A knowledge of the toxicity of haloaldehydes is important because these compounds potentially contaminate drinking water and they are intermediates in the metabolism of liver toxins and carcinogens such as the haloethylenes. However, their toxicity is largely unknown. Aldehydes are known to directly react with amine functional groups on endogenous compounds like proteins but the presence of chlorine atoms on the alpha carbon raises the possibility of nucleophilic attack on that carbon with elimination of a chlorine ion. This could lead to crosslinking proteins.
The specific aim i s to examine the metabolism, disposition and potential interaction of chloroacealdehyde, dichloroacetaldehyde and 2-chloroacrolein in the rat and mouse. The disposition of parent compound versus total compound will be determined after oral and intravenous administration. The use of radiolabeled compounds will permit assessment of binding to tissue macromolecules both in vivo and in vitro. Products of metabolism will be identified, if possible, from excreta and after in vitro incubation with liver homogenate fractions and hepatocytes. Organ toxicity will be assessed after 30 day repeated dosing and will focus on liver, lung and any other organ which retains radioactivity as determined from the disposition studies. The toxicity will be determined from histopathology and serum enzyme indicators of liver damage and lung lavage indicators of inflammation. The toxicity and disposition should depend on the rate and route of metabolism. Inhibitors of the alcohol dehydrogenase, aldehyde dehydrogenase, mixed function oxidases, and the glutathione synthesis enzymes will be administered prior to the chloroaldehydes to examine their affect on the metabolism and toxicity of the chloroaldehydes. The exact inhibitors chosen will depend on the earlier experiments which determined the route of metabolism. For example, if the chloroaldehydes are metabolized by the mitochondria like acetaldehyde, then inhibitors of aldehyde dehydrogenase will be examined. If metabolism occurs in the microsomes, then inhibitors of mixed function oxidases will be administered. If the compounds inhibit aldehyde dehydrogenase like trichloroacetaldehyde, then enzyme isolation and purification experiments will attempt to identify the enzymes responsible for metabolism of the chloroaldehydes.
| Heinonen, J T; Sidhu, J S; Reilly, M T et al. (1996) Assessment of regional cytochrome P450 activities in rat liver slices using resorufin substrates and fluorescence confocal laser cytometry. Environ Health Perspect 104:536-43 |
| Sharpe, A L; Carter, D E (1993) Substrate specificity of rat liver aldehyde dehydrogenase with chloroacetaldehydes. J Biochem Toxicol 8:155-60 |
