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1339. Another misleading factor in toxicity testing
TOXICOLOGY, TERATOGENESIS
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acid (RNA) and protein was noted. Both I and II rapidly inhibited DNA synthesis, but whereas II had little effect on the building of DNA into cell nuclei, I had a pronounced effect. II immediately reduced the ability of DNA molecules to form RNA, and so led to a depression of protein synthesis. The principal effect of I on cells is to block their ability to form DNA, while it allows their RNA-building and protein-building capacities to proceed unimpaired. [Investigating the effect of toxic agents on protein and nucleic acid synthesis in vitro or in vivo not only throws light on the mechanism of toxic action but affords a potential biochemical index of early toxic change. This approach is being actively pursued in BIBRA's newly-created Department of Biochemical Pharmacology.] TOXICOLOGY 1339. Another misleading factor in toxicity testing Heneghan, J. B. & Gates, D. F. (1966). Effects of peracetic acid used in gnotobiotics on experimental animals. Lab. Anita. Care 16, 96. Flexible film isolators used to rear germ-free animals have been widely sterilized by means of dilute solutions of peracetic acid (I). It has been observed that although rats and mice show little sign of irritation by traces of I, dogs react by agitation, whining, sneezing and eye-rubbing, and suckhng pups have died after exposure to it. I carried into the isolator on objects during a sleeve lock entry has increased heart and breathing rates and blood pressure in dogs. In rats it has caused only a slight rise in the heart rate. It is believed that the hydrolysis products of I, acetic acid and hydro.gen peroxide, are responsible for the observed irritation. Re-routing the exit of air from the isolator through the lock to the exhaust system effectively removed I and its breakdown products and no evidence of irritation was then seen. 1340. Which solvent? Worthley, E. G. & Schott, C. D. (1966). Pharmacotoxic evaluation of nine vehicles administered intraperitoneally to mice. Lloydia 29, 123. In acute toxicity tests of compounds insoluble in water, a suitable vehicle has to be found which does not influence the toxicity of the test compound, given parenterally. With this in mind, nine vehicles were selected and a comparison made of their intraperitoneal LDo and EDo values, which represent the highest dose without mortality.or without symptomatology, respectively. Results (ml/kg) are presented in descending order of solvent toxicity, with LDo values appearing first in brackets, as follows: ethanol (0.32; 0-1); polyethylene glycol-200 (4.6; 1.0); propylene glycol (6-8 ; 0.1); dimethylsulphoxide (6.8; 0-32); sterol diluent (100; 10); distilled water (147.0; 14.7); 0"5~o methylcellulose (147.0; 1.0); isotonic saline solution (>316.0; 21.4); 3 Yo polyvinylpyrrolidone suspended in isotonic saline solution (>316.0; 31.6). Sterol diluent consisted of 9 mg benzyl alcohol, 4 mg Tween 80, 5 mg sodium carboxymethylcellulose and 9 mg sodium chloride in 1 ml of water. These data indicate a 1000-fold range in LDo values and a 300-fold range in EDo values.
TERATOGENESIS 1341. Azathioprine: When the predictable comes off Tuchmann-Duplessis, H. & Mercier-Parot, L. (1965). Dissociation des propri~t6s antitumorales et t6ratog6nes d'un antim~tabolite des purines, l'azathioprine. C.r. Sdanc. Soc. Biol. 159. 2290.
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acid (RNA) and protein was noted. Both I and II rapidly inhibited DNA synthesis, but whereas II had little effect on the building of DNA into cell nuclei, I had a pronounced effect. II immediately reduced the ability of DNA molecules to form RNA, and so led to a depression of protein synthesis. The principal effect of I on cells is to block their ability to form DNA, while it allows their RNA-building and protein-building capacities to proceed unimpaired. [Investigating the effect of toxic agents on protein and nucleic acid synthesis in vitro or in vivo not only throws light on the mechanism of toxic action but affords a potential biochemical index of early toxic change. This approach is being actively pursued in BIBRA's newly-created Department of Biochemical Pharmacology.] TOXICOLOGY 1339. Another misleading factor in toxicity testing Heneghan, J. B. & Gates, D. F. (1966). Effects of peracetic acid used in gnotobiotics on experimental animals. Lab. Anita. Care 16, 96. Flexible film isolators used to rear germ-free animals have been widely sterilized by means of dilute solutions of peracetic acid (I). It has been observed that although rats and mice show little sign of irritation by traces of I, dogs react by agitation, whining, sneezing and eye-rubbing, and suckhng pups have died after exposure to it. I carried into the isolator on objects during a sleeve lock entry has increased heart and breathing rates and blood pressure in dogs. In rats it has caused only a slight rise in the heart rate. It is believed that the hydrolysis products of I, acetic acid and hydro.gen peroxide, are responsible for the observed irritation. Re-routing the exit of air from the isolator through the lock to the exhaust system effectively removed I and its breakdown products and no evidence of irritation was then seen. 1340. Which solvent? Worthley, E. G. & Schott, C. D. (1966). Pharmacotoxic evaluation of nine vehicles administered intraperitoneally to mice. Lloydia 29, 123. In acute toxicity tests of compounds insoluble in water, a suitable vehicle has to be found which does not influence the toxicity of the test compound, given parenterally. With this in mind, nine vehicles were selected and a comparison made of their intraperitoneal LDo and EDo values, which represent the highest dose without mortality.or without symptomatology, respectively. Results (ml/kg) are presented in descending order of solvent toxicity, with LDo values appearing first in brackets, as follows: ethanol (0.32; 0-1); polyethylene glycol-200 (4.6; 1.0); propylene glycol (6-8 ; 0.1); dimethylsulphoxide (6.8; 0-32); sterol diluent (100; 10); distilled water (147.0; 14.7); 0"5~o methylcellulose (147.0; 1.0); isotonic saline solution (>316.0; 21.4); 3 Yo polyvinylpyrrolidone suspended in isotonic saline solution (>316.0; 31.6). Sterol diluent consisted of 9 mg benzyl alcohol, 4 mg Tween 80, 5 mg sodium carboxymethylcellulose and 9 mg sodium chloride in 1 ml of water. These data indicate a 1000-fold range in LDo values and a 300-fold range in EDo values.
TERATOGENESIS 1341. Azathioprine: When the predictable comes off Tuchmann-Duplessis, H. & Mercier-Parot, L. (1965). Dissociation des propri~t6s antitumorales et t6ratog6nes d'un antim~tabolite des purines, l'azathioprine. C.r. Sdanc. Soc. Biol. 159. 2290.