Document o90DZjzmOk1Ln64ZgEqxyp6J7

R&S 105725 BIO-MEDICAL RESEARCH DOCUMENT DESCRIPTION FORM 63 68 69 0 0 0 0 0 0 476 Duplicate in all cards:--> mo year as-1961- dk / File number [Right justify (Numeric onlvl Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 20 21 ^ - i f\t'1 e 'k"' l L f' <h OTk/'/j_ Af_________ ; Do bbL-7 ~ <,bco X>o6>t-/r?.$C.LL. .__ fe-a.t'X'.a. (J 40 41 . 77______ 78 L tL Sub-Index Code 60 61 62 Title of Report; end with space-hyphen-hyphen-space. Follow with Index.Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 12 / * ' ( > C^/ 1 / , ,, ' f W/ - - /-difhcb-ClhC, ( `on*., cl-\rcLj-r : o 5 rf r? . ,t\ ^ <~id fib''hr! y'r nC / i ! r L erf ___ -- X- / k dj!/ib a df%n1 J1u- i i fit !, ' `s'!'! u :r 1 r^tt^Cr / ,' - <// s-- ------------------------:--------------------^--------7* -7 ,Ci-i n t'V'y "7------------------------------------?-- /' s~~- - 61 62 21 22 23 24 Source (Journal, Vol., Number, Pages, Date ) 12________________________________________________________________ __ cl. /nfer/uu, \jriu y)}^ D i, rJc cl , l>b: C fc.d-IY ft f Op. Ll 1 $ - d f A . / i! - -/____________ 61 62 31 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 # 1S6 . CLIN' ICO- PATHCCf.N IC CONSILTPATIONS o PliLNOV.LNOh' I**.' V.OKKtlflS Or Tlic POLYVINYL CMLOP.-i 0000004 zay.vaud 1 i.NDUoTr.Y Study Conducted at the* Unified Hospital of the City of Chcorghiu-Dej Dr. F. An^helescu, Dr. M. Otoiu, Dr. HJena Dobrincscu, Dr. L, Hagi-Parr.schiv-Doss i.os, Dr, Gh. Dobrincscu and Dr. Virginia Ganeu Translation of: "Considcratii clinico-patogonicc asupra fcnomenului Raynaud la muncitorii din industria poi ici orur ii dc vinil," Medicina Interr.a, Volume 21, No. 4, Bucharest, pp. 475-482 R&S 105726 The intensive development of the polyvinyl chloride industry throughout the world raises the question of the influence exerted by these m.acromolecular compounds on the organism, that is, the aspects of toxicology and vocational pathology generated by the process of production of these plastics. The specialised medical literature affords a fairly small body of data; studies relating to the pathogenic mechanism, the intermediate metabolism, and thetoxicology of the substances produced is still in a state of observation,' and the experimental data obtained with animals arc not fully in keeping with clinical findings. Polyvinyl chloride as a polymerisation product appears to bo inert from the physiological standpoint [15, 15, 17]. The occupational hr.cards associated with its production are generated by the monomer by intermediate or derivative chemical substances arising in the course of the manufacturing process [6, 12, 15]. Cases of dermatitis, irritation of the eyes, and pulmonary changes in workers handling the finished product have nevertheless been observed [13, IS]. Studies conducted by Smirnova, Filatova, and Danishevskiv (cited by Suciu fl7]) have shown that in the process of manufacture of polyvinyl chloride the monomer, vinyl chloride, is the element that exerts an aggressive effect on the organism, especially on the central nervous system and the higher vegetative centers. Patty [15] states that in high concentrations vinyl chloride leads to depression of the central cervcus system reaching the point of narcosis, while in small concentrations it produces a state of euphoria and hepatic and renal lesions, and in direct contact is an irritant to the skin. Peripheral vascular changes have been -observed in workers in the polyvinyl chloride industry and have >ocn analyzed by Suciu [17], who observed Raynaud's phenomenon in 6% of the workers examined,*whi1e Gabor and Raucher [7] observe it in 13.41) of the workers exposed to this agent. Filatova [o] describes acrocyanosis, capi-l-hivy vascular spasms, and dermograpiiia. Rex Wilson [IS] finds .phenomena of acroostoolysis in 31 of 3,000 workers examined at a polyvinyl. * chloride enterprise, 22 of whom exhibited Raynaud's phenomenon in one or both hands. The pnrhogi nosis of these peripheral vascular nan for.rations lias been i preted by Suciu [17] and Gabor [7] as a disordering of the vasomotor centers I the hypothalamus, acro.v.pnn ied by inhibition of their reactivity, and by Filatova [AJ as a gcti'-ral vi.-gcta* i ye dy; fount ion, with i predominance of vascular disorders, while; Re/. Wilson believes that the run i fe at at i on s of ncruos t eol ys is associated with Raynaud's ph'.'.v,-:*enon are venerate'! :>/ local chemical and physical action associated with an id iocyr.crat i c factor. .`I-ation is to be made of the fact that the authors cited above find haages of tb.e scl era-derma type at the level of the hands of workers exposed to the hazn;d. In the -studies referred to in the foregoing [7, 17, 1Z] the fact is emphe.-- zed that nan i testations of the angioneurotic type have not teen found in workers handling the id iiished product, polyvinyl chloride, or in those who convert the p-jiya.ur to plastic. Despite, all the studies conducted on the angioneurotic manifestations observed in workers in the poi> -inyl ch! ovi.de industry, the pathogenic aspect is still far from being clarified. In a dditi'on, no ether affection of the peripheral circulation has been the subi ect of greater controversy than the intermittent spasm of the digital artcri civs associated with changes in color of the skin of the fingers, the so-calle a Raynaud phenomenon. From the hypothesis advanced by Raynaud who explains the pat h:.\:.enesis rf the disease as hypertonia of the vasomotor tonus of central origin . to that advanced by Lewis (cited by Allen [1]) who asserts that the primary factor is a local vascular defect of the digital arteries, to the current tin- orics additionally involving enzyme disorders in the production and destruct ion of catechol amines at the vascular level, experimental clinical research ha s not produced sufficient evidence to confirm or invalidate any of the hypothc- scs. The purpose of the present study is to analyze the clinical-pathogenic aspects of Raynaud's phenomenon observed by us in a certain number of workers at a chemical plant producing polyvinyl chloride, a plant at which all stages of manufacture are concentrate; room prosaction or acetylene, tnrougn syntnesis of the monomer, vinyl chloride, to the finished product, polyvinyl chloride. The production process utilizes acetylene, which, by reacting with hydrochloric acid, forms vinyl chloride polymerized by two processes: emulsion and suspension. The resulting latex is removed from the residue of no:i-polymericed vinyl chloride and is then centrifuged in order to eliminate the vehicular solution, after which the polyvinyl chloride is dried and packed in sacks in the form of a powder. Materials and Method Three hundred workers and technicians are employed at tho plant at which we conducted the present study, in the process of product ion of the monomer and syntheses of the polymer. The^rdrpose of cur study was to detect those clearly exhibiting1 Raynaud1s phenomenon and to analyze the clinical aspects and the changes in vascular reactivity in these persons' as a function of the working conditions and tho hazards existing in the respective departments. We did not include in the study those exhibiting debatable cutaneous vasomotor symptoms Khich depend more on the endocrine habit or constitutional state; observation of these persons over a period of time and subsequent research will enable us to make an evaluation of the occupational makeup. We observed manifest Raynaud's phenomenon in $ workers, that is, in 2.7% of the total number of personnel. Of these d workers 3 are men and 5 women, R&S 105727 2- - 1 __ ____ _ monomer product ion department (vinyl chloride), which is in the open air, we encountered the affection in only 2 workers: a female worker (who takes samples for analysis of the monomer) arid a mechanic (who is employed in repairing and maintaining the machinery). The other 6 workers were employed in the polymer-suspension depart ment, 2 in centrifuging the latex and 4 in drying it, these being work stations at which the machinery is situated in closed buildings provided with a mechanical ventilation system and at which the monomer remaining unpolymericed is removed in appreciable amounts. * *7 . 52 1 ;.i s.t. D.V. C.C. T.V, P.F- D.F.. J.N. i C.D. 2 <0 a7 so 22 sz ;; 32 It TABLE 1. A Ct'Oi'.U 3 4 *'tl 5 s/* V.'J f n. .v.e.-.ft.* intcit, :a tJ -d <1 It ixr __ V, Mr.r.ontt/ 3 1 m-.r-..-.* 13 l\ rm.-.tr 9 d` :'r 14 v:c .t?c fMrd-.t & F. IJcia 10 O.-f-v.sr, , 14 F. Wen 10 14 cIiJ.v.M F. 10 cy'*:'`e\4 3G 2Z :i 21 m 215 333 17j III 1T5 131 551 135 13<. *:* 121 551 Lu. Pu timer H 0;-k ;.Ve*rw ee.Mrlfdsl 1). J.U.-a 10. C?; 15 31 m 130 112 131 Key: 1, Name of patient; 2, age (years); 3, sex; 4, work station; 5, occupation; 6, time till appearance of symptoms (months); 7, concentration of monomer at work stations, mg/m3; S, monomer; 9, polymer drying; 10, same; 11, polymer centriguge; 12, mechanic; 13, laborer; 14, chemical worker. Commas indicate decimal points. The production process divides the group of workers exhibiting Raynaud's phenomenon into 2 categories: those who were exposed only to the.action of a monomer, vinyl chloride, and those who were exposed to the monomer and the polymer. It is to be seen from Table 1 that analysis of the air at the work stations to determine the avaunt of vinvl chloride vieldcd values exceeding the`Admissible concentration of 30 mg/m-; the values range from 112 to 554 mg/m3. The survey conducted at the work stations also reveals that all these workers, because of the specific nature of the work stations, had the skin of their hands subjected to contact with' the' monomer or the polymer still containing 3 certain percentage of vinyl chloride. The 6 workers in the polymeritat ion-suspension department cleaned the drums of the driers or latex separation centrifuges manually, without using the gloves specified in the labor safety standards:* The clinical manifestations were characterised by the occurrence of inter mittent attacks of pallor aceonpanied by paresthesia and followeJ by cyanosis at the level of the skin of the iunds, and m 5 of the patients also at the level of thb. toes and heel (fable 2). In tlie case of the hands the phenomenon 3- - is manifested on all finders, includii:,". tlie thumb (Figure 1). Anamnesis established that with all the patients the crises begun during the cold season of the year, being initiated by cold or contact wit!; cold -water. In the case of one of the patients the crises occurred spontaneously during occupational activities, without the ambient temperature being low nr.-J without the patient coming into contact with cold objects. Emotional conditions -were not found to be implicated as the initiating factor, as is found to be tine case in the basic Raynaud's disease. R&S 105729 TABLE 2. *1 lfbffcld.yV'4#tt UHr*'f.t*: i :\ ;r I ** ` )b' f-.` .1. Ii f > 2 !3 ;r i-ii. 5 f* I*V-. '%I** C 1i t * * * *\ ft 7 G Key: 1, Raynaud's phenomenon in both hands; 2, Raynaud's phenomenon in hands and rest; 5, sclcrodermia in hands; 4, cutaneous micronodules; 5, hy.pcrhyurosi s; 6, fragmenta tion of phalanges; 7, cortical finning of phalanges. . Clinical examination of the shin revealed the skin of the hands of 5 of the patients to be slightly infiltrated and rough, presenting the aspect of sclercdernia, and the phenomenon of hynerhydrosis, ar.d in 3 of .the, patients micronodules on the dorsal surface of the hands and toes, nodules of the size of a pea situated in the thickness of the skin (Figure 2) (such nodules have also been described by Rex i'.'ilson [IS]) in one of the patients studied. We must emphasize that we encountered no scleroderma! changes at the level of the skin of the feet, even if Raynaud's phenomenon was also present in the feet. j\^:i \s \ :*.. ____ \v Figurc.l* A\\jj /;, .:<?/ .1 f -o'--* ' I . * * % *. .. , Figure 2. Radiological examination reveals phenomena of acroosteolysis: in 2 of the patients fragmentation of the last phalanx (Figure 3: fragmentation of the last phalanx of the middle finger of both'hanus is'observed, as well as cortical finning of the phalanges), aiuUfinning of the cortex of the phalanges in the remaining patients. Anamnesis cstabl.i-sht'd that none of the patients exhibited manifestations of the angioneurotic type in his collateral ancestry, and the symptomatology in tpiesti on occurred only after these patients started work in these jobs. Of th& R' patients only one was a smoker. X' -4- 1 R&S 105730 r* The endocrine constitutional picture of the patient was normal , the hasal metabolism rang in;' from *2' to +10^, and the menstrual cycl s of the women were normal. e pregnane/ occurring in one of the pa ents in no way modified the nature of the angiospastic attacks. ;/ i /.i Clinical examination of the cardio vascular apparatus reveals nothing V unusual, aside from arterial hypertension Figure 3. in 3 of the patients (37-0, the tension figures being 100/60 r-n Hg, both in clinostatism and in orthostatism. ECG examination revealed a normal picture: in 5 of the patients there v/erc minor flow disturbances in the right branch which fall within the physiological limits. Clinical examination of the peripheral circulation shows the arteries to be supple and the pulsation to be normal, as is also the oscillometry. Photo- electric plethysmography detected at the level of the distal phalanx of the fingers reveals a curve of normal morphology except for the attacks (Figure 4 A). During Raynaud's phenomenon the radial, cubital, tibial, and pedal arteries were palpated, but the photoplethysmogram snowed a linear trace, Byeground examination reveals arteriolar spasms in 4 of the patients (50?j), although 2 of them were hypertensive. From the neurologic standpoint the patients exhibit headaches and dizziness, and 3 of them also phenomena of hypersomnia. 5. 1., age 40 Ui ft' /.* (Illegible) /\/yv\/WNTvJ Clinical and biological tests relating to the hepatic function, the renal function, and the matabolism in general yielded normal results; the serum lability tests /vvw /\fWV weTe negative; the GPtransaminases ranged from 6 to 22 u.R.; the total proteins *1 ranged from 7 to S.4 gV, electrophoresis with serines from 56 to 70%, and the // Y-globulins from 10 to 16i;; the Sia test /VN/v/X was negative, and the cold agglutinin test also negative. The results of the Figure 4. Kunkel and Burnstcin dyslipidemia tests fell within normal limits, and the serum cholesterol between 171 and 200 mga. The other biological tests --hcmq.gr/im, V.S.i.L., glycenia, urea, creatinin, and urine, -test were normal. Pulmonary radiological examination of the thoracic duct and of the esophagus yielded normal results. . Because of the absence of clinical of biological tests for organic lesion of the vascular apparatus, and also because of the absence of pathological pro teins or cold agglutinins, our study was air.it.-d in 2 directions: study of the general and local reactivity of the vascular apparatus on the one hand, and the anatomiconnthologijtoT aspects provided by cutaneous biopsies taken at the level on the fingers on the other. Previous studies conducted bv Sue.iu [17], Gabor [7], and Filatova [6] indicated bo^h disturbance of vasomotor activity of the central type and changes '\1. N -s- 1 R&S 105731 of the vascular vegetative t/pc. hack of reactivity or paradoxical reaction to the cold pressor test was found by buciu (17J in *,rA of workers exposed to vinyl chloride, arterial hypotension bein;; recorded iii the worker's study. In our Study of persons exhibit in;.'. Raynaud' ; phenomenon we performed the following tests of vasomotoricity: 1. The cold pressor test, using atomized ethyl chloride for a period of oneminute on the inner surface of the forearm, over an area of 30 cm2. 2. Cutaneous thermometry at the level of the dorsal surface of the hands and feet before ar.d after tests involving the-heating of the torso in a light bath at 60 for a period of 30 minutes. 3. Local vasomotor reactivity to various pharmacodynamics. 4. -Study, with the aid of the photoplethysnograph, of the local arteriolar reflexes generated by postural endovascular pressure changes (described by Comdorella [3]), Vi'c found the cold pressor to be inverted in only 3 (37%) of the patients, there being observed in these persons a decrease of 10-15 mm Hg in the systolic and diastolic arterial tension (Figure 5). An increase in tension was observed fox the remainder of the patients, on the average 15 nm Hg for the systolic and 1 10 mm Hg for the diastolic, h'e must note that, although the spraying of ethyl chloride for one minute resulted in virtual freezing of the skin in the respective area of the forearm, Raynaud's phenomenon was not initiated during this test in any of our patients. The cutaneous thermometry performed under rest conditions at an ambient temperature of 20, registration being affected with a thermistor, yielded values of 29 to 35 at the level of the dorsal surface of the hand -and 29-33 at the level of the feet. Thermal dyssymnetry, with temperature differences of up to 1, were observed in 3 of the patients. One constant clinical element noted in 6 of the patients (75%) was a sub- l febrile state, the axillary temperature ranging from 37.2 to 37.4, this not being accounted for by other:pathogenic causes. Thermoregulation changes and subfebrile states were also observed by Filatov: h'e investigated the peripheral vascular reactivity by the method of indirect heating at a distance, measuring the cutaneous temperature at the level of the extremities. At the same time, we recorded the variations ju arterial tension during the test. .` For .this purpose we made use of a light bath generating a temperature of Ji0 which we applieJ to the torsos of t-he patients; the arms and legs remained uncovered., and the temperature is measured at their level every 2 minutes. The thermal curve recorded indicates a slight reactivity of the thermal regulator and vasomoWr center, increases in peripheral temperature of only 1-2* being observed after 30 minutes of heating (Figure 6). -6iiwi-Tamcv The arterial tension of 4 of the patients (50%) increased by 5-10 ran llg during the heating test, and regained unchanged in the other patients. Testing of the cutaneous reactivity to pharmacodynamic agents by Breitman1 s method (described by Gh. Lupu) with adrenalin, dionin, and histamine yielded the results presented in Table 5. The data in this table show that our patients exhibit local vascular hyper reactivity both to adrenalin and to histamine. The local histamine reaction was intense, the papilla coming to measure 5 to 7 cm in diameter in 50% of the patients and the reaction lasting as long as 5 hours. The arteriolar reactivity to endovascular postural changes were observed by means of the photoplethysmograp'n. The phenomena of arteriolar vasoconstriction and vasodilation produced by the posture of a segment explored were found to be normal (Figure 4 3); this demonstrates on the one hand the absence of organic affection at the level of the arteriolar wall, and on the other that the arteriolar reflectivity of the local axonal type is not impaired. .Temperature *. V I Si. j; t---- * 1 1 ` ` ` - Xxz 1 l J <t Sr.,:\ Figure 5. ------right anil ------ left arm ---- right leg le/rlcg Figure 6. As regards the anatomical pathological changes, thickening of the horny layer, tones of swelling of the conjunctive tissue of the derma accentuated at the level of the nodules, were observed in skin perforations taken at the level of the. fingers and of the previously described nodules. The presence of clear zone's* of'customary coloration, which proved to be due to an accumulation of acid mucopolysaccharides, was observed at the level of the papillae corii, Lymphopolyblnseic infiltrates sometimes arranged in trains arc observed in the thickness of the derma. , '1 TABLE o.' W1 %< Im* ;i r* ^ v > * ** c ^,nit P'.**;* 1 .1 .u...- I 10 ic: f-J li 1 so i.m )i:ihr..!bi li - PJ r. *,' i .'l r4.0 i o.m A i- 3 -- ; :-C3 C tv 0 10 u!':-t an.ee; d, latency ; >er i 4, minimum latency; S, maximum latency; 6, duration (seconds) ; 7, average duration; S,, minimum duration; 0, maximum duration; 10, adrenalin; 11, dionin; Id, histamine. 7- - R&S 105732 The zones with the cutaneous nodules described by us did not diffe v- r rom the surrounding tissue; the nodules merely represented re;; ions in which the r;od i f ications referred to absvc were intensified. The arterioles exhibited no ansto.v.ical pathological changes for increase in the amount of m.ucopolysaccharLdcs in the vascular wall. The patients were observed for a period of 1-1/2 years, and at the end of this time disappearance of the cutaneous nicronodul es were observed in 2 of then (2 months after change of job), and in 3 of the patients complete disappearance of Raynaud's phenomenon. In the other patients the vasospastic attacks persisted, but with much lower intensity; obvious improvement was achieved with adrenal -blocking medication of the guanetidinc sulfate type, in doses of 10 mg daily. Findings ' . The study conducted permits us to advance the opinion that Raynaud's phenomenor occurs in persons working in the production of polyvinyl chloride, the phenomenon being generated by the monomer, vinyl chloride, which exerts a general effect by inhalation and by local action. We believe the vasospastic attacks to be generated by exaggerated peripheral vascular reactivity to adrenergic chemical mediators, a hyperreactivity caused by disruption of the central vasomotoricity coordination mechanisms. The local hyperreactivity to adrenalin nnd the efficiency of adrenal-blocking medication strengthens this assumption. The local allergy phenomena generated by the monomers could also play a part in the functional vasomotor changes going to make up the factors referred to in the foregoing. The local hyperreactivity to histamine, as well as the fact that one of the workers exhibited attacks at his job when in contact with the noxious medium at normal ambient temperature, induces us to assign the allergic factor also 1:1 a role in the pathogenic mechanism. The appearance of the anatomical pathological changes at the level of the skin of the hands, the scleroderma, the cutaneous nodules, and the osseous changes revealed by radiology we interpret on the one hand as local irrigation disturbances generated by vasospasm, and on the other by the local direct, toxic or allergic, action of vinyl chloride. The possibility is not to be excluded that the toxic action is exerted locally, on the enzyme apparatus,' which degrades the adrenergic substances at the level of the arterial. R&S 105733 -The persistence of Raygnyd's phenomenon in some of the workers after change of jo"bs;is probably of the same pathogenic type as Raynaud's phenomenon appearing :! in persons working with tools producing vibrations, in which the phenomenon appears or persists oven after the workers have been removed from the noxious medium. There is probably an occurrence- of irreversible functional changes in the central or periphcral^yasomotoricity, as well as changes in the sensitivit; of the adrenergic vascular receptor. f The normal nspert-of arteriolar reflexes of the axonal type generated by postural pressure changes, as revealed by photoplethysmography, and the data supplied by cutaneous biopsy, enable us to reject the hypothesis of organic lesions of the arterioles. \N 105734 & wI \ BlBLIC^IiAl'ifY ` 1, AM > N. Ill'<1,., -- iV'tplior.'l VjmhI if c.Mi ; 3*.l! * < n.-vp(,-.v. r;..: r>._\ 3. IIC' \"41 V/, II -- ;; % `V.; t J1. i In; r. 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