Setting safe acute exposure limits for halon replacement chemicals using physiologically based pharmacokinetic modeling.
Most proposed replacements for Halon 1301 as a fire suppressant are halogenated hydrocarbons. The acute toxic endpoint of concern for these agents is cardiac sensitization. An approach is described that links the cardiac endpoint as assessed in dogs to a target arterial concentration in humans. Linkage was made using a physiologically based pharmacokinetic (PBPK) model. Monte Carlo simulations, which account for population variability, were used to establish safe exposure times at different exposure concentrations for Halon 1301 (bromotrifluoromethane), CF(3)I (trifluoroiodomethane), HFC-125 (pentafluoroethane), HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane), and HFC-236fa (1,1,1,3,3,3-hexafluoropropane). Application of the modeling technique described here not only makes use of the conservative cardiac sensitization endpoint, but also uses an understanding of the pharmacokinetics of the chemical agents to better establish standards for safe exposure. The combined application of cardiac sensitization data and physiologically based modeling provides a quantitative approach, which can facilitate the selection and effective use of halon replacement candidates.
Vinegar
A
A
AFRL/HEST, ManTech Environmental Technology, Inc., Wright-Patterson Air Force Base, PO Box 31009, Dayton, OH 45437, USA. allen.vinegar@he.wpafb.af.mil
Jepson
G W
GW
Cisneros
M
M
Rubenstein
R
R
Brock
W J
WJ
D000818:Animals; D064228:Bromochlorofluorocarbons; D005617:Chlorofluorocarbons, Methane / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D004837:Epinephrine / Q000008:administration & dosage; D005411:Flame Retardants / Q000493:pharmacokinetics* / Q000633:toxicity; D005466:Fluorocarbons / Q000493:pharmacokinetics / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006846:Hydrocarbons, Halogenated / Q000493:pharmacokinetics / Q000633:toxicity; D019570:Inhalation Exposure; D008954:Models, Biological; D009010:Monte Carlo Method; D019055:No-Observed-Adverse-Effect Level; D012995:Solubility; D023382:Toxicity Tests, Acute; D011407:Propane / Q000031:analogs & derivatives
D064228:Bromochlorofluorocarbons; D005617:Chlorofluorocarbons, Methane; D004837:Epinephrine; D005411:Flame Retardants; D005466:Fluorocarbons; D006845:Hydrocarbons, Fluorinated; D006846:Hydrocarbons, Halogenated; C105057:trifluoroiodomethane; C034013:bromotrifluoromethane; C414673:1,1,1,3,3,3-hexafluoropropane; D011407:Propane; C078256:pentafluoroethane; C094049:apaflurane