) eta-Protein i 84.7 85.7 86.6 2.1 3.8 5*6 6.8 14.0 6.8 14.0 7-0 t 13*9 14.1 14.3 ' 15*5 X = Beyond Range of Available Data 87.6 88.5 89.4 7.3 9.0 10.8 8.1 11.0 X 13*8 13.6 13.3 18.8 25.1 X 0Z80U S3U 90.4 12.5 X 12.7 X VIII. INTERPRETATION As we review Table 8, we note six factors which appear to be related to exposure. Within the range of our study, the blood pressures, systolic and diastolic, do not appear to rise to levels which can be considered to signify overt disease. The hemoglobin likewise does not reach levels low enough to be considered significant of disease. The Beta-Protein, Icterus index and BSP lend significant support to the possibility that some hepatic injury may occur at higher levels of exposure. The BSP appears to be most significantly correlated with exposure. Within the study group we find several individuals who, after / approximately 20 years of exposure with time-weighted exposures of approximately 300 ppm of vinyl chloride during the early part of their careers (and smaller amounts of vinylidene chloride) have shown a tendency to develop laboratory abnormalities which appear to correlate with their exposure. Two of the individuals showing the highest rise in BSP were rechecked in 1968. One had essentially normal laboratory findings and the other had persistent elevation of various liver function tests in spite of removal from further exposure since 1965. This individual R&S 14087 R&S 140872 had a history of hepatitis preceeding his exposure. However, pre-exposure liver function tests were normal. Whether his abnormalities represent a result of his exposure or independent sequelae of his hepatitis cannot be ascertained. Certainly, it would be desirable that individuals with a history of hepatitis not be considered candidates for prolonged exposure to vinyl or vinylidene chloride. Unfortunately, since many cases of subclinical hepatitis occur we will always have in a working population some individuals who have had hepatitis. For most individuals in the study, the highest exposure occurred in the early phases of their careers and their later exposures have been much lower. In the final analysis much weight is placed on the readings observed for those employees who experienced high exposure levels, especially in the 1949-58 period of their careers. For example, the average time-weighted exposure level in 1950 was 155 ppm, whereas the average exposure level in 1965 was 30 ppm. X. CONCLUSIONS This study points out the risk of judging exposure effects on the basis of a comparison of an "exposed" group and a "control" group. R&S 140873 The "exposed" group, especially when drawn from an industrial setting* will contain individuals subject to a wide range of exposures, and the' mean clinical indices for the group may well mask individual differences that could be detected only by an intra-group analysis. We have attempted to correlate the clinical manifestations of a group of men for which exposure data as well as clinical measurements are available. In this refined approach, the "control" group is part of the "exposed" group, as indicated by the regression technique which treated the exposure levels, DOSE and TWA as independent variables. In spite of the shortcomings of the retrospective analysis, the study suggests that the current TLV of 500 ppm should be re-evaluated. We suggest that further studies are necessary to determine precisely an acceptable time-weighted average exposure for vinyl chloride. Our findings suggest that repeated exposure to vinyl chloride at TWA levels of 300 ppm or above for a working lifetime, may result in a future decline in the general health of some of the individuals so exposed, probably as a result of hepatic injury. We shall continue our study, but suggest that others who have a worker population exposed to vinyl chloride would perform studies which will help clarify the effects of vinyl chloride on the human organism. ACKNOWLEDGEMENTS We first recognize and underscore the progressive and cooperative spirit of the Medical, Industrial Hygiene and Toxicology functions within our Company in which this project was conceived. We wish to acknowledge those many members of the Medical Department and Environmental Research Laboratory who, over two decades, gathered the basic information that makes this study possible. Our special thanks go to Mrs. Shirley Walker, R. N. , who conditioned much of the Medical data, to Gerald Ott for his suggestions with the statistical strategies, and to our supervisors and colleagues for their steady support. R&S 140875 24 REFERENCES X. von Oettingen, W. F. The Halogenated Hydrocarbons; Toxicity and Potential Dangers. U. S. Public Health Service, Publication4l4, Government Printing Office, Washington, D-C. (1955)- 2. Mastromatteo, E-, A. M. Fisher, H- Christie, and H. Danziger: "Acute Inhalation Toxicity of Vinyl Chloride to Laboratory Animals." Amer. Ind. Hyg. Assoc. J. 21:394 (Oct., i960). 3. Torkelson, T- R., F. Oyen, and V. K. Rowa-: "The Toxicity of z Vinyl Chloride as Determined by Repeated Exposure of Laboratory Animals." Amer. Ind. Hyg. Assoc. J. 22:354 (Oct., 1961). 4. Lester, D., L. A. Greenberg, and W. R. Adams: "Effects of Single and Repeated Exposures of Humans and Rats to Vinyl Chloride." Amer. Ind. Hyg. J. 24:265 (May, 1963). 5- Committee on Threshold Limit Values: Documentation of Threshold __ Limit Values, Rev. Ed., American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio (1966). 6. Danziger, H.: "Accidental Poisoning by Vinyl Chloride: Report of Two Cases." Canadian Med. Assoc. J. 82:828 (April, i960). fr 7. Baretta, E.D., R. D. Stewart, and J. E. Mutchler: "Monitoring Exposures to Vinyl Chloride Vapor: Breath Analysis and Continuous Air Sampling, " presented at the American Industrial Hygiene Conference, May 13-17, 1968, St. Louis, Missouri (Manuscript in Preparation). 4 mer -iW, )^cj. Azs&l. J. ZC; S37(^6t) , 8. Filatova, U. S., andE. S. Gronsberg: "Hygienic Working Conditions in Polyvinyl Chloride Tar Plants, " Gig i Sanit 38-42 (Jan. , 1957). 9. Wilson, R. H., W. E. McCormick, C. F. Tatum, and J. L. Creech: "Occupational Acroosteolysis. " J. A. M. A. 201:577 (Aug., 1967). 10. Suciu, I., J. Drejman, and M. Valaski: "Contributions to the Study of Affections Caused by Vinyl Chloride, " Medicina Interne 15:967 (Aug., 1963). 11. Peterson, J. E., H. R. Hoyle, andE. J. Schneider: "The Analysis of Air for Halogenated Hydrocarbon Contaminants by Means of Absorption on Silica Gel. " Amer. Ind. Hyg. Assoc, Quart. 17:429 (Dec., 1956). S-` ------- --------- 12. Schaffer, A. W., and H. R. Hoyle: "Nine Years Experience with the Davis Halide Meter." Amer. Ind, Hyg. Assoc. J. _22:93 (April, 1961). R&S 140876 13. Peterson, J. E., H. R. Hoyle, andE. J, Schneider: "The Application of Computer Science to Industrial Hygiene. " Amer. Ind. Hyg. Assoc. J. 22:180 (March, 1966). 14. Bartlett, D., Jr., and R. E. Carroll: "Air Quality Parameters for Epidemiologic Studies. " Arch, Environ. Health 16:182 (Feb., 1968). 15. "Desirable Weights for Men of Ages 25 and Over. " Metropolitan Life Insurance Company, *- 16. Draper, N. R., and H. Smith: Applied Regression Analysis. John Wiley / and Sons, Inc,, New York (1966).