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548. Arsenic and lung cancer
CANCER RESEARCH
301
Distilled water, physiological saline, polyvinylpyrrolidone solution, dextran solution, sesame oil and Cremophor EL produced no effect; tragacanth lowered body temperature slightly. 0-1 N-Sodium hydroxide had no effect, but 0.1 N-hydrochloric acid, aseorbie acid, citric acid, succinic acid, benzoic acid, adipic acid and penicillin V acid all reduced body temperature to some extent when given as free acids in solution or suspension. When administered in neutral form (usually as the sodium salt) 0nly benzoic and succinic acids caused a reduction in temperature. The greatest temperature fall was observed after intraperitoneal injection of the histamine liberator, compound 48/80, whereas when this was administered intravenously only a slight effect was observed. The effect was found to decrease when injections were repeated (twice daily over 2 days). The weaker histamine liberators, pentamidine and hexamethylenediamine reduced the temperature to a lesser extent, but tubocurarine (known to be a powerful histamine liberator) showed no temperature effect even in very high doses. Histamine itself had only a slight effect, whilst serotonin had a moderate effect even in large doses. Injections of suspensions of barium sulphate and of highly-dispersed silicic acid showed that these substances, too, caused moderate to pronounced reductions in body temperature, but suspensions of various drugs were without effect. The intraperitoneal injection of a large volume of air reduced body temperature considerably. Other experiments were carried out using dogs, rabbits and guinea-pigs, where compound 48/80 appeared to have no effect on body temperature. It is possible that the injection of soluble substances might produce a state of shock with secondary effects on body temperature. Nevertheless it is surprising that the administration of water-insoluble materials such as barium sulphate or amorphous colloidal silicic acid should cause a fall in the rats' body temperature in the absence of any other evidence of shock. It was noted in particular that the suspension of penicillin V acid reduced body temperature, but that the same amount administered as the soluble sodium salt had no effect on temperature. It is suggested that the observed hypothermia in rats may have been caused by rupture of peritoneal mast cells and liberation of histamine and 5-hydroxytryptamine. In this connection it was found that, when large doses of heparin were injected intraperitoneally or intraveneously, there was a latent period of several hr before body temperature fell.
CANCER RESEARCH 548. Arsenic and lung cancer
Buechley, R. W. (1963). Epidemiological consequences of an arsenic-lung cancer theory. Amer. J. publ. Hlth. 53, 1229. The author reviews the evidence on which the theory is based that lung cancer in man is due to exposure to arsenic (As). Five populations display an incidence of lung cancer far in excess of what might be accounted for by cigarette smoking or urban atmospheric pollution. They are miners of nickel, cobalt, lead and copper ores, present as As compounds; workers who smelt these ores; those exposed, particularly in childhood, to air heavily polluted by smelter fumes; workers manufacturing or handling arsenical insecticides and spray operators applying these preparations. The use of arsenicals on tobacco explains how smoking leads to lung cancer. Providing that all this is true, it is possible to predict that the converse should also be true. For instance, people may mine, smelt, live in cities; make, handle and spray insecticides; as well as smoke cigarettes--all with impunity--as long as As does not enter into their lives in any of these ways. Since arsenical spraying of tobacco in the U.S.A. ceased in
302
CANCER RESEARCH
about 1950, lung cancer rates should begin to decrease in that country from about 1970 on. ward, irrespective of changes in smoking habits. Some of these predictions lend themselves to epidemiological study at the present time. The Japanese mine and smelt As on a large scale but the incidence of lung cancer among these workers is unknown. The same is true of those using lead arsenate on grapes in New York state; and, presumably, of those consuming the grapes. Finally the fact that South Africans can smoke heavily at little risk is accounted for by the circumstance that their tobacco does not require spraying with lead arsenate. [Among the world's populations there must be many more 'low-arsenic situations' where the accuracy of these predictions might be checked. It would be worth doing so in order that, if the correlation becomes fully established, the stage may thus be set for a further search--to seek the factor that renders arsenic carcinogenic. Is it the association with lead ? Could it be a potentiation of the undoubted carcinogenicity of nickel ? We have considered this question on p. 217 of this issue and remain unconvinced that arsenic as such is a systemic carcinogen in mart or animals. While on the subject of environmental carcinogens, we would direct the reader's attention to the interesting comments made in the article "Cancer in the Tropics" (Report of tile Medical Research Council for 1961-1962, London, H.M.S.O. 1963, p. 18): "These African findings are so much at variance with those from more developed countries that they are in urgent need of confirmation. The fact that rates rise steeply with age in developed countries has profoundly influenced thinking about cancer and has suggested that if everyone lived to a sufficiently advanced age everyone would develop cancer. These reports from Africa throw a tinge of doubt on this theory and suggest that the rise of cancer incidence with age may be a consequence of cumulative exposure to carcinogenic factors in the environment that do not menace the African peasant in his simpler life." Work in New Zealand and in South Africa (Dean, Brit. reed. J. 1959, ii, 852; ibm 1961, ii, 1599) has demonstrated that British immigrants have brought with them a susceptibility to lung cancer that is present to a muctl lesser degree in local populations drawn from the same stock originally but born and bred abroad. What is the factor in the British environment that gives rise to this increased susceptibility ? Even the author would hardly have us believe that it is all due to arsenic.]
549. Tumours from E/-propiolactone
Palmes, E. D., Orris, L. & Nelson, N. (1962). Skin irritation and skin tumor production by beta propiolactone (BPL). Amer. ind. Hyg. Ass. J. 23, 257. /~-Propiolactone (I) shows promise as a synthetic reagent in organic chemistry and is virucidal, fungicidal and bactericidal. Roe & Glendenning (Brit. J. Cancer 1956, 10, 357) have shown that I produces papilloma and cancers when applied to mouse skin (Cited in F.C.T. 1963, 1, 157). The use of I in many of its applications appears to involve contact with tile substance and its vapours. Hence the present study, concerned mainly with the skin, was carried out on the toxicity of I. A further report is in preparation on the effect .of I on the respiratory tract and the eye. In undiluted form, or in solution in acetone or corn oil, I was applied to clipped mouse skirt ill various doses over a period of 1-14 days. The mice were observed frequently over the next 30 days to determine the degree and persistence of primary skill irritation. In the acetone group it was found that doses of 2.5-10 mg I produced moderate to severe skin involvement, while with a dose of 0.8 mg the effect was considerably reduced. Doses of 20 mg applied once or twice produced greater effects than smaller doses given a number of times. A dose of 2.5 mg in corn oil produced a smaller reaction than the same dose in
301
Distilled water, physiological saline, polyvinylpyrrolidone solution, dextran solution, sesame oil and Cremophor EL produced no effect; tragacanth lowered body temperature slightly. 0-1 N-Sodium hydroxide had no effect, but 0.1 N-hydrochloric acid, aseorbie acid, citric acid, succinic acid, benzoic acid, adipic acid and penicillin V acid all reduced body temperature to some extent when given as free acids in solution or suspension. When administered in neutral form (usually as the sodium salt) 0nly benzoic and succinic acids caused a reduction in temperature. The greatest temperature fall was observed after intraperitoneal injection of the histamine liberator, compound 48/80, whereas when this was administered intravenously only a slight effect was observed. The effect was found to decrease when injections were repeated (twice daily over 2 days). The weaker histamine liberators, pentamidine and hexamethylenediamine reduced the temperature to a lesser extent, but tubocurarine (known to be a powerful histamine liberator) showed no temperature effect even in very high doses. Histamine itself had only a slight effect, whilst serotonin had a moderate effect even in large doses. Injections of suspensions of barium sulphate and of highly-dispersed silicic acid showed that these substances, too, caused moderate to pronounced reductions in body temperature, but suspensions of various drugs were without effect. The intraperitoneal injection of a large volume of air reduced body temperature considerably. Other experiments were carried out using dogs, rabbits and guinea-pigs, where compound 48/80 appeared to have no effect on body temperature. It is possible that the injection of soluble substances might produce a state of shock with secondary effects on body temperature. Nevertheless it is surprising that the administration of water-insoluble materials such as barium sulphate or amorphous colloidal silicic acid should cause a fall in the rats' body temperature in the absence of any other evidence of shock. It was noted in particular that the suspension of penicillin V acid reduced body temperature, but that the same amount administered as the soluble sodium salt had no effect on temperature. It is suggested that the observed hypothermia in rats may have been caused by rupture of peritoneal mast cells and liberation of histamine and 5-hydroxytryptamine. In this connection it was found that, when large doses of heparin were injected intraperitoneally or intraveneously, there was a latent period of several hr before body temperature fell.
CANCER RESEARCH 548. Arsenic and lung cancer
Buechley, R. W. (1963). Epidemiological consequences of an arsenic-lung cancer theory. Amer. J. publ. Hlth. 53, 1229. The author reviews the evidence on which the theory is based that lung cancer in man is due to exposure to arsenic (As). Five populations display an incidence of lung cancer far in excess of what might be accounted for by cigarette smoking or urban atmospheric pollution. They are miners of nickel, cobalt, lead and copper ores, present as As compounds; workers who smelt these ores; those exposed, particularly in childhood, to air heavily polluted by smelter fumes; workers manufacturing or handling arsenical insecticides and spray operators applying these preparations. The use of arsenicals on tobacco explains how smoking leads to lung cancer. Providing that all this is true, it is possible to predict that the converse should also be true. For instance, people may mine, smelt, live in cities; make, handle and spray insecticides; as well as smoke cigarettes--all with impunity--as long as As does not enter into their lives in any of these ways. Since arsenical spraying of tobacco in the U.S.A. ceased in
302
CANCER RESEARCH
about 1950, lung cancer rates should begin to decrease in that country from about 1970 on. ward, irrespective of changes in smoking habits. Some of these predictions lend themselves to epidemiological study at the present time. The Japanese mine and smelt As on a large scale but the incidence of lung cancer among these workers is unknown. The same is true of those using lead arsenate on grapes in New York state; and, presumably, of those consuming the grapes. Finally the fact that South Africans can smoke heavily at little risk is accounted for by the circumstance that their tobacco does not require spraying with lead arsenate. [Among the world's populations there must be many more 'low-arsenic situations' where the accuracy of these predictions might be checked. It would be worth doing so in order that, if the correlation becomes fully established, the stage may thus be set for a further search--to seek the factor that renders arsenic carcinogenic. Is it the association with lead ? Could it be a potentiation of the undoubted carcinogenicity of nickel ? We have considered this question on p. 217 of this issue and remain unconvinced that arsenic as such is a systemic carcinogen in mart or animals. While on the subject of environmental carcinogens, we would direct the reader's attention to the interesting comments made in the article "Cancer in the Tropics" (Report of tile Medical Research Council for 1961-1962, London, H.M.S.O. 1963, p. 18): "These African findings are so much at variance with those from more developed countries that they are in urgent need of confirmation. The fact that rates rise steeply with age in developed countries has profoundly influenced thinking about cancer and has suggested that if everyone lived to a sufficiently advanced age everyone would develop cancer. These reports from Africa throw a tinge of doubt on this theory and suggest that the rise of cancer incidence with age may be a consequence of cumulative exposure to carcinogenic factors in the environment that do not menace the African peasant in his simpler life." Work in New Zealand and in South Africa (Dean, Brit. reed. J. 1959, ii, 852; ibm 1961, ii, 1599) has demonstrated that British immigrants have brought with them a susceptibility to lung cancer that is present to a muctl lesser degree in local populations drawn from the same stock originally but born and bred abroad. What is the factor in the British environment that gives rise to this increased susceptibility ? Even the author would hardly have us believe that it is all due to arsenic.]
549. Tumours from E/-propiolactone
Palmes, E. D., Orris, L. & Nelson, N. (1962). Skin irritation and skin tumor production by beta propiolactone (BPL). Amer. ind. Hyg. Ass. J. 23, 257. /~-Propiolactone (I) shows promise as a synthetic reagent in organic chemistry and is virucidal, fungicidal and bactericidal. Roe & Glendenning (Brit. J. Cancer 1956, 10, 357) have shown that I produces papilloma and cancers when applied to mouse skin (Cited in F.C.T. 1963, 1, 157). The use of I in many of its applications appears to involve contact with tile substance and its vapours. Hence the present study, concerned mainly with the skin, was carried out on the toxicity of I. A further report is in preparation on the effect .of I on the respiratory tract and the eye. In undiluted form, or in solution in acetone or corn oil, I was applied to clipped mouse skirt ill various doses over a period of 1-14 days. The mice were observed frequently over the next 30 days to determine the degree and persistence of primary skill irritation. In the acetone group it was found that doses of 2.5-10 mg I produced moderate to severe skin involvement, while with a dose of 0.8 mg the effect was considerably reduced. Doses of 20 mg applied once or twice produced greater effects than smaller doses given a number of times. A dose of 2.5 mg in corn oil produced a smaller reaction than the same dose in