PRINCIPLES OF TOXICOLOGY

the addition of classes of functional groups to organic molecules predictably influences the toxicological
properties of the molecule. For example, amines and organic acids confer irritative or corrosive
properties when added as functional groups, while alcohol, aldehyde, and ketone groups tend to
increase the potential for damage to cell membranes by precipitating and denaturing membrane
proteins at high exposure concentrations or durations.
As noted previously for CNS-depressant actions, unsaturated compounds generally are stronger
irritants than are corresponding saturated analogs. As the size of the molecule increases, the irritant
properties typically decrease and the solvent defatting action of the hydrocarbon portion becomes more
important.
Table 16.4 presents the relative potency of selected functional groups with regard to general
CNS-depressant and irritant properties. These approximate rankings rely on basic comparisons among
the unsubstituted chemical analogs and become less applicable in broader comparisons among the
larger, more complex and multisubstituted compounds.
Carcinogenicity
As with toxicological evaluation of the other potential adverse effects of solvents, the often complex
nature of industrial exposure situations complicates most objective evaluations of malignancy with
regard to a specific solvent. Thus, many occupational studies end up considering solvent exposure as
a general “risk factor” for neoplasia, but are unable to establish “cause and effect.” Some exposure
circumstances, however, more specifically may indicate a relevant human cancer risk for industrial
activities (e.g., vinyl chloride production workers, high-level benzene exposure).
With regard to nonchlorinated hydrocarbons, there is historical documentation for benzene as a
human carcinogen under some intense exposure circumstances. Multiple factors may be responsible
for the observed effects, but the prevailing conclusion is that the metabolism of benzene to a number
of reactive metabolites (e.g., epoxides) is responsible for the myelotoxicity. An alternative or complementary
hypothesis suggests that a depressant effect by benzene or its metabolites on cell-mediated
immunity may influence basic carcinogenesis. The substituted benzene analog styrene (or vinyl
benzene) also forms reactive metabolites, notably styrene oxide. Styrene, like the other substituted
benzenes, toluene and xylene, undergoes ring hydroxylation, suggesting at first glance a common
pathway through reactive and potentially cancer-causing intermediates. Although the latter two
substances generally are not considered to be carcinogenic, a limited carcinogenic potential for styrene
TABLE 16.4 Relative CNS Depressant and
Irritant Potency of Selected Organic Solvent Classes
Decreasing CNS depressant potential
Most: halogen-substituted compounds
ethers
esters
organic acids
alcohols
alkenes
Least : alkanes
Membrane and tissue irritant potential
Most: amines
organic acids
aldehydes = ketones
alcohols
Least : alkanes
16.2 BASIC PRINCIPLES 375