Immunomodulatory Effects of Pure Cylindrospermopsin in Rats Orally Exposed for 28 Days

Cylindrospermopsin (CYN) is a ubiquitous cyanotoxin showing increasing incidence worldwide. CYN has been classified as a cytotoxin and, among its toxic effects, its immunotoxicity is scarcely studied. This work investigates for the first time the influence of oral CYN exposure (18.75; 37.5 and 75 µg/kg b.w./day, for 28 days) on the mRNA expression of selected interleukin (IL) genes (IL-1β, IL-2, IL-6, Tumor Necrosis Factor alpha (TNF-α), Interferon gamma (IFN-γ)) in the thymus and the spleen of male and female rats, by quantitative real-time polymerase chain reaction (RT-qPCR). Moreover, their serum levels were also measured by a multiplex-bead-based immunoassay, and a histopathological study was performed. CYN produced immunomodulation mainly in the thymus of rats exposed to 75 μg CYN/kg b.w./day in both sexes. However, in the spleen only IL-1β and IL-2 (males), and TNF-α and IFN-γ (females) expression was modified after CYN exposure. Only female rats exposed to 18.75 μg CYN/kg b.w./day showed a significant decrease in TNF-α serum levels. There were no significant differences in the weight or histopathology in the organs studied. Further research is needed to obtain a deeper view of the molecular mechanisms involved in CYN immunotoxicity and its consequences on long-term exposures.     

Concentration-Time Relationships for the Effects of Inhaled Trichloroethylene on Signal Detection Behavior in Rats,2

The risk from inhaled volatile organic compounds (VOCs) is presentlyassessed on the basis of lifetime exposure to average concentrationsof the vapor. This strategy yields rational predictions of riskif the product of concentration (C) and the duration of exposure(t yields constant effects on health (Haber's Rule). The validityof this assumption was evaluated by assessing the acute behavioraleffects of inhaled trichloroethylene (TCE) vapor at variousvalues of C and t. Adult male Long-Evans rats (n = 11) weretrained to perform a signal detection task in which a presson one lever produced food on trials containing a signal (abrief, unpredictable light flash); a press on a second leverproduced food on trials lacking a signal. Response time (RT)and indices of sensitivity (SI) and bias (RI) derived from thetheory of signal detection were calculated at three times duringrepeated daily 60-min tests conducted in air containing 0, 400,800, 1200,1600, 2000, or 2400 ppm TCE. Behavior remained stableduring tests in air. In TCE, SI declined and RT increased asfunctions of both C and t. RI was not affected by TCE. Effectson SI and RT were not predictable from the C x t product: bothendpoints were more affected by C than by t. To quantify thechange in the effect of TCE across exposure times, concentration-effectrelationships for inhaled TCE on SI and RT were modeled withcubic polynomial functions at each of the three exposure durations.Concentrations of inhaled TCE associated with preselected changesin SI and RT were then estimated for each animal from thesefunctions. Criterion concentrations, SI_0.1 and RT₁₀₀, were definedas the concentration of TCE associated with a 0.1-unit decreasein SI or a 100-msec increase in RT, respectively. Both SI_0.1,and RT₁₀₀ increased as exposure duration decreased, but didso more slowly than would be predicted by Haber's Rule. Thispattern indicates that application of Haber's Rule overestimatesthe concentration of inhaled TCE associated with changes insignal detection and thus underestimates the risk of behaviorchange from short-term exposures to TCE. On the other hand,the fact that SI_0.1, and RT₁₀₀ did increase with shorter exposuretimes indicates that the converse assumption, that the toxicityof inhaled TCE is independent of the duration of exposure, yieldsan overly conservative estimate of risk.     

Toxicologic and Reproductive Effects of Inhaled 1,2-Dibromo-3-chloropropane in Rats

Toxicologic and Reproductive Effects of Inhaled 1, 2-Di-bromo-3-chloropropanein Rats. Rao, K.S., Burek, J.D., Murray, F.J., John, J.A., Schwetz,B.A., Bell, T J., Potts, W.J. and Parker, CM. (1983). Fundam.Appl. Toxicol. 3:104-110. Groups of 30 male and 30 female Sprague-Dawleyrats were exposed by inhalation to 0, 0.1, 1.0 or 10 ppm of1,2-dibromo-3-chloropropane (DBCP) vapor for 6 hr/day, 5 days/weekfor 14 weeks followed by recovery periods of up to 32 weeks.The fertility of male rats was evaluated by mating trials withunexposed females. The exposed female rats were mated to unexposedmale rats at the end of the 14-week exposure period and againduring post-treatment and were allowed to deliver. Five rats/sex/exposure level were killed after 4 weeks and after 14 weeksof exposure; remaining rats were sacrificed at the end of therecovery period. DBCP did not affect the ability of males toimpregnate females; however, a dominant lethal effect was evidentat 10 ppm which tended to reverse by 5 weeks after terminationof exposure. Moderate testicular atrophy (males) and focal aggregatesof altered cells in the adrenal cortex (males and females) wereobserved in rats sacrificed immediately after exposure to 10ppm for 14 weeks, but not in those exposed to 1.0 or 0.1 ppm.Pathologic evaluation of the rats from the recovery portionof the study showed treatment-related alterations in males andfemales In the 10 and 1.0 ppm exposure groups, but not in thegroups exposed to 0.1 ppm. The testicular alterations that werepresent in the 10 ppm males after the 14-week exposure periodwere tending to reverse by the end of the recovery period. Lesionswere observed in the adrenal cortex of recovery males and femalesfrom the 10 ppm exposure level; females exposed to 1 ppm hadslight adrenal cortical lesions at the end of the recovery period.In addition, increased numbers of ovarian cysts were presentin recovery females from the 10 ppm exposure level. Brain effectsconsisting of focal or multifocal mineralized deposits werepresent in males and females in the 10 ppm exposure level. Notreatment-related alterations were recognized in any of therats from the 0.1 ppm recovery groups.     

Effects of Sulfur Dioxide and Ozone on Hypertension Sensitive and Resistant Rats

Effects of Sulfur Dioxide and Ozone on Hypertension Sensitiveand Resistant Rats. Drew, R.T., Kutzman, R.S., Costa, D.L.,and Iwai, J. (1983). Fundam. Appl Toxicol 3: 298–302.Two lines of Dahl rats, one resistant to salt-induced hypertension(DR) and one susceptible to salt-induced hypertension (DS) weresubchronically exposed to SO₂ (50 ppm, 6 hr/d, 5 d/wk for 31weeks) or ozone (2.0 ppm, 6 hr/d, 5 d/wk for 20 weeks). Subgroupsof rats were maintained on either high or low salt diets. Inrats not expected to develop hypertension, exposure to SO₂ causeda slight but consistent decrease in blood pressure. In DS ratson a high salt diet exposure to SO₂ resulted in an increasein blood pressure over that of their air exposed counterparts.All exposure-related differences in blood pressure disappearedafter the last exposure to SO₂. Exposure to ozone was fatalto all DS rats, regardless of the amount of salt in the diet.The DR rats were more resistant to ozone, with most animalssurviving the 20-week exposure. Ozone-exposed rats exhibiteda decrease in both growth rate and blood pressure in all groupswhen compared to their air-exposed counterparts. It is not knownif exposure-related blood pressure differences would persistafter ending ozone exposures. After brief exposures, ozone causedincreased lung weights in both groups, but there were no consistentchanges in pulmonary nonprotein sulfhydryl groups. Hepatic nonpro-teinsulfhydryl levels were consistently, but not significantly,lower in ozone-exposed rats.     

Deposition of Inhaled Wood Dust in the Nasal Cavity

Detailed deposition patterns of inhaled wood dust in an anatomically accurate nasal cavity were investigated using computational fluid dynamics (CFD) techniques. Three wood dusts, pine dust, heavy oak dust, and light oak dust, with a particle size distribution generated by machining (), were simulated at an inhalation flow rate of 10 L/min. It was found that the major particle deposition sites were the nasal valve region and anterior section of the middle turbinate. Wood dust depositing in these regions is physiologically removed much more slowly than in other regions. This leads to the surrounding layer of soft tissues being damaged by the deposited particles during continuous exposure to wood dust. Additionally, it was found that pine dust had a higher deposition efficiency in the nasal cavity than the two oak dusts, due to the fact that it comprises a higher proportion of larger sized particles. Therefore, this indicates that dusts with a large amount of fine particles, such as those generated by sanding, may penetrate the nasal cavity and travel further into the lung.     

Increased Immune and Inflammatory Responses to Dust Mite Antigen in Rats Exposed to 5 ppm NO2

Immune hypersensitivity to house dust mite antigen (HDM) isa frequent cause of respiratory allergy. The objective of thisstudy was to determine whether exposure to NO₂, a common indoorair pollutant, modulates immune responses to HDM and influencesimmune-mediated lung disease. Brown Norway rats were immunizedip with 100 µg semipurified antigen and Bordetella pertussisadjuvant and challenged 2 weeks later with an intratrachealinjection of 50 µg of a crude antigen preparation. Exposureto 5 ppm NO₂ for 3 hr after both immunization and challengeprocedures resulted in significantly higher levels of antigen-specificserum IgE, local IgA, IgG, and IgE antibody than air controls,and increased numbers of inflammatory cells in the lungs. Lymphocyteresponsiveness to antigen in the spleen and MLN was also significantlyhigher in NO₂-exposed animals. These data show that exposureto a common air pollutant can upregulate specific immune responsesand subsequent immune-mediated pulmonary inflammation.     

The Fate of Inhaled Azodicarbonamide in Rats

The Fate of Inhaled Azodicarbonamide in Rats. Mewhinney, J.A., AYRES, P. H., BECHTOLD, W. E., DUTCHER, J. S., CHENG, Y.S., BOND, J. A., MEDINSKY, M. A., HENDERSON, R. F., AND BIRNBAUM,L. S. (1987). Fundam. Appl. Toxicol. 8, 372–381. Azodicarbonamide(ADA) is widely used as a blowing agent in the manufacture ofexpanded foam plastics, as an aging and bleaching agent in flour,and as a bread dough conditioner. Human exposures have beenreported during manufacture as well as during use. Groups ofmale F344/N rats were administered ADA by gavage, by intratrachealinstillation, and by inhalation exposure to determine the dispositionand modes of excretion of ADA and its metabolites. At 72 hrfollowing gavage, 30% of the administered ADA was absorbed whereasfollowing intratracheal instillation, absorption was 90%. Comparisonbetween groups of rats exposed by inhalation to ADA to achievebody burdens of 24 or 1230 µg showed no significant differencesin modes or rates of excretion of [¹⁴C]ADA equivalents. ADAwas readily converted to biurea under physiological conditionsand biurea was the only ¹⁴C-labeled compound present in excreta.[¹⁴C]ADA equivalents were present in all examined tissues immediatelyafter inhalation exposure, and clearance half-times on the orderof 1 day were evident for all tissues investigated. Storagedepots for [¹⁴C]ADA equivalents were not observed. The rateof buildup of [¹⁴C]ADA equivalents in blood was linearly relatedto the lung content as measured from rats withdrawn at selectedtimes during a 6-hr inhalation exposure at an aerosol concentrationof 25 µg, ADA/liter. In a study extending 102 days afterexposure, retention of [¹⁴C]ADA equivalents in tissues was describedby a two-component negative exponential function. The resultsfrom this study indicate that upon inhalation, ADA is rapidlyconverted to biurea and that biurea is then eliminated rapidlyfrom all tissues with the majority of the elimination via theurine.     

Changes in the Response of Lung Mast Cells Isolated from Rats and Guinea Pigs Exposed to Nitrogen Dioxide

Abstract

To clarify the relationship between exposure to nitrogen dioxide (NO₂) and mast-cell responses, rats and guinea pigs were exposed to 0, 1.0, 2.0, and 4.0 ppm NO₂ for 12 wk. Although lung wet weights were not changed in both rats and guinea pigs, the number of lung cells from 2.0 and 4.0 ppm NO₂-exposed rats were significantly decreased compared to that of control. No difference was observed in the number of lung mast cells from rats and guinea pigs exposed to NO₂. in lung mast cells from rats, immunoglobulin E (IgE) mediated histamine release was slightly decreased, but A23187-induced histamine release was not changed. On the contrary, in lung mast cells from guinea pigs, IgE-mediated histamine release was increased in a dose-dependent fashion, though no changes in A23187-induced histamine release were observed. These results suggest that different sensitivity for NO₂ exposure exists in lung mast cells from rats and guinea pigs.     

Peracute Toxic Effects of Inhaled Hydrogen Sulfide and Injected Sodium Hydrosulfide on the Lungs of Rats

Peracute Toxic Effects of Inhaled Hydrogen Sulfide and InjectedSodium Hydrosulfide on the Lungs of Rats. LOPEZ, A., PRIOR,M. G., REIFFENSEIN, R. J., AND GOODWIN, L. R. (1989). FundamAppl Toxicol. 12, 367–373. This study was designed totest whether intraperitoneally injected sodium hydrosulfide(NaHS) would mimic the pulmonary alterations induced by lethalperacute exposure to an atmosphere containing hydrogen sulfide.Groups of five Sprague- Dawley rats were exposed to an atmosphereof either 2317.6 ± 547.3 mg m^-3 H₂S (H₂S group) or noH₂S (air group), or were injected intraperitoneally with a solutioncontaining 30 mg kg^-1 sodium hydrosulfide (NaHS group) or salinesolution (vehicle control). Rats of the air and saline groupswere killed by cervical dislocation. All rats exposed to H²Sor injected with NaHS died within 3 min; however, only ratsexposed to H²S showed severe respiratory distress in the agonicphase preceding death. In addition, rats in the H²S group hada notable discharge of serous fluid from the mouth and nostrils.At necropsy, all rats in the H²S group had gross and histologicevidence of pulmonary edema characterized by massive extravasationof eosinophilic fluid into the bronchcalveolar space. In contrastthe lungs of rats injected with NaHS or saline or exposed toair were unaffected. It was concluded that the edematogeniceffect of H²S in the lungs cannot be reproduced by injectionof NaHS. The severity of lung edema induced by a peracute exposureto H² was extensive enough to account for death.     

Reproduction in Fischer-344 Rats Exposed to Methyl Chloride by Inhalation For Two Generations

Reproduction in Fischer-344 Rats Exposed to Methyl Chlorideby Inhalation For Two Generations. HAMM, T. E., JR., RAYNOR,T. H., PHELPS, M. C, AUMAN, C. D., ADAMS, W. T., PROCTOR, J.E., AND WOLKOWSKI-TYL, R. (1985) Fund. Appl. Toxicol. 5, 568–577.Male and female Fischer-344 rats were exposed to methyl chlorideby inhalation (0, 150, 475, or 1500 ppm, 6 hr/day, 5 days/week,40 males and 80 females per group). The only treatment-relatedclinical signs were a 10 to 20% body weight gain depression(BWGD) in both males and females exposed to 1500 ppm at allweekly weighings after 2 weeks of exposure and a 5–7%BWGD in 475-ppm exposed animals after Day 57. After 10 weeksthe exposure schedule was changed to 6 hr/day, 7 days/week andeach male was mated to two exposed females. The mating periodwas ended after 2 weeks, at which point 10 males/group werenecropsied. The only tratment-related lesions Found were severebilateral testicular degeneration (10/10) and granulomas inthe epididymis (3/10) in the 1500-ppm males. The remaining 30males per group were then removed from exposure and mated duringa 2-week period with 60 unexposed females. The exposed femaleswere continued on exposure from the start of mating to PostnatalDay 28 (6 hr/day, 7 days/week). The females were not exposedfrom Gestation Day 18 to Postnatal Day 4, and the pups werenever directly exposed prior to weaning. There were no significantdifferences between groups in the number of exposed or unexposedfemales that mated, as evidenced by copulation plugs. No litterswere born to exposed or unexposed females mated to the 1500-ppmmales. There was no significant difference in the number oflitters produced by the 150-ppm groups when compared to thecontrol groups. Fewer litters were born in the 475-ppm groupsthan in the control groups. No differences in litter size, sexratio, pup viability, or pup growth were Found among the 475-ppm,150-ppm, or control F₀ groups. When bred 10 weeks after thecessation of exposures, 5 to 20 1500-ppm F₀ males had regainedthe ability to sire normal litters. The same number of 475-ppmF₀ males proved as fertile (15/ 20) as control F₀ males (13/20).After weaning, F₁ pups from the 475-, 150-, and 0-ppm groupswere exposed to the same concentrations of methyl chloride For10 weeks and then mated. A trend toward decreased fertilitywas Found in the 475-ppm F₁ group     

Genotoxic and Cytotoxic Effects in Exfoliated Buccal and Nasal Cells of Chromium and Cobalt Exposed Electroplaters

ABSTRACT

Results of a number of studies indicate that electroplaters have increased cancer risks as a consequence of exposure to genotoxic metals such as chromium (VI) and nickel. These effects may be due to induction of damage of the genetic material which plays a key role in the etiology of cancer, and it was found that workers in galvanization factories exhibited increased levels of DNA damage. The aim of the present study was to investigate genetic stability in workers of a bright plating factory who are exposed to chromium (Cr) and cobalt (Co). Exfoliated cells were collected from the buccal and nasal mucosa of workers (n = 42) and matched controls (n = 43) and analyzed for induction of micronuclei (MN) which are formed as a consequence of chromosomal aberrations. In addition, other nuclear anomalies namely nuclear buds (Nbuds) which are formed as a consequence of gene amplification and markers indicating different stages of cell death (condensed chromatin, karyorrhexis, karyolysis, and pyknosis) were also assessed. No evidence was noted for induction of MN, but significantly increased rates of Nbuds in cells from both, buccal and nasal mucosa, were found. Parameters which are indicative for cytotoxic effects were more pronounced in nasal cells and rose with duration of employment period. Overall, our findings indicated that no apparent chromosomal damage occurred in bright electroplaters. However, data demonstrated that acute cytotoxic effects may lead to inflammations and/or lesions in epithelia of the respiratory tract of the workers.     

Systemic Effects of Inhaled Ultrafine Particles in Two Compromised,Aged Rat Strains

Epidemiological studies associate morbidity and mortality with exposure to particulate air pollution in elderly individuals with existing cardiopulmonary disease. These associations led to the hypothesis that inhaled particles can exert adverse effects outside of the lung, particularly on the cardiovascular system. We tested this hypothesis by examining the pulmonary and peripheral effects of inhaled ultrafine carbon particles in old rats that were injected with endotoxin (lipopolysaccharide, LPS) to model systemic gram-negative bacterial infection. Fischer 344 rats (23 mo) and spontaneously hypertensive (SH) rats (11–14 mo) were injected with LPS (2 mg/kg, ip) immediately before being exposed to inhaled ultrafine carbon particles for 6 h (150 μg/m³, CMD = 36 nm). Controls were injected with sterile saline or were sham exposed. Twenty-four hours after LPS injection, bronchoalveolar lavage (BAL) fluid, cells, and blood were obtained to assess endpoints of inflammation, oxidant stress, coagulability, and the acute-phase response. LPS did not cause an influx of neutrophils (PMNs) into the alveolar space, but did increase the number and percentage of circulating PMNs and the concentration of plasma fibrinogen in both rat strains. Inhaled ultrafine particles did not induce lung inflammation in either rat strain. In both strains, ultrafine particles (UFP) were found to decrease the number of blood PMNs, increase the intracellular oxidation of a fluorescent dye (DCFD) in blood PMNs, and affect plasma thrombin–anti-thrombin (TAT) complex and fibrinogen levels. UFP were also found to interact with ip LPS with respect to plasma TAT complex levels and blood PMN DCFD oxidation. Differences between the two rat strains were also found for TAT complex levels, BAL cell reactive oxygen species release, and DCFD oxidation in both BAL macrophages and blood PMNs. These results suggest that inhaled ultrafine carbon particles inhaled at concentrations mimicking high episodic increases in urban air can exert extrapulmonary effects in old rats and that they can change the systemic response to an inflammatory stimulus.     

Pulmonary Toxicity of Inhaled Polypropylene Fibers in Rats

This study was initiated to assess the pulmonary toxicity ofpolyolefin fiber composed of polypropylene in male Fischer 344rats after 90 days of inhalation exposure. To increase fiberrespirability in the rodent, polypropylene fibers were size-selectedbefore aerosolization to have a geometric mean diameter of 1.6m (46% <1 µm) and a geometric mean length of 30.3 µm.Three groups of animals were exposed in nose-only inhalationchambers, 6 hr/day, 5 days/week, for 90 days to 15, 30, or 60mg/m³ of polypropylene, or filtered air (negative control).Microscopic examination of the polypropylene fiber-exposed lungsrevealed that, at all time points examined in the study, therewas a dose-dependent increase in pulmonary macrophages. Theseminimal or mild increases in cellularity appeared to be reversible,especially at the lower doses 30 days post exposure. No fibrosiswas observed in any of the groups. A strong correlation wasfound between the external exposure concentration, the timeexposure, and the lung fiber burden. The number of partiallydegraded (segmented) fibers within the lung increased with theexposure concentration and period of exposure, as well as withthe period of recovery after termination of exposure at 90 days.Fibers were recovered from exposed lungs using a hypochloritedigestion technique.     

Relative Developmental Toxicities of Inhaled Aliphatic Mononitriles in Rats

The developmental toxicities of eight aliphatic raononitrileswere studied in Sprague-Dawley rats after inhalation exposurefor 6 hr/day, during Days 6 to 20 of gestation. The range ofexposure concentrations for acetonitrile was 900 to 1800 ppm;for propionitrile and n-butyronitrile, 50 to 200 ppm; for isobutyronitrile,50 to 300 ppm; for acrylonitrile and methacryloni-trile, 12to 100 ppm; for allylnitrile 12 to 50 ppm; and for 2-chloroacrylonitrile,1 to 12 ppm. Embryolethality was observed after exposure to1800 ppm acetonitrile, 200 ppm propionitrile, 300 ppm isobutyronitrile;fetotoxicity was observed after exposure to 200 ppm propionitrile,n-butyronitrile, or isobutyronitrile, or to 25 ppm acrylonitrile,in the presence of overt signs of maternal toxicity. In theabsence of significant maternal toxicity, allylnitrile causedembryolethality, fetotoxicity, and clear teratogenicity at 50ppm, and n-butyronitrile and methacrylonitrile caused fetotoxicityat 200 ppm and 100 ppm, respectively. While maternal toxicitywas observed for 2-chloroacrylonitrile, it did not cause significantembryonal or fetal toxicity up to 12 ppm.     

Teratogenic Potential of Inhaled Dichlorobenzenes in Rats and Rabbits

Teratogenic Potential of Inhaled Dichlorobenzenes in Rats andRabbits. HAYES, W. C., HANLEY, T. R., JR., GUSHOW, T. S., JOHNSON,K. A., AND JOHN, J. A. (1985). Fundam. Appl. Toxicol. 5, 190–202.Orthodichlorobenzene (ODCB) and paradichlorobenzene (PDCB) wereevaluated for teratogenic potential in rats (ODCB only) andrabbits. Groups of bred rats and inseminated rabbits were exposedto 0, 100, 200, or 400 ppm of ODCB; groups of inseminated rabbitswere exposed to 0, 100, 300, or 800 ppm of PDCB. Animals wereexposed for 6 hr/ day on Days 6 through 15 (rats) or 6 through18 (rabbits) of gestation. Maternal toxicity, as evidenced bya significant decrease in body weight gain, was observed inall groups of ODCB-exposed rats and liver weight was significantlyincreased in the 400-ppm ODCB-exposed group. Slight maternaltoxicity was observed in groups of rabbits exposed to 400 ppmODCB or 800 ppm PDCB as indicated by significantly decreasedbody weight gain during the first 3 days of exposure. Inhalationof up to 400 ppm of ODCB was not teratogenic or fetotoxic inrats, and neither ODCB nor PDCB was teratogenic or fetotoxicin rabbits at exposure levels up to 400 or 800 ppm, respectively.     

The Acute Toxicity of Inhaled Beryllium Metal in Rats

The Acute Toxicity of Inhaled Beryllium Metal in Rats. HALEY,P. J., FINCH, G. L., HOOVER, M. D., AND CUDDIHY, R. G. (1990).Fundam. Appl. Toxicol. 15, 767–778. We exposed rats onceby nose only for 50 min to a mean concentration of 800 µg/m³of beryllium metal (initial lung burden, 625 µg) to characterizethe acute toxic effects within the lung. Histological changeswithin the lung and enzyme changes within bronchoalveolar lavage(BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and171 days postexposure (dpe). Beryllium metal-exposed rats developedacute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolarfibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesionswere replaced by minimal interstitial and intraalveolar fibrosis.Necrotizing inflammation was observed again at 59 dpe whichprogressed to chronic-active inflammation by 115 dpe. This inflammationworsened progressively, as did alveolar macrophage and epithelialhyperplasia, becoming severe at 171 dpe. Low numbers of diffuselydistributed lymphocytes were also present but they were notassociated with granulomas as is observed in beryllium-induceddisease in man. Throughout the experiment, total numbers ofcells were elevated within the BAL samples due primarily toincreased numbers of neutrophils. Lymphocytes were not elevatedin BAL samples collected from beryllium-exposed rats at anytime after exposure. Lactate dehydrogenase (LDH), ß-glucuronidase,and protein levels were elevated in BAL fluid from 3 through14 dpe but returned to near normal levels by 31 dpe. LDH increasedonce again at 59 dpe and remained elevated at 171 dpe. ß-Glucuronidaseand protein levels were slightly, but not significantly, elevatedfrom 31 through 171 dpe. Results indicate that inhalation ofberyllium metal by rats results in severe, acute chemical pneumonitisthat is followed by a quiescent period of minimal inflammationand mild fibrosis. Progressive, chronic-active, fibrosing pneumonitisis observed later. Chronic beryllium lung disease of man isan immunologically mediated granulomatous lung disease, whereasberyllium-induced lung lesions in rats appear to be due to directchemical toxicity and foreign-body-type reactions.     

Modulation of the Inflammatory Effects of Inhaled Ozone in Rats by Subcutaneous Prolactin-Secreting, Pituitary-Derived Tumors

Rats are more sensitive to ozone-induced pulmonary inflammationand damage during late pregnancy and throughout lactation thanin pre- or early pregnancy or post lactation. This window ofsensitivity coincides with a period of elevated levels of pituitaryderivedprolactin or placental lactogen. In this study, we investigatedthe hypothesis that prolactin exerts an enhancing effect onozone-induced pulmonary inflammation and damage, thus presentinga plausible explanation for the sensitivity profile observedin rats. Hyperprolactinemia was achieved by using rats withsubcutaneous tumors that were derived from the MMQ tumor modelpreviously described by Adler and co-workers (Adler, R. A.,Krieg, R. J., Farrell, M. E., Deiss, W. P., and MacLeod, R.M., Metabolism 40, 286–291, 1991). A variant of the MMQtumor, the MMQ_r tumor, which appeared spontaneously from a singlepassage of MMQ tumor tissue, produced elevated levels of corticosteronein addition to high levels of prolactin. These two subcutaneoustumors had markedly different effects on adrenal, thymus, andspleen weights because of the different hormonal milieu theygenerated. There was also a significant difference between MMQ-and MMQ_r-bearing rats in their inflammatory response to acuteozone exposure as assessed by polymorphonuclear leukocytes (PMNs)in the airways. Rats with MMQ tumors were not significantlydifferent from non-tumor-bearing controls in their baselinelevel of airway PMNs and PMN inflammation following ozone exposure,whereas MMQ_r-bearing rats had significantly elevated baselinePMNs in their airways and a greater PMN response to inhaledozone. The hormonal milieu and elevated PMNs in the airwaysof both unexposed and ozone-exposed rats with MMQ_r tumors weresimilar to levels observed in lactating rats. The role of corticosteronein pulmonary inflammation in this model was investigated furtherby treating MMQ tumor-bearing rats with dexamethasone. Dexamethasonewas effective in producing changes in organ weights similarto those observed in MMQ_r rats, but did not elicit higher airwayPMN concentrations in unexposed rats as observed in the MMQ_rrats. We conclude that in this animal model prolactin did notsignificantly elevate airway PMN inflammation induced by ozone,and supplementation with exogenous glucocorticoid did not duplicatethe endogenous airway PMNs numbers observed in MMQ_r-bearingrats or lactating rats.     

Developmental Toxicity Evaluation of Inhaled Nitrobenzene in CD Rats

Developmental Toxicity Evaluation of Inhaled Nitrobenzene inCD Rats. TYL, R. W., FRANCE, K. A., FISHER, L. C., DODD, D.E., PRITTS, I. M, LYON, J. P., O'NEAL, F. O., and KIMMERLE,G. (1987). Fundam. Appl. Toxicol. 8, 482–492. PregnantCD (Sprague–Dawley) rats were exposed to nitrobenzenevapor (CAS Registry No. 98-95-3) at 0, 1, 10, and 40 ppm (meananalytical values of 0.0, 1.06, 9.8, and 39.4 ppm, respectively)on gestational days (gd) 6 through 15 for 6 hr/day. At sacrificeon gd 21, fetuses were evaluated for external, visceral, andskeletal malformations and variations. Maternal toxicity wasobserved: weight gain was reduced during exposure (gd 6–9and 6–15) to 40 ppm, with full recovery by gd 21, andabsolute and relative spleen weights were increased at 10 and40 ppm. There was no effect of treatment on maternal liver,kidney, or gravid uterine weights, on pre- or postimplantationloss including resorptions or dead fetuses, on sex ratio oflive fetuses, or on fetal body weights (male, female, or total)per litter. There were also no treatment-related effects onthe incidence of fetal malformations or variations. In summary,during organogenesis in CD rats, there was no developmentaltoxicity (including teratogenicity) associated with exposureto nitrobenzene concentrations that produced some maternal toxicity(10 and 40 ppm) or that produced no observable maternal toxicity(1 ppm).     

Chronic Toxicity and Oncogenicity Study on Inhaled Vinylidene Chloride in Rats

Chronic Toxicity and Oncogenicity Study on Inhaled VinylideneChloride in Rats. QUAST, J. F., MCKENNA, M. J., RAMPY, L. W.,AND NORRIS, J. M. (1986). Fundam. Appl. Toxicol. 6, 105–144.Male and female Sprague—Dawley rats (Spartan substrain)were exposed to vinylidene chloride (VDC) by inhalation for18 months to assess chronic toxicity and oncogenic potentialof the subject test material. Interim sacrifices were performedat 1, 6, and 12 months. Rats were exposed to VDC concentrationsof 10 and 40 ppm for 6 hr/day, 5 days/week for the first 5 weeksof the study. Based upon the absence of observable treatment-relatedeffects among rats sacrificed after 1 month of exposure, theexposure concentrations were increased to 25 and 75 ppm VDC.Exposures were continued at these concentrations through the18th month of the study after which the surviving animals wereheld until 24 months and then sacrificed. Cytogenetic evaluationswere performed on a separate group of animals, four rats/sex,exposed to 0, 25, or 75 ppm VDC for 6 months. There were noexposure-related changes in the following parameters: mortality,appearance and demeanor, body weight data, clinical chemistrydeterminations, hematologic evaluations, urinalysis, or cytogeneticevaluation of bone marrow preparations. A target organ effect,characterized by hepatocellular fatty change in the midzonalregion of the hepatic lobule which was minimal in severity,was observed in both male and female rats of both the 25- and75-ppm exposure groups as early as the 6-month interim sacrifice.The midzonal fatty change was also observed at the 12-monthsacrifice but no indication of progression of this lesion ineither severity or incidence was apparent. During the last 6months of the study, after exposures had been discontinued,this effect was no longer discernible; therefore this alterationwas readily reversible. The incidences of several tumors and/ortumor types were statistically increased or decreased in VDC-exposedrats when compared to their respective control groups; noneof these differences were judged to be attributable to VDC exposure.     

Distribution and Genotoxic Effects After Successive Exposure to Different Uranium Oxide Particles Inhaled by Rats

In nuclear fuel cycle facilities, workers may inhale airborne uranium compounds that lead to internal contamination, with various exposure scenarios depending on the workplace. These exposures can be chronic, repeated, or acute, and can involve many different compounds. The effect of uranium after multiple scenarios of exposure is unknown. The aim of this study, therefore, was to investigate the genotoxic and biokinetics consequences of exposure to depleted insoluble uranium dioxide (UO₂) by repeated or acute inhalation on subsequent acute inhalation of moderately soluble uranium peroxide (UO₄) in rats. The results show that UO₂ repeated preexposure by inhalation increases the genotoxic effects of UO₄ inhalation, assessed by comet assay, in different cell types, when UO₄ exposure alone has no effect. At the same time, the study of UO₄ bioaccumulation showed that the UO₄ biokinetics in the kidneys, gastrointestinal tract, and excreta, but not in the lungs, were slightly modified by previous UO₂ exposures. All these results show that both genotoxic and biokinetics effects of uranium may depend on preexposure and that repeated exposure induces a potentiation effect compared with acute exposure.