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.

Reciprocal translocations in somatic and germ cells of mice chronically exposed by inhalation to ethylene oxide: implications for risk assessment.

Groups of male B6C3F1 mice were exposed by inhalation to 0, 25, 50, 100 or 200 p.p.m. ethylene oxide (EO) for up to 48 weeks (6 hours/day, 5 days/week). Animals were sacrificed at 6, 12, 24 and 48 weeks after the start of the exposure for analyses of reciprocal translocations in peripheral blood lymphocytes and germ cells. The frequency of the total chromosomal aberrations in the peripheral blood lymphocytes was significantly increased at the 100 and 200 p.p.m. exposure concentrations at the 12-week time point, at 50, 100 and 200 p.p.m. at the 24-week time point and at all EO concentrations at the 48-week time point. The frequency of stable reciprocal translocations, which can be used as biomarkers, was increased (P < 0.05) at 100 and 200 p.p.m. at the 12-week time point, at 100 and 200 p.p.m. at the 24-week time point and at 50, 100 and 200 p.p.m. at the 48-week time point. No statistically significant increase could be observed in translocation frequencies at the 6-week time point in the peripheral blood lymphocytes. The exposure-response curves were non-linear when the frequencies of translocations were plotted against EO exposure durations or against EO exposure concentrations. There was no effect of exposure concentration rate on reciprocal translocation frequency. Reciprocal translocations induced in spermatogonial stem cells (observed at the sprematocyte stage) showed significant increases in translocation frequencies over controls at all EO concentrations at 48 weeks. However, increases were small and they did not occur in a dose-responsive manner. The statistically significant increase observed at 12 weeks in the spermatocytes was equivocal. This study provides low-level chronic exposure somatic cytogenetic data generated in mice that can be used to support the shape of the tumour dose-response in rodents and humans The germ cell cytogenetic data are discussed in terms of its relevance for a threshold response for genetic effects at low exposures.

The effect of ethylene exposure on ethylene oxide in blood and on hepatic cytochrome p450 in Fischer rats.

Ethylene (74-85-1) is an important petrochemical and is produced endogenously. It is metabolized to ethylene oxide (EO) by cytochrome P450. We studied the inhibition of cytochrome P450 activity during exposure to ethylene, and verified that this inhibition was reflected in the concentration of EO in the blood. Male F344 rats were exposed to 1000, 600, and 300 ppm ethylene by nose-only inhalation for up to 6 h. Blood samples were obtained during exposure. On exposure to 600 ppm ethylene, blood EO concentration increased during the first hour of exposure and then decreased to approximately half of the peak blood concentration. A less pronounced decrease was observed at 300 ppm, and at 1000 ppm little change was observed between 10 min and 6 h of exposure. For the analysis of cytochrome P450 and isozyme-specific substrate activities, groups of four male F344 rats were removed for the collection of liver at various times after exposure to 300, 600, or 1000 ppm ethylene. At all concentrations, liver microsomal cytochrome P450 decreased during exposure. Of the various monooxygenase activities measured, 4-nitrophenol hydroxylase was the one most consistently altered, with maximal inhibition (approximately 50%) at 2 h of exposure to 1000 ppm ethylene, 4 h at 600 ppm, and 6 h at 300 ppm. Activity recovered to control levels by 6 h after exposure. Cytochrome P450 2E1 appears to be the major isoform of cytochrome P450 inhibited by exposure to ethylene, and this may explain in part the observed alteration in EO blood kinetics.

Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats.

This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identification study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD(Sprague-Dawley) rats and CD-1 mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6-16 (mice) or 6-19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no-observable-adverse-effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near-term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, significantly reduced fetal body weights per litter and increased incidences of cleft palate (classified as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study.