Pulmonary Response to Toner upon Chronic Inhalation Exposure in Rats

Pulmonary Response to Toner upon Chronic Inhalation Exposurein Rats. MUHLE, H., BELLMANN, B., CREUTZENBERG, O., DASENBROCK,C., ERNST, H., KILPPER, R., MACKENZIE, J. C., MORROW, P., MOHR,U., TAKENAKA, S., AND MERMELSTEIN, R., Fundam. Appl. Toxicol.17, 280–299. A chronic inhalation study of a test tonerwas conducted by exposure of groups of F-344 rats for 6 hr/day,5 days/week for 24 months The test toner was a special Xerox9000 type xerographic toner, enriched in respirable-sized particlescompared to commercial toner, such that it was about 35% respirableaccording to the ACGlH criteria. The target test aerosol exposureconcentrations were 0, 1.0 (low), 4.0 (medium), and 16.0 (high)mg/m³. Titamum dioxide (5 mg/m³) and crystalline silicon dioxide(1 mg/m³), used as negative and pasitive controls for fibrogenicity,were also evaluated. Inhalation of the test toner or the controlmaterials showed no signs of overt toxicity. Body weight, clinicalchemistry values, food consumption, and organ weights were normalin the toner- and TiO₂-exposed groups, except for a 40% increasein lung weight in the toner highexposure group. All of the changesin the toner-exposed groups were restricted to the lungs orassociated lymph nodes. A chronic inflammatory response wasevident from the bronchoalveolar lavage parameters for the tonerhigh-exposure group. The incidence of primary lung tumors wascomparable among the three toner-exposed groups and the TiO²-exposed,and air-only controls, as well as consistent with historicalbackground levels A mild to moderate degree of lung fibrosiswas observed in 92% of the rats in the toner high-exposure group,and a minimal to mild degree of fibrosis was noted in 22% ofthe animals in the toner high-exposure group. The pulmonarychanges in the toner high-exposure group were smaller in magnitudethan those found in the crystalline silica-exposed group. Thecomparative fibrogenic potency of TiO², toner, and SiO² wasestimated to be 1:5:418 using a dasimetric model and assuminga common mechanistic basis. There were no pulmonary changesof any type at the toncr low-exposure level, which is most relevantin regard to potential human exposures The lung alterationsin the toner high-exposure group are interpreted in terms of"lung overloading," a generic response of the respiratory systemto saturation of its detoxification capacity. The maximum tolerateddose (MTD) criterion was met at the toner high (16 mg/m³)-exposurelevel.     

Chronic Toxicity/Oncogenicity of Dimethylformamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylformamide(DMF) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 400 ppm DMF for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanasiafor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks, 3 months, and 12 months.No compound-related effects on clinical observations or survivalwere observed. Body weights of rats exposed to 100 (males only)and 400 ppm were reduced. Conversely, body weights were increasedin 400 ppm mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 100 or 400 ppm. There were no compound-relatedeffects on the estrous cycle of rats or mice at any concentration.Compound-related morphological changes were observed only inthe liver. In rats, exposure to 100 and 400 ppm produced increasedrelative liver weights, centrilobular hepatocellular hypertrophy,lipofuscin/hemosiderin accumulation in Kupifer cells, and centrilobularsingle cell necrosis (400 ppm only). In mice, increased liverweights (100 ppm males, 400 ppm both sexes), centrilobular hepatocellularhypertrophy, accumulation of lipofuscin/hemosiderin in Kupffercells, and centrilobular single cell necrosis were observedin all exposure groups. These observations occurred in a dose-responsefashion and were minimal at 25 ppm. No increase in hepatic cellproliferation was seen in mice or female rats. Slightly higherproliferation was seen in male rats exposed to 400 ppm at 2weeks and 3 months but not at 12 months. Dimethylformamide wasnot oncogenic under these experimental conditions in eitherthe rat or mouse.     

Chronic Toxicity/Oncogenicity of Dimethylacetamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylacetamide(DMAC) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 350 ppm DMAC for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanizationfor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks and 3 and 12 months.No compound-related effects on survival were observed. Ratsexposed to 350 ppm had lower body weight and/or body weightgain. There were no compound-related effects on body weightor weight gain in mice at any concentration. There were no compound-relatedadverse effects on the incidence of clinical signs of toxicityin rats or mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 350 ppm. Serum cholesterol and glucose concentrationswere significantly higher in 100 and 350 ppm female rats. Compound-relatedmorphological changes were observed in the liver. In rats, exposureto 100 or 350 ppm produced increased absolute and/or relativeliver weights, hepatic focal cystic degeneration, hepatic peliosis,biliary hyperplasia (350 ppm only), and lipofuscin/hemosiderinaccumulation in Kupffer cells. In mice, exposure to 100 or 350ppm produced increased absolute and relative liver weights (350ppm females only), accumulation of lipofuscin/hemosiderin inKupifer cells, and centrilobular single cell necrosis. Malerats exposed to 350 ppm also had significantly higher absoluteand relative kidney weights which correlated with the grossand microscopic changes resulting from a compound-related increasein severity of chronic progressive nephropathy. Female miceexposed to 350 ppm had an increased incidence of bilateral,diffuse retinal atrophy. No increase in hepatic cell proliferationwas seen in mice or rats at any exposure concentration. DMACwas not oncogenic under these experimental conditions in eitherthe rat or mouse. The NOAEL for male and female rats and miceis 25 ppm.     

Ozone Adaptation in Rats after Chronic Exposure to a Simulated Urban Profile of Ozone

Studies in both humans and rats have indicated that certainpulmonary responses induced by exposure to an acute provocativeconcentration of ozone (O₃) will eventually attenuate if theexposure is repeated on a daily basis. This phenomenon is commonlyreferred to as O₃ adaptation. Whether or not a "state" of adaptationdevelops due to long-term low level O₃ exposure is unknown.Two human studies have reported adaptation in subjects livingin Los Angeles during periods when ambient O₃ concentrationshave been relatively high. At present, however, we are not awareof comparable information from rats. This study assessed O₃adaptation in rats following chronic (12 or 18 months) exposureand after a 4-month recovery period. A chronic exposure pattern,similar to that found in an urban area during the summer (0.06ppm O₃ for 13 hr/day, 7 days/week; Monday–Friday, peakto 0.25 ppm O₃, over 9 hr), was used. To assess whether adaptationhad occurred and/or persisted, awake rats were challenged withhigh provocative concentrations of O₃ for up to 2 hr. Duringa challenge, rats were monitored for typical O₃-induced alterationsin spontaneous breathing parameters (e.g., increase in breathingfrequency and decrease in tidal volume). Adaptation was definedas attenuation of breathing response during the challenge inrats chronically exposed to O₃ as compared to that in "control"rats (chronically exposed to air). Adaptation was found in therats within 8 hr following the chronic O₃ exposure but not afterthe 4-month recovery period. Spontaneous breathing parametersthat were significantly attenuated in the chronically exposedrats were breathing frequency, tidal volume, inspiratory andexpiratory times, and maximum expiratory flow. We conclude thatrats demonstrated adaptation to O₃ after long-term exposureto an urban-type O₃ profile and that the adaptation was notseen 4 months postexpo-sure. These results suggest that exposureto environmental O₃ in Los Angeles air may have been responsiblefor the adaptation found in residential subjects.     

Effect of Chronic Cigarette Smoke Exposure on Lung Clearance of Tracer Particles Inhaled by Rats

Cigarette smoking can influence the pulmonary disposition ofother inhaled materials in humans and laboratory animals. Thisstudy was undertaken to investigate the influence of cigarettesmoke exposures of rats on the pulmonary clearance of inhaled,relatively insoluble radioactive tracer particles. Following13 weeks of whole-body exposure to air or mainstream cigarettesmoke for 6 hr/day, 5 days/week at concentrations of 0, 100,or 250 mg total particulate matter (TPM)/m³, rats were acutelyexposed pernasally to ⁸⁵Sr-labeled fused aluminosilicate (⁸⁵Sr-FAP)tracer particles, then air or smoke exposures were resumed.A separate group of rats was exposed to the ⁸⁵Sr-FAP then seriallyeuthanized through 6 months after exposure to confirm the relativeinsolubility of the tracer particles. We observed decreasedtracer particle clearance from the lungs that was smoke concentration-dependent.By 180 days after exposure to the tracer aerosol, about 14,20, and 40% of the initial activity of tracer was present incontrol, 100 mg TPM/m³, and 250 mg TPM/m³ groups, respectively.Body weight gains were less in smoke-exposed rats than in controls.Smoke exposure produced lung lesions which included increasednumbers of pigmented alveolar macrophages distributed throughoutthe parenchyma and focal collections of enlarged alveolar macrophageswith concomitant alveolar epithelial hyperplasia and neutro-philicalveolitis. The severity of the lesions increased with smokeexposure duration and concentration to include interstitialaggregates of pigmented macrophages and interstitial fibrosis.Our data confirm previous findings that exposure to cigarettesmoke decreases the ability of the lungs to clear inhaled materials.We further demonstrate an exposure-concentration related magnitudeof effect, suggesting that the cigarette smoke-exposed rat constitutesa useful model for studies of the effects of cigarette smokeon the disposition of inhaled particles.     

Effect of Acute and Chronic Lead Exposure on Apomorphine‐Induced Sniffing in Rats

Abstract: Sniffing is a behaviour which can be induced by dopamine D_1/D₂ receptor agonists. In order to test the effect of chronic lead exposure on dopamine receptor subtypes, we studied the effects of acute and chronic lead exposure on sniffing induced by apomorphine, a dopamine receptor agonist. Intraperitoneal injection of the dopaminergic receptor agonist, apomorphine (0.25–1 mg/kg), induced dose‐dependent the sniffing behaviour in rats. Acute administration of lead acetate (50, 100 and 200 mg/kg) decreased the apomorphine‐induced sniffing. Chronic lead (0.25%) exposure also decreased the apomophine response. Dopamine D₁ or D₂ receptor antagonists reduced the apomorphine effect. Lead exposure could not potentiate the blockade induced by the dopamine receptor antagonists. It is concluded that the response of lead is not mediated by alteration of dopamine receptors.     

Effects of Coumarin Following Perinatal and Chronic Exposure in Sprague-Dawley Rats and CD-1 Mice

Coumarin, a naturally occurring substance most frequently usedas a fragrance enhancer and stabilizer, was administered inthe diet of Sprague-Dawley rats at dose levels of 0, 333, 1000,2000, 3000, and 5000 ppm or in the diet of CD-1 mice at doselevels of 0, 300, 1000, or 3000 ppm. Rats receiving 333, 1000,and 2000 ppm coumarin were exposed to these dose levels in uteroand during the lactational period, then chronically followingweaning. Rats in the 3000- and 5000-ppm dose groups and allmice received only postweanlng chronic exposure. All male ratswere terminated after 104 weeks of postweaning exposure; femalerats were terminated after 110 weeks. Male mice were terminatedat Week 101 and female mice at Week 109. Among rats, survivalwas decreased at 333 ppm, but signilicantly increased amongrats in the 3000- and 5000-ppm dose groups. Dramatic dose-relateddecreases in body weight gain were recorded for rats receiving2000, 3000, and 5000 ppm, clearly indicating that the MTD (maximumtolerated dose, as indicated by a body weight decrement of greaterthan 10–15%) was exceeded. Food consumption also was decreasedat the three highest dose levels, although body weight decrementwas disproportionately large compared to changes in food consumption.Treatment-related decreases in hemoglobin were recorded fromWeek 6 onward. Minimal treatment-related changes in he matologyand clinical chemistry were recorded. Increased liver weightswere observed for male and female rats receiving 3000 or 5000ppm and for females only at 1000 and 2000 ppm. Increased incidencesof cholanglofibroma, cholangiocarcinoma, and parenchymal livercell tumors were observed among male and female rats receiving5000 ppm. One male rat receiving 3000 ppm devel oped a cholangiocarcinoma;no tumor increase was observed in males or females at 2000 ppmor below. Coumarin, at a dose clearly exceeding the MTD can,therefore, induce liver tumors in rats, although survival, relativeto controls, was increased at the same dose levels. Among mice,a decrease in body weight gain was reported for males in the1000- and 3000-ppm dose groups during the first 52 weeks ofthe study. No dose-related abnormalities in clinical signs,clinical pathology, hematology, or gross or microscopic pathologywere noted.     

Sub‐Chronic Exposure to Methylmercury at Low Levels Decreases Butyrylcholinesterase Activity in Rats

Abstract: In this study, we examined the effects of low levels and sub‐chronic exposure to methylmercury (MeHg) on butyrylcholinesterase (BuChE) activity in rats. Moreover, we examined the relationship between BuChE activity and oxidative stress biomarkers [δ‐aminolevulinic acid dehydratase (δ‐ALA‐D) and malondialdehyde levels (MDA)] in the same animals. Rats were separated into three groups (eight animals per group): (Group I) received water by gavage; (Group II) received MeHg (30 μg/kg/day) by gavage; (Group III) received MeHg (100 μg/kg/day). The time of exposure was 90 days. BuChE and ALA‐D activities were measured in serum and blood, respectively; whereas MDA levels were measured in plasma. We found BuChE and ALA‐D activities decreased in groups II and III compared to the control group. Moreover, we found an interesting negative correlation between plasmatic BuChE activity and MDA (r = ?0.85; p < 0.01) and a positive correlation between plasmatic BuChE activity and ALA‐D activities (r = 0.78; p < 0.01), thus suggesting a possible relationship between oxidative damage promoted by MeHg exposure and the decrease of BuChE activity. In conclusion, long‐term exposure to low doses of MeHg decreases plasmatic BuChE activity. Moreover, the decrease in the enzyme is strongly correlated with the oxidative stress promoted by the metal exposure. This preliminary finding highlights a possible mechanism for MeHg to reduce BuChE activity in plasma. Additionally, this enzyme could be an auxiliary biomarker on the evaluation of MeHg exposure.     

Chronic Exposure to Low Doses of Mercury Impairs Sperm Quality and Induces Oxidative Stress in Rats

Mercury (Hg) is a widespread environmental pollutant that adversely affects the male reproductive system. The precise mechanisms underlying mercuric chloride (HgCl₂)-induced toxicity are not fully understood; however, evidence indicates that oxidative stress may be involved in this process. Although the adverse effects of high levels of inorganic Hg on the male reproductive system have been investigated, the effects of low levels of exposure are unknown. Therefore, the aim of this study was to investigate the effects of chronic exposure to low concentrations of HgCl₂ on sperm parameters, lipid peroxidation, and antioxidant activity of male rats. Three-month-old male Wistar rats were treated for 30 d and divided into groups: control (saline, i.m.) and HgCl₂ group (i.m., first dose 4.6 μg/kg, subsequent doses 0.07 μg/kg/d). Sperm parameters (count, motility and morphology) and biomarkers of oxidative stress in testis, epididymis, prostate, and vas deferens were analyzed. Mercury treatment produced a reduction in sperm quantity (testis and epididymis) and daily sperm production, following by decrease in sperm motility and increase on head and tail morphologic abnormalities. HgCl₂ exposure was correlated with enhanced oxidative stress in reproductive organs, represented not only by augmented lipid peroxidation but also by changes in antioxidant enzymes activity superoxide dismutase (SOD) and catalase (CAT) and nonprotein thiol levels. In conclusion, chronic exposure to low doses of Hg impaired sperm quality and adversely affected male reproductive functions, which may be due, at least in part, to enhanced oxidative stress.     

Chronic Exposure to a Simulated Urban Profile of Ozone Alters Ventilatory Responses to Carbon Dioxide Challenge in Rats

Chronic Exposure to a Simulated Urban Profile of Ozone AltersVentilatory Responses to Carbon Dioxide Challenge in Rats. TEPPER,J. S., WIESTER, M. J., WEBER, M. F., FITZGERALD, S., AND COSTA,D. L. (1991). Fundam. Appl. Toxicol. 17, 52–60. Male Fischer344 rats were exposed to a simulated urban profile of ozone(O³) (9-hr ramped spike, integrated concentration = 0.19 ppm)for up to 78 weeks. Small, but statistically significant, changesin breathing patterns and mechanics in unanesthetized, restrainedrats were observed at Weeks 1,3, 13, 52, and 78 during postexposurechallenge with 0, 4, and 8% carbon dioxide (CO²). The data indicatethat O³ exposure caused an overall increase in expiratory resistance(R^e), but particularly at 78 weeks. This increase in R^e mostlikely accounts for the rats' reduced ability to increase ventilationduring CO² challenge compared to control rats. Reductions inCO²-induced tidal volume increases were observed in all Orexposedanimals during postexposure challenges to 4 and 8% CO². Cumulatively,over all time points, spontaneous frequency of breathing andCO²-induced hyperventilation were also reduced. The decreasein frequency was dependent on a significant increase in theinspiratory time relative to control without a change in expiratorytime. Light microscopic evaluation of the lung did not revealany lesions associated with O³ exposure at any time point. Althoughstatistically significant effects were detected, the etiologyof the above-mentioned functional changes remains speculative.The potential relevance of these data to acute and chronic O³exposure in humans is also discussed.     

Reproduction, Growth, and Development of Rats during Chronic Exposure to Multiple Field Strengths of 60-Hz Electric Fields

Reproduction, Growth, and Development of Rats during ChronicExposure to Multiple Field Strengths of 60-Hz Electric Fields.ROMMEREIM, D. N., ROMMEREIM, R. L., SIKOV, M. R., BUSCHBOM,R. L., AND ANDERSON, L. E. (1990). Fundam. Appl. Toxicol. 14,608–621. A study with multiple exposure groups and largegroup sizes was performed to establish whether exposure to 60-Hzelectric fields would result in reproductive and developmentaltoxicity. A response model was developed from previous resultsand tested in groups of rats exposed to electric fields at variousfield strengths. Female rats were mated, and sperm-positiveanimals randomly distributed among four groups: sham-exposedor exposed to 10, 65, or 130 kV/m, 60-Hz vertical electric fields.Animals were exposed for 19 hr/day throughout the experiment.During gestation, exposure to the higher field strengths resultedin slightly depressed weight gains of dams. Offspring were bornin the field and remained with their dams through the sucklingperiod. Numbers of pups per litter and pup mortality did notdiffer among the exposure groups. Dams exposed at 65 kV/m lostslightly more weight through the lactation period than the controlgroup. Male pups exposed to higher field strengths gained slightlyless weight from 4 to 21 days of age than did sham-exposed animals.At weaning, two F₁ females per litter (randomly selected) continuedon the same exposure regimen were mated at 11 weeks of age tounexposed males, and euthanized at 20 days of gestation. Uterinecontents were evaluated, and all live fetuses were weighed andexamined for external, visceral, and skeletal malformations.Fertility and gestational weight gain of F₁ females were notaffected by exposure, nor was prenatal viability or fetal bodyweight. No significant increase in the incidence of litterswith malformations was observed. Although no developmental toxicitywas detected, exposures produced physical changes in the dams,evidenced as a rust-colored deposit on the muzzle and ears (chromodac-ryorrhea)that increased in incidence and severity at 65 and 130 kV/m.Incidence of chromodac-ryorrhea was not significantly differentbetween sham-exposed rats and those exposed at 10 kV/m.     

The Effects of Subchronic Chlorate Exposure in Sprague-Dawley Rats

ABSTRACT

Male and female Sprague-Dawley rats were exposed to drinking water containing 3.0, 12.0 or 48.0 mM sodium chlorate. The mean drinking water consumption varied between exposure groups from 100-200 ml/kg/day. Female exposure groups consistently drank more water (23-42%) than male exposure groups thereby receiving more chlorate/kg/day at every exposure level. There were no compound related deaths; however, both males and females in the high exposure groups had significant weight loss during the 90-day exposure period. Also, in these same groups females had mild but significant decreases in the following relative organ weights; adrenals, thymus and spleen, while the relative brain weight was increased. In males, the heart, kidneys and liver were mildly decreased while the brain and testes were mildly increased. Red blood cell counts and percent hematocrit were decreased in both sexes in the high dose group. Pituitary gland (pars distalis) vacuolization and thyroid gland colloid depletion were prominent in both sexes in mid and/or high dose animals. A NOAEL of 0.36 mM chlorate/kg b.w./day in males and 0.50 mM chlorate/kg b.w./day in females were established.     

Effects of Lead Exposure on Skeletal Development in Rats

The effects of lead on growth in female rats and on growth andskeletal development in their offspring were investigated. Noalteration in growth rate, compared to the growth rate in pair-fedcontrols, was observed in 48 weanling females continuously exposedto 250 or 1000 ppm lead in drinking water and fed a repletediet. After 49 days of exposure, all rats (24 pair-fed controls,12 exposed to 250 ppm lead, and 12 exposed to 1000 ppm lead)were mated with control males. At parturition, six lactatingdams each from the 250 and 1000 ppm lead groups were removedfrom lead exposure and given control drinking water, and sixlactating dams each from the control group were given either250 or 1000 ppm lead in drinking water. Exposure conditionsfor the remaining dams in the control, 250, and 1000 ppm groupswere not changed. Maternal blood lead in the continuously lead-exposedgroups was higher at the end of lactation than prior to mating.Lead exposure prior to parturition caused greater maternal tibiallead accumulation than lead exposure after parturition. In contrast,lead exposure prior to parturition had a lesser impact on offspringtibial lead accumulation than lead exposure after parturition.Decreases in tibial calcium and phosphorus were observed indams exposed continuously to 250 or 1000 ppm lead; however,there was no apparent effect of lead on maternal growth-platemorphology or on growth-plate width. Offspring body weight wasdepressed relative to controls during suckling (Day 11) andafter weaning (Day 24) in high-dose and continuously lead-exposedgroups. Continuous lead exposure caused a greater decrease inoffspring body weight than lead exposure only prior to or afterparturition. Decreased tail length growth suggested possibleeffects of lead on tail vertebral bone growth. While tibialcalcium and phosphorus levels were not changed in the weanlings,increased weanling growth-plate width, with disruption of chondrocyteorganization, and wider metaphyseal trabeculae were observed.Although the mechanisms of these effects are not known, theresults suggest that local lead-related effects on growth-platechondrogenesis and metaphyseal mineralization may be involved.     

Age-Dependence of Responses to Acute Ozone Exposure in Rats

Previous work from this laboratory demonstrated that neonatalrats and postweanling rabbits are more sensitive to ozone-inducedstimulation of pulmonary arachidonic acid (AA) metabolism thanare young adults (Fundam. Appl. Toxicol. 15, 779.) In the studyreported here, we have extended our initial investigation toinclude the influence of animal age on temporal aspects of pulmonaryAA metabolism and several other responses to brief exposuresto 1 ppm ozone. Rats of discrete ages ranging from 13 days to16 weeks were exposed to 1 ppm ozone or to air for 2, 4, or6 hr. Immediately following exposure the lungs were lavagedwith six consecutive volumes of phosphate-buffered saline andthe acellular fluid from the first lavage volume recovered wasanalyzed for its content of prostaglandin E₂ (PGE₂), protein,and lactate dehydrogenase. Leukocytes recovered by lavage werequantitated and characterized by viability and percentage ofpolymorphonuclear (PMN) cells. Several lines of evidence verifiedthat PGE₂ was produced by the lung as a consequence of ozoneexposure and that its concentration in the fluid from the firstlavage was a reasonably good index of pulmonary AA metabolismto prostanoids. We also demonstrated that the lavage processitself stimulates the lung, resulting in increased AA metabolismto prostanoids that were recovered in the second and followinglavage volumes. The time course of PGE₂ production by the ozone-exposedlung varied considerably with animal age. Neonatal rats 13 daysof age were the most sensitive to ozone stimulation. At 2 hrof exposure, PGE₂ concentration in the first lung lavage ofthese animals peaked at values approximately two orders of magnitudeabove controls and then decreased sharply with continued exposure.Adults and older neonates (18 days of age) were much less responsiveto 2-hr exposures; however, continued exposure of these ratsfor up to 6 hr resulted in increasing PGE₂ concentration inthe first lung lavage. Other responses showed various degreesof age dependence. The percentage of lavaged leukocytes thatwere nonviable (i.e., trypan blue-positive) showed a stronginverse correlation with animal age. In 13-day-old rats thatwere exposed for 6 hr, the percentage of dead leukocytes reachednearly 50%. In addition, sheets or clumps of dead cells thatwere judged to be epithelial cells were lavaged from these animals.Conversely, 16-week-old adult males exposed to ozone for 6 hrshowed little evidence of damage to cells of the respiratorytract. This order of age-dependent sensitivity to ozone-inducedcellular damage is opposite that reported by some other investigators.Other responses to ozone showed minimal or no evidence of agedependence. Ozone exposure decreased the number of leukocyteslavaged from the lung and increased the concentration of proteinin the first lung lavage, but neither variable showed any evidenceof age dependence. PMN influx into the airspaces following ozoneexposure (estimated from lavaged cells) was weakly age-dependent,with neonates demonstrating slightly greater influx than adults.However, since the time of sampling of all age groups was priorto the time of expected maximum response for both PMN influxand protein extravasation into the airspaces, the observed age-dependentpatterns of these two responses are not definitive.     

Chronic Corticosterone Exposure during Adolescence Reduces Impulsive Action but Increases Impulsive Choice and Sensitivity to Yohimbine in Male Sprague-Dawley Rats

Chronic stress during adolescence is associated with an increased risk for alcoholism and addictive disorders. Addiction is also associated with increased impulsivity, and stress during adolescence could alter cortical circuits responsible for response inhibition. Therefore, the present study determined the effect of chronic exposure to the stress hormone corticosterone (CORT) during adolescence on tests of impulsivity in adulthood and examined possible biochemical mechanisms. Male Sprague-Dawley rats were exposed to CORT by their drinking water during adolescence (post-natal day 30–50). The rats were then tested in adulthood to assess behavior on the 5-choice serial reaction time task (5CSRTT), stop-signal reaction time task (SSRTT), and the delay-discounting task, which differentially assess attention, impulsive action, and impulsive choice. Yohimbine-induced impulsivity on the 5CSRTT and biochemical analysis of the lateral orbital frontal cortex (lOFC) was also assessed owing to the ability of yohimbine to activate the hypothalamic-pituitary-adrenal axis and influence impulsivity. Adolescent CORT-treated rats were found to behave largely like controls on the 5CSRTT, but did show reduced premature responses when the intertrial interval was increased. Nevertheless, the CORT-treated rats tended to have more yohimbine-induced impulsive responses at low doses on this task, which was not found to be due to increased pCREB in the lOFC, but could be related to a higher expression/activity of the AMPA receptor subunit GluR1. Adolescent CORT-treated rats performed more accurately on the SSRTT, but showed greater impulsivity on the delay-discounting task, as indicated by steeper discounting functions. Therefore, adolescent CORT exposure reduced impulsive action but increased impulsive choice, indicating that chronic stress hormone exposure in adolescence can have long-term consequences on behavior.     

Effects of Whole-Body VX Vapor Exposure on Lethality in Rats

Male and female rats were whole-body exposed to VX vapor in a 1000-L single-pass exposure chamber. Estimated exposure dosages producing lethal (LCT₅₀) effects in 50% of exposed male and female rats were established for 10, 60, and 240 min exposure durations. A potency comparison with GB and GF shows that VX becomes increasingly more potent than these G agents with increasing exposure duration. VX is approximately 4–30 times more potent than GB and 5–15 times more potent than GF. Gender differences in the estimated median dosages were not significant at the 10, 60, and 240 min exposure durations. An empirical toxic load model was developed and the toxic load exponent for lethality (n) in the equation Cⁿ× T = k was determined to be n = 0.92. The VX–G regeneration assay was successfully used as a biomarker for the presence of VX in the blood plasma and RBC fractions of the blood 24 h postexposure.     

Teratogenic Evaluation of Tributyltin Chloride in Rats Following Oral Exposure

ABSTRACT

The teratogenicity of tri-n-butyltin chloride (TBTC1) was examined in Wistar rats. The pregnant rats were administered orally 25, 15, 9, 5 and 0(Control) mg of TBTCl/kg of body weight/day from day 7 to 15 of pregnancy. Maternal toxicity, as evidenced by both of decreased body weight gain and food consumption was observed at 25, 15 and 9 mg/kg/day dose group. However, only in the 25 mg/kg/day dose group some clinical signs of toxicity (sedation, diarrhoea and salivation) were observed and 70 percent of the dams were dead. In the 25 mg/kg/day dose group, all fetuses were dead. Statistically significant reductions in the female fetal body weight were observed in 9 and 5 mg/kg/day dose groups. In all groups treated with TBTC1 except the 25 mg/kg/day dose group, no significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the TBTC1-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any of the dose levels. However, several types of skeletal and internal variations including delayed ossifications were observed in some groups treated with TBTC1, but the incidences were not significantly different from controls. Also, two fetuses with dilatation of the renal pelvis were found in 9 and 5 mg/kg/day dose group. Statistically significant increases of placental weight in all TBTC1-treated groups were observed when compared to that of control group. In conclusion, TBTC1 administered orally to Wistar rats during days 7–15 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity and induced a marked increase in placental weight.     

Peritoneal and Systemic Responses of Obese Type II Diabetic Rats to Chronic Exposure to a Hyperbranched Polyglycerol‐Based Dialysis Solution

Metabolic syndrome (MetS) is commonly observed among peritoneal dialysis (PD) patients, and hyperbranched polyglycerol (HPG) is a promising glucose‐sparing osmotic agent for PD. However, the biocompatibility of a HPG‐based PD solution (HPG) in subjects with MetS has not been investigated. This study compared the local and systemic effects of a HPG solution with conventional physioneal (PYS) and icodextrin (ICO) PD solutions in rats with MetS. Obese type 2 diabetic ZSF1 rats received a daily intraperitoneal injection of PD solutions (10 mL) for 3 months. The peritoneal membrane (PM) function was determined by ultrafiltration (UF), and the systemic responses were determined by profiling blood metabolic substances, cytokines and oxidative status. Tissue damage was assessed by histology. At the end of the 3‐month treatment with PD solutions, PM damage and UF loss in both the PYS and ICO groups were greater than those in the HPG group. Blood analyses showed that compared to the baseline control, the rats in the HPG group exhibited a significant decrease only in serum albumin and IL‐6 and a minor glomerular injury, whereas in both the PYS and ICO groups, there were more significant decreases in serum albumin, antioxidant activity, IL‐6, KC/GRO (CXCL1) and TNF‐α (in ICO only) as well as a more substantial glomerular injury compared to the HPG group. Furthermore, PYS increased serum creatinine, serum glucose and urine production. In conclusion, compared to PYS or ICO solutions, the HPG solution had less adverse effects locally on the PM and systemically on distant organs (e.g. kidneys) and the plasma oxidative status in rats with MetS.     

Effects of Lead Exposure on Bromocriptine-Induced Penile Erection in Rats

Abstract: In the present work we have studied the effects of lead exposure on penile erection induced by bromocriptine. Intraperitoneal injection of bromocriptine (2, 3, 4 and 8 mg/kg) induced dose-related penile erection in rats. Maximum response was observed with 4 mg/kg of the drug. Lead exposure (as Pb-acetate in drinking water) for periods of 7, 14, 21 and 28 days decreased the bromocriptine-induced penile erection response. Higher concentrations of lead (0.05%) were shown to cause a more prominent decrease of penile erection. The same procedure for lead administration did not significantly alter penile erection induced by physostigmine (0.1 and 0.3 mg/kg, intraperitoneally). In a series of experiments, blood lead concentrations were measured 7 and 21 days after lead exposure. Significant increases of lead concentrations were found after lead exposure. It is concluded that lead can influence bromocriptine-induced penile erection.