Document XzDOqYwOEGVeokB8L0zOk02LR

PHARMACODYNAMICS AND UPTAKE OF VINYL CHLORIDE MONOMER ADMINISTERED BY VARIOUS ROUTES TO RATS j im R. Withcy Toxicology Division, Bureau of Chemical Safety (Poods), Health Protection Branch, Ottawa, Canada !T rinding a! Icoit 2-3 ppm and occasionally as mot h as 10-20 ppm of vinyl chloride monomer in a wide range of foodstuffs has prompted concern for o possible human health hazard, Jhc recognition of vinyl chloride as a carcinogen to humans in April 1914, following the discovery of angiosarcoma as the cause of death in at least 25 workers who had been engaged in the manufacture of polyvinyl chloride, enhanced this concern with respect to the presence of vinyl chloride monomer in foods. In assess the hazard presented by the ora! ingestion of vinyl chloride monomer, rats that had hern surgically prepared with an indwelling jugular cannula were dosed by inlragastrtc intubation with aqueous solutions containing up to 2.0 mg/mt vinyl chloride. Time-concentration curves were obtained from sequential samples of blond. The uptake of vinyl chloride by this route was found to he extremely rapid; peak concentrations were achieved less than 10 min alter administration of the dose, ttiminotion from the blood compartment appeared to he biexponential. Studies with the same animat model in a single restraint cage that allowed a "head only" exposure to concentrations of vinyl chloride up to 7,000 ppm in the gas phase have shown a similar rapid uptake Pillowed by a plateau blood concentration during several hours of exposure. On removal from the vinyl chloride atmosphere, blood levels fell rapidly to hardy detectable concentrations after 2 hr. The precise kinetic coefficients that describe the distribution and elimination rates of vinyl chloride from the blood compartment were also determined from the blood concentration data after the administration of an intravenous dose of aqueous or vegetable oil solution. I, I? I. I.'- INTRODUCTION Prior to the discovery of a connection between the induction of angiosarcoma in humans and the exposure to vinyl chloride monomer (VCM) in January 1974 (Falk ct al., 1974; Thomas et a!., 1975), the U.S. Food and Drug Administration had already withdrawn their prior sanctioned use of This paper was presented in part at the 14th Annual Meeting of The Society of Toxicology, Williamsburg, Virginia, March 9-13, 1975. It is a pleasure to acknowledge the technical assistance ol Mr. Peter Collins in this work. The interest, skill, and dedication of Mr, Henry James, who surgically prepared the animals used in this study, is also appreciated. Requests for reprints should be sent to Jim R. Withcy, Toxicology Division, Bureau of Chemical Safely (hoods), Health Protection Branch, Ottawa, Canada. 381 journal of Toxicology and Environmental Health, 1 '33 1 -394, 7976 Copyright CO 7976 by Hemisphere Publishing Corporation - 'I . I. '\ '' :; | ., ; ,, , j j`. t! j' ASI 00022234 FJ Ci'\nu'f T/-\u t >1 V.-l M pp 6 n 6 H PtTfjmon Pre". f ^ 75 Print,t! in Grc.it Hnuin ,t ^ # 4N- iii^L'.LiUL voor YocGiii^ondi'rT'.c&i A- Pablik*iun N:i L22fz- OBSER VATIONS ON THE ORAL ADMINISTRATION AND TOXICITY OF VINYL CHLORIDE IN RATS* V. J. Fl KO\. A. J. Sm K. Mariwni. I. Will,! MS. D. van BvriLM and A. J*. m. Okoot TP- z?She^ Central hurinite for Xutrmnn and fond Ret-earih (C/I U) T\0. Ulredtlwqi 4N. 7A'/\r, The Sethi-rlalulx (Reu'iud I Apiil 1975) T-:- Abstract Various possibilities were studied Air administering .iml chloride monomer (VCM) orally to rats t'pon six-rage. solutions of VCM i,i sxu.i-be.ui oil appeared 10 be cubic with respect to their VCM content and the fails acid composition of the oil. In addition no olit'omcrs of vtnv! chloride or reaction products of 'VCM xxith components of the oil were detected. Stomach intubation of such solutions was considered an acceptable method of ora! administration of VCM to rats in shyt-term toxicity studies Within a period of 4 hr following intm-a.i'trie intuhation of VCM in soya-bean oil (.41X1 mg VCM kg bodx weighti. oxer 92',, of -he \'CM administered xxas recoxcrcd from the gases excreted (mainlx exhaled.'! bv the anintals. Eructation did not appear to be inxolvcd in the excretion of VCM. VCM dissolxed in soya-bean oil xxas administered by gavaue to male and female rats at levels of 0 (controls). A' '(X) and '(X> me he hotly weight. once daily on fi days xvk for a period of 15 wk. Several haenialological. biochemical and organ xxeieht values differed to a statistically significant degree from those ot the eontrols. but these diilerenccs were considered to have only minor, if any. toxicological significance A slight increase in lixer-to-body xxeieht ratio occurred in males and females on the highest dose lex el. This increase was not accompanied hx lixer damage, as was evident from histological examination, -eii/yme histochemistry and electron microscopy. The no-c(Tcct level in this 90-dav study was conservatively placed at e(> me VCM kg body weight, but was probably higher since the cITixts occurring at 100 and }li<> mg kg body weight were of doubtful toxicological significance. Indications w.rc obtained that the (ceding of rats on dtets containing polyvinyl chloride IPVc'i now dot with a Ugh VCM content is a more practical method for the long-term oral exposure of rats to VCM than is stomach intuhation of VCM in oil. VCM was almost completely released from PVC powder during passage through the digestive tract. INTRODl CTI01S Vinyl chloride monomer (VC'M) is used in the manufacture of the resin, polyvinyl chloride (F'VC). Industrial exposure to VCM hits Iven associated with several disorder, including ucro-ostcol>sis iDirman. Cook. Whitehouse. Magnuson & Ditcheck. 1971: Harris A: Adam-. !%': I.ungc. Jiihc, Sleiti <t Vell- man. I9"7-;; Markowitz, MeDouald. 1`ethierc Kcr/ner. !'C2i and inm-Muhgr.anl liver diseases (Kramer A: Mutehler. 1972; Marsteller. Lelb;;eli. Muller. Julie. Lange. Kohner A: Yehman. 197.': Suciu. Drejman A Yalnskai. I%Ti .mu. only recently, also with angiosatcx'-ma of the hxer lBlock. 1974: Creech A: John-on. !`t74: l..ee A li.my. 19741 and tumours of the brain and lungs iMousoii. Peters A; Johnson. 1974) Dcgcnc.uti'.c eluuges in the iixet. Gxlneys. bone and brain woe dclccud in tills and labixits lol- lowing exposine t*> \C\| inn.il.ili.m (Bu-uiucx. Va/in &. Koel-etkox. i`i"2 Ei. Keyin'!-Is. Couolly. Mx'slen. S/iilv x'c Mu;:-h`.. .""4. l'x'rkelson. Uyen A: Rowe. I9M; Viola. i``"ili. Mo-cover. VCM inh ilatu'n was Ennui to mxliie.1 -.un-i'-ir. m is-tl: rau ,unl tttiee (Miilt-m; A- l.elemine. .974, \ mla. Bigx'tti A; Caputu. 197!) Mb'- si;ij. xx.o -i .uis.-u<i |.\ .j cr.nm --f eo-nos'intine 1 laixpe.in n dnsi; .es '.el;- line A1 t..iin! K -1:-1sto!!er/cuceiule li-.ilir-r-c . V ll .-!e,.4 Px-public of (leiinanx) SI u I! Nex!.-1,11-0 (. mi 1 lint. I: Stale Mines. \|,/o /out Cheiuie Nederl.iad 11 X and l)ox\ ( lieinic.il I mope S \. Certain formulations of PVC arc used widely as food-packaging materials. Residua! VCM present in the extruded polymeric product was shown .to be liable to migration into PVC-paekcd foods and drinks, especially distilled spirits (Randolph. 197a). Since no data on the oral toxicity of VCM appeared to be avaiiithle. studies were initiated to examine the sub- acme loxic properties of this compound when admin* isteied orally to rats. Oral administration is greatly hampered by the fact that VCM is a gas at room temjvrature (h.p. c.- less C) and therefore preliminary experiments were carried out to find an acceptable wav of administering the compound orally to rats. Administration in the drinking-water was consi dered m this iexpect hut was rejected because of the rather poor solubility of VCM in water (Hardie. I9tv4i and. more significantly because ol the dilliculties to Iv cxpeciext in handling the solutions and in estimat ing the quantities of VCM actually ingested by the animals. As VCM is lipophilic, we investigated the possibi lity of admimsteiing VCM as a solution in edible oii eitliei by gastric intubation or by incorporation m!u the diet. Another possibility studied was the addition to the diet s>1 a I'X (` p.-wder consuming an unusually high eoncentiatian x>l VCM. I'hc pies-ent repxirt Jescnlvs' tentative evpenments an the oral administration u| \'CN1 and presents some I'bseixiilix-iis on the fate of VCM in rats. In addition, the results are gixen of a subacute kmcity AS I 0 0 0 2 2 2 3 5 L- ; i t i \_y i ? s C* C- O 1Z O J l ''J { *w' i~ Vol. 25, No. 8 (yfK^w^ WEEKLY REPORT For Week Ending v> UV. f February 28,1976 / U S. DEPARTMENT OF HEALTH, EDUCATION, AMD WELFARE v PUBLIC HEALTH SERVICE DATE OF RELEASE: MARCH 5, 1976 - ATLANTA, GEORGIA 30333 EPIDEMIOLOGIC NOTES AND REPORTS ANGIOS' 3COMA OF THE LIVER - Wisconsin In the period June 1973-November 1975, 4 cases of angiosarcoma of the liver (ASL) were diagnosed at the Marsh field Clinic, Marshfield. Wisconsin. One was based on hepatic arteriography and 3 on tissue findings later confirmed by pathologic review at the National Cancer Institute (NCI). An additional 6 Cases, confirmed on pathologic review at NCI and identified through a national ASL case surveil lance project initiated at CDC in 1974, have been diagnosed since 1964 in Wisconsin residents. This total of 10 cases is roughly twice as large as might be expected (5.5 cases), based on CDC surveillance estimates of crude ASL incidence for the entire United States. (Five additional cases had been re contents Epidemiologic Notes and Reports Angiosarcoma of the Liver - Wisconsin.............................57 Possible Lassa Fever -- Washington, D.C.............................. 64 Current Trends Influenza -- Worldwide ...................................................... 63 International Notes Salmonella fyphimurium -- Canary Islands, Finland, and the Federal Republic of Germany .... 64 ported for Wisconsin; 4 were not confirmed, and 1 was in a resident of another state.) In view of this relative frequency of cases, together with the recent succession of cases at the Marshfield Clinic, epi demiologic information concerning each of these 10 cases TABLE L CASES OF SPECIFIED NOTIFIABLE DISEASES: UNITED STATES (Cumulative totals include revised and delayed reports through previous weeks) DISEASE WEEK ENDING February 28 1976 February 22 1975 MEDIAN 1971-1975 CUMULATIVE, FIRST 8 February 28 1976 February 22 1975 WEEKS MEDIAN 1971-1975 Aseptic meningitis.................................................... Brucellosis................................................................. Chickenpox............................................................... Diphtheria.................................................................. e . .... /Primary........................................ Encephalit.s ) Post-Infectious........................... f Type B........................................ Hepatitis, Viral j Type A....................................... 1 Type unspecified........................ Mcbria ....................................................................... Measles (rubeola) ..................................................... Meningococcal infections, total............................. Civilian.................................................................. Military................................................................. Mumps ....................................................................... Pertussis .................................................................... Rubella (German measles) ..................................... Tetanus.................................. .................................... Tuberculosis............................................................. Tularemia . , . .............. *.................... *........... Typhoid fever............................................................ Tvphus, tick-borne (Rky. Mt. spoiled fever) . . . Venereal Diseases: ,, , 1 Chilian............................................. Gonorrhea tMil;tafy............................................. S> p.hd.is...p.rimary and. second, ary {1 CMiivliitliaarny . . . Rahies in animals .................................................... 28 7 5.764 4 13 4 242 72 6 133 3 80 5 53 53 1.366 22 449 2 570 1 3 IB,313 562 528 8 39 35 2 4,311 14 17 7 210 707 150 6 578 41 41 1,425 24 285 5C5 1 Z *" 17,273 419 531 3 45 33 2 --- -6 15 5 172 j- 890 b 622 41 40 1 1,892 -- 64 5 - -- 1 4 - -- -- --- -- -- 56 307 38 39 ,288 62 129 32 1 ,935 5 ,409 1 ,365 43 4 ,318 2 84 281 3 9 ,366 194 1 ,870 6 4 ,572 21 58 3 151 ,748 4 ,708 4,13 2 64 249 292 21 29,693 64 96 33 l ,568 5,428 1,123 42 2 ,668 270 263 7 11,136 201 1 ,837 9 4,105 B 29 10 141,258 4,776 3 ,938 52 284 292 15 -- 23 120 33 1,314 } 7,619 42 4,767 270 263 9 14,24 3, 534 8 -------* 13 37 9 -- ------- ---- ------ -- 44B Anthrax: ....................................... . . Botulism:............................................ Congenita! rubella syndrome: . . . Leprosy: Pa I. Calif 2...................... leptospirosis: Hague: ......................................... TABLE II. NOTIFIABLE DISEASES OF LOW FREQUENCY Cum, Poliomyelitis, total:.................... AS1 00022236 2 4 Paralytic: N Y.C. 1.................... 5 Psittacosis: Ohin I. Calif. 3....................................................................... 20 ftohieft in man:....................................................................................... 7 Trichinosis1 N.J |................................................................................. - Typhus, murine: Tex, 1 , . ........................................................ .. . . . Cum. 2 2 19 _ 33 2 H Id iveil kepurl (nr wri-S ending 2,'2 I / Hi MAK 0 0 istCQ 58 Morbidity and Mortality Weekly Report FEBRUARY IS. 1976 ANGIOSARCOMA - Continued has been assembled through medical record review and family interview (Table I). Particular attention has been given to potential occupational or environmental exposure to chemi cals known to induce ASL (vinyl chloride, arsenic, and 'thorium dioxide). Most cases (7 of 10) were diagnosed since 1970, prob ably reflecting better case ascertainment in recent years. Ages ranged from 36-7i (mean age 58 years). All but 1 pa tient were male, and all but 1 were white, Places of usual residence for all cases were widely scattered across the state, roug.'ily corresponding with the state's population (Figure 1). One patient had a lustory of prior thorium dioxide ex posure. For none of the remaining cases was tumor etiology obvious. Occupations and histories of exposure to potential environmental toxins differed widely, with no more than 1 ca-.e associated with any particular industry or mode of exposure. In several instances, however, individual patient occupations or exposures were suggestive of possible onco genicity (Table 1). Patient 10 had had exposure to a vinyl compound; he had worked in paper and plywood products with potential contact with various chemicals, including poly vinyl acetate. Two other patients gave histories of possible exposure to arsenic: patient 9, who bad exposure to insecti cides while farming, and patient 8, who worked with wood probably treated with arsenic preservatives in the manu facture of bleachers. All but 3 of the 1 0 patients were known to have lived on farms during their lifetimes, 2 for all of their lives (Table 3). (Reported by J Fiechtner, MD, C Reyes. MD, Marshfield Chnir; K Rentmesster, MRH. HG Skinner. MD. State Epierniologist, Wisconsin State Dept of Health and Social Serv iICces; Office of Extramural Coordination and Special projects. Salior.al Institute of Safety and Health; and the Cancer and Birth Defects Div, Bur of Epidemiology, CDC.) Editorial Note These data indicate no obvious common-source origins among recent cases of ASL in Wisconsin. The marked male preponderance among cases, however, suggests occupational Figure I GEOGRAPHIC DISTRIBUTION OF CONFIRMED CASES OF ANGIOSARCOMA OF THE LIVER IN WISCONSIN RESIDENTS, 1964-1975, BY PUCE OF USUAL RESIDENCE exposure as the potential origin for at least some of the cases. Anecdotal histories of occupational and environmental exposures in several of the cases may warrant further investi gation, particularly in relation to contact with arsenic. Al though at present only vinyl chloride monomer (7), thorium dioxide (2), and arsenic {3,4) are dearly implicated as causes of ASL, investigations such as the one described here may well provide useful leads in defining further causes. References 1. Creech JL, Johnson MN: Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 16:150-151,1974 2. MacMahon HE, Murphy AS, Bates MI: Endothelijl-cell sarcoma of liver following Thorotrast injection. Am J Pathol 23:585-595, 1947. 3. Lender JJ, Stanly RJ, Sumner HW. et al: Angiosarcoma of the liver associated with Fowler's solution (potassium arsenite). Gastroenterology 68:1582-1586,1975 4. Roth F: The sequela of chronic arsenic poisoning in Moselle vinters. GerMed Mon 2:172-375,1957 Table 1 Cases of ASL in Wisconsin Residents 1964-1975 Month an 3 Year Usual Town Age at Number Diagnosis Death, Of Residence Diagnosis Race Sex Occupation Comments Farm Residence 1 4/64 2/65 Sheyhogan 7] 2 2/67 2/67 Oshkosh 61 3 6/67 6 '6 7 Necedah 36 4 7/7] 7/71 Milwaukee 68 5 4/72 4/72 Milwaukee 64 6 4/74 6/74 Brown Deer 46 7 7/74 7/74 Wausau 57 8 9/74 9/74 Waupun 46 9 8/74 8/74 Stratford 10 1 1/75 11/75 Marshfield 66 65 W M University Teacher Lived near a chemical company Youth which made plastics and resin W M Foundry Welder Exposure to welding materials None w F Secretary and resins Infectious hepatitis in childhood, Youth mother and sister had liver disease B M Hog Scalder None W M Unknown Exposure to thorium dioxide Unknown W M Lutheran Pastor Lived near a paper mill, 1955-1959 Youth W M Rock Crusher;GIue- Exposure to silica dust, rubber Youth Liner for rubber cement raincoats, 1940s W M Postal Mai! Carrier Contact with lumber, paints, wood Lifetime formerly employed preservatives, (ammoniacal-copper- by company that arsenate wood preservative) (?) made bleachers W M Retired Farmer No tissue diagnosis; ASL diagnosed Lifetime by hepatic arteriography w M Press operaior for Contact with wood, plywood, Youth paper and p!j wood glues, polyvinyl acetate, others company (23 years) AS I 00022237