Document Yr5yM819ORp0gO2pqkV75opy8

f 5^5/ > I d'"` Leonard Thiam,^ ScD.).Wjl^m .,>' . -'*.V^V . ;* - .'-v...TrnMaor; A crow Mdoml wortaftty itady i among current and former --ipkryuea^ during 1964-'19734a.pretontedr the plfrjegtfrafj tffy any angiosarcoma dMth.imOBfdP: fabricators, and (2) to examine the auto. No .angiosarcoma death*. were <<Mjf group. StteteetiyioipectfklT^wrtkjiii^i (PMR's) were computed, tiring.the tality at the standard. Among whUe emplgyea),; to be an excess hi total raiwr r shmUIII)] the digestive system. Ofasyyd -deaths^wt the expected hi cancers of the' brant aiirt artniiy organs among white females. Deficit mortality wasebeerved In cirrhosis of liver among both male and female white cm* P1***- The January 1974 disclosure of; "three deet|ov from angio sarcoma of the liver in a single vinyl chloridp^ptymerlation plane and the attention focused on this new occupitionaT.disease are well known. A significant amount of information ftpin animal ex perimentation and observation on humans engaged,tnjhe produc tion of vinyl chloride followed.1 However, there was. OP informa tion regarding the possible adverse effects on employees engaged in poiyvmyl chloride IPVC) fabrication, where potential exposures were thought to be low and to result from the release of unreact- ed monomer trapped in the resin. This issue was cbnsidered of great import because of the very iargenumberoiwarfcets believed to be engaged in fabrication. g in March 1974, representatives of PVC"producers, who are members ot the Organization Resources Counselors (ORC). Oc cupational Safety and Health Standards'Croup, contacted ORC about thefeasfcflity of a study df healthTSks' to employees'work ing with vinyl chloride and polyvinyl chloride. Srncethe National Institute for Occupational Safety and Health (NIOSHl was con ducting study of vinyl .chloride and resin producing employees, the scope of the proposed ORC study was limited toemployees of Sw Dwiwn of InMUMCi wd tpUMdopf, Ospamom-ef Cm<ixirr .MsAeMe and.AwsHuBcnrfvM--Sb. 0--fctoykof MeOe<ne. W*Mton.DC 20007 DuOaun m4 Wongi aniOiyanimiaaXmucw-Cowi- mbn, Me.. WuhMytan. DC 20006 Or. NfchoU.'- . ... ' ion of PVC resin into finished .'tfv ir ^ study designs was considered, was de^jjjgd ttij^jnjportioral mortality study would best urg^t need iev fiftorroation. The study concentrated on deaths occurring during thejten-year period 1964-1973 among ac- dye fabricating employees plus retirees. Since it was not possible to Identify those employees with only vinyl chloride exposure, the ' study focused on deceased employees who worked anywhere in those plants where PVC fabrication, was carried on. The primary .effective of the study was to determine whether or not any angio sarcoma deaths had occurred among employees of the fabricators tinder study.,A secondary objective was to examine the distribu tion of all deaths by cause. The relatively few producers of vinyl chloride monomer and of PVC resin are generally medium to large companies. PVC fabri cators, however, range from large plants of major companies to very small job shops. ven in a large plant, there may be few em ployees who are in the vicinity of PVC resins. The range of com pany plant size and number of exposed employees help to explain the wide range of estimates of total employment dependent upon PVC resins. Fabrication is geographically disbursed, with at least some operation in almost every state. Typical fabrication products include coated wire, upholstery fabrics, floor and wall coverings, pipe and other construction materials, toys, recreational equip ment, phonograph records, containers and container lining, and a myriad of novelty items. Since the fabrication of PVC resin into finished products is often a part of diversified product lines in a plant raw materials other than resin are utilized. Thus, employees may be exposed to toxic agents other than vinyl chloride. Conse quently. in the current study, it is not possible to isolate only the effect of vinyl chloride. Some departures from expectation may be due to exposures to vinyl chloride, to one or more other agents, to some combination, or to employee characteristics other than occupation. Materials and Methods The decision to focus on a crojtt-sectional mortality study rather than on an historical cohort storo derived from several con siderations. First the primary studfrgbjjeetive was to determine relatively quickly whether or not any,angiosarcoma deaths could be identified among the study group> and this was best ac complished by examining causes cm death among relatively recent tUwMMS Mm 4ovmM mt OucmocmI IMcM liMwiei 1*77 Vmmm* is. mo. e ass-taa RSV 0016565 (i.e.. past ten years) decedents. The desirability of identifying an historical cohort for follow-up was recognized, but it was deter mined that it would not be possible to identify clearly and com pletely the necessary cohort of workers within a reasonable period of time, if at all. As a consequence, this study is based upon 4.341 deaths which occurred during the period 1964-1973 among current or former employees of 17 companies engaged in PVC fabrication. A total of 55 plants supplied data on all identifiable deaths since, as was mentioned earlier, it was not possible to iden tify those emplovees with only vinyl chloride exposure for the study. In order to be included in this study, a deceased employee fell into one of the following categories: (II employee died while ac tively employed. 121 employee died after retiring from the com pany with retirement benefits, and (3) employee died after ter minating employment but with vesting in a company-sponsored life insurance plan. Deaths occurring among former employees with less than the number of years necessary for insurance vesting were not included m plant records and were, therefore, not available for this study. An attempt was made to compensate for at least some of the "leakage" due to employees leaving the industry prior to the time they were vested in any insurance program by using the following procedures. Once death records for a given company were iden tified. death certificates were obtained and separated into two groups as follows: (1) all deaths with cancer (ICDA 140-205 up to 1%7; ICDA 140-209 for 1%B on), or liver disease HCDA 580-506 up to 1967; ICDA 570-576 for 1968 on), or suspected liver con dition mentioned on the death certificate; and (2) all deaths from causes other than cancer or liver disease. Death records men tioning cancer or liver disease and giving a hospital as place of death were segregated and sorted by hospital. Where there were several death records for a single hospital or several hospitals in the same area, arrangements were made for a Registered Records Administrator (RRA) to visit the hospitals, review medical records contact the hospital pathologist and review pathology records to determine whether there were any angiosarcoma cases in the hospital's pathology records. If so, an attempt was made to deter mine whether or not the angiosarcoma possibly could be related to vmyl chloride exposure. This procedure enabled us to identify whether any employees, who had left the industry prior to vesting n an insurance program and remained in the local area, had died from angiosarcoma of the liver The hospital inquiry procedures turned up five deaths from angiosarcoma of the liver: according to company employment records, none were employed at any time in PVC fabricating plants. These deaths were reported to OSHA NIOSH. and CDC for inclusion in the nationwide angiosarcoma survey Death certificates not mentioning a hospital as a place of death required an additional step to determine whether death occurred in a hospital or if a recent hospitalization had occurred prior to death The certifying physician was queried by mail for in formation on recent hospitalization of the decedent and whether there was any indication that he or she had cancer or liver disease Additionally identified hospitals were contacted as above Originally, it was planned that death certificates would be ob tained from life insurance carriers. In practice, both company and life insurance records were used because of record retention prac tices and retrieval problems in the insurance carriers All available death certificates were examined by a trained nosoiogist for men tion of angiosarcoma anywhere on the certificate, and no angio sarcomas were found on the death certificates. Underlying cause of death was classified according to the eighth revision of the in ternational Classification of Diseases-' Over the ten-year period under study, plant size was found to have changed drastically in many cases. In one instance, a plant employing 300 employees in 1973 employed fewer than 10 in 1964. At the other extreme, one plant employing 5.000 people in 1964 had only 2.000 in 1973. Some companies had gone out of business. Such developments show not only the rapid changes taking place but also the difficulty of determining average industry employment The 17 companies covered in this report ranged from single plant small companies lone with 70 employees) to multiplant large companies lone with over 7,000 employees) Average number of employees clustered between 300 and 500 Although total employment is difficult to determine preciselv. it is estimated to have been between 65.000 and 70.000 at the end of 1973. Since the population at risk could not be determined, mortality rates as measures of risk could not be calculated Rather results were summarized in terms of Proportionate Mortatitv Ratios (PMR> adjusted for the age distribution of the study group The PMR uses relative frequencies of specific causes of death by age in a com parison population to obtain expected numbers of deaths from that cause in the study population. Selection of an appropriate comparison population poses some difficulties since it would be desirable to have a cause of death distribution for a similar group of workers dying during the same period, but not subjected to the factor under study. But such a comparison population was not available, and the study used mortality for the United States, specific for color and sex. for comparative purposes ' Despite recognized deficiencies, the PMR can provide clues on unusual distributions of causes of death where true rates cannot be calculated Results Table 1 gives the distribution of deaths among the employees of the 17 PVC fabricators within each of the ten years An increase in the proportion of deaths taking place in later years of the decade may reflect a variety of factors, such as an increasing employee population, less complete availability oi records for earlier years (e g m one company, there were no records for the first four of the ten years), increase in duration of exposure, etc. However, there is no reason to believe that any unavailable death records for earlier years would be concentrated in a few causes and thereby bias the distribution of deaths for those years TM l. -- DMMw if OmUr Amnc Empfeywt PVC Fabricators by Vaar al Otath, 1944-1973. 17 Vmt at Doatk 4IM IMS IMS 1M7 IMS IMS 1970 1971 1972 1973 ToM No. 32S MS *00 479 499 449 465 471 sn 430 4941 7.S 80 97 99 IIS 103 10 7 109 122 99 100 RSV 0016566 Tan X --Ttili min e* ttatfce tmmc Ii^Iiiim 'w4 17 PVC TihrheMn % 'Mr mV In. 1M4-U73. . .... ' * tat ~ TotM W NW*l4e IMaeOTi itm 041 9M 204 m -- Mi 367* 3241 110 241 - ' *> 'fM 663 V 601 2* 31 .OMm ' t\-. 0 0 2 The distribution of deaths in the study group by race and sex is given in Table 2. Most deaths <84.7%) occurred among males The vast maiority (66.7%) of decedents were white and there were 288 (6.6%) for whom race could not be determined. Table 3 shows this distribution of deaths by age. For both white male and white female employees, more than half of the deaths occurred*among those aged 65 and over (58.1% and 51.9% for white men and white women, respectively). The corresponding proportions of deaths which occurred after age 65 in the United States population in 1968 were 59% and 72%. respectively). The higher proportion of deaths among white women over 65 in the U S population compared to the employee population may indicate that relatively fewer women work to retirement age than do men. While the numbers of deaths among nonwhite employees are too small for any definite conclusions, the distribution of deaths bv age among nonwhite men is roughly comparable to that for the total United States. Tables 4 and 5 show the distribution of deaths for selected causes by sex for whites and nonwhites, respectively Among white men. nearly 60% of the deaths are from diseases of the cir culatory system IICDA 390-458) and 20% are deaths from cancer (ICDA 140-209) The corresponding percentages for the total U S population of white males in 1968 imidpomt of the study period1 were 54% for diseases of the circulatory svstem and 16% for can cer. Digestive and respiratory cancers account for somewhat less than two-thirds of all cancer deaths among the white males in the studv group as compared to about 59% of all cancer deaths among U S. white males in 1968. For white women, over 46% oi the deaths are from diseases of the Circulatory system (compared to 57% for all U S white women in 1968>. and 30% were from can cer (compared to 18% for all US white women in 19(>8' Somewhat over half of the cancer deaths among white women m the study were from cancers of the breast and digestive svstem. about the same proportion as for all U5. white women m 1968 About two-thirds of the deaths for both nonwhite men and women were from diseases of the circulatory system and from cancer The numbers of deaths for most causes among nonwhites however, are quite small making interpretation difficult and are presented mainly for completeness. Age-ad|usted PMRs for white male and white female employees of the 17 PVC fabricators are presented in Table 6 for selected causes of death. There were no similar analyses for nonwhites because for nearly all causes, the numbers of deaths were too small to produce stable PMRs Expected numbers of deaths have been calculated on the basis of the sex-cause-age specific distribution of deaths among U.S. whites m 1968 applied to the total number of deaths by age among white men or white women in the studv group. The midpoint of the study period (1968) was selected tor the standard, since it is representative of the studv period and provides U.S. mortality data coded according to the eighth revision of the International Classification o' Disease*- peered number* are deaths for individual causes to be expected m the studv group if the proportion of total deaths ascribed to a given cause were the same as for the corresponding U S race-sex group, while accounting for differences between the age distributions of deaths in the study groups and deaths for the United States A PMR larger than unity would indicate that the relative proportion of mortality from that particular cause in the study population is higher than would be expected based on the 1968 U S. mortality experient rStfdftron to the nurVferical value of the PMR itself, the ob served number of deaths is also of interest. The larger the number oi deaths observed, the more reliable the PMR There were two deaths oi unknown age among the white males, one a digestive cancer IICDA 153) and one an unspecified cancer (ICDA 1991. These were included in the age groups with the lowest relative frequency for those causes, that is. less than 35 vears for total can cer and digestive cancer and 65 and over for other and un specified cancer Such an assignment has a trivial effect on the ex pectation but is the most conservative wav of handling these unknowns since n serves to increase the expectation land hence lower the PMR' bv the least amount Based upon both the number of deaths and the value of the PMR tnere seems to be an important excess in total cancer morta'its among the white males in the studv group The distribution b>. specific cancer site suggests that any excess appears to be con- Cabr. tai WlXlt MM FnM Hewebut Mm ftnta Unkrmft MM fcmic Unworn Tata Ml t*i He % 1 1 1 el Deaths Mnef* EmptoyMt o* 17 PVC Fabricator! fay *t*. Color, Sax. 1964 1973. IMv IS H*. % J5-4* He X 4f 4S-5* He % 55-64 He % 65 6 tw He % 37*1 100 107 601 too 24 3.3 136 40 42 4? 36: it? 7S2 23 7 1006 SOI 70 100 166 123 70S 312 SI 9 tao too 24 100 21 6 n7 750 74 133 2 63 26 IS 6 S 70S 39 71 7 6 750 60 37 0 5 208 246 100 36 too 2 100 20 1 l It 76 SOD 5 20 S 13? 00 3? 129 4 I0S 0 *8 194 21 I 0 13: $7 0 10 47 < 00 UtUwn Ne 1* 2 01 00 00 00 12 40 2 53 t 500 RSV 0016567 centrated in digestive system cancer, given the large number ot deaths (31^ ot all cancer deaths). For each of the sites withm the digestive system, observed numbers of deaths are greater than ex pected Although, except for intestinal cancer the observed num bers of deaths are small The PMR for liver cancer is rather high out a definite conclusion is difficult with only six observed deaths On the other hand, the PMR for cirrhosis of the liver suggests a deficit in mortality from that cause. For white women, the PMR for total cancer appears high as it did for white men, with cancer of the digestive svstem and perhaps, cancer of the breast contributing a fair amount to the ex cess. The PMRs for individual sites within the digestive svstem are based upon small numbers but suggest an increase m intestinal cancer. The PMR (or urinary cancer, though based upon onlv n deaths, seems strikingly high and may be an indication for lurther investigation. On the other hand, in contrast to the observation in white men, the PMR for respiratory cancer among white women is verv close to unity. Similar to the observation in white men. mor- taluv from cirrhosis of the liver seems to be m deficit, but the corresponding ooserved number o' deaths is quite small Among both white male and female employees, diseases of the circulatory svstem account for a large percentage of total deaths In each case observed numbers of deaths are close to expected There appears to be a somewhat different pattern among men and women for deaths due to accidents, poisonings, violence with the nurnoer of deaths somewhat low among men and high among women There were 39 cancer deaths among nonwhite men, somewhat greater than expectation, although the numbers by site are too small tor meaningful analysis Mortality trom cerebrovascular disease appeared high (PMR 2 11) but the finding was based upon only 19 deaths. Discussion The present study was designed with two objectives The first was to determine whether or not any angiosarcoma deaths had RSV 0016568 Talto . -- Obaarvad aad Expect** Daatks far tilled Cmm Am* C--liyeu 1 17 FVC rtrtcmn to Sax, *Mta Oaly, 1984-1973- Cm* at baft Ml Cmm* fecal Cany M raw OittMM System Slowm Menme Rectum 1MT IhmW) System Let feme. Coma** Ten* SXn fees! treat Cemtil Orpns Urmy Oners Bum i Diner Renew System Ottw t UnseeertM IsSma Cktietes OlMflB * ttc Croiietny System CerWrmsarir Dnenst Cerhot* at ClwletithiHS. ChoMcystitft. end CiWengnu Ataaenti Pending. *nfl Viowm Arcmems Sued* KM M few. HMDS 1*0-149 SSO-ISJ IS) m 154 1SS 140-13 1S2 tro-iTt 174 ItQU? 188 189 19U92 190. 193-199 200-203 208 209 204-W? ;w 390458 430438 571 574-575 800-4999 8004949 E9504949 tftevw* m 15 209 41 73 25 205 193 24 0 44 36 16 56 42 19 4? 1931 289 4? 188 13* 40 * Mi.997 16875 162143 31507 $2528 19631 4 190 176 EST 165 566 15117 -- 52828 33131 13 885 34 607 32.382 23364 49 600 1832 5)5 292074 62821 6 349 265.346 189 268 52 325 m 119 089 1J9 130 139 127 143 116 1.17 159 083 109 MS 162 130 081 085 105 0.99 0.67 MO 0.71 071 0 76 t 181 3 53 8 24 1 0 32 12 SI 44 19 11 4 18 9 1 11 281 66 3 3 48 38 2 two* tm 1H14 137.699 1896 35 342 4.981 15 344 3 877 0.633 11888 22* 35 661 32.39? 23.297 4.537 3499 9.622 7 631 5 005 15436 309232 71.96$ 12343 1 783 40 855 27 931 9171 Ml 158 156 161 156 206 -- too 107 1 43 136 087 2 42 1 14 1.87 1U 0.20 07! 091 0.9? 0 24 1 6* l 17 1 36 0 27 PMfi is 11* ratio of observes to MOKIW mpr ine t<eitO vi'nw > ulCuUtM on in* Mm o* tor Oist'ioution c* 4atM ror Rk total IIS rr 1948 soecitic >o> uigr ui cause t'v: ate occurred among employees of the PVC fabricators under study. Since no angiosarcoma deaths were found among the employees studied, the first question has an unequivocal answer, A secondary objective was that of examining the distribution of deaths bv cause among the employees under studv. implicit in that objective is the question ot whether or not that distribution is. >n some sense, unusual. There is no unequivocal answer to ihp latter question. Whether or not an observed distribution o; causes of death is unusual clearly relates to the standard or comparison population as well as the analytic methodology - On the basis of a proportionate mortality analysis, there appear to be excesses in total cancer mortality among both white men and white women in the study, when compared to the distributions of deaths for the total United States specific for color and sex and adjusted for age Excesses in cancer mortality appear concentrated in cancers of the digestive system and. in particular. In cancers of the intestine for both men and women in addition, there is a suggestion that mortality from cancer of the breast and urinary organs among white women employees is higher than that for the total U.5. There are. however, several reasons whv definitive interpretation is difficult. It has. for example been suggested that a Proportionate Mortality Ratio based on an exter nal population mav not be sufficiently discriminating in screening for potential hazards.' In addition, an analvsis using PMRs tails to take account of the absolute risk ot dvmg in the population under study6 Furthei a number of studies have suggested an overall favorable mortality for industrial working populations, even in those where well-defined hazards increase risk for a specific cause' " Factors such as these are meant to suggest that proportionate mortality analysis must be interpreted cautiously, with the intention of providing leads for further investigation. Results consistent with those of previously published studies would be o< particular interest With no comparable working populations m the fabrication industry, potential contrasts may be round in studies of vmvl chloride workers Monson et al. provided a proportionate mortality analysis of 161 deceased workers (all presumably white males! in two plants, one where vmvl chloride monomer is produced and one where it 15 polymerized into polyvinyl chloride* Results of that studv suggest a possible excess in total cancer mortality, primarily cancer of the RSV 0016569 liver- However, there was a suggestion that cancers of the lung and brain also appeared with excess frequency The current study, while suggesting an excess in total cancer, particularly digestive cancer, does not clearly point to marked excesses for cancers of the liver, lung, and brain among white men. although the PMRs for these cancers are greater than one. The observed-to-expected PMRs reported by Monson for vascular lesions affecting the cen tral nervous system, circulatory diseases, and external causes are similar to those reported here. Tabershaw and Caffey. in a study of workers engaged in the manufacture of vinyl chloride and its polymers, conclude that no specific cause of death was statistically significantly greater than expectations based upon Standardized Mortality Ratios ISMRsi using the U S male population as the standard.* By other criteria, however, the authors conclude there may be an excess risk for mortality from digestive cancer, respiratory cancer, cancer of other and unspecified sites, and lymphomas At lower exposure levels, they suggest some excess for cancers of the buccafcavity and cancers of the other and unspecified sites The current study would seem to indicate that excesses of mor tality from cancer of the digestive system are not sex-specific and are not limited to liver cancer The maiontv of the PMRs tor cancer among both white men and white women are in excess of unitv Such resuits must be interpreted with caution but. since thev ap pear to be consistent with previous!*, studied workers thev suggest the need for continued investigation SWnmary Results of a study of 4.341 deaths occurring among current and former employees of 17 PVC fabricators during the period 1%41973 are presented The study was earned out to determine whether any angiosarcoma deaths had occurred among em ployees of these fabricators and to examine the.djstribution of deaths by cause./tqfcpgkitcoma deaths were found-gnong the stu^y populattonuistributions by cause of death among white male and white female employees were compared with those ror the entire U.5 . specific for color and sex and adjusted tor age bv means of Proportionate Mortality Ratios! rurinarydfgfiiMiy * [fib excesses were found for diseases of the cir cularory"systemThere were deficits in mortality from cirrhosis of the liver among both male and female employees and a deficit m accidents, poisonings, and violence among men The use of the Proportionate Mortality Ratio based on an external standard requires caution in interpreting these results but the need for fur ther investigations is indicated. This study *ii sponsored bv the tollowtfvft organizations Amenta* Cm Comp*"*' B F Goodrich Company Diamond Shamrock Corporation Fe*ione Tire jnd Rubhe' Comp4nv lohn* Moior VehcV MjnuiKfuffrs Aktrxuim Suurter C***nte*< Comoanv Union Cjrb*dn Corporfttaon inroprKjtntf References 1 Selikott i[ and Hammond EC (Ed* 1 Toxica* oi vinvl chloride -- polwmvl chloride Ann \ V Acad So 244 1975 2 Manual of (he International Classification of Disease* Adapted tor Use m the United States Eighth Revision Washington. DC US Cost Priming Office 1967. Vol 1 3 National Center For Health Statistic* Vital Statistic* of the United States 1966 - Volume II - Mnrtalitv Pari A Washington DC US Govt Printing Office. 1972. pp. 140-205 A Ch.azae 1. Problems oi sludv design and interpretation of industrial mortality experience. IOM 18-169-170 1976 5 Redmond Ck and BretUo PP' Comparison o' method* id assessing o< cupationa! hazards /0\ 17 313-317 1975 6 Monson RR. Peters |M. and lohnson MN Proportional mortality among, vinvi-chloride worker* lanrrr 2 397-398 1d'4 7. Llovd IW and Ciocco A Long term mortality sludv oi steelworkers I MwhodolCigv OM 11 299-130 1969 8 Redmond CK Ciocco A Llnvd IW jnd Rush H\V long term mortality studv oi vteelworkeis IV Mortality iron* malignant neoplasm* among coke oven worker* /Oif 14-621-629 19*2 9 Tabershaw IR and Caffev WR Mortality studv of workers m the manuracture oi vinvl chloride and US polymer* (O'l 16 509-51B. 1974 RSV 0016570 N t ZT OM r Of povas tim the vas aer itic ritto .tly by vas ace * in* i; 1-4 ion ;ht axe in bl ind *'cr to erdexa5> ttly ST^s^ ^JLY 6, 1968 ORIGINAL ARTICLES THE LANCET 21 Discuislon We infer that hypcrexriubility of the nervous system can be associated with hypomagnesemia without Con comitant hypocalcemia. This Observation accords with the findings of Vallee et al. (1960) but not with those of ocher workers (Hanna et al. I960, Zimmet et al. 1968) who have claimed that a low serum-calcium arising from the hypomagnesemia is necessary to produce the signs seen in the hypomagneszmic syndrome. One should not conclude from this association that the hypomagneszmia caused the tremors or convulsions, although this seems likely in view of the fan that mag nesium levels returned to normal on recovery. Further more, the dose of-magnesium in six of the cases was not large enough to cause drowsiness yet the cremors were quickly controlled. The cause of the low serum-magnesium is unknown. Since some of the cases recovered spontaneously within a day or two, it is possible, at least in some of the patients, that the hypomagneszmia was due to a transient shift of the mineral from the extracellular to the intracellular compartment. The feasibility of such shifts has been mentioned by Martin et al. (1952), and Hasselman and, Van Kampen (1958). It is possible that because of metabolic alterations in the neonatal period and in children who are ill, the magnesium homasostatic mechanism might not be functioning efficiently. A decreased serum-magnesium could, in turn, stimulate the parathyroids to release parathormone in an attempt to conserve magnesium (MacIntyre et al. 1963). At the same time the excess parathormone would raise blood-calcium, thus accounting for the elevated ultrafiltrable calcium level. The combination of hypomagneszmia and hypercalczmia is not incompatible with the production of hyperexcitabilicy of the nervous system. In magnesiumdeprivation studies in rats, the animals demonstrate hyperirritability, hypomagneszmia, and hypercalczmia (Whang and Welt 1963). -Furthermore, rhere is evidence to suggest that calcium specifically facilitates the release of acetylcholine by a nerve impulse (Fatt 1959) and that the action of excess magnesium is to cause a block in neuromuscular transmission by decreasing the amount of transmitter substance released at nerve terminals (del Castillo and Engbaek 1954). Hence a combination of hypomagneszmia and an elevated calcium concentra tion may act synergistically in facilitating acetylcholine release, thus accounting for the neuromuscular irri tability seen in our patients. This antagonistic action of magnesium and calcium at nerve-endings contrasts with their common action in raising the threshold depolarisa tion for the initiation of an action potential in a nerve or muscle fibre (Fatt 1959). We thank Prof. J. E. Gardiner for help in the preparation of the paper. REFERENCES del Catcillo, J., Engbaek, L. f 1054) J. Pkyual., Land. 124. 370. Fatt. P. 11959) in Handbook of Physiology, lection s: Neurophyiiolofy vol. t (edited by J. Field); p. 209. Washington. FUnk. E. B,, McCotliuer, R., Prasad. A. S., Melby, J. C-, Doe, R. P. (1957) Ann. inttrn. Ated. 47, 956. Hanna, S., Harrison, M., Maclmyre. I., Fraser, R. (I960) Loncti, ii, 172. Hauelman, J. J. F., Van Kampan, E. }. ; 195BI C/m. chimuo Ana. 3, 305. MacIntyre, i,, Boss, S-, Troughton, V. A. (1965' S'aiure. Lend. 196. 1058. Martin. H. ., Mehl, ]., Vt ertman. M. (1952) .Urd. Clm \. Am. 36, 1157. Monday, K. A.. Mahy, B. VC. (19641 Ch. chtmtcj Acia. 10, t4. O'Brien, D., ibbon, F. A. (1962; Laboratory Manual of Pcdiamc Micro- and Uftnmicro-Biochemical Techniques. New York. Vallee, B. L., VTacker, W. E. C.. Ulmer, D. D- (I960) Sn Enft. J. Mtd. 262. 155Wek, L. G., Gitelman, H. J. (1965) Dis. Month, May, p. 1. Whang, R., Welt, L. G. (1963) J. c/m. /. 42. 305. Zimmet, P., Breidah), H. D,, Nayler, W. G. (1966) fir. mrJ J. j, 622. AN ADVERSE EFFECT OF POLYVINYLCHLORIDE! TURIN(1 USED IN EXTRACORPOREAL CIRCULATION Helen N. Duke M.B., Ph.D. Edin. SENIOR LECTURER IN PHYSIOLOGY, MIDDLESEX HOSPITAL MEDICAL SCHOOL, LONDON W.l J, R. Vane B.Sc. Birin., B.Sc., D.Phil. Oxon. PROFESSOR OF EXPERIMENTAL PHARMACOLOGY, INSTITUTE OF BASIC MEDICAL SCIENCES, ROYAL COLLEGE Of SURGEONS OF ENGLAND, LONDON W.C.2 The pulmonary vascular resistance is ummary by ventilation hypoxia both in isolated perfused lungs from cats and in anzsthetised cats under conditions of circulatory control. This effect of hypoxia also occurs in man and dog. The pulmonary blood-vessels of isolated perfused cats' lungs do not respond to hypoxia when the perfusion circuit is partly made from polyvinylchloride (r.v.c.) tubing. Normal pulmonary vascular responses to noradrenaline, 5-hydroxy- tryptamine, and prostaglandin F;, are still obtainable when the response to hypoxia is abolished. It is suggested that a new British Standard should be devised to cover the acute effects produced by injection into the body of fluids which have been in contact with r.v.c. tubing. Introduction Adverse effects have been shown to follow the use of polyvinylchloride (r.v.c.) tubing in normal laboratory procedures. Stewart and Sturridge (1959) found, for instance, that some types of tubing caused hzmolysis of the blood perfused through them. Meigter and Durrer (1959) and Meyler et al. (1960) found that isolated rats' hearts were killed within 15 minutes when perfused with fluid delivered through some types of r.v.c. tubing, where as when the same fluid traversed glass tubing the isolated heart preparations survived many hours; they ascribed the toxicity to the presence of organic tin compounds in certain kinds of r.v.c. tubing. Haberman et al. (1968) described harmful effects of plastics and their component materials on reactions involving human and rabbit antibodies, guineapig complement, and serum-proteins. Few, if any, of the commonly used components of plastic tubing were without effect on their test systems. Bowery and Lewis (1968) found that substances were leached out of r.v.c. tubing which contracted guineapig isolated ileum and inhibited the contractions of the rat uterus induced by many substances. Considerable amounts of activity were added to plasma after 10 minutes' contact and these reached a maximum after 60 minutes. The leaching process occurred again and again each time fresh plasma was added. The amount of activity leached out was directly dependent on the protein concentration in the plasma, and this dependence was also demonstrated with purified bovine albumin solutions. Methods Isolated lungs of cats anzsthetised with chloralosc (80 mg. per kg. intraperitoncally) were perfused by the method of Duke (1951). A Dale-Shuster pump was used to perfuse rhe lungs through the pulmonary artery (fig. t). The perfusion was maintained at constant minute volume inflow with the animal's own heparinised blood (10 i.C. heparin per ml.) at a temperature of 37-39*0 The volume of blood in the apparatus was approximately 120 ml. The venous outflow from the lungs was led through a left-atrial C3nnula into a venous reservoir which RSV 0016571 JULY 6, 1968 r ORIGINAL ARTICLES THE LANCET 23 The pressor response to anoxia was also abolished when the P.v.c. (10 k.e.) tubing added to the venous reservoir had been previous!)' boiled in 2/0 sodium-bicarbonate solution. Some P.v.c. tubing contains different chemical additives from those in 10 K. The experiments were therefore repeated using one of these--N.T. 14 SH 80, which is said to be more suitable for perfusion work (Vincent 1968). In one experiment 60 cm. of this tubing abolished the pulmonary pressor response to anoxia, and in another experiment the pressor response was reduced. In both experiments there was a partial recovery of the anoxic pressor response 5 minutes after the tubing was withdrawn from the venous reservoir. Discussion Hypoxia causes an almost immediate increase of pulmonary arterial pressure in anassthetised cats (von Euler and Liljcstrand 1946, Logaras 1947) and also in anssthetised cats with left-lung perfusion (Duke 1957). In isolated lungs from cats perfused with blood at a constant minute volume, hypoxia causes a similar increase ofpulmonary vascular resistance with similar time relation ships to that in the anssthetised animal. The pulmonary pressor response to hypoxia is not accompanied by changes in bronchial resistance to airflow or left atrial pressure (Duke 1951, see also Duke and Lee 1963, Daly and Hebb 1966) and is therefore probably due to pulmonary vasoconstriction. In isolated perfused lungs from cats the pressor response to hypoxia of 3-15 minutes' duration is inversely related to the tension of oxygen in the ventilating gas mixture for gas mixtures containing less than 15p0 oxygen in nitrogen; equivalent effects are produced by ventilation of isolated perfused lungs with neon, hydrogen, or nitrogen (Duke 1951). It appears therefore that the pressor effect of ventilation hypoxia that has been studied ih the present series of experiments is a physiological response in the cat, and that the response obtained when the gas mixture is changed from air to nitrogen varies only in degree to the effects produced by changing the ventilating gas mixture from air to 15o or less oxygen in nitrogen. Evidence that pulmonary vasoconstriction to hypoxia is found in man and other species as well as cats was discussed by Duke and Lee (1963) and Daly and Hebb (1966). The present experiments show that the pulmonary pressor response to hypoxia is abolished by p.v.c. tubing. It is therefore possible that procedures involving the use of plastic tubing in man may be attended by hithertounsuspected harmful effects. Such procedures include extracorporeal circulation, renal dialysis, and even bloodtransfusion. In the present experiments two different types of tubes were used, both of which are listed in the current manu facturer's catalogues as of " surgical non-toxic quality The plasticiser was acetyl-tri-n-buryl citrate in epoxy soya-bean oil. The stabiliser in the H.E. tubing was of an occyltin type, whereas the stabiliser in NT 14 SH 80 was a calcium-zinc compound. The latter type of tubing had a less harmful effect in our preparation. The manufacturers of the tubing state (Vincent 1968) that acetyl-tri-n-butyl citrate and small amounts of epoxy soya-bean oil are listed under the U.S. Food and Drug regulations as suitable for food packaging, as is also the calcium-zinc stabiliser. Both types of tubing used in the present experiments comply with the re-' quirements of B.s. 2571: 1963 which specifies maximum permitted weight changes when a plastic disc is immersed in distilled water fot 48 hours. The tubing also con forms with the rabbit implantation test laid down in MIL-C-36145A (BuMed.) Oct. 16, 1963. In addition, the NT tubing complies with B.s. 2463 (specification for transfusion equipment) appendix F which uses a toxicity test in mice injected with eluates from rubing heated at 85aC for 1 hour. Mouse fibroblast and 10-day chickembryo tests are performed by the factory. These tests of biocompatibility are designed to establish the safety of P.v.c. either as a chronic implant or in a simple trans fusion apparatus and may be completely unsuitable for testing the potential toxicity of the large amounts of plastic tubing used acutely in an extracorporeal circula tion. British Standard 2571: 1963 allows a loss in weight in 48 hours of 20 mg. from a disc weighing about 4-4 g. In our apparatus, which might be regarded as a small-scale cardiac bypass circuit, 60-120 g. of P.v.c. tubing was used; the British Standard would have allowed the leaching out of between 1 and 3 g. of material into the circuit, to reach a concentration of 20 mg. per ml. (20) in 48 hours. Assuming steady leaching over 48 hours, the allowable concentration of material in the circulating blood could attain at least 0-4 mg. per ml. in 1 hour. Our results suggest that the toxicity of substances associated with the manufacture of P.v.c. tubing should be further investigated. They also suggest that a new British Standard should be devised to cover the use of such tubing in extracorporeal circulations. Requests for reprints should be addressed to ]. R. V., Department of Pharmacology, Royal College of Surgeons, Lincoln's Inn Fields, London 'X'.C.l. REFERENCES Bowery, N. G-. Lewis, C. P. (1968) Br. J.'Phermac. (in the press). Daly, 1. dc 8., Hebb, C. O. (1966) Pulmonary and Bronchial Vascular Systems. London. Duke, K. N. (1951) Q. Jl exp. Phyiial. 36, 75. -- (1957) J. Phyitel., Lend. I3S, 4S. -- Lee, G. de J. (1963) Br. mtd. Bull. 19. 71. Haberman, K., Guess. W. L-, Rowan. D. F., Bowman, R. O., Bower, R. K- (196S; S.P.E-Ji, 24. 62. Kontell, H., Rossler, R. (1940) Arch. tip. Path. Pharmai. 195, 71. Logans, G. (1947) Acta pnyuoL tcand 14, 120. Meigler, F. L., Durrtr, D. (1959) Vox. tan/. S, 239. Meyler, F. L., Willebrands, A. F., Durrer. D. (1960) Circulation Rtt. 8, 44. Stewan. J. VC'., Sturndge. M. F. (1959) Lanctt, i, 340. Vincent, T. VC. (1968) Personal communication. von Euler, U. S., Liljestrand, G. (1946) Acta phyiiol. stand. 12, 301. OXIDIZED GLUTATHIONE LEVELS IN ERYTHROCYTES OF GLUCOSE-6-PHOSPHATE- DEHYDROGENASE-DEFICIENT SUBJECTS Satish K. Srivastava Ph.D. Lucknow RESEARCH SCIENTIST Ernest Beutler M.D. Chicago CHAIRMAN DIVISION OF MEDICINE, CITY OF HOPE MEDICAL CENTER, DUARTE. CALIFORNIA 91010 _ Oxidised glutathione (g.s.s.g.) was esti* maced in normal erythrocytes and in erythrocytes deficient in glucose-6-phosphate dehydro genase (o.-6-P-D.) using an improved method in which the oxidation of glutathione was prevented by prior alkylation with N-ethyl-maleimide. The content of G.S.S.G. in the erythrocytes deficient in g.-6-P.d. was about 3 times that in norma! erythrocytes. RSV 0016573 34 JULY 6, 1968 ANNOTATIONS THE LANCET Annotations when ethylene oxide reacts with saline, and this substance can be expected to be present when material contaminated by ethylene oxide is in contact with tissues. Irradiation WHAT'S IN P.V.C.? (another means of sterilisation) can render P.v.c toxic Last year,' discussing situations which may airise after by the formation of hydrochloric add. Materials other prolonged endotracheal intubation or tracheostomy, we than plastic can adsorb ethylene oxide--for example, remarked particularly on the excoriation of the mucous rubber, polyethylene, and soft nylon--and all traces ofthe membrane of the trachea, which, it was suggested, resulted gas must also be extracted from these substances. Smith T from pressure necrosis, very much as in a bedsore. Since reported skin reaction in wearers of rubber surgical gloves red mineralised rubber had been suspected of causing chemical irritation of the lining of the trachea, the sterilised with ethylene oxide by a manufacturer. Over five years have passed since Little and Parkhouse * increasing use of polyvinylchloride (p.v.c.) in the manu recognised the potential hazard of inflammation caused by facture of endotracheal equipment was welcomed, for this plastic was generally held to be inert. Guess and Stetson 1 2 chemical additives is plastics and drew- attention to the 3n4ee5d6 for a standard spedficarion for plastics used now emphasise, however, that p.v.c. can contain agents medically. (such as organic compounds containing tin, added to improve flexibility and stability) which may leach out and damage tissues with which they are in contact for a Tong time. In experiments with plastics Guess and Aurian 1 observed tissue reactions which closely resembled the changes seen in the region of the glottis after prolonged endotracheal intubation; and these findings stimulated Guess and his colleagues to study the possible ha2ards of plastic in endotracheal equipment. After these investigations a committee met in New York last December to discuss a formulation of P.v.c. suitable for endotracheal use, and the American and European manufacturers present agreed that, in the absence of a relevant specifica tion of the British Standards Institute or of the U.S.A. Standards Institute, they would adopt, as an interim measure, the U.S. military specification for plastic used in endotracheal rubes/ which is based on freedom from toxicity when implanted in rabbit muscle. As RendellBaker1 points out, anyone about to use plastic endo tracheal apparatus for long-term care should verify that the p.v.c. is of the new formula. A large manufacturer in the U.K., Portland Plastics, is now making such equip ment from plastic which meets the recommended U.S. military' specification. As a result of their observations recorded on p. 21 Dr. Duke and Professor Vane suggest that a new British Standard should also be devised to cover the use of P.v.c. tubing in extracorporeal circulations. They found that the pulmonary blood-vessels of isolated perfused cats' lungs did not respond in the normal way to hypoxia when the perfusion circuit was partly made from P.v.c. tubing. In their experiments two different types of tubing were used: the plasticiser in both was acetyl-tri-n-buryl citrate in epoxy soya-bean oil *; and in one the stabiliser was of an octyitin type and in the other it was a calciumzinc compound. The second type had a less harmful effect on the cat-lung preparation. The adsorptive property of plastic introduces another possible hazard, for traces of toxic substances used in sterilisation processes may linger, despite all efforts to remove them. Cunliffe and Wesley have shown that p.v.c. sterilised with ethylene oxide always retains traces of this toxic gas and they recommend the utmost care in removing all traces by long-continued extraction. The very toxic substance, ethylene chlorohydrin, is formed THE FAMILY PLANNING ACT At the national conference of the Family Planning Association in Leicester last week, Mr. Edwin Brooks, the M.P. who sponsored the Family Planning Act, looked back on what had happened (or not happened) in the year since the Act was passed. It had never been his expectation that the Act would automatically eradicate the effects of forty years' delay and timidity on the pan of society in general, and many local authorities in particular, towanls family planning. The very success of the campaign would have lulled many local authorities into believing that the only change brought about by the Act w-as one of nomenclature and formal responsibility. Moreover, local government committees dealing with the welfare services had become accustomed to see their activities as essentially a matter of spending, of outlay, or of entries in the debit account: benefits were usually intangible--a son of social wellbeing to be measured and vindicated by largely subjective criteria, such as the relief of suffering or worry. This produced a dichotomy of approach, in which we were always conscious of the financial outlay, but rarely of the financial reward. Those who had come to think of themselves as charities for thedeserving poor were in danger of forgetting that they too were getting a return on their effons. Society as a whole --not just the woman helped, say, by a domiciliary familyplanning service--was the beneficiary of planned parenthood. In Mr. Brooks' view cost-benefit realism was generally absent from the day-to-day thinking of those who planned and controlled local-authority expenditure. A common argument about family planning was the one recently deployed in the County Councils Gazette : " Quite apart from widely held religious beliefs and long established standards of morality, as Education, Children and Health authorities they (county councils) will wish to take into account mental and physical health hazards. Rightly they will tend to proceed with caution and the Government's curbs on public expenditure will re-inforce this tendency." Justifiably, Mr. Brooks lashed into this " depressing and dated " outlook. At a time when the vast majority of educated families, of all religious persuasions, accepted contraception as one of the boons of civilisation, it was time to be a bit less timorous 1. Lancet. 1967. i, 2S8. 2. Cum,. \X'. L., Station, B.J. Am. meA. An. 1968. 204. $80. 3. Gum, V. L., Autian, J. Am. J. Hetfi. Phorm. 1964, 21, 260. 4. U.S- Military Specification lot Tube. Endotracheal, Mepll-MIL-C- 36I4SA (Bu Med), Oct. 16, 1963, amended by document 61IS-8171205, Jan. 20. 1967. 5. J. Am. med. An. 1968, 204, 624. 6. Cunliffe, A. C., Wley, F. Br. med. J. 1967, i, 575. about the " widely held religious beliefs ". With the human species on the edge of demographic disaster, with world over-population an overriding menace, it was time 7. Smith, E. A. U.S. Bureau of Science, 1968, no. 679 (Dnifi). 8. Little, K., Parfcheuie, J. Lancet, 1962, ii, 857. 9. Cawnty Cmmeih Gaxatu, May, 1966. RSV 0016574 Walhtofer, Zimni^l: Med. Klin. 72 (1977;, 4J0-*M (Nr. 10) Hatnangiosarkomatose nach Polyvinylchloridexposition ' H. Wallnofer, N. Zinnagl Medizinische Abccilung des Landeskrankenhauses Vocklabruck (Vorstand: Primarius Dr. H. Wallnofer) und Konservativ-Angioiogische Station (Lciter: Obcrarzt Dr. N. Zinnagl) der Dermatologischen Abteilung (Vorstand: Primarius Prof. Dr. J.Zelger) der Landeskrankenanstalten Salzburg Hamangiosarkomatose.nach Polyvinylchloridexposition Zusammenfassung Nach kurzer (Jbcrsicht iibcr ncoplastische Entwicklungen nach beruflicher Exposition mit Vinvlchlorid und Polyvinylchlorid wird iiber einen Fall berichtet, bei dem cine multilokularc Hamangiosarkomatose nach relaciv kurzdauernder und nur intermitticrcndcr Exposition mit Polyvinylchlorid auftrat. Das Latenzstadium betrug ctwa 15 Jahre. Betroffene Gcfaftbcrcichc waren die Aorta abdominalis, intrarenale Nicrengcfafie und inirazerebrale Gcfaftsysteme. Symptomatisch trat das Krankheitsgeschchcn untcr dem Bildc progredient fortschreitender peripherer Durchblutungssfdrungen in Erscheinung. Die Moglichkeit cines sklerotischen Vorschadens, gefordert durch Schwefelkohlenstoff wird diskuticrt. Summary: Haemangiosarcomatosis after professional exposure to polyvinylchloride After taking a cursory look at neoplastic developments particularly at professional exposure to vinylchloride and polyvinylchloride, one case is reported in which a mulrilocular haemangiosarcomatosis occurred after a relatively short and only intermittent exposure to polyvinylchloride. The latent stage lasted 15 years. The vessel areas affected were the aorta abdominalis, the intrarenal kidney vessels, and the intracerebral vessel* systems. Symptomatically, the disease presented the picture of a progrcdicmlv advancing peripheral cir culatory disturbance. Thepossibility of previous sclerotic damage caused by carbon sulphide is discussed. Vor rund 200 Jahren (1775) har Sir Parcivall Port [55] iiber die berufsbedingte Karzinogenese des Skrot.ilkarzinoms bci Londoner Rauchfangkehrern berichtet. doch erst in den lemen Jahrzehnren ist der Exposition durch kanzerogene Stoft'e m Industrie und Urmvelr niehr Beachtung bcigemessen worden 112, 30, 31]. Von kltnischen Beobachtungen geleitet, haben sich zahlreiche Ergebnisse experimentell beweisen lassen |14). Es sei in diesem Zusamnicnhang an das gehatiftc Aufrreten des Lungcnkrebses bei Erzarbeirern (11, 21] und Rauchern, von Biasenkrebs, Lungenkrebs, Karzinomen des Gastrotntestinahrakts sowie maiignen Mesorhehomen [1], Pleura- und Perironealtumoren unter Exposition von Asbest [21, 32], Benzidin [44], Anilin (36). Arsen [17, 28, 3], 34] und aromatischen Ammen und an den gcsicherten Zusammenhnng von Leberkrebs und AHatoxin erinnert. Hcuce wissen wir, dais vide der kanzeropenen Substanzen selbst in unscrein Wasser amutreffen sind [39] als Resistance gesteigerter Agrikultur, indusmeller Technologic und letztlich unkontrollierter Umweltverschmutziing durch eine fast in Exponentialfunkcion iihersteigerten Induscrieleistuog. Epidemiologischc Studien /.eigen zudem, dais es sich bei der . Karzinomentwicklunp uni cm kumpliziertes multifaktorielles Komple\eei'h?ht*n haivtrir Resulr.ire nicht notwcndiperwei.se die hinktivitar oines Agens beweisen nuissen, dais neben Risikotaktoren Ictztlich auch Jisposinonelk- Komponenten fur die Karzino genese emer Substanz verantwortheh sein kimnen- Erst m den lerzten Jahren wurdc beknnnt, dab Vinylchlond als potentes karzinogene$*Agens fur die Entstehung von Leberkrebs und Karzinomen andercr Orpane anzusprechen isr [2, 4, 10. 14. 15, 18. 22-25, 40. 43j. UrspriingItch war man der Meinunp, dais der karzinogene Effekt vorwiegend oder aiisschliclslieh dem Monomer Vjnvlchlond zukamc, m der Zwischcnzeir hat sieli a her eriviesen, dais auch die Polymerc (Polyvinylchlorid) praktisch diesclbe Kanzerogenitat hesitzen [3,6, 9. 13,16,20, 33,37,38]. Dabei handelt es sich vorwiegcnJ iim Entstehung von Angiosarkomen der Leber, des zencralen Ncrvensystems, dcr Lunge, der Nierc, aber auch der Fingerknochen. Viola et a). [41J konnten experinicntell bei Ratten Haur-, Lungcn- und Knochenkrebs durch Inhalarionsexposition innerhalb von zwolf Monaten erzeugen. Maltoni ]22-24] benchtete iiber dieselbe hepatische Ncoplasmaentwscklung im cxpenmentellen Ticrvcrsuch nach Vinvlchlorid* inhalation. Seither lassen auspedehntere cxpenmeniclle 11,,,..,.,, -i............. .. i ... RSV 0016575 Walhtofer, Zinuagt: Hanian^tosarkomitlosc nacb Polyvinylchloridcxposiiin>: Med. Klin. 72 (1977), 410-413 (Nr. 1U) sammenhang des Aupiosarkoms oder der Angiosarkomatose mit Vinylchlorid oder Polyvinylchlorid. Intcressanr dabei ist die FesrsteJIung, dafi nach entsprechender Exposition unter Umstanden etne bis zu 15jahrige Latenzzett bis zutn Atiftreten des Angiosarkoms bestehen kann. Waxweilcr ct a). [42] haben die cxperimentcllen Inhalationsstudien von Viola er al. (41}, Maltoni [22] sowic Keplinger j 14] mit Indukcion von hcpatischen Angiosarkomen, Adcnomen, Adcnokarzinomen der Lunge, Neuroblastomen des Gehirns, Lymphomen imd verscliiedenen anderen Tumoren m emer g.inzvn Kcilie vcrschicdener Tierspezies anhand einer sorgfalng gefiihrten Scudte mit Erzeugung von Krebs der Leber, Lunge, des lymphacischen und zentralnervosen Systems erweitert. Der aciologische Nachweis des exzessiven Krebsristkos durch Vinyl chlorid wurde zudem epideimologisch und histopathoiogisch gefiihrt. Infante [13] kommr aufgrund seiner Uncersuchungen bei Polyvinylchlorid zum Ergebnis, dafs Miitter, die in Siedlungen in unmirtelbarer Nachbarschaft von PVC-Produktionsstarren leben, zu emem hohen Grad Kinder mir kongcnitalen Fehlbildungen gebaren. unabhiingig von Dauer der Ehe. Rassc und anderen Fakroren. Dabei scheinen Anomahen des zentralen Nervensystems am h:\ufigsren aufzurreren. Da neben Fehlbildungen zweifelsohneauch andere Faktoren [7,8] fur mntagenc und-oder teratogene Mechanismcn der karzinogencse veranrworclicb sind, muR dem Polyvinylchlorid mcht allem die Ursache kongenitaler MiGbildungeii zukommen. Die Angiosarkomcntsteiiung der Leber durch Ymvichlond und seine Polymere wird durch Fallberichtc aus der letzren Zeic belegt [2, 10, 25]. Dabei zeigt sich. dais die Latenz2eit fi.tr sklcrodermieartigc Veranderungcn der Haut. der Hamie, Untcrarme und Wnngcn, das Ra> naud-Svndrom, Uhrglasnagd, periphere Gefals- und Knoclicmeranderungen mit Akroosreolysen, restrikme Lungmi cranderungen bis 7.ur Lungenfibrose [29, 41], Milzvergroberung. Leberschadcn [25] bis zu Hamangioendotheiionien. Thrombound Leukopenien im Durchschmtt 2 bis 5 jahre [II, 29J, fur das Aufrrcten des Angiosarkoms der Leber 10 bis 20 Jahre betragt. Oft lalst sich iaparoskopisch tme nerzfbrmige Kapselfibrose mit enicm Art Banti-Svndrom vorzeirig erkennen [5, 26. 27]. und in der Lebcrbiopsie siehr man toxtsche Schaden |39j der Lebercpuhelien. dilatierre Smusoide, pensinusoidale Kollagemsienmgs- und Proliferationsvorganpe [9. 27, 43]. ncr Oberschenkclhauptastc. AuffaUcnd \sar die starkc Progredivnz des Processes. Eine chirurgi&chv Intervention nm ptasnsolicni Ersatz der dist.ilcn Aorta, dt;r Aoricngibcl und dor heidcn Foinoralaricnen bei posiopcratrvcr Amikuigulintm brachte nur kurzfmtij: Iciehtc nbtektive tpilpatoriscH. rheopraphisvh usw.) Besscrunp. die abet subiektiv nicht in Erscheinunp trat. In Blutbild hestand erne mal'ip: Aninuc. cun- 1 cuko/.vtose izwischcn innoo his 20000) und cmc bernehtliche ScnUmn'erholntn^. konttamc Allnmiimiric <hi l p*/*,). >*rcn?.wertipc H.irnsinft- und Kreautunwcrcc. Zvwhen eines Lehcrsthadcns waren dutch pcnnvv l r.tnsammascncrho- kunp. in spaterer Folgc detuliche ErniedriRimc der (JiolmcMerase sowic vine C.-iinmaglohulinanW naehwvish.ir lire l eherhmpMc er- hr.iehte liehteiptisel'i tine fn.ihig portale llep-ums mit dem- Sielier epicheiialcr .Seh.uiigim)i mi Sinne cmk's ..iiiM^vh-inel.il'iiliselien Lchcr/vlischadcns*'. tlektrrmenopnsch war cuk- hctrjJitJiche htHcuc- runp des cndoplasti&chcn Rctikulumv mit Vcrandcrunn der Mituchon- drivu nit Sinne der roxischcn Schadipnnp zu heohaehicn. wohci zudem hesonders auffaliend die he.iehbiche Bindceewehiprulifcratuns mu starker kollapcnisicrunp des Gitieriaserperustes in Lrsclicmunp trat. Da pieichzcitin innnunolopi'clie I'arameiet iml.ipen ipimtivti C-reaklives Protein. Rheuinaf.iktor. Waaler-Kmc. trimhu- Tucrsuden aui Humankolljpen, anrnutklc-ue Faktoren und DNS-Bcnrnmn sowie erne Erholmng dvr IjiG- imd in pvnnjivni Amm.ih der IcA-Frakimn der lmtnim^li>luilinc|. svurde die Moplithkeit iinmuntilojiisciHT Phanomcne ini Sinne einer Vasculitis alierpie-i diskutivrt und ak Ultima ratio cine ImmimoMippressionvhehandliinji 11111 Az.itluuprm 'limirck'l und Gluvocunieotdcn vmjjeleitct. Erne nur kurzzeitipe llesscnmj; lies Bcfundes diesm.il sorwiepvnd suhtekm mid wemper nhiektn - wurde pefolgi von finer wcuvrcn hoeh|iridip;ii Beschwerdeprimredieii/, die Ictzilich in cm hcpatorcnalir* Syndrnni eiimiundeie. Aiuli eiiu vsif^vltomnieitr Aruin'-IlchniiiHiiii|: hriehie mir kiir7(ristti:v siil'iekrne Besserunn. Her I'.iiienr kam rund drei laiue n.ieh Aufirccen dci crsifn Symptomc durch Rsiptur ores Aneun shun der 15.in hiuru .id e\mim. Der Ohdukiioiisheluiiii (Prof. Dr. !. Tluirncr, ''ai/hnrp; di.kie mm erne Hamanisioeiisloilii Is.irkom.iKise nielirt.ieher t.et.ifshcreishv .ml ;m (ie)iirn, Nierc, Lef'er si> n im Hervicli der m-iselil<issenen I- \n, imi.itenftetal'e und der Airn.i OhJtikdimspromku!!. H.ini.iiieH'endi'iiii l'.irk mn.ii i>vc mu n.u hycsvicseneni, ucirjtehcnJ nckrotiwliein Sarkunuhruini'iis in iler Bauthaorta (Anrt.i Atsdonmiiiis im Bercieli ones Bi/urk.iiiiiiis-Pspri's Mjllstandip sersetih'.-en' nut Befall z.ihlreieher imr.ircn.iler N lerenpet Jl'e. inch uitr.i/eis Inaler Ciel.ihe , niehrcrc I'is cibscupti'i'e Bliiinnpen in der RinJc liml un Mark heiilcr (.roldiir nluiiiis|'h.in n - Urn I lir rijrtuki. Allpemein luii h-lci.idice Artcri(.kliT>ii mu' ir\lUemm u->m nm 11 r,i liicdeileil sckuikl.i ien Ftilpe /u*taiuls n 1. dii'iind il.ieli Anlepiine iiiio a>'i t <I c'm- u .1)1 n liilu rk n iixis-lU pass: Gelahprnt hese von s.irkimi.Ui m m. vieHjiehvnd ik knui\, hem Gewebe verleci. Aorta ohcrhalh der An.istomosi ,ok I'lkie llukilirtcricn then I alls nm si rk o mi to sen t hr nmhotisi lien A h-i iu nl mi ecu 2. \V.dniilsj.rtjtses. rupiurienes Aii.isiimioseii.uieiir\mii.i hi Jci ohvrcn AiisehiuPstiilc der Clefllsprui hese nut liinl.i n^er Kuplnr der Aneurvsmaw.vij. nut retroperityneiler Wiihll'lutiuii: mid m knnd.ircm F.mbrueh der Blurmiii m die trcic B.uishhnhle (Hnimipcrifoneiini 2'UU ml tlussijies liiiit Soeenii'inti- Eijivnfarhc pnrenehi iii.iionst i I'c.inv. 1 Aim i hrombose der Arreri.i tciuhs deMi.i ohm- u.icIumisI'.iic Ausn irku i>n inf die rechic Nirri i reehte Nierc 141)^. Imke N'terv 150 stk Fallbcricht ''Oiltritier Minn, der xeir 1 Vf 1 icier In >h im M.irmn.rrcr Kch.imilling sreht. Lot symptom smJ periphere Dur, hhlmniii:di>runpi.ii der K ide n unreren F\rrenut.ueu. die ils Burpcr-AA mi w.iru < SunJnmi rmp.-ipmchcn wurden. D.iyu hopischiuerz. Sehw mdet. iuh.ui" .it vi id In he Snhu bniuai Angiopr.tphixsh l.md sii.ll eim liMihundici Skli-r--, d : Wm dcsccn- 4. Mjl'ii>(indij:c cxzvtttrisclie Lnikslier/ln perrrophu (Imke k.inuner* wand In mm. rechte Kanainerwand 4 mm, Her/jivwicht ItKIpj. kerne Myocirdseh widen. Diskusston Trocz wicderholter st.itmnnrcr Atifnnhnu'ii unci tihernus RSV 0016576 i \\\ithtof,'i,Ziwiagh I Hiinunfiiosarkonialose nacb Polyvinylcbloridexposhion Me,!. Klin. 72 (1977), 410-413 (Nr. W) eines iibernus reichhalcigcn Unrersuchungsprogrammes war die Diagnose intra vitam nicht zu stellen. Sie wurde zunachst nicht eintnal in die diffcrenrialdtagnostische Erwagtmgcingeschlossen. Erst durch die KenntnisdesObduktionshefundes wurden weirere Nachforschungen und F.rhebungen betrieben. Der Patient lebr suit mchr als 20 Jaliren in der itnmirtelbaren Umgebung eincr Faserstoff- und ZeiUvoBcfabrik. wo cr auch beschaftigt war. In den letzten 15 Jahren war er allerdings nur mehr zur Buroarbeit citigesetzt. Die Exposition durch Schwefclsroffe. vorwiegend Schwefelkohlenstoff (CSp ist erhoht und war in den letzten Jahren turn Teil fiir die Anramcr und Bcvblkenmg der unmittclbaren Umgebung hclastigcnd. Eine Grolszahl aus dieser Bcvulkerungsgruppe 1 icfs im Zuge durchgefiihrrer hioprischer llnrersuchungen dcr Leber deutlichc Hinweisc auf eine Leberzellsehadigu ng. besonders elektronenoprisch, erkennen. Die Erweitcrung des rauhwandigen endoplasmatischen Rerikulums und letztiieh Veranderungcn der Mitochondrion gelegentlich begleitet von leichten biochemischen Reaktionen, wit geringe Elevation von SGPT. manchmal auch SGOT und GDH. selten eine leiehre Verminderung der Cholinesterase standen im Vordergrund. Diese iihcrzufalligc Hautung derartiger - vorwiegend elektroncnoptischer - Lcbcrbefunde berraf auch jencu Patientcnkreis. der aus ganz anderen Ursachen ins Krankenhaus autgenommen war. Reknnnt bei hohergrndiger F \pir-mon schwcfelhaltigcr Mihstanzeii, vorwiegend Seliw el'elkohlenstoH', isr das criiohte Risiko von Gefabarhcrogemtat. Wit Polvvinvlchlorid ist der Patient 15 Jab re zuvor. wenn auch niehr haufig. so doch in einem gewissen Ausinnl.- konfroimcrt worden. so dab die Expositionsrarc an sich als gering und Jurchaus nicht pertnancni an/.usprcehen ist. Folgr man aber Jer Inzidcnzrate auch bei relariv geringer Exposition nacli den Lircrarurhinwcisen, so wiirde auch das Lntenz-radium von erwa 15 Jahren die hochgradige W'ahrschemlichkcst ernes Zusamnienlianges ergeben. Bei eincr heuti angenommenen Morbiditatsrate von 10% [20, 33, 38), zeigr .sich. dais nebcn tier F.xpnsirion .inch andcre Fakroren fur die Emwieklung dcs Angtosarkonis cutschetdcnd sein mtissen, da sclbst bei dauernder Exposition rund90% cine neoplastische Entwicklung vermissen lasseru Im vorliegenden Fall laftt sich mil hoher Wahrschcinlichkeit folgetvier pathogenctischet Zusnromenhang vermmen: In Analogic zur zunehmenden Hiiufung dcs primaren Lebcrkarzinoins bei Leberzirrhosen und der hohen L117idenzrate durch Atlatoxin (fast "0%!). wo der gestbrren Biotransformntion der krnnken Leber die fclilcndc Metabolisierung kanzerogener Stoffc zugeschricben wird, die dann als Mutanonskarzinogene unabgcbaot liegenbleihen und zur Entwicklung des Hcpntonis fiihrcn. konnre im vorliegenden Fall an sich schon die Predisposition ztir pramnturen Sklerose und Athcromacosc vorgelcgen haben. Die Athcrogcnitiit und die Progredienz der prnmaruren GefaRsklcrosc konnre durch Schwefelkoblenstoffcxposicion dnrehaus geforderr worden sein. Moglicherwcise Uegen anch immunphanomcnologischc Kaktoren ciner Arr Burgcr-Wimwarter-Syndrom zugrunde. Aui diesem niehr oder minder ubiipiirar gefnlssklcrotischen Schndcn wiirje eme - unrer Unistanden auch knrze und imermittiercnde Exposition mit Polyvinylchlorid ausrcichen. uni diese toxische und kanzerogene Subsranz m ilie Gef.ibw.md unabgebaur ein/iilngeni, da eine Mecaholisicrung tnfolgc des gestbrren Biocransformanonsvcrmogeiis /nniindest viclerous unmbglieh ist. Damn ware ein Kn.-tsl.tuf geschlossen, dcr einen pathogeneti.sehen Mechamsmus kennzcichnet, in weieheni der nuilcifakioneUcn Genc-e der Entstehung von Angiosarkomcn Redlining getragen wnd, wobei deni Polyviiivtahlorid nls kanzerogene Substatu aber letztiieh die Schliissdstellung der tieopl.istis.chen Entstchung znkomint. Wir il.inkim Hi'ini I'rol. | >r. ]. Tlnirnii. \m-r^nj il-i I'.i i Imlnci.. 'u-n Id-tium- Ji'i l..nnii'-l.T.ini.in.in-i.ilicn s.il/nurj;. Inr ilti \ orn.ilimi ilo' (UxluklKin uihI ilu- I'l'i-rl.i--imp do 0)\iiiLiiun-pi<in>k<>ll- Luer.uiT 1. Itonhu. 1 1 . \ . I I l.ililvri. P. 1 ).iik|iit'ii. I . I i.nn, l. Hm/ : I'.pidi'iiiinlit", ol ni.iliun.ini nil'obii iium.i m H.tmlvre. I nnrmim. Ko < ;|M"u 2. Rr.ivhni'A I'pio-k, |. An^u'-.lruim.i i>1 iliv In or. h illouinu ran I shlir illcvt-i-mih | Anu'i incil. A -- . 22^ ; I '.,-4 . - t- -4 >. < i uli-r li>- Dill',Hi- t.Miiirn!. A iiuun.l ninli.i nl tlu' Iiut iimniii; iK uml ililiviiU w in ki-r-'Ki-miii k-. Muil'iiliu .nul Mnu.iiiii Wnkli Jl JU-J- 4.1 A. C i-niiT loi lli-v.isi- C murnl Niui'n'-iri um.i < >1 ilu- In i-r-t oiiik. (mii . Morbiilm .uij Mnri.ihii \S n-k.li 2 ' ' t'>"4 . 2 In. 2K-. ,V t.rvtvh ir.. |.l MX. |i>lni'.,,n Aiic.u>v.irvmii.i <>| In-t in tlu m.imi- f.utnre >l fnl' Mm! stili'niU- I. oicnp. Mill. 16 r 1ltd 111 6. (. rs'i't h | r.. | l... J . .\ t .i kk 1 n i*i ii i.i ,i\i- .mn mu pi ill \ i m 1 u i >i k i*r -. Ann. N .'l . Ai.nl. Sh 24 : in*-'. SS Pnc.ilni.in. A., k lln-ilimn.l. |.Sil,k.--ll \ im I , lil.-r nK i\|mimihjnd Ilu in.in ilmimnu im, ,il'i 11 ,i; mm . Mm.r.ntn IU> 'I I'1" ' . ) r. ir-' 6. I uiil'A Miniiii. I , l\ t .utll'un. | ItilibU'U. I I lir.-nlvic, \.T. N.ll.U.U.lll.S t )-U i ni.in-t mlk.ir : t hi mill I'onu .ilu i r.il mm in n <u ki rwpiiiiil i<> i im I i litnndi. I .UK ii 1 (!->"-]. 4t'J. V. Gi-iUnk. t*. K. Mullir. H bivliii'IshiinHi Murplmlnpi <il Inpr d.inl.i|li' .mum" p<'K uni I i111iindi' umLlh Ann. X . 'l . U ul. Sn 246 2*S- 2-< II). ( Imili ml) I ..I I'. I linm.ii. . Kent. | k .il.indi i. K. )' iliu. I I. I't ppir Hip.nil .liv;iii..il,nm.l 111 m.in .liul indl'lll- tnllnu nip |i| i ill nlpi'd i vpnsiiri' in uni I Lhluriilt. <nsirniutLrni<ie' W 111)"4 . A. 11. (-I.irrinp. I . I I.. \\ . I li-ssv. Our l mip.inkt i-l-i, ilit I'n'i ukr.inkliin in it in Si'luK'il'iruir l.rulvn. V(m lit. poniiiil. \K-d. " 11 j, 2'V '*11^. II iix-vi. m2 -111 mr. 12. Hm'piT. W . C . < 'ii iip.innn.il mini n \ ,md .illu .1 din -.in - I lurk . L. Tlmin.is. Sprni"lii lil. III. I-1-42 I 1. 111 l.i 111 I . I1. I . I 'n. npiiiu .111,1 mtil.l^i i >1, r Ilk I I :i I Piiniunniri - nil pub iin I i lilnridi' p/oiln, linn ].i. ihii. . \iin. \ 'i A- i.i Sii 2" | ` | RSV 0016577 Wdllndfcr, Zinndxl: Med. Klin. 72 (1977), 410-413 (Nr. 10) Hdmangiosarkontatosr nacb Volyvinylchloridexpositiou 14. Kcplinpcr, M. L., J. W. Goode. D.F.. Gordon, J.C. Calandra: Interim results of exposure of rats, hamsters, and mice to vinyl chloride. Ann. N.Y. Acad. Sci. 246 (1975), 219-220. 15. Kramer, C.G.J.F. Mutehler: The correlation of clinical and environ mental measurements for workers exposed ro vinyl chloride. Amer. industr. Hyp. Ass. J. 33 (1972). 19-30, 16. Lange. C.E., S. Juhe, G. Stein. G. Velrman: Further results in poly vinyl chloride production workers. Ann. N.Y. Acad. Sci 246 (1975), 18-21. 17. Lee. A.M., J.F. Frsumcm: Arsenic and respiratory cancer in man - an occupational study. J. nat. Cancer Inst. 42 (1969). 1045-1052. IS. Lester, D., L.A. Greenberg, W.R. Adams: Effects of single and repeated exposure* of humans and rats to vinyl chloride. Amer. industr. Hyp. Ass. |. 24 (146.3!. 265-275. I*'. Lichen. U H. Pistawka . Mesothelioma and asbestos exposure. Arch, environm. HIth 14 il%"i,55> 'i->. 20. Lilis, R., H. Anderson. \Y. |. Nicholson. S. Daunt, A.S. Fischbein, l.J. Sehkoff: Prevalence of disease among vinyl chloride and poly vinyl chloride workers. Ann. N.Y. Acad. Sci. 246 (1975), 22-41. 21. Lloyd, Long-term mortality study of steel workers. V. Re spiratory cancer m coke plant workers. J. occup. Med. 13 (1971), 53- 68. 22. Maltnni, C.: Preliminary report on the carcmogemctrv hu>.assays of vinyl chloride. U.S. Dept, of Labor- Informal Fact-Finding Hearing on Possible Hazards of Vinvl Chloride Manufacture and Use. 1974. 23. Mai tom. C..G. Lefcnunc: Carcmogcnicits bioaavsof vinyl chloride: Current results. Ann. N.Y. Acad. Sci. 246 (1975), (95-218. 24. Mnltoin. C.. G. Lefcnunc. Carcinogenicity biciass.n * of vinyl chloride. 1. Research plan and early results. F.nvironm. Kfs. r (1974;, 387-405. 25. Markoff. N.: Die Vinylchlondlcber. em herufsbedmgter Umwelr- schaden. Hippokrates (Stutcg.' 47 (197b), 77-80. 2h. Marstellcr. H.J.. VI .K. Ldbach. Unusual spk-nomegahe liver disease as evidence by pcnroneoscopv and guided liver biopsy among poly vinyl chloride production workers. In: Program of New York Academy of Sciences Working Croup on Toxicitv of Vinvl Chloride- Polyvinyl Chloride. New York. N.Y. M.iv 10-11. 1974. 2". Marsteller. H.J.. W-K. Lclb.ich. K. Muller. P. Gvvhgk. Unusual splcnomegalic liver disease .n evidence bv peritoneoscopy and guided liver biopsy among pniyvinvl chloride production workers. Ann. N.Y. Acad. So. 246 U9*'5).95 134. 2S. Milium. S.. T. Strong Human arsenic exposure in relation to a copper smelter. Env ironm. Ro. 7 ; I9"4j, l-6-(82. 29. Miller, A., A.S. Ticrstcm. M. Chuang. l.J. Sehkoff, R. Warshaw: Changes in pulmonary function in w orkers exposed to v utv| chloride and polv vinyl chloride. Ann. N.Y. Acad. Sci. 246 (I 9"m, 42-52. 30. Murray, H.M.: Report of the department committee on compensa tion for industrial disease. Her Maiesrv's Stationary Office, London 1907. 31. NationaUnstitutefor Occupational Safety and Health: Occupational exposure to inorganic arsenic: 16. Stock pn )"33-4XX)30. U.S. Govern ment Printing OfBee. Washington. D.C 19"3. 32. New-house. M.L., H. Thompson: Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area. Brit. J. industr. Med. 22 (1965). 261-269. 33. Nicholson. Vt'.J., E-C. Hammond, H. Sculman, 1.1. Sehkoff: Mottahrv experience of a cohort of vinvl chloridc-polv vinvl chloride workers. Ann. N.Y. Acad. Sci. 246 (1975), 225-2.3(1. 34. On, M.G.. B.B. Holder, H.L. Gordon- Respiratory cancer and occupational exposure ro arsenical*. Arch, cm ironm. Hhh 29 (1474). 250- 255. *5. Pon. 1'..- ('.nicer scroll In: Otinngu.il 11bs,-r m.'iis, p. 63-<S. Hawes. Clarke Sc Collins, London l-_5. 36. Rehn, L-: Btasengeschwulste bei Amlmarbeitern. Arch. klm. Chir. 50 (1895).588-600. 37. Sehkoff, I.J.. E.C. Hammond (Eds.- Toxiciiy of vinvl chloride polvvmyl chloride. Ann. N.Y. Acad. So. 246 I197 3i. 1-3.36. 38. Tabcrshaw. I.R., W.R. Gattcy: Morialuv smjv of workers in the manufacture of vinyl chloride and ns polymers. J. occup. Med. 16 (1974). 509-5)8. 39. Llmted Stares Department of Laboi. I'roveedmg* nf standards ad visory commirtee on carcinogens. Washington, l).( . |973. 4(1. Ychm.in. G-, C.F.. Lange. S Julie. G Stem. I'. ISa,liner: Clinical m.viulcstationv and unnsr nf viny 1 chlon.iv disease. Ann. N.Y. Acad. Sci. 246 (197.5). 6-17. 41. Viola, P.I... A. Biogoin, A. Capimi- Oncogenic r^paiisf of rat skin, lungs, and bones to vinvl chloride. Lancer i<i >. 3 I (14~ h, 3 |6-S 19. 42. Waxwciler, R.J.. W. Stringer, J.K Wagoner, j. Jones: Neoplastic risk among workers exposed n > vim I chi"rule. Ann. N. Y. Acad. Sci. 2TI 4.3. Young. R.S-. .1- ('re cell. I. |. VhkoK. H I a Ik. I'll. W niaiubv. H. Pop per. 1.. Thomas. Viml ciiloriji-as-n, utvJ Incr disease. Ann. intern. Med. X4 ll9"6i.T-"'l 44. Zavon. M. R.. U. Hncgg. 1 Bingham I'u-n/uiinc ex pi 'sure as a cause of bladder tumors. At,h. env ironm. f III li 2" I,J_ VCciterc l ucratvir: Uyuip.miMul v.iMiiivivi'v-" Aiuv N.\. Acad. Sci. 2" I (1976), 1-516. ho ilu- \Y/.i.er . ('run.urns (>i If V\ .iffito/, /, f .m.li ->L.tnki'ilb.ms, A--M4tl \ <i,'bl.ihru.'k. RSV 0016578