|Abstract or Summary
- Hydrocarbon solvents are widely used in the production of paints,
adhesives, dyes, polymers, plastics, textiles, printing inks, agricultural products and
pharmaceuticals. While the neuropathic potential of aliphatic solvents was shown
in the 1970s, little is known about the neuropathic potential of aromatic solvents.
The present study examines such solvents, 1,2-diethylbenzene (DEB) and
its metabolite 1,2-diacetylbenzene (DAB), to determine (a) the neuropathological
evidence for peripheral neuropathy in rodents treated with 1,2-DAB, (b) the
neurochemical basis for the neurotoxic properties of this compound, and (c) the
structural requirements for nerve fiber damage. The properties of 1,2-DAB and 2,5-
hexanedione (HD) are also compared.
A key finding of this thesis is that 1,2-DAB induces a 2,5-HD-like pattern
of nerve damage of motor and sensory axons with focal swellings containing
neurofilaments. Whereas nerve damage begins distally in 2,5-HD intoxication,
with 1,2-DAB treatment axonal swellings begin intraspinally and in the proximal
ventral roots of motor nerve fibers.
A second key finding is the reactivity of 1,2-DAB with amino acids,
notably lysine, a property that is shared with 2,5-HD. 1,2-DAB and 2,5-HD react
with amino acids and proteins to form blue and yellow chromophores, respectively.
Relative to 2,5-HD, 1,2-DAB is three orders of magnitude more reactive in forming
1,2-DAB treatment of spinal cord slices in vitro and intact sciatic nerve
in vivo showed that neurofilament proteins react more readily than beta-tubulin.
The heavy and medium subunits of neurofilament protein were more reactive than
the light subunit. The reactivity of these four axonal proteins was in proportion to
their lysine content. These data are consistent with selective accumulation of
neurofilaments in giant axonal swellings.
In summary, these studies have shown a relationship between the
chromogenic and neuropathic properties of two gamma-diketones, one aliphatic
(2,5-HD) the other aromatic (1,2-DAB). These studies are relevant to occupational
and public health for at least two reasons. First, urinary chromogens generated by
neuropathic aliphatic and aromatic hydrocarbons could serve as biological markers
of exposure to solvents with neuropathic potential, and second, other chromogenic
solvents (such as tetralin) should be considered for neuropathic potential.