subregions. Respiratory-tract uptake is described on a breath-by-breath basis that allows successful simulation of exhaled-breath concentration of agent during the first minute of exposure.

The model was used to simulate exposure of two persons who were trapped in an armored personnel carrier in Israel after the release of a fire extinguishing agent, Halon 1211; one of them died (Vinegar et al. 1998). The investigators re-enacted the release in an identical vehicle. They measured the Halon 1211 concentrations in various portions of the vehicle and found very high concentrations—exceeding 50,000 ppm—within 1 min of the release. Later, they used the PBPK model to simulate the arterial blood concentration at the lowest-observed-adverse-effect level (LOAEL) of Halon 1211 (1.0% or 10,000 ppm). The cardiac-sensitization LOAEL was determined with the Reinhardt et al. (1971) protocol described in Chapter 4. With this PBPK simulation, the authors reported that within 5 min, the arterial blood concentration of Halon 1211 would be about 22 mg/L, which is the critical blood concentration for inducing cardiac sensitization as determined in the dog. At 1 min, the blood concentration would be about 15 mg/L. The investigators then simulated the blood concentrations at the airborne concentrations encountered in the vehicle. In this simulation, the survivor’s arterial concentration at 1 min approached 80 mg/L, at about 20 sec it was closer to 20 mg/L. Hence, this person was able to survive the incident because escape from the vehicle was presumably very quick. For the other person, however, the arterial blood concentration rose very rapidly in the first few seconds to about 30 mg/L, which exceeded the critical blood concentration; at 1 min, the arterial blood concentration was about 170 mg/L. The person died from the exposure because his escape was impaired either because of the physical environment or because of nervous system effects (central nervous system depression) of Halon 1211. The cause of death was judged to be due to cardiac sensitization. The authors suggested that the simulation under actual exposure conditions was consistent with the model predictions when compared with the simulation conducted at the cardiac-sensitization LOAEL.

The validated PBPK model can be used to assess exposure to cardiac-sensitizing agents in a number of ways. Each method, however, depends on the determination of the critical blood concentration, typically the peak (steady-state) blood concentration resulting from exposure to the LOAEL. Such data are not often available from dog studies and less often available on humans, the target population. The most direct way to obtain them is to perform a pharmacokinetic study with arterial blood samples taken at various times during exposure. Because the exposure of interest is the threshold concentration or LOAEL, the pharmacokinetic study in dogs



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