350

local concentration of p.G.F2cx in the intestinal wall mayrise before and during menstruation, in the same way asthe concentration rises in the uterus. The fact thatdiarrhoea and vomiting were markedly reduced in morethan half the affected patients by the use ofprostaglandin-synthetase inhibitors supports the hypothesis that suchsymptoms are prostaglandin-dependent in manypatients.

Flufenamic acid produced few side-effects and thesewere sufficiently mild to be regarded as unimportant. Nopatient asked to withdraw from the study because of theside-effects of the treatment.

It has been suggested that fenamates can reduce men-strual loss.14 We have found a slight but insignificantreduction in the duration and amount of the menstrualloss, the latter being assessed by the number of padsused per day, but this method is very approximate com-pared with the techniques used by Anderson et al.14However, in the occasional patient we found a pro-nounced reduction in the duration and amount of men-strual loss while on flufenamic acid.We conclude that the fenamates, and in particular

flufenamic acid, are safe and effective in most patientsfor the relief of primary spasmodic dysmenorrhoea andits associated gastrointestinal side-effects and are a greatimprovement on current therapy.We thank Parke-Davis & Co., Pontypool, for supplies of flufenamic

acid (’Arlef) and placebo capsules.

REFERENCES

1. Pickles, V. R. Nature, 1957, 180, 1198.2. Pickles, V. R., Hall, W. J., Best, F. A., Smith, G. N. J. Obstet. Gynæc. Br.

Commonw. 1965, 72, 185.3. British Medical Journal, 1977, i, 65.4. Halbert, D. R., Demers, L. M., Darnell Jones, D. E. Obstet. Gynæc. Surv.

1976, 31, 77.5. Vane, J. R. Nature new Biol. 1971, 231, 232.6. Collier, H. O. J., Sweatman, W. J. F. Nature, 1968, 219, 864.7. Christensen, A. Ugeskr. Læg. 1974, 136, 592.8. Schwartz, A., Sor, U., Lindner, H. R., Naor, S. Obstet. Gynæc. 1974, 44,

709.9. Csapo, A. I., Pulkkinen, M. O., Henzl, M. R. Prostaglandins, 1977, 13, 193.

10. Henzl, M. R., Buttram, V., Segre, E. J., Bessler, S. Am. J. Obstet. Gynec.1977, 127, 818.

11. Lundstrom, V., Green, K., Wiqvist, M. Prostaglandins, 1976, 11, 893.12. Downie, J., Poyser, L., Wunderlich, M. J. Physiol. 1974, 236, 465.13. Sanner, J. H. Archs intern. Med. 1974, 133, 133.14. Anderson, A. B. M., Haynes, P. J. Guillebaud, J., Turnbull, A. C. Lancet

1976, i, 774.

CONTACT WITH HOSPITAL, DRUGS, ANDCHEMICALS AS ÆTIOLOGICAL FACTORS IN

LEUKÆMIA

TIMO T. T. TIMONEN MIRJA ILVONEN

Department of Medicine, University of Oulu, 90220 Oulu,Finland

Summary 45 adults with acute leukæmia or

chronic myeloid leukæmia and a controlgroup of patients from the same hospital were askedabout the people they had close social contact withbefore their illness, and about their use of drugs andchemicals. 18 (40%) leukæmia and 6 (13%) control pa-tients had close social contact with hospital personnel orleukæmia patients. 8 (18%) leukæmia patients, but nocontrol patients, had been in close contact with hæmato-

logical ward personnel. These differences were statisti-cally significant. 9 (20%) leukæmia and 4 (9%) controlpatients lived in the same house as healthy personsworking in a hospital. No conclusion could be drawnfrom differences between the two groups in their use of

drugs, since the possibility that they were used to treatinitial symptoms of leukæmia could not be excluded.

Exposure to chemicals, including weed-killers and agri-cultural insecticides containing a benzene-ring known tobe leukæmogenic, was about the same in the two groups.

Introduction

ATTEMPTS to transmit leukaemia to human volunteershave been unsuccessful.’ However, the clustering ofcases of malignant blood diseases suggests that it may becaused by,environmental factors.2-6 Schimpff et al.fromBaltimore showed that 64% of patients with varioustypes of leukaemia and lymphoma had direct or indirectclose personal contacts with leukxmia patients beforethe onset of their illness. Their study has been criticisedbecause there were no controls. Heath and Hasterlik8did not find that schoolchildren with leukaemia had hadcontact with other cases, although definite clusteringwas observed; they speculated that the disease might becaused by an agent with high infectivity but low patho-genicity. Smith et al.,9 in a case-control study, could notfind any evidence to support the hypothesis that Hodg-kin’s disease is transmissible, but they suggested thattheir finding does not exclude an infective aetiology,since the agent may be transmitted by healthy carriers.

Acute leukaemia developed in a sister of a physiothera-pist working in the haematological ward of our hospitalfour years ago. We therefore decided to carry out a sur-

vey of those with whom acute leukaemia and chronic

myeloid leukaemia patients had been in close contactbefore their illness. Since there have been a few reportson drugs and chemicals which might be leukaemogenic,1Owe also investigated the exposure of leukaemia patientsto chemical agents.

Patients and Methods

This study was carried out at the University Central Hospi-tal of Oulu in North Finland, an area with approximately400 000 inhabitants. According to the Finnish Cancer

Registry" the incidence of leukaemia in this area is the sameas that of the whole of Finland-in 1973, 7-4 per 100 000 inmales and 5.1 per 100 000 in females. The county of Oulu isa developing area with a population of low mobility.

50 adult patients admitted consecutively to the UniversityHospital between January, 1973, and May, 1977, for eitheracute leuksmia or chronic myeloid leukaemia were asked, byquestionnaire, for information on their close social contactsand their use of drugs and chemicals in the two years beforeonset of their leukaemia. The questionnaire was given to thepatient or, if the patient was dead, to his closest relative. Infor-mation asked for included patient’s employment and dwelling-place, malignant blood-disease in relatives, and whether thepatient had been in close social contact with persons workingin a hospital before illness. From the replies, contacts could bedivided into three groups:1. Healthy contacts living in the same house as the patient andworking in a hospital.2. Persons in close social contact with the patient (but not liv-ing in the same house) and having some connection with hospi-tals.3. Close relatives with leukaemia.

45 replies were obtained (28 from patients and 17 from rela-

351

tives) ; no reply was received from relatives of 5 deceased pa-tients. The age at diagnosis ranged from 17 to 75 years (mean41.7). There were 21 women and 24 men. 23 lived in town and22 in the country. 37 had acute leukaemia (30 acute myeloid,5 acute lymphoblastic 1 acute myelomonocytic, and 1 acute

monocytic), and 8 chronic myeloid leukaemia.45 consecutive patients admitted to the same hospital for

overnight observation for cardiovascular and acute illnesses(none had blood or other malignant disease) served as controls.There were 26 males and 19 females whose ages ranged from15 to 72 years (mean 49-8). 25 lived in the country and 20 intown.

Results

Table i shows that 9 leukxmia patients lived in thesame house as a healthy person working in a hospital.7 of these patients had been in contact with nurses: pa-tient 32 had 4 sisters working in hospital, 2 physio-therapists (1 in the haematological ward of our hospital),and 2 nurses in a psychiatric hospital; patient 21’s sisterwas a laboratory nurse in our hospital; patient 2, whosemother worked in a medical ward for chronic patients,also had a nurse from a medical ward living in the same

TABLE I-PRE-ILLNESS HOSPITAL CONTACT FOR LEUKAMIA AND

CONTROL PATIENTS

house; patient 43’s wife worked in a paediatric depart-ment for infectious diseases where patients with haema-tological disorders complicated by infection were treat-ed ; and of the other 3 nurses, 1 was a deaconess, 1 a

theatre nurse, and 1 a nurse in a hospital for chronic dis-ease. The 2 medical-student contacts had just done theirtraining in the haematological ward of our hospitalwhere they took medical histories, examined patients,and took blood and did sternal, punctures. Thus, 6leukaemia patients had household members who hadcontact with other haematological cases.

4 patients were in close contact with, but not, sharingthe same house as, persons connected with hospitals. In1 instance (patient 20) the contact was a brother-in-lawwith leuksemia, while in another (patient 17), the con-tact was a nurse in a haematological ward who used tovisit the patient regularly.

5 patients had siblings with leukaemia. Patient 38cared for patient 15 when the latter had leukaemia. Theother 3 patients did not live with their siblings. No rela-tion could be found between employment or dwellingplace and leukaemia.

TABLE II-PRE-DIAGNOSIS EXPOSURE TO DRUGS AND OTHER

CHEMICALS IN LEUKAMIA PATIENTS AND IN CONTROLS

1. Paints containing benzene derivatives and lead.2.4-chlor-2-methyl-phenoxy-acetic acid (M.C.P.A.).3. ’Lindane’ (hexachlorbenzene).4. ’Parathion’ (diethyl-4-nitrophenylphosphorothionate).5. 2,4,5,-T (2,4,5-trichlorphenoxyacetic acid).6. 2,4-D (2,4-dichlorphenoxyacetic acid).

352

Only 4 controls had household contacts who workedin a hospital, but none in a haematological ward. No con-trol had other close social contacts with a nurse, but twohad siblings with leukaemia.

18 (40%) of our leukaemia patients and 6 (13%) of thecontrols had close social contact with hospital personnelor leukaemia patients (table i). The difference is statisti-cally significant (8-182 in x2 contingency table,p<0-01). 8 (18%) leukaemia patients (patients 2, 9, 17,21, 23, 32, 33, and 43), but no control patient, had beenin close contact with hxmatological ward personnel.This difference is also statistically significant (8-780 in1..2 contingency table, p<0-01).

Table 11 shows that 14 leukaemia patients, but only 4controls, had used drugs possibly toxic to the bone-mar-row. The difference is statistically significant (6-944 inx2 contingency table, p<0-01). 9 leukaemia patients and7 controls had handled chemical agents possibly toxic tobone-marrow. In 7 leukaemia patients and in 3 controlsthe chemicals were weed-killers or agricultural insecti-cides containing a benzene-ring known to be leukaemo-genic. 6 leukaemia patients had exposure to both peoplein contact with hasmatological disease and to chemicalsor drugs; only 2 of the controls had been exposed to bothof these factors. No patient nor any control had beenexposed to radiation.

Discussion

Feline leukaemia virus can be transmitted via cat

saliva and urine.12,i3 However, human leukaemia has notbeen shown to be viral in origin. Our findings show sta-tistically significant differences in the degree to whichleukaemia patients and controls had had contact withhospitals via their social contacts. 6 patients had house-hold members and 2 had other contacts who worked ina hxmatological ward. None of the hospital personnelhad malignant disease, but they could have been healthycarriers of infectious agents.

Unlike other studies2-6.7.14 ours did not show a geo-graphical clustering of social contacts or of patients: 1

patient (patient 20) had a brother-in-law with leukaemiawho used to visit regularly, but only two siblings withleukaemia lived together (patients 15 and 38). The 5 pa-tients with siblings similarly affected (all had myeloidleukaemia) suggest that genetic predisposition may havea role. Genetic influences are stronger in chronic lym-phocytic leukaemia than in other leukaemias1s althoughthere have been reports of several families with 3 ormore cases of acute leukaemias.16.17The leukaemia group had used significantly more

drugs (mainly analgesics and antihistamines) than thecontrol group (table 11), but since it is impossible to tellwhether they were used for very early symptoms ofleukxmia, no conclusion can be drawn about the aetio-logical role of drugs. Cronkitell stated that any drug orchemical capable of inducing bone-marrow damagemust be assumed to be potentially leukxmogenic. Theonly enviromental agents known to produce leukxmia inman are -irradiation, benzene and its hydrocarbons,and alkylating agents.19 The leukaemogenic effect ofchemicals in man is difficult to prove especially as fewpatients can recall the names of the number of toxins towhich they have been exposed months or years pre-viously. We found no significant difference in the use ofchemicals between the 2 groups, although weed-killers

or agricultural insecticides were used by 7 leukaemia, but3 control, patients.Our controlled study has shown a statistically signifi-

cant difference, not previously reported, in the extent towhich leukaemia and control groups have had contactwith hospitals. In most cases the contact was throughnurses working in hmmatological wards. If leukaemia isone day proven to be infectious in origin, our resultssupport the view that infectivity and pathogenicity aretwo different things.

REFERENCES

1. Bierman, H. R., Byron, R. L., Lanmon, J. T., Morrow, P. L. Am. J. Med.1950, 8, 522.

2. Vianna, N. J., Greenwald, P., Brandy, J., Polan, A. K., Dwork, A., Mauro,J., Davies, J. N. P. Ann. intern. Med. 1972, 77, 169.

3. Vianna, N. J., Polan, A. K. New Engl. J. Med. 1973, 289, 499.4. Klinger, R. J., Minton, J. P. Lancet, 1973, i, 168.5. Bartsch, D. C., Springher, F., Falk, H. J. Am. med. Ass. 1975, 232, 13336. Evans, A. R., Hancock, B. W., Brown, M. J., Richmond, J. Br. med. J. 1977,

i, 1056.7. Schimpff, S. C., Schimpff, C. R., Brager, D. M., Wiernik, P. H. Lancet,

1975, i, 124.8. Heath, C. W., Hasterlik, R.J. Am. J. Med 1963, 34, 796.9. Smith, P. G., Pike, M. C., Kinlen, L. J., Jones, A., Harris, R. Lancet, 1977,

ii, 59.10. See ibid. 1977, i, 519.11. Finnish Cancer Registry. Cancer incidence in Finland, 1973. 1976.12. Hardy, W. D., Hess, P. W. Essex, M., Cotter, S. Nature, 1973, 244, 266.13. Hardy, W. D., Geering, G., Old, L. S., de Harven, E., Brodey, R. S.,

McDonough, S. Science, 1969, 166, 1019.14. Schimpff, S. C., Brager, D. M., Schimpff, C. R., Comstock, G. W., Wiernik,

P. H. Ann. intern. Med. 1976, 84, 547.15. Gunz, F. W., Veale, A. M. O. J. Natn. Cancer Inst. 1969, 42, 517.16. Gunz, F. W., Gunz, J. P., Veale, A. M. O., Scand. J. H&aelig;mat. 1975, 15, 117.17. Pendergrass, T. W., Stoller, R., Mann, D., Halterman, R. H., Raumeni,

J. F. Jr. Lancet, 1975, ii, 429.18. Cronkite, E. P. Archs envir. Hlth. 1961, 3, 297.19. Wintrobe, M. M. Clinical Hematology; p. 1455, Philadelphia 1974.

HYCANTHONE DOSE-RESPONSE INSCHISTOSOMA MANSONI INFECTION IN

KENYA

K. S. WARREN*

J. H. OUMAT. K. ARAP SIONGOK

H. B. HOUSER

Division of Geographic Medicine, Department of Medicineand Department of Biometry, Case Western Reserve

University, Cleveland, Ohio, U.S.A.; and Division of Vector-borne Diseases, Ministry of Health, Nairobi, Kenya

*Present address: Rockefeller Foundation, 1133 Avenue of the Amer-icas, New York City, New York 10036, U.S.A.

Summary The recommended doses of the drugsnow used to cure schistosomiasis man-

soni may be associated with toxic side-effects. SinceSchistosoma mansoni does not multiply in the humanhost and the disease seems to be closely associated withthe intensity of infection, it may not be necessary to use100% lethal antischistosomal doses, particularly in en-demic areas. A dose-response to the antischistosomal drug,hycanthone was established for three different doses in169 patients with heavy S. mansoni infections in theMachakos district of Kenya. The highest dose used (1&middot;5mg/kg or half the recommended package-insert dose)resulted in a 96% decrease in egg output (equivalent todeath of the worms); 0&middot;75 mg/kg in an 85% decrease;and 0&middot;375 mg/kg in an 11% decrease one month after