Prenatal Exposure to Silver Nanoparticles Causes Depression Like Responses in Mice

Despite increasing studies on silver nanoparticles, their mechanism of action is not so clear, especially their probable toxicity on reproduction procedure, developmental process and offspring behavior. Therefore in the present study the effect of silver nanoparticles exposure during gestational period on offspring''s depression behavior was assessed. Thirty virgin female mice were divided into three groups (n=10 for each group) including: one control and two experimental groups, which received an equal volume (0.2 ml) of suspension containing 0, 0.2 and 2 mg/kg of silver nanoparticles, respectively. After mating, the suspension was injected and repeated every 3 days till accouchement. Depression behaviors were assessed by tail suspension test and forced swimming test, in 45-day-old male and female progenies (6 groups, n=10). In males, both dose of silver nanoparticles (0.2 and 2 mg/kg) decreased mobility and increased immobility time in forced swimming test (P<0.05), but in female no effects were observed in mobility and immobility time. In tail suspension test, 2 mg/kg of silver nanoparticles lead to decrease of mobility time (P<0.05) and increase of immobility time (P<0.05) in female offspring but in males no significant effect was observed on mobility and immobility time. We may concluded that the prenatal exposure to silver nanoparticles probably cause gender-specific depression like behaviors in offspring, possibly through neurotoxic effect during neuronal development.     

Arsine: Absence of Developmental Toxicity in Rats and Mice

Arsine: Absence of Developmental Toxicity in Rats and Mice.MORRISSEY, R. E., FOWLER, B. A., HARRIS, M. W., MOORMAN, M.P., JAMESON, C. W., AND SCHWETZ, B. A. (1990). Fun-dam. Appl.Toxicol. 15, 350–356. Arsine gas is a potent hemolyticagent but the effects of exposure to tolerated concentrationson pregnancy and prenatal development have not been reported.In the present evaluation, groups of bred mice and rats wereexposed to arsine at concentrations of 0.025, 0.5, or 2.5 ppmon Gestation Days (gd) 6 through 15. Animals were killed ongd 17 (mice) or on gd 20 (rats) and endpoints of maternal anddevelopmental toxicity were evaluated. In rats, maternal spleenswere enlarged in the 2.5 ppm group and there was a decreasein packed red cell volume in pregnant rats. Fetuses weighedmore than in the control group but other endpoints of developmentaltoxicity were not affected by arsine exposure. In another experimentinvolving separate groups of rats, the arsenic content of maternalblood and fetal livers increased with increasing atmosphericarsine concentrations, as assessed on gd 20. In mice, maternalspleen size was significantly increased in the 2.5 ppm group.The number of live fetuses, mean fetal body weight, and percentagesof resorptions or malformations per litter were not affectedby arsine exposure. In conclusion, arsine at atmospheric concentrationsthat caused increases in maternal spleen size and measureablelevels of arsenic in maternal blood and fetal livers did notadversely affect endpoints of developmental toxicity     

Specific Antibody Responses to Subtilisin Carlsberg (Alcalase) in Mice: Development of an Intranasal Exposure Model

An intranasal (i.n.) dosing model was developed in mice as apotential alternative to more difficult, time-consuming, andcostly guinea pig intratracheal (GPIT) or mouse intratrachealmodels for assessment of the respiratory immunogenicity of detergentenzymes. Using a benchmark enzyme, Alcalase (protease subtilisinCarlsberg), studies were conducted to standardize the modelin terms of mouse strain, dosing and serum harvest regimen,and the primary immunoglobulin endpoint to use. The primaryassay endpoint selected was the enzyme-specific IgG1 titer determinedby an Alcalase-specific ELISA. This is not the primary allergenicantibody in mice (IgE is); however, IgG1 is coregulated withIgE via the IL-4/TH2 pathway and may have a role in mediatingallergic-type responses. BDF1 mice (C57B1/6 x DBA/2) were selectedas representative of high responder strains, with high responseassociated with the H-2^b (C57B1/6) parent. The dosing regimenused for most studies incorporated three i.n. exposures (Days1, 3, and 10) and bleeding of the animals on Day 15. The animalswere anesthetized and then immunized by allowing them to inhale5-µl aliquots of dosing solution into each nostril ateach immunization. Positioning of the animals with their headsdown (vs up) may have allowed more of the dosing solution toremain in the nasal region for a slightly longer period of time,but did not change the eventual GI tract migration and excretionof each dose. The presence of a detergent matrix in the enzymedosing solution enhanced the IgG1 response. Immunizing withenzyme plus detergent gave highly consistent dose-response curvesfor Alcalase when evaluated over many studies. An enzyme-specificallergic antibody (IgE) response was weak and inconsistent underthe dosing regimen used to generate the IgG1 response, but wasstronger with longer-term dosing, consistent with the delayin IgE vs IgG1 responses seen in some other studies. Using IgG1as a surrogate for allergic sensitization, we have preliminarydata showing similar differential potencies between Alcalaseand other test enzymes as detected in previous GPIT tests. Onthe basis of these data, we believe the i.n. immunization/IgG1response model is a robust technique that may be useful in determiningthe relative immunogenicities of detergent enzymes and otherproteins.     

Immunoglobulin and Lymphocyte Responses Following Silica Exposure in New Zealand Mixed Mice

Epidemiological studies have shown strong associations between silica exposure and several autoimmune diseases, including scleroderma and systemic lupus erythematosus.We previously reported that the New Zealand mixed (NZM) mouse develops silicosis and exacerbated autoimmunity following crystalline silica exposure, including increased levels of autoantibodies, proteinuria, circulating immune complexes, pulmonary fibrosis, and glomerulonephritis. In this study, the NZM mouse was used to examine changes in immune activation following silica exposure by measuring levels of immunoglobulin, cytokines and lymphocyte populations. Levels of immunoglobulin (Ig) G1 were significantly decreased from 1124 ± 244 µg/ml in saline exposed mice to 614 ± 204 µg/ml in silica-exposed mice, suggesting a decrease in the Th2 response. The levels of tumor necrosis factor (TNF)-α were significantly increased (1.5-fold) in the bronchoalveolar lavage fluid of the silica-exposed mice as compared to the saline-exposed mice. The number of B1a B cells were significantly increased sixfold within the superficial cervical lymph nodes of silica-exposed mice as compared with saline-exposed mice. Following silica exposure, CD4+T cells significantly increased threefold within the superficial cervical lymph nodes. During this increase in the number of CD4+T cells, the number of CD4+CD25+ regulatory T cells was not significantly changed, altering the ratio of regulatory T cells to T helper cells from 1:5 to 1:8 following silica exposure. Therefore, the silica-induced alterations in immunoglobulin levels, increased TNF-α, increased B1a B cells and CD4+ T cells, with decreased regulatory T cells, may provide an environment that allows for increased autoreactivity. These studies begin to provide possible mechanisms for environmentally induced autoimmune diseases that have been reported in many epidemiological studies.     

The Effect of Perinatal Exposure to Tetrachlorodibenzo-p-Dioxin on the Immune Response of Young Mice

ABSTRACT

The immunocompetence of 5 week old offspring from mice fed control chow or chow containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was evaluated. The 5 ppb maternal feeding level was the only level that produced symptoms of intoxication in the offspring (i.e., facial alopecia and periorbital edema). Mice from mothers fed either 2.5 or 5 ppb of TCDD demonstrated thymus cortex atrophy and a significantly reduced spleen anti-SRBC plaque forming cell (PFC) response, but had normal serum anti-SRBC antibody levels following primary and secondary immunization. Contact sensitivity response to DNFB was significantly reduced only in offspring from mothers fed 5 ppb of TCDD. The blastogenio response of splenic T- and B-lymphocytes to concanavalin-A and E. coli lipopolysaccharide was unaffected by perinatal TCDD exposure. This correlated with the normal appearance of the T- and B-cell dependent areas of the spleens from these animals. There was no significant difference in the differential white blood cell counts between control and TCDD-exposed offspring. Offspring from mothers fed up to 5 ppb of TCDD withstood a live Listeria challenge as well as controls. However, maternal feeding levels as low as 1 ppb of TCDD rendered offspring more sensitive to an endotoxin challenge.     

Exposure of Adult Mice to Environmental Tobacco Smoke Fails to Enhance the Immune Response to Inhaled Antigen

Epidemiologic evidence supports a role for environmental tobacco smoke (ETS) in the occurrence and severity of allergies/asthma. However, neither the precise combination of ETS and allergen exposure nor the mechanism (or mechanisms) by which these factors interact and contribute to asthma induction is known. Animal model studies have failed to establish a convincing relationship between ETS exposure and asthma induction, perhaps because of methodological inadequacies. Here, we tested the hypothesis that ETS inhalation would provoke an asthmatic response by overcoming normal airway tolerance to inhaled antigens. Our protocol combined daily ETS exposure with nose-only sensitization to ovalbumin. Three strains of mice were tested, each with a different level of susceptibility to airway hypersensitivity. Immunological responses were assessed by immunoglobulin production. Airway inflammation was assessed by bronchoalveolar lavage differentials and lung histopathology. Airway hyperresponsiveness was determined by methacholine challenge. The mice produced ovalbumin-specific antibodies following ovalbumin exposure in a strain-dependent manner. Only the A/J mice produced detectable levels of ovalbumin-specific immunoglobulin (Ig) E. Both A/J and BALB/c mice produced ovalbumin-specific IgG1 antibodies. The C57Bl/6 mice did not produce detectable levels of antibodies. The A/J mice also exhibited airway inflammation following ovalbumin exposure. Neither the C57Bl/6 nor the BALB/c mice exhibited signs of airway inflammation. Exposure to ETS failed to enhance ovalbumin-specific antibody production, airway inflammation, or hyperresponsiveness. Together these results indicate that ETS exposure accompanied by nose-only allergen sensitization fails to overcome aerosol tolerance in adult mice.     

Specific IgE and IgG1 Responses to Subtilisin Carlsberg (Alcalase) in Mice: Development of an Intratracheal Exposure Model

The primary objective of this study was to examine the feasibilityof using a mouse model to evaluate the immunogenicity of proteinsas a potential method to determine occupational exposure guidelines.Mice were intratracheally administered a benchmark protein allergen,subtilisin Carlsberg (Alcalase) in detergent matrix once a weekfor 4 to 6 weeks and specific IgE and IgG1 levels were determined.In all experiments, specific IgE levels were determined by usinga rat basophilic leukemia cell (RBL) release assay, while specificIgG1 was measured by an ELISA. A good correlation was observedbetween IgE titers determined by the RBL assay and rat passivecutaneous anaphylaxis assay. Intratracheal administration ofprotease with detergent matrix was found to result in significantIgE and IgG1 responses that were dose related. Detergent matrixwas found to enhance the Alcalase-specific IgE and IgG1 responsewhen administered by the intratracheal route. The IgG1 responsewas much more robust, easier to measure, and found to followthe IgE response. These results suggest that a mouse intratrachealmodel is a feasible approach to examining the immunogenic potencyof enzymes using specific IgE or IgG1 as the end points. Additionaldevelopment and validation of the mouse model with other typesof proteins will be pursued.     

Cardiovascular Responses to Short-Term Fumonisin Exposure in Swine

The cardiovascular effects of the mycotoxin fumonisin were examinedin male cross-bred pigs fed 20 mg/kg of fumonisincontainingculture material for 7 days. On Day 8, pigs were anesthetizedwith halothane and surgically catheterized. Cardiovascular measurementsand blood gas analyses were obtained during halothane anesthesiaand 18 hr after recovery from anesthesia. Pigs fed fumonisinhad significant (p<0.05) decreases in maximal rate of changeof left ventricular pressure, heart rate, cardiac output, andmean aortic pressure, a significant increase in mean pulmonaryartery pressure and pulmonary vascular resistance, and no changein left ventricular end-diastolic pressure, pulmonary wedgepressure, and central venous pressure. Treated pigs also hadsignificant decreases in both arterial and mixed venous bloodO₂ tension, and systemic oxygen delivery, but significantlyincreased oxygen consumption and oxygen extraction ratio. Theseresults suggest that fumonisin increases oxygen consumptionand is a negative inotropic and chronotropic agent in pigs.Because fumonisin is a naturally occurring inhibitor of theenzyme sphingosine N-acyltransferase, thereby increasing sphingosineconcentrations in vivo, we speculate that the observed cardiovasculareffects were mediated in part by a fumonisin-induced increasein tissue sphingosine concentrations.     

Response of Fecal Bacterial Flora to the Exposure of Fumonisin B1 in BALB/c Mice

Fumonisins are a kind of mycotoxin that has harmful influence on the health of humans and animals. Although some research studies associated with fumonisins have been reported, the regulatory limits of fumonisins are imperfect, and the effects of fumonisins on fecal bacterial flora of mice have not been suggested. In this study, in order to investigate the effects of fumonisin B1 (FB1) on fecal bacterial flora, BALB/c mice were randomly divided into seven groups, which were fed intragastrically with 0 mg/kg, 0.018 mg/kg, 0.054 mg/kg, 0.162 mg/kg, 0.486 mg/kg, 1.458 mg/kg and 4.374 mg/kg of FB1 solutions, once a day for 8 weeks. Subsequently, feces were collected for analysis of microflora. The V3-V4 16S rRNA of fecal bacterial flora was sequenced using the Illumina MiSeq platform. The results revealed that fecal bacterial flora of mice treated with FB1 presented high diversity. Additionally, the composition of fecal bacterial flora of FB1 exposure groups showed marked differences from that of the control group, especially for the genus types including Alloprevotella, Prevotellaceae_NK3B31_group, Rikenellaceae_RC9_gut_group, Parabacteroides and phylum types including Cyanobacteria. In conclusion, our data indicate that FB1 alters the diversity and composition of fecal microbiota in mice. Moreover, the minimum dose of FB1 exposure also causes changes in fecal microbiota to some extent. This study is the first to focus on the dose-related effect of FB1 exposure on fecal microbiota in rodent animals and gives references to the regulatory doses of fumonisins for better protection of human and animal health.     

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.     

Effects of Intranasal Exposure to Spores ofStachybotrys atrain Mice

The effects of highly toxic and nontoxic spores ofStachybotrys atrawere investigated in mice after six intranasal administrations of 1 × 10⁵and 1 × 10³spores in phosphate-buffered saline during a 3-week period. Toxic spores contained the trichothecene mycotoxins, satratoxins G and H, as well as the immunosuppressant stachybotrylactones and -lactams. No trichothecenes were detected in the nontoxic spores, and they contained only minor amounts of stachybotrylactones and -lactams. In mice injected with toxic and nontoxic spores, the platelet count was decreased and leucocyte and erythrocyte counts, hemoglobin concentration, and hematocrit were increased. No IgG antibodies toS. atrawere detected in sera of mice exposed intranasally to spores. No histological changes were detected in spleen, thymus, or intestines of mice. The mice receiving 1 × 10⁵toxic spores intranasally developed severe inflammatory changes within both bronchioles and alveoli. Hemorrhage was detected in alveoli. The mice receiving 1 × 10⁵nontoxic spores also developed inflammatory changes in the lungs, but these changes were significantly milder than those in mice receiving toxic spores. The mice receiving 1 × 10³toxic spores developed inflammatory changes in the lungs that were less severe than those in the mice receiving 1 × 10⁵toxic spores. No inflammatory changes were detected in the mice receiving 1 × 10³of nontoxic spores. The present findings indicate that exposure toS. atraspores containing toxins (satratoxins) can be a significant health risk.     

Effects of Intranasal Exposure to Spores of Stachybotrys atra in Mice

The effects of highly toxic and nontoxic spores of Stachybotrysatra were investigated in mice after six intranasal administrationsof 1 x 10⁵ and 1 x 10³ spores in phosphate-buffered saline duringa 3-week period. Toxic spores contained the trichothecene mycotoxins,satratoxins G and H, as well as the immunosuppressant stachybotrylactonesand-lactams. No trichothecenes were detected in the nontoxicspores, and they contained only minor amounts of stachybotrylactonesand-lactams. In mice injected with toxic and nontoxic spores,the platelet count was decreased and leucocyte and erythrocytecounts, hemoglobin concentration, and hematocrit were increased.No IgG antibodies to S. atra were detected in sera of mice exposedintranasally to spores. No histological changes were detectedin spleen, thymus, or intestines of mice. The mice receiving1 x 10⁵ toxic spores intranasally developed severe inflammatorychanges within both bronchioles and alveoli. Hemorrhage wasdetected in alveoli. The mice receiving 1 x 10⁵ nontoxic sporesalso developed inflammatory changes in the lungs, but thesechanges were significantly milder than those in mice receivingtoxic spores. The mice receiving 1 x 10³ toxic spores developedinflammatory changes in the lungs that were less severe thanthose in the mice receiving 1 x 10³ toxic spores. No inflammatorychanges were detected in the mice receiving 1 x 10³ of nontoxicspores. The present findings indicate that exposure to S. atraspores containing toxins (satratoxins) can be a significanthealth risk.     

Influence of Chronic Exposure to Uranium on Male Reproduction in Mice

Influence of Chronic Exposure to Uranium on Male Reproductionin Mice. Llobet, J. M., Sirvent, J. J., Ortega, A., and Domingo,J. L. (1991). Fundam Appl. Toxicol. 16, 821–829. Relativelyfew data are available concerning the reproductive and developmentaltoxicity of uranium. The present study was designed to evaluatethe reproductive effects of this metal in male Swiss mice. Theanimals were treated with uranyl acetate dihydrate at dosesof 0, 10, 20, 40, and 80 mg/kg/day given in the drinking waterfor 64 days. To evaluate the fertility of the uraniumtreatedmales, mice were mated with untreated females for 4 days. Therewas a significant but non-dose-related decrease in the pregnancyrate of these animals. Body weights were significantly depressedonly in the 80 mg/kg/day group. Testicular function/spermatogenesiswas not affected by uranium at any dose, as evidenced by normaltestes and epididymis weights and normal spermatogenesis, whereasinterstitial alterations and vacuolization of Leydig cells wereseen at 80 mg/kg/day. The results of this investigation indicatethat uranium does not cause any adverse effect on testicularfunction in mice at the concentrations usually ingested in thediet and drinking water, with a safety factor of more than 1000.However, although spermatogenesis was not affected by uraniumadministration, uranium produces a significant decrease in thepregnancy rate at 10, 20, 40, or 80 mg/kg/day.     

Influence of Low-Level Exposure to Fusarium Mycotoxins on Selected Immunological and Hematological Parameters in Young Swine

The effects of low dietary concentrations of Fusarium myco toxins(deoxynivalenol (DON), 1 5-acetyl-DON, and zearalenone) on growth,immunological, and hematological parameters were determinedin young pigs during a 28-day feeding experiment. Clean andnaturally contaminated corn were incorporated into basal dietsformulated to contain 0.00, 0.75, 1.50, and 3.00 mg DON/kg diet.A pair-fed control animal was used for comparison with eachanimal receiving the highest level of contamination (diet 4).Skin temperature, measured during the first week of the experiment,decreased linearly as the dietary mycotoxin concentration increased.Several other linear effects were observed: depressed feed intakethroughout the experiment, reduction in thyroid size (absolute/relative),and changes in the appearance of the esophageal region of thestomach (thicker and higher degree of folding with increasingtoxin concentration). Serum T₄ (thyroxine) levels increasedquadratically after 7 and 28 days of exposure compared to controlanimals. This change coincided with an increase in albumin levels,a decrease in -globulin levels, and an overall increase in albumin/globulinratio as the level of contamination increased. After immunizationwith sheep red blood cells (SRBC), animals fed contaminateddiets showed a delayed response in peak titers. At the end ofthe experiment an increase in the segmented neutrophil countwas observed. The following observations were made for ani malsconsuming diet 4 as compared to the pair-fed controls: lowerskin temperature, better feed efficiency, more corrugated stomachs,reduced -globulin levels, and lower antibody titers to SRBC.The study showed a physiobiochemical adaptation response ofanimals exposed to mycotoxin-contaminated diets. Although mostchanges seem to be related to the nutritional status of theanimal, others such as reduced skin temperature, altered stomachcondition, and reduced -globulin levels suggest specific effectsdue to the Fusarium toxins. The pair-feeding treatment was importantin reaching these conclusions, but it is also evident that thetreatment itself introduces changes in response to a reducedfeed intake.     

Pathophysiologic Responses of Sheep to Brief High-Level Nitrogen Dioxide Exposure

Abstract

The cardiopulmonary response to short-duration, high-concentration nitrogen dioxide (NO₂) exposure was examined in conscious domestic sheep (Ovis aries). Six intubated animals in each of 3 groups were given a 15-min exposure to either air (control) or approximately 700 or 500 ppm NO_2? Pulmonary and systemic hemody-namics, pulmonary mechanics, blood gases, and hematologic variables were measured immediately before and after exposure and at 1, 4, and 24 h after exposure. Minute ventilation was monitored during exposure, and a pulmonary histopathologic examination was performed 24 h postexposure. Negligible effects were observed in the control group. Exposure to 100 ppm NO₂ caused a modest increase in minute ventilation during exposure, and an increased number of leukocytes was found within interalveolar capillaries upon histologic examination. Exposure to 500 pprn NO₂ induced an immediate and profound lung irritant response characterized by an increase in lung resistance, respiratory rate, and minute ventilation. The exposure was marked by a statistically significant, but small, increase in methemoglobin concentration. Pulmonary function progressively deteriorated in the 24-h period following exposure to 500 ppm NO₂, and a significant arterial oxygen tension reduction and pulmonary artery pressure increase occurred at 24 h postexposure. Histologic examination after 500 ppm NO₂ revealed patchy lobular exudation and accumulation of leukocytes in both alveolar sacs and interalveolar capillaries.     

Contact Hypersensitivity Response to Isophorone Diisocyanate in Mice

ABSTRACT

Isophorone diisocyanate was evaluated for its potential as a sensitizing agent for allergic contact hypersensitivity in mice. Female B6C3F1 mice were sensitized with 0.1, 0.3, and 1.0% isophorone diisocyanate and challenged with 3.0% isophorone diisocyanate. Doses of isophorone diisocyanate were selected from assays for primary irritancy. Mice received 20 u.l by direct dermal application, for 5 days, to sites prepared by shaving, dermabrading and, in some mice, with intra dermal injection of complete Freund's adjuvant. The rest period was 7 days. Measurement of the contact hypersensitivity response in mice was by radioisotopic assay two days after challenge and mouse ear swelling one and two days after challenge. Mice demonstrated statistically significant dose-dependent contact hypersensitivity responses to isophorone diisocyanate with or without adjuvant pretreatment.     

Physiologic Responses of Sheep to Two Different Methods of Papain Exposure

Human emphysema is a progressive, destructive lung disease that produces morphologic and functional heterogeneity throughout its course. Consequently, the mature form of the disease is described by a broad range of anatomic, radiological, and physiologic patterns. This report describes the development and characterization of a sheep model of emphysema that represents many of the essential features of both homogeneous and heterogeneous emphysema. Emphysema was produced by two different techniques of papain exposure: (1) aerosol (75 IU/kg) given weekly for 4 treatments (HM) or (2) aerosol (75 IU/kg) weekly for 3 treatments following subsegmental intrabronchial instillations, 75 IU (in 10 saline) per lobe in 6 lobes (HT). Dexamethasone (0.06 mg/kg iv) was administered prior intrabronchial instillations only. On computed tomography, the HM group had homogeneous emphysema, the HT group gross nonuniformity of disease and bullae formation. Both groups demonstrated a significant (p < .05) increase in residual volume (HM, +38%; HT, +30%). There was a significant increase (p = .002) in total lung capacity per kilogram for the HM group. Emphysema had no effect on active or passive chest wall compliances. Diffusion capacity was significantly (p < .05) reduced in both groups. Both elastic (p = .066) and resistive (p = .025) components of impedance were increased in the HT, and airway resistance increased significantly in the HM groups. The HM model demonstrated gas trapping, a characteristic feature of emphysema, but failed to replicate the alterations in lung dynamics observed in the human form of this disease. The HT model demonstrated less static hyperinflation but significant frequency dependence and hence appeared to better represent the dynamic characteristics of human emphysema.     

Effect of Acute Propanil Exposure on the Immune Response of C57BI/6 Mice

Effect of Acute Propanil Exposure on the Immune Response ofC57BI/6 Mice. BARNETT, J. B., AND GANDY, J. (1989). Fundam.Appl. Toxicol. 12, 757–764. Propanil is a herbicide thatis used extensively in rice farming to kill weeds without damagingthe rice plant The immunotoxic effects of acute exposure topropanil were determined in adult C57B1/6 female mice exposedintraperitoneally to propanil at doses of 0, 10, 25, 50, 100,200,or 400 mg/kg body wt. One week following exposure, the immunecompetency of the animals was assessed. Contact hypersensitivityresponse (CHR), blastogenic response to T- and B-cell-specificmitogens, and mixed lymphocyte reaction (MLR) were significantlydepressed only in propanil-treated animals at 400 mg/kg. However,the number of splenic antibody-producing cells was also significantlydepressed in a dose-dependent manner at the lower doses of 50,100, and 200 mg/kg. In addition, a significant reduction inthe thymus weight and an increase in absolute and relative spleenweight were also measured in animals treated with 200 and 400mg/kg. The increase in spleen weight also showed a concomitantrise in spleen cellularity. These data indicate that propanilhas a dose-dependent immunotoxic effect on the adult mouse thataffects primarily the humoral response     

Comparative Toxicity of Arsine Gas in B6C3F1 Mice, Fischer 344 Rats, and Syrian Golden Hamsters: System Organ Studies and Comparison of Clinical Indices of Exposure

Comparative Toxicity of Arsine Gas in B6C3F₁ Mice, Fischer 344Rats, and Syrian Golden Hamsters: System Organ Studies and Comparisonof Clinical Indices of Exposure. BLAIR, P. C, THOMPSON, M. B.,MORRISSEY, R. E., MOORMAN, M. P., SLOANE, R. A., AND FOWLER,B. a. (1990). Fundam. Appl. Toxicol. 14, 776–787. In orderto examine possible species differences in response to arsineexposure, multiple inhalation studies consisting of acute (1-day),subacute (14- and 28-day), and subchronic (90-day) exposuresto this agent were conducted using three different species ofrodents. Evaluations of hematopoietic organs and alterationsin the heme biosynthetic pathway were the focus of these studies.Species used were B6C3F₁ mice (exposed 1, 14, or 90 days), Fischer344 rats (exposed 14, 28, or 90 days), and Syrian Golden hamsters(exposed 28 days). All arsine exposures were at concentrationsof 0.5, 2.5, or 5.0 ppm except for 90-day studies, in whichconcentrations were lowered to 0.025, 0.5, or 2.5 ppm. No changesin body weight gain were observed in either sex of mice or hamsters.The only decrease in body weight gain occurred in male ratsexposed to 5.0 ppm arsine for 28 days. Significant exposure-relatedincreases in relative spleen weights occurred in both sexesof mice and rats in the 0.5 (except 14-day female rats), 2.5,and 5.0 ppm exposure groups from all studies and in hamstersin the 2.5 and 5.0 ppm exposure groups. Generally, increasesin relative liver weight occurred in fewer exposure groups andwere of a lesser magnitude than increases in spleen weight.Other parameters affected included decreased packed cell volumes(mice, rats, and hamsters), hematol-ogy profiles (rats), andan increase in 6-aminolevulinic acid dehydratase activity inall species. Arsenic content was measured in livers of ratsafter 90 days of exposure. Concentrations increased in relationto atmospheric concentrations of arsine. Histopathological changesincluded increased hemosiderosis and extramedullary hematopoiesisin spleen and intracanalicular bile stasis (mice only) in liver.Additionally, bone marrow hyperplasia was observed in rats.Effects on other organs were not observed, suggesting that thehematopoietic system is the primary target for arsine. In conclusion,we have determined that the effects of arsine exposure uponmice, rats, and hamsters are similar. Most importantly, eventhough no effects on the hematopoietic system were observedfollowing a single exposure to 0.5 ppm arsine which is 10 timesthe Threshold Limit Value (TLV) set by the American Conferenceof Governmental Industrial Hygienists, repeated exposure to0.025 ppm (one-half the TLV) caused a significant anemia inrats.