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939 Dichlorobenzene: Urinary metabolite as index of occupational exposure
AGRICULTURAL CHEMICALS
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6,6-hexakis(l-aziridinyl)-l,3,5,2,4,6-triazatriphosphorine; III) appear to be the most promising for dealing with both flies and mosquitoes. Acute toxicity experiments with ], H and III in rats indicated that the oral toxicity of I is approximately the same as that of DDT but, unlike DDT, it is almost as toxic by the dermal route. Both the oral and dermal toxicities of II are similar'to those of dieldrin, while III has an oral toxicity intermediate between I and II but is distinctly less toxic by the dermal route. In the first of three short-term studies with I in rats, graded dietary levels of 0-2000 ppm I were given for 108 days. The most outstanding histological finding was testicular atrophy, which occurred at and above 400 ppm. Unspecified damage to the ovaries and marked hypoplasia of all components of the bone marrow were observed only at the two highest levels. No damage to the intestinal epithelium (a frequent effect of alkylating agents) was seen except following a single lethal dose. There was no evidence of histological damage to other organs and in the two subsequent studies histological examination was confined to the testis. The second study compared the effect of the administration of I for 105 days at levels of 5, 10 and 20 mg/kg/day by stomach tube with dietary levels equivalent to 16.2, 32.3 and 76.4 mg/kg/day. The lowest dietary level was the only dose of I which failed to cause testicular atrophy. I was much more toxic when administered by stomach tube than when given in the diet; mortality at I0 mg/kg/day by stomach tube being greater than at the dietary level of 76.4 mg/kg/day or 1000 ppm. The third study involved graded doses of 0.31-2.5 mg/kg]day administered by stomach tube for 197 days. A higher dose level of 5 mg/kg/day (0.04 LDs0), which was introduced after 112 days, produced severe reduction of fertility in the males after 22 days, sterility after 70 and testicular atrophy after 77 days. The effects on fertility and on the testis at 197 days were far less pronounced at 2.5 mg/kg/ day and were completely absent at 1.25 mg/kg/day. The survival of the newborn was not affected by any dose given to the fathers. In a recovery experiment extending to 100 days after treatment with 1000 ppm I in the diet for 66 days, reversal of testicular atrophy was observed at 50 days and in a greater proportion of animals at 100 days. The results of blood tests suggest that a white cell count might serve as an early warning system of excessive absorption of I. At a dose of 5 mg/kg/day, by stomach tube, 8-16 doses proved fatal. A second group of rats, however, survived when the dosage of I was stopped after the white cell count had fallen precipitously; by day 7 following the last dose of I the white cell count started to recover, returning to its pretreatment level by day 20. 939. Dichlorobenzene: Urinary metabolite as index of occupational exposure Pagnotto, L. D. & Walkley, Janet E. (1965). Urinary dichlorophenol as an index of paradichlorobenzene exposure. Am. ind. Hyg. Ass. J. 26, 137. 2,5-Dichlorobenzene (I) is widely used as an insecticide in the home, as a moth deterrent and deodorant. Prolonged occupational exposure to I may cause headache, nausea, vomiting, weakness, portal cirrhosis, subacute yellow atrophy of the liver, cataracti pulmonary granulomatosis, anaemia and granulocytopenia. It may also cause irritation to the skin, eyes and throat. In the rabbit, more than 30% of an oral dose of I is metabolized to 2,5-dichlorophenol (II) and about 6% to dichloroqulnol, both of which are excreted in the urine (Azouz et al. Biochem. J. 1955, 59, 410). The present authors have investigated the value of measuring the urinary excretion of II as an index of industrial exposure to I. Their study involved workers engaged in a chemical plant manufacturing I, in a household products packaging factory using I and in a plant employing I for abrasive wheel manufacture, exposure being highest in the first of these (24-34 ppm I). Exposure was almost exclusively due to inhalation of the vapour. II was excreted in the urine soon after exposure
110
FEED ADDIT,VES
to I began and rose to a maximum (up to 103 mg II/l) at the end of the working shift. Excretion then decreased, at first rapidly and then more slowly over a period of several days. The results showed a fairly good correlation between the average air concentration of I and the excretion of II at the end of the exposure period. It would seem that urinary excretion of II can serve as an index of occupational exposure to I and may be a useful adjunct to the monitoring of air samples. 940. Studies on nicotine and cotinine Truhaut, R., De Clercq, M. & Loisillier, F. (1964). Sur les toxicitrs aigu8 et chronique de la cotinine, et sur son effet cancrrigrne chez le rat. Path. Biol., Paris, 12, 39. Andersson, G., Hansson, E. & Schmiterl/Sw, C. G. (1965). Gastric excretion of C~4-nicotine. Experientia 21, 211. Nicotine (I) is still widely used as an insecticide and is also of course present in small amounts in tobacco smoke. It has been suggested that I may be a factor in causing peptic ulcers and tumours, although there is evidence against the existence of carcinogenic effect (Cited in F.C.T. 1963, 1, 341). It is readily transferred across the placenta (ibid 1963, 1, 258) and is teratogenic in mice, but only in very high doses, much greater than could possibly be inhaled by the human mother (ibid 1964, 2, 80). Its chief metabolite is cotinine (II). The present studies are concerned with the carcinogenicity of II and with the excretion of I into the stomach. When II was administered to rats for prolonged periods in the drinking water in a relatively high concentration (0.5 g/l) (Trtthaut et al. cited above), 12/15 animals that died after 8-18 months had developed malignant tumours. These were principally lymphosarcomas located in the alimentary tract, particularly in the large intestine, often with metastases in the intestinal ganglia. Lymphoid leukaemia of the liver and spleen, epithelioma of the neck and cheek and reticulo-lymphosarcoma of the lungs were found in 3 animals. This is an extension of previous work (Truhaut & De Clercq, C.r. hebd. Sdanc. A cad. Sci., Paris, 1961, 253, 1506), in which sarcomas of the intestine were produced in rats after administration of small amounts of a mixture of pyrolysis products of I, prepared at 700 ° to simulate conditions of cigarette smoking. Acute toxicity tests in mice showed that II produced the same neuropharmacological effects as I although it was only about 2% as toxic as I when administered subcutaneously (LDs0, 1.5 g II/kg). In another study (Andersson et al. cited above), I labelled with carbon-14 0aC) in the methyl group was injected intravenously into mice, rats and cats. Whole-body autoradiography (Cited in F.C.T. 1964, 2, 73) revealed that 14C was concentrated in the stomach. After 15 rain it was mainly localized in the gastric mucosa but was rapidly excreted into the stomach contents. Perfusion experiments showed that z4C was excreted into the stomach most readily at pH 1 (4-4% of the administered dose) and that this declined progressively on increasing the pH. The peak excretion occurred approximately 1 hr after the injection of I, at which time only 25% of the ~4C was present in I, the rest being found in II, the only metabolite that was detected. Although these findings indicate that substantial amounts of I are excreted via the gastric mucosa into the stomach, no conclusions can yet be drawn regarding the importance of I as a factor in the pathogenesis of peptic ulcers.
FEED ADDITIVES 941. Stilboestrol metabolism in the ruminant
Hinds, F. C., Draper, H. H., Mitchell, G. E., Jr. & Neumann, A. L. (1965). Metabolism of labelled diethylstilbestrol in ruminants. J. agric. Fd Chem. 13, 256. Diethylstilboestrol (DES) labelled with tritium was given intravenously to two lambs at
109
6,6-hexakis(l-aziridinyl)-l,3,5,2,4,6-triazatriphosphorine; III) appear to be the most promising for dealing with both flies and mosquitoes. Acute toxicity experiments with ], H and III in rats indicated that the oral toxicity of I is approximately the same as that of DDT but, unlike DDT, it is almost as toxic by the dermal route. Both the oral and dermal toxicities of II are similar'to those of dieldrin, while III has an oral toxicity intermediate between I and II but is distinctly less toxic by the dermal route. In the first of three short-term studies with I in rats, graded dietary levels of 0-2000 ppm I were given for 108 days. The most outstanding histological finding was testicular atrophy, which occurred at and above 400 ppm. Unspecified damage to the ovaries and marked hypoplasia of all components of the bone marrow were observed only at the two highest levels. No damage to the intestinal epithelium (a frequent effect of alkylating agents) was seen except following a single lethal dose. There was no evidence of histological damage to other organs and in the two subsequent studies histological examination was confined to the testis. The second study compared the effect of the administration of I for 105 days at levels of 5, 10 and 20 mg/kg/day by stomach tube with dietary levels equivalent to 16.2, 32.3 and 76.4 mg/kg/day. The lowest dietary level was the only dose of I which failed to cause testicular atrophy. I was much more toxic when administered by stomach tube than when given in the diet; mortality at I0 mg/kg/day by stomach tube being greater than at the dietary level of 76.4 mg/kg/day or 1000 ppm. The third study involved graded doses of 0.31-2.5 mg/kg]day administered by stomach tube for 197 days. A higher dose level of 5 mg/kg/day (0.04 LDs0), which was introduced after 112 days, produced severe reduction of fertility in the males after 22 days, sterility after 70 and testicular atrophy after 77 days. The effects on fertility and on the testis at 197 days were far less pronounced at 2.5 mg/kg/ day and were completely absent at 1.25 mg/kg/day. The survival of the newborn was not affected by any dose given to the fathers. In a recovery experiment extending to 100 days after treatment with 1000 ppm I in the diet for 66 days, reversal of testicular atrophy was observed at 50 days and in a greater proportion of animals at 100 days. The results of blood tests suggest that a white cell count might serve as an early warning system of excessive absorption of I. At a dose of 5 mg/kg/day, by stomach tube, 8-16 doses proved fatal. A second group of rats, however, survived when the dosage of I was stopped after the white cell count had fallen precipitously; by day 7 following the last dose of I the white cell count started to recover, returning to its pretreatment level by day 20. 939. Dichlorobenzene: Urinary metabolite as index of occupational exposure Pagnotto, L. D. & Walkley, Janet E. (1965). Urinary dichlorophenol as an index of paradichlorobenzene exposure. Am. ind. Hyg. Ass. J. 26, 137. 2,5-Dichlorobenzene (I) is widely used as an insecticide in the home, as a moth deterrent and deodorant. Prolonged occupational exposure to I may cause headache, nausea, vomiting, weakness, portal cirrhosis, subacute yellow atrophy of the liver, cataracti pulmonary granulomatosis, anaemia and granulocytopenia. It may also cause irritation to the skin, eyes and throat. In the rabbit, more than 30% of an oral dose of I is metabolized to 2,5-dichlorophenol (II) and about 6% to dichloroqulnol, both of which are excreted in the urine (Azouz et al. Biochem. J. 1955, 59, 410). The present authors have investigated the value of measuring the urinary excretion of II as an index of industrial exposure to I. Their study involved workers engaged in a chemical plant manufacturing I, in a household products packaging factory using I and in a plant employing I for abrasive wheel manufacture, exposure being highest in the first of these (24-34 ppm I). Exposure was almost exclusively due to inhalation of the vapour. II was excreted in the urine soon after exposure
110
FEED ADDIT,VES
to I began and rose to a maximum (up to 103 mg II/l) at the end of the working shift. Excretion then decreased, at first rapidly and then more slowly over a period of several days. The results showed a fairly good correlation between the average air concentration of I and the excretion of II at the end of the exposure period. It would seem that urinary excretion of II can serve as an index of occupational exposure to I and may be a useful adjunct to the monitoring of air samples. 940. Studies on nicotine and cotinine Truhaut, R., De Clercq, M. & Loisillier, F. (1964). Sur les toxicitrs aigu8 et chronique de la cotinine, et sur son effet cancrrigrne chez le rat. Path. Biol., Paris, 12, 39. Andersson, G., Hansson, E. & Schmiterl/Sw, C. G. (1965). Gastric excretion of C~4-nicotine. Experientia 21, 211. Nicotine (I) is still widely used as an insecticide and is also of course present in small amounts in tobacco smoke. It has been suggested that I may be a factor in causing peptic ulcers and tumours, although there is evidence against the existence of carcinogenic effect (Cited in F.C.T. 1963, 1, 341). It is readily transferred across the placenta (ibid 1963, 1, 258) and is teratogenic in mice, but only in very high doses, much greater than could possibly be inhaled by the human mother (ibid 1964, 2, 80). Its chief metabolite is cotinine (II). The present studies are concerned with the carcinogenicity of II and with the excretion of I into the stomach. When II was administered to rats for prolonged periods in the drinking water in a relatively high concentration (0.5 g/l) (Trtthaut et al. cited above), 12/15 animals that died after 8-18 months had developed malignant tumours. These were principally lymphosarcomas located in the alimentary tract, particularly in the large intestine, often with metastases in the intestinal ganglia. Lymphoid leukaemia of the liver and spleen, epithelioma of the neck and cheek and reticulo-lymphosarcoma of the lungs were found in 3 animals. This is an extension of previous work (Truhaut & De Clercq, C.r. hebd. Sdanc. A cad. Sci., Paris, 1961, 253, 1506), in which sarcomas of the intestine were produced in rats after administration of small amounts of a mixture of pyrolysis products of I, prepared at 700 ° to simulate conditions of cigarette smoking. Acute toxicity tests in mice showed that II produced the same neuropharmacological effects as I although it was only about 2% as toxic as I when administered subcutaneously (LDs0, 1.5 g II/kg). In another study (Andersson et al. cited above), I labelled with carbon-14 0aC) in the methyl group was injected intravenously into mice, rats and cats. Whole-body autoradiography (Cited in F.C.T. 1964, 2, 73) revealed that 14C was concentrated in the stomach. After 15 rain it was mainly localized in the gastric mucosa but was rapidly excreted into the stomach contents. Perfusion experiments showed that z4C was excreted into the stomach most readily at pH 1 (4-4% of the administered dose) and that this declined progressively on increasing the pH. The peak excretion occurred approximately 1 hr after the injection of I, at which time only 25% of the ~4C was present in I, the rest being found in II, the only metabolite that was detected. Although these findings indicate that substantial amounts of I are excreted via the gastric mucosa into the stomach, no conclusions can yet be drawn regarding the importance of I as a factor in the pathogenesis of peptic ulcers.
FEED ADDITIVES 941. Stilboestrol metabolism in the ruminant
Hinds, F. C., Draper, H. H., Mitchell, G. E., Jr. & Neumann, A. L. (1965). Metabolism of labelled diethylstilbestrol in ruminants. J. agric. Fd Chem. 13, 256. Diethylstilboestrol (DES) labelled with tritium was given intravenously to two lambs at