Document yk39Vj21YXJ0rEk1w3JE7oxYn
; `Hi urn*
{ Cryoglobulinemia in Raynaud's Phenomenon due to Vinyl Chloride
H. LANGAUER-LEWOWICKA, Z. DUD2IAK, Z. BYCZKOWSKA. and J. MARKS
institute of Occupational Medicine in the Mining and Metallurgical industry, Sosnowiec, Department of Microbiology of Silesion Medical Academy, Katowice (Head of Institute: Prof. K. Szymczykievicz, M.D; Head of Clinical Department: Doc. K. Marek, M.D.,- Head of Department of Microbiology: Prof. J. Szaflarski, V.D.;
Received August 1, 1975 / Accepted October 2, 1975
Summary. Raynaud's phenomenon was described in 22 workers engaged in vi nyl chloride polymerization. Within this group, prodromal signs have been seen in 6 persons, typical Raynaud's syndrome in 10 persons. In the re call'd ng 6 persons in addition to Raynaud's phenomenon sierodermalike changes in upper extremities and acro-oct.eolysic of distal phalanges of fingers were observed.
immunoelectrophoretic findings displayed increase in the levels of orosomucoid, ceruloplasmin, total lipids, and lipoproteins. Latent cryo globulinemia, detectable after Sephadex G-200 filtraticn, was found in IS sera (81,6`t). The majority of precipitates was polyclonal, chiefly composed of immunoglobulin A and G. In 5 cases including '< with. ,, ;ro- osteolysis a substantial increase in serum igG level was seen. The authors express the opinion that Raynaud's phenomenon due to tin" toxic effect of vinyl chloride is conditioned by cryoglobulinemia. It is as sumed that tile toxic mechanism of vinyl chloride is due to disturbances in humoral resistance of the organism.
i.Vy words-. Vinyl chloride disease - Cryoglobulinemia - P.aynaui'j ti ..vm-
Raynaud's phenomenon is the most frequently observed symptom of vinyl chloride disease; consequently sclerodermalike skin changes particularly in distal parts of extremities, aeroj osteolysis of distal phalanges, trombocytopenia, periportal liver fibrosis accompanied by secondary esophageal varices and pulmonary insufficiency may be seen ^6,12,14,22].
Recently not only experimental investigations [_23' but also I clinical observations indicate, that vinyi chloride fv.c.) may I have carcinogenic properties y4,2.3,24].
197
R&S 114895
Rayn.tud's phenomenon appears to be the earliest symptom ct
putholojic disturbances caused by vinyl chloride intoxication-,,
The pathogenesis of vinyl chloride disease, and Raynaud's
phenomenon particularly, is unknown.
This caper presents results of studies or. pathogenesis of .
Raynaud'u phenomenon due to vinyl chloride.
*
MATERIALS ANb Mr.'THObS
4
Raynaud'sdisease has been found in 22 workers employed in
polymerization of vinyl chloride. There were 18 men and 4
women. Affected personnel ranged in age from 22-61 years
(average 14.2). Only 3 persons were over 50. The time of
professional exposure to v.c. varied between 2 and TO years
(average 4.7). At the time of medical examination, 15 people
have not been working with v.c. for periods of 2 weeks to
18 months. Five workers retired due to professional disease.
In all the patients general medical and neurologic examin
ation as well as capillaroscopy of nail beds were carried out.
The laboratory investigations have been directed toward
detecting changes in serum proteins. They included total seruns
protein concentration, paper electrophoresis, immunoelectro-
phoresis with estimation of prealbumin, orosomucoid, anti
tripsin, haptoglobin, ceruloplasmin, and transferin fractions-
Other immunologic studies covered heterologic antiglobulins
for sheep erythrocytes sensibilized with rabbit antibody (SSFm t
homo logic antiglobulins for latex covered with human gamma
globulin (latex fixation tesej, cold agglutinins f15J, cryo
globulins in serum detectable by spontaneous precipitation at
+4C, as well as latent cryoglobulins, detectable after fil
tration of the serum through .a Sephadex G-200 column and in
cubation of the effluent at +40C [8j.
The cryoglobulins were identified by their immunoglobulin
set-up by immunoelectrophoresis double diffusion precipi
tation in gel in micromodification according to Scheidegger
[21 j. For immunoglobulin identification specific antisera for
IgA, IgC,, lyM 'fliomed-Po!and have been used.
The concentrations of serum immunoglobulins A, G, M have
been determined by single radial diffusion method using Beh-
ringwerkc (CFR) partigen plates.
RESULTS
According to the degree of clinical changes, 3 groups of patients could be observed. They display, respectively: 1. prodromal signs of Raynaud's .phenomenon (n = 6);
2. typi3. Rayn
acro-os * Ther
tinued . to v.c. taneous' sensiti spasticloops c. part of ances h..
Amor. workint: fessior.,Apart f: naud's parts c curred . room to hyperex iodic pilla^JP
phic co. . skin ch\ mities: esthesi
Ther on the left tr jectivo Apart ysmal Giant ;< ; them a*: in dist or exc-. norma 1, tienth
Thr . muscul. acro-otients
Con quent r album!: album
^ypicalvRaynaud
'
-
>n:dauxdic, sa' t*ciiovv'n.* *-.>>^1,
'^3 Raynaud' s phenomenon acro-oste6lysis (n'= 6)
*"4-:
There were 6 people in the f irst group.;;' Four of- them con- -?
;is of
tinued working with v.c., and the other T remained unexposed
to v.c. for the last month. All patients reported that spon
taneous coldness provoked numbness as well as having hyper
sensitivity to cold. Capillaries of nail beds in 1 case were
spastic with atonic component, in another giqantic Raynaud's
loops could be seen. Apart from hypoesthesia of the dorsal
. o>-ed in
part of the hand in 1 patient, no other neurologic disturb
. and 4
ances have been found.
. 1 years
Among the 10 patients of the second group, 2 continued
: P.'.t! Of
working with v.c., the others were removed from the pro
'0 years
fessional exposure to v.c. for several weeks to 18 months.
i 5 people
Apart from the same troubles as in the first group, here Ray
vks to
naud's phenomenon was described as skin-blanching distal
: disease,
parts of upper and even lower extremities. This symptom oc
examin-
curred most frequently by coolinq, rarely spontaneously in
ntried out.
room temperature. The patients complained also of drowsiness,
: toward
hyperexcitability, pains in the heart area, dizziness, per
-.oral serum
iodic muscular and joint pains, stiffness of the hands. Ca
.-electro-
pillaries of nail beds were spastic in 7 persons, with atro
, anti-
phic component in 2 of them. There were moderate vegetative
fractions, skin changes in the distal parts of upp-. r and lower extre
lobulins
mities: the skin was unusually damp, cool, and pale. Hypo
.uody (S3E), esthesia of the fingers was found in 4 patients.
: ; gamna-
There were 6 persons in the third group; v of them retired
'>_ , cryo-
pion at
tr fil: and in-
on the grounds of suffering from professional disease and left the job with v.c. for periods from 6-18 months. Sub jective symptoms were similar to those in the previous group. Apart from skin-blanching the patients complained of parox
ysmal cyanosis and a feeling of stiffness of the fingers.
. jlobulin
Giant Raynaud's loops were observed in 3 persons, in 1 of
vc ipi-
them atrophic changes too. There were severe trophic troubles
--ldegger
in distal parts of extremities. The skin was cyanotic, dry,
isera for
or exceedingly damp, usually cold, fingers were thicker than
normal, distal phalanx swollen, cr shortened. In some pa
t x have
tients the matrix of the fingernails was lacking.
sing Beh-
Three patients had ropelike stiffening of the forearms,
muscular atrophy of hands and forearms. Roentgenograph really,
acro-osteolysis in distal phalanges of fingers in all 6 pa
tients has been found.
Concerning investigations of serum proteins the most fre
quent disturbances were cryoglobulinemia (53.8%), increased
albumin in Immunoelectrophoresis accompanied by uncnanqed
albumin to globulin ratio (63.6%), increase'.: or os v, n:oi d
R&S 114897
199
-jS
i i'
s-t. i Wr.
I
3} fio
C/3
4* 00 CO 00
(54.5'i) and ceruloplasmin (36.3%) fractions. The proteinogram
displayed a small drop in the a - and 3-globulir. fractions
(36.3%) and increased immunoglobulin IgG level (22.7%) (see
Table 1).
An increased level of total lipids (61%) and 1-lipoproteins
was noted as wall.
At the stage of prodromal signs of Raynaud's disease, cryo-
globulinemia was a general finding except in 1 parson. Immuno-
electrophoretic hyperalburainer.tia with normal albumin to globu
lin ratio was coexistent with a threefold increased oroso-
mucoid and a twofold increased ceruloplasmin level. In a
single case a substantial increase of the immunoglobulin IgM
("!Q.2 mg1-.) has been found (Table 2).
In advanced Raynaud's syndrome (second group), in addition
to Cryoglobulinemia (9x), the following changes were seen:
Increased orosomucoid (6x) and ceruloplasmin (4x), both in
creased and decreased haptoglobin, decreased 2~ and S-globu-
lins (4x), as well as a clear increase of the immunoglobulin
IgG level (2:<) (Table 3).
In the third group (sclerodcrmalike changes) again cryo
globulin was evident (4x) as well as increased orosomucoid
(3xj and ceruloplasmin (2x) . The drop in the j2" ard 6-globu
lins was more frequent (4x) . Special attention should be paid
to the increase of clans G immunoglobulins in 50% of the cases
of this group (Taule 4). In 2 sera no cryoprecipitates were
found.
One of the sera belonged to a worker whose exposure to v.c.
was stopped 18 months earlier. In the second case cryoprecipi-
tates had been positive 12 months earlier. Since then exposure
to-v.c. had been stopped as well.-
, -
.
...
.v
/
::v. .W-V
-A'J-'Vs-!
i<rut
4<J0
U o
JZ
T<30 8*
10 -oH
o
V
C
3 u
u a)
aao,
<D a (l - *C u
ft 0 U' u U5
oh
n y;
0 (D
on V rt
a o
0n w H- <
r h H* n ft J *
o U c Si
p rt
o
c
3 (fl
ao
P f--
fD a 3 3
w rt
1U c
cr i o O
S fD m
on
ft M H-
fD
aV Of SU
O a0
cr t
w H- c
fD a. i
Cn
t: Eu
ti D
0a
aj ^--' IU
01
ccr
tq J"*
M0
H- tr
3c
j
ft
tr ft
0 ft W
ro ID H* 3 3 1
3
ft
a & H*
rt H0 3
h a c M 1--
% u. St W tft
tr H* O fD
toa M 0 3 3 Hi
t~* 3 n
*
H* O rr
fD
3 ft VI O H "*
M
o
1
Ua4 |~ *
9
O
lQ X
/yr"rI'
c 3
3 t
O f
0 i
1 h-* t-- *u 0 Ko
0 rt fD H3 to
! J * *i t; M
-J P o
ftC*P O rt ft P- H-
-- 0 3 v> 3 0 fD W eQ
o ft
3
Trvt>lrt '2* vinyl chloride OLsenso. Ciinic<il data in patients with prodromal signs of Raynaud's phenomenon
oc
Cj foij ic-" oianCu
<OO'
p w
*N-> 3*H
aV3?4 ta
'rHa-4 H
xoa w
JJ 0
O' nfi O'
GH +<jy
. 'Hco-
0p 0p
ryaoaHH1 l
a r-f ud o H
Paper electrophoresis {%)
H g HX3J <
iHcH JH303 O
s< OJ 4<J3
CM
a
Immunoelectro- mg phoresis
c
N a
Gfril
Hi3J 0nt
U cu
cR3H XHI <
0o0HOtPft 0p o
HicoriH
tv
0 *J
a Xd
FUT) d Hoa U3PO
D 6! 6 26 5 ?4 -1 lo i 44 4
7 60 459 780 405 1050 414 820 4i;i 1440 718 1780 91(,
7.5 7.3 7.3 7. 1 7.3 7.3
71.0 69. G 68.6 72.0 69.0 58.5
29.0 2.41 30.4 2.28 31.8 2.13 2H.0 2.5/ J1 .O 2.22 41.5 1.40
3.3 3.1 3.7 4.2 1.2 3.1!
5.5 8. t 5.2 7.3 4.9 . 8.7 5 . i 7.1 5.ft 9.3 (1.4 13.9
14.0 14.6 15.5 11.2 12.7 15.2
0.62 N O. 58 N 0.55- H O. H / M O. 70 N 0.80 N
+i *N NN tN
N
N N 1327 NN N 1370 M t 1 370 N N 1 327 N N 1083
17C.5 -
218.2
- nl *J|
- . + '.i'-iS
177.2 257.6
127.7 fi
71.3
198.0 205.1
114.3 101.4
+ / r*
R&S 114899
`;^
j' W- . s n .4,' tjpm/m .'fr- it- { 'j
-' . * ' .'/ * /`
... rtf ,
R&S 114900
i*y:
Table 3. Vinyl chloride disease. Clinical data in patients with typical Raynaud's phenomenon
Paper electrophoresis {%)
c-
cr^
VS
M
S X> -H
Q,
0U1l
rl H
pVI H
00 a +J *0 w C*'
&
tn
in cC
H H
0) 0
+J
,0 0 V4
au
n0a-l
H
rH ' 4AJ3
1o m t-
Immunoelectro mg % phoresis
**oo00aH10uH1ft
HbcoH O'
H Hr1V<ao430I
+aJ X
uw031
S*1f
1 2 3
3 25 2.5 1040 540 7*6 66.0 >4.4 1.91 8.5 5.7 9.5 13.3 0.34 N t + N t 1415 138.5 77.1 + -
5 34 10
1780 873 7.6 67.9 32.1 2.11 3.8 4.7 6.6 17.0 0.50 N N f) N i 2166 227.0 194.0 + -
6 26 6
1360 585 7.9 57.0 43.3 1. 33 5.7 7.4 10.7 18.2 0.71 N N H K N 1591 351.0 170.8 + -
4 7 22 5
1000 441 6.9 66.2 33.8 1.95 3.1 4.3 7.4 19.0 0.39 N t + - - -
-
-
+-
i.v;:'.
5 11 51 5 6 12 23 3 7 13 25 3
HOO 450 7.9 64.5 35.5 1.01 3.5 6.5 800 325 8.6 74.5 25.5 2.92 2.5 4.6
1100 495 7.3 71.0 29.0 2.44 5.3 4.4
9.4 16.1 0.62 M t + + + 1924 265.5 141.8 + . 7.0 11 .4 0.62 N A 't * t 1546 281.6 77.1 + -
7.1 12.2 0.79 N + + N + 1501 289.8 101.4 + -
8 15 32 6
1440 756 6.9 72.0 28.0 2.57 3.6 5.2 9.2 10.0 0.88 N + N N N 1244 157.4 77.1 + -
9 20 41 4 io 23 26 4
1260 423 7.6 63.0 37.0 1.70 3.6 6.2 10.0 14.2 0.69 H +1
N N 1203 265.5 89.0 + -
940 342 6.3 65*0 35.0 1.85 4.7 7.5 9.2 13.6 0.89 t H N N N 1083 219.6 77.1 - -
,,*rl
*,*<**>
fable 4 Vinyl chloride disease. Clinical data in patients with Raynaud's phenomenon, sclerodermia-like changes and acro-
mmm r5
-fc *;
li e > '
wi+.'VSS
10 23 26 4
940 342 6.3 65.0 35.C
I 85 4.7 7.5. 3.2 13.6 0.89 4 H H H ft 10B3 21?
b7.i f-i' i'*Jav*S5:
- . :*. 1 ' . ; ;
..........itl
:> 1 r Table A
i iw .................
'r' i' J
l!-, t- .
.1' . ..'r-'J ' -,.i.it->i.
i V.fcK L`tl.
Vinyl
chloride
disease,
Clinical
data
In
patients
with
Raynaud's
phenomenon,
sclerodermla- like
changes
-- - - 7* y/i and aero-. *taa3
osteolysis
. *. *' - iKfJ1 trtnf?&.ht<,Hi-s5b:.
^ Paper electrophoresis (%)
Immunoelectro- mg t
phoresis
o, &
C
-Ch
e
5-ourt e-aho -<tn
Jh33 -chs 3oa woq> <(o-1t,
"5 9 +j 3
A O ft H O
iP*i fdi oJs t#e - o w&
m osq
8 56 6 1440 765 7.6 68.3 31.7 2.15 3.6 5.4 9 31 2 BBO 297 7.6 67.2 32.0 2.04 3.7 4.1 10 39 3 940 449 8.2 71.3 28.2 2.54 2.7 3.8 18 36 2 1190 666 8.25 74.0 26.0 2.84 2.2 4.1
8.3 14.4 0.62 N t1 H N U 1778 163.9 178.4 'i+A 7.2 17.0 0.43 N N | tJ H 2012 351.0 170.0 7.6 14.1 0.46 N 4| N N N 2166 265.5 107.8'^"1 7,2 12.5 0.50 N 4 4 4 4 1285 163.9 71.3 .|;+|
22 30 5 1110 540 7.9 63.2 36.8 1.71 4.2 6.6 10.4 15.fi 0.69 N N 4i N N 1370 298.1 155-9xf
24 27 4
920 441 6.6 61.0 39.0 1.56 5.6 8.8
8.6
16.0 0.90
NN
1
N
4 t
1546
177.2
155.9.],
t fyjt 4.:ri-- ,
''-`'V T -
R&S 114901
' *T*yjh
1 v*~
1 TV* V4
th in:..- <if the i nvest. igut ed cases were cold agglutinins
largei
loued. in'jvleetrophoretic identification of 12 cryoprecipi"
rales waj,oi-formed using anti-IgA, anti-IgO, and anti-IgM
sera. `i'i.u remuinine 6 ccyoprecipitates have not been invest!"
gate.! 1.cause ol' the small amounts of cryoglobulins obtained,
ir.is van
evident in the third group fTable 4).
. :/(,; r`vi ;-i i at.es wore monoclonal, that: is composed of
l i Ly; * ho other 10 were polyclonal. They were com-
Rayna. periov nature
[2].
Ththe o* ductio
s.c.,'.-1 o; class A, d, and N immunoglobulins m 1 case, in the
of iirr,
rOK iii.it: ; ones a clear IgA + fgG band was visible. It should fj t, \.t V-*' * *. hat crycprecipitation was present in fractions 5-12 of sera bolonuing to the first group, in fractions 5-11 in tie seo."id one and in fractions 5-8 exclusively in the third
globu ation
Than ism
i rerun.
Rayna u
nolog::
the fi:
DISCCSS ION
the ca
It follows from these observations that Raynaud's phenomenon
scribe naud's
is the dominant clinical sign in vinyl chloride intoxication
where.ii
3J. Raynaud's phenomenon is known as accompanying many sys
with
temic diseases especially those marked as autoaggression dis
like
eases oonditionnod by alterations in the reactivity of the organism 8,9^..
scribe of 7 p
The moat frequent cause of apparent pathologic changes
coproi
during cooling down are cryoglobulins or cold agglutinins plOj. The presence of cryoglobulins at great concentrations
which eases
is manifested by a characteristic clinical picture: In ad
proces.
dition to Raynaud's phenomenon, aseptic finger necrosis, and
Acc
skin u 1 ee ill i oris, other symptoms such as stasis in the reti
is sti:-
nal blood vessels, haemorrhagic diathesis, ar.d alterations in
other
blood vessels of the lungs, the kidney, the coronaries, and ever, brain, and trophic nerve trunk vessels can be seen [1,4, 5, i y j .
eluded in peo [4].
The similarity in syndrome between chronic vinyl chloride intoxication and the above described cryoglobulinemia prompted
Inv toxica
the search for a connection between the 2 diseases. The in-
It mat-
vcitigat ion confirmed this assumption. Cryoglobulins were
cess fu
found in the sera of 81 'i of cases examined. According to nu
merous authors, spontaneous and latent cryoprecupitaticn may
be distinguished ^S,16j. The latter does not result in a spon
REFEP.et
taneous precipitation in scrum after cooling. It can only be
detected after filtration through a Sephaaex G-2CO column.
1. Ab.-n
In this investigation latent crvoprccipitation in serum
vase
was found exclusively.
2. Biij
The polyclonal character of most cryoprecipitates testifies
veil
undoubtedly to their pathologic nature MOj. Quantitatively
r,,'-d ,.i.
8SA11
* vJ&EKff'*lf-
' ^Hprecipi-
: j-igw iestiLned.
.Bed of re comin the should ;ns 5-12
1 1 in third
'.onancn ,cation *t y s y s /jr: dis; the
: loride prompted
t Raynaud's phenomenon;, it|receded -inlihcase. after `a.'12imonthsAp^ period. These observations are in1 accord with the;-t.ransioh^^v'^^
nature of cryoglobulinemia in different pathologic conditions t
W- -
1 The presence of cryoglobulins shows that the reactivity of
the organism has been altered. It is assumed that the pro
duction of cryoglobulins is caused by a fault in the synthesis ; of immunoglobin l 1,173- Mst probably the engagement of anti
globulin antibodies arising in the process of hycorimmuniz-
ation plays also an important role [10_! .
These considerations justify the assumption * hat the mech
anism of the toxic effect of vinyl chloride in qor.'~ral and of
Raynaud's phenomenon in particular lies in the altered imnuy
nologic response of the organism. This is also confirmed by
the finding of increased serum immunoglobulin levels both in
the cases mentioned in this report as well as in those de-
| scribed by Lange et al. [j 5j - In the prodromal period of Ray
naud's syndrome a net increase of IqM in 1 cnsr war soon
'
whereas increased class IgG levels were observed
patients
' with advanced pathologic symptoms, particularly scleroderma-
like changes and acro-osteolysis. Similarly, in the cases doI scribed by Lange et al., high IgG levels were found in G out
; of 7 persons with acro-osteolysis. The increase of serum gly-
* coproteins as well as of orosomucoid and ceruloplasmin levels
! which are considered a sign of exacerbation in collagen dis
eases may also be interpreted as signs of a general .pathologic process [7].
According to the authors' observations the humoral immunity
: is stimulated under the toxic action cf vinyl chloride. On the
j other hand, participation of cellular inununity may not be ex! eluded if we keep in mind the generation of malignant tumors
; in people exposed to vinyl chloride (liver angiosarcomata) i f 1 l L-J
' Investigations on the pathogenesis of vinyl chloride in
toxication should be continued not only for theoretic reasens. j it may be anticipated that this will create a basin t'orsuc; cessful treatment and prophylaxis.
references
e-> t i f ies : vely
I. Abram.sky, o,,
ishn-.u, Y., :,,n-y, ; c,y
vascular d.rideut. Ccnfin.ucuro1.
.u!-.
Bird, ]., Kalcicr, I., THruk, i..: "2z c.t.y. vpnorool. 2, lr.9-1()3 i i
1 . ..or rp*i
i/
205
I
R&S 114903
A.'
/
Oik
'I. C;> ;;, .1.1,., .Johns ci. M.N.: Angiosarcoma of live; m i o.` i - lyvinvl chloride. J.occvp.Med. 16, 150-151 (!9~4)
atrudnionytl 464 (1974) ; manufacture
len.a wit!* 4 J.Dent. 3^.
cropethie *
j,wj yvinyliqu. profess tone lie. 3ull .Dermato leg.Syphi 1 igrap. 79,
I 7 7-I ft, i ! 1` V
7. i,.' ..c , M. , K :-_harn, E. : Cer'J I op I a zta i::a w werunkcteh prawidiewyeh 1
sT:ri patoicgieznych. Wiad.Lek. 26, 1505-1 503 (1 ?~ 3>
3 IX: he i -.V,, 2..- Czyunik reu.'.id toiua1 ny a antvpr zeciwci a-Ta . Praca habiii"
tricyjr.-i, Zabrze 11967)
9. Dudeick, 3.: Spontaniczna ptecypitacja czyr.nika reu.~atoi.ialr.ego z
surowic lud/.l.L.-h w trakcie f iltracji poprzez koluirnc Sephadex G-20C-.
* '
i
XVI. Xj mi Tow. Mikrobielogow, Lublin (1967)
'. vi;i;:s, 3.; Kri~1 ohul i n er. i d a przectvciafa antvgltbulinowe. Pol.Tyg. c. XI, 1193 11973;
11. o-
ij, I..K., Harnett, K.V. : Essential cryoglobulinemia. Arch.Int.
Mi; 1. j_23, 155-150 (1970)
12. Hair is, D.K., Aiiru, W.G.F. : Aero-osteolysis occurring in men engaged ^
i.'. polym-:: .ration or vinyl chloride. Brit.med.J. _3, 712-714
i i; 1
li. - Ji , X., Air. j", c.i;.: EkU'i i.iormie-artige Haiitvor.'lnderuiiaon, Ray-
i i ,V< t oosreolysen bei Arboltorn dvr P.'Ohutstellender.
Ind i:;i r io. o: . . h.m-'-.J.Wsv hr. 9j, 1922-1923 (1972)
14. 1-tamer. G.G. , Matohler, J.E.: The correlation c: clinical and envirorc
mental me isus ..taut s for workers exposed to vinyl chloride. Amor. ir.dustr-
Hyg.Ass.j. i_i, 19-30 (1972)
:
I". K: ... /yr.r.ki , J., i. Lhsk i , T. : 1, iboratoryjr.o metody diogr.ostyczne.
V.' irs.'.jWd: P'. IV.' : 2 A
!G. Lange, C.E., Juhe, 5., Stein, G., Veltmar., G. : Die soger.annte Vinyl-
chi* ;; .J-Krunkneit - eine hurufsbedingto Systems'*lemse? Int.Arch.Ar-
boitsi'.e-J. 32, 1 - i.: (1974)
17. I.err.or, A.B., 9;rr.ur:, C.P. , Watson, C.J.: Studies of cryoglobulins.
II. The sr,onto .our. precipitation on protein ftoir, serum at 5C in various nisease states. Alter.J.red.Sci. 214, 416-41? (1947)
13. Meitner, M., iranklin, E.C.: Cryoglobulinemia - A study of twentynine patients. I. igG and igM cryoglobulins and factors affecting
>
cryoproeipitabi1ity. Amer.J.Med. 40, 328-333 (1966)
19. Ravenna, C., Testa, G.F.: Polyneuritis in essential Cryoglobulinemia:
a cljr.ical irc.vjnoelsctrophoretic and electromyographic study with
report cf acase.Europ.Neurol. _7 241-264 (1972)
,
20. Rit;'.Tciu:*, st.E., Levin, w.C.: Cryopathics: A review. Arch.Int.Med.
-107,754-772 (1761) 1-
1 ,
' '`V` '< `f'/l" .\v? A` >
- :.
) l i
rfaaBtS
21. Sc: Ar
22. Sr. by
23. Ta ma So
24. Vi (1
25. Vi le
Dr, H. Wolnos 41-80:.: