Toxicity of benzyl alcohol in adult and neonatal mice
Description
Benzyl alcohol (BA) is an aromatic alcohol, which is used as a bacteriostat in a variety of parenteral preparations. In 1982, it was implicated as the agent responsible for precipitating 'The Gasping Syndrome' in premature neonates To investigate further this toxicity, BA was administered, intraperitoneally, to adult and neonatal CD-1 male mice. Gross behavioral changes were monitored. Low doses ($<$800 mg/kg) produced minimal toxic effects within an initial 4 hour observation period. At the end of this time, the LD$\sb{50}$ was determined to be 1000 mg/kg for both age groups. Death was due to respiratory arrest in all cases Rapid absorption and conversion of BA to its primary metabolite, benzaldehyde, was demonstrated by gas chromatographic analysis of plasma from both experimental groups. The conversion of BA to benzaldehyde was confirmed in in vitro by using both horse-liver and mouse liver ADH The inhibition of alcohol dehydrogenase (ADH) by pyrazole was similarly demonstrated in both enzyme systems $\sp{14}$C-labelled BA was utilized to determine the distribution of BA and its metabolites in the body, and to possibly pinpoint a target organ of toxicity. Levels found in both the kidneys and liver were markedly increased, as were plasma values. This suggests the importance of metabolism in the detoxification and excretion of BA In an attempt to alter the toxicity of BA, pyrazole and disulfiram were used to inhibit the activities of ADH and aldehyde dehydrogenase, respectively. N-acetylcysteine was also utilized to investigate the possible role of the aldehyde in BA toxicity. Pretreatment with pyrazole, before BA exposure, resulted in BA levels increasing to 203% of control and toxicity to BA increasing markedly These data, along with the fact that BA plasma levels increase disproportionately relative to the dose administered, imply that the acute toxicity of BA, which includes sedation, dyspnea, and loss of motor function, is due to BA itself and not to its metabolite, benzaldehyde. Additionally, it may be suggested that the greater susceptibility of premature human neonates to BA, as proposed in 'The Gasping Syndrome', is related to an excessive body burden relative to weight, rather than to metabolic differences. (Abstract shortened with permission of author.)