Document NeY9oDabN15RqEGZgoqMDGrmQ

BUS 107204 BIO-MEDICAL RESEARCH DOCUMENT DESCRIPTION FORM 63 68 69 Duplicate in all cards:--> year as-1961- File number [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space l-leio d 20 21 A . _. /)/V| 40 41 77 78 Sub-Index Code 60 61 62 11 12 13 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 61 62 (_ hu r_FL : C r > i < . i > 1 , ' ' i r ft ( \, < i p ; i ; t r ' <' 1 r 21 c '/ fi `, t t ( '/-/.us*.3/} Sty Tg V i JI d? / 22 23 24 Source (Journal, Vol., Number, Pages, Date ) 12 f-Vr b< (15 rre citrih frrnk' tr4-| \) > nn fried i z ( n , 61 62 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 R&S 107205 ' ooooilo gS'j-n- j. Fleig and A. M. Thiess: Chromosome analysis after vinyl chloride exposure* [Chromosomen-Untersuchungen bei VinylchloridExposition] Arbeitsmedizin, Sozialmedizin, Praventivsmedizin# 9_ (12), 280-283 (1974) *From the Medical Division of the BASF Joint Stock Company, Ludwigshafen, Directorate: Prof. Dr. med. Alfred M. Thiess Translated from German by The Ralph McElroy Co., Custom Division, 2102 Rio Grande, Austin, Texas 78705 USA R&S 107206 Code: 101-5056-1 CHROMOSOME ANALYSIS AFTER VINYL CHLORIDE EXPOSURE To clarify the question of whether a connection between mutagenesis and carcinogenesis exists, the chromosomes of chemists who for decades had contact with VC/PVC as well as co-workers from the VC/PVC section were analyzed. We used the method of Moorhead ei at. [30] and of de Jong and Anders [18]. According to the present results - the group in question here is small - there is no increased rate of abnormality found in the VC-exposed group in the BASF compared with the control group. This indicates that under the working conditions existing at our companyt the in fluence of VC has no mutagenic effect. However, a final position can only he taken after the analysis of all VC exposed workers in our production plant. 1. Introduction and proposals Mutations are essential to evolution. This means that they also have a positive effect. In general, however, the change of hereditary components is a negative effect. Mutations may be "spontaneous", which means there is no recognizable cause [41], they may be initiated by ionizing radiation [7], or some special cytostatics as well as chemical substances [5,22,23,42]. Changes in chromosomes can also occur due to certain virus infections. When used oh animals, some chemicals for instance alkylat ing compounds like nitrosoamines and nitrosoamides are known to induce chromosome aberrations [31]. They can also cause carcinoma [14]. An example that can be named is ethylnitrosourea (Figure 1). In the organism the compound will in a short time hydrolytically decompose and will thereby develop a highly reactive alkyl group which reacts with the base guanine contained in DNA [6,12,35]. This creates a faulty base pairing or no base pairing at all. Therefore, mutation occurs during the nec,,essary replica tion of DNA during subsequent cell division. At the same time, in R&S 107207 \ Page 2 1974 in extensive experimental studies on animals by Rajewsky and Goth [16] it was demonstrated that ethylnitrosourea after a single injection in rats almost always induces brain tumors. Tissue analyses by which changed bases were only detected in the brain gave proof that the previously described reactions would also have to be responsible for the carcinogenicity of the compound. Irreversible changes in chromosomes could also be the primary biological basis for carcinogenic processes. This indicates a certain correlation between mutagenesis and carcinogenesis [11,17]. Since the beginning of the sixties it has been known that vinyl chloride - upon appropriate exposure and dose-effectiveness induces the so-called VC-disease [1,2,3,4,8,9,13,19,20,21,22,23,24, 27,29,36,37,38,39,40], and since the beginning of this year we have also known that VC is able to cause, the development of Haemangioendotheliosarcomas of the liver in animal and humans. Up to now we have 24 cases of Haemangioendotheliosarcoma registered from all over the world [10,25,26]. From this point of view, the study suggests the possibility that vinyl chloride exposure over a long period of time could also be a source for chromosome aberrations. We, therefore, con ducted chromosome tests on our coworkers in VC/PVC production areas. In 1972 Gath and Thiess [15] gave information about chromosome tests on coworkers after possible contact with ethylenimine, lead, benzene, and dimethyl sulfate at the first MedichemSymposium. 2. Total number of VC/PVC coworkers The exact number of workers in the world's VC/PVC production areas at this time is difficult to estimate and can only be ap proximated. The main reason is that up to now no categorization has been made among the workers in the VC/PVC field. According to the press, in the U.S.A. approximately 20,000 coworkers are at this time employed in VC/PVC production. Starting from the premise that the production share of the U.S.A. falls in the range of 23% the number 20,000 would have to be multiplied by 4. it could be said here that at this time about 100,000 persons over the entire Page 3 world work with VC/PVC and about 2 to 3 million are working in PVC manufacturing. The world production of VC in 1971 was estimated at 6,765 million tons. Of this, the U.S.A. accounts for 1,969 million tons and West Europe for 2,497 million tons. 3. VC exposure Also, with reference to VC exposure in the past decade, no results of exact tests are available. The average concentration of VC in the air of the working areas were according to the esti mates of Chemical Industries Association Limited as follows: 1945-55 1955-60 1960-70 middle of 1973 presently 1000 ppm 400-500 ppm 200-400 ppm 150 ppm 50 ppm and less With regard to the VC exposure since 1968 in the BASF production areas, continuous reliable data is available. This has been measured with (R) URAS, an infrared absorption recorder in order to prevent VC explosions. It can be assumed with certainty that since that time the VC concentration lies under 500 ppm possibly under 100 ppm - according to the lower sensitivity limit of the instrument. Since the beginning of 1974 the VC content in the air in the range of 1-100 ppm is continuously measured with the (R) lonoflux instrument. It became evident that the VC con centration was under 25 ppm and in the last month even as low as 10 ppm. Here and there some rare stray shots with values up to 70 ppm may be found, but work to reduce those values continues. R&S 107208 4. Test results To display the chromosomes, we also selected at this time, the culture of lymphocytes from venous blood in comnination with the cytologic technique. With reference to this method, we allude to the work of Moorehead et al. [30] and de Jong and Anders [18] . Figure 2 shows a normal chromosome set from lymphocytes. A Page 4 prerequisite for the display of the chromosomes is an actual ^ dividing cell, since only in the metaphase stage is a clear iden-^ tification of the chromosome possible. Of each man who is exposed to VC/PVC, 50 metaphases should always be analyzed and should be photographed for documentation. The chromosomes are arranged according to the Denver nomenclature. The sex chromosomes are marked with X and Y; the autosomes are in the numerical order from 1 to 22. The most important morphologic principle of order is the size of the chromosome. Next to that is the importance of the position of the centromere (Figure 3). We began with the exam ination of the chemists who had worked in the production of PVC from the beginning and had been exposed almost continuously to VC/PVC for many years. It has to be mentioned that those chemists were, in both the laboratory and the production and technical field, more often in contact with VC. According to a statement of one of the chemists, they have, especially in the first years, really dabbled with VC "in the laboratory." The test results of workers in the PVC production are il lustrated in Figure 4. In the 6 individuals - the longest VC exposure lasted 34 years - an increase in the rate of chromosome abnormality rate could not be detected since the frequency of the structural abnormalities is between 0 and 5% and therefore lies in the range of the normal spontaneous abnormality rate. The results of the test files from workers in PVC manufacture are shown in Figure 5. Here too, no chromosome changes were detectable which would have been above the normal rate in the average population. The VC measurement results in the area of the PVC manufac turing in the experimental technical section show at different measuring points an ambient VC concentration below 1 ppm to 26 ppm (Figure 6). Four coworkers had been chosen for the control group. They have been working for several years in diverse production plants. The percentage of the chromosome aberration lies between 0 and 5% and therefore agrees with the findings on the VC/PVC exposed persons (Figure 7) . R&S 107209 R&S 107210 Page 5 5. Discussion of the test results The chromosome tests have been conducted by us in order to determine if there is a correlation between mutagenesis and carcinogenesis in VC exposure. When Maltoni [28] with reference to VC says, "It's only a tree in the large forest of all compounds of the carbonchloride group", there can hardly be any doubt left that there is a casual connection between VC influence and Haemangioendotheliosacoma development. In the U.S.A. the annually expected frequency of angiosarcoma of the liver in the entire population is 0.0014% per 100,000 (U.S. National Cancer Institute) or nearly 25 to 30 cases per year out of the total population of the U.S.A. Since the total number of the VC workers is approximately 20,000, only 0.03 cases in ten years should be expected. Actually, however, 13 cases have been found. This means a risk rate of 400 to 1. In Germany, 3 cases of Haemangioendotheliosarcoma due to VC exposure have been confirmed. But the epidemiology tests by Dr. Reinl and Dr. Weber are still in process and a final opinion cannot yet be given. According to our test results it can be determined that the rate of chromosome abnormality of the chemists and the employees in PVC manufacture examined by us is not higher than that in the control group. Dr. Irving J. Selikoff [35a] of the Mount Sinai School of Medicine has, however, according to an announcement in the Chemical Engineering News from September 2, 1974, discovered in tests on 11 workers that "early findings may indicate that vinyl chloride may be mutagenic as well as carcinogenic". Further, Selikoff has referred to laboratory tests in Sweden which verify the mutagenic effect of VC in a Salmonella test system. From the notes of Selikoff it can be concluded that because VC is a highly reactive molecule, it belongs to the group of chemical substances that show mutagenic as well as carcinogenic activity. Our results indicate, however, that we have only begun Page 6 R&S 107211 to analyze the situation. The final results will be given when the tests are concluded. 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AiheUsmed. 32 (1974) I--Mr --* : ) I.un^r, C.'.'tl., 5. Jithe uikJ f#. Vrhmmtn: Uher das Aiilirctcii von Anjttosarkomeu der I eber bei /wei Arbetietn det I'VC-heisleOctHlen huluslrie. I)MW. lid. 'M. II. 31. S. -mi (1974\. - ') /.er, I.. I). S. Hurrv: Anetosaicnnia of tlte liver m a \invi-chlnride worker. I ancet I* 1316-(1974). -- Lrfrrrr. M. /.; Diaum^ttc radiolouit|ue el evolution ile cas d`aciiHMeol>M-. Voiitai*. I. Int. .S\m|Hsium der Werksiir/ie der ehemiMhen Imlusiiie. 27.-29. 4. 72. Lodwitrdtafcit. -- "') Militant, C\; I low ihev lound vinyl-cancer link, C hemical Week 17. 7. 74. 30--32. - s') A/m,wW/. r, II. J.. IV. K. I.cltuuh, K. A/iiZ/rr. S. Jtthr, C,-Il. Imumv. G. It. lUthurr und G. Vrltmutitt: OImIi, med. WmIu. 9S (1**73) 2MI--2314. - Afirrh.W. P, S,, P. C. Nan'rH. IK. J. i\Irilumtt. /), A/, /hu/tpi aiul /*. ,1. Hu't^rr- ft/nl; C liroimtMune preparations uf leukocytes euhureil from |>cri* plural bUmtl. I*,\p. Cell. kes. 2tl, (>I3--hlh (IVAII). -- Ji) Ntthoh, llr. N.: The ride of vnuses in the etiology of chromosmnal abnor malities, Amvr. J. Hum. (icnct. IK. l-*4 (19<>h>. -- *> /hnpp.'ne. P., G. Hiihr/uttn. and II. tliisrlntitirr: Comparative investi^alions on die chemical mJuctiou ol )mm| imitations and ilommaiii lethal mu* lations in mice, Molec. ?:ch. Cienei. 117, |*)7 -OtW (1972). -- ") linhr* horn. CT: C hetnische konstnuium und nmta^ene SViikung. Klassi* ii/ieriiiuisvvrsuch dtemischer Muiapenc lisivrunentij /A. 523-*529 (I9()0). -- *') HAItt hut it, G.: (iber moeliclie mulaueiie Nehetiwokmi' ^en von Ai/neiumiel beim Mensehen. Ilitmaii^eneiik /, 2U5--231 (19o5a). -- '*) Ri'ththtnit, G.: Ihtuheimeal mcvliamsms of mmaiioit In: (`hetnical Mutagenesis in Mammals and Man. (I:d.: t. I`o.eW and G. /Ai/zi/mnt) I--2. Ikrlin lleukllvre New York. 1970. Sprin- gcr-Vcrhit!, -- l^) Srltkafl. /. J. JC hemical l-'nitineerin|* N,eW!t{l974). -- **) Surin, /.. I. Oirfriittnn, St. I *ihtskui; Med. Interna 6, Nr. M H962I 963--977 (Oheiset/un;! dnrch I elevic 1965), -- j:) Sttritt, J. Phrintuittt. M. \'ul,i\ktn: (\miribuiti sludiul inioluasirilor produse de domra de vinil. Med. Intern. 15. ST 967--97s (1973). -- *) .Vicr/i, G,, S, Jtihr. C.*tl. I.umtr mid G. IV/imumi; l orischr. Kiinijjcnsir. Ilk (1973) WK-63. - ") Vulrmttt. It.. tt\ KUtMrrkiUtrr. G. Lrh* iirrt. It. Prttv. J. liniritlmitz ntnl II. Aibeilsmedi/in, *1 liieme Vli:,, Sliiiigait 1**71. *-) Ho/. /*, /,,; Med. d. I.avaro 61 ||970) |74--ISI). -- ") I'mr/- K; Spontaneous mulaltuit in man. In: Chemical tmilaccnvsis m mammals amt man. lids. t\ Voxrl and G. Ktihrharu. |9f*S. |lerlin-lleideUvr^-Nex* York: Springer 19711, -- L`| ISn,*(7, I(i. Halttlnutt und AV/i/rinuiiii/tcr: (Miemisch-iiuUi* /ierte Mlilaiioneii bci Sanger und Meiis.h, Naiiirwisscnschaftcn 5A.' 131--141 11971). Anschrifl der Vcrfusser: Ar/iliclie Abteiluug der IIASI* AG. l.ud- vigshafen. `* Der Werksarzt Der Betriebsarzt Aus der Praxis Fur die Praxis . 17 000 Kriilircnlncr dnrch Atcniwccscrkrunkuiif'cn Erkriinkunucn ilcr Alcmwcyc mcIico mIs Ur\:idic fiir ArhcilstmEihi^kcil an crslcr Slcllc der SiuiNlik der I'llitlilmilplieder von Oriskrnnktfnkiisvcii. Allcrdings lind Nt1.! dicscr l-'rki'iinkungvn akulc F;illw`, wic KuCirrlic und grippulc Infuktc. Hie gcMindhcil\- und Mt/iulpolitisdic Kcdculiing der dironisdiL'n AlcinwcgscrkrunkungL'ii M;md ini Mitlclpnnkt cincr I'odiunisdisLussion hoi der Dculsdicn Thcriipiewodic in K;ii Krnlic. Her AbtcilungMiircktor hei der l.iindevversicherunpviinsull Wiiritcinbcrp. I)r. V/. Kulpc, mnditc unhund von /..dilen dentlidt, dull audi die dironisdicn Alcmwepserkriinkungen voii cnornier polilisdier llcdculiing %ind. Ak Cirund fiir Kentcn wcgvn Herufv und l-Twcrhstinniliigkeil. uniersnidi Dr. Kulpe, Mclicn die unspe/ilisdien l-'rkrunkungen der Alnmngsorgnne bei Miinnern ;ui driller, bei l r;iuen ;m siebler Stelle. Jiiliriidi werden durdi \ic rmul 17 COO Miinner und l;r;uien /u Kentnern. duvou I.SIHKI in der Arheilerrenienver* yidiernng und 20011 bei den Angt^leOleu. Ituml 7l>'< der I'iille sind mil dironisdie llnuidiilis oder l-'inpliysenibroiieliilis leine Spiiiforni dor diroukdicn iironehitiv) /urin.'k/.uriihren. Aiterding% erfavie die Stmi\iik inir die lluiipiili:i> guose. l-"s gebe auUerdem geniigend Hille, ineinte tier Medi/iner, bei denen die dironixdie lirondiiik /weilkrankheil ist. Da\ durehxdmiiilidic Kenien/ugangxal* ler bei Hrkrankungon der Alnutngsorgane liugi fiir Miinner bei 5H.5. fiir b'rauen bei 5A.5 Jaliren. Diese Krankheiten inadien audi emen erbehlidien Teil der Mutioiiiireti lleilverfahren der Itenlenverxidierungxiriiger aus. (ienaii 1(1% von WilllKM) Kureii im Jalire 1072 eilllielen auf diese Ursadie, duvou wieder auf dironisdie limndiilis und ihre Spalforin. Allerdings gelit seil 1972 die /atil der Meilbeliandlungen wegen Aieuiwegxerkr.inkungen bci Miinnern /uruek, hislier elwa uni 25'7. bei I'raiien aber sieigl die /aid erliehlieh an (27'!). dpa Arbeiismcdizin Sozialincdi/in I'riivcntivnicdi/in (~Asf'`D 74 J 28.Vt"- R&S 107213 Page 7 Mutation mechanism of alkylating compounds o*g- othylnitrosourea 0=C CH2 - CH, ~N - N = O 'NH2 01 HN^^C- h2n-cI t CHj O Oh tI CN HN' ''C-' ' CH-- I /V Ni CHj i ch2 /v -LH\r" '"0" |l C* N Alkyiated~guanme act's like adenine-faultyj base pairing Depurinization no base pairing -----------------------------------------1 \X Mutagenic. ------- effni-1- Figure 1 Mutagenesis .*.'>'4^ 3 * * ir r o ^^ l) -si 7 > P < *< , .a 0 (/ jJ *? f) 9 ^ ^ K GO i X? "* *>X *. ~ Xj 0-i 311 tt$ Da 3a us i fe? ~ 1? '"rr". i -- ~"iru'Xyj7-^ Figure 2 Normal metaphase of a healthy nan areas' --s-aa-aa- 1> . 4 ', r , 14 17 . !!*: .V:. .-rxxx -3 S--^3- ' $.""<3 $rr 7? ' ** r ; Karyotype: 46 XY . * Evaluation: normal karyogram Figure 3 Normal karyogram of a healthy man (Denver scheme) Page 8 r--i No Hame Sirtl date a iiryeartJVC"from - Expos to - ppmm ; c "d V e ; : O L 06 OS 23 o 02 55 7 oy *5 2 5 none 01 2 Dr A H 5 10 31 IS 03 d 1j3$-W4 i-1 u CX o B o9 33 none! 3 C' ,V 5 T7 03 3: 01 C? M <1> QJ B OS oB 4 none 4 :> ;/ D Or* 07 23 :s Cl i; ;3 n$6-is7: a) U C oB 0 none cO *H $ 0t K H & n it 13 03 23 34 1340*r?7: jj W t>9 oB 0 none s OCX 02 S2X1 Ot 03 63 i n7o~n7i e* 9 o3 5 none Figure 4 Chromosome tests on VC-exposed workers in PYC production Legend: a - employment date at BASF b - clinical findings c - laboratory findings d - Chrom. Aberrat. in % e - Remarks R&S 107214 f. kirt '""jdatc i a n year from - Expos to - in ppm b nj c r: rd"[7" i UOTJt 119$* if ,Jr*tW9t l?/p;*" A a A 0 none / >t*9 sOlC*$i !<** ft| mo-m* 0 0 J none 7 <tstjt 01<4*0 /rrmr t4* XfiQpr* *0 * 0 4 r^W B 4*0 10 0* JO *4 JO JJJ4-IT74 *#. *0 0 none 5 noncj Figure 5 Chromosome test on VC-exposcd workers in PVC manufacture Legend: a - employment data at BASF b - clinical findings c - laboratory findings d - Chrom. Aberrat. in X e - Remarks Page 9 a mFliuxeidr d e f s h .b /i <1 3 Notes < k 17 1 at head level of -he < t employees < / t <M m <n *' Figure 6 Measurement of VC-concentration in the room air in the area of the KAF-Technicians Legend: a - measuring point; b - VC concentration in ppm; c - Fluid mixer exit; d - Mixing roller directly above the slot; e - Calender rise f - Calender outlet; g - Extrusion jet; h - Extrusion filling funnel; i - At head level on a standing location of service personnel; j - At head level on a' standing location of service personnel (after the mixing has been completed); k - At head level on a standing location of service personnel; 1 - No standing location or breathing area of personnel; m - Only at times a possible standing location of service personnel; n - Only at times a possible standing location of service personnel R&S 107215 Name 3irtl a to date Wo rking place b C / Or. C V/ 1109 23 OIOSS7 /HtteeDca-npMmnri.qnSgi alt 2 C H l< 12 21 10 01 SI ;DV/Mmoerneo- oB technical 3 H K (13 09 29 nass f,nss oft oB A 1/5 IS 0132 hoi, j? Chamber o 3 O0 Looer:,,. fcions D61. d 0 2J 0 5 totes None None None None Figure 7 Chromosome tests on the control group Legend: a - BASF entrance b - Clinical findings c - Laboratory findings d - Chrom. Aberration in X