Document rpxMxDJjB6kgk5R2OQJdqGj7G

SEP 10, 1780 01.23.07 FILE NUMBER /t 109^Y AUTHOirR<is) t FtmtES-CCRRAVIOTO. F.; LAMBERT, B.; LINDSTEN, J.; EHRENBERG, L. AL TITLE CHROMOSOME ABERRATIONS IN WORKERS EXPOSED TO VINYL CHLORIDE ET PUBLICATION SOURCE : LANCET 1<7904):459, 1975 LANGUAGE : ENG COUNTRY : SUE -K-.*..*.-*. EXPERIMENTAL DESIGN TO DETERMINE IF A HIGHER FREQUENCY OF CHROMOSOME ABERRATIONS OCCURRED IN VC POLYMERIZATION WORKERS THE PERIPHERAL LYMPHOCYTES OF 7 OCCUPATIONALLY EXPOSED AND 3 NON-EXPOSED CONTROL SUBJECTS, ALL EMPLOYED IN THE SAME FACTORY, WERE STUDIED. THE AIR CONCENTRATION OF VC IN THE POLYMERIZATION DEPARTMENT WAS ESTIMATED TO BE AROUND 20 TO 30 PPir.. THE DURATION OF EMPLOYMENT IN VC WORK RANGED FROM 9 TO 29 YEARS. NONE OF THE WORKERS HAD ABNORMAL CLINICAL EXAMINATIONS, EXCEPT FOR CASE A WHO HAD THROMBOCYTOPENIA AND ALPHA 1 - ANTITRYPSIN DEFICIENCY. CHROMOSOMAL ANALYSES WERE MADE ON 48 AND 72 HOUR CULTURES WHICH WERE CODED AND ANALYZED BLINDLY. THE DATA FROM THE CONTROL SUBJECTS (566 CELLS) WERE HOMOGENOUS AND THEREFORE POOLED. IN CELLS FROM THE EXPOSED GROUP THERE WAS NOT FOUND IN ANY CASE A STA TISTICALLY SIGNIFICANT DIFFERENCE IN THE FREQUENCY OF ABERRATIONS BETWEEN 48 AND 72 HOURS CULTURES, AND THEREFORE THEY WERE POOLED. -*** KEYWORDS ->(**( VINYL CHLORIDE; HUMAN STUDY; OCCUPATIONAL EXPOSURE; CHROMOSOME ABERRATIONS; THROMBOCYTOPENIA; ALPHA 1 ANTITRYPSIN DEFICIENCY; `PERIPHERAL LYMPHOCYTES; X RAYS; CHROMATID GAPS; ISOCHROMATID GAPS; CHROMATID BREAKS; CHROMATID EXCHANGES; ISOCHROMATID BREAKS; DICENTRIC CHROMOSOMES; RING CHROMOSOMES. -x- m- x--H- AE?.ST R ACTS hk--*--* THE RESULTS OF THIS ANALYSIS ON A SMALL GROUP OF VC EXPOSED WORKERS INDICATES THERE IS AN INCREASED FREQUENCY OF CHROMOSOMAL ABERRATIONS. IN 566 CELLS OF CONTROL WORKERS THERE WERE 11 ABNORMAL CELLS (1.947.) AND IN 1450 CELLS* COMBINING THE DATA FROM THE 7 CASES OF EXPOSED VC WORKERS THERE ARE 31S ABNORMAL CELLS (9.527.). THE FOLLOWING FREQ UENCY OF ABERRATIONS IN THE CONTROL POPULATION CORRESPONDED TO- THAT FOUND IN THE GENERAL POPULATION. IN THE EXPOSED POPULATION THE FREQUENCY OF CHROMOSOME ABERRATION WERE FOUND HIGHER IN CHROMOTID AND ISOCHROMATID GAPS AND BREAKS, BUT NOT FOR THE OTHER TYPES TESTED. THE HIGHEST FREQUENCY OF ABNORMAL CELLS WERE FOUND IN THE TWO INDIVIDUALS WITH THE SHORTEST DURATION OF EXPOSURE (9 YEARS) AND TWO INDIV- SPI-04715 IDUALS) ONE.WITH 12 YRS. AND THE OTHER 20 YRS. EXPOSURE) DID NOT DIFFER SIGNIFICANTLY FROM THE CONTROLS. A TEST OF HETEROGENEITY GAVE A CHI SQUARED= 47.72 p LESS THAN 0.001. HIS NEGATIVE CORRELATION OF THE FREQUENCY OF ABNORMAL CELLS WITH THE TIME OF EXPOSURE WAS NOT SIGNIFICANT. NOTE: THE AUTHORS MENTION PREVIOUS DIAGNOSTIC X-RAYS AS A POSSIBLE EXPLANATION OF CHROMOSOMAL ABERRATIONS IN THE CONTROL GROUP. SUBJECTS WITH CURRENT DRUG INTAKE OR PRE VIOUS X-RAYS ARE NOT INDICATED AS EXCLUDED FROM THESE STUDIES. THERE IS ALSO A THIRD EXPOSED SUBJECT) CASE E) THAT DOES NOT APPEAR TO DIFFER SIGNIFICANTLY FROM CONTROLS. SPI-04716 U J U. ;cd > :1 ;*.! . >. *ic : -At TtC OU4 i.n,.i!C .irr lift , iii: ' 'l THE LANCET, FE3RUASY 22, 1075 */Oj 459 release of low conccnrrarions of proteolytic enzymes in the skin due co the non-specific cytotoxic effects of biic salts could account for both u\c pigmentation and the pruritus of patients with chronic obstructive jaundice. n** Drrrmcclogy, i'rr-toi iv>., 1 lr.f.rnvtry, Heistol i>S2 8KW. J. L. Burton K.-R3T. CHROMOSOME A32RRATIONS IN WORKERS EXPOSED TO VINYL CHLORIDE S:r,--Epidemiological evidence suggests that the risk of msiignancy is increased in workers chronically exposed to vinyl chloride (v.c.).1"*** 4T5h6e carcinogenicity of v.c. has been demonstrated in animal experiments.* In-vitro ' and in-vivo * experiments suggest that the carcinogenicity ox v.c. probably depends on rhe formation of an alkylating compound, presumably chloroethylene oxide. Since carcinogenic chemicals are often mutagenic,* we wondered ;f v.c. is also mutagenic. In fact v.c. has been reported is inducing mutations in Salmonella typhimurium in the presence of metabolicaliy active liver homogenates.1* if alkylation of data, by V.C. metabolites also produces chromosomal aberrations in man, chromosomal analyses could oe used as an indicator of risk and also possibly be helpful in establishing a genetically meaningful maxi mum allowable concentration of v.c. We report an in creased frequency of chromosomal aberrations in workers exposed to v.c. Seven occupationally exposed male workers and three ion-exposed control subjects, all employed in the same factory, were studied. The level of exposure to v.c. had continuously decreased during past years. In the weeks preceding the collection of blood-samples for chromosomal analysis (before the summer holidays in 1974) the air concentration in the polymerisation department was estimated to be 20-30 p.p.m. Workers had been exposed I. Creech, J. L., Johnson, At. N. J. ceeap. Mid. 1974, IS, ISO. t Lee, F. I., Hurry, D. S. Lancer, 1974, i, 1314. 1. Monson, it. it., Peters, J. M., Johnson, M. M. ibid. 1974, ii, 397. 4. Block. J. B. J. An. mrd. Ait. 1974, 22*, S3. 5. Holmhery, 8.. Molina, G. Wk. tnviron. HUM. 1974,11, 138. 6. Maltoni, G, Lefcmine, G. Environ. Fit. 1974, 7, 387. 1. Gvthe, R., Callsman, C. J , Hhrenberf. L., 96*ichmcisler, C A. AnMe, 1974, 3, 234. I. Ostcrman.Golkar, S., SegerbSck, D., Ehrcnbcr*. L. Unpublished, e. Miller, B. C., Miller, J. A. m Chemical Mutagen*, Principle* and Methods for their Detection (edited by A. HoUaender); voi, 1, p. S3. New York, 1971. is. Rannug, U., Johanasoa, A., Rarad, C., Vadmseiaser, C A. Ambie, 1974. 3, 194. to v.c. ror 9-23 years. Clinical examinations hi,. been carried out at regular intervals. None of the workers had showed disturbed liver function, signs of acro-osteriysis or htematological changes, except for A in which there was siicht thromaocytopenia and an .,-aatitryp..::. defei- eacy. Chromosomal analyses were mace on eiii. , :e-.- ver.tidr.ai lymphocyte-cultures incubated for .S er d 7g hours. Ail blood specimens and slides were coded and analysed blindly'. Tl:e result oi the chromosome analysis is give,", in the accompanying table. The data for the control sub- rets were homogenous and therefore pooled. Altogether they comprised 566 ceils, U of which (T9-t%) contained chro mosomal aberrations. Tnis finding might be explained by previous diagnostic X-rays. The frequency of aberra tions nevertheless accorded with that of a male population selected at random.11 1450 cciis from die group exposed to v.c. were analysed, 800 in the 43-hour cultures and 650 in the 72-bour cultures. In none of the cases was there a statistically significant difference in the frequency of aberrations between the 43 and 72 hour cultures. Therefore these data were pooled. The frequency of abnormal cells in the group exposed to V.C. (9-52%) was significantly greater chan in the controls (? < 0 001). This was also true for chromatid and isochromatid breaks when analysed separately, but not for the remaining types of aberrations. The highest frequency of abnormal cells was found in those subjects who had the shortest duration of exposure (see tabic), and two cases (C and F) did not differ signific antly from the controls. A x` test of the frequencies of abnormal cells also revealed a significant deviation from homogeneity (p< 0-001). The negative correlation of the frequency of abnormal cells with the rime of exposure was not significant. Therefore, on the basis of the present data it is not possible to discuss the biological background of this heterogeneity. We thank the staff at KcmaXord, Srockviksverkcs, for cooperation and Miss Anita Tillberg for technical assistance. The expenses for the present study were covered by grants from the Swedish Medical Research Council (3681) and the Swedish Board of Occupational Safety and Health. Francisco Funes-Cravioto Department of Clinical Generics, Karolinska Hospital, Bo Lambert Stockholm, Swedot. Jan Lindsten. Department of Radiobiology, Tallenberg Laboratory, University of Stockholm, Sweden. Lars Ehrenberg A. T. Natarajan Siv Osterman-Golkar. 11. Court-Brown, VT. M. Human Population Cytogenetics; p. 17. Amsterdam, 1967. CHROMOSOMAL ABERRATIONS Of WORKERS EXPOSED TO VINYL CHLORIDE Subject? uwm'r (7) \ B c D E F G Titai (A-G) (7) Gaps No. of different types of aberrations of ea> penn <yr.) 0 9 9 12 IS 19 20 29 cell* analysed S66 200 250 250 200 150 200 200 1450 Chroma tid 5 22 IS 4 8 3 1 9 62 Isochromatid Chroma tid breaks Chro matid ex changes 1t liochro-j Dicentric* Ring jmatid | chromo- chxomcH breaks j some* tomes _________l * 4 4 l 4 2i l l 8 19 2 19 0 ! 0 14 24 l 17 5 l 6 5t 5 12 l 2 40 l 00 12 7 0 5 2; l 9 01 0 50 O 01 0 9 1j1 48 71 s 65 6 | 3 1 * A tot of heterogeneity gave j*47-72, 6 d.f., p <0*001. Other types 0 t 2 0 2 2 2 1 10 Total 12 41 48 14 24 11 3 19 160 No. of abnormal cells Total % 11 1-94 36 18-00 37 14-30 12 4 80 22 U-00 11 7-33 3 1*50 17 8-50 318 9-52* SPI-04717 TICE LANCET, FEBRUARY 22, 1975 */o? 459 . v: .1 .cs ...a. :cd ;,'C ,:h ,1c -iC ..out ..I, ..ills l.ti.,1'tc .>; lit . r. ru..u:i i; :,i .l-.tlA ,inld ..-y/.-l. r release of 'aw concentrations of proteolytic enzymes ir. the skin dee to the non-specific cytotoxic effects of bile salts couiii account for both 4'.c pigmentation and the pruritus of patients with chronic abstractive jaundice. Depirtniffl' ; Ottmatelovy, itr''1''i .-t'l'.u IrS.n-.iary, Bristol BS2 SHW. J. L. Button J. KtMV. CHROMOSOME ASET*RATIONS IN WORKERS EXPOSED TO VINYL CHLORIDE S;r,--Epidemiological evidence suggests that the risk of malignancy is increased in workers chronically exposed to vinyl chloride (v.c.).1-1 The carcinogenicity of v.c. has been demonstrated in animal experiments.* In-vitro ' and in-vivo * experiments suggest that the carcinogenicity of v.c. probably depends on the formation of an alkylating compound, presumably chloroethylene oxide. Since carcinogenic chemicals are often mutagenic,* we wondered if v.c. (i also mutagenic. In fact v.c. has been reported as inducing mutations in Satmmella typhimtrium in the presence of merabolicatiy active liver homogenates.1* If alkylation of d.n.a. by v.c. metabolites also produces chromosomal aberrations in man, chromosomal analyses could be used as an indicator of risk and also possibly be helpful in establishing a genetically meaningful maxi mum allowable concentration of v.c. We report an in creased frequency of chromosomal aberrations in workers exposed to V.C. Seven occupationally exposed male workers and three son-exposed control subjects, all employed in the same factory! were studied. The level of exposure to v.c. had continuously decreased during past years. In the weeks preceding the collection of blood-samples for chromosomal analysis (before the summer holidays in 1974) the air concentration in the polymerisation department was estimated to be 20-30 p.p.m. Workers had been exposed I. Creech, J. L., Johnson, M. N. J. eeciip. Mod. 1974,18,150. I. Lee. F. I.. Hnrrv, D. S. Loj-xtt. 1974. i, UlS. 3. Morion, R. A., Peters, J. M., Johnson, M. N. ibid. 1974, ii, 397. 4. Block, ). B.J. An. mod. An. 1974, 229, S3. 5. Holmberg, B., Molina, G. IFk. tnciron. HUH. 1974, II, 139. 3 Maltoni, C., Lefemine, G. Environ. Ra. 1974,7, 387. 7. Goihe, R., Calteman, C. J., Ehrenbcrg, L-, Wachmcister, G A. Amino, 1974, 3, 234. 4 Overman-Golkar, 5., SegerbJck, D., Ebrenberg, L. Unpublished. s. Miller, E. G, Miller, J. A. in Chemical Mutagens, Principles and Methods for their Detection (edited by A- Hollaemler); vol. 1, p. 83. New York, 1971. >0. Rannue, U., Johansson, A., Kamel, G, Wachmeiiter, C. A. Ambit, 1974, 3, 194. to v.c. for 9-29 years. Clinical examinations hid been carried our at regular intervals. None of the workers had showed disturbed liver function, signs of scro-oit ulysis or hxmitoiogicai changes, except for cate A in wh:rh there was slight thrombocytopenia ana ar. ..-br.titrm : . ni- ency. Chromosomal analyses were rrj.ee on cci:. . ventionai lymphocyte-culrare* incubated for A o.-a. 72 hours. Ail blood specimens and slides were codec usd analysed blindly. The result of the chromosome analysis is giver, in the accompanying tabic. The data for the control uro -cts were homogenous and therefore pooled. Altogether they comprised 566 cells, 11 of which (1-94%) contained ci.-c- moscmal aberrations. This finding might be expliir.es by previous diagnostic X-rays. Tac frequency of aberra tions nevertheless accorded with that of a male population selected a: random.11 1450 ceiis from the group exposed to v.c. were analysed, 800 in the 48-hour cultures and 650 in the 72-hour cu! cures. In none of the cases was there a statistically significant difference in the frequency of aberrations between the 43 and 72 hour cultures. Therefore these data were pooled. The frequency of abnormal cells in die group exposed to v.c. (9-52%) was significantly greater than in the controls (p< 0-001). This was also true for chromatid and isochro matid breaks when analysed separately, but not for the remaining types of aberrations. The highest frequency of abnormal cells was found in those subjects wbo had die shortest duration of exposure (see table), and two cases (C and F) did not differ signific antly from the controls. A g1 test of the frequencies of abnormal cells also revealed a significant deviation from homogeneity (P< 0-001). The negative correlation of the frequency of abnormal cells with the time of exposure was not significant. Therefore, on the basis of the present dura it is not possible to discuss the biological background of this heterogeneity. We thank the staff at KemaNord, Stockviksverken, for cooperation and Miss Anita Tiilberg for technical assistance. The expensea for the present study were covered by grants from the Swedish Medical Research Council (3681) and the Swedish Board of Occupational Safety and Health. Francisco Fcnzs-Cravioto Department of Qiiucsl Genetics, Karolinska Hospital, Bo Lambert Stockholm, Sweden. Jan Lindsten. Department of Radiohiology. Wallenberg Laboratory, University of Stockholm. Sweden. Lars Ehrenberg A. T. Natarajan Siv Osterman-Golkar. 11. Court-Brown, V7. M, Human Population Cytogenetics; p. 17. Amsterdam, 1967. CHROMOSOMAL AMRJtATTONS IN WORKERS EXPOSED TO VINYL CHLORID1 Subjects CtrtrL'vt (J) -Wsed: A 3 C O E F G tnot(A-G) (7) of ca poaure (rr.) No. of ceUa tnilywd Gtpc Chroma IsochnH tid matid No. of different type* of aberrations Chroma tid breaks Chro matid ex changes Iiochro-, Dicentric macid i chromobreaks | some* Ring chroma somes Other typ* O 564 5 4 41 42 9 200 22 3 19 2 19 0 9 250 15 14 24 1 17 1 12 250 13 200 4 3 6 51 5 12 1 52 90 19 150 3 2 40 50 20 200 i 1 00 l0 29 200 9 12 70 91 1450 62 48 71 5 65 6 10 01 12 1 02 02 0Z l1 3 10 Total 12 41 48 14 24 u 3 19 160 No. of abnormal eelk Total i-94 36 18-00 IVW 12 4-80 22 1100 u 733 3 1-50 17 3-50 318 9-52* A test of heteroeeneity gave x* " 47-72, 6 d.f., r < 00OI. - .---runti-- SPI-04718