Document npRrEay2owZQ9L8Rng4VjDo5X

410 AUGUST 30, 19 of experiments was performed according to the following schedule: --24 hour* intrammcular tranylcypromine (20 mg. per J-gOi 0 hour inimvenous tranylcypromine (10 mg. per kg.)t 1 hour intravenous procyclidine (5 mg. per kp.) 4 hours intravenous tranylcypromine (10 wg. per kg.). The neuroleptics were injected at different tunes before the rectal temperature was recorded. Intramuscular administration of o-flupcnlhixol (0*3 mg. per kg.), given at --1 hour, did not change the temperature course during the experiment; neither did a-flupenth!xol decanoatc in oil (10 mg. per kg.) given intramuscularly 3 days before. The following depot neuroleptics were given intramuscularly at --1 hour; -fUipcnthixol dccanoite (r.r.T.-l>, 10 mg. per kg.), fluphennrine decanoate (r.rj.-D, 2*5 mg. per kg.), pipothurine palmitite (p.r.z.- p, 10 ing. per kg.), end Ousptrileno (F.S.L., 2 mg. per kg.>. jam did not influence the response to procyclidine, but there was a more striking rise in temperature after the last dose of tranylcypromiue. Five out of six rabbits given neutolcptles end only one of the six controls had a tempera ture exceeding 40C. In the r.r.z.-l> group one of six rabbits died shortly after the administration of procydidinc (40-7 *C). Death may have been caused by a cardio vascular effect, since a preliminary experiment in this laboratory demonstrated that such a drug combination may produce dramatic tachycardia. Another animal died In hyperthermia (43 4*0 after tranylcypromine. In the T.Vi.-r group fatal hyperthermia developed in two of six xabbits (42-9 and 43-7'C) Id response to procyclidine. There was a slightly brisker and more pronounced response to the administration of procyclidine in rabbits treated with P4.L. compared with the controls and after the lust dose of tranylcypromine fatal hyperthermia (44'3-44`5'C) rapidly developed In all rabbits. Thus, in a total of twenty-eight rabbits pretreated with two doses of tranylcypromine, administration of procycli dine resulted in a moderate hyperthermia (temperature not exceeding 41-4C) in some animals. After injection of a further dose of tranylcypromine 3 hours after procyclidine. only cases of moderate hyperthermia were recorded, except in animals which had also been treated with a depot neuro leptic preparation on the day of recording. Severe hyper thermia either In response to the administration of pro cyclidineor to the last dose oftranylcypromine was recorded in some of these rabbits. It it remarkable that FJP.T.-D injected 3 days before the experiment did not Influence the temperature course, whereas Injection of any of the depot preparations 1 hour before appeared to do so. In a period ofa few hours, only minute amounts of active substance could have been released from the intramuscular depot, whereas an amount sufficient to establish neuroleptic efleet would have been released after 3 days.*"* Under certain conditions neuroleptics may possibly aggravate the Interaction between antiparkinson drugs and r.a.o.r.s. The reason for this is unknown. However, all three types of drugs may affect dopaminergic neuron systems in the brain. Treatment with an mjuclI. increases the concentration of dopamine. In addition to the anucboiiuergtc effect many antiparkinson drugs inhibit dop amine uptake,* leading to an increased amount of dopamine in the synoptic elctt. An interncurooal feedback mechanism due to postsynaptic receptor blockade by the neuroleptics it probably not cpc-ning, since a receptor blockade can be demonstrated pharmacologically only about 24 h - its after Injeetion of a depot neuroleptic.1 * E* v4id5e*n7c8e 9in* ing the existence of a feedback control mediated via . ynaptic 1. Kjmnrk, At., F(*k, K. F, P !*cn. V,, Bonk, V,, Mallei Nkltcn, I. Ada rt nnat. utu *973, S3, 361. 1. laretntca. A* Fie '' nOwfisKHJicn,V.ili'i.mi,8!),3M, >, Jttrcensen, A., Go -.C. G. PuwA.'ffarmdrfffoia, 1972, S7,1. 4. Puxt, K.| GoLlu. LiuncdflHl, A, Uff Sti. 1970, V, ail. dopamine receptors, tins been reported.*** Minute amounts of the neuroleptics liberated from the depot during rite first few hours nuiy possibly block the prcsynaptic receptors, resulting in an increased formation of dopamine. Since dopaminergic agonists increase body-temperature in rabbits,* the hyperthermia recorded in the present experi ments might bedue to an exaggerated dopamine response. Department of Ptarroacology and Tericotary, H. LuadbeJc It Co* 7-9 OuiliaveJ, DK 2500 Copenhsaea-VaUw, Denimtic. V. Pedersen I. Moller Nielsen. r CHROMOSOMAL AND DOMINANT LETHAL EFFECTS OF VINYL CHLORIDE Sir,--Vinyl-chloride monomer (V.C.M.) is carcinogenic to rats * and epidemiological evidence has demonstrated its carcinogenicity to roan.* It is known that most carcino gens are mutagenic, and therefore evidence of mutagenic effects in man and animals lias been sought. In relatively limited studies Funcs-Cravioto etal.1' and Ducatman et al.11 12 have described chromosomal aberrations in man exposed to V.'C.M. during the manufacture of polyvinyl chloride (r.v.c.). We have examined a larger number of workers and extended the observations to dominant lethal studies in mice exposed tBVAM. We have studied 80 workers, 56 of whom had been work ing in the manufacture of P.v.a, and were thus exposed to Y.C.M.: the remainder were working in plants and labora tories where exposure to V.C.M. did not occur. The exposed group consisted of autodaw workers, maintenance workers, and workers associated with the manufacture of vinyl chloride. Blood samples were taken and lymphocyte cultures prepared using standard Difco kits (Difco Labora tories, Detroit, Michigan, U.S.A.). Lymphocytes were CHROMOSOMAL. ABZREATXOK* IH VIKYL-CHLOJUDB-XXFOSED WORKEU AMD CONTROLS MOT XXVdSED TO V1XYL CHLORIDE Expofur, category Exposed .. .. Nan-exposed .. No. 56 24 % S edls 6-30 Ml % CuceUi 1-43 0-46 % Cs mils o-so 0-09 cultured for 46 or 72 hours. AH slides were coded before scoring to ensure unbiased analyses, and 100 cells from each individual were analysed using the classification of Buckton and Pike.11 Workers who bad been exposed to X rays, prolonged drug treatment, or recent viral infections were excluded from the study. The results from 48 and 72 hour cultures were nor signifi cantly different and these data have been pooled. The results are given in the accompanying table where it can be seen that there is a significantly increased (p < 0-05) percentage of B, Gu, and Cs cells in the exposed workers. These results, which confirm those of the previous suggest that vinyl chloride has a detectable effect on ehromoidftUI BbfifTH IlOns in man. To encck W!uim any genetic tllc^U. cutild be induced in .he germ cells we carried out a dominant IcthaCHudy in 5. Carls,cf', \ , Kchr, V4 UnSsulii, M. 7 P&avmac. Frit. IW4, 5, np! sh, S. tPiltd Fnih, K. K.7. rkarme Thtr. 1974, SSI, 8Z. 7. Qvocl , ; <i| A. Seitnci, 19 <3, SB. 8. Mal(Oi:i. . I c. -*ir,a. limiwn. K '*74,7,307. 9. Creech, J L., Jul ja, M. N " .v. up. >974. 16,150. JO. Funn-Claviole, Lunbv . 1.mitten, Ji lihrcnbcrf, L. Kittnlift, A. T., (htcntui. 1 .in, S. Ismi, 1975, j, <59, 11, Ducitmin, A, Hinehhom, 7. -ililMlT, 1. |, IlMtlwn Art. 1975, 31, 163. 12. Bukktan, K. E.,Filtc, M. C hit.J.Rad.BM. 1964,8,434. i f i AP00008444 TJIK LANCLT, AUGUST 30, 1975 4 mice. Fifteen male mice per ireauncnt group were cxjxscd to level# of 30 CGO, 10 000, and 3000 p.p.m. of v.c.at. for hours a day on 5 consecutive day*, and an examination fur dominant lethal effects in two females mated with each male for 8 consecutive week* was carried out. There was r*o significant increase in the number of early deaths per implantation compared will) a control group exposed to air Slone, indicating that V.C.M. does not produce dominant lethal mutations in mice even at these exceptionally high levels. It appears, therefore, that the mutagenic effect* of vinyl chloride, expressed as chromosomal aberrations in lymphocytes, do not occur in the germ colit. The reason for this could well be that active metabolites of vinyl chloride are responsible for the toxic effects and these do not reach the testis. The potential danger of mutagenic effects on the fetus via the spenn does not diireforc seem to exist. Imperial Chemical Indu,tries limited, Ceotrri Torireiecy Laboratory, Aldcrky Park, Nr. Mecrictfidd, ChetWre SK10 4TJ. I. F. H. Purchase C. R. Richardson D. Anderson. THYROID-CELL-MEMBRANE ANTIBODIES SIK,--Attention has been drawn ** to an association between venous types of thyroid disease and infection with Ytrwda tnuracoiiiica serotype 3. Lidman et ].* have also shown, using an indirect immuaofluorcscem technique, that * high percentage of the sera containing agglutinating antibodies to Y. enicrocelitica serotype 3 have antibodies which react with the membrane region of thyrotoxic thyroid epithelial cells. Following lieat inactivation of complement, smooth-muscle antibody (s.m.a.) positive sera can be shown 411 served tty Biberfcld ct at.* (see accompanying figure;). 'Hie 40 seta investigated in thfat study were collected over a four-month period, Their sclctiiuu wns simply on the basis of the brightness of the thyroid-membrane fluorescence on initial screening. The indireet-immunofluoreseonce tech nique used was similar to that described by Beck.* To determine the immunoglobulin class of the antibodies, specific antisera to G, A, and M were obtained from Wellcome Reagents Ltd, and D and E from Bchtingwerkc AG. As observed by Biberfcld et ah4 some thyrotoxic thyroids used as substrates gave no staining of thyroidcell membrane with positive sera and therefore, once a thyrotoxic thyroid was found suitable, it was used through out the study. The mean age of the patients was 59-2 years (range 18-69); the 46 patients comprised 26 females and 20 male*. The clinical diagnoses are shown In table j. table i Clinicri dbgnori* Tkjrteid diuatu Thyreioxiceil* ....................... Hypothyroidism................................. Ifaspeeiflet! ....................... .. Otter guwtrummt diieaitt: Pernicious tnxmls ....................... Rheumatoid sethriti* -...................... Autoimmune hxmalyttc tnarai* Oucnlc active hepatitis....................... Alopecia erects................................. Melitnani dmeii ,. ....................... Veieulor dii/eit .. .. li/<etititt4nnMt .. ...................... MitctHantcm .. .. No, of patient* U f a 6 t 3 1 S 4 3 11 TABU U--ASSOCIATED AVTOAKTUODIES Ocean*epedfie Thyroid ndanomal Clitric parietal cdl 4* IS Noa^rfian-apeciRc Antinudeer Smooth muscle Miiochotwlrial Reticulin 13 11 1 a True fieducwqr erf thii antibody could not be determined since when there - bright cyioplesmle fluorescence due to mierowmat antibody this obscured cell-meabnne sulniag. thlx4 mcUm et tkyntwde thyroid displayed by indirect Imuuaepcraxldsfc iccbaEtjae, Note the linear staining of epithelial cell membranes. x440. to produce identical staining of thy vid-eell membranes.4'1 * 3 However, >' n dear that this is * (Terent antibody since not Only o be removed by ab-- ^lioa with pig stomach but also i. ..,iear* to be inhibited by cotn'-irmeat,* We repc;: here our studies on an antfood,, found r- sen tent to. our laboratory r routine autoa- idy stiJies, which produces an id -.1 staining pack. . to that ob 1. Bach, K., Larsen, f. XL. swn, J. M Nmp, J. Unttt, 1974, ii, 431. t. Udmtn, K., EdksMa, U, Fiirwni, A, Norberf, R. M 1974, If, 1449. 3. ven Honitforff, XL, Pritnen, C. ih'd. p. 1W6. J Bibtiftld, G, I'tfiMtu, A , Lrotci, K. CUh, txf. Awm. 1974, 10, >71. Sutton, It. " P., Emond, R. T. D, Thomas, D. It., Dtalidt, It Out 14 17, 437. It Is evident that some 52% of patients with this particular antibody have cltnicat autoimmune disease. The mean antibody titre was 1/64 (range 1/8-1/512). The immuno globulin class of the thyroid-membrane antibodies was as follows: G-45, A-34, Ai-16, D-6, and E-28. The nature and frequency of associated autoantibodk* are shown in table U. Like Biberfcld et al.4 we have observed tbit, following heat inactivation of complement, 32 out of 44 sera contain ing smooth-muscle aatibo ", reacted with sectioned thyro toxic cells to produce an ' ical staining pattern, but this antibody does not show . ide a spectrum of immuno globulin clast as that foi. . fhe other group and is mainly of thi- ' :G class. Clear:. -.waver, there is some vmbp sinc< ' of the unheatv-w rert which were pesV-` for thyr. - -ell-mcmbranc antibody also contained a.v Tlu. .'isocintion between Y. t>utrccoh'tiea scroty, and thyrotd-ccU-n nbrane antibody** U of inttrtst Ac tion with th rdcutar organism la common ir adi- navla, but tT " does not appear to be so in iced Kingdom.1 C JO sera (10 positive for thy,- - cm- brane antibody, 10 positive for smouth-mi dy, and 10 negative for all aucoatiiibodics) screens . .<ee of infection with this organism none was positive. er. i Seek, 1. S. Atweiitln of CUeieal Feriiolngiitv Brndthtct, 1974, no. 69. 7. Malt, N. s. Pmotul eommunieitiwi. (p LJ*d. y.C. UT L cytogenetic studies of bone marrow cells FROM RATS EXPOSED TO VINYL CHLORIDE R. V. .Johnston, D.V.M., D. J. Mcnoik, U.S., M. N. Pinkerton, B.S., Ti. B. WhorUm, Or., Ph.]).* Dow Chemical U.S.A.. Texas Division - Freeport, Texas 77541 Industrial Health and Medicine Department Biomedical and Comparative Toxicology Research Laboratory The Biomedical and Comparative Toxicology Research Laboratory of the Texas Division of Dow Chemical U.S.A. was asked by the Manufacturing Chemists Association to conduct cytogenetic studies on some of the rats which had been exposed to vinyl chloride at Industrial BIO-TEST Laboratories, Decatur, Illinois. The details of the exposure levels and pathological findings will be reported separately. Preliminary reports have appeared in Chemical Week (115:30, July 17, 1974) and in the Annate of the New York Academy of Sciences, Volume 246, page 219. The test animals were Charles River CD outbred albino rats which had been exposed to vinyl chloride gas for 7 hours per day, 5 days per week for one year at 0, 50, 200 and 2500 ppm in air. Cytogenetic studies on 5 males and 5 females from each group showed that there was no statistically significant increase in the chromosomal aberration rates in <bone marrow cellg^of the exposed rats. ._ . *Associate Professor and Director Division of Biometry Department of Preventive Medicine and Community Health University of Texas Medical Branch Galveston, Texas 77550 AP00008446