PRINCIPLES OF TOXICOLOGY - Biology East Borneo

380 PROPERTIES AND EFFECTS OF ORGANIC SOLVENTSwith observations in humans where lethal effects are observed at about 20,000 ppm within 5–10 minof exposure. Air concentrations on the order of 250 ppm often produce vertigo, drowsiness, headache,nausea, and mucous membrane irritation. Ingested benzene exhibits comparatively greater systemictoxicity than the corresponding aliphatic homologs, and the fatal adult human dose usually is reportedto be on the order of 0.2 ml/kg (about 10–15 mL). Although CNS effects generally dominate over othersystemic toxic effects in acute exposure circumstances, cardiac sensitization and cardiac arrhythmiasalso may be observed, particularly in severe intoxication cases. Pathology observed in acutely poisonedbenzene victims includes severe respiratory irritation, pulmonary edema and hemorrhage, renalcongestion, 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 analogousalkylbenzenes) may result in lesions that resemble first- or second-degree thermal burns, and skinsensitization has been reported, though rarely. If splashed into the eyes, it may produce a transientcorneal injury.Benzene differs from most other organic solvents in that it is a myelotoxin, with effects on theblood-forming organs (e.g., marrow). The hematological findings following chronic exposure arevariable, but effects have been noted in red cell count (which may be 50 percent of normal), decreasedhemoglobin levels, reduced platelet counts, and altered leukocyte counts. The most commonly reportedeffect at significant, acute, repeated exposure is a fall in white blood cell count. In fact, in an exampleof what later was recognized to be misguided therapeutics, benzene actually was used in the early1900s to decrease numbers of circulating leukocytes in leukemia patients.Three separate stages or degrees of severity usually can be identified in the benzene-induced changein blood-forming tissues. Initially, there may be reversible blood-clotting defects, as well as a decreaseof all blood components (mild pancytopenia or aplastic anemia). With continued exposure, the bonemarrow may first become hyperplastic and a stimulation of leukocyte formation may be the earliestclinical observation. While chronic benzene exposure probably is best known for its link to specifictypes of leukemia, aplastic anemia actually is a more likely chronic observation. Several metabolitesof benzene have been implicated as the putative causative agents in these effects. Leukopenia andanemia in animals have been reported following chronic hydroquinone and pyrocatechol administration,both of which are benzene metabolites. However, the benzene syndrome has not been observedin humans exposed to phenol, hydroquinone, or catechol.Urinary phenol, expressed in conjunction with urinary creatinine, represents an acceptable measureof industrial exposure.Selected Substituted Aromatic CompoundsThe 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 vinylbenzene), cumene (or isopropylbenzene) and many others. Unlike benzene, these substances areseldom considered as carcinogens and rarely cause effects in genotoxicity assays. However, tolueneexerts a more powerful CNS-depressant effect than benzene, and human exposures at 200 ppm forperiods 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.