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More about propylene glycol in animal experimentation
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Antioxidants
it has been assumed that the alcohol poses no genetic Although the pharmacological effects of propylene hazard. That this view may not be wholly justified glycol (l,2-propanediol; P G ) a r e slight, warnings have is indicated by the study cited above, which shows been given that the possible interference of this solthat under certain conditions ethanol can act as a vent in the results of pharmacological testing should mutagen. not be completely discounted (Cited in F.C.T. 1972, Male mice were given 0.1 ml of 40 or 60% ethanol 10, 715). The authors cited above have reported sigby gastric intubation on three consecutive days and nificant effects from PG used as a solvent for comwere then mated with untreated females. The litter pounds that are metabolized by the hepatic micrososizes following matings on days 14-17 after ethanol mal enzymes. treatment differed significantly from those in the conMicrosomal preparations from the livers of rats trol (water-treated) group, the mean value being 4.4 treated ip with 4 ml PG/kg twice daily for 3 days compared with a control mean of 7.8. A two- to four- showed a significant increase in their ability to metafold increase in the number of dead implantations bolize aniline and p-nitroanisole in vitro. Aminopyrine was found in females mated 4-13 days after ethanol demethylation, however, was significantly reduced. treatment of the males, and this was associated with The metabolism of p-nitrobenzoic acid was not a proportional decrease in the number of live • affected. When given at a dose level of 1, 2 or 6 ml/kg, embryos. The calculated dominant lethal mutation in- P G had less effect on the metabolism of aniline and dex was increased for matings taking place between p-nitroanisole than at 4 ml/kg. Aminopyrine demethydays 1 and 13 in the group treated with 40% ethanol, lase, however, showed a progressive decrease with inwith a peak for matings on days 9-13. In the 60%- creasing dose, while p-nitrobenzoic acid metabolism ethanol group, the index increased more rapidly and showed a biphasic response, with values somewhat abruptly, with frequencies at days 4-8 and 9-13 of below the control of 2 ml/kg and slightly raised at 57.4 and 67-3, respectively, compared with 30'6 and 6 ml/kg. PG treatment of the rats did not change the 46.3 for the 40%-ethanol group at the same mating microsomal concentration of cytochrome P-450. When P G was added in vitro to isolated liver-microintervals. These figures indicate a positive dos~response somal preparations, it failed to induce the changes relationship between ethanol and dominant lethal seen after animal dosing. mutation. It also appears that ethanol induces Hexobarbitone sleeping time and zoxazolamine dominant lethal mutations both in the epididymal paralysis time were increased in rats treated with PG. spermatozoan and late spermatid stage of spermato- When phenobarbitone (75 mg/kg) was given concurgenesis, the induction being more pronounced in the rently with 4 ml PG/kg on three successive days, the latter stage. Further investigations will be required increase in metabolism of aniline and p-nitroanisole to determine whether ethanol might produce a wider was found to be additive when compared with that range of genetic effects than dominant lethal produced by either drug alone, but the depression of aminopyrine demethylation associated with PG mutation. alone was reversed by concurrent administration of phenobarbitone. Thus, despite the apparent suitability of PG for use 2902. More about propylene glycol in animal experias a solvent in animal experiments, it cannot be mentation regarded as completely inert in the rat. Its effect on Dean, Margaret E. & Stock, B. H. (1974). Propylene liver metabolism resembles that of dimethyl sulphoxglycol as a drug solvent in the study of hepatic micro- ide, and may be attributable to some physical distorsomal enzyme metabolism in the rat. Toxic. appl. tion produced in the endoplasmic reticulum of the Pharmac. 28, 44. liver.
ANTIOXIDANTS
2903. Behavioural effects of BHA and BHT Stokes, J. D & Scudder, C. L. (1974). The effect of butylated hydroxyanisole and butylated hydroxytoluene on behavioral development of mice. Dev. Psychobiol. 7, 343. The principal effect of both butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in experimental animals is a stimulation of the microsoreal enzymes of the liver, with an associated enlargement of that organ (Allen & Engblom, Fd Cosmet. Toxicol. 1972, 10, 769). However, neither this nor other adverse effect has so far been detected in rats and mice maintained on dietary levels of 0.5% BHA or BHT, and on this basis the Joint FAO/WHO Expert Committee on Food Additives has estimated
the total acceptable daily intake of BHA and/or BHT for man to be up to 0"5 mg/kg. In the study cited above, a dietary level of 0.5% BHA or BHT was fed for 3 wk to weanling mice, whose parents had been maintained on the same level of BHA or BHT during the entire mating, gestation and pre-weaning period. Assessments were then made of social behaviour, learning ability (conditioned avoidance of electric shocks in a multi-chambered climbing apparatus), aggression after a 3-wk period of isolation, orientation reflexes and psychomotor activity. BHA treatment was associated with a significant increase in exploration activity, a decrease in sleeping and self-grooming, slower learning and a decrease in the orientation reflex. BHT also decreased sleeping, increased social and isolation-induced
Antioxidants
it has been assumed that the alcohol poses no genetic Although the pharmacological effects of propylene hazard. That this view may not be wholly justified glycol (l,2-propanediol; P G ) a r e slight, warnings have is indicated by the study cited above, which shows been given that the possible interference of this solthat under certain conditions ethanol can act as a vent in the results of pharmacological testing should mutagen. not be completely discounted (Cited in F.C.T. 1972, Male mice were given 0.1 ml of 40 or 60% ethanol 10, 715). The authors cited above have reported sigby gastric intubation on three consecutive days and nificant effects from PG used as a solvent for comwere then mated with untreated females. The litter pounds that are metabolized by the hepatic micrososizes following matings on days 14-17 after ethanol mal enzymes. treatment differed significantly from those in the conMicrosomal preparations from the livers of rats trol (water-treated) group, the mean value being 4.4 treated ip with 4 ml PG/kg twice daily for 3 days compared with a control mean of 7.8. A two- to four- showed a significant increase in their ability to metafold increase in the number of dead implantations bolize aniline and p-nitroanisole in vitro. Aminopyrine was found in females mated 4-13 days after ethanol demethylation, however, was significantly reduced. treatment of the males, and this was associated with The metabolism of p-nitrobenzoic acid was not a proportional decrease in the number of live • affected. When given at a dose level of 1, 2 or 6 ml/kg, embryos. The calculated dominant lethal mutation in- P G had less effect on the metabolism of aniline and dex was increased for matings taking place between p-nitroanisole than at 4 ml/kg. Aminopyrine demethydays 1 and 13 in the group treated with 40% ethanol, lase, however, showed a progressive decrease with inwith a peak for matings on days 9-13. In the 60%- creasing dose, while p-nitrobenzoic acid metabolism ethanol group, the index increased more rapidly and showed a biphasic response, with values somewhat abruptly, with frequencies at days 4-8 and 9-13 of below the control of 2 ml/kg and slightly raised at 57.4 and 67-3, respectively, compared with 30'6 and 6 ml/kg. PG treatment of the rats did not change the 46.3 for the 40%-ethanol group at the same mating microsomal concentration of cytochrome P-450. When P G was added in vitro to isolated liver-microintervals. These figures indicate a positive dos~response somal preparations, it failed to induce the changes relationship between ethanol and dominant lethal seen after animal dosing. mutation. It also appears that ethanol induces Hexobarbitone sleeping time and zoxazolamine dominant lethal mutations both in the epididymal paralysis time were increased in rats treated with PG. spermatozoan and late spermatid stage of spermato- When phenobarbitone (75 mg/kg) was given concurgenesis, the induction being more pronounced in the rently with 4 ml PG/kg on three successive days, the latter stage. Further investigations will be required increase in metabolism of aniline and p-nitroanisole to determine whether ethanol might produce a wider was found to be additive when compared with that range of genetic effects than dominant lethal produced by either drug alone, but the depression of aminopyrine demethylation associated with PG mutation. alone was reversed by concurrent administration of phenobarbitone. Thus, despite the apparent suitability of PG for use 2902. More about propylene glycol in animal experias a solvent in animal experiments, it cannot be mentation regarded as completely inert in the rat. Its effect on Dean, Margaret E. & Stock, B. H. (1974). Propylene liver metabolism resembles that of dimethyl sulphoxglycol as a drug solvent in the study of hepatic micro- ide, and may be attributable to some physical distorsomal enzyme metabolism in the rat. Toxic. appl. tion produced in the endoplasmic reticulum of the Pharmac. 28, 44. liver.
ANTIOXIDANTS
2903. Behavioural effects of BHA and BHT Stokes, J. D & Scudder, C. L. (1974). The effect of butylated hydroxyanisole and butylated hydroxytoluene on behavioral development of mice. Dev. Psychobiol. 7, 343. The principal effect of both butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in experimental animals is a stimulation of the microsoreal enzymes of the liver, with an associated enlargement of that organ (Allen & Engblom, Fd Cosmet. Toxicol. 1972, 10, 769). However, neither this nor other adverse effect has so far been detected in rats and mice maintained on dietary levels of 0.5% BHA or BHT, and on this basis the Joint FAO/WHO Expert Committee on Food Additives has estimated
the total acceptable daily intake of BHA and/or BHT for man to be up to 0"5 mg/kg. In the study cited above, a dietary level of 0.5% BHA or BHT was fed for 3 wk to weanling mice, whose parents had been maintained on the same level of BHA or BHT during the entire mating, gestation and pre-weaning period. Assessments were then made of social behaviour, learning ability (conditioned avoidance of electric shocks in a multi-chambered climbing apparatus), aggression after a 3-wk period of isolation, orientation reflexes and psychomotor activity. BHA treatment was associated with a significant increase in exploration activity, a decrease in sleeping and self-grooming, slower learning and a decrease in the orientation reflex. BHT also decreased sleeping, increased social and isolation-induced