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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 resorj)tion, ie, acroosteolysis.(AGL).1'1 Re cently, a systemic effect of VG 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.Furthermore, animal From the Division ol Rheumatology and Im munology, Department of Medicine. Medical University of South Carolina. Charleston (Drs Maricq and LeRoy), The B. F. Goodrich Com pany, Akron. Ohio (Dr Johnson); and Contmeotal 0*1 Company. Ponca City, Okia (Dr Whet stone) Reprmt requests to Division ot Rheumatology and Immunology. Department of Medicine, Medical University of South CaroJma, 80 Barre St, Charleston. SC 29401 (Dr Maricq) experiments have demonstrated that VC can produce a variety of tumors in rodents."'3 There are several similarities be tween VC disease and scleroderma (systemic sclerosis): Raynaud phe nomenon is prominent among the symptoms associated with AOL3 '1 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."'" " In scleroderma, changes in small blond 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 witli Raynaud syn drome and scleroderma have been demonstrated."1 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." 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. The* specific questions of this study were the following: (1) Do symptomatic VC workers have finger-skin-capillary 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 the polyvinyl chloride industry for 5 to 28 years (mean, 15 years). A history of past reactor-cleaning experience (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 1)V Question- 1368 JAMA. Sept 20. 1976-Vo! 236. No. 12 Capillary Abnormalities--Maricq et al SL 027981 it mi c |ti -- IUO).--I Ih'Se Slllijccl.x wore, '.scli-cted on the bnsis of their answers lo :i questionnaire used ill tin: jMilyvinyl chloride production plant to de led- early AOL. All availahle siihjods who hail given one or more allirmativc answers to tin; questionnaire (Q + ) were examined, a total of CO subjects. Seventy-one subjects were examined from a random selection of those who had given 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 108 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 Wide-field Capillary Microscopy.--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 mi crovessels and the. absence, of capillary loops, without attempting, to measure alisolute 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'liotugrapli) <>T Microvessels.--The widefield photographic technique as previously described" was used lo photograph at least one finger of each subject. All photographs were coded for blind comparison of capil- lary findings in VC workers and control subjects. Clinical and Occupational Data.--AH suls jects were interviewed as to length of em ployment, jol) assignment, general state of health, presence or absence of Kaynaud phenomenon, and smoking and drinking Table Findiocjs and Complaint ol Group 1 Vinyl Chloride Workers' No. ol Subjects No, of Sub With Capillary jects Examined Changest Seville AOL wiih H.iynnud phenomenon o< Sclorodorma-hko skin lesions with Raynaud phenomenon 54 Liver abnormalitiest 65 Subtotal - 17 13 Healed AOL with Raynaud phenomenon 60 Healed AOL without Raynaud phenomenon 10 Raynaud phenomenon alono 93 Nonspecific skin rashes without Raynaud phenomenon 7 1 Miscellaneous complaints 40 Subtotal 27 4 Total 44 17 . *AOL indicates acroosteolysis. fOI 17 subjecls with abnormal capillaries, ten had scattered changes (8/13 and 2/4 of tho two groups above) and seven had isolated changes. JTwo patients with angiosarcoma ol the liver and one each with (1) portal fibrosis and en larged spleen. (2) portal fibrosis with early cirrhosis and tatty metamorphosis, (3) thrombosis of the splenic vein, mild liver damage, and reticuloendothelial cell hyperplasia, (4) fatty metamorphosis with focal capsular and subcapsular fibrosis and splenomegaly with vascular congestion. Table 2.--Comparison ol Capillary Observations Between VC Workers and Controls* Scattered capillary abnormalities Abnormal capillaries present, but lew in number No capillary abnormalities seen Total Employees ol VC Industry 11 27 70 108 Manual Workars Nol Exposed to VC 0 3 47 SO *VC indicates vinyl chloride. Difference in the prevalence of capillary abnormalities be tween VC workers and controls is statistically significant (x* = 1S.S0, PC.OQ1). I 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 Group I (VC Workers Selected by Symptom*).--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 must pa tients with scleroderma. They were seen more frequently in subjects with severe AOL, liver abnormalities (as defined in Table 1) and scleroderma like lesions (13/17) than in those with healed AOL, nonspecific skin rashes, or Raynaud phenomenon alone (4/27; X'" = 14-iJl, /-l<.001). Moreover, 5 of C 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 tho 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 produc- JAMA. Sept 20. 1976-Vol 236, No, 12 SL 027982 Capiiiary Abnormalities--Maricq et at 1369 ^ v'cr' o l> (i_f ,,-(/ <k w~ "(6 l. (O-j-rTi wt is 11- (-|^t_ 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. 13/0 JAMA, Sept 20, 1976-Vol 236, No. 12 SL 027983 Capillary Abnormalities--Maricq et al lion workers had fewer microvustatlur tilted photographs of VC workers abnormalities (3/22) than production wore mixed with 120 photographs of workers (3fi/8(I, xJ = /b40, /'<.<>5); control subjects and 120 photographs however, production workers showed of patients with scleroderma and re no dilTerenees in capillary abnormal lated diseases; all photographs were ities according to job category. There rated for the presence of capillary was no significant difference (x',, = abnormalities. The results demon 1.32, /'> .5) between employees who strated that significantly more VC had been classified as Q+ or Q- on workers (29/152) than control so In the basis of the questionnaire. It was jects (3/50) had capillary abnormal noted, however, that there was little ities (x:*=7.09, /'<.01). Although ob or no correlation between the re jective, for technical reasons, sponses regarding Raynaud phenom photographs are slightly less sensi enon obtained from the questionnaire tive than direct observations in de and those obtained from the inter tecting capillary abnormalities. view at the time of examination. Physical examination disclosed two COMMENT workers with AOL (one "active" and The results of this study demon one "healing" by rocntgcnographic strate that capillary abnormalities examination) and papular skin le seen in the finger skin by in vivo mi sions, and ton workers with hepato croscopy are present in VC workers megaly (4 cm or more below the right more frequently than in control sub costal margin). The subject with ac jects. These capillary abnormalities tive AOL showed scattered capillary are not exclusively related to pe changes, the subject with healing ripheral pathological conditions such AOL had a "normal" capillary exami as AOL, scleroderma-like lesions nation. There was no correlation be of hands, and Raynaud phenomenon, tween hepatomegaly and capillary but are also found in subjects with findings. liver abnormalities (as defined in Comparison of VC Workers With Table 1) and in subjects who have Control Subjects.--Capillary abnor papular lesions elsewhere on the malities in group 2 VC workers were body. Microscopic papular or fibrotic significantly more frequent than in lesions can also,be observed in VC the control manual workers examined workers. In 33% of the subjects who (x" = 15.50, P< .001) (Table 2). show any capillary' changes, the pat Analysis of Photographic Data.-- tern appears similar to the micro- Three hundred seventeen uniden-1 2 3va4sc5u6lar7, changes seen in scleroderma; in the remaining majority, changes consist of a few diluted capillaries only; very few control subjects show even these minimal capillary abnor malities. Since mimwascular changes occur more frequently than overt VCassociated pathologic conditions in VC workers, they may represent an early manifestation of the VC effect. More work is needed to determine the nature and evolution of such miirovascular 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 lie used as a re producible, noninvasive technique to monitor VC workers and to identify VC-associated peripheral ami visceral disease in susceptible individuals at an early and possibly preventable stage. This investigation was sup|>ortcd in part by' the Charlotte and Sidney Lifschuttz Foundation, National Institutes of Health grant AM 1S904, the South Carolina Slate appropriation for re search, and the RGK foundation. Irving J. Sclikolf. MD. supplied 24 control industrial workers for capillar}* examination. Karen Month. Eleanor Gatloni.and Villa Maricq provided technical assistance. 1. Harris DR, Adams WGF: Acru-i>stcolysis occurring in men engaged in the polymerisation of vinyl chloride. Br Mot J 712-714. 1967. 2. Wilson RH, McCormick WE, Tatum CF, et al: Occupational acrooslcolysis: Rejiort of 31 cases. JAMA 201:577*561, 19117. 3. Dinman HD. Cook WA. Whitehouso WM, ct al: Occupational acrooslcolysis: I. An epidemio logical study. Arch Environ lltnllk 22:61-73, 1971. 4. Falk H, Creech JL, Heath CW, ct al: He patic disease among workers al a vinyl chloride polymerization plant. JAMA 23069-63. 1974. 5. Lange CE, Juhc S, Stein C, el al: Die sogenannte Vinyl-chlorid-Krankhcit-eine bcrurshodinglo Svstrtnsklcrosc? Int Arch Ar hitsinol 32.l-.Ti. 1974. 6. l.ilis II. Audi- rw*n 11. Nicholson W.l. et al: l'revidenee of disease among vinyl chloride and polyvinyl chloride workers. Ann AT Aoi,l Sii 246:22-41. 1973. 7. Marsteller 11.1, Lclharh WK, Muller II. et al: Unusual splenomegrtlic liver disease as evi- References dcnccd by peritoneoscopy ami guided liver biopsy among polyvinyl chloride production workers. Ann AT Acnrl Sri 246:95-134, 1975. 8. Miller A, Tcinrtein AS. Chuang M, ct al: Changes in pulmonary function in workers ex posed to vinyl chloride and polyvinyl chloride. Ann NY Acini Sri 216:45-52. 1975 9. Suciu I, I'rudan I,, [lea E, ct al: Clinical manifestations in vir.vl chloride poisoning. Ann NY Aonl Sri 246:53-69, 1975. 10. Thomas LH, Popper H, Berk I'D, et ah Vinyl-chloride-induecd liver disease; From idio pathic portal hypertension (Danti's syndrome) to angiosarcomas. N Engl./ Mot 292:17-22, 1975. 11. Viola I'l,, Higolli A, Cnpulo A: Oncogenic response of rat skin, lungs, and hones to vinyl chloride. Co tn-rr Ih n 31:516-522, 1971. 12. Malloni l\ Lefoininc li: Carcinogenicity hioassavs of vinyl chloride: Current results. .-Inn NY Actttl Sri 246:195-2IS, 1975. 13. Markowitz KK, McDonald C.l. Fctlncrc W, et al: Occupational acrooslcolysis. Arr/i Ili-rnt 106:219-223. 1972. 14. iiodnan (IP: Progressive systemic sclerosis (scleroderma) and calcinosis, in Hollander JL, McCarty DJ Jr (rds): Arthritis amt Alliot CnnHitimis, oil 8. Philadelphia, Loa & Fcbigcr. 1972. pp 962- 11X15. 15. David E, l-aridau J: CUuicat CapHturi/ Mi- msm/ii/. Springfield, III, Charles C Thomas J'ultlisher. 1966. 16. Marin) HR, Leltoy EC: Patterns of finger capillary abnormalities in connective tissue dis ease by widchthl microscopy. Arthritis Rheum 16.619*629. 1973. 17. Marini HR. Spencer-Green G. LcKoy EC: Relation entre la dislrilsmon des capillaires annrmaux et le degre d'envahissement sysU-uiiipic dans la sch'-rodermio (progressive gincraliscc). J Sri Mol l.illr 93:263-266. 1975. 1. Marini Hit: "Wide-field" photography of na n fold capillary hint and a scale of plexus visu alization scores (PVK). Mirrurusr Rrs 2:335-310, 19711, JAMA. Sept 20. 1976-Vot 236. No. 12 SL 027984 Capillary Abnormalities--Maricq et al 1371