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PubMed1998

Correspondence between occupational exposure limit and biological action level values for alkoxyethanols and their acetates.

OBJECTIVES: The Finnish occupational exposure limit (OEL) values for alkoxyethanols and their acetates were lowered in 1996. A reevaluation of the correspondence between the new OEL value and the biological action level (BAL) was thus needed. This study was conducted in silkscreen printing enterprises, where 2-alkoxyethanols and their acetates are mainly used as solvents. The air/urine correlations between 2-methoxyethylacetate, 2-ethoxyethylacetate, 2-butoxyethanol, 2-butoxyethylacetate, and 2-methoxyacetic (MAA), 2-ethoxyacetic (EAA), and 2-butoxyacetic acid (BAA) were evaluated on an individual and time-related basis at four different enterprises. METHODS: Inhalation exposure to alkoxyalcohols and their acetates was monitored with diffusion badges (n = 38) for an entire work week. Urinary excretion of alkoxyacetic acids immediatley after the shift and at 14-16 h after exposure (n = 112) was analyzed by a gas chromatograph equipped with a flame-ionization detector. RESULTS: Inhalation exposure to 2-methoxyethylacetate at 0.5 cm3/m3 corresponded to MAA excretion of 3 mmol/mol creatinine in urine at 14 to 16 hours after exposure. The next-morning urinary EAA excretion of 37 mmol/mol creatinine corresponded to an 8-h 2-ethoxyethylacetate exposure of 2 cm3/m3 when all collected data were included. This average EAA excretion was 69% of the German BAT value and only 34% of the American biological exposure index (BEI) value. Urinary EAA excretion was 30-40% lower at the beginning of the work week than at the end of the work week. On the other hand, EAA excretion was 10-20% higher than that measured at 14-16 h after exposure. Urinary BAA excretion of 75 mmol/mol creatinine in postshift urine corresponded to an 8-h 2-butoxyethanol and 2-butoxyethylacetate exposure of 5 cm3/m3. This BAA excretion was 87% of the German BAT value. CONCLUSION: According to these results, it seems that the BAL for MAA and EAA should be 3 and 50 mmol/mol creatinine as measured at 14-16 h after exposure, respectively. The BAL value for BAA seems to be 70 mmol/mol creatinine in postshift samples. These recommendations are valid only if samples are collected at the end of the work week.

Acetates↗
PubMed2001

Inflammatory macrophage nuclear factor-kappaB and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite.

A history of abuse of nitrite inhalants has been correlated with HIV seropositivity and Kaposi's sarcoma. A series of 14 daily, 45-min exposures of mice to 900-ppm isobutyl nitrite in an inhalation chamber reduced the number of peritoneal exudate macrophages (PEM) by 35% and the number of resident peritoneal macrophages (RPM) by 18%. Although the tumoricidal activity of RPM was not affected by the inhalant, the cytotoxicity of PEM was reduced by 26%. The induction of nitric oxide (NO) and the inducible NO synthase (iNOS) protein in PEM were inhibited by the inhalant to a similar extent. Inhibition of NF-kappaB activation in PEM from mice exposed to the inhalant corresponded to reduced degradation of the NF-kappaB inhibitor, IkappaB alpha. Proteasome-associated, enzymatic activity was compromised in PEM from inhalant-exposed mice, suggesting that inhaled isobutyl nitrite compromised macrophage, tumoricidal activity by inhibiting proteasomal degradation of the NF-kappaB inhibitor, IkappaB alpha.

Administration, Inhalation↗
PubMed1998

Assessment of pyrethroid-induced paraesthesias: comparison of animal model and human data.

The quantification of upper respiratory tract (URT) sensory irritation is considered to be important in rodent inhalation studies, since it may be also used as an endpoint mimicking trigeminal paraesthesias observed in humans. URT sensory irritation is known to be associated with rodent-specific secondary physiological effects such as depression of body temperature and changes in heart rate. In acutely exposed rats, these endpoints have been addressed by telemetrical measurements. The analysis of the ventilation pattern during acute inhalation studies of rats exposed to the alpha-cyano-pyrethroid cyfluthrin demonstrates that concentration-dependent URT sensory irritation was associated with a hypothermic response. The no-effect levels (NO(A)EL) based on the URT sensory irritation endpoint following acute inhalation exposure for 1 h and following a repeated 4-week or 13-week inhalation exposure for 6 h/day on 5 days week were virtually identical (approximately 0.1 mg/m3 air). An additional objective was to examine whether human volunteers experience comparable signs when acutely exposed for 1 h to airborne concentrations slightly above or in the range of the NO(A)EL. In human volunteers there were no clinically significant or pyrethroid related abnormalities in vital signs, ECG's or in any clinical laboratory tests after either exposure, although transient effects related to URT (sensory) irritation were reported. In conclusion, an initial actual exposure concentration of approximately 0.1 mg cyfluthrin/m3 air appears to be in the range of the sensory irritant threshold concentration for both rats and humans. Thus, with regard to physiological afferent portal-of-entry effects, the interspecies response was consistent.

Administration, Inhalation↗
PubMed1999

Physiologically based toxicokinetic modeling of inhaled ethyl tertiary-butyl ether in humans.

A physiologically based toxicokinetic (PBTK) model was developed for evaluation of inhalation exposure in humans to the gasoline additive, ethyl tertiary-butyl ether (ETBE). PBTK models are useful tools to relate external exposure to internal doses and biological markers of exposure in humans. To describe the kinetics of ETBE, the following compartments were used: lungs (including arterial blood), liver, fat, rapidly perfused tissues, resting muscles, and working muscles. The same set of compartments and, in addition, a urinary excretion compartment were used for the metabolite tertiary-butyl alcohol (TBA). First order metabolism was assumed in the model, since linear kinetics has been shown experimentally in humans after inhalation exposure up to 50 ppm ETBE. Organ volumes and blood flows were calculated from individual body composition based on published equations, and tissue/blood partition coefficients were calculated from liquid/air partition coefficients and tissue composition. Estimates of individual metabolite parameters of 8 subjects were obtained by fitting the PBTK model to experimental data from humans (5, 25, 50 ppm ETBE, 2-h exposure; Nihlén et al., Toxicol. Sci., 1998; 46, 1-10). The PBTK model was then used to predict levels of the biomarkers ETBE and TBA in blood, urine, and exhaled air after various scenarios, such as prolonged exposure, fluctuating exposure, and exposure during physical activity. In addition, the interindividual variability in biomarker levels was predicted, in the eight experimentally exposed subjects after a working week. According to the model, raising the work load from rest to heavy exercise increases all biomarker levels by approximately 2-fold at the end of the work shift, and by 3-fold the next morning. A small accumulation of all biomarkers was seen during one week of simulated exposure. Further predictions suggested that the interindividual variability in biomarker levels would be higher the next morning than at the end of the work shift, and higher for TBA than for ETBE. Monte Carlo simulations were used to describe fluctuating exposure scenarios. These simulations suggest that ETBE levels in blood and exhaled air at the end of the working day are highly sensitive to exposure fluctuations, whereas ETBE levels the next morning and TBA in urine and blood are less sensitive. Considering these simulations, data from the previous toxicokinetic study and practical issues, we suggest that TBA in urine is a suitable biomarker for exposure to ETBE and gasoline vapor.

Biomarkers↗
PubMed1999

Potential operator exposure to procymidone in greenhouses.

Recent legislation in the European Union requires regulators of member states to carry out risk assessments using data for actual or potential operator exposure, or estimates of exposure from models. However, the existing models have few datasets from studies carried out on greenhouse or indoor crops, particularly in southern Europe. In this study potential dermal and inhalatory exposures were measured in two trials in Italian greenhouses. The total potential dermal operator exposure of the applicator, measured with a whole-body passive dosimetry method, was 15.4 and 37.1 mL/h of the diluted pesticide mixture. The majority of the contamination was on the hands and on the lower part of the coverall. Approximately 0. 003% of the active ingredient (ai) applied to the crop area contaminated the coverall worn by the operator. The potential dermal exposure during the mixing and loading phase accounted for 6-8% of the total potential dermal exposure during the whole process. Inhalation exposure accounted for only 0.05-0.07% of the total potential operator exposure. Model predictions of the potential operator exposure using a modified version of the German model overestimate the mixing-loading exposure while underestimating the application exposure. These data are evidence that the estimation coefficient set for hand-held application to ornamental and horticultural crops may be inadequate for the agronomic conditions of southern Europe.

Agriculture↗
PubMed2005

Derivation of a human equivalent concentration for n-butanol using a physiologically based pharmacokinetic model for n-butyl acetate and metabolites n-butanol and n-butyric acid.

The metabolic series approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic (PK) data for each compound and toxicity data for the parent compound. The metabolic series approach for n-butyl acetate and its subsequent metabolites, n-butanol and n-butyric acid (the butyl series), was first demonstrated using a provisional physiologically based pharmacokinetic (PBPK) model for the butyl series. The objective of this work was to complete development of the PBPK model for the butyl series. Rats were administered test compounds by iv bolus dose, iv infusion, or by inhalation in a recirculating closed chamber. Hepatic, vascular, and extravascular metabolic constants for metabolism were estimated by fitting the model to the blood time course data from these experiments. The respiratory bioavailability of n-butyl acetate (100% of alveolar ventilation) and n-butanol (50% of alveolar ventilation) was estimated from closed chamber inhalation studies and measured ventilation rates. The resulting butyl series PBPK model successfully reproduces the blood time course of these compounds following iv administration and inhalation exposure to n-butyl acetate and n-butanol in rats and arterial blood n-butanol kinetics following inhalation exposure to n-butanol in humans. These validated inhalation route models can be used to support species and dose-route extrapolations required for risk assessment of butyl series family of compounds. Human equivalent concentrations of 169 ppm and 1066 ppm n-butanol corresponding to the rat n-butyl acetate NOAELs of 500 and 3000 ppm were derived using the models.

1-Butanol↗
PubMed2001

Chronic pulmonary effects of respirable methylene diphenyl diisocyanate (MDI) aerosol in rats: combination of findings from two bioassays.

Two independent bioassays are available which have examined the potential carcinogenicity of monomeric and polymeric methylene diphenyl diisocyanate (MDI) following long-term inhalation exposure in rats. These studies are not directly comparable, however, due to differences in design and conduct of the in-life phase, and differences in nomenclature used for some of the histopathological findings. This paper presents a definitive overview ofthe pulmonary toxicity of MDI developed following a thorough review of both investigations. As part of this process, the test materials and the designs of the studies were compared, and an in-depth review of lung lesions was conducted by an independent reviewing pathologist. This included the re-examination of the original lung slides, supported by an analysis of the exposure regimens, the results of which were used to develop an accurate profile of the doses received by the animals in the two studies. Histopathological findings were then combined with this information to give an overall dose-response curve for both studies as a whole. The range of total inhalation exposures to MDI was calculated as 559, 1972, 2881, 6001, 17,575 and 17,728 mgh/m3. Major pulmonary effects included increased lung weights together with bronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis which occurred consistently in both studies, indicating a very similar qualitative response of the lungs to polymeric and monomeric MDI. The quantitative response of the lung was clearly dose-related in each study, and when the studies were considered as a whole a reasonable overall dose-response relationship was apparent for major lung lesions. Lung tumours (in low incidences) only occurred at the highest dose level in both studies (17,575 and 17,728 mgh/m3). For inflammatory and other non-neoplastic pulmonary changes, the lowest dose examined (559 mgh/m3) was regarded as a no-observed-adverse-effect-level for both polymeric and monomeric MDI. It was concluded that the results of the two studies could be combined to serve as a basis for human risk assessment of MDI.

Adenoma↗
PubMed1986

Unscheduled DNA synthesis in rat tracheal epithelial cells, hepatocytes and spermatocytes following exposure to methyl chloride in vitro and in vivo.

Measurement of DNA repair as unscheduled DNA synthesis (UDS) in vitro following exposure in vivo in multiple tissues from the same treated animal can provide valuable information relating to the tissue- and organ-specificity of chemically induced DNA damage. UDS was evaluated in primary cultures of rat tracheal epithelial cells, hepatocytes and pachytene spermatocytes after exposure in vitro to methyl chloride (MeCl), and after isolation from the same treated animal following inhalation exposure in vivo. Concentrations of 1-10% MeCl in vitro induced UDS in hepatocytes and spermatocytes, but not in tracheal epithelial cells. Inhalation exposure to MeCl in vivo (3000-3500 ppm 6 h/day for 5 successive days) failed to induce DNA repair in any cell type. In vivo exposure to 15 000 ppm MeCl for 3 h also failed to induce UDS in tracheal epithelial cells and spermatocytes, but did cause a marginal increase in UDS in hepatocytes. Thus, MeCl appears to be a weak, direct-acting genotoxicant. While activity could be measured in hepatocytes and spermatocytes directly in vitro, only extremely high concentrations of MeCl elicited a response in the whole animal, and then only in hepatocytes.

Animals↗
PubMed1998

Peroxyacetyl nitrate: review of toxicity.

PAN is one of a class of common air pollutants formed by the action of sunlight on volatile organic compounds and nitrogen oxides. No toxicokinetic studies have been found in the available literature. The acute toxicity of PAN is less than that of ozone, similar to NO2 and higher than SO2. The LC30, in mice and rats were 718-743 mg/m3 (for 2 h) and 470 mg/m3 (for 4 h), respectively. Following acute exposure, severe lung lesions and, at the higher levels, damage to the epithelium of upper parts of the respiratory tract were found in animals. It seems that concentrations of 1.19-1.49 mg/m3 lie not far from the threshold required for pulmonary function effects in sensitive individuals. However, these PAN concentrations are well above the maximum ambient concentrations usually experienced within the USA and Canada (0.003-0.078 mg/m3). It appears unlikely that present ambient PAN concentrations would affect pulmonary functions responses to ambient ozone. In human, the lowest level causing eye irritations was 0.64 mg/m3 for 2 h. Concentrations of 0.99 and 4.95 mg/m3 were identified as no-observed-effect level (NOEL) and no-observed-adverse-effect level (NOAEL) for pathological and histological changes in the respiratory system (nasal passages) of rats during subchronic exposures to PAN, but were not considered to be relevant to derivation of a RfC for chronic inhalation exposure. PAN is a weak point mutagen or clastogen. The data are not sufficient to evaluate its carcinogenicity. No study was found which could be used for the derivation of a RfC for acute or chronic inhalation exposure to PAN.

Administration, Inhalation↗
PubMed2005

DNA damage in mice treated with sulfur dioxide by inhalation.

Sulfur dioxide (SO2) is a ubiquitous air pollutant produced by the burning of fossil fuels. In this study, single-cell gel electrophoresis (the Comet assay) was used to evaluate the DNA damage produced by inhalation exposure of mice to SO2. Male and female mice were housed in exposure chambers and treated with 14.00 +/- 1.25, 28.00 +/- 1.98, 56.00 +/- 3.11, and 112.00 +/- 3.69 mg/m3 SO2 for 6 hr/day for 7 days, while control groups were exposed to filtered air. Comet assays were performed on blood lymphocytes and cells from the brain, lung, liver, spleen, kidney, intestine, and testicles of the animals. SO2 caused significant, dose-dependent increases in DNA damage, as measured by Olive tail moment, in all the cell types analyzed from both sexes of mice. The results indicate that inhalation exposure to SO2 damages the DNA of multiple organs in addition to the lung, and suggests that this damage could result in mutation, cancer, and other diseases related to DNA damage. Further work will be required to understand the ultimate toxicological significance of this damage. These data also suggest that detecting DNA damage in blood lymphocytes, using the Comet assay, may serve as a useful tool for evaluating the impact of pulmonary SO2 exposure in human biomonitoring studies.

Air Pollutants↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Toluene (CAS No.108-88-3) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Toluene is used to back-blend gasoline, as a chemical intermediate, and as a solvent; 920 million gallons were produced in the United States in 1988. Toxicology studies were conducted by administering toluene (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or by whole-body inhalation exposure for 14 or 15 weeks. NTP Toxicology and Carcinogenesis studies were conducted by whole-body inhalation exposure of F344/N rats and B6C3F1 mice of each sex for 15 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells. Thirteen-Week Gavage Studies: All rats that received the top dose of 5,000 mg/kg died during the first week, and 8/10 male rats that received 2,500 mg/kg died early. The final mean body weight of male rats that received 2,500 mg/kg was 19% lower than that of vehicle controls. Relative liver, kidney, and heart (female only) weights for rats that received the higher doses were greater than those for vehicle controls. Necrosis of the brain and hemorrhage of the urinary bladder were seen at increased incidences in dosed rats. All mice that received the top dose of 5,000 mg/kg died during the first week, and 40% of those that received 2,500 mg/kg died before the end of the 13-week gavage studies. The final mean body weight of males at 2,500 mg/kg was 16% lower than that of vehicle controls. At the higher doses, relative liver weights were increased for mice. Fifteen-Week and Fourteen-Week Inhalation Studies: Eight of 10 male rats exposed at the top exposure concentration of 3,000 ppm died during week 2. Final mean body weights of rats exposed at concentrations of 2,500 or 3,000 ppm were 14%-25% lower than that of controls. As in the gavage studies, the relative liver, kidney, and heart weights for rats exposed at the top two concentrations were increased compared with those for controls. No compound-related effects were seen on sperm; no adverse effects on the estrous cycle were observed. Five of 10 male mice and all female mice exposed at 3,000 ppm and 70% of female mice at 2,500 ppm died during the first 2 weeks. Final mean body weights of all exposed groups were 7%-13% lower than those of controls. Relative liver weights for mice exposed at 625 ppm or higher, relative lung weights for mice exposed at 1,250 ppm or higher, and relative kidney weights for female mice exposed at 1,250 ppm or higher were greater than those for controls. Centrilobular hypertrophy of the liver was observed in all male mice exposed at 2,500 ppm and 70% of male mice exposed at 3,000 ppm. No effects on sperm or the estrous cycle were observed. Fifteen-Month and Two-Year Inhalation Studies: Long-term studies were conducted by exposing groups of 60 rats of each sex to 0, 600, or 1,200 ppm toluene by inhalation, 6.5 hours per day, 5 days per week. Groups of 60 mice of each sex were exposed at 0, 120, 600, or 1,200 ppm on the same schedule. Ten animals per group (except male mice) were removed for toxicologic evaluation after being exposed for 15 months. All other animals were exposed to toluene for 103 weeks. In the 15-month inhalation studies, the incidences and severity of nonneoplastic lesions of the nasal cavity (degeneration of olfactory and respiratory epithelium and goblet cell hyperplasia) were increased in exposed rats. Minimal hyperplasia of the bronchial epithelium was seen in 4/10 female mice at 1,200 ppm. The severity of nephropathy was slightly increased in exposed female rats. No chemical-induced neoplasms were observed. Body Weight and Survival in the Two-Year Studies: Mean body weights of rats and mice were generally similar (yearly averages within 5%) among groups throughout the 2-year studies. No significant differences in survival were observed among rats or mice of either sex, although survival in all groups of male mice was lower than usual (male rats: control, 30/50; 600 ppm, 28/50; 1,200 ppm, 22/50; female rats: 33/50; 35/50; 30/50; male mice: control, 17/60; 120 ppm, 22/50; female rats: 33/50; 35/50; 30/50; male mice: control, 17/60; 120 ppm, 22/60; 600 ppm, 16/60; 1,200 ppm, 19/60; female mice: 30/50; 33/50; 24/50; 32/50). Scrotal, preputial, and penile lesions observed in male mice were associated with many of the early deaths and with animals killed in a moribund condition. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy was seen in almost all rats, and the severity was somewhat increased in exposed rats. A rare renal tubular cell carcinoma in a female rat and an equally uncommon sarcoma of the kidney in another female rat were seen in the 1,200-ppm exposure group. Erosion of the olfactory epithelium and degeneration of the respiratory epithelium were increased in exposed rats. Inflammation of the nasal mucosa and metaplasia of the olfactory epithelium were increased in exposed female rats. A rare squamous cell carcinoma of the nasal mucosa was seen in one female rat at 1,200 ppm. A squamous cell papilloma of the forestomach was observed in one female rat at 1,200 ppm, and a squamous cell carcinoma was observed in a second female rat at 1,200 ppm. No chemically related neoplasms were found in male rats, and the one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with inhalation exposed to toluene. For mice, no biologically important increases were observed for any nonneoplastic or neoplastic lesions. Genetic Toxicology: Toluene did not induce gene mutations in S. typhimurium strain TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In the mouse lymphoma assay, toluene gave an equivocal response with and without exogenous metabolic activation. Toluene did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity for male or female F344/N rats exposed to toluene at concentrations of 600 or 1,200 ppm. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed by inhalation to toluene at concentrations of 120, 600, or 1,200 ppm for 2 years. Synonyms: monomethylbenzene; methylbenzene; toluol; phenylmethane; tolueen (Dutch); toluen (Czech), tolueno (Spanish); toluolo (Italian) Trade Name: Methacide

Journal Article↗
PubMed1986

Physiologically based pharmacokinetic modeling of inhaled 2-butoxyethanol in man.

The arterial blood concentration of 2-butoxyethanol (ethylene glycol monobutyl ether) was simulated in a physiologically based pharmacokinetic model developed for a 70-kg man. Elimination data (Vmax and Km) were extrapolated from the perfused rat liver, while flows and volumes were from the literature. Simulated inhalation exposure to 2-butoxyethanol at 20 ppm (0.8 mmol/m3) and physical exercise at 50 W agrees well with the results from experimental exposure of human volunteers under identical conditions. In further simulations, the marked effects of physical exercise and co-exposure to ethanol are illustrated. The relatively rapid decay of 2-butoxyethanol in all compartments indicates that the parent compound is not likely to accumulate in the body. Further, linear kinetics may be expected at occupational inhalation exposure to 2-butoxyethanol. The study serves as an example of how a physiologically based pharmacokinetic model may be used to illustrate some aspects of occupational solvent exposure.

Administration, Inhalation↗
PubMed1993

In vitro kinetics of styrene and styrene oxide metabolism in rat, mouse, and human.

Styrene oxide (SO), a labile metabolite of styrene, is generally accepted as being responsible for any genotoxicity associated with styrene. To better define the hazard associated with styrene, the activity of the enzymes involved in the formation (monooxygenase) and destruction of SO (epoxide hydrolase and glutathione-S-transferase) were measured in the liver and lungs from naive and styrene-exposed male Sprague-Dawley rats and B6C3F1 mice (three daily 6-h inhalation exposures at up to 600 ppm styrene) and Fischer 344 rats (four daily 6-h inhalation exposures at up to 1000 ppm styrene), and in samples of human liver tissue. Additionally, the time course of styrene and SO in the blood was measured following oral administration of 500 mg styrene/kg body weight to naive Fischer rats and rats previously exposed to 1000 ppm styrene. The affinity of hepatic monooxygenase for styrene, as measured by the Michaelis constant (Km), was similar in the rat, mouse, and human. Based on the Vmax for monooxygenase activity and the relative liver and body size, the mouse had the greatest capacity and humans the lowest capacity to form SO from styrene. In contrast, human epoxide hydrolase and a greater affinity (i.e., lower Km) for SO than epoxide hydrolase from rats or mice while the apparent Vmax for epoxide hydrolase was similar in the rat, mouse, and human liver. However, the activity of epoxide hydrolase relative to monooxygenase activity was much greater in the human than in the rodent liver. Hepatic glutathione-S-transferase activity, as indicated by the Vmax, was 6- to 33-fold higher than epoxide hydrolase activity. However, the significance of the high glutathione-S-transferase activity is unknown because hydrolysis, rather than conjugation, is the primary pathway for SO detoxification in vivo. Human hepatic glutathione-S-transferase activity was extremely variable between individual human livers and much lower than in rat or mouse liver. Prior exposure to styrene had no effect on monooxygenase activity or on blood styrene levels in rats given a large oral dose of styrene. In contrast, prior exposure to styrene increased hepatic epoxide hydrolase activity 1.6-fold and resulted in lower (0.1 > P > 0.05) blood SO levels in rats given a large oral dose of styrene. Qualitatively, these data indicate that the mouse has the greatest capacity and the human the lowest capacity to form SO. In addition, human liver should be more effective than rodent liver in hydrolyzing low levels of SO.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed1992

Aflatoxin B1--DNA adduct formation in rat liver following exposure by aerosol inhalation.

There is growing concern that human exposure to respirable grain dust contaminated with aflatoxin B1 (AFB1), a potent hepatocarcinogen, may be a risk factor for a number of human diseases. The objective of this study was to determine if liver DNA adduct formation occurs in rats following either intratracheal injection or nose-only aerosol inhalation exposure to AFB1. Male Fischer 344 rats were exposed by both routes of administration, and in preliminary data using intratracheal instillation, up to 2% of the administered dose became bound to liver DNA. In the nose-only aerosol inhalation experiments, rats were exposed for up to 120 min. Immediately after exposure, four animals were killed at each time point and their livers removed, DNA isolated and purified and analyzed for aflatoxin-DNA adducts by HPLC. A linear dose-response relationship was observed with a correlation coefficient of 0.96 between increasing length of exposure, and the amount of aflatoxin-N7-guanine adducts formed per mg DNA, the mean values and standard errors were 4.2 +/- 0.18, 15.3 +/- 4.3, 21.6 +/- 2.8 and 56.8 +/- 4.6 pmol aflatoxin-DNA adducts per mg DNA for the 20, 40, 60 and 120 min exposures respectively. The amounts of aflatoxin-DNA adducts formed were statistically significantly different (P less than 0.01) among the treated groups. These results indicate that aerosol inhalation is an effective route of exposure to AFB1 in rats that results in genotoxic damage in the liver.

Administration, Inhalation↗
PubMed1994

Non-occupational exposures to pesticides for residents of two U.S. cities.

The Non-Occupational Pesticide Exposure Study, funded by the U.S. Environmental Protection Agency, was designed to assess total human exposures to 32 pesticides and pesticide degradation products in the non-occupational environment; however, the study focused primarily on inhalation exposures. Two sites--Jacksonville, Florida (USA) and Springfield/Chicopee, Massachusetts (USA)--were studied during three seasons: Summer 1986 (Jacksonville only), Spring 1987, and Winter 1988. Probability samples of 49 to 72 persons participated in individual site/seasons. The primary environmental monitoring consisted of 24-hr indoor, personal, and outdoor air samples analyzed by gas chromatography/mass spectrometry and gas chromatography/electron capture detection. Indoor and personal air concentrations tended to be higher in Jacksonville than in Springfield/Chicopee. Concentrations tended to be highest in summer, lower in spring, and lowest in winter. Indoor and personal air concentrations were generally comparable and were usually much higher than outdoor air concentrations. Inhalation exposure exceeded dietary exposure for cyclodiene termiticides and for pesticides used mainly in the home. Dietary exposures were greater for many of the other pesticides. Inhalation risks were uncertain for termiticides (depending on rates of degradation) but were negligible for other pesticides. The data were insufficient to support risk assessments for food, dermal contact, or house dust exposures.

Adolescent↗
PubMed2003

Risk assessment dosimetry model for inhaled particulate matter: I. Human subjects.

Pollutant particulate matter (PM) is a serious global problem, presenting a threat to the health and well being of human subjects. Inhalation exposures tests with surrogate animals can be performed to estimate the threat. However, it is difficult to extrapolate the findings of animal tests to human conditions. In this two-part series, interspecies dosimetry models especially designed for implementation with risk assessment protocols are presented. In Part I, the mathematical integrity of the source model per se was tested with data from human subjects, and theoretical predictions agreed well with experimental measurements. In Part II, for surrogate (rat) simulations, appropriate algorithms for morphologies and ventilatory parameters were used as subroutines in the validated model. We conducted a comprehensive series of computer simulations describing the behavior of a representative air pollutant, secondary cigarette smoke. For risk assessment interests, a range of states from rest to exercise was considered. PM hygroscopicity had a pronounced effect on deposition in a complex but systematic manner, in humans and rats: deposition was increased for particles larger than about 1 microm, but was decreased for particles smaller than about 0.1 microm. The results clearly indicate that dosimetry models can be effectively used to a priori determine the laboratory conditions necessary for animals tests to accurately mimic human conditions. Moreover, the use of interspecies models is very cost effective. We propose, therefore, that mathematical models be used in a complementary manner with inhalation exposure experiments and be actively integrated into PM risk assessment protocols.

Air Pollutants↗
PubMed1998

[Occupational exposure to inhalation anesthetics at the work-place of veterinary surgery].

In a prospective study we evaluated the work-place pollution by isoflurane and nitrous oxide during various anaesthetic procedures in animal surgery. The study was conducted during one working week at an University Animal Department. Trace concentrations of isoflurane and nitrous oxide were directly measured every minute in the breathing zone by means of a photoacoustic infrared spectrometer in two different operating rooms (OR) with an air turnover of 17 changes per hour. In one OR the 8-hour time-weighted average (mean +/- SEM) was calculated to be 12.3 +/- 9.9 ppm nitrous oxide and 1.9 +/- 2.5 ppm isoflurane. The other OR, where only isoflurane was used, was contaminated with 5.3 +/- 8.1 ppm isoflurane. In the first OR, the trace gas concentrations were low and comparable to values obtained under human anaesthesia in adults and children. The higher contamination in the second OR resulted from performing inhalational anaesthesia with an open mask system in birds and small animals. Although the mean values were below the recommended occupational exposure standards, some high peak values (> 300 ppm isoflurane) violated these threshold limits. We recommend the use of a local scavenging device, if other alternatives such as total intravenous anaesthesia are not possible.

Adult↗
PubMed2003

Mode of action and pharmacokinetic studies of 2-butoxyethanol in the mouse with an emphasis on forestomach dosimetry.

Chronic inhalation studies with 2-butoxyethanol (BE) conducted by the National Toxicology Program identified the forestomach and liver of B6C3F1 mice as target organs for tumorigenicity (NTP, 2000). Previous studies have shown that the liver tumors likely resulted from chronic hemolysis-induced oxidative stress. For the forestomach lesions seen in mice, chronic contact irritation (cytotoxicity) and regenerative hyperplasia are hypothesized to result in forestomach tumor development. To test this hypothesis, several experiments were conducted to address the sensitivity of the mouse forestomach to BE administered by various routes. Oral administration of undiluted BE was shown to cause irritation and a compensatory proliferative response in the mouse forestomach, confirming that direct contact between the forestomach and BE, which can occur via grooming of BE condensed on the fur during inhalation exposures, can cause irritation. However, only small amounts of BE (<10 mg/kg) were detected on the fur of mice at the end of 6-h, whole-body or nose-only inhalation exposures to the highest concentration used in the NTP chronic inhalation studies (250 ppm). Furthermore, no significant differences were detected in the end-exposure blood concentrations of BE and butoxyacetic acid (BAA) between these types of exposures. In addition, parenteral administration of BE (ip and sc injection) also resulted in forestomach lesions, indicating that there may be sources other than grooming for BE- or BAA-induced forestomach irritation. In the pharmacokinetic study, BE and, to a lesser extent, BAA was eliminated more slowly from the forestomach tissue of mice than from blood or other tissues, following either oral gavage or ip injection. The forestomach was the only tissue with detectable levels of BE at 24 h. BE and BAA were both excreted in the saliva and were present in stomach contents for a prolonged period of time following these routes of exposure, which may further contribute to forestomach tissue dosimetry. Thus, there appear to be multiple mechanisms behind the increased levels of BE and BAA in the forestomach tissue of mice, which together can contribute to a prolonged contact irritation, compensatory hyperplasia, and tumorigenicity in mice. The relevance of these effects in humans, who lack a forestomach, is questionable.

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