Document e5gXqzqvQOd7xgeBV2znv9r7y

ITEM 3 7>:. COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE TECHNICAL PANEL, NOVEMBER IX, 1976, MR. MILTON FREIFELD 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 wlde-field capillary microscopy ol the hands of 152 workers In vinyl chloride (VC) polymerization plants demonstrated scat-' tered, scleroderma-like mlcrovascular 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 (angl sarcoma or fibrosis of liver, acroosteolysis, or scleroderma-like skin le sions) were observed to have mlcrovascular 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)., :` 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.*"1 Furthermore, animal From the Division ol Rneumatology and Im munology. Department ol Medicine. Medical University ol South Carolina, Charleston (Dra Mancq and LeRoy). The B. F. Goodrich Com pany. Akron, Ohio (Dr Johnson): and Continen tal Oil Company, Ponca City. OXIa (Or Whet stone). Reprint requests to Division ol Rheumatology and Immunology. Department ol Medicine. Med ical University of South Carolina. 80 Barra St, Charleston, SC 29401 (Dr Maricq). experiments have demonstrated that VC can produce a variety of tumors in rodents."-12 There are several similarities be tween VC disease and scleroderma (systemic sclerosis): Raynaud phe nomenon is prominent among the symptoms associated with AOL11 ,-'-11; localized scleroderma-like lesions have been reported in some patients with AOL1'"; and, in both VC-associ ated disease and scleroderma, smallblood-vessel lesions and interstitial fibrosis are thought to be important in pathogenesis.1"1211 In scleroderma, changes in small blood vessels of the skin have been observed in vivo by capillary microscopy.1*-1* Using the technique of widefield capillary microscopy, distinctive abnormal capillary patterns in the fingers 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." The possibility that VCassociated disease might be charac terized by tnicrovaseular 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) Are 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 23 years (mean, 15 years). A history' ofpast 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 by Question- 136* JAMA. Sept 20. 1976-Vol 236, No. 12 Capillary Abnormalities--Maricq et at BOR 010352 nairc (n" 108).--Those subjects wore selected on the basis of their answers t a questionnaire used in the poly vinyl chloride production plant to de tect early AOL. Ail available subjects who had given one or more affirma tive answers to the questionnaire *--(Q+) were examined, a total of G6 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-ficld 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 X12. 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 ab solute 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. Photography of Microvessels.--The aidefield photographic technique as previously described'* was used to 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.--All sub jects were interviewed as to length of em ployment, job assignment, general state of health, presence or absence of Raynaud phenomenon, and smoking and drinking Tabic 1.--Clinical Findings and Complaints of Group 1 Vinyl Chloride Workers' No. of Subiccls No. ol Sub- With Capillary feels Examined Changes! Severe AOL with Raynaud phenomenon 64 Scleroderma-like skin lesions with Raynaud phenomenon 54 Liver abnormalities? 65 Subtotal 17 13 Healed AOL with Raynaud phenomenon 60 Healed AOL without Raynaud phenomenon 10 Raynaud phenomenon atone 93 Nonspecific skin rashes without Raynaud phenomenon 7 1 Miscellaneous complaints 40 Subtotal 27 4 Total 44 17 *AOL indicates acroosteolysls. fOf 17 subjects with abnormal capillaries, ten had scattered changes (8/13 and 2/4 ot the two groups above) and seven had isolated changes. JTwo patients with angiosarcoma of the liver and one each with (1) portal fibrosis and en larged spleen, (2) portal fibrosis with early cirrhosis and fatty 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 of Capillary Observations Between VC Workers and Controls* Scattered capillary abnormalities Abnormal capillaries present, but tew in number No capillary abnormalities seen Total Employees of VC Industry 11 27 70 108 Manual Workers Not Exposed to VC 0 3 47 50 *VC Indicates vinyl chloride. Difference in the prevalence of capillary abnormalities be tween VC workers and controls is statistically significant (x1 = 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 Group 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; X1-H.21, P < .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). Croup 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 produc- BOR 0 1 0 3 5 3 JAMA. Sept 20.1976-Vol 236, No. 12 Capillaiy Abnormalities--Maricq et al 1369 .V'. 1 r ;ii - *vJ : '"-1 -^\,,v - .1 L > --> ' f i?****.* ^^ J Li- & ;> * *.: v, i 4 '. '' ***fi*, i U>?^ff%ia2X3K&>x3'<X'-T il Fig 2.--Lett, Dorsum of middle phalanx in normal subject. Center. Cluster of dilated capillaries in same anatomical site in patient-witn 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. BOR 010354 1370 JAMA, Sept 20, 1976-Vol 236. No. 12 Capillary Abnormalities--Mancq et al lion workers had fewer microvnscular abnormalities (11/22) ilian production workers (35/t>fi, x = -S-nt*. /' < .05); however, production workers showed no differences in capillary abnormal ities according to job category. There was no significant difference (x ,, = 1.32, P>.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 roentgenographic examination) and papular skin le sions, and ten workers with hepato megaly (4 cm or more below the right costal 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 Suhjccts.-Capillary abnor malities in group 2 VC workers were significantly more frequent than in the control manual workers examined (Xs = 15.50, P<.001) (Tahle 2). Anal}sis of Photographic Data.-- Three hundred seventeen uniden tified photographs of VC workers were mixed with 13(1 photographs <>f control subjects and 130 photographs of patients with sekroth rma and re lated diseases; all photographs were rated for the presence of capillary abnormalities. The results demon strated that significantly more VC workers (39/152) than control sub jects (3/50) had capillary abnormal ities (x; = 7.69, PC.01). Although ob jective, for technical reasons, photographs arc 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, scleroderma-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 fibrotic lesions can also be observed in VC workers. In 33^ of the subjects who show any capillar}' 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 subji i ts -how oven these minimal capillary al,nor malities. Since microvascular 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 mi crovascular 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 I.if.whultz Foundation. National Institutes of Health grant AM 1.'904, the South Carolina State appropriation for re search, and the RGK foundation. Irving J. Selikoff, MD. supplied 24 control industrial workers for capillary exammatinn, Karen Month, Eleanor Gattoni, and Villu Maricq provided technical assistance. 1. Harris DK, Adams WGF: Aero-osteolysis occurring in men engaged tn the polymerization of vinyl chloride. Br M>d J 3 712-714, 1967. 2. Wilson HH, McCormick WE, Tatum CF. ct aJt Occupational acroosteolysis: Report of 31 cases. /AA/A 201:377-351, 1967. 3. Dinman BD, Cook WA, Whilehouse WM, et al: Occupational acroosteolysis: I. An epidemio logical study. Arch Environ Health 22.61-73, 1971. 4. Falk H, Creech JL. Heath CW. et al: He patic disease among- workers at a vinyl chloride polymerization plant. JAMA 230.59-63, 1974. 5. Lange CK, Juhe S. Stein G. et al: Die Sogenannie Vm\l-chlorid-Krankhoit-tine berufsbedir.gte Systemsklcrose? Int Arch Arbeitrmcd 32:1-32. 1974. 6. Lilis R, Anderson H. Nicholson WJ, et al: Prevalence of disease among vinyl chlonde and polwinvl chloride workers, Ann XY Acad Sci 24622-41, 1975. 7. Marsteller HJ, Lelbach WK, Muller R, ct al: Unusual splenomegalic liver disease as evi- References dented by peritoneoscopy and guided liver hiopsy among polyvinyl chloride production workers. Ann XY Acad Sci 246 9.5-134, 1975. 8. Miller A, Teirstein AS, Chuang M, et ah Changes in pulmonary function in workers ex posed to vinyl chloride and polvvinjl chloride. Ann XY Acad Sci 246 43-52, 1975, 9. Suciu I, Prodan L, Ilea E, ct ah Clinical manifestations in vinyl chloride poisoning. Ann NY Acad Sn 246.53-69. 1975. 10. Thomas LB, Puppcr H. Eerk TD, et ah Vinyl-chlonde-induced liver disease: Frum idio pathic portal hypertension (Banti's syndrome) to angiosarcomas. X Engl J Med 292:17-22, 1975. 11. Viola PL. Bigotti A, Csputo A: Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31.516-522, 1971, 12. Maltoni C. Lefi-mino G: Carcinogenicity bioassass of \in\l chloride: Current results. Ann XY Aciid Sci 246 195-218, 1975. 13. Markowitz SS, McDonald CJ, Fethiere W, et ah Occupational acroosteolysis. Arch Derm 106.219-223, 1972. 14. Rodnan GP; Progressive systemic sclerosis (scleroderma) and calcinosis, in Hollander JL, McCarty DJ Jr (eds): Arthritis and Allied Con ditions. ed S. Philadelphia, Lea & Febigcr, 1972, pp 962-1605. 15. David E, Landau J: Clinical Capillary Mi crocopy Springfield, 111, Charles C Thomas Pub lisher, 1966. 16 Maricq HR, LeRoy EC: Patterns of finger capillary abnormalities in connective tissue dis ease hy widcfield microscopy. Arthritis Rheum 16.619-629, 1973. 17. Maricq HR, S|ioncer*Green G, LeP.oy EC: Relation entre la distribution dos rapi'laires anormaux et le degre d'envahisscment systf-mique dans la sclerodermic (nrogressivo general ist), J Sci Med Lille 93-2a3-2?6, 1975. 18. Maricq HR: "Wide-field'1 2p3ho4to5g6ra7phy of nailfold capillary bed and a scale of plexus visu alization scores (PVS). Microvase Res 2.335-340, 1970. BOR 010355 JAMA, Sept 20, 1976-Vol 236, No. 12 Capillary Abnormalities--Maricq et al 1371