Document rxLq1nvr2X10nJp9dZRDLxv9E

Hal, in reviewing some literature recently, I came across the following item in the Industrial Hygiene Digest (July 1976). Workers Exposed to Vinyl Chloride Exhibit Skin Disease Changes. Chemical and Engineering News 54; 20. June 14. 1976. " Workers exposed to vinyl chloride exhibit skin disease changes that accompany scleroderms-a form nf arthritis characterized by excess production of collagen. Dr. Hildegard R. Maricq of the Medical University of South Carolina: Charleston, told the annual scientific meeting of the Arthritis Foundation last week in Chicago that the finding may lead to a new model for studying scleroderma. It also may provide an early warning sign of vinvl chloride disease. Of 129 vinyl chloride plant employees studies bv Dr. Maricq. 17% had.definite skin capillary changes and 22.5% had minimal changes, but only 2% in a ` control group showed such changes. The vascular changes observed in the workers. Dr. Maricq savs, seems to precede the more serious forms ofvinyl chloridejiisease--angiosarcoma of the liver and acroosteolysis, a condition in which the tips of finger bones wear away. Have you ever noticed this disease manifested among the vinyl chloride workers? Do you feel that there is anything to Dr. Maricq's findings? Nothing is mentioned in the article as to what form of dermatosclerosis is implicated. I'm sure you have read about this finding, but if not, I thought you might be interested. FORM 503 - A R(iV 6-1-70 SL 072528 Capillary Abnormalities in Polyvinyl Chloride Production Workers Examination by In Vivo Microscopy Hildegard R. Maricq, MD; Maurice N. Johnson, MD; Charles L. Whetstone, MD; E. Carwile LeRoy, MD Examination by wide-field capillary microscopy of the hands of 152 workers in vinyl chloride (VC) polymerization plants demonstrated scat tered, scleroderma-like microvascular abnormalities in 21 workers and iso lated capillary abnormalities In 27, as compared with only three isolated ab normalities in 50 manual workers not exposed to vinyl chloride. Thirteen of 17 VC workers with objective evidence of VC-associated abnormalities (an giosarcoma or fibrosis of liver, acroosteolysis, or scleroderma-like skin le sions) were observed to have microvascular abnormalities. If prospective studies confirm the implications of this study, capillary mi croscopy may become a useful mass-screening procedure in the early de tection and prevention of VC-associated disease. (JAMA 236:1368-1371, 1976) INITIAL reports of human disease in which vinyl chloride (VC) has been implicated as pathogenetic were lim ited to descriptions of such peripheral changes-as distal phalangeal resorp tion, ie, acroosteolysis (AOL).' 3 Re cently, a systemic effect of VC has been suggested by an unusual pat tern of hepatic portal, intralobular, and capsular fibrosis; angiosarcoma of the liver; and pulmonary functional abnormalities suggesting early pul monary fibrosis, all of which occur more frequently among workers em ployed in polyvinyl chloride produc tion plants than among the general population.4 '" Furthermore, animal From the Division ol Rfieumaioloijy and ImmunoloQy, Dcpartmenl of Medicine, Merticj! University of Sooth Carolina, Charleston (Drs Maricq and LeRoy), The B F Goodrich Com pany, Akron, Ohio {Dr Johnson): and Confined' tat Oil Company, Ponca City, Okla (Dr Whet stone) Reprint requests to Division of Rheumatology and Immunology Department of Medicine, Med ical University of South Carolina. 80 Barre St. Charleston, SC 29401 (Dr Mancq). experiments have demonstrated that VC can produce a variety of tumors in rodents. There are several similarities be tween VC disease and scleroderma (systemic sclerosis): Raynaud phe nomenon is prominent among the symptoms associated with AOL1,,' r"'''"; localized scleroderma-like lesions have been reported in some patients with AOL'' and, in both VC-associ ated disease and scleroderma, smallblood-vessel lesions and interstitial fibrosis are thought to be important in pathogenesis."1'1 11 In scleroderma, changes in small blood vessels of the skin have been observed in vivo by capillary micros copy."'1" Using the technique of widefield capillary microscopy, distinctive abnormal capillary patterns in the lingers of patients with Raynaud syn drome and scleroderma have been demonstrated.'" Furthermore, a posi tive correlation is noted between the severity of capillary pattern abnor malities and multisystem involve ment in these connective-tissue dis orders.'7 The possibility that VCassociated disease might be charac terized by microvascular abnormal ities similar to those observed in scleroderma led to the present study of VC workers, using techniques of wide-field capillary microscopy. Thespecific questions of this study were the following: (1) Do symptomatic VC workers have fingor-skin-capil'.ary abnormalities? (2) Are the abnormal ities similar to or different from those seen in patients with idiopathic scleroderma and Raynaud syndrome? (3) Are microvascular abnormalities related to the type of VC-associated abnormality (peripheral vs systemic), especially liver abnormalities? (4) Arc microvascular abnormalities related to the nature and duration of VC-exposure? (5) Are microvascular abnor malities found in a control group of manual workers not exposed to VC? SUBJECTS VC Workers Selected by Symptoms (n = 44).--The 44 subjects in this group gave a history of symptoms and signs possibly related to VC exposure. They were 31- to 57-year-old men (mean age, 42 years) who had worked in Lite polyvinyl chloride industry for 5 to 23 years (mean, 15 years). A history of past reaetor-eleaning experier.ee (ranging from 0.2 to 8 years; mean, 2.5 years) was present in 35 of 44 workers. Table 1 shows the com plaints and the pathologic findings in group 1. VC Workers Selected by Question less JAMA, Sepl 20, 1976-Vol 236, No 12 Capillary Abnormalities--Maricq e: al Ituite (u -- MS).--These subjects were selected un the Itttsis of tlii'ir unswers to a ((tioKliimttaiiY used in tin; poly vinyl chloride production plant to de tect early AOL All available subjects who had given ore or inure nfhniintive answers to the quest ion uni re (Q + ) were examined, a total of 6(> subjects. Seventy-one subjects were examined from a random selection of those who had Riven negative an swers to all questions (Q-)- Data on 29 of the 137 subjects examined were excluded because of unreliable obser vations caused by skin injuries or deep pigmentation, leaving 10S em ployees (50 Q+ and 58 Q-) in this group. Control Manual Workers (n = 50).-- The possibility that repeated minor injuries associated with manual labor might contribute to the abnormal findings seen in VC workers led to the examination of workers from compa nies making neither VC nor polyvinyl chloride and hospital employees work ing as carpenters, truck drivers, and maintenance men, a total of 50 work ers. All were men and ranged in age from 19 to 62 years (mean age, 43 years). METHODS Witlc-fieltl Capillar) Microsctip).--The technique of wide-field capillary micros copy as previously reported"' consists of the observation of selected skin sites under immersion oil, using a stereo wide-field mi croscope at magnification x 12. Wide-field microscopy permits the detection of microvascular patterns, such as the presence and distribution of dilated or deformed microvcssels and the absence of capillary loops, without attempting to measure airsolute vessel dimensions. The technique is rapid and suitable for mass screening. Twelve standard sites were examined in each subject: four nailfolds and two each of the following sites: dorsum of the distal phalanx other than the nailfold, dorsum of the middle phalanx, dorsum of the proxi mal interphalangeal joint, and the finger pad. I'holtigrajiliy uf Micrinvv>ck.--The wideheld photographic technique ns previously described" was used to photograph at least one linger of each subject All photographs were coded Tor blind comparison of cnpil- lary findings in VC workers and control subjects. Clinic,il and Occupational Data.--All su!>jocts were interviewed as to length of em ployment, job assignment, general state of health, presence or absence of Kaynaud phenomenon, and smoking and drinking T.iblc 1.--Clinical Findings ;ind Cornplnints of Group 1 Vinyl Chloride Workers* No. ol Subject} No. Ol Sub- Wilh Capillary jccls Examined Changes!- Severe AOl will M./nnud phenomenon 4c 4 SclOfGUerm.vhko r.km losioni with R.iynaud phenomenon 54 Liver nbnormtilitiesp 65 Subtotal 17 13 Healed AOL with Rjynnud phenomenon 60 Healed AOl without Raynaud phenomenon 10 Raynaud phenomenon alone 93 Nonspecific skin rashe* without Raynaud phenomenon 7 1 Miscellaneous complaints A0 Subtotal 27 4 Total 44 17 'AOl indicates acroosteolysis. fOI 17 subjects with abnormal capillaries, ten had scattered changes (8/13 and 2/4 of the two groups above) and seven had isolated changes. tTwO patients with angiosarcoma ot tne liver and one each with (1) portal tibrosis and en larged spleen, (2) portal fibrosis with early cirrhosis and tatty metamorphosis, (3) thrombosis ot the splenic vein, mild liver damage, and reticuloendothelial cell hyperplasia. [A) tatty metamorphosis with focal capsular and subcapsular tibrosis and splenomegaly with vascular congestion. Table 2.---Comparison of Capillary Observations Between VC Workers and Controls* Scattered capillary abnormalities Abnormal capillaries present, but few in number No capillary abnormalities seen Total Employees ol VC Industry 11 27 70 108 Manual Workers Not Exposed to VC 0 3 47 50 *VC Indicates vinyl chloride. Ditlerence in the prevalence ot capillary abnormalities be tween VC workers and controls is statistically significant (x2 = 15,50, PC.001). habits. A limited physical examination was performed. All data were coded for later analysis and were unknown to the capil lary observer and photographer. RESULTS Croup 1 (VC Workers Selected by Symptoms).--Examination of group 1 subjects showed scattered capillary abnormalities similar to those found in scleroderma (Fig 1 and 2). Defi nitely dilated capillary loops were seen in the nailfold and in other fin ger sites, contrasting with the sur rounding normal vasculature. Pale avascular areas were frequently ob served. The capillary abnormalities were usually more discrete and less numerous than those seen in most pa tients with scleroderma They were seen more frequently in subjects with severe AOL. liver abnormalities (as defined in Table 1) and sclerodermalike lesions (13/17) than in those with healed AOL, nonspecific skin rashes, or Raynaud phenomenon alone (4/27; X' = 14.21, A* < .001). Moreover, 5 of 6 subjects with liver abnormalities ver ified by biopsy specimens had microvascular abnormalities (Table 1). In a few subjects, lesions resem bling mini versions of clinically vis ible papular skin lesions were ob served microscopically (Fig 3, left). In two subjects with active AOL, capil lary hemorrhages were observed un der the proximal nail plate in addi tion to the common type of "splinter hemorrhages" under the distal nail plate (Fig 3, center). Group 2 (VC Workers Selected by Questionnaire').--Dilated capillaries were observed in 38 of 108 group 2 workers; both the number and distri bution of dilated capillaries differed from those observed in most sclero derma patients. Many group 2 work ers had isolated, extremely dilated capillaries (Fig 3, right and Table 2). No correlation was found between the length of time employed as a reactorcleaner (or the length of time with the company) and the capillary abnor malities. Office and supervisory per sonnel who had never been procuc- JAMA, Sept 20. 1976-Vol 236, No. 12 Capillary Abnormalities--Maricq et al 1369 ee^'ts ^ as OliftA. <K ^ r^L- ^ss"^lvU^ N 'X Fig 1.--Top left, Wide-field view of nailfold area in normal sub ject. Bottom left, Nailfold capillaries of patient with sclero derma. Bottom right, Nailfold capillary pattern in worker of polyvinyl chloride production plant. Note similarity with pat tern seen in scleroderma patients. Fig 2.--Left, Dorsum of middle phalanx in normal subject. Center, Cluster of dilated capillaries in same anatomical site in patient with scleroderma. Right, Vinyl chloride worker with pattern similar to that seen in scleroderma. Fig 3 --Left, Miniplaque on dorsum of distal phalanx in VC worker with acroosteolysis (AOL). Cen ter, Capillary hemorrhages under both distal and proximal nail plate in a vinyl chloride (VC) worker with AOL. Right, Single extremely dilated capillary in nailfold of VC worker with liver abnormalities. 1370 JAMA. Sept 20, 1976-Vol 236, No. 12 Capillary Abnormalities--Maricq et al SL 072531 lion workers had fewer mierovaseular abnormalities (d/22) than production workers (35/Sf>, = 4 .'ll), )'<.0f>); however, production workers showed no dilforenees in capillary ahnormaiities according to joh category. There was no significant difference (x',it = 1.32, /*>.5) between employees who had been classified as Q+ or Q- on the basis of the questionnaire. It was noted, however, that there was little or no correlation between the re sponses regarding Raynaud phenom enon obtained from the questionnaire and those obtained from the inter view at the time of examination. Physical examination disclosed two workers with AOL (one "active" and one "healing" by rocntgenographic examination) and papular skin le sions, and ten workers with hepato megaly (4 cm or more below the right costa) margin). The subject with ac tive AOL showed scattered capillary changes, the subject with healing AOL had a "normal" capillary exami nation. There was no correlation be tween hepatomegaly and capillary findings. Comparison of VC Workers With Control Subjects.--Capillary abnor malities in group 2 VC workers were significantly more frequent than in the control manual workers examined (x1=2135.4505, *P7<.001) (Table 2). Analysis of Photographic Data,-- Three hundred seventeen uniden- tilled phologr iphs of VC workers were mixed will 13(1 photographs of eoiitrol snhjeels uni! 130 photographs of patients with scleroderma am! re lated diseases; all photographs were rated for the presence oT capillary abnormalities. The results demon strated that significantly more VC workers (30/152) than control sulr* jeets (3/50) had capillary abnormal ities (x;=7.f)0, /'<,01). Although ob jective, for technical reasons, photographs are slightly less sensi tive than direct observations in de tecting capillary abnormalities. COMMENT The results of this study demon strate that capillary abnormalities seen in the finger skin by in vivo mi croscopy are present in VC workers more frequently than in control sub jects. These capillary abnormalities are not exclusively related to pe ripheral pathological conditions such as AOL, sderoderma-like lesions of hands, and Raynaud phenomenon, but are also found in subjects with liver abnormalities (as defined in Table 1) and in subjects who have papular lesions elsewhere on the body. Microscopic papular or fibrotie lesions can also.be observed in VC workers. In 33% of the subjects who show any capillary changes, the pat tern appears similar to the microvascular, changes seen in scleroderma; in the remaining majority, changes consist. of a few dilated capillaries only; very few control subjects show even these minimal capillary abnor malities. Since mierovaseular changes occur more frequently than overt VCassociated pathologic conditions in VC workers, they may represent an early manifestation of the VC elTeet. More work is needed to determine the nature and evolution of such microvascular abnormalities, their rela tionship to VC-associated disease (as opposed to a transient reaction to VC exposure), and their relationship to the subject's susceptibility to VC dis ease. Further studies are also needed to compare the capillary changes re ported here with those seen in small blood vessels and endothelia of ani mals exposed to VC." Capillary mi croscopy might then be used as a re producible, noninvasivc technique to monitor VC workers and to identify VC-associated peripheral and visceral disease in susceptible individuals at an early and possibly preventable stage. This investigation was supported in part by the Charlotte and Sidney Lifschultz Foundation, National Institutes of Health grant AM 18904, the South Carolina Stale appropriation for re search, and the KGK foundation Irving J. Selikoir, Mil, supplied 24 control industrial workers for capillary cNuminalion. Karen Menth, Hieanor Gatloni, and Villu Marictf provided technical assistance. 1. Hams DK, Adams WGF: Aero-osteolysis occurring in men ongaKixl in the polymerization of vinyl chloride. Br Mnl J 3.712-714* 11*67* 2. Wilson RH, McCormick WE, Tatum OF, et al: Occupational acronsleolvsis: Report of 111 eases. JAMA 20hV?7-rXt, 1067 3. Dinman Ilf), Cook WA, WhiLchouhe WM, et al* Occupational ocroostco))sis* 1. An epidemio logical study. Arch Environ Jim IfII 2261 -73, 1971. 4. Falk H, Creech JL, Heath CW* et ah He patic disease amontf workers at a tinyl chloride polymerization plant JAMA 230 ofl-fiil, 11*74 5. Lanffo CE, Julio S. Stein G, el a!: Die fcotffnannto Vihyl-ch]tr'ui-KrunkhciL-eino hcrufshedin^lt' Rystrinsklerosc? Inf Arch /Jrhnt*wnl 32 l-TJ, 1**74 d Lths K, Andei`Mni II. NiehMsun W.l, el id' 1'ri`v,deuce of iliseu'-c .uium^ vijni i Monde and polj\ inyl chloride workers Amt A')* Ann! St I iWii 22- il. 107'> 7, MiirsUTter li.l, Kelhach WK, Muller K, eL al. Unusual splenonu'^.ihc liver di>cu>c as evi- References denced b\ peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers. /Inn NY Aim! So 2''.0:95-134, ISIS. 8. Miller A, Teirstcm AS. Chuang M, el al. Changes in pulmonary function in workers ex posed to vinyl chloride and polyvinyl chloride. Ann NY Am,I Sri 21f,'47-52. 1977. 9. Sucni I, I'rodan L, Ilea , cl al Clinical manifestations in vinyl chloride poisoning. Ann NY Amil Sri 240 53-69, 1975 10. Thomas LB, Popper II, Berk I'D, et al, Vinyl-chlonde-indured Uver disease, From idio pathic portal hypertension fB,inti's sv mlrfi-oe) to angiosarcomas Ar Emit./ Mrd 292 17-22, 1971. 11. Viola f*L, fligotti A, CapuLo A: Oncogenic response of rat skin, longs, and bones to vinyl chloride t'nvrrr /,'< , ,'i 1 7 1 n-722, 1971 ,11C MalLooi C, Lefeininc ll, ( amnogetiioily luuassa.vs of vinyl chloride; Current results, H NY Ar,III Si i 216:1' '5-21S, 197.7 1.1 Markon it-/ SS, Meilonald C.l, 1'etlncro W, el al; Oceupatlonal ncioostenlysis Airh llrnti lU6.219.ga3. 1972. 14 Ifodnau l!P` Progressive systemic sclerosis Isclerodermu) and calcinosis, ir, Hollander JL, McCarty D.J Jr feds). Arthritis cm/ Altirit Cunftitimiy, cd S. Philadelphia, Lea & Fchiger, 1972, pp W>2- 11X17. 15. David F,, Landau ,1; Clinirnl C'lt/ullnr,/ Mirrovvnp;; Kpnngliuld, 111, Charles C Thomas i'uli- lisher, 1966 16. Maricq HR, LcKny LC I'aUerns of finger capillary abnormalities in connective tissue cliscasc hv widcficld microscopy. Arthritis Rheum 16.619-029, 197:1 17. Mariaj Hit. Spencer-Green G, Loltoy HC: P.etnlion emre la distribution des capdiaircs aimrrnuus et ie degre d'env ahisscmenl systemI'pie dans la sclerodermic (progressive gCneralimV). ./ s-i hint i.nir !W.2s;t-2w;. 197.7 Is, Maria) Hit `'Wide-held" photography of nailfohl capillary bed ami a scale of ple.sws visw- aliaaljon scores (I'VS). ,Vo /urn,v AVs g tld.V-ti 11), 19711. \ JAMA, Sept 20, 1976-Vol 256, No 12 Capillary Abnormalities--Maricq et at 1371 SL 072532