- Email: [email protected]
RADIATION DOSES AFTER THREE MILE ISLAND
1039 from one strain of pneumococci can change the behavof other strains. Genetic engineering, with all its dangers, depends on such prowess. Now that progress has been made towards easier determination of pathogenicity in strains of E. histolytica, the way is open for attempts to transform (or transduce) commensal strains into invasive E. histolytica, and so to identify the obviously labile trigger agent. D.x.A.
iour
causative link is almost unthinkable. Moreover, the background of reported cases of gastric cancer associated with a history of duodenal ulcer,4the sequence of events in their first case provides no substantial grounds for suspecting that cimetidine treatment triggered the cancer. All in all, I feel that the juxtaposition of the three case reports and the speculation(s) with regard to the formation of a gastric carcinogen from cimetidine is both misleading and
Thus,
a
against
scientifically unjustifiable.
Amœbiasis Research Unit, Durban, South Africa
R. ELSDON-DEW*
4
Kings Road, SW19 8QN
FRANCIS J. C. ROE
Wimbledon *Present address. Kwazulu
Pathology Laboratory Services,
Private
Bag X9020,
Pietermariszburg 3200, South Africa.
RADIATION DOSES AFTER THREE MILE ISLAND
CIMETIDINE AND GASTRIC CANCER
SIR,-The manufacturers of cimetidine, Smith Kline & French Laboratories, have asked me to comment on the paper by Mr Elder and his colleagues on p. 1005 of this week’s issue. Several important points need to be made. Firstly, insofar as cimetidine can ease symptoms caused by gastric cancer, there is a danger that its use will delay the diagnosis of malignancy. In their data sheet on ’Tagamet’ the manufacturers of cimetidine specifically warn users of this danger,’ and reports of such cases have been published’ prior to the three now described by Elder et alIt is right that such cases should be publicised to remind clinicians of the need to check the accuracy of diagnosis before embarking on cimetidine therapy and to maintain close observation of patients while treatment continues. Another feature of the paper is of more debatable merit, however. It is well-known that many drugs which are secondary (or tertiary) amines (or amides) might, theoretically at least, be converted to nitroso-derivatives within the highly acidic conditions of the stomach by reaction with nitrite from saliva, food, drinking water, tobacco smoke, and such.2 Cimetidme falls into this category, but whether nitrosation occurs in vivo, and, if so, the extent to which it occurs, are unknown. Furthermore, there is no evidence that any nitroso-compound which could conceivably be formed from cimetidine in the stomach would behave biologically like N-methyl-N’-nitro-N-nitrosoguanidine, irrespective of its arguably analogous chemical structure. While such uncertainties exist it is difficult to iustify the speculations in Elder’s paper. N-nitrosamines are remarkable for the specificity of their organotropy and one really could not predict that a ’mono nitrosocimetidine’ would be especially likely to cause cancers specifically of the stomach. Indeed, this is irrelevant: if the administration of cimetidine led to the production of biologically significant quantities of a carcinogenic nitrosamine, one would be concerned, irrespective of its particular organotropy. Clearly it is data and not speculations that are needed. Is cimetidine nitrosated to a significant extent in vivo? Is the product formed carcinogenic? If so, which is or are) the target organ(s)? One way of obtaining such information is to study the effect of the drug in laboratory animals. This has been done in a large, well-designed, multi-dose, long-term study in rats without evidence of increased risk of malignancy.2 The results of this study provide persuasive evidence that, in doses equivalent to over 60 times those used chmcatly, cimetidine is safe from the viewpoint of carcinogenicity. No experienced cancer researcher would expect cancer to arise in a human as a consequence of exposure to even a potent chemical carcinogen within a period from first exposure measured in weeks or months. The intervals from first exposure to cimetidine to diagnosisof gastric cancer in the three cases reported by Elder et al. ranged from 10 weeks to 11 months. 1 Taylor, R H.,
Menzies-Gow, N., Lowell, D., La Brooy, S. J., Misiewicz, J Lancet, 1978, i, 686. 2 Tjinsky, W. Cancer Res. 1974, 34, 255. 3. Brmblecombe, R. W., Duncan, W. A. M., Durant, G. J., Emmett, J. C., Ganellin, C. R., Leslie, G. B., Parsons, M. E. Gastroenterology 1978, 74, 339-347.
recent accident the Three Mile Island nuclear power station in Pennsylvania includes data on the radiation exposure of members of the public. According to information received from Federal agencies in the United States, the value quoted of 80 mrem is the estimated maximum exposure to any individual and is not the average to the population in the area. Furthermore, the collective dose to the population of approximately 2 million living within a radius of 50 miles (80 km) of the plant has been estimated at between 2000 and 3000 person-rem. According to the most recent estimates of UNSCEAR and I.C.R.P., this implies that there is about one chance in four that there will eventually be one extra death from cancer in this population in addition to the expectation of approximately 500 000 deaths from cancers from all causes.
SiR,—Your editorial of April 28 about the
at
National
Radiological
Protection
Harwell, Didcot, Oxfordshire OX11 0RQ
Board,
A. S. MCLEAN
&agr;2-ANTIPLASMIN INHIBITOR DEFICIENCY SiR,-Koie et al.l described the first case of deficiency of OC2-antiplasmin (the designation used for the fast-acting plasmin inhibitor in plasma previously called antiplasmin, &agr;2-plasmin inhibitor, or primary plasmin inhibitor as suggested by the International Committee on Thrombosis and Haemostasis in Thromb. Haemostas. 1978, 39, 524) in a patient who presented with haemorrhagic diathesis. Plasma-fibrinogen and fibrinogen-degradation products in serum were, however, normal. Koie et al. suggested that the bleeding in their patient might be due to increased fibrinolysis of the hxmostatic plugs in the absence of the fast-acting plasmin inhibitor. The absence of systemic fibrinogen breakdown was explained by the presence of other protease inhibitors in the circulation. Dr Lipinski and Dr Gurewich (Feb. 10, p. 329) suggest another explanation. They and othersz had observed that, in the presence of increased plasminogen-activator levels in the blood, fibrinolysis is much more enhanced than fibrinogenolysis. This preferential action on fibrin is explained by postulating the formation of an antiactivator-activator complex which dissociates in the presence of fibrin. The evidence for the existence of a specific inhibitor of plasminogen activator in the blood remains, however, indirect, and such a substance has not been isolated or characterised. During the past few years specific interactions at the molecular level have been demonstrated between the different components of the fibrinolytic system. The developments permit a molecular model for the directed action of the fibrinolytic system towards fibrin in vivo.3 In this model, the fibrinolytic sys4.
Ellts, D. J., Kingston, R. D., Brookes, V. S., Waterhouse, J. A. H. Br. J.
Surg. 1979, 66, 117. Kamiya, T., Ogata, K., Takamatsu, J., Kohakura, M. Lancet, 1978, ii, 1334. 2. Müllertz, S. Acta physiol. scand. 1956, 38, suppl. 10. 3. Wiman, B., Collen, D. Nature, 1978, 272, 549. 1. Koie, K.,
iour
causative link is almost unthinkable. Moreover, the background of reported cases of gastric cancer associated with a history of duodenal ulcer,4the sequence of events in their first case provides no substantial grounds for suspecting that cimetidine treatment triggered the cancer. All in all, I feel that the juxtaposition of the three case reports and the speculation(s) with regard to the formation of a gastric carcinogen from cimetidine is both misleading and
Thus,
a
against
scientifically unjustifiable.
Amœbiasis Research Unit, Durban, South Africa
R. ELSDON-DEW*
4
Kings Road, SW19 8QN
FRANCIS J. C. ROE
Wimbledon *Present address. Kwazulu
Pathology Laboratory Services,
Private
Bag X9020,
Pietermariszburg 3200, South Africa.
RADIATION DOSES AFTER THREE MILE ISLAND
CIMETIDINE AND GASTRIC CANCER
SIR,-The manufacturers of cimetidine, Smith Kline & French Laboratories, have asked me to comment on the paper by Mr Elder and his colleagues on p. 1005 of this week’s issue. Several important points need to be made. Firstly, insofar as cimetidine can ease symptoms caused by gastric cancer, there is a danger that its use will delay the diagnosis of malignancy. In their data sheet on ’Tagamet’ the manufacturers of cimetidine specifically warn users of this danger,’ and reports of such cases have been published’ prior to the three now described by Elder et alIt is right that such cases should be publicised to remind clinicians of the need to check the accuracy of diagnosis before embarking on cimetidine therapy and to maintain close observation of patients while treatment continues. Another feature of the paper is of more debatable merit, however. It is well-known that many drugs which are secondary (or tertiary) amines (or amides) might, theoretically at least, be converted to nitroso-derivatives within the highly acidic conditions of the stomach by reaction with nitrite from saliva, food, drinking water, tobacco smoke, and such.2 Cimetidme falls into this category, but whether nitrosation occurs in vivo, and, if so, the extent to which it occurs, are unknown. Furthermore, there is no evidence that any nitroso-compound which could conceivably be formed from cimetidine in the stomach would behave biologically like N-methyl-N’-nitro-N-nitrosoguanidine, irrespective of its arguably analogous chemical structure. While such uncertainties exist it is difficult to iustify the speculations in Elder’s paper. N-nitrosamines are remarkable for the specificity of their organotropy and one really could not predict that a ’mono nitrosocimetidine’ would be especially likely to cause cancers specifically of the stomach. Indeed, this is irrelevant: if the administration of cimetidine led to the production of biologically significant quantities of a carcinogenic nitrosamine, one would be concerned, irrespective of its particular organotropy. Clearly it is data and not speculations that are needed. Is cimetidine nitrosated to a significant extent in vivo? Is the product formed carcinogenic? If so, which is or are) the target organ(s)? One way of obtaining such information is to study the effect of the drug in laboratory animals. This has been done in a large, well-designed, multi-dose, long-term study in rats without evidence of increased risk of malignancy.2 The results of this study provide persuasive evidence that, in doses equivalent to over 60 times those used chmcatly, cimetidine is safe from the viewpoint of carcinogenicity. No experienced cancer researcher would expect cancer to arise in a human as a consequence of exposure to even a potent chemical carcinogen within a period from first exposure measured in weeks or months. The intervals from first exposure to cimetidine to diagnosisof gastric cancer in the three cases reported by Elder et al. ranged from 10 weeks to 11 months. 1 Taylor, R H.,
Menzies-Gow, N., Lowell, D., La Brooy, S. J., Misiewicz, J Lancet, 1978, i, 686. 2 Tjinsky, W. Cancer Res. 1974, 34, 255. 3. Brmblecombe, R. W., Duncan, W. A. M., Durant, G. J., Emmett, J. C., Ganellin, C. R., Leslie, G. B., Parsons, M. E. Gastroenterology 1978, 74, 339-347.
recent accident the Three Mile Island nuclear power station in Pennsylvania includes data on the radiation exposure of members of the public. According to information received from Federal agencies in the United States, the value quoted of 80 mrem is the estimated maximum exposure to any individual and is not the average to the population in the area. Furthermore, the collective dose to the population of approximately 2 million living within a radius of 50 miles (80 km) of the plant has been estimated at between 2000 and 3000 person-rem. According to the most recent estimates of UNSCEAR and I.C.R.P., this implies that there is about one chance in four that there will eventually be one extra death from cancer in this population in addition to the expectation of approximately 500 000 deaths from cancers from all causes.
SiR,—Your editorial of April 28 about the
at
National
Radiological
Protection
Harwell, Didcot, Oxfordshire OX11 0RQ
Board,
A. S. MCLEAN
&agr;2-ANTIPLASMIN INHIBITOR DEFICIENCY SiR,-Koie et al.l described the first case of deficiency of OC2-antiplasmin (the designation used for the fast-acting plasmin inhibitor in plasma previously called antiplasmin, &agr;2-plasmin inhibitor, or primary plasmin inhibitor as suggested by the International Committee on Thrombosis and Haemostasis in Thromb. Haemostas. 1978, 39, 524) in a patient who presented with haemorrhagic diathesis. Plasma-fibrinogen and fibrinogen-degradation products in serum were, however, normal. Koie et al. suggested that the bleeding in their patient might be due to increased fibrinolysis of the hxmostatic plugs in the absence of the fast-acting plasmin inhibitor. The absence of systemic fibrinogen breakdown was explained by the presence of other protease inhibitors in the circulation. Dr Lipinski and Dr Gurewich (Feb. 10, p. 329) suggest another explanation. They and othersz had observed that, in the presence of increased plasminogen-activator levels in the blood, fibrinolysis is much more enhanced than fibrinogenolysis. This preferential action on fibrin is explained by postulating the formation of an antiactivator-activator complex which dissociates in the presence of fibrin. The evidence for the existence of a specific inhibitor of plasminogen activator in the blood remains, however, indirect, and such a substance has not been isolated or characterised. During the past few years specific interactions at the molecular level have been demonstrated between the different components of the fibrinolytic system. The developments permit a molecular model for the directed action of the fibrinolytic system towards fibrin in vivo.3 In this model, the fibrinolytic sys4.
Ellts, D. J., Kingston, R. D., Brookes, V. S., Waterhouse, J. A. H. Br. J.
Surg. 1979, 66, 117. Kamiya, T., Ogata, K., Takamatsu, J., Kohakura, M. Lancet, 1978, ii, 1334. 2. Müllertz, S. Acta physiol. scand. 1956, 38, suppl. 10. 3. Wiman, B., Collen, D. Nature, 1978, 272, 549. 1. Koie, K.,