Toxicity and occupational exposure assessment for hydroprocessed esters and fatty acids (HEFA) alternative jet fuels.

The U.S. Air Force (USAF) has pursued development of alternative fuels to augment or replace petroleum-based jet fuels. Hydroprocessed esters and fatty acids (HEFA) renewable jet fuel is certified for use in commercial and USAF aircraft. HEFA feedstocks include camelina seed oil (Camelina sativa, HEFA-C); rendered animal fat (tallow, HEFA-T); and mixed fats and oils (HEFA-F). The aim of this study was to examine potential toxic effects associated with HEFA fuels exposures. All 3 HEFA fuels were less dermally irritating to rabbits than petroleum-derived JP-8 currently in use. Inhalation studies using male and female Fischer-344 rats included acute (1 day, with and without an 11-day recovery), 5-, 10- or 90-day durations. Rats were exposed to 0, 200, 700 or 2000 mg/m3 HEFA-F (6 hr/day, 5 days/week). Acute, 5 - and 10-day responses included minor urinalysis effects. Kidney weight increases might be attributed to male rat specific hyaline droplet formation. Nasal cavity changes included olfactory epithelial degeneration at 2000 mg/m3. Alveolar inflammation was observed at ≥700 mg/m3. For the 90-day study using HEFA-C, no significant neurobehavioral effects were detected. Minimal histopathological effects at 2000 mg/m3 included nasal epithelium goblet cell hyperplasia and olfactory epithelium degeneration. A concurrent micronucleus test was negative for evidence of genotoxicity. All HEFA fuels were negative for mutagenicity (Ames test). Sensory irritation (RD50) values were determined to be 9578 mg/m3 for HEFA-C and greater than 10,000 mg/m3 for HEFA-T and HEFA-F in male Swiss-Webster mice. Overall, HEFA jet fuel was less toxic than JP-8. Occupational exposure levels of 200 mg/m3 for vapor and 5 mg/m3 for aerosol are recommended for HEFA-based jet fuels.

Incorporation of in vitro metabolism data and physiologically based pharmacokinetic modeling in a risk assessment for chloroprene.

Objective: To develop a physiologically based pharmacokinetic (PBPK) model for chloroprene in the mouse, rat and human, relying only on in vitro data to estimate tissue metabolism rates and partitioning, and to apply the model to calculate an inhalation unit risk (IUR) for chloroprene.Materials and methods: Female B6C3F1 mice were the most sensitive species/gender for lung tumors in the 2-year bioassay conducted with chloroprene. The PBPK model included tissue metabolism rate constants for chloroprene estimated from results of in vitro gas uptake studies using liver and lung microsomes. To assess the validity of the PBPK model, a 6-hr, nose-only chloroprene inhalation study was conducted with female B6C3F1 mice in which both chloroprene blood concentrations and ventilation rates were measured. The PBPK model was then used to predict dose measures - amounts of chloroprene metabolized in lungs per unit time - in mice and humans.Results: The mouse PBPK model accurately predicted in vivo pharmacokinetic data from the 6-hr, nose-only chloroprene inhalation study. The PBPK model was used to conduct a cancer risk assessment based on metabolism of chloroprene to reactive epoxides in the lung, the target tissue in mice. The IUR was over100-fold lower than the IUR from the EPA Integrated Risk Information System (IRIS), which was based on inhaled chloroprene concentration. The different result from the PBPK model risk assessment arises from use of the more relevant tissue dose metric, amount metabolized, rather than inhaled concentrationDiscussion and conclusions: The revised chloroprene PBPK model is based on the best available science, including new test animal in vivo validation, updated literature review and a Markov-Chain Monte Carlo analysis to assess parameter uncertainty. Relying on both mouse and human metabolism data also provides an important advancement in the use of quantitative in vitro to in vivo extrapolation (QIVIVE). Inclusion of the best available science is especially important when deriving a toxicity value based on species extrapolation for the potential carcinogenicity of a reactive metabolite.

Toxicity and occupational exposure assessment for Fischer-Tropsch synthetic paraffinic kerosene.

Fischer-Tropsch (FT) Synthetic Paraffinic Kerosene (SPK) jet fuel is a synthetic organic mixture intended to augment petroleum-derived JP-8 jet fuel use by the U.S. armed forces. The FT SPK testing program goal was to develop a comparative toxicity database with petroleum-derived jet fuels that may be used to calculate an occupational exposure limit (OEL). Toxicity investigations included the dermal irritation test (FT vs. JP-8 vs. 50:50 blend), 2 in vitro genotoxicity tests, acute inhalation study, short-term (2-week) inhalation range finder study with measurement of bone marrow micronuclei, 90-day inhalation toxicity, and sensory irritation assay. Dermal irritation was slight to moderate. All genotoxicity studies were negative. An acute inhalation study with F344 rats exposed at 2000 mg/m3 for 4 hr resulted in no abnormal clinical observations. Based on a 2-week range-finder, F344 rats were exposed for 6 hr per day, 5 days per week, for 90 days to an aerosol-vapor mixture of FT SPK jet fuel (0, 200, 700 or 2000 mg/m3). Effects on the nasal cavities were minimal (700 mg/m3) to mild (2000 mg/m3); only high exposure produced multifocal inflammatory cell infiltration in rat lungs (both genders). The RD50 (50% respiratory rate depression) value for the sensory irritation assay, calculated to be 10,939 mg/m3, indicated the FT SPK fuel is less irritating than JP-8. Based upon the proposed use as a 50:50 blend with JP-8, a FT SPK jet fuel OEL is recommended at 200 mg/m3 vapor and 5 mg/m3 aerosol, in concurrence with the current JP-8 OEL.

Strain-related differences in mouse lung gene expression over a two-year period of inhalation exposure to styrene: Relevance to human risk assessment.

Both CD-1 and C57BL/6 wildtype (C57BL/6-WT) mice show equivalent short-term lung toxicity from exposures to styrene, while long-term tumor responses are greater in CD-1 mice. We analyzed lung gene expression from styrene exposures lasting from 1-day to 2-years in male mice from these two strains, including a Cyp2f2(-/-) knockout (C57BL/6-KO) and a Cyp2F1/2A13/2B6 transgenic mouse (C57BL/6-TG). With short term exposures (1-day to 1-week), CD-1 and C57BL/6-WT mice had thousands of differentially expressed genes (DEGs), consistent with changes in pathways for cell proliferation, cellular lipid metabolism, DNA-replication and inflammation. C57BL/6-WT mice responded within a single day; CD-1 mice required several days of exposure. The numbers of exposure related DEGs were greatly reduced at longer times (4-weeks to 2-years) with enrichment only for biological oxidations in C57BL/6-WT and metabolism of lipids and lipoproteins in CD-1. Gene expression results indicate a non-genotoxic, mouse specific mode of action for short-term styrene responses related to activation of nuclear receptor signaling and cell proliferation. Greater tumor susceptibility in CD-1 mice correlated with the presence of the Pas1 loci, differential Cytochrome P450 gene expression, down-regulation of Nr4a, and greater inflammatory pathway activation. Very few exposure-related responses occurred at any time in C57BL/6-KO or -TG mice indicating that neither the short term nor long term responses of styrene in mice are relevant endpoints for assessing human risks.