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PubMed2006

Human exposure to phthalates via consumer products.

Phthalate exposures in the general population and in subpopulations are ubiquitous and widely variable. Many consumer products contain specific members of this family of chemicals, including building materials, household furnishings, clothing, cosmetics, pharmaceuticals, nutritional supplements, medical devices, dentures, children's toys, glow sticks, modelling clay, food packaging, automobiles, lubricants, waxes, cleaning materials and insecticides. Consumer products containing phthalates can result in human exposures through direct contact and use, indirectly through leaching into other products, or general environmental contamination. Historically, the diet has been considered the major source of phthalate exposure in the general population, but all sources, pathways, and their relative contributions to human exposures are not well understood. Medical devices containing di-(2-ethylhexyl) phthalate are a source of significant exposure in a susceptible subpopulation of individuals. Cosmetics, personal care products, pharmaceuticals, nutritional supplements, herbal remedies and insecticides, may result in significant but poorly quantified human exposures to dibutyl phthalate, diethyl phthalate, or dimethyl phthalate. Oven baking of polymer clays may cause short-term, high-level inhalation exposures to higher molecular weight phthalates.

Chemistry, Pharmaceutical↗
PubMed1996

[Methods of extrapolating risk from from high to low doses and their effect on determining MAC values].

The author discussed problems arising from the use of different mathematical dose-response models for extrapolation of cancer risk from high to low doses. On the one hand, a linearized, multistage model, commonly used for evaluating cancer risk resulting from exposure to chemical carcinogens in the communal environment, frequently underestimates a real risk. On the other hand, the application of nonlinear models for describing the relationship between exposure and response sizes in occupational exposures, and linearized ones in communal exposures leads to ridiculous assessments, namely it sometimes appears that an inhabitant of Lodz is at the same cancer risk caused by inhalation exposure to benzo(a)pyrene like a worker employed in the coke-chemical industry and exposed to doses a dozen times higher than MAC values. A considerable overestimation of risk will also yield additional problems related with the acceptance of these values. Therefore, the author proposed to use, whenever possible, nonlinear models for establishing dose-response relationships both in communal and occupational exposures, and maximum likelihood method for estimating model parameters.

Air Pollutants↗
PubMed1977

Beryllium carcinogenesis.

Beryllium is a proven bone carcinogen in rabbits, and proven pulmonary carcinogen in rats. Median effective doses or concentrations can be computed only with considerable uncertainty; they appear to be in the 10 mg area (as total dose, in divided intravenous injections, expressed as Be for zinc beryllium silicate) for rabbits, and in the 20 alpha/m3 area (as atmospheric concentration for inhalation exposures lasting for at least three months, expressed as Be for beryllium sulfate) for rats. It is also proven that, at least from inhalation, guinea pigs do not develop beryllium cancers. Epidemiologic studies in humans are thus far unconfirmed but do not show increased cancer morbidity among beryllium workers. Current research is aimed at explaining the mechanism of carcinogenic action in the susceptible species, which seems to involve nucleic acid transcriptional interference, or the species specificity, which seems to involve immune mechanisms. No experiments were reported thus far besides the carcinogenesis studies to show that beryllium is a chemical mutagen. In the species thus far tested, there appeared to be mutual exclusion of development of a delayed (cell-mediated) hypersensitivity to beryllium and development of neoplasia from beryllium. Further research on this subject might lead to new possibilities in the understanding of cancer susceptibility.

Adenocarcinoma↗
PubMed2003

Short-term inhalation of particulate transition metals has little effect on the electrocardiograms of dogs having preexisting cardiac abnormalities.

There is growing epidemiological evidence for statistical associations between increases in air pollution, especially particulate matter, and increases in cardiovascular morbidity and mortality. Laboratory studies have shown that transition metals contribute strongly to the effects of high lung doses of model particles on changes in the electrocardiograms of animals. The present study evaluated the effects of short-term inhalation exposure to respirable particles of specific oxide and sulfate forms of transition metals on heart rate and the electrocardiogram of old dogs having preexisting cardiac abnormalities. Conscious beagle dogs were exposed by oral inhalation for 3 h on each of 3 successive days to aerosols of manganese, nickel, vanadium, iron, and copper oxides, and nickel and vanadium sulfates as single compounds at concentrations of 0.05 mg/m(3). Electrocardiograms were recorded and evaluated for exposure-related changes in heart rate, heart rate variability, and abnormalities of waveforms. Although the electrocardiograms of this population of dogs having potential age and cardiovascular susceptibility factors reflected their underlying clinical abnormalities, no significant effect of exposure to the transition metal aerosols was observed.

Administration, Inhalation↗
PubMed1996

In vivo and in vitro kinetics of ethylene oxide metabolism in rats and mice.

Ethylene oxide (EO) is a direct-acting mutagen and animal carcinogen used as an industrial intermediate and sterilant with a high potential for human exposure. Kinetics of EO metabolism in rodents can be used to develop human EO dosimetry models. This study examined the kinetics of EO metabolism in vivo and in vitro in male and female F-344 rats and B6C3F1 mice. In vivo studies measured blood and tissue EO levels during and 2-20 min following whole-body inhalation exposure (4 hr, 100 or 330 ppm EO). At 100 ppm EO, the half-life of elimination (t1/2) in rats was 13.8 +/- 0.3 (mean +/- SD) and 10.8 +/- 2.4 min for males and females, respectively, compared to a t1/2 in mice of 3.12 +/- 0.2 and 2.4 +/- 0.2 min in males and females, respectively. On exposure to 330 ppm EO, the t1/2 in mice increased approx twofold, while no change in t1/2 was observed in rats. In vitro kinetic parameters (Vmax and KM) of EO metabolism were determined using tissue cytosol and microsomes. EO metabolism in vitro occurred primarily via cytosolic glutathione S-transferase-mediated EO-GSH conjugation (cGST-EO), with highest activity in the liver. Liver cGST-EO activity (Vmax) was 258 +/- 86.9 and 287 +/- 49.0 nmol/mg protein/min (mean +/- SD) in male and female mice, respectively, compared to 52.7 +/- 10.8 and 29.3 +/- 4.9 in male and female rats, respectively. In rats, but not mice, there was a statistically significant (p < 0.05) gender difference in the Vmax for liver cGST. The KM for liver cGST-EO was approximately 10 mM in both species. The higher Vmax values observed in mice are consistent with the more rapid elimination of EO observed for this species in vivo compared to rats.

Administration, Inhalation↗
PubMedDate not supplied

A physiologically based pharmacokinetic model for chloropentafluorobenzene in primates to be used in the evaluation of protective equipment against toxic gases.

Chloropentafluorobenzene (CPFB) has been proposed as an innocuous simulant for the uptake of toxic gases. Exposure to CPFB in a training exercise could be inferred afterwards from a measurement of CPFB in expired breath. To understand the relationship between exposure and measurement, we have developed a physiologically-based pharmacokinetic (PB-PK) model for CPFB in primates. To test the model, inhalation exposures were conducted on anesthetized rhesus monkeys. CPFB concentration in expired breath was measured during and after exposure. Simulations of CPFB uptake and clearance agreed with experimental measurements in seven of eight monkeys. A human version of the model was used to simulate exposures consisting of a single breath or a few breaths. By showing a measurable CPFB concentration in expired breath after several hours of clearance, simulations with the human model indicated the suitability of CPFB as a simulant for toxic gases.

Animals↗
PubMed1992

The utility of animal inhalation studies to assess the risk of mineral fiber-induced pulmonary cancer.

Animal inhalation exposures to fibrous materials such as crocidolite and erionite produce lesions similar to those found in exposed humans. This indicates that the animal inhalation model is relevant for identifying hazardous fibrous materials. Intratracheal instillations and intracoelomic injections are alternative bioassays that can be used to screen for the most biologically active materials. These nonphysiological routes of administration can give false positive results; therefore, animal inhalation studies should be the ultimate bioassay used in the absence of appropriate epidemiological data.

Animals↗
PubMed2006

Serum and breast milk levels of methylmethacrylate following surgeon exposure during arthroplasty.

BACKGROUND: Although pregnant personnel are commonly encouraged to leave the operating room during the mixing and application of polymethylmethacrylate, we are not aware of any information regarding the safety of exposure to methylmethacrylate fumes for breastfeeding women. The present study was performed to investigate the concentrations of methylmethacrylate in serum and breast milk following exposure during total joint arthroplasty. METHODS: A survey designed to determine present-day attitudes to polymethylmethacrylate exposure during pregnancy and lactation was sent to members of the Ruth Jackson Orthopaedic Society and the National Association of Orthopaedic Nurses. To define the presence or absence of a scientific basis for this behavior, serum and breast milk samples were collected from two lactating surgeons at selected intervals after exposure to methylmethacrylate during eight total joint arthroplasty procedures. Two healthy breastfeeding women without exposure to methylmethacrylate served as controls. All twenty-five samples were analyzed for methylmethacrylate with use of a previously published headspace gas chromatography protocol. RESULTS: The gas chromatography protocol detected methylmethacrylate at levels as low as 0.5 part per million. No serum or breast milk sample demonstrated evidence of methylmethacrylate at that level, nor did any surgeon sample test at a higher level than the control specimens. Serum and milk samples spiked with methylmethacrylate yielded the analyte peak as expected, evidencing no interference from either matrix. CONCLUSIONS: Methylmethacrylate was not detectable at the 0.5-part-per-million level in serum or breast milk following inhalational exposure during total joint arthroplasty. Although a controlled longitudinal relative risk analysis was not performed and the sample size was relatively small, pregnant or breastfeeding women may use this information to make an informed decision regarding such exposure. LEVEL OF EVIDENCE: Therapeutic Level II.

Adult↗
PubMed1998

Silicosis in mice: effects of dose, time, and genetic strain.

Experimental silicosis allows study of the mechanisms of lung injury, inflammation, and fibrosis. Inbred mice are an attractive species in which to study these mechanisms because of recent progress in murine immunology, molecular biology, and genetics. We exposed mice to an aerosol of silica and examined the effects of exposure dose, the evolution of disease features over time, and the variation in responses among four inbred strains. In C3H/HeN mice incremental cumulative exposure doses of cristobalite silica caused increased initial lung dust burden 12 to 16 weeks post-exposure, progressively intense pathological responses, and increased total lung collagen (hydroxyproline). The histopathological changes and total lung collagen increased progressively over time after exposure. We compared the features of silicosis in four strains of inbred mice selected for common use or immunologic reactivity 16 weeks after aerosol inhalation exposure to crystalline cristobalite silica (70 mg/m3, 5 hours/day, 12 days). C3H/HeN mice demonstrated histopathological silicotic lesions and enlarged intrapulmonary lymphoid tissue, and increased lung wet weight, bronchoalveolar lavage (BAL) recovery of macrophages, lymphocytes, and neutrophils, and total lung collagen (hydroxyproline). BALB/c mice developed slight pulmonary lesions; MRL/MpJ mice demonstrated prominent pulmonary infiltrates with lymphocytes; New Zealand Black mice developed extensive alveolar proteinaceous deposits, inflammation, and fibrosis. Our findings demonstrate orderly dose-time-response relationships, and a substantial variation of responses among inbred strains of mice. This model should prove valuable for future experimental interventions into the mechanisms of silicosis.

Administration, Inhalation↗
PubMed1999

Estimation of the dermal absorption of m-xylene vapor in humans using breath sampling and physiologically based pharmacokinetic analysis.

A physiologically-based pharmacokinetic model, containing a skin compartment, was derived and used to simulate experimentally determined exposure to m-xylene, using human volunteers exposed under controlled conditions. Biological monitoring was conducted by sampling, in exhaled alveolar air and blood, m-xylene and urinary methyl hippuric acid concentrations. The dermal absorption of m-xylene vapor was successfully and conveniently studied using a breath sampling technique, and the contribution to m-xylene body burden from the dermal route of exposure was estimated to be 1.8%. The model was used to investigate the protection afforded by an air-fed, half-face mask. By iteratively changing the dermal exposure concentration, it was possible to predict the ambient concentration that was required to deliver the observed urinary excretion of methylhippuric acid, during and following inhalation exposure to 50 ppm m-xylene vapor. This latter extrapolation demonstrates how physiologically-based pharmacokinetic modeling can be applied in a practical and occupationally relevant way, and permitted a further step not possible with biological monitoring alone. The ability of the model to extrapolate an ambient exposure concentration was dependent upon human metabolism data, thereby demonstrating the mechanistic toxicological basis of model output. The methyl hydroxylation of m-xylene is catalyzed by the hepatic mixed function oxidase enzyme, cytochrome P450 2E1 and is active in the occupationally relevant, (<100 ppm) exposure range of m-xylene. The use of a scaled-up in vitro maximum rate of metabolism (Vmaxc) in the model also demonstrates the increasingly valuable potential utility of biokinetic data determined using alternative, non-animal methods in human chemical-risk assessment.

Administration, Cutaneous↗
PubMed2000

A rat nasal epithelial model for predicting upper respiratory tract toxicity: in vivo-in vitro correlations.

An in vitro model of the rat nasal cavity has been used to compare the responses of nasal tissues in vitro, using loss of intracellular ATP and potassium as indices of toxicity, with the pathological changes occurring following in vivo exposure to four test compounds. Turbinates were incubated in vitro with the test compounds for 4 h, for 24 h or for 4 h followed by 20 h in fresh medium. Titanium dioxide caused little or no loss of ATP in either olfactory epithelium (OE) or respiratory epithelium (RE). Sodium carbonate decreased olfactory, but not respiratory ATP, while acetic acid and 3-methylindole markedly decreased ATP in both tissues. Intracellular potassium concentrations were generally affected to a lesser degree. In vivo, no morphological changes were observed in the nasal cavity following inhalation exposure to either titanium dioxide or sodium carbonate. Inhalation of acetic acid resulted in a very focal lesion in the RE of the dorsal meatus of level 1, while administration of 3-methylindole by intraperitoneal injection caused severe degeneration of OE. In further experiments olfactory turbinates were exposed to a range of concentrations (0-100 mM) of sodium carbonate, acetic acid and 3-methylindole for 4 h and ATP concentrations determined. Concentration-dependent decreases in ATP were observed for sodium carbonate and 3-methylindole, with EC(50) values estimated as 2.57 and 0.91 mM, respectively. Acetic acid only decreased ATP significantly at the 100-mM concentration. In summary, this in vitro model has predicted the nasal toxicity of several compounds, including both direct-acting agents (sodium carbonate, acetic acid) and one requiring metabolic activation (3-methylindole). However, the lack of airflow-dependent dosimetry, results in some lack of discrimination between the different regions of the nasal cavity and may make this model overly sensitive.

Acetic Acid↗
PubMed1998

Exposure assessment model for odor causing VOCs volatilization from stored pig slurry.

A mathematical model taking into account source depletion with time and the actual thickness of manure layer was derived to evaluate indoor inhalation exposure dynamics to three selected odor causing volatile organic compounds (VOC-odors) of p-cresol, toluene, and xylene volatilization from stored pig slurry. The model assumes that pig slurry is undisturbed and the VOC-odors released in a contaminated layer and transported through a clean layer as well as a manure-air interface boundary. The model simulates time-dependent volatilization, the depletion of source contaminant via both volatilization and degradation, and could be used with a contaminated zone of finite thickness. For a given VOC-odor, the predicted total exposure and resulting manure cleanup criteria can be a large variability depending on the model whether a finite or infinite manure layer thickness was considered. Results obtained from model comparisons suggest that the model incorporating depth-varying of manure layer and contaminant source depletion is more suitable to evaluate the VOC-odor exposure dynamics in swine housing bioclimate.

Air Pollution, Indoor↗
PubMed1995

Assessment of the developmental toxicity and placental transfer of 1,2-dichloroethane in rats.

This study evaluates the developmental toxicity and placental transfer of 1,2-dichloroethane (DCE) in rats. Sprague-Dawley rats were given 0-2.4 mmol DCE kg-1 day-1 by gavage, or were exposed for 6 hr per day to 0-300 ppm DCE by inhalation, from Day 6 to 20 of gestation. Maternal toxicity was observed after inhalation exposure to 300 ppm DCE and oral administration of 2.0 or 2.4 mmol DCE kg-1. There was no evidence of altered growth nor teratogenic effects after either inhalation or oral administration of DCE at any concentration tested. The time course disposition of 14C was examined over a 48-hr period in 12- and 18-day pregnant rats after a single oral dose of 1.6 mmol [14C]DCE kg-1. Peak concentrations of radiocarbon occurred between 2 and 4 hr postdose. Conceptus (Day 12) and fetal (Day 18) tissues accounted for 0.06 and 0.4% of the administered dose, respectively. Up to 4 hr, levels of radiocarbon in placenta and fetus were slightly less than in maternal plasma of 18-day pregnant rats and were two to five times higher at later periods. At 2 hr, unchanged DCE accounted for most of radioactivity (78-86%) recovered in maternal plasma, placenta, and fetus. Acidic metabolites and radioactivity bound to macromolecules increased up to 24 hr (0.01 mumol-eq DCE g-1) in either placental or fetal tissues. Thereafter, their levels declined more slowly than those in the maternal plasma. Results from this developmental toxicity study in rats confirm embryonic exposure to radiocarbon associated with [14C]DCE and/or its metabolites and has demonstrated the lack of observable teratogenic effects.

Administration, Inhalation↗
PubMed1991

Inhalation toxicity of methyl isocyanate: biochemical and cytological profile of bronchoalveolar lavage fluid in rats.

Acute pulmonary injury in rats following a single inhalation exposure to methyl isocyanate (3.2 mg l-1) was reflected by alterations in the biochemical and cytological constituents of bronchoalveolar lavage fluid (BALF) over a period of 30 days. Total protein, sialic acid and lactic acid contents of BALF were increased followed by a gradual decline to normalcy between day 3 and day 30 post-exposure. The activity of lactic dehydrogenase also increased progressively with time. The cellularity of BALF was increased significantly and primarily comprised of polymorphonuclear neutrophils at 8 days. The adherence of macrophages was unchanged but their viability was lowered at 30 days post-exposure. The results indicate the significance of bronchoalveolar lavage analysis in monitoring pulmonary toxicity by methyl isocyanate, which is characterized by the hypoxic condition and reduced cellular defence. Some toxic manifestations are potentially reversible with time after cessation of exposure.

Administration, Inhalation↗
PubMed1999

A physiological model for tert-amyl methyl ether and tert-amyl alcohol: hypothesis testing of model structures.

The oxygenate tert-amyl methyl ether (TAME) is a gasoline fuel additive used to reduce carbon monoxide in automobile emissions. To evaluate the relative health risk of TAME as a gasoline additive, information is needed on its pharmacokinetics and toxicity. The objective of this study was to use a physiologically-based pharmacokinetic (PBPK) model to describe the disposition of TAME and its major metabolite, tert-amyl alcohol (TAA), in male Fischer-344 rats. The model compartments for TAME and TAA were flow-limited. The TAME physiological model had 6 compartments: lung, liver, rapidly perfused tissues, slowly perfused tissues, fat, and kidney. The TAA model had 3 compartments: lung, liver, and total-body water. The 2 models were linked through metabolism of TAME to TAA in the liver. Model simulations were compared with data on blood concentrations of TAME and TAA taken from male Fischer-344 rats during and after a 6-hour inhalation exposure to 2500, 500, or 100 ppm TAME. The PBPK model predicted TAME pharmacokinetics when 2 saturable pathways for TAME oxidation were included. The TAA model, which included pathways for oxidation and glucuronide conjugation of TAA, underpredicted the experimental data collected at later times postexposure. To account for biological processes occurring during this time, three hypotheses were developed: nonspecific binding of TAA, diffusion-limited transport of TAA, and enterohepatic circulation of TAA glucuronide. These hypotheses were tested using three different model structures. Visual inspection and statistical evaluation involving maximum likelihood techniques indicated that the model incorporating nonspecific binding of TAA provided the best fit to the data. A correct model structure, based upon experimental data, statistical analyses, and biological interpretation, will allow a more accurate extrapolation to humans and, consequently, a greater understanding of human risk from exposure to TAME.

Administration, Inhalation↗
PubMed1999

Inhaled nitric oxide reduces tyrosine nitration after lipopolysaccharide instillation into lungs of rats.

Nitric oxide (NO) may either protect against or contribute to inflammatory lung injury. In this study we investigated whether inhalation of 20 ppm NO alters tyrosine nitration, and we assessed the degree of lung inflammation and edema in rats after lipopolysaccharide (LPS) instillation. The amount of nitrotyrosine relative to the total amount of tyrosine was measured in lung homogenates, and lung tissue sections were stained for nitrotyrosine and aminotyrosine (a reduced form of nitrotyrosine). Leukocytes in bronchoalveolar lavage fluid (BALF) were counted, and myeloperoxidase activity was measured in lung homogenate. Lung edema and inflammatory cell accumulation in lung tissue were estimated by extravascular lung water weight (EVLW) and extravascular dry lung weight (EVDW), respectively. LPS instillation caused increases in nitrotyrosine concentration and immunohistochemical staining of nitrotyrosine and aminotyrosine in the lungs. LPS instillation increased the BALF leukocyte count, myeloperoxidase activity in lung tissue, and both EVLW and EVDW. Inhalational exposure to 20 ppm NO induced nitrotyrosine and aminotyrosine formation only in bronchial epithelial cell surface of the lungs not instilled with LPS. NO inhalation reduced the increases in nitrotyrosine and aminotyrosine in LPS-instilled lung tissue as well as the leukocyte count in BALF and myeloperoxidase activity in lung tissue, but it did not significantly change EVLW or EVDW. Leukocyte depletion in LPS-instilled rats reduced interstitial inflammatory cells, which were stained with nitrotyrosine and aminotyrosine, and attenuated the nitrotyrosine staining of alveolar capillaries. These results suggest that inhalation of 20 ppm NO reduces leukocyte accumulation in the lungs and inhibits tyrosine nitration caused by LPS instillation.

Administration, Inhalation↗
PubMed1979

Investigations on the lung and kidney function in workers exposed to cadmium.

The kidney seems more sensitive to the chronic effect of cadmium than the lung. Only minor impairments of lung function (mild form of obstructive lung disease) were found after long-term occupational exposure (less than 20 yr) to moderate concentration of cadmium oxide dust and fume. This conclusion, cannot, however be extrapolated to acute or subacute inhalational exposure. The nephrotoxicity of cadmium consists in a tubular dysfunction characterized by an increased excretion of beta 2-microglobulin and giving rise to the classical tubular proteinuria and in a glomerular dysfunction evidenced by an increased excretion of high molecular weight proteins and increased levels of beta 2-microglobulin and creatinine in plasma and giving rise to a glomerular type proteinuria. These renal changes were mainly found in workers whose cadmium concentration at time of the survey exceeded 1 microgram Cd/100 ml in blood and 10 microgram Cd/g creatinine in urine. It should, however, be stressed that higher levels of Cd in blood and in urine are not necessarily associated with the presence of excessive proteinuria. In newly exposed workers, the Cd level in blood increases progressively to a plateau after several weeks. Cadmium level in urine fluctuates more. In workers exposed for several months to an airborne concentration exceeding 200 microgram/m3, Cd concentration in urine seems mainly influenced by recent exposure.

Adult↗
PubMed1985

Ambient sulfate aerosol deposition in man: modeling the influence of hygroscopicity.

Atmospheric sulfate aerosols [H2SO4, (NH4)2SO4, and NH4HSO4] are of international concern because of their global prevalence and potential irritant or toxic effects on humans. To assess hazards following inhalation exposure, the total dose delivered to the human respiratory tract and its regional distribution must be determined. The mass median aerodynamic diameter of the inhaled aerosol will influence the sites of deposition in the respiratory tract. Atmospheric sulfate aerosols are hygroscopic and will have changing particle sizes and densities as they absorb water vapor in the humid environment of the human respiratory tract. Experimental and theoretical data that describe particle size as a function of temperature and relative humidity were used in computer subroutines of an aerosol deposition model in order to calculate the dose dispersion of H2SO4, (NH4)2SO4, and NH4HSO4 aerosols in man. Different temperature and relative humidity environments that approximately correspond to nasal and oral breathing were studied. The predicted deposition patterns are very different from those of nonhygroscopic aerosols with identical inhaled mass median aerodynamic diameter values.

Aerosols↗