PRINCIPLES OF TOXICOLOGY

16.5 TOXIC PROPERTIES OF REPRESENTATIVE AROMATIC HYDROCARBON SOLVENTS 381
extreme fatigue, confusion, exhilaration, nausea, headache, and dizziness may result within a short
time. In comparison, the acute toxicity of the xylene isomers is qualitatively similar to that of toluene,
although they are less potent. In addition to considerations of occupational exposure, concern recently
has been directed toward the reports of intentional inhalant abuse of alkylbenzenes and alkylbenzenecontaining
products.
A number of indicators of industrially important exposure have been developed for the alkylbenzenes,
including urinary hippuric acid (toluene, xylenes), mandelic acid (ethylbenzene, styrene), and
phenylglyoxylic acid (styrene).
Polycyclic Aromatic Hydrocarbon (PAH) Compounds
This chemical class includes many members, all of which are cyclic-substituted benzenes. While this
group often is not commonly classed with solvents, many of the PAHs are common components of
petroleum fuels and some solvent mixtures, and are presented here for comparative purposes (see also
Figure 16.4).
The PAHs are nonpolar, lipid-soluble compounds that may be absorbed via the skin, lungs, or
digestive tract. Once absorbed, they can be concentrated in organs with a high lipid content. They
are metabolized by a subpopulation of cytochrome P450 enzymes, which they also induce. These
cytochromes are commonly referred to generically as aryl hydrocarbon hydroxylase (AHH), or
cytochrome P448. Since PAHs are composed of aromatic rings with limited available sites for
metabolism, hydroxylation is the prevalent physiological means to initiate metabolism of PAHs
to more water-soluble forms that facilitate excretion. In this process, potentially toxic and
carcinogenic epoxide metabolites may be formed. While the ubiquitous environmental presence
of the PAHs suggests that regular exposure would more commonly lead to adverse effects, other
routes of metabolism have been identified that appear to act as protective mechanisms by
degrading these reactive PAH metabolites. Similarly, natural or added constituents of foods such
as flavenoids; selenium; vitamins A, C, and E; phenolic antioxidants; and food additives (e.g.,
BHT, BHA) all can exert protective effects against these metabolites. Recent evidence indicates
that the simple, initial epoxide metabolites of PAHs are not the ultimate carcinogens because
secondary metabolites of PAHs have been shown to be more potent mutagenic and carcinogenic
agents, and because they form DNA adducts, which are more resistant to DNA-repair processes.
However, a detailed discussion of these processes is beyond the scope of this chapter. The reader
is referred to the bibliography at the end of this chapter for further references in this area, such
as the ATSDR Toxicological Profiles.
Naphthalene is the simplest member of the PAHs (two phenyl rings) and is a common fuel
component, as well as a commercial moth repellent. Naphthalene inhalation at sufficient concentration
may cause headache, confusion, nausea, and profuse perspiration. Severe exposures may cause optic
neuritis and hematuria. Cataracts have been produced experimentally following naphthalene exposure
in rabbits and at least one case has been reported in humans. Naphthalene is an irritant and
hypersensitivity has been reported, though rarely. The teratogenic and embryotoxic effects of PAHs
have only been documented for a few of the more potent, carcinogenic PAH compounds, and then only
in extreme exposure regimes in animal studies.
Figure 16.4 Naphthalene and benzo[a]pyrene.