Document KGD06Rda1VzyxyNjGgOKBEj5o

Effects of Single and Repealed Exposures of Humans and Rais to Vinyl Chloride D. LESTER, l'h.I).,* L. A. GREENBERG, l'h.I).,* and \V. ROBERT ADAMS, M.D.t Laboratory of Applied Bindynamics, Yule University rind Department of Pathology, ScRool of Medicine, Yale University, Nett' Haven, Connecticut @ Rais exposed eight Hours daily to vinyl chloride at concentrations of 2% for three months and 5% for 19 days exhibited changes in liver and spleen weight and in red and white ceil counts. Except in the case of liver, tissue alterations did not accompany these changes. The alterations in liver morphology were within the normal range and were not pathologic in character. Because other facets of the animals' response, such as rate of grosvth, scrum transaminase and hemoglobin, were unchanged, it is suggested that the present threshold limit value of 0.03% need not be lowered. Introduction together with a trace of air and carbon THE TOXICITY of vinyl chloride has been reviewed recently.1,1,5 Because die dioxide. Txni.r. I threshold limit value of 500 ppm is based Analysis of Vinyl Chloride Monomer on limited data'1 using vinyl chloride less pure than that now obtainable5 the effects of acute exposure in man and rats and long term exposure in rats was investigated by us in 1959 and is described here. Our data do not support the conclusion of Torkclson, cf a/.5 that the threshold limit value should Acid Aceiviene Aldehyde Sulfur Phenol Non. Vol. Waler A nay 5.Z ppm 0.0 1.9 ppm 0.0 0.0 60 ppm II ppm 170 ppm w.w 99 + % be reduced ten-fold; indeed their data indi cate a need for further studies prior to any revision of the threshold limit value. Methods Experimental Material The vinyl chloride monomer was supplied by the Perkins Plant of Solway Process Di vision, Allied Chemical Corporation, in four 100 lb, cylinders with the characteristics shown in Tallin I, presumably differing ma terially from the vinyl chloride used by Torkclson, rt al.3 only in the presence of (JO ppm nf the inhibitor, phenol. Gas chro matography of the liquid phase indicated the presence of more than 99r/o vinyl chloride, Prttrnlrs! at (he THrnty-tltinl Annual Mertinc of the American huiusiii.tl IRirinie A'tnriaiioit, Wadiituiion, D. c:.. May, iy;2. Tim *ri 'va in part by a rr\rnteU grunl from ('lumuitl (!mi pnr.ti im .uni in ji.irt by U. S. I'wblir Hixiilft Scivnc (ir.mf (b"27(5H. jfJtlrru: lliurhetirntry .iikI IMutiolnuy, Jn'cUoii lUohvtY R\tu?MvTW blatu Utmcnity, New llrunwirk, Nfw |rrv. tltcri|)unt of l/. S. Public JU.tlih Service Senior Keonrcli Kellouyhii) So. Sl'`*37. Desired concentrations were obtained by metering air and vinyl chloride through flow meters calibrated for these gases and pass ing the appropriate flows through a 2-litcr mixing chamber. The concentration was also continuously monitored by a thermal conductivity meter calibrated for vinyl chlo ride versus air. The desired concentration of vinyl chloride was maintained with less titan 5% deviation. The total gas flow was about 50 liters per minute (1pm) in all but one of the experiments. Five experiments were conducted: (1) a live-minute exposure of human beings to concentrations of vinyl chloride tanging from 0.0 to 2.0/r ; ^2) au exposure of rats (Sher man strain rats from Rockland Farm, New CUy, N. Y.) for as long as two hours with concentrations up to I5f/c ; and (5, 4, and 5) 265 266 May-Jurtc, 1963 exposures of rats to concentrations of 8 to slides of the liver, spleen, and kidney were 10% for 15 days. 5% for 19 consecutive examined and classified, then recoded and days and 2% for 92 days. re-examined; in this manner a measure of the consistence and reliability of the. pathol Pathological ogist's technique was obtained. This con The experimental and control animals were killed by ether inhalation after expos ures lo 2, 5 and 8 to 10% vinyl chloride were completed. Each animal was autopsied according to standard practice. In addition sistency was nearly perfect in the ease of liver slides, and only slightly less so for spleen and kidney. The results of these 'examina tions arc reported in the appropriate follow ing sections. to the gross examination of ail animals, all the livers, kidneys and spleens were examined microscopically and some animals received Results Experiment I a complete microscopic examination. Heart, because the main objective was the deter lung, liver, spleen, urinary bladder, testes, mination of the effect of long term exposure prostate, ovary, brain, spinal coicl, pituitary, to vinyl chloride, the maximum concentra tibia, pancreas, stomach, small and large tion of the gas to which humans might intestine, adrenals, kidneys, uterus, fallopian conceivably be exposed without any imme tubes, thymus, thyroid, parathyroid, eye, knee diate acute effects was determined; this con joint, bone marrow, skeletal muscle, salivary centration then became the basis for deter glands and skin were removed from each mining the concentration used during the animal and preserved in 10% buffered for 92-day exposure of rats. malin. All tissues were examined grossly Three men (26, 35, 50 years; 86, 78, 73 both at autopsy and after formalin fixation. Kg.) and three women (25, 40, 55 years; Following fixation, representative samples of 64, 52, 61 Kg.) were exposed twice each all tissues were processed according to stand ard histological procedure and stained with hematoxylin and eosin; separate specimens day, separated by a 6-hour interval, for three successive days to six different con centrations of vinyl chloride: 0.0, 0.4, 0.8, of liver were stained for fat with the Flam 1.2, 1.6 and 2.0%. The concentrations were ing Red technique. The animals receiving presented in a different order to each sub such a complete examination of the tissues ject to make it possible to factor out any listed included two males and one female rat possible adaptation to either the gas or the that had been exposed 15 times and one experimental situation; the 0.0% concentra female rat exposed len times to the 0 to tion was included so that some assessment 10% level; eight experimental and nine, of suggestibility could he made. contrbl animals surviving the 5% exposure; Until its conclusion, the subjects were told and 20 randomly selected rats, equally di neither the effects to expect from the expos vided as to experimental and control groups ure nor the purpose of the experiment; nor and to sex, exposed to 2% vinyl chloride. was information vouchsafed as to the con The marked increases in liver weight ac centrations that were used at any time. The companying the exposures to 2% and 5% subjects each sat in a chair separated from of the gas, the decrease in spleen weight in the gas mixing equipment by a screen, a the 2% expsoure and the reported kidney simple plastic breathing mask affixed over changes in'exposure to 500 ppm* led us to the face, rovering the mouth and nose. The examine these particular tissues with a blind rate of air or air-gas mixture passed through technique, thus excluding the operation of the mask was sufficient (50 !|>m) to prevent any bias or prejudice from the judgments. any dilution effects from the atmosphere. Alt slides, including duplicates, were ran After five minutes of breathing the mixture, domly numbered so that it was impossible the exposure was terminated anti the sub to distinguish, without the1 code, which had jects were asked to compare their feeling- ( been experimental and which control. The ul this time to the time itnmnlialeU AP00023598 Industrial Hygiene Journal 267 prior to putting on the mask; no suggestions of any kind were made. The responses of the subjects arc summarized in Table II. It is apparent that the maximum concentra tion causing no ciTcct in any subject lies be tween 0.8 and 1.2%. From the responses it is evident that vinyl chloride causes clearcut intoxicating symptoms which can serve as adequate warning signs of its presence. thesia for two hours; on removal to air, there was an uneventful and prompt recov ery. Experiment 3 Some notion of the distinctive and specific pathology that might be caused by vinyl chloride was our object in exposing rats to a concentration of 10%. Table II Responses of Humin Subjects to Varying Concentrations of Vinyl Chloride Per Crnt Concentration Ktiponie 00 No tliftrrcneei reported by Subjects 1, 2, 4, 3 and 6. Subject 3: "ilUHilv dirty"* 0.4 No dittVrence* reported by tU subject!. OS No diflcrences reported hv Subject* 1. 2, 4, S and ft. Subject j: "sliicJiflr .heady". 1.2 N'ft ihUVrence* reported bv Subject* 1. 3, 4 and 5. Subject 2 unsure, somrwrhat diriy in middle of exposure. Subject 6, reeli**, wimming head, "just like tettinc tax". 1.6 Xo eilect reported by Subject 3. All other* report variou* lirgccc* of intoxication with di/zine**, liijhU bradeditett. tone naiuea. dulling of tisual anil audi* tory cue*,' thee tvmptoms diiappezred rapidly upon termination of tbe expotvre. 3.0 All subjects reported intoxicating rfTeeU. Subject 1 reporting a headache that permted for 30 minutet. These symptoms appeared earlier in ttie exposure titan at 1.6% and the symptoms were more intense tbaa at 1.6%. Experiment 2 Thirty-six rats, equally divided as to sex, were divided randomly into an experimental and a control group; the 18 experimental rats were exposed to the gas in a 1100-liter steel chamber. The concentration was initial ly raised rapidly to the desired level by ad mitting vinyl chloride without admixture with air until the effluent from the chamber attained the desired level as noted on the thermal conductivity meter. A fan within the chamber, connected by a flexible cable to an electric motor outside of the chamber (thus avoiding the hazard of an explosion), mixed the vinyl chloride svith the air with in the chamber. Thereafter, the effluent from the 2-liter mixing vessel was admitted to the chamber; to conserve gas, the through put of this highest concentration was 20 To gain further insight into the intoxicat ing efTects of vinyl chloride rats were ex posed to varying concentrations of vinyl chloride for periods up to two hours. The effluent gas from the mixing chamber, at the desired concentration, was passed through a 10-liter all-glass ex[>osurc chamber con taining two rats. At a 5% concentration in toxication is moderate but the righting re flex is lost; intoxication is more intense at 6% but the righting reflex is still present. This reflex is lost at a concentration of 7%; the comcal reflex disappears at a concentra tion of 10%. On removal from the chamber, the animals return to the pic-exposure state rapidly. One-animal was sacrificed after ex posure to the 10% concentration and showed no visible gross pathology. F.x|iostirc to a concentration of 13% resulted in deep anes thesia within five minutes. Effusion of fluid from the mouth preceded respiratory failure in one rat after '12 minutes; autopsy revealed edema and c ongestion of the lungs. Tin: sec ond rat was maintained under this deep anes lpm. The experimental rats were exposed daily from 0830 to 1630 hours while the control animals were exposed from 0000 to 0000 hours. At 'this concentration, as already noted, rats lose consciousness, regaining it five to ten minutes after removal to air. After two consecutive 8-hour exposures, how ever, the appearance of the animals sug gested that there would be no survivors if this concentration were maintained for the con templated 15-day period; consequently, be ginning with the third exposure, the con centration was reduced to 8%. The test was interrupted for one day after the sev enth daily exposure because of a mechanical breakdown. Of the group exposed in this fashion, three female rats died, after the sec ond, fifth and fmirtei-mli exposures; the two animals that died earliest were replaced with substitutes bn tin; remaining exposure pe riod; eight female rats were thus alive at the end of the fifteenth exposure. Female rats exposed 10 and 15 times were autopsied 2C>!1 Alny-Junr, Tahix II! Cln'-MfiriuUm n( Morphologic <.Ilinnm- in T.ivrr* Clin Deirrintimi 1 No >v<l!ni, no v.iruolri, innviuU \ imIiIc. 2 Slight swelling of edit, only a few f.iirt vacuoles or none, sinusoids visible hut eoitiptcurti. 3 Moderate swelling id cells, most nils with definite fine to medium vacuoles, sinusoids eoniprcived. 4 Marked swelling of edit, large irregular "vacuolei" or char spaces, compression of sinusoids. Chances focal In distribution. 5 Similar to 4 but changes more widespread and diffuse. Tam ; IV Clasxifictitimi of M"rpli<>l";ic. Oh.itu;c* in Chis Drscript inn 1 Cells well preserved, no vacuoles, glomeruli normal. 2 Vaeuoliiation and "pykitom" of some collecting lubulcs. Otherwise at 1. 3 As 2 hut with more extrusive vaeuoliiation and "pyknom" including proximal collecting tubules in cortex. 1 4 Ai 3 but with vaeuoiitation and "pykitosts" exlead ing to coftvolutcd tubules. pleural adhesions which were interpreted as at the termination of the exposure; the re representing regions of healed pneumonia. maining six rats were autopsied 15 days later, five of these rats having been exposed 15 times and the sixth rat 13 times. The All other organs and tissues were within normal limits, with no differences between experimental and control animals. mortality was greater among the male rats: The experimental animals sacrificed at the only two males survived 15 exposures, the termination of the exposure received a com remaining males, and their replacements, plete histologic examination. The lesions in surviving only an average of eight exjxrsurcs. the lungs of the three animals in this group The two male rats exposed 15 times were showing gross pleural pathology were seen autopsied at the termination of the exposure. to be due to acute focal necrotizing pneu There was no weight gain in the initial monia in varying stages of organization. days of the exposure to this concentration, al Some pulmonary edetna was present as well though after the ninth day some resumption as diffuse infiltrates of mononuclear cells of growth seemed to occur, possibly an in in the alveolar septne. Some areas of meta dication of the development of tolerance to plasia were present in and near the regions the effects of the gas as the exposure con of pneumonia and were interpreted as secon tinued. Upon termination of the exposure, dary to the pneumonia. growth resumed promptly at the same rate as the control animals. Iloth at the 16th and at the 30th days, there appeared to be no differences in liver: body weight ratios between experimental and control rats, al though too few livers were weighed at tho termination of the experiment to make mean ingful comparisons of this ratio. The external appearance, coat and tail, of all the animals was within normal limits. The parasitic liver cysts seen grossly were confirmed microscopically. The liver sections stained for fat revealed individual variation of some degree but no significant deviation from normal. The coded slides of the livers were classed according to the descriptions in Table III while kidney and spleen were judged according to the criteria in Tables IV and V; Figures 1, 2, 3, 4, and 5 arc About a third of the. animals had parasitic liver cysts. No differences in appearance, color, consistency or degree of congestion Tadlk V CUisifiratinn nf Morphologic Changes in Spleen were observed between the livers of experi- Clasi Dearnplion . mental and control animals. The lungs of three experimental animals sacrificed im mediately upon cessation of the exposure had numerous focal fibrinous pleural exu dates overlaying nodular yellow-brown pa renchymal lesions which had the appearance of regions of nettle necrotizing foeal pneu monia. Of the six experimental animals sacrificed two weeks after the exposure, the lungs of two revealed a few adherent fibrous 1 Avenge .sire follicle*, little or no congestion. hahiiire between lytiiplinryira, germinal epithelium ami tuter* ttitial tiuiu-. . 2 Obvioua im chance m follicle* or e|itnri- um, volume of uenuiiMl tvnlfia K*m th.ui volume ol jieriphrr.il Nmphocvui. 3 Criminal jspproxiinaiely mr volume as fieri* phrr.il hiuphftrvii**, modiTiitr rimc'itin. ,. 4 Iuerr.iwtl mtinhrr of iMuphurjtes. I>|erjhisia m grrmiu.il n-uim (greater than tolume of jitTMimTiil 5 lvmphorvte*). ... Aetivr livpcrpt.iM.i: 2 Haws of iymplinc>te*. (1)^ -i roue iimmtli.itelv around germinal center* coutainim: young iyimiliotMt'*> mm i minded hy (2) A piTijmcrut rum* of mi.til il.tik Iviiiplmcvtes. 6 Lymph**'! )i>|>rrpJ,iM rMemliiig to include mo>i of ihr iiili-ikliliiiiit. AP00023600 Industrial Hygiene Journal 269 Fioukcs 1-5. Rat livers, illustrating the morphologi cal classes described in Table III; (1) Class 1; (2) Class 2; (3) Class 3: (4) Class 4; (5) Class 5. H it stain, x 200. illustrative of the class descriptions in Table vinyl chloride in air for 19 consecutive days. III. There were no significant differences The experimental animals were placed with in the scoring of the groups, although there in the chamber at 0830 and removed at 1630 was a class "5" and no class "3" in the rats and the control animals from 0000 to 0800 killed at the termination of the exposure, hours. To prevent contamination of food whereas there were no livers in class "5" or water, both groups of animals were placed among the control animals. There were no within the chamber in empty cages; lienee class "5" livers among the experimental rats experimental and control animals were de killed two weeks after the exposure; the prived of food and water for eight hours slides were evenly divided between scores daily. The requisite concentration of the of 3 and 4. vinyl Chloride was attained initially as in Ex Kidney slides from the experimental ani periment 3, but the chamber was ventilated mals were not graded differently than from at 50 1pm. the controls but all spleen slides from ex Although the body weight of the experi perimental animals received the highest mental rats decreased initially, this trend was score, differing significantly from the con reversed by the fourth exposure, the rate of trol spleens, although some controls also growth thereafter being no dilTcrent than the received such high scores. controls. The drop in weight at the start and the subsequent resumption of growth Experiment 4 1 was paralleled by an apparent increasing tol erance to the gas as the exposures continued. These-preliminary tests seemed to intlirate At the start, the intoxication of the rats was that vinyl chloride was an anesthetic gas marked, instability of the hind legs being a which might also act as a lung irritant, fn prominent feature of the exposure. With order tr> assess this feature; of its action, to each exposure, however, there was an obvious highlight significant pathological features and diminution of these symptoms, so that hy the to avoid the potentiality of damage arising fifth or sixth exposure, it was not possible from anesthesia alone, live female and five to distinguish any evident symptoms of neu male rats, matched with controls, were ex rological deficit. posed for eight hours daily to live per cent Hemoglobin determinations during the ox- AP0002360I 272 May-Junc, 1963 ology being evident in either experimental to produce some singular or characteristic or control animals. pathology. It cannot be said that this goal The parasitic liver t:ysts seen grossly were was achieved, the results being questionable confirmed microscopically. I.iver sections and uncertain. Lung lesions were certainly stained for fat revealed normal variation, hut present but these could not be ascribed with no animals had increased intracellular fat nor certainty to any irritant properties of the gas were there differences between the experi since they might well have arisen from the mental and control animals. Graded in long-continued anesthesia; there was an ap- accord with the morphology in Table III, parent regression of these lesions in rats al the liver slides revealed differences between lowed a 14-day recovery period. ^Thc pres the groups. The mean score of the control ence of pneumonia certainly raises the pos group was 1.58, that of the experimental sibility of an acute toxic cfTcct on lung tis group 3.63. No liver in the control group sue at these concentrations; however, the scored more than 2 and none in the ex pneumonia could just as well be caused by perimental group scored less than 3; one liv secondary infection during the severe cen er scored 5. Because there was no overlap tral nervous system and respiratory depres the differences between the means are high sion, an interpretation favored somewhat by ly significant. the diffuse lesions and by the irregular oc There were no differences in score for the currence of the pneumonia. spleens in the two groups, but the kidney The kidney and liver changes described slides of the experimental animals scored by Mastromatteo, et al.* in rats exposed for significantly less than their controls. 30 minutes to 20, 30 and 40% of vinyl chloride, were not observed here, althougii Discussion 15 repeated 8-hour exposures to an anesthe tic concentration is also a relatively severe The data from the present investigation stimulus. The findings in the lungs agree confirm the acute effects to be expected from with the relative lack of effect found by 4 various concentrations of vinyl chloride: Mastromatteo et al. in rats exposed for 30 concentrations below 1 %, when exposure minutes to 10% vinyl chloride, except that is limited to five minutes, cause no ob continued exposure, for days, docs result in servable intoxicating effects; live minutes, mortality. The relative lack of pathology as however, is shorter than the time necessary the result of 30 minute exposure, at 10% to reach an equilibrium level in the circula found by Mastromatteo et al. would seem tion ; from behavioral observations in the to support the view that lung lesions found rat, it may be estimated that in five minutes after repeated exposures could well arise some two-thirds of the equilibrium level is from the anesthesia and not from some ac reached; consequently a concentration of 0.6 tion peculiar to vinyl chloride. There was to 0.7%, if long continued would not pro no indication at either the 2% or 5% level duce intoxication. As the concentration rises of any untoward or odier effects upon the above this level the intensity of the intoxicat lung tissue. ing signs increases until at a concentration of As an overall measure of general health, 7% the righting reflex is lost; at 10% the body weight and rate of growth arc sensitive corneal reflex disappears and at rnneentra- indicants. Rven in the exposure to a con tions of 15% and above respiratory failure centration of 5%, which at first produces a takes place. Vinyl chloride thus act* as an marked and severe intoxication, the sharp ancthrtir. gas, its depressant action increasing drop in the weight of male experimental with increasing concentration of the gas in animals seen at the start of the exposure was the air breathed, the coi responding innvas- soon reversed so that hy the end of the Ifl- ing neurological deficits ending in death at day exposure there was no difference be concentrations greater than 15%.. The pur- tween experimental and control rats of |X>se in exposing rats to concentrations caus either sex. Body weight and rale of growth ing anesthesia (H to 10%) was an attempt similarly showed no dill'crences between the 4 liidintiinl tlyifirnr Journal 273 gioups in the 2(/h exposure. It must be em view of the wide range that the liver: ii'*dy phasized again that the growth ol the nits weight ratio may encompass (Table VII). during the 5'I, o.\|XKurc support the ubserva- liatlicr this iucreasn may signify a non-spe- lion of the rat's behavior which indicated cilic response In melalxilie derangements oc that there was a rapid development of toler casioned by mild and moderate intoxication ance to the intoxicating effects of this con for daily 8-hour periods. From the dnta ob centration. tained here, it is not certain that histopatho- Neither the 2c/o nor the 5% concentrations logical change would have occurred had ex caused changes in the prothrombin time, posures been carried out for longer times. hematocrit or hemoglobin values. At both In the paper by Torkclson ct al., histo- the 2c/o and the h% concentrations, the pathological changes in the liver and in white cell count was lowered significantly, although still well within the normal range. The increase in red cells, although signifi cantly elevated in the br/o exposure, was not correlated with changes in the hemoglobin creased liver: body weight ratios arc re ported in male rats exposed to 500 ppm vinyl chloride for 4.5 months. That there is no causal relation between the reported hislopnthology and the increases in liver: body content. The increase in concentration of weight ratio is evident from the extensive the vinyl chloride is associated with a greater data gathered by these investigators. Female fall in the white cells and a greater (and rats exposed to 500 ppm vinyl chloride for significant) increase in the red cells at the 4.5 months showed no statistically significant 5% level. Although lymphocytes and neu increase in liver weight but are reported to trophils are increased, only the change at have histopathological changes in the liver. the 2c/c concentration unlike the previous Female rats exposed to lower concentrations cell changes, reaches the statistically signifi (100 and 200 ppm) for six months had sig cant level. It is difficult to know if these nificantly increased liver: body weight ratios changes have any toxic significance, since no but no pathology. On the other hand, rab tissue changes were seen upon microscopic examination that would account or be as sociated with a drop in the white cells or an bits of both sexes exhibited liver pathology without showing any increase in liver weight after cxisosiirc' for six months to a concen increase in red cells. The decrease in spleen: tration of 200 ppm. Tito authors correctly body weight ratio is in a direction opposite to point out that organ:body weight ratios may that usually associated with a severe drop well be nrtefnctunl, illustrating the point by in white ceils; although the white cell count tlx: significant deereas-.: in kidney weight did not suffer a severe drop, the decrease was found pi female nils exposetl to 50 ppm for substantial at the termination of the ex six months: such rats exhibited tin changes posure. when exposed to higher concentrations. Ily The only finding suggesting a specific toxic action of vinyl chloride is the increase in liver weight on exposure to 5r/o for 19 days and to 2% over 92 days. The increase in liver weight is not only highly significant statistically but is also substantial, amounting to a 30% increase over the controls. It is unfortunate that no information is available as to whether this increase is reversed on dis continuing the exposure. The increase in liver weight may lx- interpreted as indicating the same token, lmt overlooked by the authors, the increased liver:body weight ratio in female rats at 100 and 200 ppm is with erpial reason artefact because no sta tistically significant increase occurred at 500 ppm. Apparently, also, species differences are of importance in the reactivity to vinyl chloride, male guinea pigs suffering a signi ficant decrease in their liver: body weight ratio when exposed to 100 ppm for six months. alterations in water, electrolytes and protein There are six possible combinations of the content of the liver parenchyma, but that presence or absence of pathology and in such changes presage tile development of creases, decreases and no change in liver actual histologic lesions is not certain in weight. The one combination not observed APOOC 274 May-Junc, I'Mi.i by Torkelson, it al. is liisto|>:itIioloi;iml 40 times those* used by Torkelson, ct al. ll change associated with a decrease in liver any reliance is to be placed in a dose-ell'eet weight. Obviously, if five of the six possible relationship, pathology of some ronsiilrtniilc combinations have been observed in a rela degree should have been found in our ex tively small sample, no causal connection periments. Yet only morphological altera can be said to exist between these two tions of the character already described and measures. pictured were seen, which, in our knowledge Changes in the liver:body weight ratio may well have some toxic significance, but if they are unaccompanied by histopathological alterations, increased fat content or scrum transaminase changes it is impossible to conclude that taken alone they signify much. Reference to Table VII will show and experience, are of no pathrfiogica! signi ficance. Whether the explanation resides in a difference between the rat strains used by us and by Torkelson rt at. or elsewhere is not known, but without additional data it is impossible to resolve, the contradiction. On the basis of the present data, and the. that the liver:body weight ratios of the rats seeming unimportance of the liver weight used as control animals in the 5% exposure changes seen by Torkelson et al., and with were significantly higher than the experi out further evidence, a change of the pres mental animals in the 2% exposure. This ent threshold limit value of 500 ppm seems illustrates well the fact that though control unwarranted. animals arc used, unknown and non-specific, changes in the environment, time of the year, Summary temperature, diet, etc., may be responsible for changes in organ: body weight ratio with out at the same time producing pathological alterations in the organ. From 5-minute exposures of human sub jects to concentrations of vinyl chloride rang ing from 0.0 to 2.0%, it is estimated that it prolonged exposure to a level of more than Similar considerations apply to the de crease in spleen weight; here, not only was pathology not observed, but there was no difference in the morphological character at cither the 2% or 5% level between the experimental and control groups. 0.6% is necessary to produce minimum symptoms of intoxication. Rats exposed for up to two hours to higher concentrations ex hibited moderate intoxication at 5%, lost their righting reflex at 7% and the corneal reflex at 10%. Respiratory failure occurred at 15%, If the exposure to 10% svas long Unlike the interstitial anti tubular changes in kidneys of rats exposed to .500 ppm of vinyl chloride reported by Torkelson, ft al., was the lack of any pathology in our animals continued (two 8-hour daily exposures), mortality increased; death was apparently caused by a pneumonic process, but it was impossible to decide whether this was the exposed to 2% and 5% and tin: fact that result of a primary action or secondary to the the only morphological alteration in which a ancthcsia. significant difference between control and experimental animals occurred (kidney at 2%) indicated that the control animals were further from "normal". Because it is un reasonable to attach toxic significance to changes associated with a control air ex posure, if is our belief dial the morphologi cal alterations we have observed should not be interpreted as manifestations of pathol ogy* Rats exposed eight hours daily to 5%. for 19 days or to 2% over 92 days did not show any lung involvement. These levels had no effects upon growth rate, hemoglobin, hema tocrit or prothrombin time. At both con centrations there were increases in the liver: hotly weight ratio and decreases in tin* white cells; at 2% the spleen:body weight ratio deereased ittitl at 5% there 'was an increase in red cells. The concentrations to which the ruts weie N'o gross or microscopic changes were subjected in these expel imenls were al least found in any tissue that was correlated with APOOO Industrial Hygiene Journal 275 the dianges in the formed elements of the blood. The increases in liver: body weight ratios ivm: associated with morphological alu'ialiens in tin: liver which upjx'arctl lo have no pathological significance, while no meaningful morphological alterations were evident in either kidneys or spleens. Because, in the long term exposures, it was impossible to attach any toxic significance to the changes noted or to observe any histopathology, and because other aspects of the animals' reactions, such as growth rate, were unimpaired, the presently accepted threshold limit value of 500 ppm for vinyl chloride, one-fortieth of the concentration tested here, seems to offer an adequate margin of safety for human exposure. Acknowledgment It is a pleasure to acknowledge the tech nical assistance of , Malcolm Nicholson, Frederick A. Putt and Miss l.illemor tVnlltnark. References 1. vox Oittismv, W. F.t The hnm: Toxicity Pnttnlitl liengeri. 5. Public Hraltli Srrvirr, I'uUirntinn 414. Government Printing Office, WafrUiituton, D. C. 2. MMivoMvm.o, K., A. M. Kmtrjt. H. Ciiusmt, and if. Dankic^s: Acme In Ha Inti cm Vntieity oi Vinyl ChUrkir to Laboratory Animals. Amer. Ini, llyg. Atttit. J. 211 m (On. lOGO). 3. ToaKKt-HOf*. T. R.. F. OrtN, and V. K. Rowr: The Toxicity nf Vinyl CHlnrkie s Drtrrminrd by Repealed Fxpufure nf I.itlmrmnry Animals. Amtr, Ind, Ityg, Au*e. J. 23: 1.V4 (Oct. 19GI). 4. Smyth, H. F., Ja.: Improved Communiralian--Hy- fiene Standard* for Only Inh.iljtian. Amer. Ind. ftyg. Aunc. j. It: IJ'J (l!)Jfi*. 5. Fatty, F. A., W. I*. Yant, and C. P. Waitij Acute Rf*|xn* nf Oiiiiten I'itjj to Vaimrt nf Some New 0>m- merrisl Or:nie. OMnivmtuiv V. Vinyl Chlnridr. tie Health Hepattt (U.S.) 45: IOCS (Auf. 19J0). Sources and Use of Toxicological Information The New' York University Medical Center in cooperation with the American Industrial Hygiene Association will present a course on Sources and Use of Toxicological Information. The course will be given October 14-18, 1963, at the Onchiota Conference Center, Sterling Forest, Tuxedo, New York. The course is designed to acquaint those concerned with advanced methods of securing and interpreting pertinent toxicological information. Application and principles will be stressed rather than details of experimental toxicology. The design of the course eliminates the need for specialized scientific back ground so that all administrative and technical persons having responsibilities for use of toxicological information can benefit. Guest lecturers w ho arc spe cialists in selected fields will supplement the staff of N.Y.U. Institute of Indus trial Medicine for presentation of the subject material. Areas to he covered are: biological principles involved, sources of toxicological information, appli cations to in-plant problems, Federal regulations, and requirements of various agencies. Inquiries and registrations should he directed to New- York University Medical Center, Institute of Industrial Medicine. f>f)0 First Avenue, New York 16, New York. The registration fee is $150 with a deposit of $25 required. Ac commodations (double occupancy) at the Onchiota Conference Center for the evening (dinner) October 13 through lunch October 111 arc available at $21 per day including meals (payable to the Center on departure). Documentation of the Threshold Limit Value American Conference of Governmental Indus trial Hygienists Third Edition, 1971. VINYL CHLORIDE CH2CI!C1 200 ppm (Approximately 770 mg/m^) Vinyl chloride is a flammable gas with anesthetic properties at high concentrations. At anes thetic concentrations (8 to 127o) it has serious effects on cardiac muscle resulting in arrythmias and sensitization in dogs(l,2). There is a wide margin between anesthetic and lethal concentrations (30-407oK3). Torkelson, Oyen and Ro\ve(4) reported that repeated seven-houV exposures for six months at 200 ppm resulted in histologic changes in the central lobular region of the livers of rabbits, but not in rats, guinea pigs and dogs. At 100 ppm there was only slight liver enlarge ment. A subsequent report by Lester, Greenberg and Adams(5) on the effects of repeated ex posure of rats to vinyl chloride assaying 99 + percent purity at 2 and 5?0 concentration stated that, although liver changes were noted, they were not considered to be of pathological signif icance. In their opinion, a recommended TLV of 500 ppm was satisfactory for worker exposure. An interim report was made by Mutchler and Kramer(6) of long industrial health experience with vinyl chloride workers. Beginning in 1950, continuous monitoring was begun at five or six stations and the results compared with breath analyses(7) for vinyl chloride for 50 workers. Between 1950 and 1967 the mean air concentration was 160 ppm, with one maximal peak at 600 ppm of vinyl chloride and with great daily variation from 30 to 170 ppm, on the average. During part of this time vinylidene chloride* was an associated air contaminant estimated at around 5 ppm. Twenty-one clinical parameters were measured for comparison with the environmental data, and relationships were obtained by stepwise multiple linear regression analysis. Of medical examinations numbering 404 on 97 workers, 66 were used for comparison with 650 controls. These examinations with final diagnoses made according to the international classification of diseases, failed to reveal any overt condition attributable to vinyl chloride (or vinylidene chloride) ex posure. No differences of physiologic significance were found in blood pressure, hemoglobin, electrocardiograms, and no body abnormalities (acro-osteolysis) appeared.No one was clinically ill. Six clinical parameters appeared to be altered, however. Among those, beta lipoprotein, icterus index, and bromosulfalcin retention time may have some physiologic significance. The investigators felt, from a review of the interim findings, that a time-weighted average exposure concentration at 300 ppm (combined vinyl chloride and 5 ppm vinylidene chloride) could result in some degree of liver dysfunction. The multiphasio screening tests are continuing on all ex posed workers, and analysis of the findings is being made on an individual worker basis. In the meantime, a time-weighted average threshold limit value of 200 ppm vinyl chloride (with a few ppm vinylidene chloride) seems appropriate to prevent adverse systemic effects from longcontinued daily exposure. (* A 90-day animal inhalation exposure to vinylidene chloride at 5 ppm was without observable effect.) References: 1. Oster, R.H., Carr, C.J., Krantz, J.C., Sauerwald, Anesthesiol. ,8, 359 (1947). 2. Carr, J., Burgison, R.M., Vitcha, I.F., Krantz, J.C.: J. Pharm. Exptl. Thcr. 97, 1 (1949). 3. Mastromatteo, E., Fisher, A.M., Christie, H., Danziger, H.: Am. Ind, Hyg. Assn. J. 21, 394 (1960). 4. Torkclson, T.R., Oyen, F., Rowe, V.K.: ibid. 22, 354 (1961), 5. Lester, D., Greenberg, L.A., Adams, W.R.: ibid., 2_4, 265 (1963). 6. Mutchler, J.E., Kramer, C.G.: Report on Relation of Exposure to State of Health of Dow Chemi cal Workers, Gordon Conf., Tilton, N.H. (August, 1968). 7. Baretta, E.D., Stewart, R.D., Mutchler, J.E.: Am. Ind. Hyg. Assn. J. 30, 537 (1969). AP00023606 The Correlation of Clinical arid Environmental Measurements for Workers Exposed to Vinyl Chloride C. G. KRAMER, M.D., and i. E. MUTCH LER<\ rhr Dow Chrmieal Company. Midland. Miohiyan 48640 method is described far (be statistical consolidation and correlation of viy environmental measurements and clinical findings using as an example u group of health) mule workers 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 vinylldcne chloride. introduction For validating an industrial hygiene standard, it is essential to perform careful and comprehensive studies of the possible effects of substances on exposed workmen. In practice, however, very few substances have been the object of sufficient study to furnish reliable guidelines. Today, specialists in occupational heallh must recognize the need to develop programs which will better identify the relation between stresses acting on the human body in the work environment and physical changes that can be measured clinically, to explain the significance of these changes and use the results to help refine our guidelines for environmental control. Although toxicologists are constantly predicting what exposures are likely to be safe for people, there will always be some doubt about their predictions until enough human experience has been gained to prove their accuracy. The "proof of the pudding" should result from the correlation of good environmental measurements with the results of a well planned medical surveillance program. It is likely that such feedback from human experience will differ from the animal experimental data in that it will nut define a level of exposure which will actually cause injury, at least frank injury. However, except in cases where an industrial hygiene standard Present Address George D. Clayton nd Associates, 25711 Southfield Road. Southfield, Michigan 4SQ7S has not been applied, the feedback from human experience could be expected to describe levels of exposure which have been shown to be cither acceptable or marginally unacceptable. This information would be valuable to toxicologists because it would strengthen their skills in predicting from experimental animal data effects of substances on humans. In a broader sense, it would be useful in substantiating criteria to be used for industrial hygiene standards. For several years The Dow Chemical Company's medical and environmental health groups have been conducting concurrent medical and environmental surveillance of a large worker population exposed to many different chemicals. The project described in this paper analyzes the information already gained from concurrent surveillance and relates it to the determination of acceptable levels of exposure. A method is described for the statistical consolidation and correlation of environmental measurements and clinical findings, using as an example a group of 98 healthy male workers who had been exposed routinely to vinyl chloride for periods up to 25 years. Retrospective in nature, the study reveals several statistically significant clinical changes due to chronic exposures to vinyl chloride and smaller amounts of vinylidene chloride. By isolating these apparent effects and examining them in the light of our medical interpretation, we have developed what appears to be a promising technique for printed from the American Industrial Hygiene Association Journal Vol. 33 (l) 19-30 AP00023607 relating clinical information to worker narcosis upon acute exposure. However, at exposures to achieve a more refined industrial least two industrial deaths have been reported hygiene standard. from overexposure to vinyl chloride* In a controlled study; Lester, et al..* exposed six Vinyl Chloride Vinyl chloride (CH,"CHC1) 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 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, a/.,7 exposed human volunteers to 50, 250 and 500 ppm for 7 1/2 hours in an of copolymers such as Saran, and as a solvent. investigation concerned primarily with Animal Toxicity expired air studies. No clinical changes nor neurological responses were found in the The toxicity of vinyl chloride has been thirteen volunteers upon thorough physical reviewed by von Oettingen,1 Mastromatteo, et al.,1 and more recently by Torkelson, el al.,3 examination. Filatova and Gronsbcrg* reported and Lester, ct al.4 This gas is an anesthetic, angioneurosis of spastic character in workers and narcosis is the only reported effect of exposed to the monomer in a polyvinyl acute overexposure. chloride polymerization process. Air samples Torkelson,1 Lester,* and their co-workers usually varied between 20 ppm and 315 ppm. studied the chronic toxicity of vinyl chloride Wilson, et al,,* reported several cases of on rats. Torkelson and associates included acroosteolysis in hands of workmen working rabbits, guinea pigs and dogs in a study of in vinyl chloride polymerization processes. No effects from repeated exposure, i.e., using vinyl chloride exposure estimates are cited, controlled concentrations of 50-500 ppm. but the nature of the disorder and the They found that repeated seven-hour exposure circumstances of its appearance suggest that i to 220 ppm caused micropathological changes the effect may have resulted from a in the livers of rabbits, and at 100 ppm, noted "combination of physical insult, chemical slight but statistically significant increases in insult, and personal idiosyncrasy." Dinman, cr the average weight of rat livers, Other animals al.," Cook, et at.," and Dodson, et al..'1 were unaffected by 100 ppm. Using reported on a comprehensive epidemiological, concentrations of 20,000 and 50,000 ppm, industrial hygiene and clinical study of over Lester found no evidence of effects on lungs 5,000 employees engaged in vinyl chloride or other vital organs upon repeated daily and polyvinyl chloride manufacturing exposures lasting 92 days at the lower throughout the -United States and Canada. A concentration and 19 days at the higher level. clear association of acroosteolysis and manual Like Torkelson, however, he detected some cleaning of polymerization reactors was increase in relative weights of the rat liver revealed, with an expected prevalence of one and, in addition, of the rat spleen. The case per 37 reactor cleaners. The study did Committee on Threshold Limit Values not implicate vinyl chloride as the etiological (American Conference of Governmental agent but, using certain assumptions about the Industrial Hygienists), weighing both studies, monomeric content of polymer residue within concluded that "although the experimental data arc conflicting, the -preponderance the reactors, there appeared to be a semiquantitative correlation between the indicates a compound of relatively low toxicity with which a threshold limit of 500 prevalence of acroosteolysis and the degree of degassing prior to vessel entry.11 ppm is consistent." 1 Suciu, ct a!.,13 studied the clinical Human Toxicity manifestations of a group of 186 male employees working in polyvinyl chloride hew effects have been reported ns ii result of plants. They reported the presence of the human exposure to vinyl chloride except for "narcotic syndrome," asthenic nervous ( AP00023608 symptoms, Raynaud's syndrome and hepatomegaly, but did not furnish data regarding the number of exposures to vinyl chloride and other substances in the work environment. Environmental Aspects The Work Environment Subjects included in our investigation had worked in one or both of two manufacturing facilities which had been using vinyl chloride in polymerization processes. In both plants the environmental stresses of the work area were essentially equivalent. There were two airborne materials present in the work environment, vinyl chloride and vinylidene chloride. The concentrations of vinyl chloride were much higher than those of vinylidene chloride, due to the much larger quantities of vinyl chloride used and its greater volatility. During the first of two decades covered in the present study, the exposure of the workers to vinyl chloride and vinylidene chloride were estimated solely by nonspecific combustion techniques.,1',` The concentrations were expressed as vinyl chloride, although both materials were known to be present. In more recent measurements, infrared and gas chromatographic techniques have established that the vinyl chloride concentrations average 10 ppm, while vittually all vinylidene chloride concentrations amount to less than 5 ppm. and most frequently are 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 be viewed in the proper context -- that is, a work environment with two airborne materials: vinyl chloride in substantial amounts combined with very small amounts of vinylidene chloride. It should be noted, however, that a continuous 90-day inhalation exposure of rats and guinea pigs, at a concentration of 5 ppm vinylidene chloride,14 revealed no significant changes in hematologic, biochemical, pathologic and growth-rate parameters. Environmental Surveillance Industrial hygiene surveys of the operations in which the workers under study were exposed started in 1950. From that time until 1959, environmental surveillance was conducted on a regular basis, but using only the traditional techniques of grab sampling and portable anaiyzers.1,,* Since 1959, permanent multipoint continuous monitors have been used to estimate the exposures received by the workers studied. The application of data processing and computer technology to environmental control has allowed us to document the intensity of exposures more thoroughly and validate our continuous monitoring technique by breath sampling surveys.''1' The environmental sampling related to this investigation has focused on the exposure levels of men working in eight critical job classifications. Sampling for one or more of these classifications was performed in 1950, 1951, 1952, 1953, 1954, 1955, 1958, 1959, and each year (hereafter. Before continuous monitors were installed in 1959, the periodic exposure estimates were based on job studies supplemented by the examination of several discreet samples gathered over a few days. In later surveys, the exposure estimates were based on hundreds of thousands of samples gathered on a continuous basis over long time periods using multi-point analyzers. Thus the quantity of environmental sampling has increased and the quality has improved over the years in a manner that parallels the intensification of the medical surveillance program. Suitable Air Quality Parameters Obviously, a study of the possible effects of repeated inhalation of an airborne material which varies in concentration requires the use of a quantitative expression of air quality. We also recognize the need for an expression of air quality that will help characterize the tremendous variation in vinyl chloride concentration that may occur, together with a measure of central tendency. Wc base our choice, the "time-weighted average concentration'' (TWA), on consideration both of the problem under study and of availability of data. For this study, from a practical viewpoint, the heterogeneity of the environmental sampling limits our choice of an air-quality parameter to the lime-weighted AP00023609 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 docs, 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 3s 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. Wc now have a program in which all employees, in addition to this basic examination, receive a far more complete battery of tests. Wc include nil 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 fervour 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 comparahle data. Moreover, this type of analysis has the disadvantage of masking variation within the "exposed" group -- variation which couid 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 wc are seeking to establish a method with which wc 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 and correction of some obvious abnormalities. However, less obvious effects may have been missed. Though wc' had no ideal control group, we compared the results of the examinations on 66 Qf the individuals in the study group who had had examinations during 1965 and 1966 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 Table 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 tinted vital capacities of the study group and of the overall group. The study group also showed an AP00023610 TABLKI Factors in Wliiih VCI (5 roup Differed Sir.mfieanlly . from tlie "Gintrnl Croup" (8 <0.0S) Number of Exams History: Asthma Stomach, liver, intestinal trouble Kidney atone, bloody urine Nervous trouble of any sort Have you ever worked with radioactive substance* Physical: Anus-rectum Identifying body mirks VCI Group, *> 66 10.8 6.2 9.2 4.6 i.s 13.8 7.7 "Control Group, 60S 2.6 18.0 3.0 13.4 1S.S 6.1 18.7 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 abnormalitic' of the anus and rectum. Again, since this finding was not borne out in the final diagnostic categories, it would indicate that the various examiners did not consider these findings to be of clinical significance. There was no difference in overall diagnostic categories except for diseases of the digestive system, where fewer specific diagnoses were recorded for the study group than for the comparison group. There were no group differences 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. For comparing the mean BSP of the study group with that of the comparison group, only 116 measurements were available for the comparison group. The mean BSP for the study groups was 2.73 (50 observations), and the mean for the control group was 2.89 (116 observations). Although all records were individually reviewed for data which had not been processed statistically, no significant additional findings were noted. 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. 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, we recognize the need for including a record of age and obesity (important nonenvironmental 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. AP0002361I V TABLE It "step-wise multiple linear regression analysis." Twrnly-one Clinical Parameters Screened for __________ Correlation with Exposure This procedure, made powerful by the advent of digital computers, systematically builds a mathematical model from a choice of Ten independent variable terms based on the Physical Systolic blood pressure Diastolic blood pressure Timed vita! capacity Chemical Uromsulphalein (BSP) Icterus index Alkaline phosphatase Scrum glut oxai tran (SCOT) Thymol turbidity Protein, serum total albumin globulin alpha I alpha 1 beta gamma AG ratio fundamental independent variables. In the step-wise regression procedure, the independent variable (X,) most highly correlated with the response i^ entered into the model, and the coefficients are determined by the method of least squares. Using partial correlation coefficients, the next variable (X,) to enter the regression is that whose partial correlation with the response is highest. Given the regression equation Y-f(X,, X,). the 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 Hematological Hemoglobin Hematocrit Red blood cells White blood ceils Prothrombin time Urine Specific gravity most highly partially correlated with the response. At each stage, the "best" regression equation Y-f (X,, X,, ... X. ) is determined by the method of least squares, after checking the partial F criterion for each variable to verify the significance of each term included.1* The object of this technique is to express a relationship by some relatively simple Data Format At this point we had prepared two concurrent sets of data for each man: medical mathematical function such as polynominal which contains appropriate variables and which approximates the true response of the dependent variable over some limited ranges information and environmental information. of all ihe 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 from 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, il, -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 ( AP00023612 TABLE III Correlation of All Dependent Va rubles with All Independent Variable* (P<0.05) Test Age Oli TWA Dose Physical Systolic blood pressure Diastolic Mood pressure Timed vital capacity 4 4 - + 4 0 44 44 00 Chemical Bromsulphalein (BSP) 0 4 4 4 Icterus index 00 44 Alkaline phosphitise Serum elut oxal tran (SCOT) 00 00 00 00 Thymol turbidity Protein, serum total albumin globulin alphi 1 alpha 2 beta gimma AG ratio 00 00 40 00 04 -0 00 00 00 00 00 44 00 00 Hematological Hemoglobin Hematocrit Red blood cells White blood cells Prothrombin time --0 ---- 00 00 00 00 00 00 00 00 Urine Specific gravity 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 (PS0.05) 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, thre.e showed correlation with age and four with obesity. Three other clinical parameters were significantly associated with *geThe correlation-screening procedure helped us develop and show that tty: "independent" and "dependent" variables are interrelated. Table IV shows the correlation matrix (PS0.05) 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 l5os.e UPS HP,) BSP 11 lib 0 I'rotvin Age 004 4 400 0 on .* 0 04 44 40 0 tv/a 0 0 4 4 4 4 4 --4 Dose 4 4 4 4 4 4 4 --4 Bl*s 44 44 4 40 00 UPn 4 4 4 4 4 40 00 BSP II 04 44 00 4 44 00 000 00 I 111 -0 - - 0 0 0 0 0 P I'rou* in 0 4 4 00 Q 0 * I'hmIiv*' a'ornt.ition I* *0.05 0 Nn correlation I* Co.OS - Negative correlation I* Co.OS AP00023613 TABLE V Humber of Subjects end Number of Clinical Tests within the Study Group Test Total Number of Observations Number of Subjects & Number of Randomly Selected Observations Systolic blood pressure Diastolic blood pressure Bromsulphalein Icterus index Hemoglobin Bcts-proiein 323 323 97 79 145 $8 98 98 65 IS 53 58 independent variable terms as possible so that reliable values could be predicted. 2. For simplicity and ease 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)* + (TWA) (Age) 1C, (OB)- D,) Diastolic Blood Pressure BP, -A.+ B, (Age)H (OB)+C, (TWA) (OB) Bromsulphalein BSP-Aj+B, (Age) (Dose) Icterus Index II = A, + B, (TWAP Hemoglobin Hb-A,+B, (Agc)W-C,(TWA)* Beta-protein Beta-protein-A+B, (Dose)' Figures I, 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 be attached to the regression models? Three useful indices arc the standard error of regression, Se, the overall F-Statistie, and the coefficient of multiple determination. AP00023614 R'. These insures of the "goodness oF fit" for each model of the clinical variables are listed in Table VI. All of the 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 VU. 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-ycar span. For effects which are cumulative, as most of those isolated in thisHtudy 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 prcdiclive 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, wc 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) Hemoglobin -13.97 - 0.0000000457339 (TWA)3 Beta-protein -14.15 + 0.000001371545 (TWA)1 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 Statistical Significance of the Repression Models Model . Systolic blood pressure Diastolic blood pressure Bromsulphnlcin Icterus index Hemoglobin Uetuprnti'in V <0.001 *'r* Q.QJ Number uf Observations Standard Error of Regression 98 12.9 98 9.6 65 l.S 25 1.6 83 0.83 58 2.6 Overall F-Statistic 24.S3 (3:94)* 39.46 (2:95)* 43.85 (U6J)* 5.66 (1 ;33* 8.95 Onto)* 12.65 (l;56)` Coefficient of Multiple De terminati4n 0.180 0.193 0.401 0.1 9 i 0.162 0.170 AP00023615 " 35 %, 9^*' - * 5=T. c5. rzr ff ~8 5 o _ 3 gp^MQB A e*<o tG/> r OM --9> --><(> Ott | * * ! 4 4Mk t*040 *00-t <ca&/r> oo,<j o p a O'* o* e> M^WViMUl E 3 gA00 sr 9 3, (A o* a 5 ? U A IA M (A ut o `*j w o o a H0 K> M *v> K> K> W 3 U O (A IA VI u S. O^ gO(^ai/<ijQgaOo swi* OV. O-J UU O-J MU-J (c/> -I > 8W W*- MO> W* Mvl W-J UOO MIA C 3 the scope of this study the predicted >A-,-s pressures, systolic and diastolic, did not .* levels which would be considered abio/ri-.< The hemoglobin, though statisto.i: decreased, docs not fall outside the tt'nnn limits for our laboratory. The significaii'.e <' the change in ratio of the beta-protein it r.w known. We are left with two factor! which some cause for concern. The changes in ti,*. Icterus Index and in the BSP lend yme. support to the hypothesis that some change-. ,i liver function have occurred in a levindividuals exposed at the higher levels. I i,< BSP appears to be most significantly correlated with exposure. Within the study group were sevetal individuals who, after approximately 20 yi:u of exposure with time-weighted exposures ul 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 curiam laboratory tests which appear to be related to their exposure. Reference to Figures M indicates that our interpretation of the clinical changes must be tempered by the fact that only a small number of individuals experienced tin: highest exposures. Two of the individuals showing the highest rise in BSP were rcchecked in 1968. One had essentially normal laboratory findings ami tinother showed persistent elevation of various liver function tests, even though both hail been removed from further exposure since lut>v The individual whose liver function tests remained elevated had a history of hepatuis preceding his exposure, although his pie exposure liver function tests had been no min I Whether his abnormalities represented a result of his exposure or independent sequelae oi hepatitis cannot be ascertained. Certainly it would be desirable not to consider indis idu.ils with a history of hepatitis as candidates lot prolonged exposure to vinyl or vinylnlene chloride. Unfortunately, since many eases >>i subciinical hepatitis occur, there mas .ilwass be some individuals in a working poptil.tiiou who have had hepatitis. For most individuals in the study, the highest exposure occurred in the early phases of then careers and their later exposures were f'u.h lower. In the final analysis, much weight \s.l TABLE Vlll Expected Response of Clinical Tests as a Function of Career TWA TWA, l'PM Vinyl Chloride Test Systolic blood pressure (Age s 60. ODES = 1.06) Diastolic blood pressure (Ape = 60, ODES 1.06) Bromsulphalein (TOJ * 20, Age 60) Icterus index Hemoglobin Beta-protein 0 136.B 1 84.? so 13S.S 85.7 100 140.2 86.6 ISO 141.9 87.6 200 14 3.6 88.5 250 300 I4S.3 - 89.4 147.0 '0.4 2.1 e.s 14.0 14.1 3.8 . a 14.0 14.3 5.6 7.3 9.0 10.8 7.0 13.9 IS.S 8.1 13.6 18.8 11.0 13.6 25.1 X 13.3 X X * beyond range of availsble data 12.5 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 lew 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, but 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 exposed workmen based on an analysis which is intended to account for individual levels of exposure" rather than relying on a collective comparison with a so-c.'lled "control" population. The "exposed" group, especially when it is 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 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 welt 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 this application lies in the 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 group 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 pronming as a needed improvement in our quest to make AP00023617 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 and colleagues for their steady support. References J. von Oetlingen, W.F.: Tht Halogenattd Hydrocarbons; Toxicity and Potential Dangers. U.S. Public Health Service. Publication 4U, Government Printing Office, Washington, D C. U95S). 2. Majuomatteo. .. A.M. Fisher. H. Christie, and H. Danzlget: Acute inhalation Toxicity of Vinyl Chloride to Laboratory Animals. Amer. Ind. Hyg. Assoc. J. (Oct. 1960). 5. Torkelson. T.R., F. Oyen, and V.K. Rowe: Tte Toxieiiy tf Vinyl Chloride As Determined By Repeated Exposure of Laboratory Animals. Amir. inti. Hyg. Assoc. J. 22:2$4 (Oct 1961). 4. Lester, D., L.A. Greenberg, and W,R. Adams: Effect) of Single and Repeated Exposures of Humana and Rtu to Vinyl Chloride. Amer. Ind. Hyg. Assoe. J. 34 26$ <My 1963). 5. Committee on Threshold Limit Values: Documentation of Threshold Limit Values. Rev. Ed., American Conference of Governments! industrial Hygienists, Cincinnati, Ohio (1966). 6. Damziger. H.: Accidental Poisoning by Vinyl Chloride: Report of Two Cases. Canadian Med. Assoc. J. 82:128 (April i960). 7. BaretU. E D.. R D Stewart, and I E Mutchlcr Monitoring Exposures io Vinyl Chloride Vapor: Breath Analysis and Continuous Air Sampling. Amer. /fid. Hyg. Auoe. J. JO. 537 (1969) I. Filatova, U.S.. and E.S. Gronsherg' Hygienic Working Conditions in Polyvinyl Chloride Tsr Plants. Gig i Samis 3**42 (Jan 1957). 9. Wilson. R.H.. W.E. McCormick, C-F. Tatus. and J.L. Creech: Occupational Acroosteolysis. J.A.M.A. 20/.577 (Aug 1967). !0. Dinman, B.D., W,A. Cook, W.M. Whitehouse. H.l. Magnuson. and T. Diicheck: Occupational Acrootteolysis: An Epidemiological Siudy. Arch. Environ. Health 72.61 (fan 1971). II. Cook, W.A . P.M. Giever, B D. ^Dinman, and H.l. Magnuson: Occupational Acroostrolysii: An Industrial Hygiene Study. Arch. Environ. Health. 22:74 (Jan 1971). 12. Dodson, V.N., B.D. Dinman, W M. Whitehouse, A.N.M. Hasr, and H.J. Magnuson: Occupational Acreosicolysis: A Clinical Study. Arch. Environ. Health. 22:8) (Jan 1971). 15. Suciu, I., J. Drcjman. and M. Vaiaski: Contributions to the Study of Affections Caused by Vinyl Chloride. Medicines Interne 13.967 (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, 1.1,l-Trichloroethane. Dichlorodifiuoro* methane. and I ,!>Dichloroeihylene. TdnYof. and Afipt. Phatm. 10.210 (March 1967). 15. Peterson, J.E., H.R. Hoyle, and EJ. Schneider: The Analysis of Air for Hslogenattd Hydrocarbon Comsminints by Mtsns of Absorption nf Silica Gel. Amer Ind. Hyg. Assoc. Quatt. 17.429 (Dec 1956). 16. Schaffer, A.W., and H.R. Hoyle: Nine Years Experience with the Davis Halide Meter. Amer Ind. Hyg. Assoc. J. 22:93 (April 1961). 17. Ptterson, J.E., H.R. Hoyle, and E.) Schneider: The Application of Computer Science to Industrial Hygiene. Amer. Ind. Hyg. Assoc. J. 22:180 (March 1966). IS. Bartlett. D., It., and R..E. Carroll: Air Quality Parameters for Epidemiologic Studies. Arch. Environ. Health 16.162 (Feb. 196ft). 19. Desirable Weights for Men of Ago 25 and Over. Metropolitan Life Insurance Company. 20. Draper, N.R.. and H. Smith: Applied Regression Analysis. John Wiley and Sons., Inc., New York (1966). Received May 21. 1971 d AP00023618 CASE REPORTS Hepatic Angiosarcoma LAWRENCEF. NESHiWAT, M.D., Bridgeport. Connecticut. MlCHAELL. FRIEDLAND.' M.D., Beth SCHORR-LESNICK, M.D., Valhalla, New York, SAUL FELDMAN, M.D., William j. glucksman, m.d., Robert d. Russo, Jr., m.d., Bridgeport, Connecticut A patient with hepatic angiosarcoma if de scribed, The significant aspects of this malig nancy are delineated. This tumor constitutes only 2% of all primary tumors of the liver. The association with exposure to vinyl chloride and other carcinogens is reviewed. Diagnostic and therapeutic modalities are discussed. Angiosarcoma of the liver is a^rare tumor with a rapidly fatal course. A review of the English literature reveals only 103 such cases. This report describes a case of hepatic angiosarcoma notable for its brief duration of antecedent symptoms and pre sents a review of the etiologic, diagnostic, and ther apeutic features. From tho Oopartmtnt of Internal Medicine (IFN, MLF). the Depart* ment of Radiology (WJQ. RDR). and the Division of Gastroenterology (SF). St. Vincent's Medical Center. Bridgeport, Connecticut and the Dapartment of Internal Medicine (MLF, BS*l), New York Medical College, Valhalla. New York. Requests for reprints should be addressed to Michael l. Friedland, M.D., Department of Internal Mediant. St. Vincent's Medical Center. 2800 Main Street, Bridgeport. Connecticut 06606. Manuscript submitted November 7, 1990, and accepted in revised form April 16.1991. CASE REPORT A 43-year-old man with a past medical history of non-insulin-dependent diabetes mellitus, nephroli thiasis, cholecystectomy, and appendectomy pre sented to St. Vincent's Medical Center, Bridgeport, Connecticut, with right-eided flank and abdominal pain of 1 day's duration. He described the pain as sharp, persistent, nonradiating, and not associated with position or meals. He had experienced similar pain 1 month previously, which had resolved with out treatment He denied weight loss, anorexia, me lons, vomiting, or a change in bowel habits. Glipi zide was the only medication he waa taking at the time. A Navy veteran and later a machinist in a brake manufacturing company, he denied knowl edge of exposure to chemical toxins. Physical examination was significant for a soft abdomen with a well-healed midline surgical scar, tenderness to palpation in the right upper quad rant normoactive bowel sounds, and no abdominal bruita. His liver waa palpable 5 cm below the right costal margin and was firm and had a smooth sur face. Splenomegaly was not present Costovertebral angle tenderness was elicited on the right side. The remainder of the physical examination was normal. The initial laboratory tests revealed a hemoglo bin of 15.4 g/dL (normal: 14 to 18); glucose of 325 mg/dL (normal: 70 to 108); lipase 206 IU/dL (nor mal 23 to 208); serum glutamic oxaloacetic trans aminase 27 IU/dL (normal: 12 to 45); serum glutam ic pyruvic transminaae 36 IU/dL (normal: 7 to 40); total bilirubin 6.4 g/dL (normal: 6.1 to 8); and alka line phosphatase 70IU/L (normal: 37 to 107IU/L). Urine analysis showed 0.5% glucose, traces of blood, and no protein. Radiologic evaluation included abdominal radio graphs that were normal. An abdominal ultrasound revealed a 10-cm round mass in the right lobe of the liver, with a well-defined margin and a homoge- Augutt 1992 Thi Amtrietn Jouratl of Madlein* Volume 93 219 AP00023619 HEPATIC ANGIOSARCOMA / NESHIWAT FT XL FV pli ce tv er P* st re Figure 1. Top, computed tomo graphic scan of a hepatic angiosar coma with contrast showing tnhomogenous contrast enhancement of mass lesion, which Is indicative of its vascular nature. Bottom, computed tomographic scan with out contrast showing a predomi nantly homogenous 10-cm mass le sion in the right lobe of the liver that is of greater density than the remaining liver parenchyma. neous pattern of echogenicity. A computed tomo graphic (CD scan of the abdomen with and without contrast (Figure 1) confirmed its presence. The predominantly homogeneous mass lesion showed inhomogeneous contrast enhancement, indicating its vascular nature. The remainder of the liver appearod fatty. Subsequently, a CT-guided needle aspirate biop sy was performed that demonstrated a pleomorphic malignant cellular process with vascular channels and scant to abundant cytoplasm. No normal tissue was present (Figure 2). A diagnosis of hepatic an giosarcoma was made on the basis of hematoxylin and eosin, factor VD, and immunoperoxidase his tologic studies. To further assess this mass, hepatic arteriogra phy was performed. This showed a large neoplastic lesion in the right lobe of the liver, with accumula- 220 Augini 1M2 Thi Amsrlean Journal of Modlelnt Volumo S3 Fir tt P tv V ir t v i I s I ( 1 f ( t AP00023620 Ftgure 2. Angiosarcoma. Histologic pleomorphic cellular malignant pro cess with the suggestion of vascu lar channels and hyaline pink to lav ender, scant to abundant cyto plasm (hematoxylin and eosin stain; original magnification X400, reduced by 30%). HEPATIC ANGIOSARCOMA / NESHHIAT ET M. omoosartnhomant : stive tom, withJomiss leliver n the mels issue : ancylin his- igiaastic uila- Figure 3. Hepatic angiogram show ing a large 10-cm vascular mass in the right lobe of the liver with dis placement of the normal vascula ture and the presence of multiple vascular lakes. The left lobe is not involved. tion of contrast in small "lakes" (Figure 3). There was no evidence of left-sided or portal vein involvement. The patient was referred to Yale-New Haven Hospital for surgical consultation. Based on the as sessment that the disease was limited to one lobe and that the remainder of the liver was essentially normal, a right lobectomy was performed. COMMENTS Angiosarcoma of the liver, which is also known as hemangioendothelial sarcoma, constitutes only 2% of all primary tumors of the liver [1]. Metastatic cancer is the most common neoplasm of the liver and is responsible for 38% of all tumors in the liver. Worldwide, hepatocellular carcinoma accounts for less than 2% of all malignancies and is responsible for 1,250,000 deaths per year in the United States. About 90% of primary carcinomas of the liver are hepatocellular carcinoma and 7% are cholangiocaicinomas; less common tumors include hepatoblas toma, angiosarcoma, and sarcoma [2], Angiosarcoma of the liver has demonstrated the intimate relationship that exists between environ ment and malignant transformation. This neo plasm was first reported in association with expo sure to thorotrast [3] and arsenic [4], and later with vinyl chloride by Creech and Johnson in 1974 [5], Their studies demonstrated an increased risk of liv er angiosarcoma and cancer of other sites among August 1992 The American Journal of Medlcln* Voluma 93 221 AP00023621 HEPATIC ANGIOSARCOMA / NESHIWAT ET Al employees of vinyl chloride polymerization facili was limited to one lobe and who was not considered ties. The risk approaches 10 to 15 times that of the a candidate for surgical resection. However, subse general population (for angiosarcoma of the liver) quent histologic examination at the time of autopsy [6]. This rare neoplasm has also been associated showed no viable hepatocytes, although there were with systemic diseases, i.e., hemochromatosis [7] tumor cells in the irradiated lobe [11], and von Recklinghausen's disease [8]. It is also not Angiosarcoma of the liver may also be surgically ed to bo four times more prevalent in middle-aged resected. Bonneton et al [13] reported on the suc men than middle-aged women [2]. cessful removal of a tumor by right hepatic lobecto Clinically, patients with hepatic angiosarcoma my in a worker exposed to vinyl ^hlorid*. However, generally present with nonspecific symptoms. the patient died weeks later of bleeding varices. No Prominent among the symptoms noted in a study of tumor was found in the liver or elsewhere at autopsy 103 patients were abdominal pain (the most preva [5]. Surgery may be an option when the angiogram lent), weakness, fatigue, and weight loss. Hepato has revealed that the tumor is localized to one lobe megaly, ascites, and jaundice were the three most and the remainder of the liver is not compromised common presenting signs [1]. Additionally, audible [12]. hepatic bruits on auscultation reflect the arteriove Further therapeutic approaches using neoadju nous shunting created by these highly vascular vant chemotherapy via a hepatic artery catheter tumors. may prove useful in permitting resection in more Hepatic arteriography provides the best tool for cases. This option needs more research, although diagnosing vascular lesions [9]. Typically, there is the relative scarcity of this neoplasm will add to the movement of contrast into small "vascular lakes," difficulty in evaluating this approach. central areas of hypovascularity, and peripheral contrast staining. The hepatic artery may often be displaced by the tumor. This may be observed on ACKNOWLEDGMENT angiography [10]. Locker et al [1], in their review of We thank George Van Der Aim. M.D.. of the Department of Pethotosy lor hie patients with hepatic angiosarcoma, found that lab contribution to the illustrations. oratory data occasionally suggested liver disease but were often nonspecific indicators. MicTcecopic examination reveala malignant cells invading liver parenchyma and vasoformative areas, with vessels lined by malignant endothelial cells. The sinusoids are lined by enlarged anaplastic tumor cells, with nuclear hyperchromatism and a high nuclear-to-cytoplasmic ratio [l]. The histolog ic changes seen after exposure to vinyl chloride usu ally begin with focal hyperplasia in both hepatocytes and sinusoidal cells. These lesions are usually irregularly siized cavities within the liver paren chyma. The irregular and often striking sinusoidal dilatation is a frequently associated finding. The REFERENCES 1. Locker GT. Deroshew JH, Zwelling LA The dinleal feature! of hepatic angio sarcoma: a report of four cases and a review of the English literature. Medicine (Baltimore) 1979: 58:48-63. 2. Wenebe HJ. Falkson 0. Order SE. Cancer of the hepatic biliary system. 3rd ed. In: DeVita VT Jr. Heilman S. Rosenberg SA editors. Cancer prindeles and practtoe of oncology- Phfadelphia: JB Lippincott. 1989:836-68. 3. MacMahon HE. Murphy AS. Bates Ml. Endothelialcell sarcoma of tsier follow ing thorotrast injections. Am J Pathol 1947: 23: 585-611. 4. Regefson W. Kim U. Ospina J. Holland JF. Hemangioendothelial sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Cancer 1968: 21: 514-22. 5. Creech JL Jr, Johnson MN. Argasarcoma of the liver In the manufacture of pofy vinyl chloride. J Occup Mad 1974:16: 150-1. 6. Tamburrs CH. Relationship of vinyl monomer and Svar cancers: anposar- malignant transformation is believed to originate from this lesion. The prognosis of patients with hepatic angiosar coma is poor. There is often a rapid decline in the patient's condition after diagnosis, with a median survival of only 6 months. It is essentially an incur able disease that is often unresectable at the time of diagnosis. However, in a small series of patients, intravenous doxorubicin, given for 3 to 4 weeks in combination with cyclophosphamide, has had some benefit in causing temporary regression of the tu mor size. This regimen of chemotherapy has im proved median survival to 13 months [6]. Hepatic angiosarcoma is relatively radioresistant. Radio therapy was attempted in one patient whoee tumor eoma and hepatocellular eardnoma. Semin Liver DIs 1934; 4:153-89. 7. Sussman EB. Nydck I. Gray OF. Hemangioendothelial earcoma of tha liver and hemochromatosis. Arch Pathol Lab Mad 1974; 97:39-42 A LedermanSM. M*tgkiEC. Uftey KT. etaf. Hepaticneurofibromatosis, malig nant schwannoma, and angiosarcoma in Recklinghausen's disease. Gastroen terology 1987; 92: 234-9. 9. Freany PC. Angiography of hepatic neoplasms. Semin Roentgenol 1983; 18: 114-21. 10. Whelan JG. Greach JL Tamburro CH. Angiographic and radtonucfide charac teristic o( hepatic angosarccmt found in vinyl chloride workers. Radiology 1976; 118: 549-57. 1L Mcheer GP. Cantin J. Chu F, Nickson JJ. Effectiveness ol radiation therapy in the management of sarcoma ol the soft somatic tissues. Cancer 1968:22: 391-7. lZAdson AM. Seert WR Jr. Elective hepatic resections. SurgCSn North Am 1977; 57: 339-58. 11 Bometon G. Champetiar J. Sotto JJ. et at Un cos de rupture ipontan4e d'angosarcomt Mpatiqua chez un travailleur expose au chlorure da vinyla. Chirurge 1975; 101: 936-42. 222 August 1992 The American Journal et Medleint Voluma S3 1f si G N it te AP00023622 Januars /',* re of effccti'. cr. n, which deptr. bending stutr.t the surface. M. ms on the nir. pacts over a sh> uively revcrhers; of the integral:and the rorm. >f the effecthen. ;y noise reducn. n is a function md the chance o date, support;nal, more detail from laborat,ress which snot iation. : Interaction of SolClap. 11 lit Nette Hd. McGraw-H lit. Sn ; (Coiner is a twoncepts of f lawsuits ering, the umber of lives and cepticisms The book bility for gal trends to protect incepts of egligence, he textual han 4,000' iduct. Thej,. make this ufacturing Notice: This materiel may be protected by copyright law (Titl \7 U.S. Code) The Correlation of Clinical and Environmental Measurements for Workers Exposed to Vinyl Chloride C. G. KRAMER, M.D., and J. E. MUTCHLER* The Daw Chemical Company. Midland. Michigan 48640 method is described for the statistical consolidation and correlation of \? environmental measurements and clinical findings using as an example a group of health) male workers 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. laAnedartion For validating an industrial hygiene standard, it is essential to perform careful comprehensive studies of the possible rfVcts of substances on exposed workmen. In r*cticc. however, very few substances have wa the object of sufficient study to furnish reliable guidelines. Today, specialists in .-scBpational health must recognize the need uoclop programs which will better identify ts relation between stresses acting on the icnar. body in the work environment and atssical changes that can be measured Ufcitaliy. to explain the significance of these Udtepes and use the results to help refine our p*ielincs for environmental control. Alihough toxicologists are constantly *tding what exposures are likely to be safe x* people, there will always be some doubt their predictions until enough human experience has been gained to prove their westacy. The "proof of Ihe pudding" should rr*cli from the correlation of good r`Uunmenial measurements with the results *4 % well planned medical surveillance **wPm. U is likely that such feedback from *eun txpeiience will differ from the animal ctPeTimenial data in that it will not define a *>cl f exposure which will actually cause *?Sr)'. at least frank injury. However, except * c*sa where an industrial hygiene standard anr?!_t5drc": Geor*e D- cuyton and Auociitn towhfKid Road, Southfield, Michifsn 48075 has not been applied, the feedback from human experience could be expected to describe levels of exposure which have been shown to be either acceptable or marginally unacceptable. This information would be valuable to toxicologists because it would strengthen their skills in predicting from experimental animal data effects of substances on humans. In a broader sense, it would be useful in substantiating criteria to be used for industrial hygiene standards. For several years The Dow Chemical Company's medical and environmental health groups have been conducting concurrent medical and environmental surveillance of a large worker population exposed to many different chemicals. The project described in this paper analyzes the information already gained from concurrent surveillance and relates it to the determination of acceptable levels of exposure. A method is described for the statistical consolidation and correlation of environmental measurements and clinical findings, using as an example a group of 98 healthy male workers who had been exposed routinely to vinyl chloride for periods up to 25 years. Retrospective in nature, the study reveals several statistically significant clinical changes due to chronic exposures to vinyl chloride and smaller amounts of vinylidene chloride. By isolating these apparent effects and examining them in the light of our medical interpretation, we have developed what appears to be a promising technique for 19 20 relating clinical information to worker exposures to achieve a more refined industrial hygiene standard. Vinyl Chloride Vinyl chloride (CHj"CHCl) 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, and as a solvent. Animal Toxicity The toxicity of vinyl chloride has been reviewed by von Oettingen,1 Mastromatteo, et al.,1 and more recently by Torkelson, et al and Lester, et al.4 This gas is an anesthetic, and narcosis is the only reported effect of acute overexposure. Torkelson,1 Lester,' 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 5Ci,OCO 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 January, 1972 4 narcosis upon acute exposure.. However, ar least two industrial deaths have been reported from overexposure to vinyl chloride.* In,at controlled study, Lester, et aL,* 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 intoxicatioir appear at 8,000-12,000 ppm. No other effects! were reported. f Baretta, et al.? exposed human volunteers to. 50, 250 and 500 ppm for 7 1/2 hours in am investigation concerned primarily with; expired air 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 workersexposed to the monomer in a polyvinyl chloride polymerization process. Air sampler! usually varied between 20 ppm and 315 ppm. Wilson, et al. * reported several cases of. acroosteolysis in hands of workmen working-, in 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." Dinman, et al.,' Cook, et al.," and Dodson, et al.," .reported on a comprehensive epidemiological,; industrial hygiene and clinical- stu^y of over 5,000 employees engaged in vinyl chloride1 and polyvinyl chloride manufacturing throughout the United States and Canada. A clear association of 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 but, using certain assumptions about the monomeric content of polymer residue within the reactors, there appeared to be a semi quantitative correlation between the prevalence of acroosteolysis and the degree of. degassing prior to vessel entry.11 Suciu, et al.,13 studied the clinical manifestations of a group of 186 male employees working in polyvinyl chloride plants. They reported the presence of the ' "narcotic syndrome," asthenic nervous f -,Ta rcfJt Chios cnvit Kn*i The Su* jei! m p* cnvi esse jtrb cnvi vhk uer; chU un< D the to v CM I :ec* e\p mat rec .hr '.ha !0 arr Cbt as rr.i '.s. M hg e\ vf rt hi St E u -7 AP00023624 or. Industrial Hygiene Association Journal 21 'ever. . reporit. e.` In . 'osed i. to 4.Cm ppm ixicau :r eflfec ntcers ;rs ;n j:ly uf ige' r. ir, l: ph\iii. eporu-. worker oluir; tampk IJ ppr scs *X>rkir; ;sscs. N re cite: ind tr: jest ih. from : rhenticnmnn. > er ci/.. ologica of V'N c chloric: cturtni made. > 1 manm ors "a t of or.; udy dia .olocica bout lb: .e with'" a sort'.: en lb-' iegree o' c lin i o -* 6 nab ;hlprid< ' of tb; nervou; ,,t=pic>ms. Raynaud's syndrome and a-yotomegaly. but did not furnish data .girding the number of exposures to vinyl iii.-ode and other substances in the work leiircmmcnt tsiinamtntal Aspects ; Work Environment S^Sectt included in our investigation had -t.ed in one or both of two manufacturing Unieies which had been using vinyl chloride polymerization processes. In both plants the neuron mental stresses of the work area were (Medially equivalent. There were two eftwrne materials present in the work nrufonment vinyl chloride and vinylidene ;*ionde. The concentrations of vinyl chloride ere much higher than those of vinylidene ,*xide. due to the much larger quantities of *yi chloride used and its greater volatility. During the first of two decades covered in vtr prevent study, the exposure of the workers v- ur.j I chloride and vinylidene chloride were cmuted solely by nonspecific combustion ifcaaiques.,5,, The concentrations were rtprrssed as vinyl chloride, although both Mienais were known to be present, In more ueer.t measurements, infrared and gas -ameuiographic techniques have established **** ihe vinyl chloride concentrations average '> ppm. while virtually all vinylidene chloride ,c**lrtions amount to less than 5 ppm, and ""** frequently are detectable only in trace **0ts. For this reason, all exposure r*"ue* used in this study have been indexed *"Vinyl chloride" Our conclusions, however, "a be viewed in the proper context -- that a work environment with two airborne ***leriils: vinyl chloride in substantial *"unts combined with very small amounts of 'ylidcne chloride. It should be noted, U'wtver, hat a continuous 90-day inhalation !^>Uire ,0^ rats and guinea pigs, at a ."ceniration of 5 ppm vinylidene chloride,14 'r'ealed^ no significant changes in *ioiogic, biochemical, pathologic and tr^nh-nte parameters. *"'onmtntat Surveillance hygiene surveys of the operation* hich the workers under study were exposed started in 1950. From that time until 1959, environmental surveillance was 1 conducted on a regular basis, but using only the traditional techniques of grab sampling and portable analyzers.,4'u Since 1959, permanent multipoint continuous monitors have been used to estimate the exposures received by the workers studied. The application of data processing and computer technology to environmental control has allowed us to document the intensity of exposures more thoroughly -and validate our continuous monitoring technique by breath sampling surveys.7'17 The environmental sampling related to this investigation has focused on the exposure levels of men working in eight critical job classifications.. Sampling for one or more of these classifications was performed in 1950, 1951, 1952, 1953, 1954, 1955, 1958, 1959, and each year thereafter. Before continuous monitors were installed in 1959, the periodic exposure estimates were based on job studies supplemented by the examination of several discreet samples gathered over a few days. In later surveys, the exposure estimates were based on hundreds of thousands of samples gathered on a continuous basis over long time periods using multi-point analyzers. Thus the quantity of environmental sampling has increased and the quality has improved over the years in a manner that parallels the intensification of the medical surveillance program. Suitable Air Quality Parameters Obviously, a study of the possible effects of repeated inhalation of an airborne material which varies in concentration requires the use of a quantitative expression bf air quality. We also recognize the need for an expression of air quality that will help characterize the tremendous variation in vinyl chloride concentration that may occur, together with a measure of central tendency. We base our choice, the "time-weighted average concentration" (TV/A), on consideration both of the problem under study and of availability of data. For this study, from a practical viewpoint, the heterogeneity of the environmental sampling limits our choice of an air-quality parameter to the time-weighted 4* m : :3a* AP00023625 22 January, 197} 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 Carroll11 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 yearlyexposure 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 mayhave 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 fat mprq. complete battery of tests. We include all individuals : 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 fortproviding 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 and correction of some obvious abnormalities. However, less obvious effects may have been missed. Though we had no ideal control group, we compared the results of the examinations on 66 of the individuals in the study groim who had had examinations during 1965 and 1966 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 Table 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 overall group. The study group also showed an mere ti-iii mi> ..iiee :v-p -t,ii- nor'.vjrr. MP.vC final V;at lb klLiu! AP00023626 industrial Hygiene Association Journal 23 in -Ah: is ^ -orp;v ia ;K r : pv 0 X Jk* . -k:* s- .nu cl- :* i'L .! im r. 'o: *"< pui.ili. np.irai h... : ith::: : Cf'L.vi c i; 'r-r thi-os : scoici'. :nr -it. Owr " oncJ r -eaiih j in r oK u*. js c::i.v roup. ' itior- -oup und ^ >m "itu ns i:: !" s oi tS ibor.no: sor. " bctwee ion. 1`- show1' intr.-iH- item > cici if. was Jr the HUH-- nd i-i *' ho'^si s' TABLE I Factors in Which VC1 Group Differed Significantly from the "Control Group" (P <0.0S) Number oC Exams Hisiory: 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 VC1 Group, % 66 10.8 6.2 9.2 4.6 1.5 13.S 7.7 "Control Group,"% 60S 2.6 18.0 3.0 13.4 15.5 S.l 1C.7 ncTtrxv in positive responses to the history tr-= "kidney stone or bloody urine." Again, *s not reflected in the diagnostic ijBtpjetes. There was a decrease in number of responses to the history questions on 'Meuch. liver, and intestinal trouble" and *rssxrs trouble of any sort." On physical ation. the only category in which more <rxnes were recorded was that involving alitics of the anus and rectum. Again, this finding was not borne out in the W diagnostic categories, it would indicate cat the various examiners did not consider or*c findings to be of clinical significance. There was no difference in overall *>Paic categories except for diseases of the *cniive system, where fewer specific ^xafooies were recorded for the study group k>r the comparison group. There were no differences in the electrocardiograms or *** 1,r*>t Hand x-rays on the individuals in *r "exposed" group showed no significant "ormalities and no case of acroosteolysis. comparing the mean BSP of the study with that of the comparison group, only :lfc measurements were available for the """prison group. The mean BSP for the , ***? groups was 2.73 (50 observations), and *e Bean for the control group was 2.89 (116 Although all records were "Covduaily reviewed for data which had not ee processed statistically, no significant *"-*nal findings were noted. Considering oafl) factors studied, some differences *ld 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. 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 It. Independent Variables In identifying factors which could explain some or all of the variation in the observed clinical variables, we recognize the need for including a record of age and obesity (important nonenvironmental 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. t 23 TABLE 11 Twenty-one Ginical Parameters Screened for Correlation with Exposure Physical Systolic blood pressure Diastolic blood pressure Timed vital capacity Chemical Bromsulphalein (BSP) Icterus index Alkaline phosphatase Serum glut oxsl Iran (SGOT) Thymol turbidity Protein, serum total albumin globulin alpha 1 alpha 2 beta gamma AG ratio January, 197}. "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 j independent variable terms .based on the ' fundamental independent variables. Iif the step-wise regression procedure, . the independent variable (Xt) 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 (X,) to enter the regression is that whose partialcorrelation with the response is highest. Given the regression equation Y-- f(X,, X,), the method now examines the contribution X, would have made if Xt had been entered first. Repeatedly, the step-wise method selects as the next variable in the regression the on: most highly partially correlated with the response. At each stage, the "best" regression equation Y = f(X,, Xj, ... X. ) is determined by the method of least squares, after checking 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 mathematical function such as polynomial which contains appropriate variables and which approximates the true response of thedependent variable over some limited ranges of all the variables involved. Since this approach is empirical, the resulting equation might be considered to be physically meaningless; nevertheless, it may prove extremely valuable for predicting the values of some dependent variable from knowledge cf other variables, at least under certain stated restrictions. In using the technique, it was kept In mind that, just because a particular functional relationship has been developed and a specific computational procedure is followed, it cannot be concluded that a causal relationship exists among the variables. After data had been accumulated and a strategy had been selected for analysis of the information, the remaining steps could be broadly classified as screening and refinement. Correlation Matrix The first step in analyzing the consolidated information was to examine the linear AP00023628 tnrr,,,n Industrial Hygiene Association Journal anal;. MS the acscr / builds , hoicc , d on it; S. In IF; lure, ih; st hichl. tered in; etermir.tc ng pi-rtie iabic X. )se p:-.rtii test. 0 :\e- i X,). d, bution X tered Try selects i 1 the sir.-. with th: regrcssu" etermne. l' chec^irt, jariable ; noluded" express . y simp!-. lynon.int jibles art. !nse o' tbt ted ranee: ince thf equatio: hysicail lay pro': l* values s ' wledgc s' :ain state. ,t was kep Iparticuii' develops icedure u it a causa Mes. A lie' rategy hat pormatior classify nsoliditeie line*' TABLE III Correlation of All Dependent Variables with At! Independent Variables (P<o.os) Test Age OB TWA Dose yg^cOiC blood pressure + i- rv.tfK'lie Hood pressure 4 4- 4- Tw4 vital capacity --0 0 0 jw--ral Iroaiulphtltin iBSPj 0 * + 4 Uterus index lUt-alrt* phosphatase swam glut oxal Iran 0 0 V 40000 0000 (SCOT) Tkrmol turbidity 0 000 tortfcin, serum total albumin 0 0 00 globulin alpha 1 4 000 alpha 2 heta 00Q0 0 4- f 4 gamma A^ ratio ft- 0 0 0 00 0 wniolopcal Hemoglobin >4rautocrit Hood cells vfetr blood cells Ftotbrombin time -0 -0 000 0 00 0 0 000 0 00 0 .WM Specific privity 0000 correUtion matrix for all the independent and e*pedem variables available. This screening wchctque revealed several clinical variables wu appeared to be related to exposure. The .rcrelxion matrix is shown in Table III. i<a clinical parameters of the 21 under study '*"**d significant correlations (P^O.OS) with r 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- i The correlation-screening procedure helped us develop and show that the '`independent" and "dependent'' variables are interrelated. Table IV shows the correlation matrix (P^0.05). 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 wfyich 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 Mstrlx - Crucial Variables Age OB TWA Dose BPS BPD BSP ii Hb 0 Protein Age 004+ 40 0 0 OB 0 0444400 4 _TWA 0 0 44444 Dose 4 4 4 4 4 4- 4 4 4 js + + 4 4 44 00 0 bpd + 4 4- 4 4 4 00 0 BSP iI 04 44 44 00 4 0 0 4- + 0 0 0 00 Hb 0 000 0 0 $ Protein 0 + 4 4 0 0 4 0 0 + Positive correlation P <0.05 0 No correlation P <0.0S -- Negative correlation P<0.05 AP00023629 i" 26 January, lijj TABLE V Number of Subjects and Number of Clinical Tests within the Study Group Tost Total Number of Observations Number of Subjects &. Number of Randomly Selected Observations Systolic blood pressure . Diastolic blood pressure Bromsulphalein Icterus index Hemoglobin Beta-protoin 323 323 92 29 145 58 98 98 Vis 25 83 S8 independent variable terms as possible so that reliable values could be predicted. 2. For simplicity and ease 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, (Agey +{TWA) (Age) 1C, (OB)- D, ] Diastolic Blood Pressure BP,, -- A,+ B, (Age)% (OB) * +C, (TWA) (OB) Bromsulphalein BSP--Aj+Bj (Age) (Dose) Icterus Index II-A^+B^ (TWA)* Hemoglobin Hb-A.,+B, (Age)W-Q(TWAV 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. 1 'll rritrtsrsri TT . ; ! *1 is-5'?-- . | i * YI ` j | rr i 1 1 I >0 T0JT*W6C. II l tlO*4 j* la i :1 1 I ( Figure 1. Regression model for bromsulphileii retention. "I I I liCTSMI vwrg| ri 0 |0 *0 40 ao <00 l 140 40 110 r*a. aao vet Figure 2. Regression model for icterus index. 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 regression, Se, the overall F-Statistic, and the coefficient of multiple determination. Fi> AP00023630 4/ntricvn Industrial Hygiene Association Journal 27 %r~ i, ; V r , *> - .. ;.,r" xt >! i :i -- . !! i i i 1 Figure 3. Regression model for beta-protein. V. These measures of the "goodness of fit" for a:h model of the clinical variables are listed t Table VI. All of the regression models are ijnificant at the P--0.001 level, except the iaerus Index model, which is significant at the 0.03 level. lility of the Models The regression models must be used with aeretion. Since the least square regression ^efficients are adjusted for other variables in it regression procedure, attempting to irdict the response by changing only one triable arbitrarily may be misleading, tcause of this, we must specify the prediction ajge for each variable under investigation, ixh prediction ranges are shown in Table '>H. To relate the statistical results to the saciical 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 3!ocd Pressure -136.80 4- 0.034035 (TWA) Diastolic Blood Pressure -84.74 4- 0.018845 (TWA) Bromsulphalein -2.12 + 0.034599 (TWA) Icterus Index -6.82 + 0.000000002309522 (TWA) * Hemoglobin -13.97 - 0.00000004S7339 (TWA)J Beta-protein =14.15 4- 0.000001371545 (TWA)1 These clinical changes arc 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 Statistical Significance of the Regression Models Model Systolic blood pressure Diastolic blood pressure Bromsulphalein Icterus index He/nogiobtri Beta-protein *T< O.OOl **P = O.03 Number of Observations Standard Error of Regression 98 12.9 98 7.6 65 1.5 23 1.6 83 0.83 58 2.6 Overall F'Statistic 24.53 (3;94)* 39.46 (2;95)* 43.8S (1;63)* 5.66 (l;23)** 8.95 (2;80)* 12.6S (1;56>* Coefficient of Multiple Determination 0.180 0.193 0.40? 0.191 0.162 0.170 \v -i ? AP00023631 28 IPSafSS 3SS!S issl oh 2s. ~ s ; Zs?f -3 0 3 113 &a -^o r r* W <*-x h00i -J M O UI V SD L im it 188 109 9.4 11.1 16.4 22.6 S w 6 -- e 3s jJ -- o Cc/3 > 3 <A A Isl VI tf> M t. h) sC tS 3 yt A y yi b oo w o b C! MUQNtNAVh)ilnVk)i 9 v} (a ^ a 9i OOViWOO Xt3oi -O .k -J -j -j OSVI0MIA 2 > 0w-0 Au> w w O m 0 o i/i in rot sn lim it January, tjjjl rj the scope of this study the predicted blooc pressures, systolic and diastolic, did pot risetc levels which would be considered abnormal The hemoglobin, though statistical!) decreased, does not fall outside the normal limits for our laboratory. The significance of the change in ratio of the beta-protem 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 is liver function have occurred in a fe 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 yean of exposure with time-weighted exposures of 1 approximately 300 ppm of vinyl chloride and smaller amounts of vinylidene chloride during the early part of their careen, 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 rechecked In 1968. One had essentially normal laboratory findings and the other showed persistent elevat'or. of various liver function tests, even though both had beenremoved from further exposure since 1965. The individual whose liver function tests remained elevated had a history of hepatitis preceding his exposure, although his preexposure 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 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 were much lower. In the final analysis, much weight had AP00023632 Industrial Hygiene Association Journal TABLE VIII Expected Response of Clinical Tests as a Function of Career TWA TWA, PPM Vinyl Chloride Tt Systolic blood preuuie (Aje * 60, ORES * 1.06) l>a*lollc blood prniure (Age * 60, OBES= 1.06) Bromsulphalein (TOJ = 20, Age - 60) Icterus index Hemoglobin protein O 1 36.8 50 138.5 100 I4Q.2 150 141.9 200 143.6 250 145.3 300 147.0 84.7 85.7 86.6 87.6 88.5 89.4 90.4 2-1 6.S 14.0 14.1 3.8 6.S 14.0 14.3 5.6 7.3 9.0 10.8 7.0 13.9 15.5 3.1 13.8 18.8 11.0 13.6 25.1 X 13.3 X X = beyond range of available data 12.5 X 12.7 X 29 to be placed on the readings observed for hose employees who experienced high exposure levels, especially during the period 1950-58. For example, the average timetighied exposure level in 1950 was 155 ppm, hereas the average exposure level in 1965 u 50 ppm. Our findings suggest that repeated exposure to vinyl chloride at TV/A levels of 300 ppm or above for a working lifetime together with a wry low level of vinylidene chloride may mult in slight changes in certain physiologic aad clinical laboratory parameters. The possibility of some impairment in liver function tests must be considered, even though oovert clinical disease was evident in any of the individuals studied. We shall continue our study, but 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 exposed workmen based on an analysis which "intended to account for individual levels of exposure rather than relying on a collective comparison with a so-called ``control" population. TJte "exposed" group, especially *hen it is drawn from an industrial setting, *ri,l 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 this application lies in the 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 group 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 improvement in our quest to make iT?. >-*! AP00023633 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 and colleagues for their steady support. References 1. ven Oeuingcn. W.F.: The Hologtnated Hydrocarbons: Toilcity end Pe ten del Dangers. U.S. Public Health Service. Publication 414, Government Printing Office, Washington, DC. 0933). 2. Mastromatteo, .* AM. Fisher, H. Christie, and H. Danxiger: Acute Inhalation Toxicity of Vinyl Chloride 10 Laboratory Animals. Amer. tnd. Hyg. Assoc. J. 21:394 (Oct. 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. tnd. Hyg. Assoc. J. 22:354 (Oct 1961). 4. Lester. D,, L.A. Greenberg, end W.R. Adams: Effects or Single and Repeated Exposures of Humans and Rats to Vinyl Chloride. Amer. fnrf. Hyg. Assoc. J. 34:263 (May 1963). 5. Committee on Threshold Limit Values: Documentation of Threshold Limit Values, Rev. Ed., American Conference of Governmental Industrial H)fienists* Cincinnati, Ohio (1966). C. Damztgcr, H.: Accidental Poisoning by Vinyl Chloride: Report of Two Cases. Canadian Med. Assoc. J. 2:828 (April I960). W January, 1972' 7. Baretta. E.D., R.D. Stewart, and J.E. Mutehlrr Monitoring Exposures to Vinyl Chloride Vapor Breath Analysis and Continuous Air Sampling. Amer tnd. Hyg. Assoc. J. 30:537 (1969). I. Filatova. U.S., and E.S. Otonsbecg: Hygienic Working Conditions in Polyvinyl Chloride Tar Plants.. Gig } Sanit 3&M2 (Jan 1937). 9. Wilson. R.H., W.E. McCormick, CF. Tat us. and J.L. Creech: Occupational Acroostcolysli. J.A.M.a, 201:577 (Aug 196?). 10. Dinman. B.D.. W.A. Cook, W.M. Whitehousc, HJ. Magttuson, and T. DUchaek: Occupations! Acroosteolyais: 'An Epidemiological Study. Arek. Environ. Health 22:61 (fan 1971). It. Cook. W.A., P.M. Gicver, B.D. Dinman, tnd HJ. Magnuioo: Occupational Acroosteolyais: An loduatrin Hygiene Study. Arch. Environ. Health. 22:74 (Jji 1971). J. 12. Dodson. V.N., B.D. Dlnmait, W.M. Whitchoutc- A.N.M. Near, and H.J. Magauson: Occupational- Acroosteolyais: A Clinical Study. Arch. Environ. Health. 22:83 (Jan 1971). T 13. Suciu. I., J. Drejman, and M. Valaald; Contributions to the Study of Affections Caused by Vinyl Chloric*.- Medicine interne JJ.967 (Aug 1963). U. Prendcrgasu J.A.. R.A. Jones. LJ. Jenkins. Jr., and h- Sltgel*. Effects on Experimental Animals of Long-Terra* Inhalation of Trichloroetbylene, Carbon Tetra.' chloride, I,M-Trichlcroethine, DlchlorodiHuoro*- methane, and l,l*Dichloroethylen. Toxicol. and Appl. Pharm. 10:270 (March 1967). 15. Peterson, J.E, H.R. Hoyle, and E.J. Schneider: The Analysis of Air for Hatogenated Hydrocarbon- Contamlnanu by Means of Absorption of Silica Gel.* Amer Ind. Hyg. Assoc. Quart. 17:429 (Dec 1956). 16. Schaffer, A.W., and H.R. Hoyle: Nine Years Experience with the Davis Halide Meter. Amer tnd. Hyg. Assoc. J. 22:93 (April 1961). 17. Peterson, J.E.. H.R. Hoyle, and E.J. Schneider: The Application of Computer Science to Industrial Hygiene. Amer. tnd. Hyg. Assoe. J. 22:180 (March 1966). ; 18. Bartlett, D., Jr., tod R.E. Carroll: Air Quality Parameters for Epidemiologic Studies. Arch. Environ. Health /6; 182 (Feb. 1968). 19. Desirable Weights for Men of Ages 25 and OverMetropolitan Life Insurance Company. 20. Draper, N.R., n4 H. Smith: Applied P.tgttssio* Analysis. John Wiley and Sons^ Inc., New York (1966). . Received May 28, Wr it ll It tr U < V Course on Effects of Nonionizing Radiations The Massachusetts Institute of Technology will present a special two-week program on Biological Effects and Medical Applications of Nonionizing 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 Regulatory Agencies. Detailed information is available from the Director of the Summer Session, Room E19-356, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139. AP00023634 Such particles are found in "quartz-typical cells" very rarely or not at all. The authors nake no definite statement that the par ticles are PVPNO, but if they are, they were not stained by hematoxylin-eosin, aniline blue, silver impregnation or Pori*1 s' stain. Weller and Ullmer (Ann. A'.V Acad. Scl. 200, 624-632, 1972) mention only the presence of foam cells. I should recommend to try the Ammon-Mohn technique in FVPNO. 3. Polyvinyl chloride (PVC) There is an enormous technical literature on polyvinyl polymers; PVC is not mentioned in tho last 4 years of Medical Abstracts and I could not find any biomedical titles in Chemical Abstracts. How ever, Dr. Volkhcimer has studied PVC particles and their persorption (see G. Volkheimer's monograph "Persorption" G. Thiemo Verlag, Stuttgart, 1972). On p. 7 the PVC particles (globules) are depicted. The elimination of PVC globules (5-110 pn diameter)in the urine was detected already 1 hour after oral administration (Volkheimer et al., Deutsch. Gesundh. 20, 21-2S, 1965). PVC caused also liver damage (personal communication) apparently unusual cell proliferations sur rounding the globules. I don't know yet whether this observation has been published by the investigating pathologist; Volkheimer also told me that he did not succeed in staining PVC. Since colored AP00023635 4 plastics exist, also PVC derivatives, e.g. CaNa poly-(vinyl methyl cthcr-.v.nleato) one may liave to try histological staining procedures. The above named co-polymer is widely used in dental practice ^for fastening dental plates otc. and may easily be ingested. The monomer vinylchloride (VC) is a gas and is unlikely to form cell inclusions. Its toxic effect is evaluated by studying the cell injury. Publications on histochemical work have still to be checked; in the recent paper by Marstellcr et al. (Deutsch. Med. Vfschr. 913, 2311-2319, 1973) cytoplasmic inclusions of liver cells are not mentioned AP00023636 Letters Letters, if clearly marked 'Tor Publication," will be published as space permits and at the discretion of the editor. They should be typewritten double-spaced, with Jive or fewer references, should not exceed 500 words in length, and will be subject to editing. Letters are not acknowledged. of work remains to be done to make both natural and synthetic materials safer to use. W. R. SOOtMOK. PhD Conttnantal Oil Compuiy Ponca City. Okla 1. Ceraiifc BH, Ab&r EX: Tcxieity o{ pjntytis prod uct! at Tiojrl plixtiea. Arek funrcm Htaiik 19;15-21, im Polyvinyl Chloride In Fire* To the Editor.-The article "Polyvinyl Chloride Toxicity in Fires" by Dyer and Esch (235:393-397, 1976) contains a number of factual errors and cer tain misleading inferences. In three places, the combustion of polyvinyl chloride (PVC) is said to produce chlorine and phosgene. In fact, these two materials have never been demonstrated to occur in the py rolysis or combustion of PVC (Jour nal of Polymer Science 8:1887-1890, 1970; Journal ofApplied Polymer Sci ence 13:377-391,1969; British, Polymer Journal 3:186-193, 1971; Journal of Applied Chemistry 17:366, 1967). The authors point out, correctly, that hy drochloric acid and carbon monoxide are the main toxic combustion prod ucts of PVC but tie these to possible toxic synergy with chlorine or phos gene. It is wrong to raise the specter of toxicants which are not really there. In another instance, vinyl chlo ride is said to be produced. In work by Boettner et al (Journal of Applied Polymer Science 13:377-391, 1969), vi nyl chloride was found in the combus tion products of PVC corresponding to about 0.02% to 0.06% by weight of the original polymer. Carbon monox ide and HC1 were formed at about 45% and 58%, respectively. The vinyl chloride was thus present at a tiny fraction of the primary toxicants and may indeed represent residual vinyl chloride from the original poly merization. The present-day levels of residual vinyl chloride in PVC are .01 or less the levels typical in 1969, when Boettner's work was done. Thus, whether vinyl chloride is a combus tion product needs confirmation. A discussion of the fuel loading in fire situations owing to the presence of plastics carries the statement that ". .. plastics posses a heat of combus tion 214 times that of other combus tibles." The matter is not so simple. According to the National Bureau of Standards (Modem Plastics 52:81-82, 1975), the heats of combustion of PVC and some common materials, includ ing other plastics, are Edited by John . Archer, MO. Senior Editor Cotton PVC Wood Wool Polyester fiber Polyurethane Polyethylene 7,122-BTU/lb 7,720 BTU/lb 8,825 BTU/lb 8,972 BTU/lb 9,300 BTU/lb 16,000 BTU/lb 20,050 BTU/lb One can conclude from this that, on a pound-for-pound basis, PVC contrib utes less to fuel loading than many other materials in common use. The assignment of sk, flat 214-fold factor for plastics over other materials in heat of combustion is, to say the least, misleading. \ The authors cite work by Cornish and Abar1 on exposure of rats to CO and HC1 from pyrolysis in air or oxygen of pure and formulated PVC. This work pointed out that death from pure PVC pyrolysis was due to CO inhalation unless oxygen was added to the gas stream to keep car- boxyhemoglobin blood levels low. It should be noted that when PVC for mulated for wire insulation or floor tile was pyrolyzed, higher exposure levels were tolerated before death oc curred. Thus, formulated PVC is ap parently less toxic in fires than pure PVC and the former should be the subject of research rather than the latter, which is never used commer cially. The commercial impact of PVC ib exaggerated. The 8.3 billion kg/yr stated as the annual production in the United States translates to 17.6 bil lion kg/yr in contrast to the 3.7 bil lion kg/yr actually estimated for 1975 for all uses. Roughly 123 billion lb/yr of lumber and plywood were used for construction alone. Upholstered chairs are not stuffed with PVC, as claimed in the article. Chair covering is often PVC-based; the stuffing is usually rubber, urethane, or a nonsynthetic. We want to make it dear that we do not take lightly the potential prob lem that may occur from the combus tion of articles made from PVC. We stress, however, the need for dis semination of accurate information. It's reasonable to think that society can cope with the true problem, accu rately understood, as well as it has with the toxicity problems from con ventional materials. That means a lot Cardiac Care Units To the Editor.-Frieden and Cooper (235:816,1976) stated that "recent ex periences with monitored cardiac care units have demonstrated that mortal ity can be reduced in the first few days after an acute myocardial in farction." However, critical review of articles on coronary care units fails to confirm a properly designed trial that supports that statement. Adler et al (Br Med Bull 30:242, 1974), in a re view dealing with research on medi cal care, point out: Mortality within most coronary care units has declined over the years, but there has also been a parallel reduction in mortality in patients suffering from myocardial in farction, who are nursed In conventional wards (MacMillan & Brown, 1971). There is no evidence that hospitals play any part in altering the total picture of tie disease. In fact, the first randomized con trolled trial comparing home care vs that in cardiac care units (Mather et al cited by Adler et al Br Med J 3:334, 1971) showed no striking difference in case fatality ratios between groups treated in the two settings. There may be other impressive ad vantages to grouping patients, equip ment, and trained personnel in one location within the hospital setting. Grouping makes sense. However, re duced case fatality ratios have not been demonstrated. The conviction that cardiac care units are effective has been associated with the view that trials are not only unnecessary but unethical. It is un fortunate that rigorous evaluation was not carried out when units were first introduced, but British experi ence suggests that it is not too late to start. ROMKT osusonn, md MeGW Unlvareity Montreal In Reply.--It is important to delineate the perspective in which a situation is viewed. It is generally agreed that the majority of cardiac deaths occur early and. outside of hospitals. Our report and the reports of the cited authors deal with the subgroup of treated patients. I believe that one should first determine whether or not we are helping these patients. If we JAMA, Sept 27, 1976-Vol 236. No. 13 Letters 1449 AP00023637