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HOME > PAST ISSUE > July-August 2013 > Article Detail


Solvents, Ethanol, Car Crashes & Tolerance

How risky is inhalation of organic solvents?

Philip J. Bushnell

Developing Tolerance

In rats, toluene metabolism can be increased four-fold during continuous exposure. However, simulations with our PBPK model showed that this increase would raise the concentration of inhaled toluene needed to elevate brain toluene concentrations to levels that increase the risk of fatal car crashes only to about 0.5 ppm.

In contrast, evidence from many studies of ethanol and several with solvents suggest that the nervous system has a surprising capacity to compensate for impairment of the cognitive and motor functions involved in driving a vehicle that are caused by these chemicals. Dynamic tolerance can develop acutely—during a single episode of intoxication—and after a series of exposures, which involves learning processes. Both of these types of tolerance to the effects of ethanol have been documented in experimental animals and in human volunteers.

In addition to metabolic tolerance, rats that were exposed to toluene for 24 hours developed acute dynamic tolerance. That is, 80 percent more toluene was needed to double their response times at the end of the 24-hour exposure than after 1 hour of exposure. However, simulations revealed that increasing the brain toluene concentration by 80 percent to account for this shift in sensitivity requires air toluene concentrations of just 0.789 ppm.

This value remains below the EPA’s RfC for toluene (1.06 ppm) and lies far below occupational exposure limits. Thus metabolic and acute dynamic tolerance, even from prolonged exposure at very high concentrations, does not increase the detrimental airborne concentration of toluene above concentrations considered “safe.” It is therefore unlikely that occasional exposure to toluene at lower concentrations would yield tolerance sufficient to protect an individual from its effects on risky behaviors like driving.

2013-07BushnellF9.jpgClick to Enlarge ImageHowever, in addition to the rapid changes in sensitivity to chemicals described above, tolerance is well known to develop with repeated exposure to a drug or chemical. This slower, adaptive process, known as “chronic” tolerance, depends heavily on learning processes. Both humans and rats can learn to overcome many of the behavioral impairments caused by ethanol and solvents; indeed, tolerant rats can perform tasks accurately under conditions of exposure that seriously impair naive ones, and this tolerance can last for weeks. However, for both ethanol and toluene, tolerance develops for the accuracy-reducing effects of intoxication but not the slowing of responses, indicating that the performance of “tolerant” animals is not completely normal. Nevertheless, it may be sufficient to reduce the impact of intoxication on complex behaviors like driving a car.

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