Pharmacokinetics of radiolabeled tungsten ((188)W) in male Sprague-Dawley rats following acute sodium tungstate inhalation.

Aerosol cloud formation may occur when certain tungsten munitions strike hard targets, placing military personnel at increased risk of exposure. Although the pharmacokinetics of various forms of tungsten have been studied in animals following intravenous and oral administration, tungsten disposition following inhalation remains incompletely characterized. The objective of this study was to evaluate the pharmacokinetics of inhaled tungstate (WO(4)) in rats. Male, 16-wk-old, CD rats (n = 7 rats/time point) underwent a single, 90-min, nose-only exposure to an aerosol (mass median aerodynamic diameter [MMAD] 1.50 mum ) containing 256 mg W/m(3) as radiolabeled sodium tungstate (Na(2)(188)WO(4)). (188)W tissue concentrations were determined at 0, 1, 3, 7, and 21 days postexposure by gamma spectrometry. The thyroid and urine had the highest (188)W levels postexposure, and urinary excretion was the primary route of (188)W elimination. The pharmacokinetics of tungsten in most tissues was best described with a two-compartment pharmacokinetic model with initial phase half-lives of approximately 4 to 6 h and a longer terminal phase with half-lives of approximately 6 to 67 days. The kidney, adrenal, spleen, femur, lymph nodes, and brain continued to accumulate small amounts of tungsten as reflected by tissue:blood activity ratios that increased throughout the 21-day period. At day 21 all tissues except the thyroid, urine, lung, femur, and spleen had only trace levels of (188)W. Data from this study can be used for development and refinement of pharmacokinetic models for tungsten inhalation exposure in environmental and occupational settings.

Reproductive toxicity and pharmacokinetics of di-n-butyl phthalate (DBP) following dietary exposure of pregnant rats.

Most rodent developmental toxicity studies of dibutylphthalate (DBP) have relied on bolus gavage dosing. This study characterized the developmental toxicity of dietary DBP. Pregnant CD rats were given nominal doses of 0, 100, or 500 mg DBP/kg/day in diet (actual intake 0, 112, and 582 mg/kg/day) from gestational day (GD) 12 through the morning of GD 19. Rats were killed 4 or 24 hr thereafter. DBP dietary exposure resulted in significant dose-dependent reductions in testicular mRNA concentration of scavenger receptor class B, member 1; steroidogenic acute regulatory protein; cytochrome P450, family 11, subfamily a, polypeptide 1; and cytochrome P450 family 17, subfamily a, polypeptide 1. These effects were most pronounced 4 hr after the end of exposure. Testicular testosterone was reduced 24 hr post-exposure in both DBP dose groups and 4 hr after termination of the 500-mg DBP/kg/day exposure. Maternal exposure to 500 mg DBP/kg/day induced a significant reduction in male offspring's anogenital distance indicating in utero disruption of androgen function. Leydig cell aggregates, increased cord diameters, and multinucleated gonocytes were present in DBP-treated rats. Monobutyl phthalate, the developmentally toxic metabolite of DBP, and its glucuronide conjugate were found in maternal and fetal plasma, amniotic fluid, and maternal urine. Our results, when compared to previously conducted gavage studies, indicate that approximately equal doses of oral DBP exposure of pregnant rats, from diet or gavage, result in similar responses in male offspring.

Acute sodium tungstate inhalation is associated with minimal olfactory transport of tungsten (188W) to the rat brain.

Olfactory transport of represents an important mechanism for direct delivery of certain metals to the central nervous system (CNS). The objective of this study was to determine whether inhaled tungsten (W) undergoes olfactory uptake and transport to the rat brain. Male, 16-week-old, Sprague-Dawley rats underwent a single, 90-min, nose-only exposure to a Na(2)(188)WO(4) aerosol (256 mg W/m(3)). Rats had the right nostril plugged to prevent nasal deposition of (188)W on the occluded side. The left and right sides of the nose and brain, including the olfactory pathway and striatum, were sampled at 0, 1, 3, 7, and 21 days post-exposure. Gamma spectrometry (n=7 rats/time point) was used to compare the levels of (188)W found on the left and right sides of the nose and brain and blood to determine the contribution of olfactory uptake to brain (188)W levels. Respiratory and olfactory epithelial samples from the side with the occluded nostril had significantly lower end-of-exposure (188)W levels confirming the occlusion procedure. Olfactory bulb, olfactory tract/tubercle, striatum, cerebellum, rest of brain (188)W levels paralleled blood (188)W concentrations at approximately 2-3% of measured blood levels. Brain (188)W concentrations were highest immediately following exposure, and returned to near background concentrations within 3 days. A statistically significant difference in olfactory bulb (188)W concentration was seen at 3 days post-exposure. At this time, (188)W concentrations in the olfactory bulb from the side ipsilateral to the unoccluded nostril were approximately 4-fold higher than those seen in the contralateral olfactory bulb. Our data suggest that the concentration of (188)W in the olfactory bulb remained low throughout the experiment, i.e., approximately 1-3% of the amount of tungsten seen in the olfactory epithelium suggesting that olfactory transport plays a minimal role in delivering tungsten to the rat brain.

Metabolomic analyses of body fluids after subchronic manganese inhalation in rhesus monkeys.

Neurotoxicity is linked with high-dose manganese inhalation. There are few biomarkers that correlate with manganese exposure. Blood manganese concentrations depend upon the magnitude and duration of the manganese exposure and inconsistently reflect manganese exposure concentrations. The objective of this study was to search for novel biomarkers of manganese exposure in the urine and blood obtained from rhesus monkeys following subchronic manganese sulfate (MnSO(4)) inhalation. Liquid chromatography-mass spectrometry was used to identify putative biomarkers. Juvenile rhesus monkeys were exposed 5 days/week to airborne MnSO(4) at 0, 0.06, 0.3, or 1.5 mg Mn/m(3) for 65 exposure days or 1.5 mg Mn/m(3) for 15 or 33 days. Monkeys exposed to MnSO(4) at >or= 0.06 mg Mn/m(3) developed increased brain manganese concentrations. A total of 1097 parent peaks were identified in whole blood and 2462 peaks in urine. Principal component analysis was performed on a subset of 113 peaks that were found to be significantly changed following subchronic manganese exposure. Using the Nearest Centroid analysis, the subset of 113 significantly perturbed components predicted globus pallidus manganese concentrations with 72.9% accuracy for all subchronically exposed monkeys. Using the five confirmed components, the prediction rate for high brain manganese levels remained > 70%. Three of the five identified components, guanosine, disaccharides, and phenylpyruvate, were significantly correlated with brain manganese levels. In all, 27 metabolites with statistically significant expression differences were structurally confirmed by MS-MS methods. Biochemical changes identified in manganese-exposed monkeys included endpoints relate to oxidative stress (e.g., oxidized glutathione) and neurotransmission (aminobutyrate, glutamine, phenylalanine).

Genotoxicity of intermittent co-exposure to benzene and toluene in male CD-1 mice.

Benzene is an important industrial chemical. At certain levels, benzene has been found to produce aplastic anemia, pancytopenia, myeloblastic anemia and genotoxic effects in humans. Metabolism by cytochrome P450 monooxygenases and myeloperoxidase to hydroquinone, phenol, and other metabolites contributes to benzene toxicity. Other xenobiotic substrates for cytochrome P450 can alter benzene metabolism. At high concentrations, toluene has been shown to inhibit benzene metabolism and benzene-induced toxicities. The present study investigated the genotoxicity of exposure to benzene and toluene at lower and intermittent co-exposures. Mice were exposed via whole-body inhalation for 6h/day for 8 days (over a 15-day time period) to air, 50 ppm benzene, 100 ppm toluene, 50 ppm benzene and 50 ppm toluene, or 50 ppm benzene and 100 ppm toluene. Mice exposed to 50 ppm benzene exhibited an increased frequency (2.4-fold) of micronucleated polychromatic erythrocytes (PCE) and increased levels of urinary metabolites (t,t-muconic acid, hydroquinone, and s-phenylmercapturic acid) vs. air-exposed controls. Benzene co-exposure with 100 ppm toluene resulted in similar urinary metabolite levels but a 3.7-fold increase in frequency of micronucleated PCE. Benzene co-exposure with 50 ppm toluene resulted in a similar elevation of micronuclei frequency as with 100 ppm toluene which did not differ significantly from 50 ppm benzene exposure alone. Both co-exposures - 50 ppm benzene with 50 or 100 ppm toluene - resulted in significantly elevated CYP2E1 activities that did not occur following benzene or toluene exposure alone. Whole blood glutathione (GSH) levels were similarly decreased following exposure to 50 ppm benzene and/or 100 ppm toluene, while co-exposure to 50 ppm benzene and 100 ppm toluene significantly decreased GSSG levels and increased the GSH/GSSG ratio. The higher frequency of micronucleated PCE following benzene and toluene co-exposure when compared with mice exposed to benzene or toluene alone suggests that, at the doses used in this study, toluene can enhance benzene-induced clastogenic or aneugenic bone marrow injury. These findings exemplify the importance of studying the effects of binary chemical interactions in animals exposed to lower exposure concentrations of benzene and toluene on benzene metabolism and clastogenicity. The relevance of these data on interactions for humans exposed at low benzene concentrations can be best assessed only when the mechanism of interaction is understood at a quantitative level and incorporated within a biologically based modeling framework.

Respiratory tract responses in male rats following subchronic acrolein inhalation.

The goal of this study was to characterize the respiratory tract toxicity of acrolein, including nasal and pulmonary effects, in adult male F344 rats. Animals underwent whole-body exposure to 0, 0.02, 0.06, 0.2, 0.6, or 1.8 ppm acrolein for 6 hr/day, five days/week for up to 65 exposure days (13 exposure weeks). Respiratory tract histopathology was evaluated after 4, 14, 30, and 65 exposure days, as well as 60 days after the end of the 13 week exposure. Acrolein exposure was associated with reduced body weight gain. Rats exposed to > or = 0.06 ppm acrolein had depressed terminal body weights when compared with air-exposed controls. Histologic evaluation of the nasal cavity showed olfactory epithelial inflammation and olfactory neuronal loss (ONL) following exposure to 1.8 ppm acrolein. Moderately severe ONL in the dorsal meatus and ethmoid turbinates occurred within four days while septal involvement developed with ongoing exposure. A rostral-caudal gradient in lesion severity was noted, with the anterior portion of the nasal cavity being more severely affected. Acrolein exposure was associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. The lateral wall was amongst the most sensitive locations for these responses and increased respiratory epithelial cell proliferation occurred at this site following 4 to 30 days of exposure to > or = 0.6 ppm acrolein. The NOAEL for nasal pathology seen in this study was 0.2 ppm acrolein.

Nasal uptake of inhaled acrolein in rats.

An improved understanding of the relationship between inspired concentration of the potent nasal toxicant acrolein and delivered dose is needed to support quantitative risk assessments. The uptake efficiency (UE) of 0.6, 1.8, or 3.6 ppm acrolein was measured in the isolated upper respiratory tract (URT) of anesthetized naive rats under constant-velocity unidirectional inspiratory flow rates of 100 or 300 ml/min for up to 80 min. An additional group of animals was exposed to 0.6 or 1.8 ppm acrolein, 6 h/day, 5 days/wk, for 14 days prior to performing nasal uptake studies (with 1.8 or 3.6 ppm acrolein) at a 100 ml/min airflow rate. Olfactory and respiratory glutathione (GSH) concentrations were also evaluated in naive and acrolein-preexposed rats. Acrolein UE in naive animals was dependent on the concentration of inspired acrolein, airflow rate, and duration of exposure, with increased UE occurring with lower acrolein exposure concentrations. A statistically significant decline in UE occurred during the exposures. Exposure to acrolein vapor resulted in reduced respiratory epithelial GSH concentrations. In acrolein-preexposed animals, URT acrolein UE was also dependent on the acrolein concentration used prior to the uptake exposure, with preexposed rats having higher UE than their naive counterparts. Despite having increased acrolein UE, GSH concentrations in the respiratory epithelium of acrolein preexposed rats were higher at the end of the 80 min acrolein uptake experiment than their in naive rat counterparts, suggesting that an adaptive response in GSH metabolism occurred following acrolein preexposure.

Derivation of an inhalation reference concentration based upon olfactory neuronal loss in male rats following subchronic acetaldehyde inhalation.

Acetaldehyde inhalation induces neoplastic and nonneoplastic responses in the rodent nasal cavity. This experiment further characterizes the dose-response relationship for nasal pathology, nasal epithelial cell proliferation, and DNA-protein cross-link formation in F-344 rats exposed subchronically to acetaldehyde. Animals underwent whole-body exposure to 0, 50, 150, 500, or 1500 ppm acetaldehyde for 6 h/day, 5 days/wk for up to 65 exposure days. Respiratory tract histopathology was evaluated after 4, 9, 14, 30, and 65 exposure days. Acetaldehyde exposure was not associated with reduced body weight gain or other evidence of systemic toxicity. Histologic evaluation of the nasal cavity showed an increased incidence of olfactory neuronal loss (ONL) following acute to subchronic exposure to > or = 150 ppm acetaldehyde and increased olfactory epithelial cell proliferation following exposure to 1500 ppm acetaldehyde. The severity of the ONL demonstrated dose- and temporal-dependent behaviors, with minimal effects noted at 150-500 ppm acetaldehyde and moderately severe lesions seen in the highest exposure group, with increased lesion severity and extent as the exposure duration increased. Acetaldehyde exposure was also associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. These responses were seen in animals exposed to > or = 500 ppm acetaldehyde. Acetaldehyde exposure was not associated with increased DNA-protein cross-link formation in the respiratory or olfactory epithelium. A model of acetaldehyde pharmacokinetics in the nose was used to derive an inhalation reference concentration (RfC) of 0.4 ppm, based on the no-observed-adverse-effect level (NOAEL) of 50 ppm for the nasal pathology seen in this study.

Basal ganglia neurotransmitter concentrations in rhesus monkeys following subchronic manganese sulfate inhalation.

BACKGROUND: Manganese neurotoxicity in humans is recognized as a form of parkinsonism with lesions occurring predominantly within the globus pallidus, subthalamic nucleus, putamen, and caudate nucleus. METHODS: This study evaluated dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, norepinephrine, 5-hydroxyindoleacetic acid, gamma-aminobutyric acid (GABA), and glutamate concentrations in the globus pallidus, caudate, and putamen of male rhesus monkeys exposed subchronically to either air or manganese sulfate (MnSO4) at 0.06, 0.3, or 1.5 mg Mn/m3. RESULTS: An approximate 1.5-6-fold increase (vs. air-exposed controls) in mean brain manganese concentration was observed following subchronic MnSO4 exposure. A marginally significant (P < 0.1) decrease in pallidal GABA and 5-hydroxyindoleacetic acid concentration and caudate norepinephrine concentration occurred in monkeys exposed to MnSO4 at 1.5 mg Mn/m3. CONCLUSIONS: Despite the presence of increased tissue manganese concentrations, high-dose exposure to MnSO4 was associated with relatively few changes in basal ganglial neurotransmitter concentrations.

Preliminary investigation of changes in the sexually dimorphic nucleus of the rat medial preoptic area following prenatal exposure to fenitrothion.

In vitro, the organophosphate insecticide fenitrothion is a potent competitive androgen receptor antagonist, whereas in vivo it affects the development of the male rat reproductive system. The purpose of this pilot study was to determine whether prenatal exposure to fenitrothion affects development of the rat sexually dimorphic nucleus of the medial preoptic area (SDN-POA). Pregnant rats (n = 5-6 litters/group) were orally dosed with corn oil (vehicle) or fenitrothion (20 or 25 mg kg(-1) day(-1)) from gestation day (GD) 12-21. Offspring were euthanized after reaching sexual maturity (females 60-65 days old and males 96-105 days old) and the SDN-POA volumes determined for two rats/sex/litter. Tremors, increased lacrimation and decreased body weight gain were observed in dams from both fenitrothion exposure groups. Reproductive effects in male offspring, including reduced anogenital distance on postnatal day (PND) 1 and increased retention of areolae (PND 13) were observed following fenitrothion exposure at these dose levels. These effects did not persist into adulthood. There was a dose-related increase in the SDN-POA volume in males and a dose-related decrease in SDN-POA volume in females exposed to fenitrothion. These SDN-POA volume changes contrast with those seen with flutamide, another potent anti-androgen, and suggest that fenitrothion may have mixed endocrine effects on the developing brain.

Tissue manganese concentrations in young male rhesus monkeys following subchronic manganese sulfate inhalation.

High-dose human exposure to manganese results in manganese accumulation in the basal ganglia and dopaminergic neuropathology. Occupational manganese neurotoxicity is most frequently linked with manganese oxide inhalation; however, exposure to other forms of manganese may lead to higher body burdens. The objective of this study was to determine tissue manganese concentrations in rhesus monkeys following subchronic (6 h/day, 5 days/week) manganese sulfate (MnSO(4)) inhalation. A group of monkeys were exposed to either air or MnSO(4) (0.06, 0.3, or 1.5 mg Mn/m(3)) for 65 exposure days before tissue analysis. Additional monkeys were exposed to MnSO(4) at 1.5 mg Mn/m(3) for 15 or 33 exposure days and evaluated immediately thereafter or for 65 exposure days followed by a 45- or 90-day delay before evaluation. Tissue manganese concentrations depended upon the aerosol concentration, exposure duration, and tissue. Monkeys exposed to MnSO(4) at > or = 0.06 mg Mn/m(3) for 65 exposure days or to MnSO(4) at 1.5 mg Mn/m(3) for > or = 15 exposure days developed increased manganese concentrations in the olfactory epithelium, olfactory bulb, olfactory cortex, globus pallidus, putamen, and cerebellum. The olfactory epithelium, olfactory bulb, globus pallidus, caudate, putamen, pituitary gland, and bile developed the greatest relative increase in manganese concentration following MnSO(4) exposure. Tissue manganese concentrations returned to levels observed in the air-exposed animals by 90 days after the end of the subchronic MnSO(4) exposure. These results provide an improved understanding of MnSO(4) exposure conditions that lead to increased concentrations of manganese within the nonhuman primate brain and other tissues.

Correlation of brain magnetic resonance imaging changes with pallidal manganese concentrations in rhesus monkeys following subchronic manganese inhalation.

High-dose manganese exposure is associated with parkinsonism. Because manganese is paramagnetic, its relative distribution within the brain can be examined using magnetic resonance imaging (MRI). Herein, we present the first comprehensive study to use MRI, pallidal index (PI), and T(1) relaxation rate (R1) in concert with chemical analysis to establish a direct association between MRI changes and pallidal manganese concentration in rhesus monkeys following subchronic inhalation of manganese sulfate (MnSO(4)). Monkeys exposed to MnSO(4) at > or = 0.06 mg Mn/m(3) developed increased manganese concentrations in the globus pallidus, putamen, olfactory epithelium, olfactory bulb, and cerebellum. Manganese concentrations within the olfactory system of the MnSO(4)-exposed monkeys demonstrated a decreasing rostral-caudal concentration gradient, a finding consistent with olfactory transport of inhaled manganese. Marked MRI signal hyperintensities were seen within the olfactory bulb and the globus pallidus; however, comparable changes could not be discerned in the intervening tissue. The R1 and PI were correlated with the pallidal manganese concentration. However, increases in white matter manganese concentrations in MnSO(4)-exposed monkeys confounded the PI measurement and may lead to underestimation of pallidal manganese accumulation. Our results indicate that the R1 can be used to estimate regional brain manganese concentrations and may be a reliable biomarker of occupational manganese exposure. To our knowledge, this study is the first to provide evidence of direct olfactory transport of an inhaled metal in a nonhuman primate. Pallidal delivery of manganese, however, likely arises primarily from systemic delivery and not directly from olfactory transport.

Application of pharmacokinetic data to the risk assessment of inhaled manganese.

There is increased interest within the scientific community concerning the neurotoxicity of manganese owing in part to the use of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline fuel additive and an enhanced awareness that this essential metal may play a role in hepatic encephalopathy and other neurologic diseases. Neurotoxicity generally arises over a prolonged period of time and results when manganese intake exceeds its elimination leading to increases in brain manganese concentration. Neurotoxicity can occur following high dose oral, inhalation, or parenteral exposure or when hepatobiliary clearance of this metal is impaired. Studies completed during the past several years have substantially improved our understanding of the health risks posed by inhaled manganese by determining exposure conditions that lead to increased concentrations of manganese within the central nervous system and other target organs. Many of these studies focused on phosphates, sulfates, and oxides of manganese since these are formed and emitted following MMT combustion by an automobile. These studies have evaluated the role of direct nose-to-brain transport of inhaled manganese and have examined differences in manganese toxicokinetics in potentially sensitive subpopulations (e.g., fetuses, neonates, individuals with compromised hepatic function or sub-optimal manganese intake, and the aged). This manuscript reviews the U.S. Environmental Protection Agency's current risk assessment for inhaled manganese, summarizes these contemporary pharmacokinetic studies, and considers how these data could inform future risk assessments of this metal following inhalation.

Sub-chronic inhalation of high concentrations of manganese sulfate induces lower airway pathology in rhesus monkeys.

BACKGROUND: Neurotoxicity and pulmonary dysfunction are well-recognized problems associated with prolonged human exposure to high concentrations of airborne manganese. Surprisingly, histological characterization of pulmonary responses induced by manganese remains incomplete. The primary objective of this study was to characterize histologic changes in the monkey respiratory tract following manganese inhalation. METHODS: Subchronic (6 hr/day, 5 days/week) inhalation exposure of young male rhesus monkeys to manganese sulfate was performed. One cohort of monkeys (n = 4-6 animals/exposure concentration) was exposed to air or manganese sulfate at 0.06, 0.3, or 1.5 mg Mn/m3 for 65 exposure days. Another eight monkeys were exposed to manganese sulfate at 1.5 mg Mn/m3 for 65 exposure days and held for 45 or 90 days before evaluation. A second cohort (n = 4 monkeys per time point) was exposed to manganese sulfate at 1.5 mg Mn/m3 and evaluated after 15 or 33 exposure days. Evaluations included measurement of lung manganese concentrations and evaluation of respiratory histologic changes. Tissue manganese concentrations were compared for the exposure and control groups by tests for homogeneity of variance, analysis of variance, followed by Dunnett's multiple comparison. Histopathological findings were evaluated using a Pearson's Chi-Square test. RESULTS: Animals exposed to manganese sulfate at > or = 0.3 mg Mn/m3 for 65 days had increased lung manganese concentrations. Exposure to manganese sulfate at 1.5 mg Mn/m3 for > or = 15 exposure days resulted in increased lung manganese concentrations, mild subacute bronchiolitis, alveolar duct inflammation, and proliferation of bronchus-associated lymphoid tissue. Bronchiolitis and alveolar duct inflammatory changes were absent 45 days post-exposure, suggesting that these lesions are reversible upon cessation of subchronic high-dose manganese exposure. CONCLUSION: High-dose subchronic manganese sulfate inhalation is associated with increased lung manganese concentrations and small airway inflammatory changes in the absence of observable clinical signs. Subchronic exposure to manganese sulfate at exposure concentrations (< or = 0.3 mg Mn/m3) similar to the current 8-hr occupational threshold limit value established for inhaled manganese was not associated with pulmonary pathology.

Maternal-fetal distribution of manganese in the rat following inhalation exposure to manganese sulfate.

Studies examining the pharmacokinetics of manganese during pregnancy have largely focused on the oral route of exposure and have shown that the amount of manganese that crosses the rodent placenta is low. However, limited information exists regarding the distribution of manganese in fetal tissues following inhalation. The objective of this study was to determine manganese body burden in CD rats and fetuses following inhalation of a MnSO4 aerosol during pregnancy. Animals were evaluated following pre-breeding (2 weeks), mating (up to 14 days) and gestational (from gestation day (GD) 0 though 20) exposure to air or MnSO4 (0.05, 0.5, or 1 mg Mn/m(3)) for 6h/day, 7 days/week. The following maternal samples were collected for manganese analysis: whole blood, lung, pancreas, liver, brain, femur, and placenta. Fetal tissues were examined on GD 20 and included whole blood, lung, liver, brain, and skull cap. Maternal lung manganese concentrations were increased following exposure to MnSO4 at >or=0.05 mg Mn/m(3). Maternal brain and placenta manganese concentrations were increased following exposure of pregnant rats to MnSO4 at >or=0.5 mg Mn/m(3). Increased fetal liver manganese concentrations were observed following in utero exposure to MnSO4 at >or=0.5 mg Mn/m(3). Manganese concentrations within all other fetal tissues were not different from air-exposed controls. The results of this study demonstrate that the placenta partially sequesters inhaled manganese, thereby limiting exposure to the fetus.

Tissue manganese concentrations in lactating rats and their offspring following combined in utero and lactation exposure to inhaled manganese sulfate.

There is little information regarding the tissue distribution of manganese in neonates following inhalation. This study determined tissue manganese concentrations in lactating CD rats and their offspring following manganese sulfate (MnSO4) aerosol inhalation. Except for the period of parturition, dams and their offspring were exposed to air or MnSO4 (0.05, 0.5, or 1 mg Mn/m3) for 6 h/day, 7 days/week starting 28 days prior to breeding through postnatal day (PND) 18. Despite increased manganese concentrations in several maternal tissues, MnSO4 inhalation exposure did not affect body weight gain, terminal (PND 18) body weight, or organ weights in the dams. Exposure to MnSO4 at 1 mg Mn/m3 resulted in decreased pup body weights on PND 19 and decreased brain weights in some PND 14 to PND 45 pups. Exposure to MnSO4 at > or =0.05 mg Mn/m3 was associated with increased stomach content, blood, liver, and skull cap manganese concentrations in PND 1 pups, increased brain, lung, and femur manganese concentrations in PND 14 pups, and elevated olfactory bulb, cerebellum, and striatum manganese concentrations in PND 19 pups. When compared to controls, MnSO4 exposure to > or =0.5 mg Mn/m3 increased liver and blood manganese concentrations in PND 14 pups and increased liver, pancreas, and femur manganese concentrations in PND 19 pups. Manganese concentrations returned to control values in all offspring tissues by PND 45 +/- 1. Our data demonstrate that neonatal tissue manganese concentrations observed following MnSO4 inhalation are dependent on the MnSO4 exposure concentration and the age of the animal.

Respiratory tract toxicity of inhaled hydrogen sulfide in Fischer-344 rats, Sprague-Dawley rats, and B6C3F1 mice following subchronic (90-day) exposure.

The goal of this study was to characterize the toxicity of hydrogen sulfide (H2S), including nasal and pulmonary effects, in adult male and female Fischer-344 and Sprague-Dawley rats and B6C3F1 mice. Animals underwent whole-body exposure to 0, 10, 30, or 80 ppm H2S for 6 h/day for at least 90 days. Exposure to 80 ppm H2S was associated with reduced feed consumption during either the first exposure week (rats) or throughout the 90-day exposure (mice). Male Fischer-344 rats, female Sprague-Dawley rats, and female B6C3F1 mice exposed to 80 ppm H2S had depressed terminal body weights when compared with air-exposed controls. Subchronic H2S inhalation did not result in toxicologically relevant alterations in hematological indices, serum chemistries, or gross pathology. Histologic evaluation of the nose showed an exposure-related increased incidence of olfactory neuronal loss (ONL) and rhinitis. ONL occurred following exposure to > or =30 ppm H2S in both sexes of all experimental groups, with one exception, male Sprague-Dawley rats demonstrated ONL following exposure to 80 ppm H2S only. A 100% incidence of rhinitis was found in the male and female B6C3F1 mice exposed to 80 ppm H2S. In the lung, exposure to H2S was associated with bronchiolar epithelial hypertrophy and hyperplasia in male and female Sprague-Dawley rats following exposure to > or =30 ppm H2S and in male Fischer-344 rats exposed to 80 ppm H2S. Our results confirm that the rodent nose, and less so the lung, are highly sensitive to H2S-induced toxicity, with 10 ppm representing the NOAEL for ONL following subchronic inhalation.

Old age and gender influence the pharmacokinetics of inhaled manganese sulfate and manganese phosphate in rats.

In this study, we examined whether gender or age influences the pharmacokinetics of manganese sulfate (MnSO(4)) or manganese phosphate (as the mineral form hureaulite). Young male and female rats and aged male rats (16 months old) were exposed 6 h day(-1) for 5 days week(-1) to air, MnSO(4) (at 0.01, 0.1, or 0.5 mg Mn m(-3)), or hureaulite (0.1 mg Mn m(-3)). Tissue manganese concentrations were determined in all groups at the end of the 90-day exposure and 45 days later. Tissue manganese concentrations were also determined in young male rats following 32 exposure days and 91 days after the 90-day exposure. Intravenous (54)Mn tracer studies were also performed in all groups immediately after the 90-day inhalation to assess whole-body manganese clearance rates. Gender and age did not affect manganese delivery to the striatum, a known target site for neurotoxicity in humans, but did influence manganese concentrations in other tissues. End-of-exposure olfactory bulb, lung, and blood manganese concentrations were higher in young male rats than in female or aged male rats and may reflect a portal-of-entry effect. Old male rats had higher testis but lower pancreas manganese concentrations when compared with young males. Young male and female rats exposed to MnSO(4) at 0.5 mg Mn m(-3) had increased (54)Mn clearance rates when compared with air-exposed controls, while senescent males did not develop higher (54)Mn clearance rates. Data from this study should prove useful in developing dosimetry models for manganese that consider age or gender as potential sensitivity factors.

Brain manganese concentrations in rats following manganese tetroxide inhalation are unaffected by dietary manganese intake.

Manganese-deficient individuals have decreased manganese elimination. This observation has prompted suggestions that relative manganese deficiency may increase the risk for manganese neurotoxicity following inhalation exposure. The objective of this study was to determine whether dietary manganese intake influences the pharmacokinetics of inhaled manganese tetroxide (Mn3O4). Postnatal day (PND) 10 rats were placed on either a low (2 ppm), sufficient (10 ppm), or high-normal (100 ppm) manganese diet for 2 months. Beginning on PND 77 +/- 2, male littermates were exposed 6 h per day for 14 consecutive days to 0, 0.042, or 0.42 mg Mn3O4/m3. End-of-exposure tissue manganese concentrations and whole-body 54Mn elimination rates were determined. Tissue manganese concentrations were dependent on the dietary intake of manganese, thus confirming that altered hepatic manganese disposition or metabolism occurred. Male rats given 100 ppm manganese diet developed increased manganese concentrations in the femur, liver, and bile and had elevated whole-body 54Mn clearance rates when compared to animals given 2 ppm manganese diet. Male rats exposed to 0.42 mg Mn3O4/m3 had increased manganese concentrations in the olfactory bulb, lung, liver, and bile when compared to air-exposed male rats. A significant interaction between the concentration of inhaled Mn3O4 and dietary manganese level was observed only with the end-of-exposure liver manganese concentration. Our results indicate that animals maintained on either a manganese-deficient or high manganese diet do not appear to be at increased risk for elevated brain manganese concentrations following inhalation exposure to high levels of Mn3O4.

Effects of in utero exposure to the organophosphate insecticide fenitrothion on androgen-dependent reproductive development in the Crl:CD(SD)BR rat.

Fenitrothion [0,0-dimethyl-O-(4-nitro-m-tolyl) phosphorothioate] is an organophosphate insecticide that has been shown to have antiandrogenic activity using in vitro and in vivo screening assays. Studies were performed to evaluate the ability of fenitrothion to disrupt androgen-dependent sexual differentiation in the male rat. Pregnant Crl:CD(SD)BR rats were administered fenitrothion by gavage at 0, 5, 10, 15, 20, or 25 mg/kg/day ( n = 6-11/group) from gestation day (GD) 12 to 21. Maternal toxicity was observed in the dams treated with 20 and 25 mg fenitrothion/kg/day based on muscle tremors and decreases in body weight gain from GD 12 to 21. Fetal death was increased in the 20 and 25 mg/kg/day exposure groups, as evidenced by a decrease in the proportion of pups born alive. Androgen-mediated development of the reproductive tract was altered in male offspring exposed in utero to maternally toxic levels of fenitrothion (25 mg/kg/day), as evidenced by reduction in anogenital distance on postnatal day (PND) 1 and retention of areolae on PND 13. However, these effects were only transient, and there were no indications of abnormal phenotypes or development of androgen-dependent tissues on PND 100. At the dose levels evaluated in this study, fenitrothion was only weakly antiandrogenic in vivo compared with other androgen receptor antagonists such as flutamide, linuron, and vinclozolin. Based on observed fetotoxicity at 20 mg/kg/day, the lowest observed adverse effect level (LOAEL) for developmental effects can be lowered from 25 to 20 mg/kg/day.