Iodotrifluoromethane Toxicity Review (2004) / Chapter Skim
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5 Physiologically Based Pharmacokinetic Modeling
5 Physiologically Based Pharmacokinetic Modeling
Pages 49-57
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From page 49... ...
This chapter discusses the application of a PBPK model to estimate blood concentrations of halocarbons after exposure to them at various concentrations. PBPK MODEL~IG OF EXPOSURE TO FIRE SUPPRESSANTS Modeling of airborne exposure to cardiac sensitizing agents requires that accounting for short-term (up to 5 mm)
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From page 50... ...
With this PBPK simulation, the authors reported that withm 5 min. the arterial blood concentration of Halon 1211 would be about 22 mgL, which is the critical blood concentration for inducing cardiac sensitization as determined in the dog.
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From page 51... ...
Use of a PBPK model to simulate human blood concentrations based on dog and rodent data is a scientifically based approach to assess human health risk from exposure to CF31 and other compounds for which human data are unavailable. With the target arterial concentration determined either experimentally or by simulation, various exposure scenarios can be exarnmea Vinegar and Jepson (1996)
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From page 52... ...
However, Monte Carlo simulations included lognormal distributions of values for each tissue partition coefficient with upper and lower limits of two geometric standard devia6Ons. Therefore, experimental deterrr.ination of human tissue partition coefficients would probably not change the model predictions as determined with rodent tissue partition coefficients.
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From page 53... ...
Based on arterial blood concentrations in dogs exposed to the cardiac-sensitrzation LOAEL bBased on cardiac-sensitization studies in dogs. "'Safe" human egress times, based on lowest measured 5-min arterial blood concentration in exposed dogs.
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From page 54... ...
Establishing egress times by using PBPK modeling predictions based on the human blood:air partition coefficients in combination with Monte Carlo simulations to account for sensitive individuals m the population adds a level of quantification to the risk assessment for the safe use of fire-suppression agents. Inthe designofcardiac-sensitizationstudies, an airborne concentra60n is selected for administration on the basis of the test compound's structural relationship with other compounds, the known acute toxicity of the compound in question, and the physical and chemical properties of the material.
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From page 55... ...
In the absence of such data, the NOAEL would be the conservative determinant for establishing egress time for fire-suppression. A validated PBPK model does exist for determining arterial blood concentrations of CF31 and other baton replacements during short-term exposure, and arterial concentrations of CF31 in dogs during the first 5 min of exposure m the absence of an epinephrine challenge are also available.
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From page 56... ...
Please comment on the use ofthese data in PBPK modeling to estimate bloodconcenfrafions, whichpose a threat to human health. The subcommittee finds that although the dog cardiac-sensitization model was developed to rank the potency of halons and not as a risk assessment tool, nevertheless, these data are available and cannot be ignored and are appropriate for use m a PBPK model.
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From page 57... ...
According to the PBPK model, people could be safely exposed at 0.4% for about 51 see before the critical blood CF31 concentration for cardiac sensitization is reached. Furthermore, people could be exposed to concentrations as high as 0.3% for more than 5 mm without reaching the critical blood concentration.
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