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PubMedDate not supplied

A combined reproduction, neonatal development, and neurotoxicity study with 1,6-hexamethylene diisocyanate (HDI) in the rat.

1,6-Hexamethylene diisocyanate (HDI), a chemical widely used in commercial polyurethane products, was evaluated in a combined reproductive/developmental/neurotoxicity study. Sprague-Dawley rats (n = 120; 15 per sex/dose group) were administered via whole-body inhalation exposure either 0, 0.005, 0.05, or 0.3 ppm HDI for 6 h/day during a 14-day premating phase, up to a 14-day mating phase, and a 21-day gestation phase. The dams and their litters were maintained for a 4-day lactation phase during which exposure to HDI was discontinued. Neurobehavioral testing (automated measures of activity and a functional observational battery) was conducted before exposure, after the premating phase, and before termination. Body weight and clinical observations were recorded throughout the study. Terminal examinations included a gross necropsy, hematology, and clinical chemistry. Tissues retained for microscopic examination included the reproductive organs, neural tissues, nasal turbinates (multiple sections), trachea, larynx, and lung. The animals were also evaluated for effects on mating, fertility, gestation length, litter size, pup sex ratio, and pup viability. In the 0.300 ppm dose group a statistically significant decrease in body weight was observed in the females on day 4 of the study. Also observed at this dose level, in both males and females, were microscopic alterations in the nasal cavity, primarily epithelial hyperplasia, squamous metaplasia, chronic-active inflammation, and more seriously, degeneration of the olfactory epithelium. Similar microscopic effects were also observed, albeit to a lesser extent, in the males and females of the 0.05 ppm dose level. No histopathologic effects were observed in the 0.005 ppm dose level. No effects on any reproductive or neurotoxicologic parameters, hematology, clinical chemistry, or any effects on pup growth and development were observed at any exposure level.

Administration, Inhalation↗
PubMed2001

Bioavailability of octamethylcyclotetrasiloxane (D(4)) after exposure to silicones by inhalation and implantation.

We developed a physiologically based pharmacokinetic (PBPK) model to predict the target organ doses of octamethylcyclotetrasiloxane (D(4)) after intravenous (IV), inhalation, or implantation exposures. The model used (14)C-D(4) IV disposition data in rats to estimate tissue distribution coefficients, metabolism, and excretion parameters. We validated the model by comparing the predicted blood and tissues concentrations of D(4) after inhalation to experimental results in both rats and humans. We then used the model to simulate D(4) kinetics after single and/or repeated D(4) exposures in rats and humans. The model predicted bioaccumulation of D(4) in fatty tissues (e.g., breast), especially in women. Because of its high lipid solubility (Log P(oct/water) = 5.1), D(4) persisted in fat with a half life of 11.1 days after inhalation and 18.2 days after breast implant exposure. Metabolism and excretion remained constant with repeated exposures, larger doses, and/or different routes of exposure. The accumulation of D(4) in fatty tissues should play an important role in the risk assessment of D(4) especially in women exposed daily to multiple personal care products and silicone breast implants.

Adipose Tissue↗
PubMed1996

The adjuvancy of silicones: dependency on compartmentalization.

Studies have been conducted in mice (B6C3F1) and rats (Sprague Dawley, Fischer 344) to investigate the adjuvancy potential of silicone mammary gel and the low molecular weight silicone fluid, octamethylcyclotetrasiloxane (D4). Dependent on the experimental conditions employed, a divergent data profile emerges. If the antigen (bovine serum albumin, BSA) is emulsified with either the gel or the D4 prior to intramuscular immunization, an amplified anti-BSA IgG antibody response, as measured by multipoint ELISA methodology, is noted over the 8 week measurement period. In parallel studies, a variety of non-silicone personal care ingredients (lanolin, white mineral oil, isopropyl palmitate) were also capable of amplifying this humoral response relative to the non-adjuvant phosphate buffered saline control. These observations are consistent with the empirical knowledge that hydrophobic substances tend to augment immune responses. However, under conditions in which the antigen is not blended with the silicone prior to immunization, normal immune responses are noted. In short (10 day) and long (180 day) term gel implant studies, the optimal IgM and IgG antibody responses, as determined in the antibody forming cell assay, were equivalent between the gel implanted and control animals. Moreover, under similar exposure conditions, no adjuvancy was noted in the three Host Resistance models (B16F10 Melanoma, Listeria monocytogenes, and Streptococcus pneumoniae) tested. Antibody forming cell studies conducted after 28 days of oral or inhalation exposure to D4 have also yielded responses similar to the non-silicone exposed vehicle controls. Collectively, these data suggest that in the absence of premixing the antigen with the silicone test material, there does not appear to be any silicone induced adjuvant response.

Adjuvants, Immunologic↗
PubMed1985

Free lung cell phagocytosis and lysosomal enzyme activity after inhalation of lipopolysaccharide in guinea-pigs.

Free lung cells were studied in guinea-pigs different times after an inhalation exposure to bacterial endotoxin yielding a dose of about 1 microgram/animal. After exposure the number of alveolar macrophages (AM) and neutrophils was increased. The phagocytosis capacity of the lung was increased, mainly due to the influx of neutrophils. The activity of N-acetyl-beta-D-glucosaminidase from exposed animals was decreased in AM cell cultures and increased in lavage fluid 2 hours and later after exposure. Cathepsin D activity was also decreased in AM cell cultures but did not change in lavage fluid. Lactate dehydrogenase was increased in lung lavage fluid. The results show that LPS inhalation activates AM and that increased amounts of lysosomal enzymes are present in the airways.

Acetylglucosaminidase↗
PubMed1992

Upper respiratory tract deposition of inspired acetaldehyde.

Inhalation exposure of rodents to high concentrations of acetaldehyde produces lesions in the upper respiratory tract (URT, all regions of the respiratory tract anterior to and including the larynx). Information on the inhalation dosimetric relationships for this vapor are needed for a comprehensive understanding of its inhalation toxicity. Toward this end, uptake of acetaldehyde was measured in the surgically isolated URT of the urethane-anesthetized male F344 rat under unidirectional (50, 100, 200, or 300 ml/min) and cyclic (100 ml/min) flow conditions at inspired concentrations of 1, 10, 100, or 1000 ppm. Under all flow conditions URT deposition efficiency was strongly dependent on inspired concentration. URT deposition efficiency (under cyclic flow) averaged 76, 48, 41, and 26% at 1, 10, 100, and 1000 ppm, respectively. Nasal acetaldehyde dehydrogenase activity averaged 1.2 micrograms/min. Absolute acetaldehyde deposition rates (micrograms/min) at 100 and 1000 ppm exceeded this activity by 5- to 100-fold, suggesting a possible mechanism for the reduced deposition efficiency at high concentrations. URT deposition under unidirectional flow was strongly dependent on the inspiratory flow rate. The effect of flow rate on deposition was reasonably predicted by the mass-transfer model of Aharonson et al. (J. Appl. Physiol. 37, 654-657, 1974). The uptake coefficients determined from the unidirectional flow studies were used to predict uptake under cyclic flow by integration of the model. The predicted cyclic deposition efficiencies differed from the observed efficiencies by 2.3 +/- 4.3% (mean +/- SEM), suggesting this model might provide a reasonable first approximation for acetaldehyde uptake under cyclic breathing conditions.

Acetaldehyde↗
PubMed1997

Physiologically based pharmacokinetic analysis of the concentration-dependent metabolism of halothane.

1. Previous studies with the halothane analogue and chlorofluorocarbon replacement 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) have shown that there are concentration-dependent, sex-specific differences in the rate of uptake during inhalation exposure in rat. Since it is well established that there are sex-specific differences in the control of enzyme activity in drug metabolism, male and female rats were exposed by inhalation to halothane concentrations ranging from 500 to 4000 ppm. 2. A physiologically based pharmacokinetic model describing the concentration-dependent reduction in uptake and metabolism of halothane in male and female rats was developed. The in vivo metabolic rate constants obtained were: for male rats, Km = 0.4 mg litre-1 (2.03 mumol litre-1) and Vmaxc = 9.2 mg kg1 h-1 (46.6 mumol kg1 h-1); for female rats, Km = 0.4 mg litre-1 (2.03 mumol litre-1) and Vmaxc = 10.2 mg kg-1 h-1 (51.7 mumol kg-1 h-1). 3. An equation describing the concentration-dependent decrease of hepatic metabolism of halothane successfully simulated the gas-uptake data. Simulation of cumulative urinary excretion of the major metabolite, trifluoroacetic acid, required introduction of a proportionality constant to limit the extent of reduction of halothane metabolism to 20% of the amount of enzyme activity. Good simulation of urinary excretion data was achieved, which was interpreted to indicate that, when only 20% of the enzyme is inactivated, the rate of enzyme resynthesis was adequate to replenish enzyme activity within 24 h. 4. A rapidly reversible, non-biological inactivation mechanism called "physical toxicity' is discussed as a possible explanation of concentration-dependent gas uptake.

Animals↗
PubMed1997

[Allergic conditions for diseases of the respiratory tract from occupational exposure to acid anhydrides].

Acid anhydrides are highly reactive, low molecular weight compounds that are used widely in industry. Work-related exposure to this group of substances may cause occupational asthma. Because of low molecular weight, these compounds are not able to induce antibody responses without conjugating with human proteins. Acid anhydrides may act as haptens when conjugated with human serum albumin (HSA). The induction mechanism of immediate and late bronchial hyperresponsiveness to acid anhydrides appears to be at least partly mediated by IgE antibodies. Other clinical syndromes, which may be caused by acid anhydrides such as pulmonary disease-anemia (PDA), and late respiratory systemic syndrome (LRSS) associated with TMA exposure, appear to be associated with IgG antibodies to TMA as well as with IgE. Significant cross-reaction occurs between different compounds of this group, particularly regarding IgE antibodies. As inhalational exposure to acid anhydrides may result in serious pulmonary disease, adequate protection of potentially exposed workers or their removal, if affected, from exposure is essential.

Allergens↗
PubMed1995

Effects of exposure to NO2 or SO2 on bronchopulmonary reaction induced by Candida albicans in guinea pigs.

The effects of NO2 or SO2 on the bronchopulmonary reactions induced by Candida albicans in guinea pigs were evaluated. Thirty-six guinea pigs (3 groups of 12 animals each) were sensitized with intraperitoneal injection of 10 mg of C. albicans, given twice. Two groups of animals were exposed to about 5 ppm of NO2 or SO2 for 4 h/d, 5 d/wk; this exposure was conducted a total of 30 times during the study. The third group served as the control and was not exposed to these pollutants. Two weeks after the second sensitization, all the animals were subjected to inhalation exposure to C. albicans. For 42 h after the antigen challenge, the respiratory rates and expiration/inspiration ratios of the animals were automatically monitored. The number of animals showing tachypnea was significantly higher in the NO2 exposure group than in the control from 15 h after antigen challenge. In the SO2 exposure group, the number of animals showing prolonged expiration or prolonged inspiration, or both, was significantly higher than that in the control group, and the symptoms were observed from approximately 15 h after antigen challenge. These findings showed that delayed-type dyspneic symptoms in guinea pigs were increased by exposure to NO2 or SO2, although the symptoms and degree of dyspnea were different for the two gases.

Administration, Inhalation↗
PubMed1996

Chronic inhalation toxicity and carcinogenicity testing of respirable fibrous particles. Workshop report.

On May 8-10, 1995, a workshop on chronic inhalation toxicity and carcinogenicity testing of respirable fibrous particles was held in Chapel Hill, North Carolina. The workshop was sponsored by the Office of Pollution Prevention and Toxics, U.S. Environmental Protection Agency (EPA), in collaboration with the National Institute of Environmental Health Sciences (NIEHS), the National Institute for Occupational Safety and Health (NIOSH), and the Occupational Safety and Health Administration (OSHA). The goal of the workshop was to obtain input from the scientific community on a number of issues related to fiber testing. Major issues for discussion were: (i) the optimal design and conduct of studies of the health effects of chronic inhalation exposure of animals to fibers; (ii) preliminary studies which would be useful guides in designing the chronic exposure study; (iii) mechanistic studies which would be important adjuncts to the chronic exposure study to enable better interpretation of study results and extrapolation of potential effects in exposed humans; and (iv) available screening tests which can be used to develop a minimum data set for (a) making decisions about the potential health hazard of the fibers and (b) prioritizing the need for further testing in a chronic inhalation study. After extensive discussion and debate of the workshop issues, the general consensus of the expert panel is that chronic inhalation studies of fibers in the rat are the most appropriate tests for predicting inhalation hazard and risk of fibers to humans. A number of guidances specific for the design and conduct of prechronic and chronic inhalation studies of fibers in rodents were recommended. For instance, it was recommended that along with other information (decrease in body weight, systemic toxicity, etc.), data should be obtained on lung burdens and bronchoalveolar lavage fluid analysis to assist in establishing the chronic exposure levels. Lung burden data are also important for quantifying aspects of risk assessment related to dosimetric adjustments before extrapolation. Although mechanistic studies are not recommended as part of the standard chronic inhalation studies, the expert panel stressed the need for obtaining mechanistic information as far as possible during the course of subchronic or chronic inhalation studies. At present, no single assay and battery of short-term assays can predict the outcome of a chronic inhalation bioassay with respect to carcinogenic effects. Meanwhile, several short-term in vitro and in vivo studies that may be useful to assess the relative potential of fibrous substances to cause lung toxicity/carcinogenicity have been identified.

Administration, Inhalation↗
PubMed1996

Biopersistence of man-made vitreous fibers and crocidolite asbestos in the rat lung following inhalation.

This study investigated possible relationships between fiber bio-persistence in the lung and previously observed differences in pulmonary toxicity between asbestos and man-made vitreous fibers (MMVF) following inhalation exposure. Fischer 344/N rats were exposed nose only, 6 hr/day for 5 days to 30 mg/m3 MMVF (two fiberglass compositions, rock wool, or slag wool) or to 10 mg/m3 crocidolite asbestos. At eight time points up to 1 year postexposure, lung fiber burdens were analyzed for number/lung and bivariate dimensions using scanning electron microscopy (SEM) and for chemical composition using SEM energy dispersive spectroscopy. After 365 days, > 95% of long (> 20 microns) MMVFs had disappeared from the lung compared to only 17% of long crocidolite fibers. Longer MMVFs disappeared more rapidly than short MMVFs, suggesting that long fibers were dissolving or breaking. Mean diameters and lengths of the MMVFs decreased with time, while the mean diameter of crocidolite remained unchanged and its mean length showed an apparent increase, probably related to macrophage-mediated clearance of short fibers. Leaching of oxides occurred in the fibrous glasses and slag wool and correlated with morphological changes in the fibers over time. No chemical or morphological changes were observed in crocidolite fibers. These changes in MMVF number, chemistry, and morphology over time in lung tissue compared to crocidolite asbestos demonstrate the relatively low biological persistence of some MMVFs in the lung and may explain why these MMVFs are not tumorigenic in rats, even after chronic exposure at high concentrations.

Administration, Inhalation↗
PubMed1992

Exposure to soluble barium compounds: an interventional study in arc welders.

Soluble barium (Ba) compounds are well-known toxicants. Intoxications are mainly known in an acute form from casual or suicidal oral ingestion. No scientifically based data are available on possible health effects of inhalative exposure to soluble Ba salts at the workplace. Therefore, we investigated 18 welders in an interventional study over 1 week. They performed welding of Ba-containing stick electrodes and self-shielded flux cored wires under conditions similar to real working conditions. The welding fumes contained 31%-37% Ba, more than 90% of which was soluble in acids. Without appropriate preventive measures, a high rate of measurements exceeded the TLV values for total welding fumes of 5 mg/m3 and for soluble Ba of 0.5 mg/m3. The median fume concentrations were 13.2 mg/m3 in stick electrode welding and 12.3 mg/m3 in flux cored wire welding. The median Ba concentrations were 4.4 and 2.0 mg/m3 respectively. An integrated exhaust system built into the gun proved to be efficient in flux cored wire welding. The internal exposure to Ba reached median urine levels up to 101.7 micrograms/l (normal: below 20 micrograms/l) and median plasma concentrations of up to 24.7 micrograms/l (normal: below 8 micrograms/l). No health impact on the welders could be proven, but hypokalemia may have occurred as a result of the Ba exposure.

Air Pollutants, Occupational↗
PubMed1987

Kinetics of inhaled lipopolysaccharide in the guinea pig.

The kinetics of endotoxin in the airway and the blood was studied after an inhalation exposure using guinea pigs. The amounts of endotoxin in the pulmonary lavage fluid, and in arterial and venous blood were determined. Forty minutes after the start of exposure to 400 micrograms/m3 of Escherichia coli 026:B6-LPS, 7.7 +/- 2.9 ng/ml of lipopolysaccharide (LPS) could be demonstrated in the pulmonary lavage fluid, and 60 minutes afterwards, the amount was 4.9 +/- 1.4 ng/ml. In the arterial blood, the amounts at 10 and 40 minutes of exposure, and 60 minutes afterwards were 21.2 +/- 23.8 pg/ml, 29.2 +/- 31.8 pg/ml, and 1.1 +/- 1.0 pg/ml, respectively. There was no significant difference of LPS content in the arterial and venous blood. The results demonstrate that the lung is a potent barrier for penetration of endotoxins into the body. The experimental model enables studies of how other exposures such as mineral dusts, tobacco smoke, or viral or bacterial infections might affect this defense.

Administration, Inhalation↗
PubMedDate not supplied

Gasoline-contaminated ground water as a source of residential benzene exposure: a case study.

In a private residence using gasoline-contaminated ground water (approximately 300 micrograms/l benzene), a series of experiments were performed to assess the potential benzene exposures that may occur in the shower stall, bathroom, master bedroom, and living room as a result of a single 20-min, shower. Integrated fixed site SUMMA TM-polished canister and Tenax GC air samples were collected in the target microenvironments over 20, 60, and 240 min. periods. These results were compared with the long-term personal Tenax GC samples (6 h) and grab samples collected with glass, gas-tight syringes at 0, 10, 18, 20, 25, 25.5, and 30 min. Maximum benzene concentrations occurred in the shower stall (758-1670 micrograms/m3) and bathroom (366-498 micrograms/m3) during and immediately after the shower. Inhalation exposures in the shower stall during the 20-min. shower were 2.1-4.9 times higher than corresponding 20-min, bathroom exposures. The total benzene dose resulting from the shower was estimated to be approximately 281 micrograms, with 40% via inhalation and 60% via the dermal pathway. This total is 2 to 3.5 times higher than the mean inhalation dose received during a concurrent 6 h occupation of the house. These results indicate that domestic use of gasoline-contaminated water can produce relatively high benzene exposures that vary significantly according to an individual's proximity to the water use zone. The information in this document has been funded wholly or in part by the U.S. Environmental Protection Agency. It has been subjected to Agency review and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. The entire experiment was reviewed and approved by the Research Triangle Institute Human Subjects Review Committee.

Air Pollution↗
PubMed2002

Histochemical localisation of carboxylesterase activity in rat and mouse oral cavity mucosa.

Vinyl acetate (VA) is widely used within the chemical industry, in the manufacture of polyvinyl alcohol, and as polyvinyl acetate emulsions in latex paints, adhesives, paper and paper board coatings. Chronic oral exposure of rodents to high concentrations of VA induces tumours within the oral cavity. Carboxylesterase-dependent hydrolysis of VA is thought to be critical in the development of nasal tumours following inhalation exposure of animals to VA. Therefore, carboxylesterase activity was determined histochemically in the oral cavities of male F344 rats and BDF mice in order to explore the potential role of carboxylesterase-dependent hydrolysis of VA in the development of oral tumours. Following fixation in 10% neutral buffered formalin heads were decalcified in neutral saturated EDTA, embedded in resin, sectioned at six levels (three each for the upper and lower jaws), and carboxylesterase activity revealed in the tissue using alpha-naphthyl butyrate as substrate. The localisation of carboxylesterase activity in freshly dissected rat oral tissue was compared to that of the resin sections and found to be identical, thus validating the decalcification process. A similar pattern of carboxylesterase activity was observed for the two species. Staining was low in areas surrounding the teeth, and medium/high in the buccal mucosa, the central/posterior upper palate and those regions of the lower jaw not proximal to the teeth. In general the intensity of staining was greater in sections from the rat compared to those from the mouse. By comparison, carboxylesterase activity was considerably higher in mouse nasal olfactory epithelium than in any of the oral tissues. Thus the mucosa of the oral cavity has the potential to hydrolyse VA to its metabolites, acetic acid and acetaldehyde, and the presence of carboxylesterases at this site is consistent with, and may be an important determining factor in, the development of oral cavity tumours following exposure to VA.

Animals↗
PubMed1992

Histological sectioning of the rodent larynx for inhalation toxicity testing.

In rodents, the larynx is a major site of histopathologic alteration following inhalation exposure to particulates, vapors, and aerosols. Specifically, the epithelial lining of a narrowly delineated region on the ventral floor of the larynges of rats and mice appears to be especially vulnerable to inhaled materials, and is recognized as a preferred site for histopathological evaluation in inhalation studies. This site is located at the base of the epiglottis, cranial to the ventral laryngeal diverticulum (ventral pouch). The presence of underlying seromucinous glands is critical for histologic identification of this site. We report a histologic sectioning technique, using the ventral laryngeal diverticulum as the anatomical landmark, to obtain tissue sections from this area of predilection in rats and in mice.

Administration, Inhalation↗
PubMed2003

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of 1-Bromopropane (1-BP).

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for 1-bromopropane to cause adverse effects on reproduction and development in humans. 1-Bromopropane was selected for evaluation due to recent consideration of 1-bromopropane as a replacement chemical for hydrochlorofluorocarbons and chlorinated solvents. 1-Bromopropane is used in spray adhesives and in cleaning metal and electronic components; as a solvent for fats, waxes, or resins; and as an intermediate in the synthesis of pharmaceuticals, insecticides, quaternary ammonium compounds, flavors, or fragrances. The results of this evaluation on 1-brompropane are published in a NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of 1-Bromopropane, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to 1-bromopropane on human development and reproduction. No data were available on 1-bromopropane exposures in the general US population. Therefore, conclusions were based on the available occupational exposure data and on studies in humans and laboratory animals. First, there is serious concern for reproductive and developmental effects at the upper end of the human occupational exposure range (18-381 ppm). Adverse developmental and/or reproductive effects have been reported in animal studies at exposure levels of >/=200 ppm. Second, there is minimal concern for reproductive and developmental effects when humans are exposed at the lower end of the human occupational exposure range (0.04-0.63 ppm). This level is at least 300- fold lower than the no effect level identified from reproductive studies in laboratory animals. These conclusions are based upon limited occupational inhalation exposure data. It is likely that worker exposures also occur through dermal contact with 1-bromopropane. However, no information was available on dermal exposures. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Journal Article↗
PubMed1994

Distribution and reactivity of inhaled 14C-labeled toluene diisocyanate (TDI) in rats.

Inhalation exposure to toluene diisocyanate (TDI) can result in a variety of airway diseases. Concern has been expressed that a putative carcinogenic potential of TDI exists as a result of the formation of toluenediamine (TDA) by hydrolysis of the isocyanate in the body. Results from long-term bioassays (TDI inhalation versus gavage in rats and mice) are contradictory and discrepancies do exist concerning the interpretation of adverse effects. This study was performed to analyze the distribution and reactivity of radioactively-labeled TDI using vapor exposure in a rat model system. Rats were exposed to 14C-TDI vapors at concentrations ranging from 0.026 to 0.821 ppm for 4 h. All tissues examined showed detectable quantities of radioactivity, with the airways, gastrointestinal system and blood having the highest levels which increased with exposure concentration. The concentration of radioactivity in the bloodstream after exposure was linear with respect to dose. The majority (74-87%) of the label associated with the blood was recovered in the plasma, and of this, 97-100% of the 14C existed in the form of biomolecular conjugates. Analysis of stomach contents shows that the majority of the label is also associated with high (> 10 kDa) molecular weight species. While a larger percentage (28%) of the label is found in the low molecular weight fraction relative to blood, this low molecular weight labeled material represents at least eight different components. Thus, over the vapor exposure concentrations and time tested, it appears that conjugation is the predominant reaction and that free TDA is not a primary in vivo reaction product under the conditions tested.

Administration, Inhalation↗
PubMed1985

Neonatal exposure to toluene: effects on the development of liver microsomal cytochrome P-450 and serum hormone levels in the rat.

Lactating Sprague-Dawley rats and their pups were exposed on postnatal days 1-7, 6 h/day, to 80, 500 and 1000 ppm toluene, respectively, by inhalation. Exposure to 80 ppm toluene decreased the liver microsomal AHH activity and the rate of 7 alpha- and 6 beta-hydroxylation of androstenedione in 8-day-old-pups. On the other hand, neonatal exposure to 500 or 1000 ppm toluene resulted in a significant increase in AHH and 7-ethoxyresorufin O-deethylase activities and in the formation of 16-oxygenated metabolites of androstenedione in 8-day-old animals. Exposure to toluene increased the cytochrome P-450 content at all 3 dose levels in male but not in female pups. Twenty-one days after neonatal exposure no such effects were seen in young animals of either sex. In 56-day-old male rats, however, neonatal exposure to 80 ppm toluene resulted in a decreased rate of 6 beta-hydroxylation of androstenedione and a reduced AHH activity. No such effects were seen in female rats of the same age. Neonatal exposure to toluene affected the body and liver weights in 8-day-old pups of both sexes but had no effect on these parameters in 21-day-old animals of either sex. Exposure to 80 ppm toluene during the neonatal period gave a significantly increased body weight of 56-day-old male but not of female rats of the same age although this treatment increased liver weight in both sexes at this age. Serum testosterone levels were decreased in 21-day-old male rats following neonatal exposure to 80 or 500 ppm toluene and in 56-day-old male rats exposed neonatally to 1000 ppm toluene. In conclusion, exposure to toluene during the first week of life caused significant changes in various liver microsomal cytochrome P-450 dependent enzyme activities in 8-day-old pups, whereas the long-term effects on liver metabolism of the adult animal were small.

Androstenedione↗