Pulmonary response to inhaled Kevlar aramid synthetic fibers in rats

Groups of male rats were exposed to specially prepared ultrafine Kevlar pulp fibers (du Pont's registered trademark for certain aramid fibers) at atmospheric concentrations of either 0.1, 0.5, 3.0, or 18 mg/m3 for 2 weeks. Rats were killed at 0 and 2 weeks and 3 and 6 months postexposure (PE) except the rats exposed to 18 mg/m3, which were killed 0, 4, and 14 days and 1, 3, and 6 months PE. Another group of male rats was exposed to 18 mg/m3 (respirable dust approximately 2.5 mg/m3) of commercial Kevlar fibers for 2 weeks and were killed at 0 and 2 weeks and 3 and 6 months PE. Inhaled ultrafine Kevlar fibers were mostly phagocytized by alveolar macrophages (dust cells) in the alveolar ducts and adjoining alveoli after exposure to either 0.1 or 0.5 micrograms/m3. Most dust cells had disappeared and lungs showed a normal appearance throughout 6 months PE. The pulmonary response almost satisfied the biological criteria for a nuisance dust. Rats exposed to 3 mg/m3 ultrafine Kevlar fibers revealed occasional patchy thickening of alveolar ducts with dust cells and inflammatory cells but with no collagen fibers deposited throughout 6 months PE. After exposure to 18 mg/m3 ultrafine Kevlar, the respiratory bronchioles, alveolar ducts, and adjoining alveoli showed granulomatous lesions with dust cells by 2 weeks PE. The granulomatous lesions converted to patchy fibrotic thickening with dust cells after 1 month PE. The fibrotic lesions were markedly reduced in cellularity, size, and numbers from 3 to 6 months PE but revealed networks of reticulum fibers with slight collagen fiber deposition.     

Pulmonary biochemical effects of inhaled phosgene in rats

Three exposure regimens were used to study the time course of indicators of lung damage and recovery response to single or repeated exposures to phosgene (COCl2). Rats were sacrificed immediately or throughout a 38-d recovery period after inhalation of 1 ppm COCl2 for 4 h, at intervals during a 7-h exposure to 1 ppm phosgene, or at several time points throughout a 17-d exposure to 0.125 and 0.25 ppm COCl2 (4 h/d, 5 d/wk) and during a 21-d recovery period. Regimen 1 revealed significantly elevated lung wet weight, lung nonprotein sulfhydryl (NPSH) content, and glucose-6-phosphate dehydrogenase (G6PD) activity that stayed elevated for up to 14 d. A significant decrease in body weight and food intake was observed 1 d after exposure. Regimen 2 caused a slight depression in NPSH content but did not affect G6PD activity. Regimen 3 animals showed sustained elevations in lung wet weight, NPSH content, and G6PD activity after 7 d of exposure. No significant changes in these endpoints were observed for the 0.125 ppm COCl2 group. No consistent elevation in hydroxyproline content was seen at either exposure concentration. Light microscopic examination of lung tissue exposed to 0.25 ppm COCl2 for 17 d revealed moderate multifocal accumulation of mononuclear cells in the centriacinar region. In summary, exposure to COCl2 caused changes similar in most ways to those observed for other lower-respiratory-tract irritants.     

Pulmonary exposures to Sepiolite nanoclay particulates in rats: Resolution following multinucleate giant cell formation

Sepiolite is a magnesium silicate-containing nanoclay mineral and is utilized as a nanofiller for nanocomposite applications. We postulated that lung exposures to Sepiolite clay samples could produce sustained effects. Accordingly, the pulmonary and extrapulmonary systemic impacts in rats of intratracheally instilled Sepiolite nanoclay samples were compared with quartz or ultrafine (uf) titanium dioxide particle-types at doses of 1 mg/kg or 5 mg/kg. All particulates were well characterized, and dedicated groups were evaluated by bronchoalveolar lavage, lung cell proliferation, macrophage functional assays and full body histopathology at selected times postexposure (pe). Bronchoalveolar lavage results demonstrated that quartz particles produced persistent, dose-dependent lung inflammatory responses measured from 24 h through 3 months pe. Exposures to uf TiO₂ particles or Sepiolite samples produced transient neutrophilic responses at 24-h pe; however, unlike the other particle-types, Sepiolite exposures produced macrophage-agglomerates or multinucleate giant cells at 1 week, 5 weeks and 3 months pe. In vitro alveolar macrophage functional studies demonstrated that mononuclear cells recovered from quartz but not Sepiolite or uf TiO₂-exposed rats were deficient in their chemotactic capacities. Moreover, lung parenchymal cell proliferation rates were increased in rats exposed to quartz but not Sepiolite or uf TiO₂ particles. Histopathological evaluation of lung tissues revealed that pulmonary exposures to Sepiolite nanoclay or quartz samples produced inflammation in centriacinar regions at 24-h pe but the effects decreased in severity over time for Sepiolite and increased for quartz-exposed rats. The quartz-induced lesions were progressive and were characterized at 3 months by acinar foamy alveolar macrophage accumulation and septal thickening due to inflammation, alveolar Type II cell hyperplasia and collagen deposition. In the Sepiolite nanoclay group, the finding of multinucleated giant cell accumulation associated with minor collagen deposition in acinar regions was rarely observed. Exposures to ultrafine TiO₂ produced minimal effects characterized by the occurrence of phagocytic macrophages in alveolar ducts. Full body histopathology studies were conducted at 24 h and 3 months post particle exposures. Histopathological evaluations revealed minor particle accumulations in some mediastinal or thoracic lymph nodes. However, it is noteworthy that no extrapulmonary target organ effects were observed in any of the particle-exposed groups at 3 months postexposure.     

Pulmonary deposition and effects of inhaled silica particles after short-term exposures in the rat

The present study was designed to evaluate the pulmonary deposition and the effects of inhaled silica particles in the rat model. Wistar (W/M strain) rats were exposed to silica aerosols generated from a fluidized bed dust generator for 1 hr a day, intermittently for 6 days, using a "nose-only" inhalation chamber. After the cessation of the exposures, analysis of lavaged bronchoalveolar cells (BAC) and histological examinations of lungs and tracheobronchial lymph nodes (TBLN) were performed during a period of 6 months. Total cell yields and the proportions of alveolar macrophages (AM) in BAC were not altered, whereas the proportions of lymphocytes in BAC were significantly increased in the exposed animals. Although the proportions of silica-laden AM in BAC were gradually decreased during the 6 months, particle-laden AM were predominantly and persistently observed in the alveoli under light microscopy. Silica particles were also identified in macrophages of granulomatous nodules in pulmonary peribronchial lymphoid tissues(PBLT) and TBLN, indicating the translocation of particles via the lymph. Associated with pulmonary particle deposition, some characteristic histopathological features were evident, including thickening of alveolar duct bifurcations and lymphocyte infiltrations both in the alveolar sacs and around the interstitial blood vessels. At later months after the exposures, the alveolar interstitium was thickened with the increase of fibroblasts and collagen. These results implicate that short-term exposures of silica particles in the rat can evoke histopathologic changes in the lungs and lymphatic tissues, associated with their deposition and translocation.     

Pulmonary effects of ultrafine and fine ammonium salts aerosols in healthy and monocrotaline-treated rats following short-term exposure

In the present study the effects of a 3-day inhalation exposure to model compounds for ambient particulate matter were investigated: ammonium bisulfate, ammonium ferrosulfate, and ammonium nitrate, all components of the secondary aerosol fraction of ambient particulate matter (PM), and carbon black (CB, model aerosol for primary PM). The objective of this study was to test the hypothesis that secondary model aerosols exert acute pulmonary adverse effects in rats, and that rats with pulmonary hypertension (PH), induced by monocrotaline (MCT), are more sensitive to these components than normal healthy animals. An additional aim was to test the hypothesis that fine particles exert more effects than ultrafines. Healthy and PH rats were exposed to ultrafine (mass median diameter [MMD] approximate, equals 0.07-0.10 microm; 4 x 10(5) particles/cm(3)) and fine (MMD approximate, equals 0.57-0.64 micro;m; 9 x 10(3) particles/cm(3)) ammonium aerosols during 4 h/day for 3 consecutive days. The mean mass concentrations ranged from 70 to 420 microg/m(3), respectively, for ultrafine ammonium bisulfate, nitrate, and ferrosulfate and from 275 to 410 microg/m(3) for fine-mode aerosols. In an additional experiment, simultaneous exposure to a fine CB aerosol (0.6 microm; 2-9 mg/m(3)) and ammonium nitrate (0.4-18 mg/m(3)) was performed. Bronchoalveolar lavage fluid (BALF) analysis and histopathological examination were performed on animals sacrificed 1 day after the last exposure. Histopathology of the lungs did not reveal test atmosphere-related abnormalities in either healthy or PH rats exposed to the ammonium salts, or to a combination of CB + nitrate. Alveolar macrophages in rats exposed to CB only revealed the presence of black material in their cytoplasm. There were no signs of cytotoxicity due to the aerosol exposures (as measured with lactate dehydrogenase [LDH], protein, and albumin contents in BALF). Macrophages were not activated after MCT treatment or the test atmospheres, since no changes were observed in N-acetyl glucosaminidase (NAG). Cell differentiation profiles were inconsistent, partly caused by an already present infection with Haemophilus sp. However, we believe that the test atmospheres did not affect cell differentiation or total cell counts. The results show that at exposure levels of ammonium salts at least one order of magnitude higher than ambient levels, marked adverse health effects were absent in both healthy and PH rats.     

Pulmonary effects of inhaled limonene ozone reaction products in elderly rats

d-Limonene is an unsaturated volatile organic chemical found in cleaning products, air fresheners and soaps. It is oxidized by ozone to secondary organic aerosols consisting of aldehydes, acids, oxidants and fine and ultra fine particles. The lung irritant effects of these limonene ozone reaction products (LOP) were investigated. Female F344 rats (2- and 18-month-old) were exposed for 3 h to air or LOP formed by reacting 6 ppm d-limonene and 0.8 ppm ozone. BAL fluid, lung tissue and cells were analyzed 0 h and 20 h later. Inhalation of LOP increased TNF-alpha, cyclooxygenase-2, and superoxide dismutase in alveolar macrophages (AM) and Type II cells. Responses of older animals were attenuated when compared to younger animals. LOP also decreased p38 MAP kinase in AM from both younger and older animals. In contrast, while LOP increased p44/42 MAP kinase in AM from younger rats, expression decreased in AM and Type II cells from older animals. NF-kappaB and C/EBP activity also increased in AM from younger animals following LOP exposure but decreased or was unaffected in Type II cells. Whereas in younger animals LOP caused endothelial cell hypertrophy, perivascular and pleural edema and thickening of alveolar septal walls, in lungs from older animals, patchy accumulation of fluid within septal walls in alveolar sacs and subtle pleural edema were noted. LOP are pulmonary irritants inducing distinct inflammatory responses in younger and older animals. This may contribute to the differential sensitivity of these populations to pulmonary irritants.     

Nonlinear kinetics of inhaled propylene glycol monomethyl ether in Fischer 344 rats following single and repeated exposures

The kinetics of propylene glycol monomethyl ether (PGME) and its demethylated metabolite, propylene glycol (PGLY), were investigated with the aim of describing concentration- and treatment-related changes in absorption and clearance. Groups of Fischer 344 rats received either 1 or 10 daily 6-hr inhalation exposures to PGME. Single exposures were performed using both nose-only (300, 750, 1500, and 3000 ppm) and whole-body (300 and 3000 ppm) inhalation techniques, whereas multiple exposures (300 and 3000 ppm) were confined to the whole-body procedure. PGME blood levels failed to plateau during a 6-hr inhalation exposure, indicating that absorption was limited by respiration. The clearance of PGME from the blood could be described as a pseudo-zero-order process following each exposure concentration and treatment regimen examined. PGLY blood levels indicated that the demethylation of PGME to PGLY was saturated at exposure concentrations exceeding 1500 ppm. PGME blood levels were higher in male than in female rats receiving a single 3000 ppm exposure. Unlike the results from a single exposure, PGME elimination was essentially complete 24 hr after the last of 10 consecutive 3000 ppm exposures. The changes in PGME elimination following multiple 3000 ppm exposures were associated with higher in vitro levels of cytochrome P-450 and mixed-function oxidase activity. Multiple exposures to 300 ppm did not affect PGME elimination or in vitro microsomal metabolism.     

Pulmonary responses of acute exposure to ultrafine iron particles in healthy adult rats

As critical constituents of ambient particulate matter, transition metals such as iron may play an important role in health outcomes associated with air pollution. The purpose of this study was to determine the respiratory effects of inhaled ultrafine iron particles in rats. Sprague Dawley rats 10-12 weeks of age were exposed by inhalation to iron particles (57 and 90 microg/m(3), respectively) or filtered air (FA) for 6 h/day for 3 days. The median diameter of particles generated was 72 nm. Exposure to iron particles at a concentration of 90 microg/m(3) resulted in a significant decrease in total antioxidant power along with a significant induction in ferritin expression, GST activity, and IL-1beta levels in lungs compared with lungs of the FA control or of animals exposed to iron particles at 57 microg/m(3). NFkappaB-DNA binding activity was elevated 1.3-fold compared with that of control animals following exposure to 90 microg/m(3) of iron, but this change was not statistically significant. We concluded that inhalation of iron particles leads to oxidative stress associated with a proinflammatory response in a dose-dependent manner. The activation of NFkappaB may be involved in iron-induced respiratory responses, but further studies are merited.     

Hemodynamic effects of aerosol propellants. II. Pulmonary circulation in the dog.

The inhalation of trichlorofluoromethane (FC11), dichlorotetrafluoroethane (FC114) and dichlorodifluoromethane (FC12) caused a reduction in mean aortic blood pressure but only FC11 and FC114 caused a reduction in mean pulmonary arterial pressure. The primary cause of the fall is a decrease in pulmonary blood flow. When blood flow to a lobe is kept constant and the adrenergic alpha receptors are blocked by injection of phentolamine, the inhalation of FC11 caused vasodilation. In the intact circulation, the vasodilation is masked by release of catecholamines which constrict the pulmonary blood vessels.     

Neurochemical effects in rats following gestational exposure to styrene.

Styrene was evaluated for the reproductive effects of pregnant rats and the neurochemical effects in the offspring of rats exposed during gestation. Pregnant Wistar rats were exposed to 0, 50, or 300 ppm styrene for 6 h/day during days 7 to 21 of gestation. No significant differences in the number of offspring delivered were observed between the exposed and control groups. Body weights at 1 day of age of the offspring whose mothers were exposed to styrene were significantly lower than those of the control group. Although, there were neither statistically significant differences of protein contents nor brain weights among styrene-exposed and their control offsprings of rats, analyses of neurotransmitter studies showed dose-dependent decreases of neuroamines, especially 5-HT (serotonin) and its metabolite 5HIAA (5-hydroxyindoleacetic acid) in the newborn offspring of styrene-exposed rats. The results suggest that gestational exposure to styrene at these concentrations does not produce apparent reproductive toxicity but affects the body weight of pups and causes lowering of the neurotransmitter levels in the brain.     

Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles.

A multispecies, subchronic, inhalation study comparing pulmonary responses to ultrafine titanium dioxide (uf-TiO(2)) was performed. Female rats, mice, and hamsters were exposed to aerosol concentrations of 0.5, 2.0, or 10 mg/m(3) uf-TiO(2) particles for 6 h/day, 5 days/week, for 13 weeks. Following the exposure period, animals were held for recovery periods of 4, 13, 26, or 52 weeks (49 weeks for the uf-TiO(2)-exposed hamsters) and, at each time point, uf-TiO(2) burdens in the lung and lymph nodes and selected lung responses were examined. The responses studied were chosen to assess a variety of pulmonary parameters, including inflammation, cytotoxicity, lung cell proliferation, and histopathological alterations. Retained lung burdens increased in a dose-dependent manner in all three species and were at a maximum at the end of exposures. Mice and rats had similar retained lung burdens at the end of the exposures when expressed as mg uf-TiO(2)/mg dry lung, whereas hamsters had retained lung burdens that were significantly lower. Lung burdens in all three species decreased with time after exposure, and, at the end of the recovery period, the percentage of the lung particle burden remaining in the 10 mg/m(3) group was 57, 45, and 3% for rat, mouse, and hamster, respectively. The retardation of particle clearance from the lungs in mice and rats of the 10 mg/m(3) group indicated that pulmonary particle overload had been achieved in these animals. Pulmonary inflammation in rats and mice exposed to 10 mg/m(3) was evidenced by increased numbers of macrophages and neutrophils and increased concentrations of soluble markers in bronchoalveolar lavage fluid (BALF). The initial neutrophil response in rats was greater than in mice, whereas the relative increase of macrophages was less than in mice. The neutrophilic response of rats, but not mice, declined in a time-dependent manner correlating with declining lung burdens; however, the fraction of recovered neutrophils at 52 weeks postexposure was equivalent in the two species. Consistent increases in soluble indicators of toxicity in the BALF (LDH and protein) occurred principally in rats and mice exposed to 10 mg/m(3) and diminished with time postexposure. There were no significant changes in cellular response or with markers indicating toxicity in hamsters, reflecting the capacity of these animals to rapidly clear particles from the lung. Progressive epithelial and fibroproliferative changes were observed in rats of the 10 mg/m(3) group. These lesions consisted of foci of alveolar epithelial proliferation of metaplastic epithelial cells (so-called alveolar bronchiolization) circumscribing aggregated foci of heavily particle-laden macrophages. The observed epithelial proliferative changes were also manifested in rats as an increase in alveolar epithelial cell labeling in cell proliferation studies. Associated with these foci of epithelial proliferation were interstitial particle accumulation and alveolar septal fibrosis. These lesions became more pronounced with increasing time postexposure. Epithelial, metaplastic, and fibroproliferative changes were not noted in either mice or hamsters. In summary, there were significant species differences in the pulmonary responses to inhaled uf-TiO(2) particles. Under conditions where the lung uf-TiO(2) burdens were equivalent, rats developed a more severe inflammatory response than mice and, subsequently, developed progressive epithelial and fibroproliferative changes. Clearance of particles from the lung was markedly impaired in mice and rats exposed to 10 mg/m(3) uf-TiO(2), whereas clearance in hamsters did not appear to be affected at any of the administered doses. These data are consistent with the results of a companion study using inhaled pigmentary (fine mode) TiO(2) (Bermudez et al., 2002) and demonstrate that the pulmonary responses of rats exposed to ultrafine particulate concentrations likely to induce pulmonary overload are different from similarly exposed mice and hamsters. These differences can be explained both by pulmonary respy response and by particle dosimetry differences among these rodent species.     

Acute pulmonary and systemic effects of inhaled coal fly ash in rats: comparison to ambient environmental particles.

Although primary particle emissions of ash from coal-fired power plants are well controlled, coal fly ash (CFA) can still remain a significant fraction of the overall particle exposure for some plant workers and highly impacted communities. The effect of CFA on pulmonary and systemic inflammation and injury was measured in male Sprague-Dawley rats exposed to filtered air or CFA for 4 h/day for 3 days. The average concentration of CFA particulate matter less than 2.5 microm (PM(2.5)) was 1400 microg/m(3), of which 600 microg/m(3) was PM(1). Animals were examined 18 and 36 h postexposure. Chemical analysis of CFA detected silicon, calcium, aluminum, and iron as major components. Total number of neutrophils in bronchoalveolar lavage fluid (BALF) following exposure to CFA was significantly increased along with significantly elevated blood neutrophils. Exposure to CFA caused slight increases in macrophage inflammatory protein-2, and marked increases in transferrin in BALF. Interleukin-1beta and total antioxidant potential in lung tissues were also increased in rats exposed to CFA. Histological examination of lung tissue demonstrated focal alveolar septal thickening and increased cellularity in select alveoli immediately beyond terminal bronchioles. These responses are consistent with the ability of CFA to induce mild neutrophilic inflammation in the lung and blood following short-term exposure at levels that could be occupationally relevant. However, when comparing the effects of CFA with those of concentrated ambient particles, CFA does not appear to have greater potency to cause pulmonary alterations. This study furthers our understanding of possible mechanisms by which specific sources of particulate air pollution affect human health.     

Long- and short-term changes in the neuroimmune-endocrine parameters following inhalation exposures of F344 rats to low-dose sarin.

Inhalation of subclinical doses of sarin suppresses the antibody-forming cell (AFC) response, T-cell mitogenesis, and serum corticosterone (CORT) levels, and high doses of sarin cause lung inflammation. However, the duration of these changes is not known. In these studies, rats were exposed to a subclinical dose of sarin (0.4 mg/m3/h/day) for 1 or 5 days, and immune and inflammatory parameters were assayed up to 8 weeks before sarin exposure. Our results showed that the effects of a 5-day sarin exposure on the AFC response and T-cell receptor (TCR)-mediated Ca2+ response disappeared within 2-4 weeks after sarin exposure, whereas the CORT and adrenocorticotropin hormone (ACTH) levels remained significantly decreased. Pretreatment of rats with chlorisondamine attenuated the effects of sarin on the AFC and the TCR-mediated Ca2+ response, implicating the autonomic nervous system (ANS) in the sarin-induced changes in T-cell function. Moreover, exposure to a single or five repeated subclinical doses of sarin upregulated the mRNA expression of proinflammatory cytokines in the lung, which is associated with the activation of NFkappaB in bronchoalveolar lavage cells. These effects were lost within 2 weeks of sarin inhalation. Our results suggest that while sarin-induced changes in T cells and cytokine gene expression were short lived, suppression of CORT and ACTH levels were relatively long lived and might represent biomarkers of sarin exposure. Moreover, while the effects of sarin on T-cell function were regulated by the ANS, the decreased CORT levels by sarin might result from its effects on the hypothalamus-pituitary-adrenal axis.     

Pulmonary responses of the guinea pig to inhaled A23187: a brief review.

The pulmonary effects of inhaled A23187 are reviewed. Guinea pigs challenged with this divalent cationic ionophore rapidly develop airway obstruction, which is maintained for at least 4 h. Pulmonary inflammation and increased airway responsiveness are also observed. Pharmacologic manipulations suggest that these actions are due to the release of multiple mediators. We have found A23187 challenge to be valuable as an approach for testing potential asthma drugs.     

Mortality effects of longer term exposures to fine particulate air pollution: review of recent epidemiological evidence

This article evaluates the dynamic exposure-response relationship between particulate matter air pollution (PM) and mortality risk by integrating epidemiological evidence from studies that use different time scales of exposure. The evidence suggests that short-term exposure studies are observing more than just harvesting or mortality displacement. There is little evidence of short-term compensatory reduction in deaths, and estimated PM effects are generally larger for intermediate and longer term time scales of exposure. Although proximity in time matters, with most recent exposure having the largest health impact, there is evidence that the short-term exposure studies capture only a small amount of the overall health effects of long-term repeated exposure to PM. The overall epidemiological evidence suggests that adverse health effects are dependent on both exposure concentrations and length of exposure, and that long-term exposures have larger, more persistent cumulative effects than short-term exposures.     

A dosimetric analysis of the acute behavioral effects of inhaled toluene in rats.

Knowledge of the appropriate metric of dose for a toxic chemical facilitates quantitative extrapolation of toxicity observed in the laboratory to the risk of adverse effects in the human population. Here, we utilize a physiologically based toxicokinetic (PBTK) model for toluene, a common volatile organic compound (VOC), to illustrate that its acute behavioral effects in rats can be quantitatively predicted on the basis of its concentration in the brain. Rats previously trained to perform a visual signal detection task for food reward performed the task while inhaling toluene (0, 1200, 1600, 2000, and 2400 ppm in different test sessions). Accuracy and speed of responding were both decreased by toluene; the magnitude of these effects increased with increasing concentration of the vapor and with increasing duration of exposure. Converting the exposure conditions to brain toluene concentration using the PBTK model yielded a family of overlapping curves for each end point, illustrating that the effects of toluene can be described quantitatively by its internal dose at the time of behavioral assessment. No other dose metric, including inhaled toluene concentration, duration of exposure, the area under the curve of either exposure (ppm h), or modeled brain toluene concentration (mg-h/kg), provided unambiguous predictions of effect. Thus, the acute behavioral effects of toluene (and of other VOCs with a similar mode of action) can be predicted for complex exposure scenarios by simulations that estimate the concentration of the VOC in the brain from the exposure scenario.     

Assessment of reproductive toxicity in male rats following acute and sub-chronic exposures to diphenyl diselenide and diphenyl ditelluride.

The present study was conducted to evaluate the toxicity of the exposure to diphenyl diselenide [(PhSe)2] and diphenyl ditelluride [(PhTe)2] on reproductive system in Wistar rats. Adult male rats were exposed intraperitonealy (acute) or subcutaneously (sub-chronic, during 4 or 8 weeks) to (PhSe)2 or (PhTe)2 prior to mating. A number of biochemical parameters in rat testes were examined, such as delta-aminolevulinate dehydratase (delta-ALA-D) activity, lipid peroxidation, glycogen content and components of the antioxidant defenses (superoxide dismutase (SOD) activity and ascorbic acid concentration). Furthermore, a possible effect on fertility and reproductive performance in male rats were studied. Sperm counts of caudal epididymis were also evaluated. No lethality was noted in any group. Reduction on body weight in rats which received (PhTe)2 was only evidenced in acute exposure, while (PhSe)2-exposed rats presented significant loss of body weight in acute and 4 week-exposure. Mating and fertility indexes were not affected after acute and sub-chronic exposure. Regarding other parameters studied, except for a decrease in testes glycogen content in acutely (PhSe)2-treated group, no alterations were found in treated groups. Sperm counts of rats treated acutely and sub-chronically were unaffected by drugs exposure. Histological evaluation revealed no modification on testicular tissue in rats exposed to (PhSe)2 and (PhTe)2. The results suggest the absence of the male reproductive toxicity induced by (PhSe)2 and (PhTe)2 administered intraperitonealy (acute) or subcutaneously (sub-chronical) to adult rats Wistar.     

Drug discrimination in rats: evidence for amphetamine-like cue state following chronic haloperidol

Two groups of male Sprague-Dawley rats were trained to discriminate which of two levers to press for milk reinforcement on a VI-20 sec schedule of reinforcement on the basis of whether they were injected intraperitoneally with d-amphetamine (0.50 mg/kg or 1.50 mg/kg) or saline 15 min prior to daily 30 min training sessions. Following acquisition of the discrimination, dose-response functions were generated for both training-dose groups during 5 min test sessions. All subjects were then injected with 1.0 mg/kg of haloperidol for ten consecutive days and retested on either saline or intermediate doses of amphetamine on days 1, 2, 4 and 7 following the final haloperidol injection. The results indicated that chronic haloperidol enhanced the discriminative stimulus properties of amphetamine in both training groups. More importantly, when tested on saline, subjects in both training groups made significantly more responses on the d-amphetamine lever than observed prior to chronic haloperidol. On the basis of linear regression analysis of the dose-response curves it was shown that rats in both groups responded as though they had been injected with 0.18 mg/kg of d-amphetamine. In a second experiment this increase in amphetamine-lever responding when animals were tested with saline following chronic haloperidol was replicated and in addition it was observed that chronic amphetamine had the opposite effect on this measure.     

Disposition of inhaled mercury vapor in pregnant rats: maternal toxicity and effects on developmental outcome.

The disposition and toxicity of inhaled elemental mercury (Hg0) vapor for pregnant Long-Evans rats, and potential adverse effects on reproductive outcome were investigated. Rats were exposed to 0, 1, 2, 4, or 8 mg Hg0/m(3) for 2 h/day from gestation day (GD) 6 through GD 15. Maternal toxicity occurred primarily in rats exposed to 4 and 8 mg/m(3) and was manifested as a concentration-related decrease in body weight gain and mild nephrotoxicity. Control rats gained about 13% of their initial body weight during the 10-day exposure. Rats exposed to 4 mg/m(3) Hg0 gained about 7% less than controls, and rats exposed to 8 mg/m(3) Hg0 lost about 17% of their initial body weight during the 10-day exposure period. Maternal kidney weights were significantly increased in the 4 and 8 mg/m(3) concentration groups, and urinalysis revealed increased levels of protein and alkaline phosphatase activity in urine of all Hg0-exposed rats. Dams exposed to 8 mg/m(3) were euthanized in moribund condition on postnatal day (PND) 1. There was no histopathological evidence of toxicity in maternal lung, liver, or kidney of exposed rats at GD 6, GD 15, or PND 1. The incidence of resorptions was significantly increased, litter size and PND 1 neonatal body weights were significantly decreased only in the 8-mg/m(3) group. Total Hg concentrations in maternal tissues increased with increasing number of exposure days and concentration. In general, approximately 70% of Hg was eliminated from maternal tissues during the week following the last exposure (GD 15 to PND 1). Elimination of Hg from maternal brain and kidney was slower than in other tissues, possibly due to higher levels of metallothionein. Total Hg concentrations in fetal tissues increased with increasing number of exposure days and concentration, demonstrating that a significant amount of Hg crossed the placenta. One week after the last exposure, significant amounts of Hg were still present in brain, liver, and kidney of PND 1 neonates. Metallothionein levels in neonatal tissues were not significantly increased by exposure to 4 mg/m(3) Hg0. The total amount of Hg in neonatal brain (ng/brain) continued to increase after termination of inhalation exposure, suggesting a redistribution of Hg from the dam to neonatal brain. These data demonstrate that inhaled Hg0 vapor is distributed to all maternal and fetal tissues in a dose-dependent manner. Adverse effects of Hg on developmental outcome occurred only at a concentration that caused maternal toxicity.