Biomedical subjects

David C Dorman

Publications and source records attributed to David C Dorman.

35 records · Page 2Linked to original sources

PubMed2004

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.

Administration, Inhalation↗

PubMed2004

Manganese exposure and induced oxidative stress in the rat brain.

Neurotoxicity linked to excessive brain manganese levels can occur as a result of high level Mn exposures and/or metabolic aberrations (liver disease and decreased biliary excretion). Increased brain manganese levels have been reported to induce oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral and motor deficits. Two putative mechanisms in which manganese can produce oxidative stress in the brain are: (1) via its oxidation of dopamine, and (2) interference with normal mitochondrial respiration. Measurements of antioxidant species (e.g., glutathione and metallothionein), and the abundance of proteins (enzymes) exquisitely sensitive to oxidation (e.g., glutamine synthetase) have been commonly used as biomarkers of oxidative stress, particularly in rat brain tissue. This paper examines the link between manganese neurotoxicity in the rat brain and common pathways to oxidative stress.

Animals↗

PubMed2004

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.

Administration, Inhalation↗

PubMed2004

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.

Administration, Inhalation↗

PubMed2004

Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following subchronic (13-week) inhalation exposure.

Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to further characterize the nasal toxicity of manganese sulfate (MnSO(4)) and manganese phosphate (as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnSO(4) (0.01, 0.1, and 0.5 mg Mn/m(3)), or hureaulite (0.1 mg Mn/m(3)). Nasal pathology, brain GFAP levels, and brain manganese concentrations were assessed immediately following the end of the 90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO(4) exposure to > or = 0.01, > or = 0.1, and 0.5 mg Mn/m(3), respectively. Exposure to MnSO(4) or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure to MnSO(4) (0.5 mg Mn/m(3)) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, we could not confirm that manganese inhalation would result in altered brain GFAP concentrations.

Air Pollutants↗

PubMed2004

Airborne manganese exposure differentially affects end points of oxidative stress in an age- and sex-dependent manner.

Juvenile female and male (young) and 16-mo-old male (old) rats inhaled manganese in the form of manganese sulfate (MnSO4) at 0, 0.01, 0.1, and 0.5 mg Mn/m3 or manganese phosphate at 0.1 mg Mn/m3 in exposures of 6 h/d, 5 d/wk for 13 wk. We assessed biochemical end points indicative of oxidative stress in five brain regions: cerebellum, hippocampus, hypothalamus, olfactory bulb, and striatum. Glutamine synthetase (GS) protein levels, metallothionein (MT) and GS mRNA levels, and total glutathione (GSH) levels were determined for all five regions. Although most brain regions in the three groups of animals were unaffected by manganese exposure in terms of GS protein levels, there was significantly increased protein (p<0.05) in the hippocampus and decreased protein in the hypothalamus of young male rats exposed to manganese phosphate as well as in the aged rats exposed to 0.1 mg/m3 MnSO4. Conversely, GS protein was elevated in the olfactory bulb of females exposed to the high dose of MnSO4. Statistically significant decreases (p<0.05) in MT and GS mRNA as a result of manganese exposure were observed in the cerebellum, olfactory bulb, and hippocampus in the young male rats, in the hypothalamus in the young female rats, and in the hippocampus in the senescent males. Total GSH levels significantly (p<0.05) decreased in the olfactory bulb of manganese exposed young male rats and increased in the olfactory bulb of female rats exposed to manganese. Both the aged and young female rats had significantly decreased (p<0.05) GSH in the striatum resulting from manganese inhalation. The old male rats also had depleted GSH levels in the cerebellum and hypothalamus as a result of the 0.1-mg/m3 manganese phosphate exposure. These results demonstrate that age and sex are variables that must be considered when assessing the neurotoxicity of manganese.

Administration, Inhalation↗

PubMed2003

Inhaled iron, unlike manganese, is not transported to the rat brain via the olfactory pathway.

Iron and manganese share structural, biochemical, and physiological similarities. The objective of this study was to determine whether iron, like manganese, is transported to the rat brain via the olfactory tract following inhalation exposure. Eight-week-old male CD rats were exposed to approximately 0.31 mg Fe per m(3) (mass median aerodynamic diameter = 2.99 microm; geometric standard deviation = 1.15) via inhalation for a target duration of 90 min. Following exposure, rats were euthanized immediately (0) or at 1, 2, 4, 8, or 21 days postexposure. In addition to nasal and regional brain tissues, blood, and viscera were also collected. 59Fe concentrations were determined by gamma spectrometry. Further, heads were collected and frozen, and autoradiograms were prepared to visualize the location of 59Fe from the nose to the brain. Finally, olfactory mucosa samples collected at 0, 2, 4, and 21 days postexposure were further analyzed using high-performance liquid chromatography (HPLC) plus gamma spectroscopy to determine the association between 59Fe and transferrin. Data obtained from gamma spectrometry revealed that most of the iron remained in the nasal regions of the olfactory system and that less than 4% of iron deposited on the olfactory mucosa was observed in the olfactory bulb. Autoradiograms confirmed the data obtained from gamma spectrometry. 59Fe activity was absent in the olfactory regions of the brain even 4 days postexposure. Further, HPLC-gamma spectroscopy analyses indicated that 59Fe in the olfactory mucosa was coeluted with transferrin. Hence iron, unlike manganese, is not readily transported to the brain via the olfactory tract.

Administration, Inhalation↗

PubMed2003

Oxidative stress is induced in the rat brain following repeated inhalation exposure to manganese sulfate.

Eight-week-old rats inhaled manganese (Mn) in the form of MnSO4 at 0, 0.03, 0.3, or 3.0 mg Mn/m3 for 6 h/d for 7 d/wk (14 consecutive exposures). Brain manganese concentrations in these animals were reported by Dorman et al. in 2001, noting the following rank order: olfactory bulb > striatum > cerebellum. We assessed biochemical end points indicative of oxidative stress in these three brain regions, as well as the hypothalamus and hippocampus. Glutamine synthetase (GS) protein levels and total glutathione (GSH) levels were determined for all five regions. GS mRNA and metallothionein (MT) mRNA levels were also evaluated for the cerebellum, hypothalamus, and hippocampus. Statistically significant increases (p<0.05) in GS protein were observed in the olfactory bulb upon exposure to the medium and high manganese doses. In the hypothalamus, statistically significant (p<0.05) but more modest increases were also noted in the medium and high manganese dose. Total GSH levels significantly (p<0.05) decreased only in the hypothalamus (high manganese dose), and MT mRNA significantly increased in the hypothalamus (medium manganese dose). No significant changes were noted in any of the measured parameters in the striatum, although manganese concentrations in this region were also increased. These results demonstrate that the olfactory bulb and hypothalamus represent potentially sensitive areas to oxidative stress induced by exceedingly high levels of inhaled manganese sulfate and that other regions, and especially the striatum, are resistant to manganese induced oxidative stress despite significant accumulation of this metal.

Animals↗

PubMed2002

Olfactory transport: a direct route of delivery of inhaled manganese phosphate to the rat brain.

Experiments examining the dosimetry of inhaled manganese generally focus on pulmonary deposition and subsequent delivery of manganese in arterial blood to the brain. Growing evidence suggests that nasal deposition and transport along olfactory neurons represents another route by which inhaled manganese is delivered to certain regions of the rat brain. The purpose of this study was to evaluate the olfactory uptake and direct brain delivery of inhaled manganese phosphate ((54)MnHPO(4)). Male, 8-wk-old, CD rats with either both nostrils patent or the right nostril occluded underwent a single, 90-min, nose-only exposure to a (54)MnHPO(4) aerosol (0.39 mg (54)Mn/m(3); MMAD 1.68 microm, sigma(g) 1.42). The left and right sides of the nose, olfactory pathway, striatum, cerebellum, and rest of the brain were evaluated immediately after the end of the (54)MnHPO(4) exposure and at 1, 2, 4, 8, and 21 d postexposure with gamma spectrometry and autoradiography. Rats with two patent nostrils had equivalent (54)Mn concentrations on both sides of the nose, olfactory bulb, and striatum, while asymmetrical (54)Mn delivery occurred in rats with one occluded nostril. High levels of (54)Mn activity were observed in the olfactory bulb and tubercle on the same side (i.e., ipsilateral) to the open nostril within 1-2 d following (54)MnHPO(4) exposure, while brain and nose samples on the side ipsilateral to the nostril occlusion had negligible levels of (54)Mn activity. Our results demonstrate that the olfactory route contributes to (54)Mn delivery to the rat olfactory bulb and tubercle. However, this pathway does not significantly contribute to striatal (54)Mn concentrations following a single, short-term inhalation exposure to (54)MnHPO(4).

Administration, Inhalation↗

PubMed2002

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.

Administration, Inhalation↗

PubMed2002

Effects of manganese (Mn) on the developing rat brain: oxidative-stress related endpoints.

We evaluated biochemical endpoints related to oxidative stress in brains of neonatal rats exposed to manganese (Mn). Oral Mn chloride (MnCl2) (0, 25, or 50 mg Mn chloride kg(-1) body weight per day) was given daily to neonatal rats throughout lactation (i.e. from postnatal day (PND) 1 to 21). As previously reported by [J. Appl. Toxicol. 20 (2000) 179], this treatment paradigm results in increased cerebral cortex (CTX) Mn concentrations in PND 21 rats from both Mn treatment groups. High dose Mn exposure also results in increased cerebellar Mn concentrations. This preliminary study determined whether this exposure paradigm also affects cerebrocortical or cerebellar metallothionein (MT) mRNA levels, glutamine synthetase (GS) activity, GS protein levels, as well as total glutathione (GSH) levels. High dose Mn exposure significantly increased (P < 0.05) total cerebrocortical GSH without accompanying changes in any of the other measured parameters. Therefore, it is unlikely that high dose Mn exposure is associated with oxidative stress in this experimental paradigm.

Animals↗

PubMed2002

Cytochrome oxidase inhibition induced by acute hydrogen sulfide inhalation: correlation with tissue sulfide concentrations in the rat brain, liver, lung, and nasal epithelium.

Hydrogen sulfide (H2S) is an important brain, lung, and nose toxicant. Inhibition of cytochrome oxidase is the primary biochemical effect associated with lethal H2S exposure. The objective of this study was to evaluate the relationship between the concentration of sulfide and cytochrome oxidase activity in target tissues following acute exposure to sublethal concentrations of inhaled H2S. Hindbrain, lung, liver, and nasal (olfactory and respiratory epithelial) cytochrome oxidase activity and sulfide concentrations were determined in adult male CD rats immediately after a 3-h exposure to H2S (10, 30, 80, 200, and 400 ppm). We also determined lung sulfide and sulfide metabolite concentrations at 0, 1.5, 3, 3.25, 3.5, 4, 5, and 7 h after the start of a 3-h H2S exposure to 400 ppm. Lung sulfide concentrations increased during H2S exposure and rapidly returned to endogenous levels within 15 min after the cessation of the 400-ppm exposure. Lung sulfide metabolite concentrations were transiently increased immediately after the end of the 3-h H2S exposure. Decreased cytochrome oxidase activity was observed in the olfactory epithelium following exposure to > or = 30 ppm H2S. Increased olfactory epithelial sulfide concentrations were observed following exposure to 400 ppm H2S. Hindbrain and nasal respiratory epithelial sulfide concentrations were unaffected by acute H2S exposure. Nasal respiratory epithelial cytochrome oxidase activity was reduced following acute exposure to > or = 30 ppm H2S. Liver sulfide concentrations were increased following exposure to > or = 200 ppm H2S and cytochrome oxidase activity was increased following inhalation exposure to > or = 10 ppm H2S. Our results suggest that cytochrome oxidase inhibition is a sensitive biomarker of H2S exposure in target tissues, and sulfide concentrations are unlikely to increase postexposure in the brain, lung, or nose following a single 3-h exposure to < or = 30 ppm H2S.

Animals↗

PubMed2002

Predicted regional flux of hydrogen sulfide correlates with distribution of nasal olfactory lesions in rats.

Hydrogen sulfide (H(2)S) is a toxic gas that is released by both natural and industrial sources. H(2)S selectively targets the olfactory system in humans and rodents. The purpose of this study was to test the hypothesis that the distribution of H(2)S-induced nasal pathology is correlated with the location of high-flux areas within the upper respiratory tract. To investigate whether the location of the olfactory lesion is dependent on regional gas uptake patterns, a comparison was made between lesion locations and regions of high H(2)S flux predicted using a 3-dimensional, anatomically accurate computational fluid dynamics (CFD) model of rat nasal passages. Rats were exposed by inhalation to 0, 10, 30, or 80 ppm H(2)S for 6 h/day for 70 days. The regional incidence of olfactory lesions and predicted H(2)S flux were determined at the mid-dorsomedial meatus and the middle portion of the ethmoid recess, and their rank correlation was evaluated. At these 2 levels, regions lined by respiratory epithelium were predicted to exhibit the highest mass flux values; however, H(2)S exposure elicited little or no response in this tissue. In contrast, regions lined by olfactory epithelium showed a close correlation between H(2)S flux and lesion incidence (p < 0.005) for both the 30 and 80-ppm exposure groups. These results indicate that airflow-driven patterns of H(2)S uptake within the inherently sensitive olfactory epithelium play an important role in the distribution of H(2)S-induced lesions and should therefore be taken into consideration when extrapolating from nasal lesions in rats to estimates of risk to human health.

Administration, Inhalation↗

PubMed2002

Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor.

Humans and wildlife are frequently exposed to mixtures of endocrine active-compounds (EAC). The objective of the present study was to investigate the potential of the phytoestrogen genistein to influence the reproductive developmental toxicity of the endocrine-active pesticide methoxychlor. Three levels of genistein (0, 300, or 800 ppm) and two levels of methoxychlor (0 or 800 ppm) were used in this study. Sprague-Dawley rats were exposed to the two compounds, either alone or in combinations, through dietary administration to dams during pregnancy and lactation and to the offspring directly after weaning. Both compounds, methoxychlor in particular, were associated with reduced body growth at 800 ppm, but pregnancy outcome was not affected by either treatment. An acceleration of vaginal opening (VO) in the exposed female offspring was the only observed effect of genistein at 300 ppm. Exposure to 800 ppm genistein or 800 ppm methoxychlor caused accelerated VO and also altered estrous cyclicity toward persistent estrus in the female offspring. The estrogenic responses to genistein and methoxychlor administered together were apparently accumulative of the effects associated with each compound alone. Methoxychlor, but not genistein, delayed preputial separation (PPS) in the male rats. When administered with methoxychlor, genistein at 800 ppm enhanced the effect of methoxychlor on delaying PPS. Genistein and methoxychlor treatment did not change gender-specific motor activity patterns in either sex. To explore possible mechanisms for interaction between the two compounds on development, we performed estrogen receptor (ER)- and androgen receptor (AR)-based in vitro transcriptional activation assays using genistein and the primary methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). While the in vitro assays supported the estrogenic effects of genistein and methoxychlor and the antiandrogenic effects of methoxychlor, the reactivity of these compounds with ERs alpha and beta could not predict the greater in vivo estrogenic potency of methoxychlor over genistein; nor could the potentiation of the methoxychlor effect on PPS by genistein be predicted based on in vitro HPTE and genistein reactions with the AR. Data from this study indicate that phytoestrogens are capable of altering the toxicological behaviors of other EACs, and the interactions of these compounds may involve complexities that are difficult to predict based on their in vitro steroid receptor reactivities.

Animals↗

PubMed2002

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.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Olfactory mucosal necrosis in male CD rats following acute inhalation exposure to hydrogen sulfide: reversibility and the possible role of regional metabolism.

Hydrogen sulfide (H2S) is a potent inhibitor of cytochrome oxidase (CO) and is associated with dysosmia and anosmia in humans and nasal lesions in exposed rodents. An improved understanding of the pathogenesis of these lesions is needed to determine their toxicological relevance. We exposed 10-week-old male CD rats to 0, 30, 80, 200, or 400 ppm H2S for 3 hours/day for 1 or 5 days consecutively. The nose was histologically examined 24 hours after H2S exposure, and lesion recovery was assessed at 2 and 6 weeks following the 5-day exposure. A single 3-hour exposure to > or = 80 ppm H2S resulted in regeneration of the respiratory mucosa and full thickness necrosis of the olfactory mucosa localized to the ventral and dorsal meatus, respectively. Repeated exposure to the same concentrations caused necrosis of the olfactory mucosa with early mucosal regeneration that extended from the dorsal medial meatus to the caudal regions of the ethmoid recess. Acute exposure to 400 ppm H2S induced severe mitochondrial swelling in sustentacular cells and olfactory neurons, which progressed to olfactory epithelial necrosis and sloughing. CO immunoreactive cells were more frequently observed in regions of the olfactory mucosa commonly affected by H2S than in regions that were not. These findings demonstrate that acute exposure to >80 ppm H2S resulted in reversible lesions in the respiratory and olfactory mucosae of the CD rat and that CO immunoreactivity may be a susceptibility factor for H2S-induced olfactory toxicity in the rat.

Administration, Inhalation↗

PubMedDate not supplied

The speciation of metals in mammals influences their toxicokinetics and toxicodynamics and therefore human health risk assessment.

Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is reviewed to illustrate how the physicochemical characteristics of metals and their handling in the body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury, arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal speciation, uptake, and toxicity are evaluated. A classification system is presented to show that the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics. Essential metals, such as iron, are considered. These metals produce low oral toxicity under most exposure conditions but become toxic when biological processes that utilize or transport them are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because speciation can influence a metal's fate and toxicity, different exposure standards should be established for different metal species. Many examples are provided which consider metal essentiality and toxicity and that illustrate how consideration of metal speciation can improve the risk assessment process. More examples are available at a website established as a repository for summaries of the literature on how the speciation of metals affects their toxicokinetics.

Biotransformation↗