Effects of Inhalation Exposures to an M1-Receptor Agonist on Ventilation in Rhesus Monkeys

ABSTRACT

Information was needed on effects of possible occupational inhalation exposure to an M]-receptor agonist (xanomeline) such as might occur during the manufacturing process. Both acute and repeated inhalation exposures to xanomeline were carried out in six male rhesus monkeys using a head-dome exposure system. Exposure concentrations ranged from 0.3 to 10 mg/m³. The exposure durations were up to 2 weeks. Decreases in tidal volume and increases in respiratory frequency were both time and concentration related during acute exposures. These effects were blocked with atropine pre-treatment. Correlation with pulmonary resistance measurements in two monkeys suggested that these were bronchoconstrictive changes that increased with severity with time at a given concentration and with concentration when measured after a constant exposure time. The dose-response was relatively steep with 10 mg/m³ becoming intolerable to the monkeys after approximately 15 minutes, but no measurable effects were observed at 0.3 mg/m³ after up to 4 hours of exposure. To investigate the effects of repeated exposures, monkeys were exposed for 4 hr/day, 5 days/wk for 2 weeks to 0.0 (air only), 0.3, and 1.2 mg xanomeline/m³ of air. When compared to the air-only exposure, 0.3 mg/m³ caused no significant changes in tidal volume. in contrast, 1.2 mg/m³ caused a rapid and significant decrease in tidal volume that was sustained throughout the 4-hr exposure. A slower rise in breathing frequency also occurred. Repeated exposures did not alter the effects seen after a single exposure. It is concluded that xanomeline, a M₁ - receptor agonist, can acutely alter normal ventilation in non-human primates at airborne concentrations ≥0.6 mg/m³ and should be carefully controlled in a manufacturing environment. The no-observed-effect concentration was 0.3 mg/m³.     

Inhalation fertility and reproduction studies with O,O′-dimethylphosphorodithioate in Sprague-Dawley rats

Groups of 15 male and 35 female Sprague-Dawley rats were exposed to O,O′-dimethylphosphorodithioate (DMPDT) 6 hr/day, 5 days/week for 11 weeks. Initial target concentrations were 0, 4, 25, and 200 mg/m³. However, because of excessive toxicity, the high-exposure level was reduced to 125 mg/m³ after 8 weeks. Exposed males were cohoused with two unexposed females immediately following the exposure period and later mated to an additional two unexposed females following a 16-week recovery period. Exposed females were cohoused with untreated males, and exposures were resumed after mating and continued during gestation. Some females were terminated at midgestation to assess fertility, while others were allowed to deliver their pups. F₁ animals were terminated for histological examination or mated to assess fertility. High-exposure level F₀ males were infertile after exposures, and there was little or no recovery. The fertility of low-exposure level males was not affected, but equivocal results were obtained at the mid-exposure level. In this study, testicular lesions were observed only in high level F₀ males. However, testicular lesions were also noted in a few males exposed to 4 and 25 mg/m³ in a concurrent subchronic toxicity study. Female fertility was apparently unaffected by exposure, and no treatment-related effects were noted in males or females exposed in utero.     

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.     

Changing the dose metric for inhalation toxicity studies: Short-term study in rats with engineered aerosolized amorphous silica nanoparticles

Inhalation toxicity and exposure assessment studies for nonfibrous particulates have traditionally been conducted using particle mass measurements as the preferred dose metric (i.e., mg or μg/m³). However, currently there is a debate regarding the appropriate dose metric for nanoparticle exposure assessment studies in the workplace. The objectives of this study were to characterize aerosol exposures and toxicity in rats of freshly generated amorphous silica (AS) nanoparticles using particle number dose metrics (3.7?×?10⁷ or 1.8?×?10⁸ particles/cm³) for 1- or 3-day exposures. In addition, the role of particle size (d₅₀?=?37 or 83?nm) on pulmonary toxicity and genotoxicity endpoints was assessed at several postexposure time points. A nanoparticle reactor capable of producing, de novo synthesized, aerosolized amorphous silica nanoparticles for inhalation toxicity studies was developed for this study. SiO₂ aerosol nanoparticle synthesis occurred via thermal decomposition of tetraethylorthosilicate (TEOS). The reactor was designed to produce aerosolized nanoparticles at two different particle size ranges, namely d₅₀?=?～30?nm and d₅₀?=?～80?nm; at particle concentrations ranging from 10⁷ to 10⁸ particles/cm³. AS particle aerosol concentrations were consistently generated by the reactor. One- or 3-day aerosol exposures produced no significant pulmonary inflammatory, genotoxic, or adverse lung histopathological effects in rats exposed to very high particle numbers corresponding to a range of mass concentrations (1.8 or 86?mg/m³). Although the present study was a short-term effort, the methodology described herein can be utilized for longer-term inhalation toxicity studies in rats such as 28-day or 90-day studies. The expansion of the concept to subchronic studies is practical, due, in part, to the consistency of the nanoparticle generation method.     

Respiratory toxicity of enzyme detergent dust.

Cynomolgus monkeys exposed 6 hr daily, 5 days/week for 6 months to atmospheres containing synthetic detergent dust at 1, 10, or 100 mg/m³ together with enzyme dust at 0.001, 0.01, 0.1, or 1 mg/m³, or to the detergent dust alone at 100 mg/m³, or to the enzyme dust alone at 1 mg/m³. The enzyme was a mixture of two enzymes manufactured for use in commercial detergents: Novo Alcalase and Milezyme 8X. The mass median (aerodynamic equivalent) diameter of the dust particles was ?3 μm. No evident adverse effects were produced by any of the mixtures of 1 mg/m³ detergent dust with as much as 0.1 mg/m³ enzyme dust. The detergent dust alone at 100 mg/m³ produced gross signs of respiratory distress, pulmonary histopathological effects, and pulmonary function impairment. This impairment, measured by the nitrogen washout method, was indicative of constricted small airways. Exposure to 10 or 100 mg/m³ detergent dust together with 0.01 or 1 mg/m³ enzyme dust produced the same effects along with diminished weight gain or weight losses. The 100 mg/m³ level of detergent dust, alone and with enzyme, caused some mortality. At least one animal in each group exposed to enzyme dust had precipitating antibodies to the enzyme. Evidence of respiratory toxicity diminished greatly in animals that were held for 4 to 6 weeks after their last exposure to the dust, but single 6-hr reexposures of some of these animals reinstated many of their overt symptoms. The dust exposures had no apparent effects on total respiratory system flow resistance, diffusion capacity, hematology, clinical chemistry, urinalysis, intradermal or skin-prick challenge test results, or chest radiographs.     

Acute Head-Only Exposure of Dogs to Phosgene. Part III. Comparison of Indicators of Lung Injury in Dogs and Rats

To better understand the relevance of phosgene-induced changes in bronchoalveolar lavage (BAL) fluid protein observed in acutely exposed rats, groups of beagle dogs were similarly exposed for 30 min to phosgene using a head-only mode of exposure. The actual exposure concentrations were 9, 16.5, and 35 mg/m³, with resultant C × t products of 270, 495, and 1050 mg/m³ × min. In rats, a C × t product of 270 mg/m³ × min caused a significant elevation of protein in the bronchoalveolar lavage (BAL) fluid, while the nonlethal threshold concentration (LCt₀₁) was estimated to be 1075 mg/m³ × min. The endpoints examined in dogs focused on changes in BAL, lung weights, arterial blood gases, and lung histopathology approximately 24 h postexposure. Mortality did not occur at any C × t product. Increased lung weights and elevations in protein, soluble collagen, and polymorphonuclear leukocyte (PMN) counts in BAL were observed at 1050 mg/m³ × min with borderline changes at 495 mg/m³ × min. Following exposure to 1050 mg/m³ × min, the analysis of arterial blood gases provided evidence of a significantly decreased arterial pO₂. Histopathology revealed a mild, although distinctive, inflammatory response at the bronchoalveolar level at 495 mg/m³ × min, whereas serofibrinous exudates and edema were observed at 1050 mg/m³ × min. The magnitude of effects correlated with the individual dogs' respiratory minute volume and breathing patterns (panting). Collectively, phosgene-induced indicators of acute lung injury appeared to be characterized best by protein in BAL fluid. With regard to both the inhaled dose and the associated increase of protein in BAL, the responses obtained in dogs appear to be more similar to humans. In contrast, elevations in BAL protein occurred in rats at three-fold lower concentrations when compared to dogs. The results of this study demonstrate that the magnitude of elevations of plasma exudate in BAL fluid following acute exposure to the pulmonary irritant phosgene is markedly more pronounced in rats when compared to the dog which is considered more human-like than rats. This is believed to be associated with the higher ventilation of small rodents and with rodent-specific sensory bronchopulmonary defense reflexes.     

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.     

Inhalation Fertility and Reproduction Studies with O,O'- Dimethylphosphorodithioate in Sprague-Dawley Rats

Inhalation Fertility and Reproduction Studies with O,O'-Dimethylphosphorodithioatein Sprague-Dawley Rats. HEYDENS, W. F., AND KRONENBERG, J. M.(1989). Fundam. Appl Toxicol. 12, 62–69. Groups of 15male and 35 female Sprague-Dawley rats were exposed to 0,0'-dimethylphosphorodithioate(DMPDT) 6 hr/day, 5 days/week for 11 weeks. Initial target concentrationswere 0, 4, 25, and 200 mg/m³ However, because of excessive toxicity,the high exposure level was reduced to 125 mg/m³ after 8 weeks.Exposed males were cohoused with two unexposed females immediatelyfollowing the exposure period and later mated to an additionaltwo unexposed females following a 16-week recovery period. Exposedfemales were cohoused with untreated males, and exposures wereresumed after mating and continued during gestation. Some femaleswere terminated at midgestation to assess fertility, while otherswere allowed to deliver their pups. F₁ animals were terminatedfor histological examination or mated to assess fertility. High-exposurelevel F₀ males were infertile after exposures, and there waslittle or no recovery. The fertility of low-exposure level maleswas not affected, but equivocal results were obtained at themid-exposure level. In this study, testicular lesions were observedonly in high level F₀ males. However, testicular lesions werealso noted in a few males exposed to 4 and 25 mg/³ in a concurrentsubchronic toxicity study. Female fertility was apparently unaffectedby exposure, and no treatment-related effects were noted inmales or females exposed in utero     

A 90-Day Inhalation Toxicity Study with Benomyl in Rats

A 90-Day Inhalation Toxiaty Study with Benomyl in Rats. WARHEIT,D. B., KELLY, D. P., CARAKOSTAS, M. C., AND SINGER, A. W. (1989).Fundam Appl Toxicol./ 12, 333-345. Benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate,CAS Registry No. 17804-35-2] is a fungicide and the possibilityfor inhalation exposure exists for field workers. To assessthe toxicity of benomyl, groups of 20 male and 20 female CDrats were exposed nose-only 6 hr a day, 5 days a week, to concentrationsof 0, 10, 50 or 200 mg/m³ of a benomyl atmosphere. At the midpoint(approximately 45 days on test) and at the end of the exposureperiod, blood and urine samples for clinical evaluation werecollected from 10 rats/group/sex, and these animals were sacrificedfor pathological examination. Similar evaluations were performadon all remaining rats at the end of the 90-day test period.After approximately 45 days on test, compoundrelated degenerationof the olfactory epithelium was observed in all males and in8 of 10 female rats exposed to 200 mg/m³ benomyl. Two male ratsexposed to 50 mg/m³ had similar, although less severe, areasof olfactory epithelial degeneration. After approximately 90days of exposure, the remaining 10 rats/group/sex were sacrificedand examined. Of these rats, all of the males and females exposedto 200 mg/m³ had olfactory degeneration, along with 3 malesexposed to 50 mg/m³ of benomyl. No other observed lesions wereinterpreted to have been caused by the benomyl exposure. Inaddition, male rats exposed to 200 mg/m³ benomyl had depressedmean body weights compared to controls and this finding correlatedwith a reduction in food consumption. Based on pathologicalobservations, 10 mg/m³ represents the no-observable-effect level(NOEL) for the male rats, and 50 mg/m³ is the NOEL for the femalerats.     

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

ABSTRACT

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.     

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.     

Effects of inhaled aerosolized carfentanil on real-time physiological responses in mice: a preliminary evaluation of naloxone

This study examined the real-time exposure–response effects of aerosolized carfentanil (CRF) on opioid-induced toxicity, respiratory dynamics and cardiac function in mice. Unrestrained, conscious male CD-1 mice (25–30?g) were exposed to 0.4 or 4.0?mg/m³ of aerosolized CRF for 15?min (Ct?=?6 or 60?mg?min/m³) in a whole-body plethysmograph chamber. Minute volume (MV), core body temperature (T_c), mean arterial blood pressure (MAP) and heart rate (HR) were evaluated in animals exposed to CRF or sterile H₂O. Loss of consciousness and Straub tail were observed in before 1?min following initiation of exposure to 6 or 60?mg?min/m³ of CRF. Clinical signs of opioid-induced toxicity were observed in a dose-dependent manner. Exposure to 6 or 60?mg?min/m³ of CRF resulted in significant decrease in MV as compared to the controls. MAP, HR and T_c decreased 24?h in animals exposed to either 6 or 60?mg?min/m³ of CRF as compared to the controls. Post-exposure administration of naloxone (NX, 0.05?mg/kg, i.m.) did not increase the MV of animals exposed to CRF to control levels within 24?h, but decreased clinical signs of opioid-induced toxicity and the duration of respiratory depression. This is the first study to evaluate real-time respiratory dynamics and cardiac function during exposure and up to 24?h post-exposure to CRF. The evaluation of toxicological signs and respiratory dynamics following exposure to CRF will be useful in the development of therapeutic strategies to counteract the ongoing threat of abuse and overuse of opioids and their synthetic variants.     

Inhalation Toxicity of 1,3-Propanediol in the Rat

1,3-Propanediol (504-63-2) was studied to determine the potential effects following repeated inhalation exposures to rats. Rats were exposed 6 hr/day, 5 days/wk for 2 wk (9 exposures) to vapor or vapor/aerosol mixtures of either 0, 41, 650, or 1800 mg 1,3-propanediol/m³. In vivo responses were observed or measured daily. Clinical pathology and tissue pathology analyses were conducted after the 9th exposure and on half of each group following an 18-day recovery (nonexposure) period. All rats showed normal body weights. No unusual external signs of response were seen, and no deaths were encountered. Clinical pathology (blood counts, serum chemical parameters) and tissue pathology (gross pathology, organ weights, and histopathology) examinations in the 1,3-propanediol exposed rats were similar to those in the unexposed controls. The highest concentration tested, 1800 mg/m³, which was the highest concentration that could practically be generated, was the no-observed-effect level (NOEL) for this study. 1,3-Propanediol does not appear to pose a significant hazard via inhalation of either the vapor or a vapor/aerosol mixture.     

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.     

Influence of ozone on pentobarbital-induced sleeping time in mice,rats, and hamsters

Studies were conducted to investigate the effect of ozone (O₃) in prolonging pentobarbital (PEN)-induced sleeping time (S.T.). Since O₃ is a common air pollutant, an O₃-induced alteration of mechanisms of drug action could have public health implications. It was shown that a 5-hr exposure to 1960 μg O₃/m³ (1 ppm) caused an increased PEN-induced S.T. in female mice (three strains), rats, and hamsters. This response was not observed in male rats or in male mice even when the latter were exposed for 5 hr/day for 3 days. Male hamsters were affected, but less so than females. Ozone concentration and time relationships were investigated in female mice. Concentrations from 196 to 9800 μg O₃/m³ (0.1 to 5 ppm) increased PEN-induced S.T. However, as the concentration was decreased, an increasing number of daily 3-hr exposures were needed to cause an effect. Once the maximal effect was observed, further daily exposures resulted in a dissipation or a disappearance of the effect. Also, recovery occurred within 24 hr after exposure ceased. Other experiments were performed in which mice received a continuous exposure to a C × T (concentration × time) of 5, ranging from 196 μg/m³ (0.1 ppm) × 50 hr to 1960 μg/m³ (1 ppm) × 5 hr. For most of the concentrations, the magnitudes of the O₃ effects were roughly equivalent. These data are interpreted as a systemic effect of O₃ on mechanisms of the termination of action of pentobarbital.     

INHALATION TOXICITY OF 1,6-HEXAMETHYLENE DIISOCYANATE HOMOPOLYMERS (HDI-IC AND HDI-BT): Results of Subacute and Subchronic Repeated Inhalation Exposure Studies

This article addresses results of two 13-wk inhalation toxicity studies in Wistar rats with aerosolized 1,6-hexamethylene diisocyanate (HDI) homopolymers using either the isocyanurate (HDI-IC) type or biuret (HDI-BT) type. Groups of 10 rats/sex/level were exposed nose-only to breathing zone concentrations of 0.5, 3.3, and 26.4 mg HDI-IC/m³ or 0.4, 3.4, and 21.0 mg HDI-BT/m³ (MMAD = 1.4–3.3 µm). The exposure regimen was 6 h/day, 5 days/wk for 13 wk. Two control groups were used in each study; one was exposed to filtered air, and the other to the vehicle acetone. In subacute pilot studies, groups of rats were exposed under identical conditions for 3 consecutive weeks using concentrations of approximately 4, 15–18, and 77–90 mg homopolymer/m³. All studies demonstrated that adverse effects were caused by irritation-related responses occurring predominantly in the lower respiratory tract. Following subchronic exposure, compound-related effects were found only at the highest concentrations used and were confined to mild respiratory distress, marginally decreased body weights, and increased lung weights. Hematological evaluation showed a marginal increase in leukocyte counts. Pulmonary function testing revealed minimal changes indicative of increases in functional residual capacity and total lung capacity but without evidence of increased bronchial hyperreactivity to acetylcholine aerosol. Histopathology demonstrated an increased recruitment of alveolar macrophages, focal interstitial fibrosis with round-cell infiltrations, and bronchiolo-alveolar proliferations at the high-level exposure groups. The no-observable-adverse-effect levels (NOAELs) of both the 3- and 13-wk studies were in the range of 3–4 mg/m³. Appreciable differences between the two types of polyisocyanates were not observed.     

Accumulation of Nicotine in Human Hair during Long-Term Controlled Exposure to a Low Concentration of Nicotine Vapour

Abstract: Hair from 5 subjects were exposed in dynamic exposure chambers to air nicotine vapour for 72 hr or 12 months at concentrations of 200 or 5μg/m³, respectively. Nicotine in the chamber air and human hair was determined by GC/ MS. A linear accumulation of nicotine in hair was found with time for all hairs during the long-term, low concentration exposure, with individual hair nicotine uptake rate constants ranging from 0.70 to 3.75×10^?3 m³/gxhr. The corresponding hair nicotine uptake rate constants during short-term, high concentration exposure, were significantly higher, ranging from 1.35 to 15.11×10^?3 m³/gxhr, showing, however, a highly significant linear correlation with the individual long-term exposure rate constants, r²=0.9961. It is indicated that long-term hair nicotine uptake rate constants calculated from controlled exposure experiments with pure nicotine vapour are adequate for estimation of individual long-term hair accumulation of nicotine from environmental tobacco smoke even at variable and intermittent exposure. Although higher than the long-term uptake rate constants, the short-term uptake rate constants seem well fitted for a differentiation between different types of hair in their ability to adsorb nicotine also during long-term exposures. The short-term uptake rate constants might also be useful parameters for establishing a reliable cut-off limit in the hair concentration of nicotine between smokers and non-smokers which otherwise seems to be overlapping.     

Development of α2u-Globulin Nephropathy and Adrenal Medullary Pheochromocytomas in Male Rats Following Exposure to Stoddard Solvent IIC

Stoddard solvent IIC is widely used as a solvent in paints and varnishes, and for dry cleaning and other grease removal applications. Because concern exists regarding the long-term effects of occupational exposure in industrial settings, the toxicity and carcinogenicity of Stoddard solvent IIC were evaluated in male and female F344/N rats and B6C3F₁ mice. Rats and mice were exposed to 0, 138, 275, 550, 1100, or 2200 mg/m³ Stoddard solvent IIC by whole-body inhalation for 3 mo, and to 0, 138 (male rats), 550, 1100, or 2200 (female rats and male and female mice) mg/m³ for 2 yr. The kidney, liver, and adrenal medulla were targets of Stoddard solvent IIC toxicity in rats. After 3 mo of exposure, male rats developed lesions characteristic of α_2u-globulin nephropathy. Male and female rats displayed increased liver weights and/or clinical pathology changes suggestive of hepatic injury, although no accompanying histopathologic changes were observed. After 2 yr, increased incidences of adrenal medullary pheochromocytomas provided some evidence of carcinogenicity in male rats. Renal tubule adenomas were slightly increased in male rats after 2 yr, and may have been related to exposure. In mice, there was no chemical-related toxicity after 3 mo, with the exception of increased liver weights in male mice exposed to 2200 mg/m³. After 2 yr, the incidences of hepatocellular adenomas were increased in female mice exposed to 2200 mg/m³; however, these increases were marginal and associated with increases in body weight. There was no evidence of Stoddard solvent IIC carcinogenicity in female rats or male mice. In summary, inhalation exposures of Stoddard solvent IIC resulted in renal toxicity and adrenal medullary pheochromocytomas in male rats. The liver also appeared to be a site of toxicity in male and female rats and mice.     

Altered lung function in rats after subacute exposure to n-butyl isocyanate

The objectives of this study were to use pulmonary function tests, blood gas measurements and bronchoalveolar lung lavage (BAL) to characterize lesions in the respiratory tract of young adult male Wistar rats as a result of a 5-day exposure (6 h/day) to 0, 1.1, 6.2, 15 or 26 mg n-butyl isocyanate (n-BIC)/m³ air. Further objectives were to probe the diagnostic sensitivities of these procedures in comparison with more traditional evaluations (clinical observation, lung weight, histopathology). Measurements were performed during post-exposure weeks 2 and 5. Most rats exposed to 26 mg/m³ died or were sacrificed in a moribund state during post-exposure week 2. All other rats survived the exposure regimen. In rats exposed to 15 and 26 mg/m³ a significant decrease in body weight, laboured breathing, hypoactivity, nasal discharge, cyanosis, and hypothermia were observed. Pulmonary function measurements revealed increased total lung capacity (TLC) and residual volume (RV), decreased forced expiratory flow rates and quasistatic compliance in rats exposed to 26 mg/m³. At the end of the observation period rats exposed to 6.2 and 15 mg/m³ air were hyperresponsive to an acetylcholine bronchoprovocation aerosol. Arterial blood gas measurements revealed an arterial hypoxia and an increase in venous admixture, suggesting a severe mismatch of the ventilation-perfusion relationship, Biochemical and cellular components in BAL fluid (BALF) indicated a concentration dependent and protracted increase of polymorphonuclear leucocytes and further inflammatory parameters. In the 1.1 mg/m³ group BALF parameters were not significantly elevated. The major histopathological lesions of the lung were thickening of septa, emphysema, and intra-alveolar oedema in rats exposed to 26 mg/m³. Collectively, these results demonstrate obstructive and progressive lung disease with associated gas trapping and severe disturbance of the ventilation perfusion relationship which is considered to be the cause of delayed mortality. In terms of variability and sensitivity the increase in BALF parameters was most sensitive in indicating the diseased state of the lung.     

Inhalation carcinogenicity study with nickel metal powder in Wistar rats

Epidemiological studies of nickel refinery workers have demonstrated an association between increased respiratory cancer risk and exposure to certain nickel compounds (later confirmed in animal studies). However, the lack of an association found in epidemiological analyses for nickel metal remained unconfirmed for lack of robust animal inhalation studies.In the present study, Wistar rats were exposed by whole-body inhalation to 0, 0.1, 0.4, and 1.0 mg Ni/m³ nickel metal powder (MMAD = 1.8 µm, GSD = 2.4 µm) for 6 h/day, 5 days/week for up to 24 months. A subsequent six-month period without exposures preceded the final euthanasia. High mortality among rats exposed to 1.0 mg Ni/m³ nickel metal resulted in the earlier termination of exposures in this group. The exposure level of 0.4 mg Ni/m³ was established as the MTD for the study. Lung alterations associated with nickel metal exposure included alveolar proteinosis, alveolar histiocytosis, chronic inflammation, and bronchiolar-alveolar hyperplasia.No increased incidence of neoplasm of the respiratory tract was observed. Adrenal gland pheochromocytomas (benign and malignant) in males and combined cortical adenomas/carcinomas in females were induced in a dose-dependent manner by the nickel metal exposure. The incidence of pheochromocytomas was statistically increased in the 0.4 mg Ni/m³ male group. Pheochromocytomas appear to be secondary to the lung toxicity associated with the exposure rather than being related to a direct nickel effect on the adrenal glands. The incidence of cortical tumors among 0.4 mg Ni/m³ females, although statistically higher compared to the concurrent controls, falls within the historical control range; therefore, in the present study, this tumor is of uncertain relationship to nickel metal exposure.The lack of respiratory tumors in the present animal study is consistent with the findings of the epidemiological studies.