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EMBER 13,1982 LANCET, NOVEMBER 13,1982 1101 best predictor of i), and significant nly one measure riate or accurate it, however, that wing conclusions il a gold standard us with as many ldation. The serum al Perth Hospital :hard E. Davis. na J. Stanley :holas de Klerk tRIE Margetts ol Bower 5) Dr Phillips and by Buss and me. the folatecontent rkslti^fcbedone accun^f as this cake to be made, as made in 1977, ten defined. Free tommended daily alth and Welfare^ age of the U.S. ; Department of 1 daily intakes for nendations were [for folic acid] are ided daily amount ) define the daily >n, together with assessment of the J. A. Spring body which binds fates erythrocytes ent on human cel] ic surveillance by t T may become fSpringer and couznan malignant mal cells.8 Our mours may have it 550 0008) on the gnesium, copper, zinc, bold supply. BrJ Nmtr rd for Canada. Ottawa; *> 8th ed. Washington, b'no 15. HMSO, 1979. no 15 (2nd impression). an Wood, ofsubstances 929; It 236. Croup MN specificities. Precursors of the blood t Twu/iuttm 1979; 1ft ERYTHROCYTES FROM CANCER PATIENTS AND FROM BLOOD DONORS: HAEMAGGLUTINATION WITH MONOCLONAL ANTIBODY Haemagglutination result Intact erythrocyte* Desialated erythrocytes Diagnosis GM+ GM+ No. of mono mono* samples clonal Ab GM clonal Ab GM Group I Leukaemia Hodgkin's disease 25/25 + +- 4/4 + - + - Non-Hodgkin's lymphoma Myeloma 2/2 1 --++-+- Ewing's sarcoma 1 +- - Wilms' tumour 1 --+- Bronchus Larynx 3/3 + - + 1 +-+- Lung Ovary 5/5 + - + 1 +-+- Breast Astrocytoma Leukaemia* Wilms' tumour* Yolk sac carcinoma* Ewing's sarcoma* Hodgkin's disease* 5/5 + +- 1 -+- 1 --+ - 1 --+ - 1 --+- 1 --+ - 1 --+- Leukaemia, relapse Group II 1 +- Blood donors 2/50 + - + - 6/50 +/- - + - Group III 42/50 - - + - Random patients 4/32 + - + - 28/32 - + *Offtreatment. GM." growth medium. i surface of their circulating erythrocytes. For these studies we first prepared a rat monoclonal antibody (an IgG) against desialated human erythrocytes. Antibody in the culture supernatant does not - agglutinate normal erythrocytes but directly agglutinates desialated : erythrocytes down to a titre of 1 in 100 (unpublished).9 Preincubation of the monoclonal antibody with purified T antigen (kindly donated by Prof. G. Springer) inhibits this agglutination. ; Blood samples obtained from 50 tumour patients (group i) and from r 50 blood donors (group H) were then tested for haemagglutination with the monoclonal antibody (unpublished). All samples were V maintained at pH 7-4 and 4C under sterile conditions and were : tested within 24 h of sampling. The results (see table) indicate that the T antigen is exposed on the erythrocytes ofpatients bearing a number oftumours, including an astrocytoma in 1 case. In this group 3 of the 5 samples were negative--2 from patients with non-Hodgkin's lymphoma and the , third from a patient 5 weeks before cessation of treatment for a [ Wilms' tumour. Ofthe 50 blooddonor samples 2 were positive and6 showed slight agglutination; the remaining 42 were negative for T. ` Besides the patients in group i, 5 out of 5 patients who had completed therapy for cancer and were offtreatment were found to , be negative for T on their erythrocytes. 1 patient, who had a relapse after 3 years off treatment for acute lymphoblastic leukaemia, was positive. A third group (group in) consisted of samples obtained from patients at random: here the samples were tested before checking ; individual diagnoses. 4 out of 32 were positive, ofwhich 1 turned 2 out to be a sample from a patient on treatment for cancer. The other 3 were a 93-year-old with a poor diet and lung collapse, a patient ( with poor vitamin intake and recurrent stomatitis, and a patient with alcoholic liver failure. The remaining 28 were negative and included patients with anaemia, pernicious anaemia, diabetes mellitus, colitis, splenomegaly, pancreatitis, liver abscess, and m. arthritis. S The exposure ofT antigen on the surface oferythrocytes ofcancer .m patients was detectable at diagnosis (i.e., before the start of, and therefore unrelated to, chemotherapy). Control tests showed that: (a) Treatment of erythrocytes from cancer patients or from normal individuals with irrelevant rat monoclooall did not cause haemagglutination. (b) Those erythrocytes that did not agglutinate with "anti-T" monoclonal antibody subsequently agglutinated following desialation. (c) Preincubation of the monoclonal antibody with purified T antigen abolished its ability to agglutinate intact erythrocytes from cancer patients. (d) Those intact erythrocytes that could be agglutinated by the monoclonal antibody were not agglutinated by autologous plasma or by naturally occurring anti-T antibodies. This last observation suggests that the epitope recognised by the monoclonal antibody is distinct from that which binds naturally occurring anti-T antibodies. Also, although the monoclonal antibody binds T antigen isolated from erythrocytes we have no direct evidence that it is binding to T on erythrocytes from cancer patients. Studies are in progress to assess the value ofthis new monoclonal antibody in monitoring patients on treatment for leukaemia. We thank the following from Addenbrooke's Hospital, Cambridge, and Cambridge University for their cooperation in obtaining blood samples: Dr N. D. Barnes, Dr V. Broadbem, Dr L. Brandt, and members of the paediatric oncology clinic; Dr J. K. H. Rees (department of haematological medicine); Dr D. G. Bratherton and Dr T. Wheeler (radiotherapeutic centre); and Dr T. Gibson (regional blood transfusion centre); and Mrs Rosamund Swcnnson for her assistance in raisingthe monoclonal antibody. This research was funded by the Cancer Research Campaign (J. M.) and by the Medical Research Council (S. M.). Division ofVirology, Department of Pathology, Univenity ofCambridge, Laboratories Block, Addenbrooke's Hospital, CambridgeCB2 2QQ Department ofSurgery, Univenity ofCambridge, Addenbrookc's Hospital Jo Milner Su Metcalfe MESOTHELIOMA IN A BRAKE REPAIR WORKER Sir,--Merewether's speculation in 19331 that asbestosis would manifest itself in industries, including the manufacture ofasbestos brake linings, where it was then unknown, was soon realised. In the United States asbesrosis was reported in a brake lining weaver in 19402 and the British Industrial Injuries Act of 1948 included asbestosis as a prescribed disease among "brake liners". Reports of lung cancer in asbestos-exposed workers closely followed those of fibrosis, but among "brake workers" such cases at first seemed to be confined to those who worked in friction product manufacture and fabrication. Subsequently there were occasional reports of lung cancer and mesothelioma among workers installing and repairing friction materials. However, asbestos-related cancer in brake repair workers has attracted little attention, in pan because of the belief that fibre remained locked into the brake lining matrix or was much altered by heat generated by braking. Dust in brake drums was observed by light microscopy to be "asbestos-free". Furthermore, the capacity ofchrysotile, the main form ofasbestos used in brake linings, to cause mesothelioma may be less strong. We describe here a diffuse pleural mesothelioma in a man whose sole exposure to asbestos was to the chrysotile form during brake maintenance and repair. A 55-year-old man was admitted to hospital in October, 1980, with right-sided chest pain and soreness when he breathed deeply. Chest X-ray revealed a right-sided pleural effusion, and a cytological diagnosis of mesothelioma was confirmed by biopsy and examination of resected tumour. The patient died in September, 1981. This man had for many years worked in used car, tyre, and car repair businesses. Since the age of 19 he had serviced automobiles, including the replacement of brake linings. He had no history of construction or shipyard work or any other occupational contact with asbestos and had never lived near an asbestos-fabricating plant. 1. Merrwetbcr ERA. A oemoraodunt on Mbewoai*. Taberck 1933; 19: 69-8). 109-18, 152-59. 2. Stone MJ. Clinical studies in asbestoais. Am Rev Tuberculosis 1940; 41: 12-21. 1102 THELANCET, NOVEMBER 13,19 SCET.NOVEMB Fig. 1--Inorganic residue* extracted from long parenchyma. Most chrysolite is present in fibril form: fibril A is 0 4fjm long, fibril B is 1 5 pro, fibril C is 12-0 pm (only 4 3 pm is shown). Additional short fibrils are scattered in matrix debris. Necropsy revealed virtual obliteration of the right pleural space by a tumour that had extended through the diaphragm and metastasised to mediastinal lymph nodes, liver, and left lung. The histological appearance was in keeping with an epithelial type diffuse malignant mesothelioma. Slight interstitial fibrosis and anthracosis was noted in the pulmonary parenchyma. No typical asbestos bodies were observed but objects resembling such bodies were seen in a stained lung tissue block. After ashing only one typical asbestos body was found. A tissue mass of 6310 mg was bulk digested.3 Only 1 -33 mg of inorganic debris was recovered (0 02%). The residue was immersed in distilled water, disrupted by sound waves(at 40 W for about 10 s), and analysed. 20 pi of suspension was put on a carbon-coated formvar support on a nickel grid and allowed to evaporate. Another coat ofcarbon was then placed over the dried residue. Electron microscopy showed the residue to be full of exogenous partides, almost all non-fibrous. Magnification to 10 000 and more revealed chrysotile fibrils among these particles (fig. 1). Preliminary identification was based on morphology3 but electron diffraction analysis confirmed the structure to be that ofchrysotile (fig. 2 and insert). Fibrils less than 1 pm long and others longer than 5 pm were present. Long fibrils have been frequently encountered in lung tissues from occupationally exposed workers4 but not in persons with only environmental exposure. 10% of the fibrils were longer than 10 pm. No amphibole fibres were found, which was consistent with the occupational history. We estimate that about 1 pg chrysotile was present per 5 g wet lung parenchyma. Although amphibole fibres (anthophyllite) were used experimentally for a brief time in the United States, to our knowledge only chrysotile has been used in brake pads since the J. I myr AM, Selikoff IJ, Sastre A. Chrysotile asbestos ia the lunp of persons in New York City. Arch Environ Health 1971; 22* HA-61. 4.Pootey FD, Oldham PD, Chang-Hyun UM, Wagner JC The detection ofaabettoa in tnaoes. In: Shapiro HA, ed. Pneumoconiosis: Proceeding* of 2nd International Conference (Johannesburg). London: Oxford University Press, 1970: 100-16. Fig. 2--Chrysotile fibre bundle in dust burden. Selected area electron diffraction pattern (insen) shows chrysotile structure Reciprocal a* axis is marked. 1940s. Under certain test conditions of brake failure free chrysotile asbestos can be liberated, as shown, for example, by the work of Lynch,5 Hatch,6 Hickish and Knight,7 Seshan,8 9and Rowson.' Some ofthese fibres are retained in drum dust10,11 and tend to be submicroscopic. However, besides this submicroscopic chrysotile fibre in brake drum housing there is a more significant source of free, unaltered fibre in the bevelling, refurbishing, and refitting of brake pads.10 1T1here is thus ample opportunity, during brake maintenance and repair, for contact with chrysotile fibre both in drum debris (where it will usually be in a transformed state) and at long and predominantly unaltered fibres liberated by machining Controversy over the potential of chrysotile to cause mesothelioma has continued despite evidence from asbestos textile fabricators thought to have used only chrysotile,12 from workers making brake pads,13 from chrysotile miners and millers,14 and from animal studies.15 5. Lynch J. Brake lining decomposition product*. J Air PoBui Control Attoc I960; !fe 824-26. 6. Hitch D. Possible alternative* to asbestos as a friction material. Ann Occnp tiyg 1971k U> 25-29. 7. Hiduah DE, Knight KL. Exposure to asbestos during brake maintenance. Ana Occnf Hyg 1970; 12: 17-21. 8. Scahao K. On tbe utility ofdsrk*field electron microscopy in the determination ofrb* degree ofdeformation in chrysotile asbestos: an environmental researchapplication Emit Ret 1978; 18: 383-92. 9. RowaonDM. Tbechrysotiiecontentoftbcweardebmofbrakeliiitnga. 9W1978;47t 315-21. 10. Rohl AN, Linger AM, WolffMS, Wetaaan I. Aabettoa exposure during brake Until maintenance and repair. Bnoir Ret 1976; 12: 110-28. 11. RohlAN, Linger AM, KlimentidisR, WolffMS, SelikoffIJ. Asbestos content ofdutf encountered ia brake maintenance and repair. Proc RoySocMed 1977; 78:32-37. 12. Ptsaj. The hygiene standard for chrysotile asbestoa. Lancet 1978; k 484-89. 13. Maacuso TF, El Attar AA. Carcinogenic risk and duration of employment ainonf aabestoa workers. In: Biological effects of asbestos: Proceeding* of Dresde* International Conference. Dresden: Anepach, 1968: 161-66. 14. McDonald AD, Harper A, El Attar, McDonald JC. Epidemiology of a primary malignant mesotheUal tumor in Canada. Cancer 1970; 26: 914-19. 15. Wagner JC. Asbestos carcinogenesis. BrJ Cancer 1975; 32: 258-59. e pathological diagi d to chrysotile fib do not form i glioma asbestosis l electron micri 1 environment Ef^ht microscopy is _e health and safety been outlined b 1*7 million wor __ y stores, and ser j and garages. The e workers seems to 1 ____ f evaluated. ^ Ibe seen in the futur smvenigsrionwassup] k Dr John H. Evans, >ntal Sciences Labor** (Sinai School of Medicine lN.Y. 10029,U.SJL i Tumour Reference Ce G>c Hotptnl, Otwwi, C `VENOUS ULCERj t,--Dr Howell and stasis is related : biochemical eras social factors, cause of venom tence of perfors of the ankle. Fa in the cui hypertension ; and tissue de{ i.2 There is nc |jtic or hypoxic, and th Mlheompetence of perf jhmbosis due to traum (iadbirth and is, there deficiency. The deep v Writ damaged valves. T jyy, therefore, be tran wU dearly be more sevi nHowell and Burton do aanys by standard m Mticular androgen prod iaa selected subgroup o The height and obesity i (this. The infertility m happens in some gener Metabolic abnormality c Wyenous thrombosis or gjfcienot done this is onl jpaliuuie being clearly ; The men in the ulcer were the controls--this, perm production. How wight prevent men frot this might also be true socioeconomic class. fhSXlsiiM ofSurgery, hkts'tHeipitil, fMMfuiq, Bma cm; 9BG SkspB C. Trouble in thus - (Dec): 21-28. R-Mkhoboa WH. Brake nail : , Wfisir and maintenance w N.LO.S.H. (in press). L Dadd H,CoctcnFB. The p -v I --dsn; Churchill Urinj 2-Wmad KG, < l in*tt NL, Banund KG. T M iNCET, NOVEMBER 13,1982 LANCET, NOVEMBER 13,1982 1103 burden. insert) shows chrysotile structure. wake failure free chrysotile for example, by the work of it,7 Seshan,8 and Rowson.9 rum dust10,11 and tend to be is submicroscopic chrysotile a more significant source of refurU^kg, and refitting of opp^^lty, during brake with chrysotile fibre both in n a transformed state) and as res liberated by machining. of chrysotile to cause ridence from asbestos textile ' chrysotile,12 from workers : miners and millers,19 and J Air Po&ii Central Attae IMS; III fiction material. Arm Ocarp Hyg 1970; durinf broke maintenance. Ait* Ocatg fucrosepuy in the determination ofthe in environmental research applictioo. Schmotbrakelinijifs. Waarl978;47t Wwtoo exposure durinf bnke lining : 110-28. S, SelikofflJ. Asbestos content ofduS 'ProcRaySacMed 1977; 78t 32-37. tstos. Lamat 1978; i: 484-89. nd (tostko of employment smons r ssbestos: Proceeding, of Dresden >, 1968: 161-66. dd JC Epidemiology of s ptimsry e 1970-, 28: 914-19. m 1975; J*i 258-59. ' : pathological diagnosis ofasbestos-related diseases in people to chrysotile fibre is complicated by the fact that asbestos do not form readily. Furthermore, in patients with lelioma asbestosis may not always be present. As in this case, ical electron microscopy may be essential. Chrysotile in a sgical environment is degraded chemically and physically so : light microscopy is a poor guide to chrysotile exposure. : The health and safety problem of brake maintenance and repair fwofk has been outlined by Morgan.16 In the United States there are 1-7 million workers in the new and used car business, Haccessory stores, and service stations, and another 435 000 in repair and garages. The risk of malignant asbestos disease among workers seems to be low17 but mortality data have yet to be .'thoroughly evaluated. With the large numbers at risk, more cases -gjrmy be seen in the future. ^ This investigation was supported by a grant from the N.I.E.H.S., ES00928. ; tfc thank Dr John H. Evans, University ofTennessee, for the tissue samples. fwwmynmgmal Sciences Laboratory, lloonc Sinai School of Medicine, IfcwYorkyN.Y. 10029, U.S.A. ; Canadian Tummir Reference Centre, - % Ottawa Ciic Hospital, Ottawa, Canada A. M. Linger W. T. E. McCaughey VENOUS ULCERATION IN HYPOGONADAL MEN I' Sir,--Dr Howell and Dr Burton (Sept. 18, p. 630) suggest that . venous stasis is related to hypogonadism. In trying to find an -; endocrine biochemical explanation for their findings they have , underemphasised considerations of surgical pathology and f,5 powerful social factors. The cause of venous ulceration is generally accepted to be incompetence of perforating veins, most commonly on the medial aspect of the ankle. Failure of the valves in these veins causes f hypertension in the cutaneous venules and leads to ulceration.*1 1 . .Venous hypertension produces increased capillary leakage of , fibrinogen and tissue deposition offibrin, causing local hypoxia and j% ulceration.2 There is no evidence that the blood in these veins is static or hypoxic, and the term stasis ulcer is outmoded.3 Incompetence of perforating veins normally follows deep vein thrombosis due to trauma such as that which occurs in women after childbirth and is, therefore, not necessarily related to androgen j deficiency. The deep vein thrombosis resolves by recanalisation j with damaged valves. The full hydrostatic pressure from the chest J may, therefore, be transmitted to cutaneous venules; this effect S will clearly be more severe in taller men. Howell and Burton do not define hypogonadism, but testosterone T assays by standard methods showed no evidence of reduced f:; testicular androgen production, despite the fact that they were done iTon a selected subgroup ofpatients who were unmarried or infertile. The height and obesity ofthe patients cannot, therefore, be related S|4o this. The infertility might be related to a reduced sperm count as y happens in some generalised diseases (e.g., cystic fibrosis). Any .metabolic abnormality causing a low sperm count might predispose to venous thrombosis or reduce fibrinolysis, but since sperm counts Were not done this is only speculation, the two cases ofKlinefelter's St " ome being clearly exceptional. The men in the ulcer group were less likely to be married than were the controls--this, unlike fertility, cannot be directly related to sperm production. Howell and Burton discuss the fact that obesity might prevent men from marrying but ignore the possibility that ||i;this might also be true of men with venous ulceration or low ij i socioeconomic class. Dcpvtmem of Surgery, KEl John's Hospital, kChelmsford, Essex CM2 9BG A.M. C. Thomas I'fs. Morgan C. Trouble in the auto repair shop. Job Safety Health (OSHA, DOL) 1976 i-~ (Dec.): 21-28. " Nicholson WH. Brake maintenance investigation of health hazards in brake lining T repair and maintenance workers occupationally exposed to asbestos: Final report to 1 N.I.O.S.H. (in press). III. Dodd H, Cockctt FB. The pathology and surgery ofthe veins ofthe lower limb, 2nd ed. ^. London: Churchill Livingstone, 1978: 246 - 66. 12. Burnand KG, Clemcnson G, Whimster I, Browse NL. Extra vascular fibrin E p deposition in response to venous hypertension. Br J Surg 1976; 83: 660. E?* Srowae NL, Burnand KG. The cause of venous ukeratioa. Lancet 1982; ii: 243-45. VITAMIN A AND PAGET'S DISEASE Sir,--The recent resurgence ofclinical interest in vitamin A has come about primarily as a result ofimproved methodology, such as high-pressure liquid chromatography (HPLC), which has permitted the rapid separation and analysis of retinoids in small volumes ofblood and tissue extracts.1 In turn this is increasing our understanding ofvitamin A metabolismandofthe role played by the retinoids in disease--for example, the passible relation between serum retinol and the risk of cancer,2 the development of hypercalcaemia in renal failure,3 and the reduced fetal growth seen in immigrant Asians in Britain.4 5 6 7 The role of vitamin A in bone disease warrants closer examination. In vitamin A deficiency there is bulky overgrowth of bony tissue and failure of absorption ofpreviously formed bone.5 Both increased osteoblastic activity and reduced osteoclastic activity have been implicated in these changes, which are reversed in hypervitaminosis A Retinol is a membranolytic agent and in organ culture directly causes destruction and resorption ofbone. It also stimulates the release of parathyroid hormone both in man in vivo and in isolated bovine parathyroid glands.6 While studying the response ofpatients with previouslyuntreated Paget's disease to the injection ofa single dose ofcalcitonin we noted that the plasma calcium usually fell while circulating parathyroid hormone (PTH) concentrations (measured by a radioimmunoassay directed mainly at the amino-terminal of the peptide) increased. However, the magnitude of these changes and the time of peak response varied considerably from patient to patient. In view ofthe above reported effects of vitamin A, we measured (by HPLC) plasma retinol on the basal plasma samples obtained from the patients to see whether vitamin A might be a factor in this variability. So far sixteen patients have been studied. Four showed no response to calcitonin (i.e., plasma calcium and PTH values did not change). One patient showed a continuous increase in plasma PTH over the 24 h when samples were taken and was thought to have hyperparathyroidism. We excluded this patient from our calculations. The relations between the plasma retinol and changes in plasma calcium (ACa-maximum fall ofcalcium occurring at a time, Tmin Ca, after injection) and PTH (APTH - maximum rise of PTH occurring at a time T^ PTH, after injection) were as follows: Correlation (r) ACa* 0-519(p<0-05) APTH* TmmCa 0-417 (pX>-l) -0-606 (p<0 05) TnaPTH -0-953 <p<0-001) `Including tbe 4 non-responder*. Tnux PTH varied from 5 to 12 h in the eleven patients who responded to calcitonin (figure). These results support the view that vitamin A has a role in bone metabolism and PTH release. Our interpretation would be that inasmuch as plasma retinol is a measure ofvitamin A status and/or availability ofvitamin A for metabolism, the reduced interaction of - vitamin A with the parathyroid glands results in a delayed response in the release of PTH after the hypocalcaemia induced by calcitonin. This hypocalcaemic response to calcitonin is characteristic of patients with increased osteoclastic activity.7 Patients with a reduced availability of vitamin A may have less 1. De Ruyter MGM, De Leenheer AP. Simultaneous determination ofretinol and retioyl esters in serum or plasma by reversed phase high performance liquid chromatography. Ctin Cktm 1978; 24: 1920-23. 2. Kark ]D, Smith AH, Haines CG. Serum retinol and tbe inverse relationship between serum cholesterol and cancer. BrMtdJ 1982; 284: 192-54. 3. Farrington K, Miller P, Vargbese Z, Baillod RA, MoorheadJF. Vitamin A toxidty and hypercalcaemia in chronic renal failure. BrMtdJ 1982; 282: 1999-2002. 4. Maxwell JD, Ang L, Brooke OG, Brown IRF. Vitamin D supplements enhance weight gain and nutritional status in pregnant Asians. Br J Obtm Gymatcoi 1961; 88: 987-91. 5. Navis JM, Harris SS. Vitamin A influence on catena metabolism and cakifkatioo. Ann N Y Acad Sa 1980; 288: 45-54. 6. Chestow BS, Williams GA, Norris RM, Bsker GR, HargisGK. Vitamin A stimulation ofparathyroid hormone: Interaction with caktiun,hydrocortisone and vitamin E in bo^ne parathyroid tissues andeffects ofvitamiaAinman. firrjrCfm/itwsJ 1977;7: 307-14. 7. Burcfchardt PM, Singer FR, Potts JT. Parathyroid function in patients with Paget's disease treated with salmon calcitonin. Ctm Endncrimi 1973; 2: 15-22.