Effect of cytochrome P-450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female mice

The studies presented were designed to investigate the effects of cytochrome P450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female B6C3F₁ mice. Groups of female B6C3F₁ mice were exposed to dynamic atmospheres containing tetrahydrofuran (THF) concentrations of 0, 5,400 or 15,000 mg/m³ for 6 h per day, for 5 consecutive days. One-half of the animals in each THF exposure group were pretreated with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) at 100 mg/kg (i.p.) 1 h before the start of each THF exposure period. Treatment with THF at 15,000 mg/m³ caused marked microsomal enzyme induction in the liver. The cytochrome P450 content was nearly doubled (+98%), pentoxyresorufin-O-depentylase (PROD) and ethoxyresorufin-O-deethylase (EROD) activities were increased by 600% and 160%, respectively. ABT pretreatment effectively blocked microsomal enzyme induction at 15,000 mg/m³. THF exposure had no effect on the subcellular morphology of hepatocytes, whereas ABT-pretreatment caused centrilobular fatty change. THF at 15,000 mg/m³ caused increased cell proliferation in zone 3 (central vein region) of the liver (according to Rappaport), as indicated by a significantly higher PCNA (Proliferating Cell Nuclear Antigen) labelling index, but there were no effects at 5,400 ppm. ABT pretreatment prior to THF exposure at 15,000 mg/m³ caused an exacerbated proliferative response of mouse liver, significantly higher PCNA labelling indices being observed in zones 2 (midzonal region) and 3. The exacerbated proliferative response of mouse liver under conditions of inhibited THF metabolism suggests that the mitogenic effects are related to prevailing THF tissue concentrations and not to the generation of THF oxidative metabolite(s).     

Toxicological evaluation of aerosols of a tobacco extract formulation and nicotine formulation in acute and short-term inhalation studies

Abstract

A formulation of tobacco extract containing 4% nicotine (TE) and similar nicotine formulation containing vehicle and 4% nicotine (NF) were evaluated using animal inhalation assays. Two 4-h inhalation exposures at 1 and 2?mg/L aerosol exposure concentrations, respectively, of the tobacco extract with 4% nicotine formulation showed that the LC₅₀ was greater than 2?mg/L, the maximum concentration tested. All inhalation exposures were conducted using the capillary aerosol generator (CAG). Increasing aerosol TPM concentrations (0, 10, 50, 200, 1000?mg/m³ TE and 0, 50, 200, 500, 1000?mg/m³ NF) were generated via the CAG and used to expose groups of male and female rats for 4-h per day for 14 days. In life monitors for potential effects included clinical observations, weekly body weights and food consumption. Post mortem evaluations included gross tissue findings, hematology, clinical chemistry, serum plasma and nicotine levels, absolute and normalized organ and tissue weights, and histopathology of target organs. Treatment-related changes were observed in body weights, hematology, clinical chemistry, organ weights and histopathological findings for TE at the 200 and 1000?mg/m³ exposure levels, and in the 500 and 1000?mg/m³ exposure groups for NF. Under the conditions of these studies, the no-observed-adverse-effect level in the rat was approximately 50?mg/m³ for the TE aerosol-exposed groups, and approximately 200?mg/m³ in the NF aerosol-exposed groups.     

The inhalation toxicity of sulfolane (tetrahydrothiophene-1,1-dioxide)

The mean survival time (MST) of rats exposed to 11,000 mg of aerosolized sulfolane/m³ was 19.4 hr and all rats convulsed during the exposure. The sulfolane concentration expected to yield a MST of 24 hr was calculated to be 4700 mg/m³. After less than 24 hr of exposure, leukopenia and convulsions were observed in rats (3600 mg/m³) or squirrel monkeys (4850 mg/m³) exposed to high concentrations of aerosolized sulfolane. Six subacute exposures were conducted: one repeated exposure to 495 mg/m³ for 8 hr/day, 5 days/week for 27 exposure days and five 23 hr/day, continuous exposures of approximately 90-day duration to 200, 159, 20, 4.0, and 2.8 mg/m³. Squirrel monkeys convulsed, vomited, and died during the exposures to 495 and 200 mg/m³. Dogs convulsed, vomited, and were unusually aggressive during continuous exposure to 200 mg/m³, but not during repeated exposures to 495 mg/m³. Rodents did not convulse in any of these subacute exposures. Leukopenia and increased plasma transaminase activity were found in guinea pigs exposed to 200 mg/m³, but not those exposed to 159 mg/m³. Hemorrhagic, inflamed lungs were also observed in most animals exposed to the two highest concentrations. In this study, no overt toxic effects were noted during exposure of rats, guinea pigs, squirrel monkeys, or dogs to 20, 4.0, or 2.8 mg of sulfolane/m³.     

Propylene oxide in blood and soluble nonprotein thiols in nasal mucosa and other tissues of male Fischer 344/N rats exposed to propylene oxide vapors--relevance of glutathione depletion for propylene oxide-induced rat nasal tumors.

High concentrations of propylene oxide (PO) induced inflammation in the respiratory nasal mucosa (RNM) of rodents. Concentrations > or =300 ppm caused nasal tumors. In order to investigate if glutathione depletion could be relevant for these effects, we determined in PO exposed male Fischer 344/N rats PO in blood and soluble nonprotein SH-groups (NPSH) in RNM and other tissues. Rats were exposed once (6 h) to PO concentrations between 0 and 750 ppm, and repeatedly for up to 20 days (6 h, 5 days/week) to concentrations between 0 and 500 ppm. At the end of the exposures, PO in blood and NPSH in tissues were determined. PO in blood was dependent on concentration and duration of exposure. After the 1-day exposures, NPSH depletion was most distinctive (RNM > liver > lung). Compared to controls, NPSH levels were 43% at 50 ppm PO in RNM and 16% at > or =300 ppm in both RNM and liver. Lung NPSH fell linearly to 20% at 750 ppm. After repeated exposures over 3 and 20 days to 5, 25, 50, 300, and 500 ppm, NPSH losses were less pronounced. At both time points, NPSH were 90%, 70%, 50%, 30%, and 30% of the control values in RNM. Liver NPSH decreased to 80% and 50% at 300 and 500 ppm, respectively. After 20 days, lung NPSH declined to 70% (300 ppm) and 50% (500 ppm). We conclude that continuous, severe perturbation of GSH in RNM following repeated high PO exposures may lead to inflammatory lesions and cell proliferation, critical steps on the path towards tumorigenicity.     

A Phase I trial of spirogermanium administered on a continuous infusion schedule

We have evaluated the toxicity of the antitumor agent spirogermanium on a schedule of continuous intravenous administration for periods up to five days. The doses tested were between 100 mg/m²/day and 500 mg/m²/day. Peripheral vein phlebitis occurred at all dose levels and was not relieved by addition of hydrocortisone or heparin to the infusion. No phlebitis occurred when the drug was administered through a central vein. The dose limiting toxicity of spirogermanium was neurologic, notably tremors and mental confusion. These problems became progressively more severe at doses above 250 mg/m²/day. There was no discernible bone marrow, renal or hepatic toxicity. One patient developed reversible interstitial pneumonitis. The recommended Phase II dose of spirogermanium is 200 mg/m²/day for five days, with the possibility of escalation in selected patients. Because spirogermanium is more toxic to tumor cells with prolonged exposure than with intermittent exposure, this schedule could be considered for Phase II trials, particularly in diseases thought to be especially sensitive such as ovarian and prostatic carcinoma or lymphomas.     

INHALATION TOXICITY STUDIES OF AQUEOUS DISPERSION RESIN

Aqueous dispersion resin (ADR) is a water-based acrylate copolymer designed to allow a range of ethanol concentrations for hair-spray formulations. A series of inhalation (whole-body) aerosol toxicity studies, including acute, 9-day, and 90-day exposures, was conducted to determine any toxicological effects for ADR. An acute study of ADR was conducted for 4 h with a 14-day observation period. The maximum ADR aerosol concentration was 1.07 (+/- 0.04) mg/L with a mass medium aerodynamic diameter (MMAD) value of 1.46 mu m and a geometric mean (sigma_g) of 1.42. No deaths or exposure-related lesions were observed. Thus, the LC50 value was greater than 1.07 mg/L. For the 9-day study, each group contained 10 animals/sex and was exposed for 2 h/day. The mean exposure concentrations (+/- standard deviation) were 244 (+/- 39.6), 543 (+/- 71.9), and 843 (+/- 186.2) mg/m³ for the 250-, 500-, and 1000-mg/m³ groups, respectively. The mean MMADs were 2.83, 2.90, and 4.09 mu m for the 250-, 500-, and 1000-mg/m³ groups, respectively, with sigma g values ranging from 3.15 to 6.22. Unkempt fur and alopecia in the males and females from the 1000-mg/m³ group at sacrifice were the only exposure-related clinical signs observed. Increased lung weights in the 500- and 1000-mg/m³ exposure groups were found. Histopathological effects, such as alveolar histiocytosis and interstitial pneumonitis, were also noted in these two exposure groups. For the 90-day study, 10 animals per sex were included in each group with a 6-wk recovery group of 5 female rats/group. Exposures were conducted for 2 h/day. The mean exposure concentrations were 30.4 (+/- 2.3), 102 (+/- 11.6), and 308 (+/- 19.3) mg/m³ with mean MMADs of 3.09, 2.64, and 2.67 mu m and sigma_g values ranging from 3.54 to 3.90 for exposure concentrations of 30, 100, and 300 mg/m³, respectively. The only findings at the 90-day sacrifice were increased lung weights for the males and females in the 300-mg/m³ group and males in the 100-mg/m³ group. For the 6- wk recovery sacrifice of the females, the lung weights for the 300- and 100-mg/m³ groups were increased. Histopathological effects at the 90-day sacrifice included alveolar histiocytosis and lymphadenitis in the mediastinal lymph nodes in the 100- and 300-mg/m³ exposure groups for males and females, while alveolar histiocytosis, intraalveolar cellular debris, lymphadenitis in the mediastinal lymph nodes, and/or interstitial pneumonitis were noted in these 2 exposure groups of the females after the 6-wk recovery period. Animals exposed for 90 days to 100 and 300 mg/m³ for 2 h had increased lung weights. However, no effects were observed in the 30-mg/m³ exposure group. Thus, under the conditions of the present 90-day study, a no-observable-effect level (NOEL) was found to be 30 mg/m³.     

Inhalation Toxicity of Methylglutaronitrile in Rats

Abstract

Methylglutaronitrile (MGN) is a high-boiling (263°C) solvent/intermediate used in the fiber industry. Twenty male rats per group were exposed nose-only to condensation aerosol/vapor concentrations of approximately either 5, 25, or 200 mg/m³ of MGN for 6 h/day, 5 days/week over a 4-week period. Ten rats/group were sacrificed one day after the final exposure and the remaining rats after a four-week recovery period. No effects were observed in clinical observations during the exposure period, but body-weight depression was observed in the 200 mg/m³ group. The 200 mg/m³ group showed minimal decreases in red blood cell count, hemoglobin, and hematocrit values accompanied by increases in reticulocytes. There were no other effects observed in clinical or pathologic evaluations in the study. A neurobehavioral battery of tests (including grip strength, functional observational battery, and motor activity tests) given at the end of the exposure and recovery periods showed no MGN effects. During the 4-week recovery, body weights in the 200 mg/m³ group returned to normal and the hematologic findings in all groups were normal. Based on the above findings of body weight depression at 200 mg/m³, the no-observed-adverse-effect level (NOAEL) for this study was considered to be 25 mg/m³.     

Exposure assessment of workplaces manufacturing nanosized TiO2 and silver

With the increased production and widespread use of nanomaterials, human and environmental exposure to nanomaterials is inevitably increasing. Therefore, this study monitored the possible exposure to nanoparticles at workplaces that manufacture nano-TiO₂ and nano-silver. To estimate the potential exposure of workers, personal sampling, area monitoring, and real-time monitoring using a scanning mobility particle sizer (SMPS) and dust monitor were conducted at workplaces where the workers handle nanomaterials. The gravimetric concentrations of TiO₂ ranged from 0.10 to 4.99?mg/m³, which were lower than the occupational exposure limit 10?mg/m³ set by the Korean Ministry of Labor or American Conference of Governmental Industrial Hygienists (ACGIH). Meanwhile, the silver metal concentrations ranged from 0.00002 to 0.00118?mg/m³, which were also lower than the silver dust 0.1?mg/m³ and silver soluble compound 0.01?mg/m³ occupational exposure limits set by the ACGIH. The particle number concentrations at the nano-TiO₂ manufacturing workplaces ranged from 11,418 to 45,889 particles/cm³ with a size range of 15–710.5?nm during the reaction, although the concentration decreased to 14,000 particles/cm³ when the reaction was stopped. The particle concentrations at the TiO₂ manufacturing workplaces increased during the reactor and vacuum pump operations, and during the collection of the synthesized TiO₂ particles. Similarly, the particle concentrations at the silver nanoparticle manufacturing workplaces increased when the sodium citrates were weighed or reacted with the silver nitrates, and during the cleaning of the workplace. The number of silver nanoparticles in the samples obtained from the workplace manufacturing silver nanoparticles using induced coupled plasma ranged from 57,789 to 2,373,309 particles/cm³ inside the reactor with an average size of 20–30?nm and 535–25,022 particles/cm³ with a wide range of particle sizes due to agglomeration or aggregation after the release of nanoparticles into the workplace air. In contrast, the silver nanoparticles manufactured by the wet method ranged from 393 to 3526 particle/cm³ with an average size of 50?nm. Thus, when taken together, the TiO₂ and silver nanoparticle concentrations were relatively lower than existing occupational exposure limits.     

Pulmonary hypofunction due to calcium carbonate nanomaterial exposure in occupational workers: a cross-sectional study

Calcium carbonate nanomaterials (nano-CaCO₃) are widely used in both manufacturing and consumer products, but their potential health hazards remain unclear. The objective of this study was to survey workplace exposure levels and health effects of workers exposed to nano-CaCO₃. Personal and area sampling, as well as real-time and dust monitoring, were performed to characterize mass exposure, particle size distribution, and particle number exposure. A total of 56 workers (28 exposed workers and 28 unexposed controls) were studied in a cross-sectional study. They completed physical examinations, spirometry, and digital radiography. The results showed that the gravimetric nano-CaCO₃ concentration was 5.264?±?6.987?mg/m³ (0.037–22.192?mg/m³) at the workplace, and 3.577?±?2.065?mg/m³ (2.042–8.161?mg/m³) in the breathing zone of the exposed workers. The particle number concentrations ranged from 8193 to 39?621 particles/cm³ with a size range of 30–150?nm. The process of packing had the highest gravimetric and particle number concentrations. The particle number concentration positively correlated with gravimetric concentrations of nano-CaCO₃. The levels of hemoglobin, creatine phosphokinase (CK), lactate dehydrogenase, and high-density lipoprotein cholesterol (HDL-C) in the nano-CaCO₃ exposure group increased significantly, but the white blood cell count (WBC), Complement 3 (C3), total protein (TP), uric acid, and creatinine (CREA) all decreased significantly. The prevalence rate of pulmonary hypofunction was significantly higher (p?=?0.037), and the levels of vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, peak expiratory flow and forced expiratory flow 25% (FEF 25%), FEF 25–75% were negatively correlated with gravimetric concentrations of nano-CaCO₃ (p?3 exposure level was associated with pulmonary hypofunction (p?=?0.005). Meanwhile, a dose-effect relationship was found between the accumulated gravimetric concentrations of nano-CaCO₃ and the prevalence rate of pulmonary hypofunction (p?=?0.048). In conclusion, long-term and high-level nano-CaCO₃ exposure can induce pulmonary hypofunction in workers. Thus, lung function examination is suggested for occupational populations with nano-CaCO₃ exposure. Furthermore, future health protection efforts should focus on senior workers with accumulation effects of nano-CaCO₃ exposure.     

Human experimental exposure study on the uptake and urinary elimination of <Emphasis Type="Italic">N</Emphasis>-methyl-2-pyrrolidone (NMP) during simulated workplace conditions

A human experimental study was carried out with 16 volunteers to examine the elimination of N-methyl-2-pyrrolidone (NMP) after exposure to the solvent under simulated workplace conditions. The NMP concentrations were 10, 40 and 80 mg/m³ for 2 × 4 h with an exposure-free interval of 30 min. Additionally, a peak exposure scenario (25 mg/m³ baseline, 160 mg/m³ peaks for 4 × 15 min, time-weighted average: 72 mg/m³) was tested. The influence of physical activity on the uptake and elimination of NMP was studied under otherwise identical exposure conditions but involving moderate workload on a bicycle ergometer (75 W for 6 × 10 min). The peak times and biological half-lives of urinary NMP and its main metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) in urine were analysed as well as the interrelationships between exposure and biomarkers. All analytes showed a close correlation between their post-shift peak concentrations and airborne NMP. An exposure to the current German workplace limit value of 80 mg/m³ under resting conditions resulted in urinary peak concentrations of 2,400 μg/L NMP, 117 mg/g creatinine 5-HNMP and 32 mg/g creatinine 2-HMSI (workload conditions: 3,400 μg/L NMP, 150 mg/g creatinine 5-HNMP, 44 mg/g creatinine 2-HMSI). Moderate workload enhanced the total uptake of NMP by approximately one third. Differences between the estimated and the observed total amount of urinary metabolites point to a significant contribution of dermal absorption on the uptake of NMP. This aspect, together with the influence of physical workload, should be considered for the evaluation of a biological limit value for NMP.     

The Pulmonary Response and Clearance of Ludox Colloidal Silica after a 4-Week Inhalation Exposure in Rats

Rats were exposed to Ludox colloidal silica (CS) at concentrationsof 0, 10, 50, and 150 mg/m³ for 6 hr/day, 5 days/week for 4weeks. Rats were killed after 4 weeks of exposure and 10 daysor 3 months post exposure (PE). The exposure concentration of10 mg/m³ Ludox CS is considered to be the no-effect concentration.There were no exposure-related clinical signs in any group.After 4 weeks exposure, lung weights were increased significantlyin rats exposed to 50 and 150 mg/m³ Ludox CS, but lung weightswere similar to those of controls at 3 months PE. After 4 weeksexposure to 50 mg/m³ Ludox CS, a slight alveolar macrophageresponse, polymorphonuclear leukocytic infiltration, and TypeII pneumocyte hyperplasia in alveolar duct regions were present.After 3 months PE, these pulmonary lesions had almost disappearedwith removal of most dust-laden alveolar macrophages (AMs).The pulmonary response to 150 mg/m³ Ludox CS was similar incharacter but increased in magnitude from that seen at 50 mg/m³At 3 months PE, most particleladen AMs had disappeared and theremaining AMs were aggregated and sharply demarcated. A fewaggregates of particle-laden AMs appeared to transform intosilicotic nodules comprising macrophages, epithelioid cells,and lymphocytic infiltration in some animals. Some silicoticnodules showed reticular fiber networks with minute collagenfiber deposition. Tracheobronchial lymph nodes were enlargedwith aggregates of particle-laden AMs and hyperplastic histiocyticcells. Lung-deposited Ludox cleared rapidly from the lungs withhalf-times of approximately 40 and 50 days for the 50 and 150mg/m³ groups, respectively.     

Generation,Sampling, and Analysis for Low-Level GB (Sarin) and GF (Cyclosarin) Vapor for Inhalation Toxicology Studies

This study tested and optimized various methodologies to generate, sample, and characterize GB and GF test atmospheres in an inhalation chamber, particularly at low vapor levels. A syringe drive/spray atomization system produced vapor concentrations at a range of 1–50 mg/m³. A saturator cell was used to generate vapor at sub-lethal concentrations ranging from 1 mg/m³ down to low levels approaching the threshold limit value time-weighted average (TLV-TWA) of 0.0001 mg/m³ for GB. Both generation techniques demonstrated the ability to produce stable vapor concentrations over extended exposure periods. This capability was important to determine sublethal nerve agent effects, such as miosis, for inhalation toxicology studies. In addition, the techniques employed for producing and maintaining low-level agent vapor would lay the foundation for testing less volatile chemical warfare agents such as VX.     

Acute and subchronic toxicity of sulfotep

Sulfotep (TEDP) was evaluated for its acute and subchronic toxicity. The oral LD₅₀ values in laboratory animals range from 3 to 30 mg/kg body weight. The most susceptible animals tested were cats and dogs. TEDP was readily absorbed by the intact skin of rats. Following oral administration of effective doses of TEDP to male rats, the cholinesterase activity in blood showed the greatest depression, which determines the poisoning symptoms, within 24 hrs after application. The antidotes atrophie, pralidoxime, and obidoxime effectively counteracted TEDP in rats and hens. The compound did not cause any neurotoxic effects in hens or any primary damaging effects on the skin and mucous membranes of rabbits.Male and female rats were maintained for 3 months on a diet containing TEDP at concentrations of 0, 5, 10, 20, and 50 ppm, respectively. Dietary levels of 50 ppm and below did not affect the appearance, behavior, weight-gain, hematological values, composition of the urine, organ weights, and morphology of organs. There was a dose-related inhibition of the blood cholinesterase activity at 20 and 50 ppm.The following inhalation LC₅₀ values were determined for rats and mice following inhalation of TEDP aerosols: 1 hr exposure: male rats 330, female rats 160, male mice 155; 4 hr exposure: male rats 59, female rats 38, male mice 40 mg/m³ air. The exposure of rats to concentrations of 0.89, 1.94, and 2.83 mg/m³, respectively, for 12 weeks, 6 hrs daily, five times weekly, resulted only in effects on the animals inhaling aerosols of the highest concentration. This group showed some edema of the lungs and a significant depression of the plasma cholinesterase activity. The results are in agreement with the established maximum allowable concentration of 0.2 mg/m³.     

m-Xylene inhalation destroys cytochrome P-450 in rat lung at low exposure

Rats were exposed to 0, 75, 150 or 300 ppm (1 ppm=1 cm³/m³=4.35 mg/m³) m-xylene for 24 h and then killed. In the lungs, the cytochrome P-450 decreased to 45, 13 and 20% of the control value with the increasing exposure intensity and the activity of 7-ethoxycoumarin O-deethylase to 70, 27 and 14%, respectively. The activity of epoxide hydrolase increased slightly after exposures both at 150 (1.6-fold) and 300 cm³/m³ (1.4-fold), while the other measured drug-metabolizing enzyme activities showed no consistent changes. The non-protein sulfhydryl group content of the lungs was not affected. The concentrations of m-xylene in blood indicated that the solvent uptake increased in the different exposure groups more than expected, based on atmospheric concentrations alone. Morphologic studies of the lungs with scanning electron microscopy showed no apparent changes after exposure to 300 cm³/m³ or after a high oral dose (2 ml/kg/day, 3 days).Inhalation exposure to m-xylene for 5 weeks (7 h/day, 4 days/week) at a concentration of 300 ppm lowered the contents of cytochrome P-450 in rat lungs to 65% and the activity of 7-ethoxycoumarin O-deethylase to 41% without any other marked effects on the other drug-metabolizing enzymes or on the levels of non-protein sulfhydryl groups.In this study, the selective destruction of cytochrome P-450 in rat lung could be shown both after acute and subacute exposures and at concentrations low enough to warrant occupational concern.     

Nasal NPSH depletion and propylene oxide uptake in the upper respiratory tract of the mouse.

Propylene oxide is a nasal toxicant and weak site-of-contact carcinogen in the mouse and rat. To aid in inhalation risk assessment of this vapor and to provide data for comparison to the rat, the current study was aimed at providing quantitative information on upper respiratory tract (URT) dosimetry of this vapor in the mouse. Toward this end, uptake efficiencies of propylene oxide were measured in the surgically isolated URT of the male B6C3F1 mouse under constant velocity inspiratory flow conditions at flow rates of 12 and 50 ml/min and exposure concentrations of 25, 50, 100, 300, or 500 ppm. URT uptake efficiencies were measured continuously during 1 h exposure; mice were terminated immediately after exposure and nasal respiratory and olfactory mucosal nonprotein sulfhydryl (NPSH) levels were determined. Propylene oxide was scrubbed with moderate efficiency in the URT, with uptake efficiencies of < or = 33 and < or = 16% at the low and high inspiratory flow rates, respectively. Uptake efficiencies were slightly (approximately 5%) higher at low (25 or 50 ppm) than high (300 or 500 ppm) exposure concentrations, suggesting that a saturable uptake pathway may exist. Nasal tissue NPSH levels were significantly depleted at exposure concentrations of 300 and 500 ppm but not at concentrations of 100 ppm or lower. Similar levels of NPSH depletion were observed in both nasal respiratory and olfactory mucosa. These data from mouse show some key differences when compared with those reported for the rat.     

Inhalation toxicity study of disk-shaped potassium octatitanate particles (Terracess TF) in rats following 90 days of aerosol exposure

Since fibrous particles such as asbestos and some man-made fibers (MMF) have been known to produce carcinogenic or fibrogenic effects, disk-shaped potassium octatitanate (POT) particles (trade name: Terracess TF) were manufactured as nonfibrous particles. A 90-day inhalation toxicity study of Terracess TF was performed to evaluate comparative inhalation toxicity of the disk shape with a fibrous shape that was previously evaluated. Four groups of 20 male and 15 female rats each were exposed to Terracess TF aerosols at concentrations of 0, 2, 10, or 50?mg/m³ for 90 days. Ten male and 10 female rats per group were sacrificed at 90 days of exposure. After 90 days of exposure, 5 male rats per group were sacrificed at 3 wk of recovery period and 4–5 male rats per group or 5 female rats per group were sacrificed at 15?wk of recovery for lung clearance and histopathology. The mass median aerodynamic equivalent diameter (MMAED) of the aerosols of test materials ranged from 2.5 to 2.9?μm. There were no test-substance-related adverse effects on clinical observations. At the end of the 90-day exposure, a slight increase in lung-to-body weight ratios was observed at 50?mg/m³ in male but not in female rats. However, lung weights were within normal limits after 3- or 15-wk recovery periods. Microscopically, inhaled Terracess TF particles were mostly phagocytized by free alveolar macrophages (AMs) in the alveolar airspaces and alveolar walls maintained normal structure at 2 and 10?mg/m³. At 50?mg/m³, some alveoli were distended and filled with aggregates of particle-laden AMs. The alveolar walls showed slight type II pneumocyte hyperplasia, but neither proliferative inflammation nor alveolar fibrosis was present at 50?mg/m³. The clearance half-times for Terracess TF were estimated to be in the order of 6 to 9?mo for the 50-mg/m³ group and 2 to 3?mo for the 10- and 2-mg/m³ groups. The lung responses and lung clearance rate were comparable to those of “nuisance” type dusts at these concentrations. Based on interpretation that aggregated particle-laden AMs in alveoli was considered to be an early histopathological sign of lung overloading, an effect level was considered to be 50?mg/m³ and no-observed-adverse-effect level (NOAEL) was 10?mg/m³. This experiment clearly demonstrated that particle morphology was considered to be an important factor to determine inhaled particle toxicity.     

Sensory irritation, pulmonary irritation, and acute lethality of a polymeric isocyanate and sensory irritation of 2,6-toleune diisocyanate

The use of monomeric and polymeric isocyanates in a wide variety of industries has been increasing. Little is known about the toxicity of polymeric isocyanates and the widely used 2,6-toluene diisocyanate (TDI) isomer. The pulmonary and sensory irritation of an aliphatic polyisocyanate (DES-N) based on hexamethylene diisocyanate (HDI) was studied in Swiss-Webster male mice during aerosol exposures in the range of 25 to 131 mg/m³. The sensory irritation of 2,6-TDI vapor was studied in the range of 0.37 to 7.6 mg/m³ (0.05 to 1.1 ppm). The aerodynamic equivalent diameter and geometric standard deviation for the DES-N aerosol were 0.6 μm and 2.4, respectively. High-speed liquid chromatography was used to determine both free HDI in DES-N and HDI in the exposure chamber. Each exposure was for 3 hr during which the tidal volume pattern and respiratory rate of groups of four mice were recorded. Unlike the monomeric isocyanates, DES-N acted predominantly as a pulmonary irritant, evoking little sensory irritation. The concentration needed to reduce the respiratory rate 50% due to pulmonary irritation was 57.1 mg/m³. The LC50, determined by counting the number of deaths within the 24 hr period following a 4-hr exposure, was 91.2 mg/m³. In groups of animals killed 2 hr after the 4-hr exposure, the concentration of DES-N needed to increase lung weight by 50% was 45 mg/m³. Based on comparisons with another pulmonary irritant, nitrogen dioxide, the maximum concentration for DES-N permitted in industry should be 1 mg/m³ with a time-weighted average for an 8-hr period of 0.5 mg/m³. From the concentration-response relationship due to sensory irritation for 2,6-TDI, the RD50 was determined to be 1.8 mg/m³ (0.26 ppm) which is close to the value of 1.4 mg/m³ (0.20 ppm) determined previously for 2,4-TDI. No pulmonary irritation was observed. For industrial applications the exposure limit for 2,4-TDI of 0.04 mg/m³ (0.006 ppm) is also suggested as appropriate for the 2,6-TDI isomer.     

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/m^3, 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.     

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC50s,Nonlethal-Threshold Concentrations,and Analysis of Breathing Patterns

Groups of young adult Wistar rats were acutely exposed to phosgene gas using a directed-flow nose-only mode of exposure. The exposure durations used were 10, 30, 60, and 240 min and the corresponding C × t products bracketed a range from 1538 to 2854 mg/m³× min. The postexposure period was 2 wk. Subgroups of rats were subjected to respiratory function measurements. With few exceptions, mortality occurred within 24 h after exposure. The median lethal concentration (LC₅₀) and the estimated nonlethal threshold concentrations (LC₀₁) for 10, 30, 60, and 240 min were 253.3 (105.3), 54.5 (29.2), 31.3 (21.1), and 8.6 (5.3) mg/m³, respectively. With regard to the fixed outcome Cⁿ× t product, the exponent n was found to be ～0.9 for both the LC₅₀ and the LC₀₁. Due to an apparent rodent-specific transient depression in ventilation, results from 10-min exposures were excluded for the calculation of average C × t products. The average LCt₅₀ (and confidence interval 95%) and LCt₀₁ were 1741 (1547–1929) mg/m³× min and 1075 mg/m³× min, respectively, with a LCt₅₀/LCt₀₁ ratio of 1.6. Respiratory function measurements revealed an increased apnea time (AT), which is typical for lower respiratory tract irritants. This response was associated with transiently decreased respiratory minute volumes. Borderline, although distinct, changes in AT occurred at 1.2 × 30 mg/m³ × min and above, which did not show evidence of recovery during a 30-min postexposure period at 47.6 × 30 mg/m³× min and above. In an ancillary study, one group of rats was exposed to 1008 mg/m³× min (at 4.2 mg/m³ for 240 min; postexposure period 4 wk). Emphasis was on the time course of nonlethal endpoints (bronchoalveolar lavage, BAL) and histopathology of the lungs of rats sacrificed at the end of the 4-wk postexposure period. The climax of BAL protein was on the first postexposure day and exceeded approximately 70 times the control without causing mortality. The changes in BAL protein resolved within 2 wk. Histopathology did not show evidence of lung remodeling or progressive, potentially irreversible changes 4 wk postexposure. In summary, the analysis of the C × t dependent mortality revealed a steep C × t mortality relationship. The C × t product in the range of the nonlethal threshold concentration (1008 mg/m³ × min) caused pulmonary injury as indicated by markedly increased protein in BAL. Changes resolved almost entirely within the 4-wk postexposure period.     

The effects of B0, B20, and B100 soy biodiesel exhaust on aconitine-induced cardiac arrhythmia in spontaneously hypertensive rats

Abstract

Context: Diesel exhaust (DE) has been shown to increase the risk of cardiac arrhythmias. Although biodiesel has been proposed as a “safer” alternative to diesel, it is still uncertain whether it actually poses less threat.

Objective: We hypothesized that exposure to pure or 20% soy biodiesel exhaust (BDE) would cause less sensitivity to aconitine-induced arrhythmia than DE in rats.

Methods: Spontaneously hypertensive (SH) rats implanted with radiotelemeters were exposed once or for 5?d (4?h) to either 50?mg/m³ (low), 150?mg/m³ (medium), or 500?mg/m³ (high) of DE (B0), 20% (B20) or 100% (B100) soy biodiesel exhaust. Arrhythmogenesis was assessed 24?h later by continuous infusion of aconitine, an arrhythmogenic drug, while heart rate (HR), and electrocardiogram (ECG) were monitored.

Results: Rats exposed once or for 5?d to low, medium, or high B0 developed arrhythmia at significantly lower doses of aconitine than controls, whereas rats exposed to B20 were only consistently sensitive after 5?d of the high concentration. B100 caused mild arrhythmia sensitivity at the low concentration, only after 5?d of exposure at the medium concentration and after either a single or 5?d at the high concentration.

Discussion and conclusions: These data demonstrate that exposure to B20 causes less sensitivity to arrhythmia than B0 and B100. This diminished effect may be due to lower irritant components such as acrolein and nitrogen oxides. Thus, in terms of cardiac health, B20 may be a safer option than both of the pure forms.