Superfund sites commonly contain organic solvents with neurotoxic potential. These substances include aromatic hydrocarbons, such as benzene and toluene and aliphatic hydrocarbons, such as 2-butanone (methyl ethyl ketone). Neurotic benzene derivatives, such as a 1,2- diethylbenzene (1,2-DEB) and its putative metabolite 1,2-diacetylbenzene (1,2-DAB), cause a blue-green coloration (chromogenicity) of tissues and urine. The chromogenic compound 1,2-DAB is a potent neurotoxicant that induces neuropathological changes (neurofilament-filled giant axonal swellings) comparable to those found in humans and animals repeatedly exposed to the aliphatic hydrocarbon solvent n-hexane or its keto metabolite 2,5-hexanedione (2,5-HD), respectively. In concert with components of the Analytical Core, we will use male and female young adult rats, and biochemical, analytical, and morphological methods, to test the following hypotheses: (a) that a relationship exists between the structural and toxicological properties of 1,2-DAB and 2,5-HD, (b) that the chromogenic and neurotoxic properties of 1,2-DAB are directly interrelated, (c) that 1,2-DAB is the neurotoxic metabolic of 1,2-DEB, and (d) that 2-butanone and toluene, which respectively enhance and suppress the neurotoxic potential of n-hexane by altering its metabolism to 2,5-HD, modulate the neurotoxic potency of 1,2-DEB by altering its metabolism to 1,2-DAB. The major goal of this research project is to determine if the urinary chromogen (known to form in humans as well as rodents) can be used as a sensitive and specific biomarker of exposure to, and impending neuropathic effect of, aromatic hydrocarbons with neurotoxic potential. This biomarker may prove to be less invasive and more sensitive than an existing red blood cell spectrin-based biomarker of exposure to aliphatic gamma-diketones (2,5-HD). This project will also support studies in a companion research project (see Withers and Wallace, A4) that seek to determine if 1,2-DAB impacts brain development and plasticity. The long-term objective is to develop an ultra-sensitive biomarker of exposure to non-chlorinated organic solvents that can be used to identify individuals/populations at risk for neurotoxicity.
Showing the most recent 10 out of 47 publications
