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Chlorinated hydrocarbons in the body fat
254
ARTICLES OF GENERAL INTEREST
111 ; Druckrey & Preussmarm, unpublished report; Dontenwill et aL Z. Krebsforsch. 1962, 64, 499), when injected give rise to highly malignant lung tumours of exactly the same histological type as those which occur in men, namely squamous epithelial and alveolar cell carcinomas, which have hitherto not been produced in the experimental animal. Nitrosamine derivatives are the only compounds that have so far been discovered which possess such activity. Investigations into their toxicity on inhalation are now under way in the laboratory of Druckrey and his colleagues. Alkylamines of course do not occur exclusively in tobacco but are present in all living cells. The possibility therefore exists that carcinogenic nitrosamines are formed in the body when oxides of nitrogen are taken into the lungs in tobacco smoke. Highly reactive and short-lived oxides of nitrogen may well be present in fresh tobacco smoke, whereas the residual tar which is only feebly carcinogenic might only contain the reaction products of such highly active oxides. If the presence in tobacco smoke of nitrosamines were proved, and the compounds which gave rise to them or to the oxides of nitrogen were identified, it might be possible to eliminate such nitrosamine precursors from tobacco.
C H L O R I N A T E D HYDROCARBONS IN T H E BODY FAT Twelve years ago Lang et al. (Arch. industr. Hyg. 1951, 3, 245) reported the presence o f D D T in the body fat in the majority of individuals in a group of 75 Americans. None had come into contact with D D T in their work and had therefore ingested the insecticide with their food. A mean level of 5 ppm of D D T was found in the body fat of these individuals. Later however Pearce et al. (Science 1952, 116, 254) demonstrated that the assay used in the former study failed to distinguish between D D T and one of its metabolites, D D E 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene. It appeared that approximately half the material assayed in the former study as D D T was in fact DDE. Investigations of groups of Canadians and Germans also have revealed the presence of such residues in their body fat (Read & McKinley, Arch. environ. Hlth. 1961, 3, 209; MaierBode, Med. exp. 1960, 1, 148). The results have now been reported of work upon this subject undertaken in this country by Hunter et al. (Brit. med. J. 1963, 1, 221). Hunter and Iris colleagues examined at post mortem the combined levels D D T and DDE, and also the dieldrin levels in the body fat of 131 patients originating from Southern England. The patients studied had died either from natural or accidental causes. Some had lived in urban and some in semi-rural areas, but so far as it could be ascertained none had worked with either of the insecticides. The mean combined level of D D T and DDE in the body fat samples that were examined was 2.21 ppm, a figure similar to that found by Maier-Bode loc. cit. in the West German population but which was considerably below the level in American body fat. Statistical analysis revealed that the D D T and D D E content of fat taken from males was significantly higher than in the females who had lived in the same type of area. The cause of death however was without effect on the levels of D D T and D D E observed, neither was the type of living area important in that respect. In an Editorial the Brit. reed. J. (1963, 1, 205) discussed the subject of the ingestion of DDT, its pharmacology and toxicology, and calculated that if an obese man with 5 ppm of D D T in his body fat lost 2 stone (12.7 kg) in a week he would release a dose of D D T of about 0-5 mg/kg of body weight into his circulation. On the other hand individuals have been
ARTICLES OF GENERAL INTEREST
255
given 8-10 daily doses of 30-50 mg D D T / k g without ill-effects resulting. It was concluded that "by every criteria D D T is not a serious poison for mammals despite its chemical persistence and selective solubility". Hunter and his colleagues demonstrated, for the first time, that dieldrin (1, 2, 3, 4, .I0, 10-hexachloro-6, 7-epoxy-l, 4, 4a, 5, 6, 7, 8, 8a-octahydro-exo-1, 4-endo-5, 8-dimethanonaphthalene or HEOD) also accumulated in body fat. A mean level of 0.21 ppm H E O D was found in the group under study; there was no indication however that this amount was harmful. As with the D D T and D D E contents no differences were seen between types of living areas, or causes of death, but no sex difference in HEOD levels was apparent. The analysis revealed that there was a significant correlation between the various D D T and DDE and H E O D contents in the majority of samples. This strongly suggested that an equilibrium had been established between the rates of ingestion and excretion of the two agents. It was likely therefore that the fat levels truly reflected the current intakes of these agents in the diet. Turning to the question of the pharmacology of HEOD, little appears to be known of the fate of this substance in the body (Bell, Med. J. Aust. 1960, 2, 698; Brooks, Nature, Lond. 1960, 186, 96). Fletcher (Wld. Hlth. Org. Symp. Pesticides 1959, p. 103) showed that in individuals exposed to this agent the urine contained H E O D or H E O D derivatives. These data were however obtained by the determination of the total chlorine content of urine samples, a procedure which is both non-specific and insensitive. In a recent paper however Cueto & Hayes (J. agric. Fd Chem. 1962, 10, 366) of the Communicable Disease Center of the U.S. Public Health Service have described the development of a more practical assay for H E O D and its metabolites. This was based on the use of the zinc-diphenylamine colorimetric assay coupled with paper, column, or gas chromatographic separation procedures. Two neutral polar metabolites of H E O D but no unchanged HEOD were demonstrated in the urine of individuals exposed to H E O D by use of paper and column chromatographic procedures. However, dieldrin or a material having the same retention time, was detected in the urine of such by microcoulometric gas chromatography. It was thought that possible degradation due to heat of a dieldrin conjugate had liberated the free insecticide. [The Brit. med. J.'s conclusion that "by every criteria D D T is not a serious poison for mammals despite its chemical persistence and selective solubility" differs from that reached in the Fifth Report of the Joint FAO/WHO Expert Committee on the "Evaluation of the Carcinogenic Hazards of Food Additives" (Cited in F.C.T. 1963, 1, 35), namely that: "The published data indicates that D D T induces a weak carcinogenic response in rats (Fitzhugh & Nelson, J. Pharmacol. 1947, 89, 18). Information on the effect of D D T on chronic feeding to species other than the rat, if available, should be reviewed. Available information indicates that D D T has been subjected only to limited studies from the standpoint of potential carcinogenicity. More extensive work is urgently needed not only because of the ubiquitous distribution of D D T but because of its stability and tendency to concentrate in lipid depots." More work remains to be carded out on dieldrin also. I/~ a recent investigation Davis & Fitzhugh (Cited in F.C.T. 1963, 1, 128) showed that significant numbers of admittedly benign liver tumours developed in mice that were given 10 ppm dieldrin in their diet over a 2-yr period. A reduction of the mean life-span by 8 weeks occurred in the test animals compared to the average 59.8 weeks survival of the controls. There seems to be no room for complacency here.]
ARTICLES OF GENERAL INTEREST
111 ; Druckrey & Preussmarm, unpublished report; Dontenwill et aL Z. Krebsforsch. 1962, 64, 499), when injected give rise to highly malignant lung tumours of exactly the same histological type as those which occur in men, namely squamous epithelial and alveolar cell carcinomas, which have hitherto not been produced in the experimental animal. Nitrosamine derivatives are the only compounds that have so far been discovered which possess such activity. Investigations into their toxicity on inhalation are now under way in the laboratory of Druckrey and his colleagues. Alkylamines of course do not occur exclusively in tobacco but are present in all living cells. The possibility therefore exists that carcinogenic nitrosamines are formed in the body when oxides of nitrogen are taken into the lungs in tobacco smoke. Highly reactive and short-lived oxides of nitrogen may well be present in fresh tobacco smoke, whereas the residual tar which is only feebly carcinogenic might only contain the reaction products of such highly active oxides. If the presence in tobacco smoke of nitrosamines were proved, and the compounds which gave rise to them or to the oxides of nitrogen were identified, it might be possible to eliminate such nitrosamine precursors from tobacco.
C H L O R I N A T E D HYDROCARBONS IN T H E BODY FAT Twelve years ago Lang et al. (Arch. industr. Hyg. 1951, 3, 245) reported the presence o f D D T in the body fat in the majority of individuals in a group of 75 Americans. None had come into contact with D D T in their work and had therefore ingested the insecticide with their food. A mean level of 5 ppm of D D T was found in the body fat of these individuals. Later however Pearce et al. (Science 1952, 116, 254) demonstrated that the assay used in the former study failed to distinguish between D D T and one of its metabolites, D D E 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene. It appeared that approximately half the material assayed in the former study as D D T was in fact DDE. Investigations of groups of Canadians and Germans also have revealed the presence of such residues in their body fat (Read & McKinley, Arch. environ. Hlth. 1961, 3, 209; MaierBode, Med. exp. 1960, 1, 148). The results have now been reported of work upon this subject undertaken in this country by Hunter et al. (Brit. med. J. 1963, 1, 221). Hunter and Iris colleagues examined at post mortem the combined levels D D T and DDE, and also the dieldrin levels in the body fat of 131 patients originating from Southern England. The patients studied had died either from natural or accidental causes. Some had lived in urban and some in semi-rural areas, but so far as it could be ascertained none had worked with either of the insecticides. The mean combined level of D D T and DDE in the body fat samples that were examined was 2.21 ppm, a figure similar to that found by Maier-Bode loc. cit. in the West German population but which was considerably below the level in American body fat. Statistical analysis revealed that the D D T and D D E content of fat taken from males was significantly higher than in the females who had lived in the same type of area. The cause of death however was without effect on the levels of D D T and D D E observed, neither was the type of living area important in that respect. In an Editorial the Brit. reed. J. (1963, 1, 205) discussed the subject of the ingestion of DDT, its pharmacology and toxicology, and calculated that if an obese man with 5 ppm of D D T in his body fat lost 2 stone (12.7 kg) in a week he would release a dose of D D T of about 0-5 mg/kg of body weight into his circulation. On the other hand individuals have been
ARTICLES OF GENERAL INTEREST
255
given 8-10 daily doses of 30-50 mg D D T / k g without ill-effects resulting. It was concluded that "by every criteria D D T is not a serious poison for mammals despite its chemical persistence and selective solubility". Hunter and his colleagues demonstrated, for the first time, that dieldrin (1, 2, 3, 4, .I0, 10-hexachloro-6, 7-epoxy-l, 4, 4a, 5, 6, 7, 8, 8a-octahydro-exo-1, 4-endo-5, 8-dimethanonaphthalene or HEOD) also accumulated in body fat. A mean level of 0.21 ppm H E O D was found in the group under study; there was no indication however that this amount was harmful. As with the D D T and D D E contents no differences were seen between types of living areas, or causes of death, but no sex difference in HEOD levels was apparent. The analysis revealed that there was a significant correlation between the various D D T and DDE and H E O D contents in the majority of samples. This strongly suggested that an equilibrium had been established between the rates of ingestion and excretion of the two agents. It was likely therefore that the fat levels truly reflected the current intakes of these agents in the diet. Turning to the question of the pharmacology of HEOD, little appears to be known of the fate of this substance in the body (Bell, Med. J. Aust. 1960, 2, 698; Brooks, Nature, Lond. 1960, 186, 96). Fletcher (Wld. Hlth. Org. Symp. Pesticides 1959, p. 103) showed that in individuals exposed to this agent the urine contained H E O D or H E O D derivatives. These data were however obtained by the determination of the total chlorine content of urine samples, a procedure which is both non-specific and insensitive. In a recent paper however Cueto & Hayes (J. agric. Fd Chem. 1962, 10, 366) of the Communicable Disease Center of the U.S. Public Health Service have described the development of a more practical assay for H E O D and its metabolites. This was based on the use of the zinc-diphenylamine colorimetric assay coupled with paper, column, or gas chromatographic separation procedures. Two neutral polar metabolites of H E O D but no unchanged HEOD were demonstrated in the urine of individuals exposed to H E O D by use of paper and column chromatographic procedures. However, dieldrin or a material having the same retention time, was detected in the urine of such by microcoulometric gas chromatography. It was thought that possible degradation due to heat of a dieldrin conjugate had liberated the free insecticide. [The Brit. med. J.'s conclusion that "by every criteria D D T is not a serious poison for mammals despite its chemical persistence and selective solubility" differs from that reached in the Fifth Report of the Joint FAO/WHO Expert Committee on the "Evaluation of the Carcinogenic Hazards of Food Additives" (Cited in F.C.T. 1963, 1, 35), namely that: "The published data indicates that D D T induces a weak carcinogenic response in rats (Fitzhugh & Nelson, J. Pharmacol. 1947, 89, 18). Information on the effect of D D T on chronic feeding to species other than the rat, if available, should be reviewed. Available information indicates that D D T has been subjected only to limited studies from the standpoint of potential carcinogenicity. More extensive work is urgently needed not only because of the ubiquitous distribution of D D T but because of its stability and tendency to concentrate in lipid depots." More work remains to be carded out on dieldrin also. I/~ a recent investigation Davis & Fitzhugh (Cited in F.C.T. 1963, 1, 128) showed that significant numbers of admittedly benign liver tumours developed in mice that were given 10 ppm dieldrin in their diet over a 2-yr period. A reduction of the mean life-span by 8 weeks occurred in the test animals compared to the average 59.8 weeks survival of the controls. There seems to be no room for complacency here.]