Document Rwb0jEmZ34KNzOw7mdaz8OQ7

MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE, N.W. WASHINGTON, 0. C. 20009 (202) 483-6126 September 30, 1975 TO: Vinyl Chloride Technical Panel Gentlemen: In addition to the minutes of the September 9, 1975 meeting, enclosed, please find the following: 1. August 21 letter from Ralph Wands regarding the proposed 1976 international conference on vinyl chloride, 2. "Biological Reactivity of PVC Dust" from "Nature," vol. 256, August 21, 1975. 3. Table 1 from NIOSH, August 27, 1975, on "Reported Cases of Angiosarcoma of the Liver Among Vinyl Chloride Polymerization Workers." 4. Cover page and abstract from EPA's "Atmospheric Oxidation of Chlorinated Ethylenes" by Bruce w. Gay, Jz.r et al. 5. Description and cover page from OSHA pamphlet 2225 on Vinyl Chloride from their Job Health Hazard Series. Under separate cover, please find Industrial BIO-TEST Laboratories' 23-Month Status Summary on "Chronic Vapor Inhalation Toxicity Study with Vinyl Chloride (Ethylene Derived) in Albino Rats, Albino Mice and Golden Hamsters," September 23, 1975. An additional status report from IBT on histopathology is expected shortly. Sincerely, MF/etv Attachments Milton Freifeld Project Manager AUG 2 51375 NATIONAL RESEARCH COUNCIL ASSEMBLY OF LIFE SCIENCES an Conitituttod AvtKM Waiiiinften, 0. C- mil ADVISORY CENTER ON TOXICOLOGY 008 309-4751 21 August 1975 Mr. Albert C. Clark Vice President Technical Director Manufacturing Chemists Association, Inc. 1625 Connecticut Avenue, N.W. Washington, DC 20009 Dear Mr. Clark: You are cordially invited to participate in a new program of the HRC Committee on Toxicology. The Canaiittee plans to launch a major long-term program to foster the prompt, world-wide exchange of information on the health aspects of vinyl chloride and other compounds having similar biological or physicochemical properties. The initial effort will include an international meeting on current research. We expect it to be sponsored by one or more U.S. organizations and the Instltuto di Oncologia e Centro Tumor! of the University of Bologna, Italy. We plan to hold this meeting in the next 6-9 months. There will also be a series of frequent mailings of current reports and publications which we will also submit to the Toxicology Information Pro gram of the National Library of Medicine. We would appreciate your assistance by supplying us with names, addresses, and telephone numbers of anyone in your organization having an active, scientific interest in the program. Suggestions of persons outside your organization will also be appreciated. This project was approved by the Governing Board of the NRC on August 9, 1975. We have been assured of funding for this program and expect the contract negotiations to be completed shortly. In the meantime, we would be glad to receive your consents , suggestions, and contributions related to this Information exchange program. Cordially yours. ) RCW:wh Ralph C. Wands, Director Advisory Center on Toxicology RSV 0001463 Tha National Reeearch Council is the principal operating agency of the National Academy of Science* end the National Academy of Engineering to aaroa government and other organization* <(4 rcgrowthi of a peripheral nerv ads to a remarkable overproduction of Schwann cells in the distal nerve slump reaching a point ar which these cells are applied in multiple layers around each single axon. Also, in crush lesions of the abnormal ; criphcral nerve roots of dystrophic mice, where a paucity of Schwann cells and myelin segments provides much less degen erating material than in normal nerve, an increase in the number of myelin segments and. presumably. Schwann cells is minced by crush injury7. The (importance of the axon in provoking Schwann cell proliferation is also indicated by observations, on the proximal slump of severed or crushed sciatic nerve, that proliferation occurx independently of widespread nerve fibre or myelin degeneration and in con ditions in \\ hich nerve rcgcncrat ion is most actively occurring*. Our observation oftheaxon-Schwann cell interaction result ing in rnitogenesis illustrates one t.se of cultures containing either 'pure' Schwann cell populations or bare neuriie pre parations. These preparations may be useful in further analysis of the interaction between ncunic and Schwann cell, as well as in studies of the basic properties of the Schwann cell itself. This work was supported hv the National Multiple Sclerosis Society. Pathick M. Wood Richard P. Beset Department of Anatomy, Washington University School of Medicine, Sr Laois. Missouri 63!it) 'thrived Mjy *2: Mcer-ed June 16. 197?. ` I'ivihtMcY < D.. 0,-r! H-nt., 2S. 407 M9*2>. - Bun^e. R . Kk. R . WooJ p.. IViriim. H.. and K. C. -P . Brum M, 401 i1174' ' Murray. \T., juil Sl'UI. A. P.. Am. J. Fuih.. 16. 41 119491. 4 (lunge. R P,, 4nU Wood. P. M.. Hrutn Hex.. SI. 2M |I97J). ' Cj.mv, (' , re Cell i>1 Si Ii-'im* i l.is I.Jiiihurgh and London. I MOL * Thomas, i*. X... t. Amu.. 106. *n.t t iv'iti. ` St.di'rglijnns. .J.Cr. A.. trr./m Hex . Rd-Htfr. R. . *7. I JO HV71. J.. and Barr. M. L-. J. Amu.. Biological reactivity of PVC dust '"oncers has been expressed about the biological potential of .viyvinyl chloride (PVC) and its associated monomer vinyl chloride monomer <VCM)`. During the industrial processing >f PVC. workers can he exposed to varying quantities of this material in the form of a dust. At the present time, however, here is little detailed biological nr biochemical information on he effects of inhaled or ingested PVC. or on the reactivity of this dust material. The biological reactivity of other dusts <`Mlica, asbestos) have been studied by a haemolysis technique1 which is useful for assessing the degree of membrane-induced damage by a variety of toxic materials. Other in vitro screening systems using lung1 and other cells' have also provided useful information on structural and biochemical changes induced by particulate matter. Here we report on the haemolytic potential >'f PN C dust, comparison of which is made with the highh haemolytic and biologically reactive chrysotile asbestos A tUICC standard reference sample) and the eltcci of PVC on iung fibroblast cultures. The haemolysis technique used has been described in detail previously*. The degree of haemolysis was expressed as a percentage of the totally lysed sample and the results presented as the means and ranges (if any) of. at least, quadruplicate issays. Two samples of PVC were tested (KM I and KM2) botn of which were obtained as lincly-Jivided dried powders which had been formed by standard processing procedures for use rn fabrication work. The first sample (KM l) was highly haemolytic at relatively low concentrations, 100% haemolysis (over 50 min) beim tchievcd by between 7.5 and IQmg of dust (Fig. I<>). With increas mg concentrations of PVC, haemolysis seems io be reduces* "ut this effect is most likely the result of some of the release'1 haemoglobin bind ng to the dust, which is then spun down ini the pellet Sample KM 2 PVC was found to be practically no*- Suture Vof. Aukuu 21 /S7.i Dust sample imgi Time (min) Fig. I Haemolysis by PVC dusts and chrysotile asbestos a. Haemolytic potency of KM 1 (: )and KM 2(9) PVC samples after 50 min; h. change tn haemolysis w ith time by 7.5 mg samples of UICC chrysotile asbestos A and KM 1 <) PVC. Briefly, a ) % <v/v> suspension of packed rabbit eryihrocytes in veronal buffered saline. pH 7.4. was used in all the experiments. The incubation mixn re normally consisted of dust sample with I ml I*; erythrocyte suspension r) ml veronal buffered saline. After incubation and agitation for 50 min (or varying time inter, vals) at 37 C the samples were centrifuged at 2.000 r.p.m. for 20 mm and the extinction of the supernatant read at 541 nm. Controls consisting of a totally lysed sample t) ml I % erythrocyte suspension --3 ml water) and a fragility control (I ml I*, erythrocyte suspension 3 ml veronal buffered saline) were- treated identically in each experiment. haemolytic. A sample of 100 mg of KM 2 PVC gave an equiva lent haemolytic effect to l mg of sample KM I. The haemolytic activity with time of a sample of KM I PVC (7.5 mg` was compared with an equivalent mass of chrysotile asbestos A (Fig. \h). It is eviden* that the asbestos is a faster haemolytic agent, although total lysis is achieved by PVC' after I h. During the processing of different forms of PVC. a variety Fig. 2 Haemolysis by washed samples of KM I PVC dust (7.5 mg) and the resulting supernatant fluids from these washings compared with the hnemolytic activity of the untreated Just sample. KM l P\( u. Untreated; h, washed once; r, washcJ twice; </. washed 'tree times; e, wash I;/, wa-.h 2; g, wash 3. RSV 0001*64 I \utitr< l "/. 356 Auattu -I I** 5 of agents arc used which could contribute '' 'he hacmolyttc ctVcct of the dust. Therefore. sumpJes 17.5 r. jf KM I PVC were washed once, twice and three limes t5 s each wash, in 3 ml veronal buffer on a whirlimix: followed by centrifugation, 2.000 r.p.m. for 20 min) and the haemolytic potency of the washed dust samples and the supernatant fluid were compared with the lytic potential of an untreated PS'C sample (Fig. 2). After a single wash, the haemolytic potency of KM 1 PVC is reduced by over 60"0 and subsequent washes reduce the activity of the dust even further. Thus the removal of some surface-associated material, which must exist in a reasonably solub'c form, considerably reduces the biological potency of this PVC dust. It is also evident thu this material, once removed from the dust surface and diluted out m solution, has very limited haemolytic activity (Fig. 2) The effect of KM I PVC w as studied on the levels of cell mat DNA. RNA. protein and hydroxvproliitc (assessment of collagen) in lung libroblaxt cultures maintained in vitro for 24 d. The methods of isolation and cell culture and the analyses for DNA, RNA protein and hydruxyproline base been detailed previously*-*. Before addition of different concentrations of KM 1 PVC (50-200 pg ml'1 culture medium or 0.5-2.0 mg per culture) the dust sample was first washed in a balanced salt solution containing antibiotics (sec legend to Fig. 3). Other methods of dust sterilisation them, autoclaving, radiation) 24 r forms of PVC dusts exhibit a high haemolytic potential because of the presence of a read if 'able, surface-associated agent. Exposure to this type of i . dust may thus constitute an additional health hazard because of the increased biological activity of the dust. Work is in progress to determine the nature of the haemolyticaify-active agent by assessing a wide range of PVC dusts of which complete knowledge has been obtained of the chemical processing. The possibility that VC'M is the active agent has been explored, but both samples tested were found to contain immeasurable amounts of VCM (<1 p.p.m,). Nevertheless, the present study indicates that the introduction of a washing procedure after the processing of KM 1 PVC dust would certainly reduce or abolish the haemolytic activity of this material. We thunk Miss Karen Mitchell for assistance and two of us (R.D. and P.M.H.) thank the Medical Research Council for financial support. R. J. Richards Rashmiuala DtSAJ P. M. Hext F. A. Rose Department ofBiochemistry, University College, PO Bax 78, CunliJ/ Cri I XL, UK Received June 2: accepted July 14. IS7J i Seiaofl, |. J., and Hammond, E. C. ILvll, Toxn-Hy of Vimyl iftforir/r-At/rviai / ciilorui*. Ann. V. Y. ,-lruJ. i41 . 24*. Vtl (WJl. i Harmuton. J. S.. Vt liter. K... ana Ma NjH. U-. fcm-iM*. Rr.. 4. 4J.| 17 < tSTI I. 'KichstOvK Jand Morns, 1 </ .V S<12. *41-431 1197 )| * /Ol..n. A.. Haringlon. J. S-. of,l ll,riw.k. M. i.J. rtf. I!*>.. 124. 14 l-l 61 /1WWk ; Hi,.ftard. K. J , jnJ Wusten'i.i* h S.. m Ti.unr Cuhurt in MiUnul He,ro>clt. 91.94 illcinmann, London ' '74i = t41i__________ _________________ _. ii in;i 2nu n 1 iK.i ;tHi PVC I kin 1) concentration per ml culture medium I i'\ C eunccmrauon I us i>er ml culture medium) :.h :;n ;.u f uii __ ______________ i hm> :nu ii - uh> Ion PVC concent r.i ii`" nne pu vultii;.-] I'V C omu'iui jiion one ix.-v culturei Fig. 3 The effect of different concentrations of KM 1 PVC on fang fibroblast cultures. The PVC sample was first washed with an antibiotic solution 'penicillin i K)0 units) sireptomycinHOO ug) in I ml) and then added as a single tlosc to 3-d-oM cultures On logarithmic growth). Cultures were maintained <n 10 ml of 20% foetal bos me serum plus Waynouilis medium containing additional useorpic acid', changed twice weekly and removed for analysis on Jay 24. were not considered to be feasible and while the washing pro cedure undoubtedly reduces the ability of this PVC sample io damage cell membranes (Fig. 2) tihroblasl cultures treated with the dust all had lower levels of cell mat hydroxyproline after 24 d (Fig. 3). Some fluctuation in DNA levels was apparent wnh different dust concentrations but ihe significance of these is doub!!ul without further experimentation. There is little change in the level of total protein or RNA n the PVC-treate>' cultures. From these preliminary findings wc conclude that certain Mechanism of induction of haemolytic anaemia by phenylhydrazine A compound with the optical spectrum of a fcrrihaemochromc was produced when ferricyanidc-oxidised phenylhydrazine wax added to a solution of ferrihacmoglohin1. The three isomers of mclhylphenylhydrazinc similarly resulted in ferrihuemochromes. but 4-hydrazinobenzoic acid did not*. The induction of hae molytic anaemia by a substituted phenylhydrazine was related to the reactivity of its oxidised form with ferrihacmoglohin to produce a femhacmochrome1-*. Further studies of the reaction of oxidised urylhvdrazine with ferrihaemoglobin have established that the formation of a ferrihacmochrome-likc product and the character of the optical spectrum of ibis product depend on the nature and position cf substituents on the benzene ring of phenylhydrazine. Substituted pbeny)bydrazine hydrochlorides were obtained from commercial sources or were synthesised by standard procedures. Each compound was punfied by recrystallisation from 2 N HCI or ethanol, and the structure and purity of the recrystulliscd product were contirmed by its NMR spectrum, infrared spectrum, melting point, and analyses for C, H, N, and Cl. Oxvhaemoglobin solutions were deoxygenated by the passage of oxygen-free' nitrogen or helium, and the resulting fcrrohacmoglobtn was oxidised to ferrihaemoglobin by the addition of excess ferricyanide. To a solution of ferrihaemoglobin in excess ferricyanide. a solution of arylhydru/tne hydrochloride in water or ethanol was added, and the opucal spectrum that resulted was recorded with the Cary Model 17 instrument. The spectra obtained with 3- and 4-chlorophenvlhydrazine were similar to that previously reported wnh un substituted phenylhydrazine1. The spectra obtained with 3.4- and 3.5-dicltiorophenylhydra2ine were distinguished by a more prominent absorption band in the red than the others. 2-Chloro-s and 2.3-, 2,4-. and 2,5-dichlorophenylhydra/ine resulted in spectra with a single broad maximum at around 540-550 nm and without a band in the red. 2-6-Diehlorophenvlhydrazine. 2,6-dimethyiphenylhydrazme, 2-hydrazinohtrn/oic *sv 00014^5 i TALLE I REPORTED CASES OF ANGIOSARCOMA OF THE LIVER AMONG VINYL CHLORIDE POLYMERIZATION WORKERS NIOSl! August 27, 1975 COUNTRY CASE 0 Canada Canada Canada Canada C'.r.nda Ci.r.ada Canada Canada Canada Canada Czechoslovakia Czechoslovakia Jed. Rep. Germany Fed. Rep. Germany Fed. Rep. Germany Fed. Rep. Germany France France France Great Britain Great Britain Italy Italy Moi-.-ay Sweden 01* 02* 03* 04* 05* Co* 07* 08 09 10 01* 02* 01* 02* 04 05* 06* 01* 02 03 01* 03 02* 03* 01* 01* : v UK* BIRTH DATE 1st VC or PVC EXPOSURE AWAITING DETAILS AWAITING DETAILS AWAITING DETAILS AWAITING DETAILS AWMTING DETAILS AWAITING DETAILS AWAITING DETAILS AWAITING DETAILS AWAITING DETAILS AWAITING DETAILS 00-00-28 00-00-57 00-00-26 00-00-51 07-26-31 10-14-57 06-24-30 10-01-57 09-04-30 04-16-57 04-28-25 02-00-57 01-01-32 07-26-62 04-15-24 01-00-46 06-03-11 07-06-59 AWAITING DETAILS UO-UO-OI 00-00-46 06-02-37 02-00-66 11-13-29 00-00-57 03-14-20 12-23-15 00-00-53 03-00-50 03-23-27 03-14-51 I*X ANGIOSARCOMA 00-00-73 00-00-66 09-25-70 09-19-68 09-00-74 07-00-74 09-00-75 02-18-67 01-08-75 12-00-72 00-00-74 12-13-72 07-10-75 12-20-71 02- :o-70 AGE AT DX 46 40 40 38 44 49 43 43 63 71 37 43 55 56 43 YRS 1st EXP TO DX TOT YRS EXP DATE OF DEATH 16 16 00-00-74 15 15 00-00-65 13 12 12-14-71 11 11 01-25-69 17 11 11-25-74 17 12 ALIVE 13 12 01-09-75 21 19 02-19-67 15 12 01-24-75 AAOf 20 12-C3-72 9 4 12-24-74 15 6 12-03-72 22 21 07-10-75 22 21 01-04-72 13 18 10-22-70 R$V 0 0 0 1 4 6 6 TALES I (co.'.Ur.-, g) RLt'O.lf EJ CASES Or' a:JCI05APX0:-'-\ OF TiiE LIVEX AMONG VINYL CHLORIDE POLYMERIZATION V.ORNERS COUNTRY United States United States United States United States United States United States United States United States United States United States United States United States United States United States United States United States United States Yugoslavia Yugoslavia CASE v 01* 02* 03* 04* 03* 06* 07* OB* 0 9* 10* 11* 12* n* 1 17* 13* 19 01* 02* BIRTH DATE 10-17-23 08-19-33 05-25-15 01-15-24 01-25-12 . 00-00-29 05-03-22 05-06-20 11-08-31 08-16-13 05-27-09 11-17-18 12-01-21 n-o;-:7 05-00-31 04-22-28 00-00-15 04-05-14 11-15-31 1st VC or PVC EXPOSURE 12-09-48 11-15-55 11-28-45 07-06-52 06-19-44 01-17-62 08-00-44 10-07-46 09-09-54 06-12-51 10-14-46 09-13-49 OR-19-44 05-0f.-50 C5-23-55 00- 00-54 OO-OC-43 00-00-53 00-00-50 DX ANGIO SARCOMA. 03-03-73 05-00-70 12-19-73 08-19-67 04-09-64 * 02-00-74 0O-OO-6S 08-00-61 03-01-74 C5-00-68 03-00-70 05-02-69 05-00-74 00-00-69 10-11-74 00-00-75 06-19-75 04-03-73 07-12-73 AGS AT DX 49 36 58 43 52 45 45 41 43 55 61 50 52 41 43 46 60 59 42 YRS 1st EXP to d:: 22 14 28 15 20 12 24 15 17 17 23 20 30 17 19 21 32 20 23 Total Reported Ca Scs 45 Modir r. Values: 17 U.S. Cases 17 Non-U.S. Cases 34 Total Cases < 46.0 43.0 45.0 20.0 17.0 1C.0 * Indicates nicro scopic.',!ly confirmed an& ioscrcoma of the liver. "00" Indicates unkniv.m data. TOT YRS e::? 16 13 28 15 13 12 18 15 17 17 23 15 30 4 19 13 32 20 13 17,0 15.0 16.0 DATE OF DEATE 03-03-73 09-28-71 12-19-73 01-07-63 04-09-64 07-24-75 03-23-68 03-29-61 03-00-75 05-10-63 03-16-70 05-02-69 07-04-74 03-2 7-',; ALIVE ALIVE ALIVE 04-03-73 07-12-73 RSV 0001467 * *> SEP 81975 ATMOSPHERIC OXIDATION OF CHLORINATED ETHYLENES by Bruce W. Gay, Jr?^ Philip L. Hanst Joseph J. Bufalini Richard C. Noonan Environmental Protection Agency Environmental Science Research Laboratory Atmospheric Chemistry and Physics Division Research Triangle Park, N.C. 27711 w RSV 0001468 ABSTRACT Ethylene and chlorinated ethylencs were photooxidized in air in the presence of nitrogen dioxide with ultraviolet light. Analyses were performed by long-path infrared spectroscopy, wet chemical, and chemiluminescent procedures. Reactivities of the ethylene com pounds fail in this decreasing order: 1,1-dichloroethylene > 1,2dichloroethylene-trichloroethvlene > ethylene > vinyl chloride >> tetrachloroethylcnc. Reaction sequence involves photolysis of ni trogen dioxide, formation of ozone, conversion of the olefinic com pounds to a highly-oxygenated intermediate, attack by the inter mediate on olefin and nitric oxide molecules, formation of trans itory epoxides, and rearrangement of epoxides through chlorine atom movement to yield chlorinated acetaldehyde or chlorinated acetyl chloride. The chlorinated aldehyes are further oxidized to more stable final products, including a small yield of chlorinated peroxy acetyl nitrates. RSV 0001469 4 Vinyl Chloride Job Health Hazard Series U S, Department of Labor Occupational Safety and Health Administration June 1975 OSHA 2225