275 increased amniotic
A.F.P.
has
only
been shown in this type of
congenital nephrosis Children’s
Hospital, Universtiy of Helsinki, SF-00290 Helsinki 29, Finland
JUHANI RAPOLA NIILO HALLMAN
MUTAGENICITY OF METRONIDAZOLE
SIR,-Metronidazole is mutagenic in bacteria 1-4 but little is known about its effect in higher organisms. Preliminary results from patients treated with metronidazole for Crohn’s disease suggested a possible chromosome-breaking activity in human lymphocytes.5 Studies on patients receiving metronidazole for vaginal trichomoniasis, the most common indication, have now been done. Twelve patients with vaginal trichomoniasis were given metronidazole (’Flagyl’) 200 mg three times a day for 7 days. Blood-samples were taken before treatment, on the 7th day of treatment, and 3 weeks after the completion of treatment. Thus each patient was her own control and two consecutive controls were obtained for each patient (before and after treatment, no metronidazole being found in blood plasma at these times). Cultures for chromosome analysis were set up by standard techniques and 100 cells/patient analysed blind for chromosome aberrations on each sampling occasion. MEAN
FREQUENCIES
AND RANGE OF CHROMOSOME ABERRATIONS
IN PATIENTS ON METRONIDAZOLE
negative results correlate with the majority of in-vitro and invivo results available in mammalian cells 78 and thus differ from the preliminary results found in Crohn’s patients. However, in the Crohn’s study no pre-treatment values were available which made evaluation of the data inconclusive. The detailed investigation under way in Crohn’s patients should clarify this point. The observation in this material together with the negative in-vivo data in mammals, although not definite proof of nonmutagenicity/carcinogenicity, should for all practical purposes mean that we can regard metronidazole as a safe drug for short-term treatment. Aktiebolaget Leo Research Laboratories, S-251 00 Helsingborg, Sweden
BERYL HARTLEY-ASP
SCHIZOPHRENIA AND MALIGNANT NEOPLASMS IN A NORTH SWEDISH POPULATION
SIR,-Death certifications for malignant neoplasms have increasing over the past three decades. Many factors are involved-among them improvements in diagnosis and in health services, the dissemination of carcinogens as a consequence of difficulties in controlling the waste and products of technological development, and the increasing life span in developed countries. In Europe, with a generally high standard of living, malignant neoplasms cause some 200 deaths per 100 000 population per year. In countries with moderate living standards the inci-
been
dence is about 150 per 100 000. In the developing countries of Africa and Latin America incidences are below 100 (or even 50) per 100 000 (e.g., 25.9 in Guatemala in 1962 and 27.3 in 1972, and 35.5in Mexico in 1972). These differences could be caused by environmental factors and/or deficient health statistics, but differences in biological resistance against malignant neoplasms could well be a contributing factor. CAUSES OF DEATH IN A NORTH-SWEDISH POPULATION
1950-70
*From official Swedish health statistics.
The table gives the mean frequencies and ranges for all types of aberrations found. Detailed individual patient data will be presented elsewhere. No increase for any aberration type was found during metronidazole treatment for the group as a whole. The range of chromatid aberrations on sampling during and after treatment was somewhat larger than that found before treatment. This was due to a pronounced increase found for two patients, one during treatment another after treatment. The patient who exhibited an increase in her chromatid aberration frequency during treatment had, however, returned to her pre-treatment level on after-treatment sampling. The increase found for one patient on after-treatment sampling serves to demonstrate the large variation occasionally found on consecutive sampling of control women.6 Thus no chromosome-breaking activity of metronidazole was found during treatment for vaginal trichomoniasis. These 1
Voogd, C. E., 26, 483.
2 3
Rosenkranz, H. S., Speck, W. T. Biophys. Res. Comm. 1975, 66, 520. Rosenkranz, H. S., Speck, W. T., Stambaugh, J. E. Mutation Res. 1976, 38,
4.
Legator, M. S., Connor, T. H., Stoeckel, M. Science, 1975, 188, 1118. Mitelman, F., Hartley-Asp, B., Ursing, B. Lancet, 1976, i, 802. Littlefield, L. G., Goh, K.-O. Cytogenet. Cell Genet. 1973, 17, 17.
van
der
Stel, J. J., Jacobs, J. J. J. A. A. Mutation Res. 1974,
203. 5 6
The incidence of malignant neoplasms is lower in mentally populations. Several investigatorsl-4 have recorded a lower cancer mortality in schizophrenic patients. We have examined deaths caused by malignant neoplasms in a North Swedish population characterised by a high degree of inbreeding and a high incidence of schizophrenic psychoses (the morbid risk for schizophrenia was about three times that for the general Swedish population5). Among the causes of death noted by Böök2 for 38 schizophrenics in this population only 3 (9%) were malignant neoplasms. In Alstrom’s review of 774 deaths of schizophrenic patients in Swedish mental hospitals only 8-7% were due to cancer.’ When Book’s investigation was followed-up to 1975 another 36 schizophrenic patients had died but only 2 deaths were due to malignant neoplasms. During 1950-70 deaths in this population numbered 1359 and 166 were caused by malignant neoplasms, corresponding ill
J., Petzold, G. L., Brunden, M. N., Swneberg, J. A. Mutation Res. 1978, 58, 79.
7. Trzos, R.
8. Hartley-Asp, B. Mutation Res. (in the press). 1. Alström, C. H. Acta psychiat., Copenh. 1942, suppl. 24, p. 422. 2. Böök, J. A. Acta genet. 1953, 4, 1. 3. Katz, J., Kunofsky, S., Patton, R. E., Attaway, N. C. Cancer, 1967, 2194. 4. Lindelius, R., Kay, D. W. Acta psychiat. scand. 1973, 49, 315.
20,
A.F.P.
has
only
been shown in this type of
congenital nephrosis Children’s
Hospital, Universtiy of Helsinki, SF-00290 Helsinki 29, Finland
JUHANI RAPOLA NIILO HALLMAN
MUTAGENICITY OF METRONIDAZOLE
SIR,-Metronidazole is mutagenic in bacteria 1-4 but little is known about its effect in higher organisms. Preliminary results from patients treated with metronidazole for Crohn’s disease suggested a possible chromosome-breaking activity in human lymphocytes.5 Studies on patients receiving metronidazole for vaginal trichomoniasis, the most common indication, have now been done. Twelve patients with vaginal trichomoniasis were given metronidazole (’Flagyl’) 200 mg three times a day for 7 days. Blood-samples were taken before treatment, on the 7th day of treatment, and 3 weeks after the completion of treatment. Thus each patient was her own control and two consecutive controls were obtained for each patient (before and after treatment, no metronidazole being found in blood plasma at these times). Cultures for chromosome analysis were set up by standard techniques and 100 cells/patient analysed blind for chromosome aberrations on each sampling occasion. MEAN
FREQUENCIES
AND RANGE OF CHROMOSOME ABERRATIONS
IN PATIENTS ON METRONIDAZOLE
negative results correlate with the majority of in-vitro and invivo results available in mammalian cells 78 and thus differ from the preliminary results found in Crohn’s patients. However, in the Crohn’s study no pre-treatment values were available which made evaluation of the data inconclusive. The detailed investigation under way in Crohn’s patients should clarify this point. The observation in this material together with the negative in-vivo data in mammals, although not definite proof of nonmutagenicity/carcinogenicity, should for all practical purposes mean that we can regard metronidazole as a safe drug for short-term treatment. Aktiebolaget Leo Research Laboratories, S-251 00 Helsingborg, Sweden
BERYL HARTLEY-ASP
SCHIZOPHRENIA AND MALIGNANT NEOPLASMS IN A NORTH SWEDISH POPULATION
SIR,-Death certifications for malignant neoplasms have increasing over the past three decades. Many factors are involved-among them improvements in diagnosis and in health services, the dissemination of carcinogens as a consequence of difficulties in controlling the waste and products of technological development, and the increasing life span in developed countries. In Europe, with a generally high standard of living, malignant neoplasms cause some 200 deaths per 100 000 population per year. In countries with moderate living standards the inci-
been
dence is about 150 per 100 000. In the developing countries of Africa and Latin America incidences are below 100 (or even 50) per 100 000 (e.g., 25.9 in Guatemala in 1962 and 27.3 in 1972, and 35.5in Mexico in 1972). These differences could be caused by environmental factors and/or deficient health statistics, but differences in biological resistance against malignant neoplasms could well be a contributing factor. CAUSES OF DEATH IN A NORTH-SWEDISH POPULATION
1950-70
*From official Swedish health statistics.
The table gives the mean frequencies and ranges for all types of aberrations found. Detailed individual patient data will be presented elsewhere. No increase for any aberration type was found during metronidazole treatment for the group as a whole. The range of chromatid aberrations on sampling during and after treatment was somewhat larger than that found before treatment. This was due to a pronounced increase found for two patients, one during treatment another after treatment. The patient who exhibited an increase in her chromatid aberration frequency during treatment had, however, returned to her pre-treatment level on after-treatment sampling. The increase found for one patient on after-treatment sampling serves to demonstrate the large variation occasionally found on consecutive sampling of control women.6 Thus no chromosome-breaking activity of metronidazole was found during treatment for vaginal trichomoniasis. These 1
Voogd, C. E., 26, 483.
2 3
Rosenkranz, H. S., Speck, W. T. Biophys. Res. Comm. 1975, 66, 520. Rosenkranz, H. S., Speck, W. T., Stambaugh, J. E. Mutation Res. 1976, 38,
4.
Legator, M. S., Connor, T. H., Stoeckel, M. Science, 1975, 188, 1118. Mitelman, F., Hartley-Asp, B., Ursing, B. Lancet, 1976, i, 802. Littlefield, L. G., Goh, K.-O. Cytogenet. Cell Genet. 1973, 17, 17.
van
der
Stel, J. J., Jacobs, J. J. J. A. A. Mutation Res. 1974,
203. 5 6
The incidence of malignant neoplasms is lower in mentally populations. Several investigatorsl-4 have recorded a lower cancer mortality in schizophrenic patients. We have examined deaths caused by malignant neoplasms in a North Swedish population characterised by a high degree of inbreeding and a high incidence of schizophrenic psychoses (the morbid risk for schizophrenia was about three times that for the general Swedish population5). Among the causes of death noted by Böök2 for 38 schizophrenics in this population only 3 (9%) were malignant neoplasms. In Alstrom’s review of 774 deaths of schizophrenic patients in Swedish mental hospitals only 8-7% were due to cancer.’ When Book’s investigation was followed-up to 1975 another 36 schizophrenic patients had died but only 2 deaths were due to malignant neoplasms. During 1950-70 deaths in this population numbered 1359 and 166 were caused by malignant neoplasms, corresponding ill
J., Petzold, G. L., Brunden, M. N., Swneberg, J. A. Mutation Res. 1978, 58, 79.
7. Trzos, R.
8. Hartley-Asp, B. Mutation Res. (in the press). 1. Alström, C. H. Acta psychiat., Copenh. 1942, suppl. 24, p. 422. 2. Böök, J. A. Acta genet. 1953, 4, 1. 3. Katz, J., Kunofsky, S., Patton, R. E., Attaway, N. C. Cancer, 1967, 2194. 4. Lindelius, R., Kay, D. W. Acta psychiat. scand. 1973, 49, 315.
20,
