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Haloalkane toxicity in rats and chicks
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THE CHEMICAL ENVIRONMENT
oxidative demethylase and glucose 6-phosphatase, increased with decreasing effective negative charge on the halogen atoms (an index of increasing free-radical reactivity). As expected, the most extensive damage was produced by CCI~ and CHI a (iodoform). Both thioacetamide and DMNA resembled the halomethanes in reducing [14C]glycine incorporation into microsomal protein at 2 hr. With DMNA, the suppression of protein synthesis was accompanied by an enhancement in the diene-conjugate content of microsomal lipids and in cell-sap RNA. However, the hepatotoxins, bromobenzene and ethionine, and the two organic solvents, with solubility properties comparable to those of CC14, were without effect on microsomal function 2 hr after their administration, as were the two chloroethanes studied. The author concludes that his findings are compatible with the hypothesis that halomethanes damage the endoplasmic reticulum through a free-radical reaction. DMNA may have a similar mode of action, but thioacetamide and ethionine appear to exert their toxic effects by some other means.
2627. Haloalkane toxicity in rats and chicks
Nachtomi, Edna & Alumot, Eugenia (1972). Comparison of ethylene dibromide and carbon tetrachloride toxicity in rats and chicks: Blood and liver levels; lipid peroxidation. Expl tool. Path. 16, 71. As discussed above, the hepatotoxic action of carbon tetrachloride (CCI#) is generally thought to be initiated by free-radical formation and subsequent peroxidation of hepatic microsomal lipids, a process which in turn triggers various toxic responses. In the wider context of the haloalkanes, the authors cited above provide data to dispute this view, by comparing the pool size and rate of elimination of ethylene dibromide (EDB) and CC14 in the blood and liver of rats and chicks together with the levels of diene conjugates in the liver lipids. The latter species was chosen in view of its insensitivity to CC14 poisoning. Although CC14- and EDB-pool sizes were similar in rat liver, the elimination rate of EDB was more than four times greater than that of CC14, a finding indicative of a much more efficient detoxification mechanism for the former compound in rats. The pool size of EDB in the blood of both the rat and chick was at least five times that of CC14, although in each species the elimination rates of the two compounds from the blood were similar. Most prominent were the species differences with regard to the pool size of the liver. Whereas the CC14 pool in rat liver was almost twenty times as great as that in chick liver, the relevant EDB pool size in rats was only double that in chicks. Treatment of rats with EDB induced an appreciable rise in the levels of liver triglyceride within 12 hr, although the rise was somewhat less marked than that previously demonstrated in the case of CC14. Although the dibromide is much more toxic to rats than the tetrachloride, conjugated double-bond formation in microsomal liver lipids in rats treated with the former compound was only half that in CCl4-treated animals. Neither poison induced diene formation in chick-liver lipids, although chicks are as sensitive as rats to the toxicity of EDB. The authors conclude that the levels of these two compounds in the liver and the rates of their elimination from liver and blood may be primarily responsible for inter-species differences in their hepatotoxic effects. Although it is conceded that diene formation (a result of lipid peroxidation) is one reaction that may occur in microsomal lipids after haloalkane
THE CHEMICAL ENVIRONMENT
1151
administration, this study raises doubts about the theory that such conjugation is an aetiological factor in haloalkane toxicity.
2628. Monomeric methacrylates and rat reproduction Singh, A. R., Lawrence, W. H. & Autian, J. (1972). Embryonic-foetal toxicity and teratogenic effects of a group of methacrylate esters in rats. J. dent. Res. 51, 1632. Methacrylate resins are widely used for dental prostheses and contact lenses, as well as in a variety of industrial applications. It is said that by 1946, 98 ~o of all dentures contained methyl methacrylate polymers or copolymers. As with most polymers, there is a possibility that small amounts of residual monomer may be present in the polymeric product and may be leached out during use. Allergic reactions to acrylic dentures, for example, have been attributed to the presence of the monomer (Cited in F.C.T. 1971, 9, 145). The toxicity of methacrylic ester monomers, particularly of the methyl ester, has received considerable attention and it is known that acutely toxic doses given by various routes cause death by respiratory depression. Prolonged inhalation of the methyl ester leads to degenerative changes in the liver, but no pathological lesions were found in dogs fed up to 1000 ppm methyl or ethyl methacrylate in the diet for 2 yr (ibid 1964, 2, 503). However, there has been little information about the embryotoxic or teratogenic effects of these esters, and in this connexion a study now reported compares the effects of several methacrylate monomers and acrylic acid administered ip to pregnant rats. The three dose levels used were 10, 20 and 33 ~ of the acute ip LDso values, determined as 1.33, 1.22, 2.30, 1.40, 2.47 and 0.02 ml/kg for the methyl, ethyl, n-butyl, isobutyl and isodecyl methacrylates and acrylic acid, respectively. Each dose level was given undiluted to groups of five pregnant Sprague-Dawley rats on days 5, 10 and 15 of gestation, and four control groups were given cottonseed oil, distilled water, normal saline or no treatment. The animals were killed on day 20 and a careful study of resorptions, stillbirths, gross malformations, skeletal malformations and foetal size was carried out. Both acrylic acid and the methacrylate esters evoked a dose-related response in terms of resorptions and gross and skeletal malformations. In comparison with the untreated controls, all the treated groups showed adverse effects in some or all of the parameters studied. However, in an attempt to eliminate effects resulting from the trauma of injection and handling, comparisons were also made with a "volume control" derived from the pooled results of the three treated control groups, which received injections equivalent in volume to the largest doses of the test compounds. On this basis, a significantly increased incidence of resorptions was associated with all three dose levels of ethyl methacrylate, the high doses of the n-butyl and isobutyl esters and the two highest dose levels of the isodecyl ester. Gross abnormalities, of which haemangioma was the most common, were increased in all the test groups except those given the low dose of methyl methacrylate or acrylic acid and the two lowest doses of the n-butyl ester, but only the group given the top-level dose of acrylic acid showed an incidence of skeletal malformations outside the 95 ~ confidence interval (1.014.8 ~o) for the pooled volume control. Among the methacrylate esters, the isodecyl proved the most toxic to the early embryo, with a high incidence of resorptions, and the methyl and ethyl esters produced the most gross abnormalities. Of the latter two groups, only the ethyl showed skeletal abnormalities, however.
THE CHEMICAL ENVIRONMENT
oxidative demethylase and glucose 6-phosphatase, increased with decreasing effective negative charge on the halogen atoms (an index of increasing free-radical reactivity). As expected, the most extensive damage was produced by CCI~ and CHI a (iodoform). Both thioacetamide and DMNA resembled the halomethanes in reducing [14C]glycine incorporation into microsomal protein at 2 hr. With DMNA, the suppression of protein synthesis was accompanied by an enhancement in the diene-conjugate content of microsomal lipids and in cell-sap RNA. However, the hepatotoxins, bromobenzene and ethionine, and the two organic solvents, with solubility properties comparable to those of CC14, were without effect on microsomal function 2 hr after their administration, as were the two chloroethanes studied. The author concludes that his findings are compatible with the hypothesis that halomethanes damage the endoplasmic reticulum through a free-radical reaction. DMNA may have a similar mode of action, but thioacetamide and ethionine appear to exert their toxic effects by some other means.
2627. Haloalkane toxicity in rats and chicks
Nachtomi, Edna & Alumot, Eugenia (1972). Comparison of ethylene dibromide and carbon tetrachloride toxicity in rats and chicks: Blood and liver levels; lipid peroxidation. Expl tool. Path. 16, 71. As discussed above, the hepatotoxic action of carbon tetrachloride (CCI#) is generally thought to be initiated by free-radical formation and subsequent peroxidation of hepatic microsomal lipids, a process which in turn triggers various toxic responses. In the wider context of the haloalkanes, the authors cited above provide data to dispute this view, by comparing the pool size and rate of elimination of ethylene dibromide (EDB) and CC14 in the blood and liver of rats and chicks together with the levels of diene conjugates in the liver lipids. The latter species was chosen in view of its insensitivity to CC14 poisoning. Although CC14- and EDB-pool sizes were similar in rat liver, the elimination rate of EDB was more than four times greater than that of CC14, a finding indicative of a much more efficient detoxification mechanism for the former compound in rats. The pool size of EDB in the blood of both the rat and chick was at least five times that of CC14, although in each species the elimination rates of the two compounds from the blood were similar. Most prominent were the species differences with regard to the pool size of the liver. Whereas the CC14 pool in rat liver was almost twenty times as great as that in chick liver, the relevant EDB pool size in rats was only double that in chicks. Treatment of rats with EDB induced an appreciable rise in the levels of liver triglyceride within 12 hr, although the rise was somewhat less marked than that previously demonstrated in the case of CC14. Although the dibromide is much more toxic to rats than the tetrachloride, conjugated double-bond formation in microsomal liver lipids in rats treated with the former compound was only half that in CCl4-treated animals. Neither poison induced diene formation in chick-liver lipids, although chicks are as sensitive as rats to the toxicity of EDB. The authors conclude that the levels of these two compounds in the liver and the rates of their elimination from liver and blood may be primarily responsible for inter-species differences in their hepatotoxic effects. Although it is conceded that diene formation (a result of lipid peroxidation) is one reaction that may occur in microsomal lipids after haloalkane
THE CHEMICAL ENVIRONMENT
1151
administration, this study raises doubts about the theory that such conjugation is an aetiological factor in haloalkane toxicity.
2628. Monomeric methacrylates and rat reproduction Singh, A. R., Lawrence, W. H. & Autian, J. (1972). Embryonic-foetal toxicity and teratogenic effects of a group of methacrylate esters in rats. J. dent. Res. 51, 1632. Methacrylate resins are widely used for dental prostheses and contact lenses, as well as in a variety of industrial applications. It is said that by 1946, 98 ~o of all dentures contained methyl methacrylate polymers or copolymers. As with most polymers, there is a possibility that small amounts of residual monomer may be present in the polymeric product and may be leached out during use. Allergic reactions to acrylic dentures, for example, have been attributed to the presence of the monomer (Cited in F.C.T. 1971, 9, 145). The toxicity of methacrylic ester monomers, particularly of the methyl ester, has received considerable attention and it is known that acutely toxic doses given by various routes cause death by respiratory depression. Prolonged inhalation of the methyl ester leads to degenerative changes in the liver, but no pathological lesions were found in dogs fed up to 1000 ppm methyl or ethyl methacrylate in the diet for 2 yr (ibid 1964, 2, 503). However, there has been little information about the embryotoxic or teratogenic effects of these esters, and in this connexion a study now reported compares the effects of several methacrylate monomers and acrylic acid administered ip to pregnant rats. The three dose levels used were 10, 20 and 33 ~ of the acute ip LDso values, determined as 1.33, 1.22, 2.30, 1.40, 2.47 and 0.02 ml/kg for the methyl, ethyl, n-butyl, isobutyl and isodecyl methacrylates and acrylic acid, respectively. Each dose level was given undiluted to groups of five pregnant Sprague-Dawley rats on days 5, 10 and 15 of gestation, and four control groups were given cottonseed oil, distilled water, normal saline or no treatment. The animals were killed on day 20 and a careful study of resorptions, stillbirths, gross malformations, skeletal malformations and foetal size was carried out. Both acrylic acid and the methacrylate esters evoked a dose-related response in terms of resorptions and gross and skeletal malformations. In comparison with the untreated controls, all the treated groups showed adverse effects in some or all of the parameters studied. However, in an attempt to eliminate effects resulting from the trauma of injection and handling, comparisons were also made with a "volume control" derived from the pooled results of the three treated control groups, which received injections equivalent in volume to the largest doses of the test compounds. On this basis, a significantly increased incidence of resorptions was associated with all three dose levels of ethyl methacrylate, the high doses of the n-butyl and isobutyl esters and the two highest dose levels of the isodecyl ester. Gross abnormalities, of which haemangioma was the most common, were increased in all the test groups except those given the low dose of methyl methacrylate or acrylic acid and the two lowest doses of the n-butyl ester, but only the group given the top-level dose of acrylic acid showed an incidence of skeletal malformations outside the 95 ~ confidence interval (1.014.8 ~o) for the pooled volume control. Among the methacrylate esters, the isodecyl proved the most toxic to the early embryo, with a high incidence of resorptions, and the methyl and ethyl esters produced the most gross abnormalities. Of the latter two groups, only the ethyl showed skeletal abnormalities, however.