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579. Organic arsenicals: the evidence mounts up
410
AGRICULTURAL CHEMICALS
Based on effectiveness and toxicity data, a decision was made by the Minister of Agricl ture, Fisheries and Food (Hansard, Commons 1961,643 (139), Col. 983 : London, H.M.S. £ that from 1 January 1962 the use of dieldrin, aldrin, and heptachlor be forbidden duri~ spring sowings, and only be permitted in emergencies for dressing autumn and wint wheat. [The comparative ease of detoxication of y-BHC compared with that of the other chlori ated insecticides may account for the greater tolerance of wild birds to y-BHC.] 578. Insecticides in body fat Dale, W. E. & Quinby, G. E. (1963). Chlorinated insecticides in the body fat of people the United States. Science 142, 593. We have previously surveyed a series of papers (Cited in F.C.T. 1963, 1,254; ibid 1964, 71).dealing with the levels of chlorinated hydrocarbons in body fat, and this report preset further figures on the quantities of BHC, dieldrin and other chlorinated hydrocarbons the body fat of the general human population of the United States. The mean concentration of dieldrin (0.15 :k0-02 ppm) was in good agreement with the reported by Hunter et al. (Cited in F.C.T. 1963, 1, 254) for Southern England. Howew the BHC level (0.20-1-0.04 ppm) was much lower than that reported for France (1.19 ppl and there was no significant variation from place to place. Some variation was encounter in dieldrin levels, which were apparently unrelated to exposure. The ratio of o,p'- to p,p'- isomers of D D T stored in fat was not the same as the ratio technical grade D D T (20:80). In a group of 30 people, the ratio of the isomers o,p':p,p' the body fat was 1.31:1. The authors draw attention, however, to some differences betwe the two methods of estimation used. Aldrin, heptachlor, heptachlor epoxide and methoxychlor were not detected in any the samples. 579. Organic arsenicals: the evidence mounts up McChesney, E. W. & Banks, W. F., Jr. (1963). Toxicity and physiological disposition sodiumop-N-glycolylarsanilate. 1I. Absorption, excretion, and metabolism in the chick~ Toxicol. appl. Pharmacol. 5, 702. Since our last review of current papers on the toxicology and metabolism of certain co: pounds of arsenic (As) (Cited h7 F.C.T. 1964, 2, 215) art account has been published on t absorption, metabolism and excretion of sodium-p-N-glycolylarsanilate (I) in the chick~ Given orally or intravenously, I has been shown (McChesney et al. Toxicol. appl. Pharmac 1962, 4, 14) to possess a low toxicity in mice, but to be toxic to the cat, a species which sensitive to arsenicals in general. Excretion is rapid in the rat and in man, about 95 ~o bei eliminated within 3 days of administration while stability of the N-glycolyl linkage in bc species is indicated by the absence of detectable amounts of arsanilic acid in the urine. "1" possibility of using I as a feed additive for promoting growth in poultry led to the presc study of its metabolism in the chick. I was given orally (500 mg/kg) and arsenious acid (II) intramuscularly (2-65 mg/kg) groups A-D, each comprising 4 roosters whose diet contained 0.55 ppm residual As. "r treatments given, and repeated after 8 hr, were: A, I; B, I + I I ; C, II; D, I intramuscula in a dose of 50 mg/kg. Given orally or intramuscularly, 95 ~o of I was excreted within 16 hr and 98 ~ wit/ 88 hr of the final dose. Initially, elimination of II was slower, possibly due to a reversil nephrotoxic effect, but it almost attained that of I over the period of 24-96 hr. The excreti pattern of I was similar to that of aeetylarsanilic acid, but differed markedly from that arsanilic acid (III), only 50 ~o of which was excreted in 24 hr after oral administration
AGRICULTURAL CHEMICALS
411
chicks. In group A about 98.5 % I was excreted unchanged and the remaining 1.5 % as III but in group D, as much as 28 % was converted to III. At 96 hr after the last dose, the birds were killed and the tissues analysed. I given alone did not cause significant accumulation of As in the tissues, except in the liver, where it was greater in group D, in which considerable conversion to III had occurred. In group B the residues were found mainly in the kidney and muscle, with total residual As per bird slightly greater than that of group A. In further trials, broilers were fed for 9 weeks on a diet containing 60 g I/ton and thereafter killed at intervals of 0-5 days for tissue analysis. The only significant As residue was the level of 0.25 ppm found in liver immediately after the cessation of feeding I, and this had dropped to a negligible level by the third day. The maximum residues found in breast and leg muscle were about 0.03 ppm. From observations on the absorption and excretion of arsenicals from rats given : livers from chicks fed on I ; I added to livers of untreated chicks; or arsenite alone; it was concluded that As accumulated in the liver of these birds in the form of unchanged I and not arsenite. While this conclusion is tentative, in that the tests did not cover every possible metabolite of I, the data obtained do demonstrate that the hepatic residues are not present in the form of inorganic As. 580. Arsenic--not a carcinogen Baroni, C., van Esch, (3. J. & Saffiotti, U. (1963). Carcinogenesis tests of two inorganic arsenicals. Arch. environ. Hlth. 7, 668. B1BRA does not suscribe to the view that arsenic (As) is carcinogenic since attempts to induce tumours of any significance in mice and rats given a variety of inorganic arsenicals alone or in combination with initiating or promoting agents have consistently proved fruitless (Cited in F.C.T. 1964, 2, 215, 301). The present report lends strong support to the non-carcinogenic nature of As following the demonstration that two inorganic arsenicals failed to act either as complete or incomplete carcinogens in mice (see two-stage mechanism of carcinogenic action (Cited in F.C.T. 1963, 1, 106). Two routes of administration were used: 0.01% arsenious oxide in the drinking water or twice-weekly skin applications of a 1.58 % solution of sodium arsenate. Each treatment was supplemented in one of two ways: either subsequent skin application of a promoting agent, croton oil; or prior administration of an initiating agent, 7,12-dimethylbenz[a]anthracene or urethane. Appropriate controls were set up. Survival was recorded at 10weekly intervals up to 60 weeks and the incidence and types of tumours registered. Regarding the nature and yield of tumours, no significant difference was observed between controls and animals given the arsenicals with or without the potential cocarcinogen. The skirt of animals given the arsenicals either alone or i~. combination with one of the initiating agents did show a slight deglee of hyperkeratosis and occasional areas of epidmmal hyperplasia. Survival was reduced by the inorganic arsenicals; males being more affected than females. 581. Arsenic from sheep dips Hoffman, I., Carson, R. B. & Morris, R. F. (1963). The effect of arsenical dipping on the arsenic content of sheep tissues. Canad. J. Anhnal Sci. 43, 303. Arsenical dips are still widely used. It is valuable, therefore, to have available up-to-date figures for the arsenic (As) content of sheep tissues following dipping of this sort. Measurements of As in meat, kidney and liver showed that in most samples As was either not detected or present at 1 ppm or less regardless of the time since dipping. The amounts found to be present may in large part have arisen from contact of the sheep with one another, since considerable residues of As were found in the wool. Although the long per-
AGRICULTURAL CHEMICALS
Based on effectiveness and toxicity data, a decision was made by the Minister of Agricl ture, Fisheries and Food (Hansard, Commons 1961,643 (139), Col. 983 : London, H.M.S. £ that from 1 January 1962 the use of dieldrin, aldrin, and heptachlor be forbidden duri~ spring sowings, and only be permitted in emergencies for dressing autumn and wint wheat. [The comparative ease of detoxication of y-BHC compared with that of the other chlori ated insecticides may account for the greater tolerance of wild birds to y-BHC.] 578. Insecticides in body fat Dale, W. E. & Quinby, G. E. (1963). Chlorinated insecticides in the body fat of people the United States. Science 142, 593. We have previously surveyed a series of papers (Cited in F.C.T. 1963, 1,254; ibid 1964, 71).dealing with the levels of chlorinated hydrocarbons in body fat, and this report preset further figures on the quantities of BHC, dieldrin and other chlorinated hydrocarbons the body fat of the general human population of the United States. The mean concentration of dieldrin (0.15 :k0-02 ppm) was in good agreement with the reported by Hunter et al. (Cited in F.C.T. 1963, 1, 254) for Southern England. Howew the BHC level (0.20-1-0.04 ppm) was much lower than that reported for France (1.19 ppl and there was no significant variation from place to place. Some variation was encounter in dieldrin levels, which were apparently unrelated to exposure. The ratio of o,p'- to p,p'- isomers of D D T stored in fat was not the same as the ratio technical grade D D T (20:80). In a group of 30 people, the ratio of the isomers o,p':p,p' the body fat was 1.31:1. The authors draw attention, however, to some differences betwe the two methods of estimation used. Aldrin, heptachlor, heptachlor epoxide and methoxychlor were not detected in any the samples. 579. Organic arsenicals: the evidence mounts up McChesney, E. W. & Banks, W. F., Jr. (1963). Toxicity and physiological disposition sodiumop-N-glycolylarsanilate. 1I. Absorption, excretion, and metabolism in the chick~ Toxicol. appl. Pharmacol. 5, 702. Since our last review of current papers on the toxicology and metabolism of certain co: pounds of arsenic (As) (Cited h7 F.C.T. 1964, 2, 215) art account has been published on t absorption, metabolism and excretion of sodium-p-N-glycolylarsanilate (I) in the chick~ Given orally or intravenously, I has been shown (McChesney et al. Toxicol. appl. Pharmac 1962, 4, 14) to possess a low toxicity in mice, but to be toxic to the cat, a species which sensitive to arsenicals in general. Excretion is rapid in the rat and in man, about 95 ~o bei eliminated within 3 days of administration while stability of the N-glycolyl linkage in bc species is indicated by the absence of detectable amounts of arsanilic acid in the urine. "1" possibility of using I as a feed additive for promoting growth in poultry led to the presc study of its metabolism in the chick. I was given orally (500 mg/kg) and arsenious acid (II) intramuscularly (2-65 mg/kg) groups A-D, each comprising 4 roosters whose diet contained 0.55 ppm residual As. "r treatments given, and repeated after 8 hr, were: A, I; B, I + I I ; C, II; D, I intramuscula in a dose of 50 mg/kg. Given orally or intramuscularly, 95 ~o of I was excreted within 16 hr and 98 ~ wit/ 88 hr of the final dose. Initially, elimination of II was slower, possibly due to a reversil nephrotoxic effect, but it almost attained that of I over the period of 24-96 hr. The excreti pattern of I was similar to that of aeetylarsanilic acid, but differed markedly from that arsanilic acid (III), only 50 ~o of which was excreted in 24 hr after oral administration
AGRICULTURAL CHEMICALS
411
chicks. In group A about 98.5 % I was excreted unchanged and the remaining 1.5 % as III but in group D, as much as 28 % was converted to III. At 96 hr after the last dose, the birds were killed and the tissues analysed. I given alone did not cause significant accumulation of As in the tissues, except in the liver, where it was greater in group D, in which considerable conversion to III had occurred. In group B the residues were found mainly in the kidney and muscle, with total residual As per bird slightly greater than that of group A. In further trials, broilers were fed for 9 weeks on a diet containing 60 g I/ton and thereafter killed at intervals of 0-5 days for tissue analysis. The only significant As residue was the level of 0.25 ppm found in liver immediately after the cessation of feeding I, and this had dropped to a negligible level by the third day. The maximum residues found in breast and leg muscle were about 0.03 ppm. From observations on the absorption and excretion of arsenicals from rats given : livers from chicks fed on I ; I added to livers of untreated chicks; or arsenite alone; it was concluded that As accumulated in the liver of these birds in the form of unchanged I and not arsenite. While this conclusion is tentative, in that the tests did not cover every possible metabolite of I, the data obtained do demonstrate that the hepatic residues are not present in the form of inorganic As. 580. Arsenic--not a carcinogen Baroni, C., van Esch, (3. J. & Saffiotti, U. (1963). Carcinogenesis tests of two inorganic arsenicals. Arch. environ. Hlth. 7, 668. B1BRA does not suscribe to the view that arsenic (As) is carcinogenic since attempts to induce tumours of any significance in mice and rats given a variety of inorganic arsenicals alone or in combination with initiating or promoting agents have consistently proved fruitless (Cited in F.C.T. 1964, 2, 215, 301). The present report lends strong support to the non-carcinogenic nature of As following the demonstration that two inorganic arsenicals failed to act either as complete or incomplete carcinogens in mice (see two-stage mechanism of carcinogenic action (Cited in F.C.T. 1963, 1, 106). Two routes of administration were used: 0.01% arsenious oxide in the drinking water or twice-weekly skin applications of a 1.58 % solution of sodium arsenate. Each treatment was supplemented in one of two ways: either subsequent skin application of a promoting agent, croton oil; or prior administration of an initiating agent, 7,12-dimethylbenz[a]anthracene or urethane. Appropriate controls were set up. Survival was recorded at 10weekly intervals up to 60 weeks and the incidence and types of tumours registered. Regarding the nature and yield of tumours, no significant difference was observed between controls and animals given the arsenicals with or without the potential cocarcinogen. The skirt of animals given the arsenicals either alone or i~. combination with one of the initiating agents did show a slight deglee of hyperkeratosis and occasional areas of epidmmal hyperplasia. Survival was reduced by the inorganic arsenicals; males being more affected than females. 581. Arsenic from sheep dips Hoffman, I., Carson, R. B. & Morris, R. F. (1963). The effect of arsenical dipping on the arsenic content of sheep tissues. Canad. J. Anhnal Sci. 43, 303. Arsenical dips are still widely used. It is valuable, therefore, to have available up-to-date figures for the arsenic (As) content of sheep tissues following dipping of this sort. Measurements of As in meat, kidney and liver showed that in most samples As was either not detected or present at 1 ppm or less regardless of the time since dipping. The amounts found to be present may in large part have arisen from contact of the sheep with one another, since considerable residues of As were found in the wool. Although the long per-