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PubMed1997

[An evaluation of the toxic exposure to inhalation anesthetics and disinfectants on liver function. II].

The object of the study was evaluation of the functional state of the liver of surgeons and anaesthesiologists, exposed to halothane, paradise gas and disinfectants (formaldehyde). A representative group of 107 individuals was involved, distributed into two professional groups: surgeons (AcAT, AIAT, AP, gamma-GT) was determined. The analyses were performed on "Pointe 190", USA. Increased incidence and degree of deviations in the transaminases were established; a correlation between the results from the biochemical analyses and the toxicometric records. In conclusion the established correlations "dose-effect" and "dose-response" confirmed that the liver is a critical organ under the conditions of combined effect exerted by haolthane and paradise gas.

Adult↗
PubMed1987

Effect of dose on the absorption and excretion of [14C]benzene administered orally or by inhalation in rats and mice.

The effect of dose on the absorption and excretion of [14C]benzene was studied using 13-week old male F344/N rats, Sprague-Dawley rats, and B6C3F1 mice. Gastrointestinal absorption of benzene administered by gavage was greater than 97% in these species for doses between 0.5 and 150 mg benzene/kg body wt. At oral doses below 15 mg/kg, greater than 90% of the 14C excreted was in the urine as nonethylacetate extractable material. Above 15 mg/kg, in both rats and mice, an increasing percentage of the administered benzene was exhaled unmetabolized, suggesting saturation of metabolic pathways. Above 50 mg/kg, total metabolites (as determined by 14C in the urine, feces, and carcass after 2 days) were not linearly related to administered dose. Total metabolites per unit body weight was equal in F344/N rats and B6C3F1 mice at gavage doses up to 50 mg/kg; however, total metabolites in mice did not increase at higher doses. For inhalation exposures, the percentage of inhaled benzene that was absorbed and retained during a 6-hr exposure decreased from 33 +/- 6% (mean +/- standard deviation) to 15 +/- 9% in rats, and from 50 +/- 15 to 10 +/- 2% in mice as the exposure concentration was increased from approximately 26 to 2600 micrograms/liter (10 to 1000 ppm at 615 Torr, 23 degrees C). Total metabolite formation was exponentially related to the benzene exposure concentration with one-half the maximal amount of metabolite formation occurring at 220 micrograms/liter (84 ppm) for B6C3F1 mice and 650 micrograms/liter (250 ppm) for F344/N rats. Total metabolites were higher in mice than in rats at any of the vapor concentrations used due mainly to the higher amount inhaled by mice. Saturation of overall metabolism in mice but not in rats at high doses by both routes of administration indicates species differences in metabolism of benzene.

Administration, Inhalation↗
PubMed1987

The effects of marijuana smoke on gas exchange in ovine pregnancy.

The effects of marijuana smoke on maternal respiratory rate and gas exchange were examined in nine chronically instrumented, late gestation ewes carrying singletons. The magnitude of exposure was randomly varied producing peak plasma levels of delta-9-tetrahydrocannabinol (delta-9-THC) ranging from 0 to 161 ng/ml. delta-9-THC levels, respiratory rate and arterial blood gas tensions were monitored before and for two hours after inhalational exposure. When compared to placebo, marijuana smoke produced a dose dependent and sustained decrease in maternal respiratory rate and arterial oxygen tension without evidence of either systemic acidosis or carbon dioxide retention. A logarithmic relationship was observed between the blood level of delta-9-THC and the change in respiratory rate. The change plateaued at 30% of control at levels above 80 ng/ml. However, the relationship between the blood level of delta-9-THC and the change in arterial oxygen tension had a linear fit with a maximum decrease of 45% at a blood level of 160 ng/ml. No change was detected in minute ventilation. Fetal oxygen tension fell significantly and remained depressed after maternal values had returned to control levels. We conclude that, in this species, inhalational exposure to marijuana smoke induces a prolonged maternal ventilation/perfusion imbalance and limits fetal oxygen availability by one or more mechanisms.

Animals↗
PubMed2000

1,3-butadiene: cancer, mutations, and adducts. Part II: Roles of two metabolites of 1,3-butadiene in mediating its in vivo genotoxicity.

1,3-Butadiene (BD) is carcinogenic in mice and rats, with mice being more susceptible than rats to its carcinogenic effects. 1,3-Butadiene is mutagenic in the bone marrow and spleen cells of B6C3F1 lacI transgenic mice. The goal of this research was to assess the roles of two BD metabolites, 1,2-epoxy-3-butene (BDO) and 1,2,3,4-diepoxybutane (BDO2), in the mutagenicity and mutational spectrum of the parent compound BD by determining the mutagenicity and mutational spectra of BDO and BDO2 in human and rodent cells in vitro and in vivo. In human TK6 lymphoblastoid cells (TK6 cells), BDO exposure increased the frequency of G.C-->A.T transitions and A.T-->T.A transversions (Fisher exact test; p < 0.05). The most striking difference in the type of base-substitution mutations between BDO-exposed and BDO-unexposed TK6 cells was the 19-fold increase in A.T-->T.A transversions. 1,2,3,4-Diepoxybutane increased the frequency of A.T-->T.A transversions (Fisher exact test; p < 0.05) and the frequency of deletions in exposed TK6 cells compared with unexposed controls. Exposure of Rat2 lacI transgenic fibroblasts (Rat2 cells) to BDO increased the frequency of three types of base-substitution mutations: G.C-->A.T transitions, G.C-->T.A transversions, and A.T-->T.A transversions. Exposure of Rat2 cells to BDO2-induced dose-dependent increases in micronuclei at exposure levels that apparently did not induce mutagenicity at the lacI transgene. The lack of detectable mutagenicity at the lacI transgene in Rat2 cells exposed to BDO2 probably reflects the poor recovery of large deletions by this lambda phage-based mutagenicity assay. Inhalation exposure of B6C3F1 lacI transgenic mice (lacI mice) and F344 lacI transgenic rats (lacI rats) to BDO (29.9 parts per million [ppm]; 6 hours/day; 5 days/week for 2 weeks) did not increase the lacI mutant frequency (MF) in bone marrow or spleen cells of mice and rats, but in the cells of mouse lung (a tumor target organ for BD), significant mutagenicity was observed. An increased lacI MF was also observed in the bone marrow cells of rats exposed to BDO. Inhalation exposure of lacI mice and lacI rats to BDO2 (3.8 ppm; 6 hours/day; 5 days/week for 2 weeks) did not increase the lacI MF in bone marrow or spleen cells of mice or in the spleen cells of rats. An increased lacI MF was observed in the bone marrow cells of rats exposed to BDO2. In the present study, BDO specifically induced G.C-->A.T and A.T-->T.A transversions in vitro at both the endogenous hypoxanthine phosphoribosyltransferase (hprt) gene and the lacI transgene in Rat2 cells. It also induced an increased frequency of G.C-->T.A transversions in Rat2 cells. These types of mutations also occur at an increased frequency in mice exposed to the parent compound, BD. This finding demonstrates the induction of consistent mutational types across biological systems by BDO and indicates that BDO, but not BDO2, probably has a role in mediating the mutations recovered at the lacI transgene in animals exposed to the parent compound, BD. Therefore, it is apparent that in mice exposed to BD at carcinogenic levels, BDO and BDO2 act in concert to mediate the range of genotoxic responses. These data demonstrate that certain DNA adducts (guanine or adenine) may be useful biomarkers for BD genetic effects. However, other DNA lesions that can account for BDO2-induced deletions and chromosomal alterations also need to be considered as biomarkers for BD-induced genotoxicity.

Animals↗
PubMed1987

Inhalation carcinogenesis of various alkylating agents.

A series of earlier studies showed that inhalation exposures of rats to three water-reactive electrophilic compounds produced brisk yields of nasal cancer even when the animals were exposed for only 30 days (6 hr/day X 5 day/wk). In addition, carcinogenic potencies of the compounds appeared to relate to their chemical reactivities as measured by hydrolysis rates. For a further study of this phenomenon, inhalation exposures were conducted with five additional water-reactive compounds: beta-propiolactone [(BPL) CAS: 57-57-8], methylmethane sulfonate [(MMS) CAS: 66-27-3], ethylchloroformate [(ECF) CAS: 541-41-3], dichloroacetyl chloride [(DCAC) CAS: 79-36-7], and propylene oxide [(PO) CAS: 75-56-9] on male Sprague-Dawley rats. The hydrolysis rates of these compounds span 6 orders of magnitude. The compounds were administered for 30 days (6 hr/day X 5 days/wk) with the use of exposure concentrations that were inversely proportional to the respective hydrolysis rates. With this protocol, all compounds except PO (the slowest reacting compound) produced nasal cancer in rats. The concentrations of MMS and BPL employed in the studies produced similar nasal cancer yields, indicating that the carcinogenic potencies of these compounds in rat nasal mucosa were proportional to their hydrolysis rates. The nasal cancer yields of DCAC and ECF were less than expected. DCAC hydrolyzes so rapidly at in vivo temperatures (half-life much less than 0.01 min) that it may not reach target DNA in reactive form. Why the exposures to ECF produced yields of nasal cancer not predicted by its reactivity is currently under investigation. These results combined with our earlier results demonstrate that the carcinogenic potencies of some inhaled reactive electrophilic compounds are related to their hydrolysis rates.

Acetates↗
PubMed2003

Asthma following household exposure to hydrofluoric acid.

BACKGROUND: Almost all reports of respiratory health effects of hydrofluoric acid are derived from industrial settings and usually involved massive and conspicuous exposures. In the present report we describe a case of adult-onset asthma immediately following use of a household rust stain remover that contained an 8-9% aqueous solution of hydrofluoric acid (HF). METHODS: This is a case-report. A literature search of hydrogen fluoride, and reactive airways dysfunction syndrome (RADS) was performed. RESULTS: A previously healthy 26-year-old woman developed asthma immediately following inhalation exposure to hydrofluoric acid from a household cleaner, consistent with reactive airways dysfunction syndrome. The circumstances of exposure and possible mechanism of disease are discussed. CONCLUSIONS: It is likely that this patient's use of the rust stain remover resulted in inhalation exposure to hydrofluoric acid well above any applicable standard, and hence constituted a "high level" irritant exposure capable of inducing reactive airways dysfunction syndrome. In our opinion, the presence of this concentration hydrofluoric acid in a consumer product may be unduly hazardous.

Adult↗
PubMedDate not supplied

[Measurements and environmental and biological monitoring of occupational exposure to inhalation anesthetics].

This paper reports the data of nitrous oxide (N2O) environmental pollution in 269 operating rooms of 47 hospitals in Italy in 1989-91. In 40% of the operating rooms the N2O concentrations are lower than 50 ppm, limit value proposed by Health Council for new operating rooms. In 65.4% of the operating room studied, N2O mean environmental concentrations are lower than 100 ppm, value proposed by the above-mentioned Health Council as limit value for the already existing operating rooms. Concerning the biological monitoring, the authors report several N2O data in urine (2193), whose levels confirm the data obtained with environmental monitoring. The authors believe that they presently have reliable methods to perform biological and environmental monitoring: the two techniques are complementary in the assessment of the exposure. The method of measuring N2O concentrations as exposure index, both for the environmental and biological monitoring, is considered very useful to simplify the performance of the analyses. In order to assess exposure more precisely, it is however necessary also to determine the environmental and/or biological measure of the other different anaesthetics used.

Air Pollutants, Occupational↗
PubMed1983

Tetrachloroethylene: balance and tissue distribution in male Sprague-Dawley rats by drinking-water administration.

While low levels of organic contaminants have been reported to occur in drinking water, often little information is available concerning the toxicological significance of ingestion by this route. For tetrachloroethylene, considerable animal toxicity data exist for gavage or inhalation exposure. Since extrapolation of toxicity between routes of administration implies similar pharmacokinetic disposition, the pharmacokinetics of tetrachloroethylene was examined in rats following administration in the drinking water. Tetrachloro[14C]ethylene was administered to adult, male Sprague-Dawley rats in saturated drinking water solutions (approximately 150 ppm) resulting in a mean dose of 8.1 +/- 3.1 mg/kg. Within 72 hr from termination of a 12-hr drinking exposure period, approximately 88% of the body burden was eliminated as unmetabolized parent compound in expired air. As much as 96% of the activity recovered in this form was excreted during the first 24 hr. The remaining 14C activity recovered was the result of metabolic conversion to 14CO2 (2.2%), nonvolatile metabolites in urine (7.2%) and feces (1.7%), and minor amounts (0.9%) in the carcass. Radioactivity in the carcass 72 hr following termination of the exposure period was distributed within liver, kidneys, fat, lungs, heart, and adrenals. Pulmonary elimination of unchanged tetrachloroethylene was monophasic with a calculated elimination half life of 7.1 hr. The elimination kinetics were consistent with results previously generated by both gavage and inhalation exposure. The fate of tetrachloroethylene following drinking-water administration was not substantially different from the disposition resulting from these two routes of administration.

Animals↗
PubMed1984

Biokinetics of inhaled 244Cm oxide in the rat: effect of heat treatment at 1150 degrees C.

A study was conducted in rats to determine solubility and subsequent metabolism of an inhaled aerosol of curium treated at high temperatures. Young adult Fischer-344 rats received a single inhalation exposure to one of three monodisperse aerosols of 244Cm2O3 (0.70, 1.3, or 2.6 micron activity median aerodynamic diameter) heat-treated at 1150 degrees C. Animals were maintained individually in metabolism cages for excreta collection and serially sacrificed in groups of two male and two female rats from 2 to 33 days after inhalation exposure. Additionally an injection study with curium citrate was done to define the systemic behavior of Cm in this rat model. The in vivo solubility was inversely related to the aerosol particle size. The relationship of the results of this study to results from other experimental inhalation studies with curium oxide aerosols is discussed, as is the relevance to bioassay interpretation and risk assessment in man.

Aerosols↗
PubMed1997

Monitoring and analysis of occupational exposure to chain saw exhausts.

The extent of inhalation exposure to loggers from two-stroke chain saws was measured and evaluated under various conditions. Carbon monoxide, measured by personal air monitoring and determination of carboxyhemoglobin levels of the loggers, was used as an indicator of exhaust exposure. Video recordings were made to analyze the influence of varying working conditions and the individual handling of the chain saw on the amount of pollutants inhaled. The American Conference of Governmental Industrial Hygienists biological exposure index (BEI) for carboxyhemoglobin (3.5%) was exceeded during logging in heavy timber stands. When workers were paid on a piecework basis, carboxyhemoglobinemia increased to its maximum level in the first 2-3 hours of the shift and then declined. After 8 hours carboxyhemoglobin levels were 20-30% lower compared with the maximum. Increased exhaust inhalation with short-term exposures to carbon monoxide up to 400 ppm was observed in the following conditions: (1) felling operations, (2) other operations performed in a leaning of squatting position, (3) limbing in thick tops of coniferous trees, (4) working at low wind velocity, and (5) working in thick forest stands. Maximum allowable blood concentrations for carboxyhemoglobin are exceeded in chain saw operators in logging operations. Blood sampling at the end of the workday is not always suitable for determining the highest carboxyhemoglobin levels in loggers during the shift. The exposure of chain saw operators to exhaust increases under certain conditions.

Adult↗
PubMed1990

Dermal absorption potential of industrial chemicals: criteria for skin notation.

A dermal penetration rate (flux), predicted from physical properties of 132 chemicals, is suggested as an index of the dermal absorption potential of industrial chemicals. The prediction is designed for organic nonelectrolytes. Two reference values are recommended as criteria for skin notation: 1) dermal absorption potential, which relates to dermal absorption raising the dose of nonvolatile chemicals or biological levels of volatile chemicals 30% above those observed during inhalation exposure to TLV-TWA only--dermal absorption of chemicals belonging to this category should be considered when data obtained by biological monitoring are interpreted; and 2) dermal toxicity potential, which relates to dermal absorption that triples biological levels as compared with levels observed during inhalation exposure to TLV-TWA only. Chemicals belonging in this category should carry a skin notation. The toxicity criteria may not be valid for chemicals whose TLVs are based on preventing irritation and discomfort.

Environmental Exposure↗
PubMed2005

Comparison of carcinogenic and in vivo genotoxic potency estimates.

Mutagenic substances classified as carcinogens are primarily regulated on the basis of their carcinogenic effect. Regulation of mutagens that have not been tested for carcinogenicity represents a problem. In cases where a threshold cannot be identified, the substances may be banned or if their uses are deemed to be unavoidable, the exposure may be reduced to as low as technically and economically feasible. In an attempt to develop a procedure that may be helpful in regulation of mutagenic substances when studies on carcinogenicity are lacking, we have compared the lowest effective dose (LED) giving a response in an in vivo genotoxic test after oral or inhalation exposure with the carcinogenic dose descriptor T25 (the chronic daily dose which will give 25% of the animals tumours above background at a specific tissue site). The 34 carcinogens in the present analysis for which genotoxic mechanisms are likely or possible, represent different classes of carcinogens and different genotoxic endpoints, exhibiting carcinogenic and mutagenic potencies both covering a range of 10,000 between the most and least potent substances. A linear correlation was found between the lowest effective dose for in vivo genotoxicity after oral administration or inhalation exposure and the lowest dose descriptor T25 for tumour formation. The finding that the median of the ratio LED/T25 was 1.05 and that the ratio for 90% of the substances studied fell in the range 0.21 to 9.2 shows that the numerical value of LED is similar to the numerical value of T25 within a factor of 5-10. The results suggest that LED may be used as a basis for regulation of mutagens in cases where a threshold cannot be demonstrated or inferred, and where the substance has not been studied in long-term carcinogenicity studies. In such cases LED divided by a specified assessment factor may represent a virtually safe level or a tolerable risk level for a possible carcinogenic effect.

Administration, Inhalation↗
PubMed1992

Pulmonary cellular effects in rats following aerosol exposures to ultrafine Kevlar aramid fibrils: evidence for biodegradability of inhaled fibrils.

Previous chronic inhalation studies have shown that high concentrations of Kevlar fibrils produced fibrosis and cystic keratinizing tumors in rats following 2-year inhalation exposures. The current studies were undertaken to evaluate mechanisms and to assess the toxicity of inhaled Kevlar fibrils relative to other reference materials. Rats were exposed to ultrafine Kevlar fibers (fibrils) for 3 or 5 days at concentrations ranging from 600-1300 fibers/cc (gravimetric concentrations ranging from 2-13 mg/m3). A complete characterization of the fiber aerosol and dose was carried out. These measurements included gravimetric concentrations, mass median aerodynamic diameter, fiber number, and count median lengths and diameters of the aerosol. Following exposures, cells and fluids from groups of sham- and fiber-exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase (LDH), protein, and N-acetyl glucosaminidase (NAG) values were measured in BAL fluids at several time points postexposure. Alveolar macrophages were cultured and studied for morphology, chemotaxis, and phagocytosis by scanning electron microscopy. The lungs of additional exposed animals were processed for deposition, cell labeling, retained dose, and lung clearance studies, as well as fiber dimensions (from digested lung tissue), histopathology, and transmission electron microscopy. Five-day exposures to Kevlar fibrils elicited a transient granulocytic inflammatory response with concomitant increases in BAL fluid levels of alkaline phosphatase, NAG, LDH, and protein. Unlike the data from silica and asbestos exposures where inflammation persisted, biochemical parameters returned to control levels at time intervals between 1 week and 1 month postexposure. Macrophage function in Kevlar-exposed alveolar macrophages was not significantly different from sham controls at any time period. Cell labeling studies were carried out immediately after exposure, as well as 1 week and 1 month postexposure. Increased pulmonary cell labeling was measured in terminal bronchiolar cells immediately after exposure but returned to control values 1 week later. Fiber clearance studies demonstrated a transient increase in the numbers of retained fibers at 1 week postexposure, with rapid clearance of fibers thereafter. The transient increase in the number of fibers could be due to transverse cleaving of the fibers, since the average lengths of retained fibers continued to decrease over time. In this regard, a progressive decrease in the mean lengths and diameters of inhaled fibers was measured over a 6-month postexposure period.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed2002

Metal working fluids: sub-chronic effects on pulmonary functions in B6C3F1 mice given vitamin E deficient and sufficient diets.

Metal working fluids (MWFs) have been widely known to cause asthma and neoplasia of the larynx, pancreas, rectum, skin and urinary bladder (Textbook of Clinical Occupational and Environmental Medicine (1994) 814; Am. J. Ind. Med. 32 (1997) 240; Am. J. Ind. Med. 33 (1997) 282; Am. J. Ind. Med. 22 (1994) 185). Other non-neoplastic respiratory effects in industrial workers attributed to MWFs include increased rates of cough, phlegm production, wheeze, chronic bronchitis and chest tightness (Eur. J. Resir. Dis. 63(118) (1982), 79; J. Occup. Med. 24 (1982) 473; Am. J. Ind. Med. 32 (1997) 450). The epidemic and endemic nature of immune mediated lung morbidity commonly known as hypersensitivity pneumonitis in workers from several different industries using MWFs has been well documented (J. Allergy clin. Immunol. 91 (1993) 311; Chest 108 (1995) 636; MMWR45 (1996) 606; Am. J. Ind. Med. 32 (1997) 423). We studied morphological/functional and antioxidant outcomes in lungs after inhalation exposure of vitamin E deficient mice to MWF (27 mg m(-3) 17 weeks, 5 days a week, 6 h a day). Mice were given vitamin E deficient (<10 IU kg(-1) vitamin E) or basal diets (50 IU kg(-1) vitamin E) for 35 weeks. Inhalation exposure to MWF started after 18 weeks on diet. Microscopic observation of lungs from mice given vitamin E deficient or sufficient diets revealed no inflammation or morphological alteration after exposure to MWF. Mice given vitamin E deficient diet exhibited a significant decrease (P<0.05) in breathing rate, peak inspiratory/expiratory flow, minute ventilation, and tidal volume compared with sufficient controls. However, no differences were found after exposure to MWF in pulmonary function, with the exception of tidal volume which also significantly decreased (P<0.05). Exposure to MWF reduced vitamin E, protein thiol and ascorbate level in lungs. Exposure to MWF in combination with a vitamin E deficient diet resulted in significantly enhanced accumulation of peroxidative products compared with vitamin E deficient controls. This is the first report that describes the increase of oxidative stress in the lungs after MWF exposure.

Animals↗
PubMed1992

A microscopic and ultrastructural evaluation of dibasic esters (DBE) toxicity in rat nasal explants.

Dibasic esters (DBE) solvent has been demonstrated to induce a mild degeneration of the olfactory, but not the respiratory epithelium of the rat nasal cavity following a 90-day inhalation exposure. Previous work has demonstrated that acid phosphatase release is a reliable index of DBE-induced cytotoxicity in an in vitro system of rat nasal explants. In the present study, rat nasal explants were examined microscopically and ultrastructurally following incubation in varying concentrations of a representative DBE, dimethyl adipate (DMA). DMA-induced microscopic and ultrastructural changes in rat nasal explants correlated well with biochemical perturbations associated with DBE exposure in a previous study. In both studies, olfactory epithelium was more susceptible to DMA-induced toxicity than respiratory epithelium and DMA-induced nasal toxicity was attenuated by pretreatment with a carboxylesterase inhibitor. The results of this study support the hypothesis that DBE and potentially other inhaled organic esters induce nasal toxicity via a common mechanism, carboxylesterase-mediated production of toxic acid metabolites. It was established that carboxylesterase-rich sustentacular cells are the primary target cells for DBE toxicity in rat nasal explants. It was proposed that degeneration of nasal olfactory sensory cells observed in rats following 90-day inhalation exposure to DBE may be secondary to necrosis and loss of sustentacular cells.

Acid Phosphatase↗
PubMed2001

A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies.

Nonhuman primates may be used as human surrogates in inhalation exposure studies to assess either the (1) adverse health effects of airborne particulate matter or (2) therapeutic effects of aerosolized drugs and proteins. Mathematical models describing the behavior and fate of inhaled aerosols may be used to complement such laboratory investigations. For example, the optimal conditions, in terms of ventilatory parameters (e.g., breathing frequency and tidal volume) and aerosol characteristics (e.g., geometric size and density), necessary to target drug delivery to specific sites within the respiratory tract may be estimated a priori with models. In this work a mathematical description of the rhesus monkey (Macaca mulatta) lung is presented for use with an aerosol deposition model. Deposition patterns of 0.01- to 5-microm-diameter monodisperse aerosols within lungs were calculated for 3 monkey lung models (using different descriptions of alveolated regions) and compared to human lung results obtained using a previously validated mathematical model of deposition physics. Our findings suggest that there are significant differences between deposition patterns in monkeys and humans. The nonhuman primates had greater exposures to inhaled substances, particularly on the basis of deposition per unit airway surface area. However, the different alveolar volumes in the rhesus monkey models had only minor effects on aerosol dosimetry within those lungs. By being aware of such quantitative differences, investigators can employ the respective primate models (human and nonhuman) to more effectively design and interpret the results of future inhalation exposure experiments.

Aerosols↗
PubMed1992

NTP technical report on the toxicity studies of Formic Acid (CAS No. 64-18-6) Administered by Inhalation to F344/N Rats and B6C3F1 Mice.

Formic acid occurs in a variety of plants and fruits, mammalian tissues, and insect venoms. It is used industrially in preparing a variety of drugs, dyes, and chemicals; as a decalcifier; and in leather tanning. Formic acid also is an environmental contaminant of air and water and has been identified as the toxic intermediate (formate) in methanol poisoning. Two- and 13-week toxicity studies of formic acid were conducted in male and female F344/N rats and B6C3F1 mice by whole body inhalation exposure to formic acid vapors. In addition, in vitro genetic toxicity studies were performed with Salmonella typhimurium, with or without metabolic activation. Formic acid was not mutagenic in this assay. In 2-week studies, groups of 5 F344/N rats and 5 B6C3F1 mice of each sex were exposed to formic acid for 6 hours a day, 5 days a week, at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm. Deaths occurred in animals exposed to 500 ppm (rats and mice) and 250 ppm (1 female mouse). Microscopic lesions in the respiratory and olfactory epithelia occurred in rats and mice exposed to 62.5 ppm and higher concentrations, with the severity related to the exposure concentration. The lesions consisted of squamous metaplasia, necrosis, and inflammation. Exposures had minimal or no effects on coagulation times, blood pH and electrolytes, or on concentrations and activities of urine analytes in rats during the 2-week studies. In 13-week studies, groups of 10 animals of each species and sex were exposed to formic acid at concentrations of 0, 8, 16, 32, 64, and 128 ppm for 6 hours a day, 5 days a week. Two mice, 1 male and 1 female, died in the 128 ppm groups. Body weight gains were significantly decreased in mice exposed to 64 and 128 ppm formic acid. Microscopic changes in rats and mice ranged from minimal to mild in severity and generally were limited to animals in the 128 ppm groups. Lesions related to exposure to formic acid consisted of squamous metaplasia and degeneration of the respiratory and olfactory epithelia, respectively. Hematologic and serum biochemical changes at interim and terminal time points were minimal to mild and, generally, were consistent with hemoconcentration. Overall, the effects of formic acid were consistent with those of irritant chemicals administered by inhalation exposure. The no-observed-adverse-effect level (NOAEL) for respiratory injury was 32 ppm in rats and mice. There was no significant evidence of systemic toxicity in these studies. Synonyms: Aminic Acid, Formylic Acid, Methanoic Acid, Hydrogen Carboxylic Acid.

Journal Article↗
PubMed1990

Cytogenetic analyses of mice exposed to dichloromethane.

Chromosome damage was studied in female B6C3F1 mice exposed to dichloromethane (DCM) by subcutaneous or inhalation treatments. No increase in the frequency of either sister chromatid exchanges (SCEs) or chromosome aberrations (CAs) in bone marrow cells was observed after a single subcutaneous injection of 2,500 or 5,000 mg/kg DCM. Inhalation exposure to DCM for 10 days at concentrations of 4,000 or 8,000 ppm resulted in significant increases in frequencies of SCEs in lung cells and peripheral blood lymphocytes, CAs in lung and bone marrow cells, and micronuclei (MN) in peripheral blood erythrocytes. Lung cell CAs and blood erythrocyte MN reached frequencies of approximately two times control levels. Following a 3-month inhalation exposure to 2,000 ppm DCM, mice showed small but significant increases in lung cell SCEs and peripheral blood erythrocyte MN. These findings suggest that genotoxicity may play a role in the carcinogenicity of DCM in the lungs of B6C3F1 female mice.

Administration, Inhalation↗