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phrased in terms of the result for soft-tissue sarcoma being "compatible" with a causal role of chlorophenoxy herbicides. We well aware of the limitations of the study, especially, as Mr Peto notes, the small number of soft-tissue sarcomas observed. We would add the fact that misclassification in exposure assessment may have prevented a better evaluation of whether the link observed applies especially to the herbicides contaminated by TCDD, a substance for which suspicion of human carcinogenicity is increasing.2,3 As to the other incidental findings on cancers of the testicle, thyroid, other endocrine glands, and nose and nasal cavity, the verb "appeared" ("to seem, as distinguished from to be"4) as a qualifier in the summary indicates the uncertain nature of the increased risks observed. are

Unit of

Analytical Epidemiology,

International Agency for Research 69372 Lyon, France

on

Cancer,

RODOLFO SARACCI MANOLIS KOGEVINAS

1. Doll R, Peto R. The causes of cancer. Oxford: University Press, 1981 1203. 2. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. Cancer mortality among workers in chemical plant contaminated with dioxin Lancet 1991; 338: 959-64. 3. Doll R. Hazards of cancer in the chemical industry (Leon Golberg memorial lecture). BIBRA Bull 1991; 30: 183-88. 4. Onions CT, ed. The shorter Oxford English dictionary, 3rd ed. Oxford: Clarendon Press, 1965: 84.

Carcinogenicity of dioxin SIR,-Professor Manz and colleagues (Oct 19, p 959) conclude that their study of cancer mortality among chemical plant workers supports the hypothesis that dioxin (TCDD) is a human carcinogen. They state: "our results show that the increase in cancer mortality is not directed at special sites. TCDD induces tumours in different organs in animals and promotes tumour formation."This basis for their conclusion seems inconsistent with the understanding that has developed through decades of cancer research-namely, that cancers of different sites and cell types represent different diseases. We are not aware of examples in cancer in which data support a biologically plausible mechanism by which TCDD could cause an increase in overall cancer mortality through a combination of small increases in neoplasms of different cell types at many sites. The three specific sites where small increases in cancer mortality were reported by Manz et al were lung, the haematopoietic system, and breast. Toxicological studies do not fully support the premise that TCDD could have caused these increases. Rao and colleagues1 found that TCDD increased only skin squamous cell carcinomas in hamsters; Kociba et al2 recorded increases in some cancer sites in rats and mice, including the lung, but decreases in other sites, including the mammary glands; and the US National Toxicology Program3 found increases in haematopoietic lymphomas in rats and mice, but no increases in lung or mammary gland cancer. Might the slight excesses reported by Manz et al have been artifactual ? Determining cause of death by the use of medical records in the exposure cohort but by death certificate data in the national control population could mean that specific cancer deaths were more rigorously identified in the exposure cohort, leading to an overestimation of standardised mortality rates (SMR). The SMRs for the comparison with the gas worker control population might also have been artificially raised, because it is not clear from the article if follow-up of gas workers was sufficiently complete to avoid underascertainment of deaths. The absence of a clear dose-reponse and of a control for smoking further weaken support for a causal hypothesis. Health and Environmental Sciences Group Ltd, 1225 I Street NW, suite 1200, Washington, DC 20005, USA

GEORGE L. CARLO KELLY G. SUND

1. Rao

MS, Subbarao V, Prasad JD, Scarpelli DG. Carcinogenicity of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin in the Syrian golden hamster. Carcinogenesis 1988; 9: 1677-79.

2 Kociba

RJ, Keyes DG, Beyer JE, et al. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol Appl Pharmacol1978;46: 279-303.

3. NTP

(US National Toxicology Program). Carcinogenesis bioassay of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (CAS no 1746-01-6) in Osborne-Mendel rats and B6C3F1 mice (gavage study). Washington: US Government Printing Office (DHSS publication NIH 82-1765), 1982.

Leg ischaemia secondary to non-medical injection of temazepam SiR,—The misuse of temazepam by intravenous drug misusers

highlighted to the extent that the liquid formulation in a gelatin capsule was changed to a solid gel formulation.l-4 We report four intravenous drug misusers, seen within nine months, who have dissolved the new gel formulation of temazepam and injected it with devastating results. A 48-year-old man presented to casualty with an ischaemic limb 48 h after injecting 400 mg temazepam into the groin. He complained of severe pain in the leg. Purple discolouration of the leg extended to the lower abdomen. He had paralysis of his foot which was cold, despite the presence of foot pulses. The patient was treated with intravenous heparin and analgesia. On the day after admission his urine was dark and positive for myoglobin; serum creatine phosphokinase (CPK) was 28 500 U/1 (normal below 200). has been

He was put on forced diuresis. The toes remained ischaemic and had to be amputated. An area of skin necrosis mid-tibia, related to a previous injury, failed to heal and his foot remained paralysed. Two months after admission the patient had a below-knee amputation. The amputated limb showed no vasculitis or foreign-body reaction but there was ischaemic muscle necrosis. A 39-year-old man presented, 48 h after intra-arterial injection of 80 mg temazepam, with severe pain in his leg, aggravated by movement. The leg was cold and swollen with patchy purple discolouration extending to the lower abdomen. Pulses were normal. His serum CPK rose from 3080 to over 15 000 U/1 and his urine was positive for myoglobin. He was treated with forced alkaline diuresis and subcutaneous pethidine for analgesia. The limb improved and the patient was discharged using a stick. A 22-year-old woman had, four months earlier, intra-arterially injected temazepam into her right groin. An ischaemic abscess developed, requiring debridement and skin grafts and leaving a deep scar on her thigh (20 x 40 cm). She continued injecting temazepam into the left leg and subsequently presented 24 h after an intra-arterial injection of 60 mg. She had intense pain in the thigh and buttock, found it difficult to move the limb, and had reduced power in dorsiflexing the ankle. The skin was blue and mottled, the whole leg was swollen but pulses were easily palpable. Her CPK was 14 840 U/1 and she was treated with a forced diuresis and analgesia. Localised cellulitis developed requiring antibiotics. A duplex scan revealed thrombosis in her left internal iliac vein. A 30-year-old man who had injected 160 mg temazepam into the right groin had severe pain, paraesthesia, and swelling of the thigh with mottled skin. He visited casualty three days later but refused to be admitted; he returned five days later still in great pain with an oedematous leg and reduced sensation and dorsiflexion of the ankle. The skin of the right scrotum was gangrenous with cellulitis spreading onto the inner thigh. He was treated with analgesia and antibiotics but heparinisation was not thought likely to be helpful at this late stage. The scrotum was debrided. A duplex scan showed thrombosis of the femoral and iliac veins. Intravenous temazepam gives a "high" followed by peaceful sleep, and when it was formulated as a liquid in a capsule it was widely misused. However, habitual drug misusers seem prepared to dissolve the gel formulation in boiling water in an unsterile manner before injecting it. After mis-injecting a painful mottled cold limb which is oedematous and tense, develops. Pulses are usually palpable; if absent, due to oedema, the ankle-brachial pressure index is greater than one. Movement is very painful and paralysis and decreased sensation may be present. A foot-drop with reduced or absent dorsiflexion of the ankle was the commonest lesion, presumably due to the nerve compression. Muscle necrosis leads to a high serum CPK and myoglobinuria. All four patients presented 24 h or more after the injection, suggesting that the ischaemia

changes develop gradually. Once temazepam is dissolved it is still viscous and one patient described having to use two hands to force the fluid out of the

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syringe. Both temazepam and the macrogols used to increase the viscosity of the new formulation damage vascular endothelium5 Substances that cause damage by microvascular embolisation of particles are usually chalk based whilst other drugs cause a distal vasculitis. A feature of temazepam mis-injection has been major venous thrombosis, leading to oedema and venous gangrene. Management should include heparinisation to maintain collateral vessels and, if there is substantial muscle necrosis (as indicated by raised CPK and myoglobinuria), forced diuresis to prevent rhabdomyolysis. If there are symptoms of anterior compartment syndrome with foot-drop, early fasciotomy is recommended. Analgesia is a difficulty, and an infusion pump may be needed. It seems impossible to devise a truly non-misusable formulation of this drug, but the dangers should be widely publicised and clinicians should be aware of the need for forced diuresis.

S. D. BLAIR C. HOLCOMBE E. N. COOMBES M. K. O’MALLEY

Department of Surgery, Charing Cross Hospital, London W6 8RF, UK

1. Stark C, Sykes R, Mullen P. Temarepam abuse. Lancet 1987; ii: 802. 2. Robertson JR, Roberts JJK, Black H, Davitt B, Stewart N. Management of

abuse. Lancet 1987; ii: 284. 3. Black D. Temazepam capsules. Lancet 1988; i 1114. 4. Farrell M, Strang J. Misuse of temazepam. Br Med J 1988; 297: 1402. 5. Laurchburg AP, Morton FSS, Lacy JE. The development of temazepam Manufact Chem 1989 (Dec): 38-40.

CD25 +, CD29 +, and HLA-DR +). HTLV-I antibody in serum repeatedly confirmed by screening tests (Abbott and Fujirebio). The Fujirebio test demonstrated a very high titre. Positive results were also obtained by indirect immunofluorescence with HTLV-I-producing MT-2 cells. A large spectrum of HTLV-I-specific antibodies was detected by immunoblotting. The patient’s wife and his son were seropositive in all these tests but the level of virus-specific antibodies was lower and their spectrum was narrower. The presence of HTLV-1 provirus in the index patient’s lymphocytes was demonstrated by PCR with primers for gag, pol, and env genes and by Southern blot (table). Sau3AI restriction analysis of the PCR product indicates that HTLV-I (but not HTLV-II) specific information is present in the patient’s was

lymphocytes. Thus, for the first time, HTLV-I-positive ATL has been diagnosed in a European white. This case, with the HTLV-1 infections detected in two family members, suggests that HTLV-1positive ATL can develop in Europe (including the USSR) and that HTLV-1 is more widespread than hitherto supposed. Supported by grants Cancer, Lyon, France.

from the International

Agency for Research

on

drug

gelthix.

Case of adult T-cell leukaemia in HTLV-I infected family in Georgia, USSR SIR,-Human T-cell lymphotropic virus type I (HTLV-1) is associated with adult T-cell lymphoma/leukaemia (ATL) and with a tropical spastic paraparesis/myelopathy. In western Europe, however, no HTLV-I associated case of ATL has been reported so far in the local white population, and HTLV-1-specific antibodies have usually been found only in immigrants from endemic regions.2-4 For two cases of ATL in Italy an association with HTLV-1 has not been confirmed. We describe here an HTLV-1positive case of ATL in man from Georgia, USSR, among whose family were two HTLV-1 seropositive members. A 51-year-old white man, born and residing in Georgia, presented with a 4 week history of headache, progressive weakness, and deterioration in hearing. He had enlarged peripheral lymph nodes, a WCC of 16 000/1, and a follicular rash on the trunk and limbs. Biopsy revealed a diffuse infiltrate of the dermis with mononuclear, sometimes atypical, cells. Clusters of these cells have been also seen in epidermis. Bone-marrow biopsy and lymph-node histology showed infiltration by pleomorphic lymphoid cells with lobulated nuclei. The same cell type was found in blood and cerebrospinal fluid. Serum calcium was raised at 3 mmol/l. The patient progressively deteriorated and he was transferred to Geneva for chemotherapy. Analysis of the membrane surface phenotype of peripheral blood mononuclear cells revealed that most cells were HTLV-IINFECTION IN ATL PATIENT FROM GEORGIA AND HIS RELATIVES

NT= not tested, RR= repeatedly reactive WB = western blot, SB = Southern blot

helper/inducer T cell in organ (CD3 -, CD4 +, CD8 -, CD20 -,

(Abbott EIA), IF= immunofluorescence,

Laboratory of Viral Carcinogenesis, Institute of Carcinogenesis, All Union Cancer Research Centre, 114578 Moscow, USSR

NATALIA SENJUTA OLEG PAVLISH VLADIMIR GURTSEVITCH

1. Ehrlich GD, Poiesz BJ. Clinical and molecular parameters of HTLV-1 infection. Clin Lab Med 1988; 8: 65-84. 2. Cardoso EA, Robert-Guroff M, Franchini G, et al Seroprevalence of HTLV-1 in Portugal and evidence of double retrovirus infection of a healthy donor. Int J Cancer 1989; 43: 195-200. 3. Coste J, Lemaire JM, Barin F, Courouce AM. HTLV-I-II antibodies in French blood donors Lancet 1990; 335: 1167-68. 4. Von Pauli G, Ehm I, Gelderblom HR, Koch MA. HTLV-1 infections in the Federal Republic of Germany Bundesgesundheitsblatt 1990; 5: 205-09. 5. De Stasio G, Canavaggio M, Rizzi L, et al. Screening for anti-human T-lymphotropic virus antibody in blood donors and polytransfused patients in Apulia (Italy). Vox Sang 1990; 59: 167-71.

Transferrin-gallium binding

in Alzheimer’s

disease SiR,—There is considerable interest in the toxicity of aluminium (Al) but little is known about how this element is transported through the body or why it seems to be selectively taken up by the bone or brain. The Al in serum is mostly bound to transferrin, and we have found that such complexes provide a form of the metal that can readily enter cells.1,2 Farrar et aP have suggested that the transferrin of patients with Alzheimer’s disease (AD) has an abnormally low affinity for Al. They proposed that these patients would have higher levels of non-transferrin-bound low-molecular weight Al complexes in their plasma, which might more readily cross the blood-brain barrier. They used gallium-67, a radiotracer analogue of Al, and found, surprisingly, that no more than 20 % was bound by transferrin, even in controls. Furthermore, patients with AD had higher transferrin saturation with iron than did the controls. Since iron competes with and displaces all other metals from transferrin this difference might have influenced the results. In our studies on 6’Ga binding to transferrin we have paid special attention to the effects of electrolyte composition and iron saturation of transferrin, and conclude that the defect reported by Farrar et al is an artifact arising from differences in transferrin saturation between patients and controls, coupled with a failure to maintain the presence of physiological levels of bicarbonate during the assay. We have studied 6 patients with clinically confirmed AD who were on long-stay hospital wards, 5 having severe dementia. The 6 controls were matched for age and sex, had been screened for dementia and other psychiatric and neurological disorders, and all had normal computed tomographic scans (table). Serum iron (Fe) and total iron-binding capacity (TIBC) were measured in the biochemistry department, Gartnavel Hospital, by colorimetric assay. To assay binding of Ga and Fe, serum was incubated for 18hin5% CO2 and 1’2ml samples were trace labelled