PRINCIPLES OF TOXICOLOGY

380 PROPERTIES AND EFFECTS OF ORGANIC SOLVENTS
with observations in humans where lethal effects are observed at about 20,000 ppm within 5–10 min
of exposure. Air concentrations on the order of 250 ppm often produce vertigo, drowsiness, headache,
nausea, and mucous membrane irritation. Ingested benzene exhibits comparatively greater systemic
toxicity than the corresponding aliphatic homologs, and the fatal adult human dose usually is reported
to be on the order of 0.2 ml/kg (about 10–15 mL). Although CNS effects generally dominate over other
systemic toxic effects in acute exposure circumstances, cardiac sensitization and cardiac arrhythmias
also may be observed, particularly in severe intoxication cases. Pathology observed in acutely poisoned
benzene victims includes severe respiratory irritation, pulmonary edema and hemorrhage, renal
congestion, and cerebral edema.
Benzene in pure liquid form is an irritating liquid that is capable of causing dermal erythema,
vesiculation, and a dry, scaly dermatitis. Prolonged dermal contact with benzene (or analogous
alkylbenzenes) may result in lesions that resemble first- or second-degree thermal burns, and skin
sensitization has been reported, though rarely. If splashed into the eyes, it may produce a transient
corneal injury.
Benzene differs from most other organic solvents in that it is a myelotoxin, with effects on the
blood-forming organs (e.g., marrow). The hematological findings following chronic exposure are
variable, but effects have been noted in red cell count (which may be 50 percent of normal), decreased
hemoglobin levels, reduced platelet counts, and altered leukocyte counts. The most commonly reported
effect at significant, acute, repeated exposure is a fall in white blood cell count. In fact, in an example
of what later was recognized to be misguided therapeutics, benzene actually was used in the early
1900s to decrease numbers of circulating leukocytes in leukemia patients.
Three separate stages or degrees of severity usually can be identified in the benzene-induced change
in blood-forming tissues. Initially, there may be reversible blood-clotting defects, as well as a decrease
of all blood components (mild pancytopenia or aplastic anemia). With continued exposure, the bone
marrow may first become hyperplastic and a stimulation of leukocyte formation may be the earliest
clinical observation. While chronic benzene exposure probably is best known for its link to specific
types of leukemia, aplastic anemia actually is a more likely chronic observation. Several metabolites
of benzene have been implicated as the putative causative agents in these effects. Leukopenia and
anemia in animals have been reported following chronic hydroquinone and pyrocatechol administration,
both of which are benzene metabolites. However, the benzene syndrome has not been observed
in humans exposed to phenol, hydroquinone, or catechol.
Urinary phenol, expressed in conjunction with urinary creatinine, represents an acceptable measure
of industrial exposure.
Selected Substituted Aromatic Compounds
The group of aliphatic substituted benzenes, also described by the term alkylbenzenes, includes toluene
(or methyl benzene) (see Figure 16.3), ethylbenzene, xylenes or dimethylbenzenes, styrene (or vinyl
benzene), cumene (or isopropylbenzene) and many others. Unlike benzene, these substances are
seldom considered as carcinogens and rarely cause effects in genotoxicity assays. However, toluene
exerts a more powerful CNS-depressant effect than benzene, and human exposures at 200 ppm for
periods of 8 h generally will produce such symptoms as fatigue lasting for several hours, weakness,
headache, and dermal paresthesia. At 400 ppm, mental confusion becomes a symptom and at 600 ppm,
Figure 16.3 Toluene and styrene.