Permissible Exposure Levels for Selected Military Fuel Vapors (1996) / Chapter Skim
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3 Toxicokinetics of Military Fuels
3 Toxicokinetics of Military Fuels
Pages 18-35
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From page 18... ...
Thus, one of the major challenges in describing the behavior of the various hydrocarbons in these fuels is predicting the effect of other present hydrocarbons on the toxicoicinetics of each highly toxic chemical.
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From page 19... ...
Dispositional determinants include, but are not limited to, those of a physiological nature, such as alveolar ventilation, cardiac output, blood flow to organs, and organ volumes. Chemical determinants of disposition inclucle partition coefficients, which describe the distribution of the VOC between blood and air or between blood and tissue at equilibrium.
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From page 20... ...
For example, for most VOC hydrocarbons, the fat/air and fat/blood partition coefficients are large compared with partition coefficients for other tissues. Experimental studies have demonstrated that fat typically contains the highest concentrations of these chemicals following exposure.
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From page 21... ...
Cytochrome-P-450-dependent reactions cover a broad spectrum of chemicals, but the major oxidative reactions catalyzed by this enzyme are aliphatic hydroxylation, aromatic hydroxylation, epoxidation, n-dealIcylation, o-clealIcylation, deamination, sulfoxiclation, and e-oxidation. Alcohol and aldehyde dehydrogenases are also important in the metabolism of many organic alcohols.
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From page 22... ...
A substantial portion of inhaled benzene is exhaled unchanged or stored temporarily in the fat of animals and humans. The dosimetr,y of benzene and its metabolites in the target tissue of bone marrow depends on the balance between activation processes, such as cytochrome-P-450-mediated enzymatic oxidation, and deactivation processes, such as conjugation and excretion.
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From page 23... ...
The major metabolic pathways of the alicy~benzenes form metabolites that have a low order of toxicity and are readily excreted. Thus, toluene is oxidized at the methyl group and a series of oxidations lead to formation of benzoic acid, which is conjugated with glycine to form hippuric acid, which is then excretecI.
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From page 24... ...
Methoxyacetic acid is the metabolite responsible for teratogenic effects of methexyethanol. It has been shown to produce the same toxic effects of methoxyethano} on the testes of male rats.
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From page 25... ...
For example, both protein-droplet accumulation and increased cell proliferation, specifically localized in the P2 segment of the proximal tubules, have been observed in male rats exposer! to 2,2,4-trimethy~pentane, a component of jet fuels ant!
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From page 26... ...
Extrapolation issues of particular concern for chemical interactions include in-vitro-to-in-vivo, high-to-Iow-dose, and animal-tohuman extrapolation. In the case of in-vitro-to-in-vivo extrapolations, many chemical interactions can be tested rapidly and with fewer animals when in vitro systems are used.
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From page 27... ...
SIMULATED TISSUE CONCEPTIONS AFTER EXPOSURE TO COMPONENTS OF MILITARY FUELS To aid the subcommittee in understanding the relationships between vapor concentrations and the accumulation of fuel components in tissue and blood, physiologically based toxicokinetic models were used to simulate the uptake ant! metabolism of two components of the fuel vapors, toluene and nhexane.
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From page 28... ...
The time courses for simulated concentrations of n-hexane and toluene in the blood and fat of a 70-Icg man during and after these simulated exposures are shown Figures 3-l through 3-4. Simulated concentrations of both nhexane and toluene rise rapidly in blooc!
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From page 29... ...
Simulated exposures were for 15 min per clay for 10 days to binary mixtures of each chemical at 900 mgim3. The lines represent the simulated time course for each chemical in fat.
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From page 30... ...
Because military fuels are a mixture of hundreds of VOCs and not just a simple binary mixture of an aliphatic and aromatic hydrocarbon, the concentration of any single VOC in tissues will be much lower than the concentrations obtained in the mocle! simulations of two representative VOCs.
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From page 31... ...
Simulated exposures were for 8 hr per day for 10 days to binary mixtures of each chemical at 150 Miami. The lines represent the simulated time course for each chemical in blood.
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From page 32... ...
The most interesting and potentially significant model predictions are the different peak concentrations of n-hexane and toluene 12 o ~ 01 I 0 ~5 m ~ ~ ~ ~ ~ ~ ~ RTEL E 8 1 ~ S{F 40 80 120 160 200 Hours After Start of First Exposure 240 280 FIGURE 3-5 Predicted blood concentrations after repeated exposure to n-hexane. Simulated exposures were for 8 hr per day for 10 days to binary mixtures of n-hexane and toluene at 150 mg!
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From page 33... ...
As noted in Figures 3-5 and 3-6, higher blood concentrations of both n-hexane and toluene are predicted following STEL exposures compared with TWA exposures. The exact opposite exposure pattern is noted for fat (Figures 3-7 and 3-~.
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From page 34... ...
Simulated exposures were for 8 hr per day for 10 days to binary mixtures of n-hexane and toluene at 150 mg/m3 (TWA) or for 15 min per day for 10 days to binary mixtures of each chemical at 900 mg!
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From page 35... ...
concentrations due to a STEL or TWA exposure. For example, the differential is much greater for n-hexane, a VOC with limited solubility, than for toluene, a VOC with greater solubility.
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