Document Ne9oqwzdKnzNEe2ZV0475g1DV

American Industrial Hygiene Association Journal Volume 33 JANUARY, 1972 Number! Structural Damping as a Technique Tor Industrial Noise Control ..................... .. Clam E. W'tmaka, II. T. Miller and M. Zalas .Effect of Structural Damping on the Sound Radiated from Impacted Structures . C. f. tialmer and A. Lagace The Correlation of Ginical and Environmental Measurements for Workers Exposed to Vinyl Chloride'........................................................................................'........ 19 G. Kramer. M.D. and J. E. Mutchler Lead in Hair Among Exposed Workers..................................................... ......................... . Abdrl-Aziz El-Dakhakhny. Ph.D. and Yassin M. El-Sadik, M.D. 31 Hazards from Chlorinated Hydrocarbon Decomposition During Welding L. C. Rinzenta and L G. Silverstein - t Twenty Years Handling TNT in a Shell Loading Plant......................... John W. Goodwin ' .. \ 35 41 The Effect of Chemical Forms of Beryllium on the Production of the . Immunologic Response .......................................................................... Neil Krix anek and Andrew L. Reeves. Ph.D. 4 .. Hygienic Guide Series 45 53 AMERICAN INDUSTRIAL HYGIENE ASSOCIATION JOURNAL, published monthly by the American Industrial Hygiene Association. Dohrman H. Byers. Editor in Chief: }. Wesley Clayton, Jr.. Bruce A. Hertig. Robert G. Keenan. Thomas T. Mercer. James O. Pierce, and Richard F. Sclierbcrgcr. Review Editors. Editorial Offices. Department of Environmental and Industrial Health, School of Public Health. The University of Michigan. Ann Arbor, Michigan 48104. E. I_ynn Schall, Puhlt. ntinns Manager. Business Office. 210 Haddon Avenue. Westmont. New Jersey 08108. The subscription price is S20 00 per year in U.S.A. and S2I.00 elsewhere. Single copies when available may be purchased from ihc Business Office for S4.00 per copy. Copyright 1972 by the American Industrial Hygiene Association. The Association reserves the right to edit all advertisements and to retuse advertising copy when it docs not meet the high standards adopted by Ihc Association. Lihrary of Congress Catalog Number 57-3191. Office of Publication. Charles B. Slack. Inc.. Thorofare, New Jersey Second class postage paid at Camden, New Jersey. Printed for the' American industrial Hygiene Association by CHARLES B. SLACK, INC., THOROFARE, NEW JERSEY 08086 The Correlation of Clinical and Environmental Measurements for Workers Exposed to Vinyl Chloride C. G. KRAMER, M.D., and J. E. MUTCHLER* The Dow Chemical Company, Midland, Michigan 4S6dO ^CiA method is described Tor the statistical consolidation and correlation of vy entironmrntal measurements and clinical findings using as an example a group of healths mule srnrkers exposed routinely to vinyl chloride for periods up to 25 years. Retrospective in nature the study reveals several statistically significant effects from chronic exposures to vinyl chloride and traces of vinylidene chloride. Introduction has not been applied, the feedback from For validating an industrial hygiene human experience could be expected to standard, it is essential to perform careful describe levels of exposure which have been and comprehensive studies of the possible shown to be either acceptable or marginally effects of substances on exposed workmen. In unacceptable. This information would be practice h. sety few substances have valuable to toxicologists because it would been the obiecl of sufficient study to furnish strengthen their skills in predicting from reliable guidelines. Today, specialists in experimental animal data effects of substances occupatiou.il health must recognize the need on humans. In a broader sense, it would be to develop programs which will better identify useful in substantiating criteria to be used for the relation between stresses acting on the . industrial hygiene standards. .1 human body in the work environment and For several years The Dow Chemical physical changes that can be measured Company's medical and environmental health clinically, to explain the significance of these groups have been conducting concurrent changes and use the results to help refine our medical and environmental surveillance of a guidelines for environmental control. large worker population exposed to many Although toxicologists are constantly different chemicals. The project described in predicting what exposures arc likely to be safe this paper analyzes the information already for people, there will always be some doubt gained from concurrent surveillance and about thcii predictions until enough human relates it to the determination of acceptable experience has been gained to prove their levels of exposure. A method is described for accuracy. The "proof of the pudding" should the statistical consolidation and correlation of result from the correlation of good environmental measurements and clinical environmental measurements with the results findings, using as an example a group of 98 of a well planned medical surveillance healthy male workers who had been exposed program. It is likely that such feedback from routinely to vinyl chloride for periods up to human experience will differ from the animal 25 years. Retrospective in nature, the study experimental data in that it will not define a reveals several statistically significant clinical level of exposure which will actuadv cause injury, at least frank injury Howcxe*. except changes due to chronic exposures to vinyl chloride and smaller amounts of vinylidene in cases where an mduMrial hygiem standard chloride. By isolating ihese apparent effects and examining them in the light of our Proem AddfCM 23711 SouthAflti * CUytor v ?-rid, Mm >. itOTS medical interpretatign, wc have developed what appears to be a promising technique for BFG3U05 January, 1972 . relating clinical information to worker exposures to achieve a more refined industrial hygiene standard. Vinyl Chloride Vinyl chloride (CH,--CHCI) is a chemical compound of increasing industrial importance. It is a monomer used as a chemical intermediate in the polymerization of polyvinyl chloride resin, in the production of copolymers such as Saran, ant^as a solvent. Animat Toxicity The toxicity of vinyl chloride has been reviewed by von Oettingen,1 Mastromattco, et al.,1 and.more recently by Torkelson, et ai.* and Lester, et at* This gas is an anesthetic, and narcosis is the only reported effect of acute overexposure. Torkelson,J Lester,4 and their co-workers studied the chronic toxicity of vinyl chloride on rats. Torkelson and associates included rabbits, guinea pigs and dogs in a study of effects from repeated exposure, i.e.. using controlled concentrations of 50-500 ppm. They found that repeated seven-hour exposure to 220 ppm caused micropathological changes in the livers of rabbits, and at 100 ppm, 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 effects on lungs or other vital organs upon repeated daily exposures lasting 92 days at the lower concentration and 19 days at the higher level. Like Torkelson, however, he detected some increase in .relative weights of the rat liver and, in addition, of the rat 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."5 Human Toxicity Few effects have been reported as a result of human exposure to vinyl chloride except for narcosis upon acute exposure. However, at least two industrial deaths have been reported from overexposure to vinyl chloride.* In a controlled study, Lester, et at.* exposed six volunteers for five-minute periods to 4.000 8,000, 12,000, 16,000, and 20,000 ppm of vinyl chloride. The first signs of intoxication appear at 8,000-12,000 ppm. No other effects were reported. Baretta, etal.,7 exposed human volunteers to 50, 250 and 500 ppm for 7 1/2 hours in an investigation concerned primarily with expired afr studies. No clinical changes nor neurological responses were found in the thirteen volunteers upon thorough physical examination. Filatova and Gronsberg* reported angioneurosis of 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 a!.* reported several cases of acroosteolysis in hands of workmen working in vinyl chloride polymerization processes. No vinyl chloride exposure estimates arc cited, but the nature of the disorder and the circumstances of its appearance suggest that the effect may have resulted front a "combination of physical insult, chemical insult, and personal idiosyncrasy." Dimtian. ct al.,* Cook, ct al..11 and Dodson, ct at..n reported on a comprehensive epidemiological, industrial hygiene and clinical study of over 5,000 employees engaged in vinyl chloride and polyvinyl chloride manufacturing throughout the United States and Canada. A clear association ol acroosteolysis and manual cleaning of polymerization reactors was revealed, with an expected prevalence of one case per 37 reactor cleaners. The study did not implicate vinyl chloride as the etiological agent hut, using certain assumptions ahotil the monomeric content of polymer residue within the reactors, there appeared to be a semiquantitiitivc cort elation between the prevalence of acroosteolysis and the degree of degassing prior to sessel entry." Suciu, et al ." studied the clinical manifcstatuins of i gioup of 1X6 male employees working in polyvinyl chloride plants. They repotted the presence of the "narcotic syndrome." asthenic nervous 2443500.3 BFG31106 I American Industrial Hygiene Association Journal 21 symptoms, Raynaud's syndrome and"' exposed started in 1950. From that time until hepatomegaly, but did not furnish data 1959, environmental surveillance was regarding the number of exposures to vinyl conducted on a regular basis, but using only chloride, and other substances in the work the traditional techniques of grab sampling environment. and portable analyzers.Since 1959, Environmental Aspects The Work Environment permanent multipoint continuous monitors have been used to estimate the exposures received by the workers studied. The application of data processing and computer : *. Subjects included in our investigation had technology to environmental control has worked in one or both of two manufacturing allowed us to document the intensity of facilities which had been using vinyl chloride exposures more thoroughly and validate our in polymerization processes, in both plants the continuous monitoring- technique by breath environmental stresses of the work area were sampling surveys.7'17 essentially equivalent. There were two The environmental sampling related to this airborne materials present in the work investigation has focused on the exposure environment, vinyl chloride and vinylidene levels of men working in eight critical job chloride. The concentrations of vinyl chloride were much higher than those of vinylidene classifications. Sampling for one or more of these classifications was performed in 1950, * .V * :r. chloride, due to the much larger quantities of 1951, 1952, 1953, 1954, 1955, 1958, 1959, vinyl chloride used and its greater volatility. and each year thereafter. Before continuous During the first of two decades covered in monitors were installed in 1959, the periodic the present study, the exposure of the workers exposure estimates were based on job studies to vinyl chloride and vinylidene chloride were supplemented by the examination of several estimated solely by nonspecific combustion techniques.15'" The concentrations were discreet samples gathered over a few days. In later surveys, the exposure estimates were ie,. expressed as vinyl chloride, although both materials were known to be present. In more based on hundreds of thousands of samples ` gathered on a continuous basis over long time k recent measurements, infrared and gas periods using multi-point analyzers. Thus the chromatographic techniques have established that the vinyl chloride concentrations average quantity of environmental sampling has increased and the quality has improved over i 10 ppm, while virtually all vinylidene chloride the years in a manner that parallels the concentrations amount to less than S ppm. and intensification of the medical surveillance most frequently arc detectable only in trace program. amounts. For this reason, all exposure estimates used in this study have been indexed Suitable Air Quality Parameters as "vinyl chloride." Our conclusions, however, Obviously, a study of the possible effects of must be viewed in the proper context -- that repeated inhalation of an airborne material is, a work environment with two airborne which varies in concentration requires the use materials: vinyl chloride in substantial of a quantitative expression of air quality. We amounts combined with very small amounts of vinylidene chloride. It should be noted, also recognize the need for an expression of air quality that will help characterize the however, that a continuous 90-day inhalation tremendous variation in vinyl chloride exposure of rats and guinea pig', at a concentration that may occur, together with a concentration of 5 ppm vinylidene chloride.14 measure of central tendency. Wc base our revealed no significant ch'nges in choice, the "time-weighted average hematologic, biochemical, patlu-t. gic and concentration" (TWA), on consideration both growth-rate parameters. of the problem under study and of availability Environmental Surveillance Industrial hygiene surreys of '.hr 'iterations of data. For this study, from a practical viewpoint, the heterogeneity of the environmental sampling limits our choice of ft. in-which the workers under mj.iv were an air-quality parameter to the time-weighted c-a o BFG31107 77 January, 1972 average concentration, which is a convenient ' expression for integrating a variable exposure pattern. However, we wish to point out that theoretically this expression has no relationship to the degree of toxic response. 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 'Chronic effects could presumably be cumulative and progressive, a suitable parameter for the study of air quality would be the mean concentration, e.g., the timeweighted average concentration. As a result of the environmental sampling .conducted since 1950. yearly TWA estimates have been tabulated for each of the 98 individuals studied, following the work history of each man as he stayed within the group of critical job classifications during his employment. The result is a table of yearly exposure estimates for each individual. With such a table, a man's previous exposure history - is available -- both on a cumulative dosage basis (ppm-years) and as a career timeweighted average exposure. . Medical Aspects 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. In actual experience it is rare to encounter a stable population which has had' exposure to a single environmental contaminant. The population in the present study is typical in that the exposure has been mixed. Likewise, our clinical methods have varied both as to frequency of examination and use of certain laboratory tests. Until recently, our periodic medical examination consisted of a medical history, and a physical examination, including chest xray, timed vital capacity, urinalysis and minimum hematology. To this basic examination we have added those particular laboratory tests which appear justified by the particular hazard to which the worker may have been exposed. The tests have varied from year to year as the state of medical knowledge has changed. We now have a program in which all employees, in addition to this basic examination, receive a far more complete battery ol tests. Wc include all individuals in our plant, regardless of the degree or type of exposure to hazardous materials. By so doing, we hope to accumulate data that will be useful in establishing norms for our working population, and for providing better clinical data to be used in similar projects. Data on a large group of employees that would qualify as a control group would be very useful for a conventional comparison of mean clinical indices for the "control" population and the "exposed" population. Unfortunately we have no such comparable data. Moreover, this type of analysis has the disadvantage of masking variation within the "exposed" group -- variation which could be correlated with the degree of exposure if good environmental data were available. The experience discussed in this paper is based largely on our previous methods of acquiring data. At the moment we are seeking to establish a method with which we can study the data accumulated in the past. Over the years, our examinations, which have served the basic purpose of protecting the health of individual employees, have resulted in the discovery anti correction of some obvious abnormalities. However, less obvious effects may have been missed. Though we had no ideal control group, wc compared the results of the examinations on 66 of the individuals in the study group who had had examinations during 1965 and I960 with a group of 605 employees from other departments who had had examinations in the same period. Ninety-five parameters of the history, physical examination and laboratory work were studied. This comparison was carried out by a test for difference between means, using a normal approximation. The summary of significant differences is shown in Tabic I. The study group showed an increased number of responses to the history item on asthma. This, however, was not reflected in a final diagnostic category, nor was any significant difference noted between the timed vital capacities of the study group and of the JO overall group. The studv group also showed an yfc* CO on o .'V - ' - . - . . ' . ** . BV'G3"0S I American Industrial Hyitirnr Association Journal '' ; Factors in Which VCl Group Differed Significantly from the "Control Group" (P <0.05) ' ' '* * . . . * VCl Group, '% Nuiulwr at Exams -. \\ 66 History: i AMhma liver, intcMinul trouble Kidney stone, tiloody urine Nervous trouble of any sun Have you ever worked with radioactive substances Itiyxkal: Anus-rectum Identifying body marks ia< 6.2 . 9.2 4.6 1.5 <4 13.8 7.7 ' "Control Group,**% . 60S 2.6 18.0 .3.0 13.4 1S.S * 6.1 18.7 ;.. ->*. ' * ' , ..A . .. : V ; / ' ... V/V.- / V :' .. : . . \ ; .* \ .? .- * . -V*'"' V - -' . * '. v " - ` . .'V ; -. V ' ' ' ; -T'`v) . ' f> ; " * *; -* ,* , increase in positive responses to the history item "kidney stone or bloody urine." Again, this was not reflected in the diagnostic categories. There was a decrease in number of responses to the history questions on "stomach, liver, and intestinal trouble" and "nervous trouble of any sort." On physical examination, the only category in which more responses were recorded was that involving abnormalities <>f the anus and rectum. Again, since this finding was not borne out in the final diagnostic categories, it would indicate that the \nnnus examiners did not consider these findings to be of clinical significance. .. There was no difference in overall diagnostic categories except lor diseases of the digestive system, where fewer specific diagnoses were recorded for the study group than for the comparison group. There were no group iltllercnccs in the electrocardiograms or chest x-rays. Hand x-rays on the individuals in the "exposed" group showed no significant abnormalities and no case of acroosteolysis. Pm comparing the mean BSP of the study group v. uh that of the comparison group, only lift measurements were available for the comparison group. The mean BSP for the 5lu<ty gioups was 2.73 (50 observations), and the mean for the control group was 2.89 (I 10 observations). Although all records were individually reviewed for data which had been processed statistically. n.> significant additional findings were noUil Considering the many factors studied, some differences would be expected However, this conventional comparison of test means for the two groups does not suggest any basic difference between the two populations with regard to general health, and it appears that no significant disease has appeared in the study group as a result of work exposure. v ' Statistical Consolidation of Data for the Exposed Population Dependent Variables ' After the accumulated clinical data from the 98 men in this study had been compiled, there were 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 II. Independent Variables In identifying factors which could explain some or all of the variation in the observed clinical variables, w-c recognize the need for including a record of age and obesity (important nortenvironmcntal variables), and the level and duration of exposure (essential environmental variables). Age was recorded to the nearest whole year. Obesity was defined as the ratio of actual weight to "standard weight." The level of exposure was expressed as the cumulative time-weighted average concentration. The product of TWA and timeon-the-job (TOJ) gave a measure of the cumulative dosage. lr-.. i. *0 4435006 i .'* .. ... i ' January. 1972 TABLE II "step-wise multiple linear regression analysis." Twenty-one Clinical Parameters Screened for ' Correlatidn with Exposure This procedure, made powerful by the advent of digital computers, systematically builds a mathematical model from a choice of Test independent variable terms based on the Physical Systolic blood pressure Diastolic blood pressure Timed vital capacity Chemical Bromsulphalein (BSP) Icterus index Alkaline phosphatase Serum glut nxal Iran (SGOT) , Thymol turbidity Protein, scrum total albumin globulin alpha I alpha 2 ; beta . . gamma AG ratio Hematological Hemoglobin Hematocrit * Red biood celts White blood ceils Prothrombin time Urine Specific gravity - fundamental independent variables. In the " . step-wise regression procedure, the ' independent variable (X,) most highly - .correlated with the response is entered into ; ; . e W. ' . _ the model, and the coefficients arc determined by the method of least squares. Using partinl correlation coefficients, the next variable (X,) to enter the regression is that whose partial *. i ; correlation with the response is highest. Given : s :.* . . the regression equation Y*-f(X,. X,), the ' i v .* . method now examines the contribution X, ' . ** -. would have made if X, had been entered first. . Repeatedly, the step-wise method selects as '.' the next variable in the regression the one i, ' . .'...most highly partially correlated with the r . response. At each stage, the "best" regression equation Y = f (X,, X,, ... X. ) is determined . ' - . 1. - -- . V`. . by the method of least squares, after cheeking the partial F criterion for each variable to " verify the significance of each term included." : The object of this technique is to express a .. ' relationship by some relatively simple Data Formaf' mathematical function such as polynomial ' which contains appropriate variables and At this point we had prepared two which approximates the true response of the . concurrent sets of data for each man: medical dependent variable over some limited ranges information and environmental information. of all the variables involved. Since this All that remained was the individual matching approach is empirical, the resulting equation process and collective analysis. At the time of might be considered to be physically each clinical observation, both types of data meaningless; nevertheless, it may prove for each man were registered in the following extremely valuable for predicting the values of format: some dependent variable Irom knowledge of Man No., Date. Age, TOJ, TWA, Ht, Wt, other variables, at least under certain stated . Std Wt, Y, ... Y,, restrictions. In using the technique, it was kept Where TOJ time-on-job (time of in mind that, just because a particular exposure), yrs. functional relationship has been developed TWA . Career time-weighted and a specific computational procedure is - - average exposure followed, it cannot be concluded that a causal Std Wt * Standard (desired) weight as relationship exists among the variables. After . tabulated by the Metropolitan data had been accumulated and a strategy had Life Insurance Company.1' been selected for analysis of the information, Y, ** Clinical observation i, i--1, 2 ... 21. the remaining steps could he broadly classified as screening and refinement. Statistical Analysis The technique used for extracting relationships hidden in the available data was Correlation Matrix The first step in analyzing the consolidated information was to examine the linear Z.OQSS W t i American Industrial Hygiene Association Journal TABLE III Correlation of AU Dependent Variables with All Independent Variables (P<0.05) Test Physl* 4I , Svlnli<. HthkI pressure picssure riinvi \ital capacity Chvmu.il |tr<Hti'(it|*fi.itein (BSP) Ictcftl.s index AIMlioc plimphatatt Serum pint oxal inn (SUOI'i Thym*l turbidity Protein, ncruni total albumin globulin alpha 1 alpha 2 beta gamma AC ratio Hemalntogical Hemoglobin Hematocrit Red blood cells While blood cells Prothrombin time Urine Specific gravity Apt cm 44 1 -0 0 00 n0 00 00 0 0* 40 00 0 4 --0 00 0-- . 00 00 00 00 0 0 TWA Dose 4- 4 00 . 4 4 0 0 00 00 0' 0 00 00 44 00 00 -- 00 00 00 00 00 correlation matrix for all the independent and dependent variables available. This screening technique revealed several clinical variables that appeared to be related to exposure. The correlation matrix is shown in Table III. Six clinical parameters of the 21 under study showed significant correlations (P^0.05) with the exposure variables, cumulative TWA and U 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 ageThe correlation-screening procedure helped us develop and show that the "independent" and "dependent" variables are interrelated. Table IV% shows the correlation matrix (P=SO.05) for all the crucial variables, dependent and independent. The general consistency of the relationships indicated among the variables justified more rigorous analysis. 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 a model would be chosen should include the independent variables themselves, together with interaction or crossproduct terms which might be helpful in explaining variation in the observed variables. For example, we allowed for the possibility of age and exposure operating together (interacting) in a manner which would be different from that of age and exposure acting independently. However, we faced two opposing criteria for selecting a predictive model: 1. For utility and accuracy we wished our model to include as many significant TABLE IV Correlation Coefficient Matrix -- Crucial Variables Age OB TWA Dose BPS BPl) BSP 11 Hb /J Protein Aft 00 44 00 0 <HJ 0 0 4 4 4 4 0 0+ TWA 0 0 4 4 4 4 4 --4 Ihise f 4 4 ' 4 4 4 -- 4 IU'S 4> 4 4 4 . 0 0 0 nrn 4 4 4 4 O 00 IlSP O 4 4 4 0 0 it 0 0 4. l 0 0 0 00 ttb -- 0 -- - 0 0 0 0 0 P Protein 0 * 4 4 0 0 4 0 * 0 < Pmitive correlation P^0.05 N*t correlation I* ^0.05 Nrntivc correlation P ^0.05 '4 BFG3U11 26. January. 1972 TABLE v ' Number of Subjects and Number of Climcal lnu within Hi- imly Group Test . Total Number Observations Number nf Subjects & Humbert f Randomly Selected Observations Systolic blood pressure Diastolic blood pressure Bromsulphalein Icterus index Hemoglobin Beta-protein jja 32J 92 29 ' 143 58 98 . 98 . 8S ; 29 HI . tit ' independent variable terms as possible so ' that reliable values could be predicted. 2. For simplicity and ea'ie of com munication, we wanted the equation to :, include as few significant independent variable terms as possible. \! Operating largely from an empirical point of view, we drew up a list of 30 independent variable terms including transformations of the four basic independent factors. Since we - had unequal numbers of observations for each individual in any given test, 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 V. Statistical Results The results of the regression analyses for each of the six crucial clinical variables are given below: Systolic Blood Pressure : BP.-A. + B, (Age? -KTWA) (Age) 1C, (OB)-D.l Diastolic Blood Pressure BP, -- Aj4* B2 (Age)* (OB) *+Ca (TWA) (OB) Bromsulphalein BSP-A3+Ba (Age) (Dose) Icterus Index II --A,-f B4 (TWA? ' Hemoglobin '* H b - As+Bs (Age) * - C,(TWA)` Beta-protein * Beta-protein-A,+ B, (Dose? Figures 1; 2 and 3 show the regression responses for three of the above models, BSP, Icterus Index and Beta-protein, respectively. . Figure I. Regression model for bromsulphalein retention. - .Figure 2. Regression model for icterus index. Statistical Significance of Models An appropriate question is: What measures of precision can he attached to the regression models? Three useful indices arc the standard error ofregression. Sc.the overall l:-St;uistic. andthe coefficientof multipledetermination, >. ^ A CO : ot a .. Q C3 BFG31112 .# American Industrial Hygltne Association Journal t : 27. Figure 3. Regression model for beli-protein. R*. These measures of the "goodness of fit" for each model of the clinical variables are listed in Table VI. All of (he regression models are significant at the P -- 0.001 level, except the Icterus Index model, which is significant at the P-0.03 level. . Utility of the Models The regression models must be used with discretion. Since the least square regression coefficients are adjusted for other variables in the regression procedure, attempting to predict the response by changing only one variable arbitrarily may be misleading. Because of this, we must specify the prediction range for each variable under investigation. Such prediction ranges are shown in Table VII. To relate the statistical results to the practical question of an industrial hygiene standard requires careful consideration. First, an acceptable workroom air concentration must allow for men working in the environment for an entire career, up to 45 years; our data are useful only over a 20-year span. For effects which are cumulative, as most of those isolated in this study apparently are, the last part of a man's' career is the limiting consideration. In view of our data and their ranges, we can examine the clinical variables at TOJ --20, and Age --60, the highest legitimate values of our predictive parameters: 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 -136.80 + 0.034035 (TWA) Diastolic Blood Pressure -84.74 + 0.018845 (TWA) Bromsulphalein -2.12 + 0.034599 (TWA) Icterus Index -6.82 + 0.000000002309522 (TWA)4 Hemoglobin -13.97 - 0.0000000457339 (TWA)J Beta-protein --14.15 4- 0.000001371545 (TWA)J These clinical changes are tabulated in Table VIII as a function of TWA. Discussion of Clinical Changes In reviewing Table VIII, we note six factors which relate empirically to exposure. Within TABLE VI Statistics! Significance of the Regression Models Model Systolic W<kI pressure Diastolic Hood pressure llrninsutpfuiein Icterus index Hetnopliilnn Beta-proiein *1' <0.001 **P = 0.03 Number of Observations Standard Error of Rrjcression *>K 12.9 *>.6 t.s 75 1.6 RJ 0.83 <R 2.6 Overall F-St3tistic 24.S3 (3;94)* 39.46 (2;9S)* 43.S5 (1:63)* S.66(1;2J),# 8.95 (2;S0)* 12.65 (1 :S6)* Coefficient of Multiple Detcrminatibn 0.180 0.193 0.407 . , . 0.191 0.162 0.170 . r i>-. V ff- . - *' ` >' l-i ; . * ' ** If o iw .s e b frij BFG3U13 r00 s> *1 M O HU - jjpr-ooZ 0 V) o Til UW *0-\ *% NO O<0 0O0B O* * * M O - O oo--oo cM* A tMA oM toA> IA >J ^ X - o o * ^ s* s* y* O 00 o w o o *0 M O W *J K> Ul o V) VHA (A S3X2S3 IA v] Xk s4 s] s| OOVlO VIM OJ W-OM^Uv> JW-4W c 3 O VlOOMVl January, 197. :. ihe scope of this study the predicted blood 1 " ` pressures, systolic amt diastolic, did not rise to . ; levels which would he considered abnormal. '' V ; The hemo^'o'-in. though statistica ii y decreased, does not tall outside the normal . limits for our laboratory. The significance of the change ir ratio of the beta-protein is not known. We are left with two factors which give some cause for concern. The changes in the / Icterus Index and in the BSP lend some support to the hypothesis that some changes in . liver function have occurred in a few individuals exposed at the higher levels. The ' BSP appears to be most significantly ' correlated with exposure. Within the study group were several individuals who. after approximately 20 years . of exposure with time-weighted exposures of approximately 300 ppm of vinyl chloride and . . smaller amounts of vinylidene chloride during the early part of their careers, demonstrated a tendency to develop changes in certain laboratory tests which appear to be related to .their exposure. Reference to Figures 1-3 indicates that our interpretation of the clinical changes must be tempered by the fact that only a small number of individuals experienced the highest exposures. Two of the individuals showing the highest . rise in BSP were rechcckcd in 1968. One had essentially normal laboratory findings and the . other showed persistent elevation of various ; : liver function tests, even though both had been. \ ' removed from further exposure since 1965. The individual whose liver function tests ..remained elevated had a history of hepatitis preceding his exposure, although his picexposure liver function tests had been normal. Whether his abnormalities represented a result of his exposure or independent sequelae of hepatitis cannot -be ascertained. Certainly it would be desirable not to consider individuals with a history of hepatitis as candidates for prolonged exposure to vinyl or vinylidene chloride. Unfortunately, since many cases of subclinical hepatitis occur, there may always be some individuals in a working population whothavc had hepatitis. For most individuals in the study, the highest exposure occurred in the early phases of their . careers and their later exposures were much lower. In the final analysis, much weight had ss(D sew BFG31114 American Industrial Hygiene Association Journal _ 29 TABLE VIII Expected Response of Clinical Texts at a Function of Career TWA TWA, PPM Vinyl Chloride * Test .0 SO ' 100 ISO 200 250 300 Systolic prepuce (Ape 60, OIIKS- I.OM Diastolic Mood . . pressure (Age * 60, OMI S - 1.06) * Broimuiphnlcin (TOJ = 20. A(te - AO) Icterus index .'Hemoglobin Beta-protein 136.8 138.5 84.7 8S.7 140.2 86.6 141.9 87.6 143.6 88.5 145.3 89.4 147.0 V 90.4 2.1 . 6.8 14.0 14. t 3.8 6.8 (4.0 14.3 S.6 7.0 13.9 15.5 7.3 % 8.1 ' 13.8 18.* 9.0 11.0 13.6 25.1 10.8 * X 13.3 X X beyond range of available data 12.S X 12.7 X - ; to be placed on the readings observed for those employees who experienced high exposure levels, especially during the period 1950-58. For example, the average timeweighted exposure level in 1950 was 155 ppm, whereas the average exposure level in 1965 was 30 ppm. Our findings suggest that repeated exposure to vinyl chloride at TWA levels of 300 ppm or above for a working lifetime together with a very low level of vinylidene chloride may result in slight changes in certain physiologic and clinical laboratory parameters. The possibility of some impairment in liver function tests must be considered, even though no overt clinical disease was evident in any of the individuals studied. We shall continue our study, hut suggest that similar studies to help clarify the effects of this material be performed for other worker populations exposed to vinyl chloride alone. Conclusions The present study offers a technique of judging exposure effects on a group of cx(>oscd workmen based on an analysis which is intcnclcd to account for individual levels of exposure rather than relying on a collective comparison with a so-called '"control" population. The "exposed" group, especially when it is drawn from an industrial selling, will contain individuals subject- to a wide range of exposures, and the mean clinical indices for the group may well mask significant individual differences within the exposed group that could be detected only by 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 were available. With this approach, the '"exposed" group will contain some individuals whose exposures are low enough to serve as "controls," The regression technique we have employed treats the exposure levels (Dose and TWA) as independent variables, thereby providing an open format that allows inclusion of any degree of exposure, including none. The advantage of regression analysis in (his application lies in [he ability to extract more substantial information on acceptable exposure levels by relating measured clinical changes directly to measured exposure. To use this method, good environmental and medical data must be gathered and consolidated concurrently in substantial quantity. We have demonstrated the use of this statistical technique with a groufi of men exposed to vinyl chloride and trace levels of vinylidene chloride. In so doing, we have found some interesting apparent effects from chronic exposure to that system but. more importantly, the methodology looks promising as a needed improvemenj in our quest to make r ! ,4- %; ! A V'\ - V i- r- * V -s\; t or w o BFG31115 30 practical use of toxicological feedback from worker exposures. We hope that others will offer further refinements and suggestions that will help attain this goal. Acknowledgments ' We wish to acknowledge the assistance of other members of the Medical Department and Environmental Research Laboratory of The Dow Chemical Company who, over two decades, gathered the basic information which has made this study possible. Our special thanks to go Mrs. Shirley Walker, R.N.. who conditioned much of the medical data, to M. Gerald Ott for his suggestions with the statistical strategies, and to our supervisors nad colleagues for their steady support. References .1. von Ocuingcfi. W.F.: The Halogrnoted Hydrocarbons; Toxicity and Potential Dangers. US. Public Health Service. Publication 414, Government Printing Office, '/Washington, D.C. (1953). 2. MajtromaUco, .. A.M. Fisher, K. Christie, and H. Danzigerr Acute Inhalation Toxicily of Vinyl Chloride to Laboratory Animals. Amer. Ind. Hyg. Assoc. J. 21:394 (Get. I960). 3. Torkelson, T.R.. F. Oyen. and V.K. Rowe: The Toxicity of 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 Repealed Exposures of Humans and Rm to Vinyl Chloride. Amer. Ind. Hyg. Assoc. 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. Damziger. H.: Accidental Poisoning by Vinyl Chforide: Report of Two Cases. Canadian Med. Assoc. J. 82:%28 (April 1960). January, 1972 7. Rarctta, E.D., R l) Stewart, and J.E. MutcMer? Monitoring F tenures to Vinyl Chloride Vapor: Breath Analyst* and ( tmtinuous Air Sampling. Amer. . Ind Hyg. Assin J M* W (1969). I, Filatova, U S., and E.S. Gronsberg: Hygienic Working Conditions in Polyvinyl Chloride Tar Plants. Gig i ' Sanlt 38-42 (Ian 1957). 9. Wilson. R.H.. W F. McCormick, C.F. Talia, and I.L. Creech: Occupational Acroostcolysis. J.A.M.A. 20/.577 (Aug 1967). 10. Dinman. B.D.. W.A Cook. W.M. Whitehousc. ILJ. Magnuson, and T. Ditchcck: Occupational Acroosteolysis An Epidemiological Study. Arek. Environ. Health 22 61 (Jan 1971). 11. Cook, W.A.. P.M. Giever, B.D. Dinman, and H.J Magnuson: Occupatkmal Acroosteolysis: An lndutrirl Hygiene Study. Arch, iawnm. Health. 22.74 (Jan 1971). 12. Dodson, V.N., B.D. Dinman, W.M. Whitehotiie, A.N.M. Nasr. and H.J. Magnuson: Occupational Acroosteolysis: A Clinical Study. Arch. Environ. . Health. 72.83 (Jan 1971). 13 Suciu. I., J. Drejman. and M. Valaski: Contributions to tte Study of Affections Caused by Vinyl Chloride. Medlcina Interne M 967 (Aug 1963). . 14, Prendergast, J.A.. R.A. Jones. L.J. Jenkins, Jr., and J. Siegel: Effects on Experimental Animals of Long-Term Inhalation of Trichloroethylene. Carbon Tetra chloride, l.l,l*Tnchloroethanc. Dichlorodifluoro* methane, and l.l-Dichloroeihylcne. Toxicol, and Appl. Pharm. 10:210 (March 19671. 15. Peterson. 3.E., H.R. Hoyle, and E.J. Schneider: The Analysis of Air for Halogcnated Hydrocarbon Contaminants by Means uf Absorption of Silica Gel. Amer Ind. Hyg. Assoe. Quart. 17:429 (Dec 1956). 16. Schaffer, A.W., and H.R. Hoyle: Mine Years Experience with the Davis Halide Meter. Amer Ind. Hyg. Assoc. J. 22:93 (April 1961). 17. Peterson. J.E., H.R. Hoyle, end E.J. Schneider: The Application of Computer Science to Industrial Hygiene. Amer. Ind. Hyg. Assoc. J. 22.180 (Much 1966). 18. Bartlett. D., Jr., and R.E. Carroll: Air Quality Parameters for Epidemiologic Studies Arch. Environ. Health !6:\%2 (Feb. 1968). 19. Desirable Weights for Men of Ages 25 and Over. Metropolitan Life Insurance Company 20. Draper, N.R., and H. Smith: Applied Regression Analysis. John Wiley and Sons., Inc.. Hew York (1966). Received May 28. 1971 Course on Effects of Nonionizing Radinlions The Massachusetts Institute of Technology will present a special two-wcck program on Biological Effects and Medical Applications of Nonionizitig Radiations. July 31-August 11, 1972. The course will present the basic physics 'biological effects, biomedical applications and hazards of ultrasound, laser, microwaves and magnetic fields. Presentation will be in manner to be suited to individuals with clinical and physical science backgrounds. The information will also be related in context to the activities of the Federal Regulator)' Agencies. Detailed information is available from the Director of the Summer Session, Room EI9-356, Massachusetts Institute of Technology. Cambridge, Massachusetts 02139. u* btX to 07 Q hr* CO BFG3] 116 :f