1258
SUDS. There is striking inter-regional variation in the incidence of melioidosis within Thailand, the disease being commonest among rice-farmers in the north east, particularly those with underlying illnesses, such as diabetes mellitus or chronic renal disease.’ In this region, a high proportion of healthy individuals have antibodies to P pseudomallei.’ Although there are few data for regional variations in P pseudomallei seropositivity rates in Thailand, the differences Yap and colleagues report might be related to diversity in regional origin, previous occupation, or the presence of underlying disease. Secondly, there were some differences between the indirect haemagglutination technique Yap et al used and those applied in other studies (eg, turkey red blood cells). 2,3 Furthermore the cut-off titre of 1 in 4 was considerably lower than that usually used.2,3 These factors are likely to affect the specificity of the test. A small rise in P pseudomallei antibody titre might thus merely represent an anamnestic response during another illness. Finally, although, as Yap et al point out, cardiac conduction abnormality has been
reported in 1 patient with septicaemic melioidosis, in our experience over 500 prospectively studied, culture-positive patients, myocardial involvement with conduction defects is rare, and there is of
evidence that it arises in subclinical melioidosis. Only the isolation of P pseudomallei from post-mortem material would be proof that melioidosis contributed to sudden death in these previously healthy Thai men. Selective culture techniques for P pseudomallei are available4 and would help to overcome contamination. Yap and colleagues’ observations certainly warrant further investigation. no
Department of Clinical Sciences, London School of Hygiene and Tropical Medicine,
D. A. B. DANCE
London WC1E 6HT, UK Wellcome-Mahidol UniversityOxford Tropical Medicine Research Hospital for Tropical Diseases, Bangkok, Thailand
Programme,
N. J. WHITE Y. SUPUTTAMONGKOL
Department of Medicine, Sappasitprasong Hospital, Ubon Ratchatani, Thailand
W. CHAOWAGUL
1. Chaowagul W, White NJ, Dance DAB, et al. Melioidosis: a major cause of Dis 1989; 159: community-acquired septicemia in North Eastern Thailand. Infect J 890-99. 2. Alexander AD, Huxsoll DL, Warner AR, Shepler V, Dorsey A. Serological diagnosis of human melioidosis with indirect hemagglutination and complement fixation tests. Appl Microbiol 1970; 20: 825-33. 3. Appassakij H, Silpapojakul K, Wansit R, Pornpatkul M. Diagnostic value of the indirect hemagglutination test for melioidosis in an endemic area. Am J Trop Med Hyg 1990; 42: 248-53. 4. Wuthiekanun V, Dance DAB, Wattanagoon Y, Suputtamongkol Y, Chaowagul W, White NJ. The use of selective media for the isolation of Pseudomonas pseudomallei in clinical practice. J Med Microbiol 1990; 33: 121-26.
Salbutamol nebuliser and precipitation of critical cardiac ischaemia SiR,—Sackett and colleagues’ article about the safety of inhaled (3z agonists in airflow obstruction1 prompts us to report a patient who had an acute myocardial infarction on his second day in hospital after a total of five doses of nebulised &bgr;2-adrenoceptor agonist given by inhalation. A 60-year-old man presented with acute asthma. He had no history of cardiac disease, although he had received treatment with methyldopa for mild hypertension. Previous cigarette smoking was his only other risk factor for ischaemic heart disease. He was cyanosed, tachypnoeic at rest, with severely limited speech. His peak expiratory flow was unrecordable and arterial blood gas analysis showed Pa02 85 kPa breathing air. An electrocardiogram showed left axis deviation and minimum T-wave inversion in the lateral leads. He improved rapidly after treatment with oxygen, nebulised salbutamol 5 mg 4 hourly, high dose corticosteroids, and oral aminophylline. The next day his peak expiratory flow was 200 1/min. During his fifth nebuliser treatment he complained of left submammary chest pain radiating to the neck. Similar episodes of pain had followed the third and fourth nebuliser administrations, each lasting about 1 h, but not reported by the patient at the time. A further electrocardiogram showed new ST-segment elevation in leads VI-V3, and subsequent electrocardiograms and serial cardiac
enzyme estimations proved the diagnosis of acute myocardial infarction. He made a good recovery from his myocardial infarction and asthmatic exacerbation. Salbutamol inhaler 200 jig four times daily was reintroduced without ill-effect. 02-adrenoceptor agonists can provoke myocardial ischaemia by acute reduction of diastolic blood pressure, or by precipitation of cardiac rhythm disturbances.23 The Committee on Safety of Medicines and one reviewt show only nine reports since 1963 where high doses were used in patients, some of whom were known to have had severe myocardial ischaemia. However, the potential risk of myocardial ischaemia cannot be fully estimated from these reports because cardiac and respiratory disease commonly coexist (often because of cigarette smoking), and the close temporal relation between drug administration and symptoms that was seen in our patient might not be present. Nebulised salbutamol at a dose of 2.55 mg is reportedly as effective as 5 mg in the treatment of airflow obstructions6 Lower doses of &bgr;2-adrenoceptor agonists in initial therapy may be justified, especially where there are risk factors for or a history of ischaemic heart disease. We thank the Committee on supplying information.
Safety of Medicines and Allen & Hanburys for
Respiratory Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, UK
C. L. SHOVLIN F. W. K. TAM
1. Sackett
DL, Shannon HS, Browman GW. Fenoterol and fatal asthma. Lancet 1990; 335: 45-46. 2. Vincent HH, Man m’t Veld AJ, Boomsma F, Derkx FHM, Wenting GJ, Schalekamp MADH. Cardioprotection by blockade of beta2-adenoreceptors. Eur Heart J 1983;
4 (suppl D): 109-15. 3. Rolf Smith S, Ryder C, Kendall MJ, Holder R. Cardiovascular and biochemical responses to nebulised salbutamol in normal subjects. Br J Clin Pharmacol 1984; 18: 641-44. 4. Neville E, Corris PA, Vivian J, Nariman S, Gibson GJ. Nebulised salbutamol and angina. Br Med J 1982; 285: 796-97. 5 Walters EH, Cockcroft A, Griffiths T, Rocchiccioli K, Davies BH. Optimal dose of salbutamol respiratory solution comparison of three doses with plasma levels Thorax 1981; 36: 625-28. 6. Ruffin RE, Obminski G, Newhouse MT. Aerosol salbutamol administration by IPPB. lowest effective dose. Thorax 1978; 33: 689-93.
Intestinal obstruction in babies exposed in utero to methylene blue SIR,-Intra-amniotic injection of dye is used to confirm premature membranes, and, in twin pregnancies undergoing amniocentesis, to ensure that amniotic fluid is sampled from each sac.1 While indigo-carmine and Evans blue have never been associated with untoward fetal/neonatal effects, the dangers of intra-amniotic methylene blue injected in the third trimester have been reported since 1973.2 Although it has been claimed that small amounts of methylene blue are safe neonatal haemolysis and hyperbilirubinaemia, probably due to oxidation of reduced haemoglobin to methaemoglobin, have been described after intra-amniotic injection of as little as 10 mg. However, inadvertent intrauterine injection of methylene blue during the fifth week of pregnancy did not produce adverse effects,5 and all reported rupture of
neonatal complications have occurred after intervals from intraamniotic injection to delivery of less than 5 weeks. These observations suggest that methylene blue in early pregnancy is safe, and this dye is still widely used,6 presumably because of its availability in gynaecological departments. We report a complication associated with intra-amniotic methylene blue at 15-17 weeks gestation, which occurred in three separate centres. Multiple ileal occlusions were diagnosed in 7 babies born to mothers with twin pregnancies who had amniocentesis. In each, 10-30 mg (1-3 ml 1% solution) of methylene blue was injected via the amniocentesis needle into one of the amniotic sacs. Between 1982 and 1988, 21 women with twin pregnancies had diagnostic amniocentesis at the Ospedale Microcitemico, Cagliari, Italy. 4 of the babies (9-5%) later required surgery for intestinal obstruction. In 3 cases of sex-discordant twins, it was possible to document retrospectively that methylene blue had been injected into the amniotic sac of the affected twin; in the fourth the sac
1259
injected could not be identified. The other 3 babies with multiple ileal obstructions were delivered during 1988-90 in a hospital in Milan (n = 2) and another in London (n = 1). It was not possible to ascertain in which sac methylene blue had been injected, nor to determine how many twin pregnancies had amniocentesis with injection of dye during the 2-year period. The mechanism of this complication is unclear. However, if intrauterine haemolysis due to methylene-blue-related fetal methaemoglobinaemia occurred, the consequent hypoxaemia might have led to redistribution of fetal circulation with decreased bloodflow to lungs, kidneys, and digestive tractIn dogs, methylene blue has been associated with increased release of noradrenaline from sympathetic nerves supplying the mesenteric artery.a Intestinal vasoconstriction consequent to hypoxaemia might, therefore, be sustained in the presence of methylene blue, and the multiple ileal occlusions might be the long-term effect of acute intestinal hypoxia. Whatever the mechanism, the intraamniotic injection of methylene blue appears hazardous in the second trimester. Institute of Obstetrics and Gynaecology, Royal Postgraduate Medical School, Queen Charlotte’s and Chelsea Hospital, London W6 0XG, UK
UMBERTO NICOLINI
Obstetrics and
Gynaecology Service, Ospedale Microcitemico, Cagliari, Italy
GIOVANNI MONNI
1 Pijpers L, Jahoda MGJ, Vosters RPL, Niermeijer MF, Sachs ES. Genetic amniocentesis m twm pregnancies. Br J Obstet Gynaecol 1988, 95: 323-26. 2. Plunkett JD. Neonatal complications. Obstet Gynecol 1973; 41: 476-77. 3 Cowett RM, Hakanson DO, Kocon RW, Oh W. Untoward neonatal effect of intraamniotic administration of methylene blue. Obstet Gynecol 1976, 48: 74-75S. 4 Harvey SC Antiseptics and disinfectants. In. Goodman LS, Gilman A, GoodmanGilman A, eds. The pharmacologic basis of therapeutics, 6th ed. New York: Macmillar, 1980: 964-87. 5 Katz Z, Lancet M. Inadvertent intrauterine injection of methylene blue in early pregnancy. N Engl J Med 1981; 304: 1427 6 Troche BI. The methylene blue baby. N Engl J Med 1989; 320: 1756-57. 7. Peeters LLH, Sheldon FR, Jones MD, Makowsky EL, Meschia G Blood flow to fetal organs as a function of arterial oxygen content. Am J Obstet Gynecol 1979; 135: 639-46. 8 Soares-Da Silva P, Caramona MM. Effects of methylene blue on the uptake, release and metabolism of noradrenaline in mesentenc arterial vessels. J Pharm Pharmacol
1988; 40: 534-38.
Cancer and MR,—Uver
the
past
electromagnetic fields
tew
years tnere nave been
a tew senous
investigations and much more inaccurate media play on whether radiations from power lines, including the low voltages in homes, constitute a cancer risk. I agree with Dr Jauchem (Oct 6, p 884) that this is not a major human health issue. Neoplasia stems from a series of specific alterations of normal cells. A key element is a mutational alteration of the genome.1-3 No proponent of the electromagnetic field hypothesis has addressed this question or applied molecular biology techniques to examine changes in genes caused by electromagnetic fields and thus adduce evidence that such fields might be associated with an early event in carcinogenesis. On the basis of current knowledge, this would not be a plausible mode of action. The development of early cancer cells may involve a variety of enhancing mechanisms, including growth promotion, immunosuppression, and endocrine changes--again, no-one has seriously studied such essential questions. Are rates of neoplasia higher in urban areas, with a high density of such fields, than in rural areas, or different in the industrialised than in the developing world? About one-third of all cancers in the western world, and a growing fraction elsewhere, are due to tobacco use, accounting in the main for cancer of the lung and in part cancer of the pancreas, bladder, and kidneys.’5 In the western world also the traditional high-fat diet is associated with a risk of cancer of the breast, prostate, pancreas, ovary, endometrium, and colon,6--9 and elsewhere the salting and pickling of foods is a major cause of cancer of the stomach and of oesophagus. In Africa and in parts of China, the hepatitis B antigen and mycotoxins such as aflatoxin Bl are a cause of liver cancer. Popularisation of an unpromising attack on the cancer question (eg, the electromagnetic field hypothesis) leads the public
resist changing bad habits, such as tobacco use or poor nutritional practices, on the grounds that "everything causes cancer". As noted above, specific cancers have specific documented causes. to
Furthermore, with limited funds available for serious research efforts, a programme on electromagnetic fields and cancer could be counterproductive by diverting effort and money from more relevant research and public information activities. American Health Foundation, One Dana Road, Valhalla, NY 10595, USA
JOHN H. WEISBURGER
Cavenee, WK, Hastie ND, Stanbridge EJ, eds. Recessive oncogenes and tumor suppression. Cold Spring Harbor, New York: Cold Spring Harbor University
1
Press, 1989.
Weinberg RA. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res 1989; 49: 3713-21. 3. Weisburger JH. On the mechanisms of carcinogenesis and statistical data management in tobacco smoking cessation. Epidemiology 1990; 4: 314-17. 4. Hoffmann D, Harris CC, eds. Mechanisms in tobacco carcinogenesis. (Banbury rep no 23). Cold Spring Harbor Laboratory, New York, 1986. 5. Zaridze D, Peto R, eds. Tobacco; a major international health hazard. (IARC Sci Pub no 74). Lyon: IARC, 1986. 6. US Department of Health and Human Services. Surgeon General’s report on nutrition and health (Public Health Service, pub no 88-50210. Washington, DC,
2.
1988. 7. Reddy BS. Overview of diet and colon cancer. Prog Clin Biol Res 1988; 279: 111-21. 8. Schatzkin A, Greenwald P, Byar DP, Clifford CK. The dietary fat-breast cancer hypothesis is alive. JAMA 1989; 261: 3284-87. 9. Trock B, Lanza E, Greenwald P. Dietary fiber, vegetables, and colon cancer: critical review and meta-analyses of the epidemiologic evidence. J Natl Cancer Inst 1990; 82: 650-61. 10. Hayashi Y, Nagao M. Sugimura T, et al, eds. Diet and nutrition and cancer. Tokyo/Utrecht; Japan Scientific Societies Press/VNU Science Press, 1986.
SIR,-Dr Jauchem (Oct 6, p 884) writes that "by use of an evaluation process defined by the International Agency for Research on Cancer [citing a 1981 reference], investigators studying electromagnetic field effects have concluded that the limited and inconsistent data are insufficient to establish a causal association between exposure to electromagnetic fields and cancer [no reference given]". This statement is misleading. The IARC has not yet evaluated the evidence of carcinogenic risks to man of exposure to very low-frequency electric and magnetic fields; it plans to do so in 1992. Evaluations of evidence in the IARC monographs programme are by a large group of international experts in subjects such as exposure, cell biology, animal experimentation, and epidemiology, that are relevant to the exposure being considered. This is done at a meeting at which all published material is critically reviewed according to a well-defined procedure. Jauchem’s unreferenced allusion to this procedure presumably refers to an editorial by Cartwright,2 which claims to apply the criteria used in IARC monographs to evaluate possible hazards of extremely low frequency fields. Cartwright reaches the quantitative conclusion that there is "a minute risk ... verging on the point of non-existence". This view has been criticised.3 Evaluations in the IARC monographs programme are qualitative assessments of the strength of evidence for or against carcinogenicity, not evaluations of the size of the risk. Jauchem deplores the "misinformation on the alleged hazards of electromagnetic fields ... provided by the lay media". What he offers instead is an oversimplified, selective review of the scientific evidence and a summary dismissal of any possible hazard. This is hardly consistent with his own injunction that "scientists should attempt to place potential public health hazards in their proper
perspective". Units of Descriptive Epidemiology, of Biostatistics Research and Informatics, and of Carcinogen Identification and Evaluation, International Agency for Research on Cancer, 69372 Lyon, France
MICHEL P. COLEMAN ELISABETH CARDIS HARRI VAINIO
monographs on the evaluation of carcinogenic risks to humans: vol IL, chromium, nickel and welding. Lyon: IARC, 1990: 19-39. 2. Cartwright RA. Low frequency alternating electromagnetic fields and leukaemia: the saga so far. Br J Cancer 1989; 60: 649-51. 3. Bell J, Coleman MP. Extremely low frequency (ELF) electromagnetic fields and leukaemia in children. Br J Cancer 1990; 62: 331-32.
1. IARC. Premble. In: IARC
SUDS. There is striking inter-regional variation in the incidence of melioidosis within Thailand, the disease being commonest among rice-farmers in the north east, particularly those with underlying illnesses, such as diabetes mellitus or chronic renal disease.’ In this region, a high proportion of healthy individuals have antibodies to P pseudomallei.’ Although there are few data for regional variations in P pseudomallei seropositivity rates in Thailand, the differences Yap and colleagues report might be related to diversity in regional origin, previous occupation, or the presence of underlying disease. Secondly, there were some differences between the indirect haemagglutination technique Yap et al used and those applied in other studies (eg, turkey red blood cells). 2,3 Furthermore the cut-off titre of 1 in 4 was considerably lower than that usually used.2,3 These factors are likely to affect the specificity of the test. A small rise in P pseudomallei antibody titre might thus merely represent an anamnestic response during another illness. Finally, although, as Yap et al point out, cardiac conduction abnormality has been
reported in 1 patient with septicaemic melioidosis, in our experience over 500 prospectively studied, culture-positive patients, myocardial involvement with conduction defects is rare, and there is of
evidence that it arises in subclinical melioidosis. Only the isolation of P pseudomallei from post-mortem material would be proof that melioidosis contributed to sudden death in these previously healthy Thai men. Selective culture techniques for P pseudomallei are available4 and would help to overcome contamination. Yap and colleagues’ observations certainly warrant further investigation. no
Department of Clinical Sciences, London School of Hygiene and Tropical Medicine,
D. A. B. DANCE
London WC1E 6HT, UK Wellcome-Mahidol UniversityOxford Tropical Medicine Research Hospital for Tropical Diseases, Bangkok, Thailand
Programme,
N. J. WHITE Y. SUPUTTAMONGKOL
Department of Medicine, Sappasitprasong Hospital, Ubon Ratchatani, Thailand
W. CHAOWAGUL
1. Chaowagul W, White NJ, Dance DAB, et al. Melioidosis: a major cause of Dis 1989; 159: community-acquired septicemia in North Eastern Thailand. Infect J 890-99. 2. Alexander AD, Huxsoll DL, Warner AR, Shepler V, Dorsey A. Serological diagnosis of human melioidosis with indirect hemagglutination and complement fixation tests. Appl Microbiol 1970; 20: 825-33. 3. Appassakij H, Silpapojakul K, Wansit R, Pornpatkul M. Diagnostic value of the indirect hemagglutination test for melioidosis in an endemic area. Am J Trop Med Hyg 1990; 42: 248-53. 4. Wuthiekanun V, Dance DAB, Wattanagoon Y, Suputtamongkol Y, Chaowagul W, White NJ. The use of selective media for the isolation of Pseudomonas pseudomallei in clinical practice. J Med Microbiol 1990; 33: 121-26.
Salbutamol nebuliser and precipitation of critical cardiac ischaemia SiR,—Sackett and colleagues’ article about the safety of inhaled (3z agonists in airflow obstruction1 prompts us to report a patient who had an acute myocardial infarction on his second day in hospital after a total of five doses of nebulised &bgr;2-adrenoceptor agonist given by inhalation. A 60-year-old man presented with acute asthma. He had no history of cardiac disease, although he had received treatment with methyldopa for mild hypertension. Previous cigarette smoking was his only other risk factor for ischaemic heart disease. He was cyanosed, tachypnoeic at rest, with severely limited speech. His peak expiratory flow was unrecordable and arterial blood gas analysis showed Pa02 85 kPa breathing air. An electrocardiogram showed left axis deviation and minimum T-wave inversion in the lateral leads. He improved rapidly after treatment with oxygen, nebulised salbutamol 5 mg 4 hourly, high dose corticosteroids, and oral aminophylline. The next day his peak expiratory flow was 200 1/min. During his fifth nebuliser treatment he complained of left submammary chest pain radiating to the neck. Similar episodes of pain had followed the third and fourth nebuliser administrations, each lasting about 1 h, but not reported by the patient at the time. A further electrocardiogram showed new ST-segment elevation in leads VI-V3, and subsequent electrocardiograms and serial cardiac
enzyme estimations proved the diagnosis of acute myocardial infarction. He made a good recovery from his myocardial infarction and asthmatic exacerbation. Salbutamol inhaler 200 jig four times daily was reintroduced without ill-effect. 02-adrenoceptor agonists can provoke myocardial ischaemia by acute reduction of diastolic blood pressure, or by precipitation of cardiac rhythm disturbances.23 The Committee on Safety of Medicines and one reviewt show only nine reports since 1963 where high doses were used in patients, some of whom were known to have had severe myocardial ischaemia. However, the potential risk of myocardial ischaemia cannot be fully estimated from these reports because cardiac and respiratory disease commonly coexist (often because of cigarette smoking), and the close temporal relation between drug administration and symptoms that was seen in our patient might not be present. Nebulised salbutamol at a dose of 2.55 mg is reportedly as effective as 5 mg in the treatment of airflow obstructions6 Lower doses of &bgr;2-adrenoceptor agonists in initial therapy may be justified, especially where there are risk factors for or a history of ischaemic heart disease. We thank the Committee on supplying information.
Safety of Medicines and Allen & Hanburys for
Respiratory Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, UK
C. L. SHOVLIN F. W. K. TAM
1. Sackett
DL, Shannon HS, Browman GW. Fenoterol and fatal asthma. Lancet 1990; 335: 45-46. 2. Vincent HH, Man m’t Veld AJ, Boomsma F, Derkx FHM, Wenting GJ, Schalekamp MADH. Cardioprotection by blockade of beta2-adenoreceptors. Eur Heart J 1983;
4 (suppl D): 109-15. 3. Rolf Smith S, Ryder C, Kendall MJ, Holder R. Cardiovascular and biochemical responses to nebulised salbutamol in normal subjects. Br J Clin Pharmacol 1984; 18: 641-44. 4. Neville E, Corris PA, Vivian J, Nariman S, Gibson GJ. Nebulised salbutamol and angina. Br Med J 1982; 285: 796-97. 5 Walters EH, Cockcroft A, Griffiths T, Rocchiccioli K, Davies BH. Optimal dose of salbutamol respiratory solution comparison of three doses with plasma levels Thorax 1981; 36: 625-28. 6. Ruffin RE, Obminski G, Newhouse MT. Aerosol salbutamol administration by IPPB. lowest effective dose. Thorax 1978; 33: 689-93.
Intestinal obstruction in babies exposed in utero to methylene blue SIR,-Intra-amniotic injection of dye is used to confirm premature membranes, and, in twin pregnancies undergoing amniocentesis, to ensure that amniotic fluid is sampled from each sac.1 While indigo-carmine and Evans blue have never been associated with untoward fetal/neonatal effects, the dangers of intra-amniotic methylene blue injected in the third trimester have been reported since 1973.2 Although it has been claimed that small amounts of methylene blue are safe neonatal haemolysis and hyperbilirubinaemia, probably due to oxidation of reduced haemoglobin to methaemoglobin, have been described after intra-amniotic injection of as little as 10 mg. However, inadvertent intrauterine injection of methylene blue during the fifth week of pregnancy did not produce adverse effects,5 and all reported rupture of
neonatal complications have occurred after intervals from intraamniotic injection to delivery of less than 5 weeks. These observations suggest that methylene blue in early pregnancy is safe, and this dye is still widely used,6 presumably because of its availability in gynaecological departments. We report a complication associated with intra-amniotic methylene blue at 15-17 weeks gestation, which occurred in three separate centres. Multiple ileal occlusions were diagnosed in 7 babies born to mothers with twin pregnancies who had amniocentesis. In each, 10-30 mg (1-3 ml 1% solution) of methylene blue was injected via the amniocentesis needle into one of the amniotic sacs. Between 1982 and 1988, 21 women with twin pregnancies had diagnostic amniocentesis at the Ospedale Microcitemico, Cagliari, Italy. 4 of the babies (9-5%) later required surgery for intestinal obstruction. In 3 cases of sex-discordant twins, it was possible to document retrospectively that methylene blue had been injected into the amniotic sac of the affected twin; in the fourth the sac
1259
injected could not be identified. The other 3 babies with multiple ileal obstructions were delivered during 1988-90 in a hospital in Milan (n = 2) and another in London (n = 1). It was not possible to ascertain in which sac methylene blue had been injected, nor to determine how many twin pregnancies had amniocentesis with injection of dye during the 2-year period. The mechanism of this complication is unclear. However, if intrauterine haemolysis due to methylene-blue-related fetal methaemoglobinaemia occurred, the consequent hypoxaemia might have led to redistribution of fetal circulation with decreased bloodflow to lungs, kidneys, and digestive tractIn dogs, methylene blue has been associated with increased release of noradrenaline from sympathetic nerves supplying the mesenteric artery.a Intestinal vasoconstriction consequent to hypoxaemia might, therefore, be sustained in the presence of methylene blue, and the multiple ileal occlusions might be the long-term effect of acute intestinal hypoxia. Whatever the mechanism, the intraamniotic injection of methylene blue appears hazardous in the second trimester. Institute of Obstetrics and Gynaecology, Royal Postgraduate Medical School, Queen Charlotte’s and Chelsea Hospital, London W6 0XG, UK
UMBERTO NICOLINI
Obstetrics and
Gynaecology Service, Ospedale Microcitemico, Cagliari, Italy
GIOVANNI MONNI
1 Pijpers L, Jahoda MGJ, Vosters RPL, Niermeijer MF, Sachs ES. Genetic amniocentesis m twm pregnancies. Br J Obstet Gynaecol 1988, 95: 323-26. 2. Plunkett JD. Neonatal complications. Obstet Gynecol 1973; 41: 476-77. 3 Cowett RM, Hakanson DO, Kocon RW, Oh W. Untoward neonatal effect of intraamniotic administration of methylene blue. Obstet Gynecol 1976, 48: 74-75S. 4 Harvey SC Antiseptics and disinfectants. In. Goodman LS, Gilman A, GoodmanGilman A, eds. The pharmacologic basis of therapeutics, 6th ed. New York: Macmillar, 1980: 964-87. 5 Katz Z, Lancet M. Inadvertent intrauterine injection of methylene blue in early pregnancy. N Engl J Med 1981; 304: 1427 6 Troche BI. The methylene blue baby. N Engl J Med 1989; 320: 1756-57. 7. Peeters LLH, Sheldon FR, Jones MD, Makowsky EL, Meschia G Blood flow to fetal organs as a function of arterial oxygen content. Am J Obstet Gynecol 1979; 135: 639-46. 8 Soares-Da Silva P, Caramona MM. Effects of methylene blue on the uptake, release and metabolism of noradrenaline in mesentenc arterial vessels. J Pharm Pharmacol
1988; 40: 534-38.
Cancer and MR,—Uver
the
past
electromagnetic fields
tew
years tnere nave been
a tew senous
investigations and much more inaccurate media play on whether radiations from power lines, including the low voltages in homes, constitute a cancer risk. I agree with Dr Jauchem (Oct 6, p 884) that this is not a major human health issue. Neoplasia stems from a series of specific alterations of normal cells. A key element is a mutational alteration of the genome.1-3 No proponent of the electromagnetic field hypothesis has addressed this question or applied molecular biology techniques to examine changes in genes caused by electromagnetic fields and thus adduce evidence that such fields might be associated with an early event in carcinogenesis. On the basis of current knowledge, this would not be a plausible mode of action. The development of early cancer cells may involve a variety of enhancing mechanisms, including growth promotion, immunosuppression, and endocrine changes--again, no-one has seriously studied such essential questions. Are rates of neoplasia higher in urban areas, with a high density of such fields, than in rural areas, or different in the industrialised than in the developing world? About one-third of all cancers in the western world, and a growing fraction elsewhere, are due to tobacco use, accounting in the main for cancer of the lung and in part cancer of the pancreas, bladder, and kidneys.’5 In the western world also the traditional high-fat diet is associated with a risk of cancer of the breast, prostate, pancreas, ovary, endometrium, and colon,6--9 and elsewhere the salting and pickling of foods is a major cause of cancer of the stomach and of oesophagus. In Africa and in parts of China, the hepatitis B antigen and mycotoxins such as aflatoxin Bl are a cause of liver cancer. Popularisation of an unpromising attack on the cancer question (eg, the electromagnetic field hypothesis) leads the public
resist changing bad habits, such as tobacco use or poor nutritional practices, on the grounds that "everything causes cancer". As noted above, specific cancers have specific documented causes. to
Furthermore, with limited funds available for serious research efforts, a programme on electromagnetic fields and cancer could be counterproductive by diverting effort and money from more relevant research and public information activities. American Health Foundation, One Dana Road, Valhalla, NY 10595, USA
JOHN H. WEISBURGER
Cavenee, WK, Hastie ND, Stanbridge EJ, eds. Recessive oncogenes and tumor suppression. Cold Spring Harbor, New York: Cold Spring Harbor University
1
Press, 1989.
Weinberg RA. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res 1989; 49: 3713-21. 3. Weisburger JH. On the mechanisms of carcinogenesis and statistical data management in tobacco smoking cessation. Epidemiology 1990; 4: 314-17. 4. Hoffmann D, Harris CC, eds. Mechanisms in tobacco carcinogenesis. (Banbury rep no 23). Cold Spring Harbor Laboratory, New York, 1986. 5. Zaridze D, Peto R, eds. Tobacco; a major international health hazard. (IARC Sci Pub no 74). Lyon: IARC, 1986. 6. US Department of Health and Human Services. Surgeon General’s report on nutrition and health (Public Health Service, pub no 88-50210. Washington, DC,
2.
1988. 7. Reddy BS. Overview of diet and colon cancer. Prog Clin Biol Res 1988; 279: 111-21. 8. Schatzkin A, Greenwald P, Byar DP, Clifford CK. The dietary fat-breast cancer hypothesis is alive. JAMA 1989; 261: 3284-87. 9. Trock B, Lanza E, Greenwald P. Dietary fiber, vegetables, and colon cancer: critical review and meta-analyses of the epidemiologic evidence. J Natl Cancer Inst 1990; 82: 650-61. 10. Hayashi Y, Nagao M. Sugimura T, et al, eds. Diet and nutrition and cancer. Tokyo/Utrecht; Japan Scientific Societies Press/VNU Science Press, 1986.
SIR,-Dr Jauchem (Oct 6, p 884) writes that "by use of an evaluation process defined by the International Agency for Research on Cancer [citing a 1981 reference], investigators studying electromagnetic field effects have concluded that the limited and inconsistent data are insufficient to establish a causal association between exposure to electromagnetic fields and cancer [no reference given]". This statement is misleading. The IARC has not yet evaluated the evidence of carcinogenic risks to man of exposure to very low-frequency electric and magnetic fields; it plans to do so in 1992. Evaluations of evidence in the IARC monographs programme are by a large group of international experts in subjects such as exposure, cell biology, animal experimentation, and epidemiology, that are relevant to the exposure being considered. This is done at a meeting at which all published material is critically reviewed according to a well-defined procedure. Jauchem’s unreferenced allusion to this procedure presumably refers to an editorial by Cartwright,2 which claims to apply the criteria used in IARC monographs to evaluate possible hazards of extremely low frequency fields. Cartwright reaches the quantitative conclusion that there is "a minute risk ... verging on the point of non-existence". This view has been criticised.3 Evaluations in the IARC monographs programme are qualitative assessments of the strength of evidence for or against carcinogenicity, not evaluations of the size of the risk. Jauchem deplores the "misinformation on the alleged hazards of electromagnetic fields ... provided by the lay media". What he offers instead is an oversimplified, selective review of the scientific evidence and a summary dismissal of any possible hazard. This is hardly consistent with his own injunction that "scientists should attempt to place potential public health hazards in their proper
perspective". Units of Descriptive Epidemiology, of Biostatistics Research and Informatics, and of Carcinogen Identification and Evaluation, International Agency for Research on Cancer, 69372 Lyon, France
MICHEL P. COLEMAN ELISABETH CARDIS HARRI VAINIO
monographs on the evaluation of carcinogenic risks to humans: vol IL, chromium, nickel and welding. Lyon: IARC, 1990: 19-39. 2. Cartwright RA. Low frequency alternating electromagnetic fields and leukaemia: the saga so far. Br J Cancer 1989; 60: 649-51. 3. Bell J, Coleman MP. Extremely low frequency (ELF) electromagnetic fields and leukaemia in children. Br J Cancer 1990; 62: 331-32.
1. IARC. Premble. In: IARC
