Metabolism and Excretion of Gallium Arsenide and Arsenic Oxides by Hamsters following Intratracheal Instillation

The increasing use of gallium arsenide (GaAs) in the electronicsindustry has produced the need for pharmacokinetic and toxicologicdata on GaAs. The disposition in male Syrian golden hamsters(n = 4) following intratracheal instillation of GaAs (mean volumediameter 5.8 µm), arsenic(III) oxide (arsenite), and arsenic(V)oxide (arsenate) at a dose of 5 mg/kg body weight was examined.Blood, kidney, liver, and lung samples were collected at 1,2, and 4 days after administration. Excreta were collected daily.Urinary metabolite profiles were determined after separationon a mixed anion–cation-exchange column. Total As contentwas analyzed by direct hydride flame atomic absorption spectrophotometryafter digestion. Arsenic blood levels after GaAs, arsenite,and arsenate administration were 0.185 ± 0.041, 0.596± 0.117, and 0.3 10 ± 0.045 ppm, respectively,after Day 1. Arsenic blood levels after GaAs administrationincreased to 0.279 ± 0.021 ppm on Day 2 indicating continuedabsorption while levels decreased for the arsenite and arsenategroups. At Day 1 the liver contained 0.565 ± 0.036, 2.62± 0.26, and 0.579 ± 0.144% of the arsenic doseof GaAs, arsenite, and arsenate, respectively. The" arseniteand arsenate were rapidly excreted in the urine with almosthalf the dose appearing after 4 days; in contrast, only about5% of the GaAs was found at the corresponding time. Total recoveries,as arsenic equivalents, for the three compounds were between75 and 80%. Ratios of the two major urinary metabolites (dimethylarsinicacid/total Inorganic As species) were 1.41, 1.71, and 0.983for GaAs, arsenite, and arsenate, respectively. GaAs is metabolizedto the same compounds as arsenite and arsenate, and shows ametabolic profile most similar to that observed for sodium arsenite.     

Toxicity of a Quartz with Occluded Surfaces in a 90-Day Intratracheal Instillation Study in Rats

This 90-day study was aimed at characterizing the differences in biological activity between a crystalline ground reference quartz (DQ12) and a quartz with occluded surfaces (quartz isolate) obtained from a clay deposit formed 110 to 112 million years ago. In different test groups, rats were dosed with the same total mass and quartz level by intratracheal instillation, with a total high dose of 15.2 mg/kg (body weight, bw) or approximately 4.7 mg/rat of each quartz species in a saline suspension. The reference quartz was mixed with titanium dioxide to achieve a positive control mixture, which contained the same quartz content as in the quartz isolate. At 3 days post dosing, both quartz groups showed a significant inflammatory response based on total and differential cell counts from bronchoalveolar lavageate (BAL) analysis. At 28 and 90 days, the quartz isolate values were no longer statistically different from vehicle control group values; however, the positive control group values were approximately 12 and 65 times greater than those of the control group, respectively. After 28 days, histopathological evaluation showed moderate effects in the quartz isolate group compared to the saline control animals. These effects did not progress in severity at 90 days. In contrast, the positive control group exhibited more severe effects than the quartz isolate group and these effects showed a progression to a persistent and self-perpetuating inflammatory state. The toxicological properties of quartz particles can vary significantly dependent on their surface characteristics. Toxicity can range from a high-dose-induced, modest, transient inflammation from quartz with occluded surfaces, to a severe and persistent inflammatory state caused by ground quartz with fractured surfaces.     

Toxicity of an Anthraquinone Violet Dye Mixture Following Inhalation Exposure, Intratracheal Instillation, or Gavage

Anthraquinone dyes are utilized by the military in colored smokegrenades. During production, workers in munitions plants maybe exposed to fugitive emissions of these dyes or mixtures thereof.The effects of a prototype violet dye mixture (VDM) consistingof Disperse Red 11 (DR1 1), 11 ,4-diamino-2- methoxy-anthraquinone]and Disperse Blue 3 (DB3) [l-methy larnino-4-hydroxyethylarnino-anthraquinoneon F344 male and female rats have been investigated. Acute 1-dayinhalation exposures (6 hr) to VDM were conducted at 1000, 300,100, 70, 40, and 10 mg/rn with an additional exposure to 40mg/m 6 hr/day for 5 days; 4.22 ± 2.1 m (MMAD ±g). Lung burdens of dye, general histopathology, and/or liverfunction were evalu ated at 0, 3, and 7 days postexposure. Unexpectedlethality due to severe liver damage was observed with acuteexposures of 300 mg/rn and in the 5-day 40 mg/rn exposures.Centrilobular degeneration and necrosis of liver cells was concentration-dependent with inhalation of VDM?40 mg/m³ In addition, nasalolfactory epithelium exhibited degeneration and necrosis withacute exposures?10 mg/rn Lung instillations at 250, 500, and1000 zg of the VDM revealed no lung or liver toxicity. Becauseper os exposure due to preening was suspected as a major exposureroute, a gavage study with the VDM and its two component dyesDR1 1 and DB3 (800 mg/kg) was undertaken. One day followinggavage with DR1 1 or DB3, serum enzymes indicative of livertoxicity (LDH, SGPT, SDH, and ICDH) were slightly elevated (1–6xcontrol). However, rats gavaged with VDM had serum enzyme levels10–100X control by Day 1 after gavage, indicating acuteliver toxicity. Activities of liver en zymes involved in xenobioticand glutathione metabolism were also acutely affected. All ofthe dyes caused various degrees of induction of glucose-6-phosphatedehydrogenase, glutathione reductase, glutathione peroxidase,and nonprotein sulfhydryls. The enzymes involved in xenobioticmetabolism (glutathione S-transferase, NADPH cytochrome-c reductase,and P450) were also elevated by the two component dyes, in contrastto their significant depression with VDM treatment. The similaritybetween the liver and olfactory epithelium effects of thesecompounds and the lack of pulmonary tissue effects is not fullyunderstood, but the interaction of the individual dyes as VDMemphasizes the need to assess chemicals such as the anthraquinones as their likely-to-be-encountered mixtures.     

Improved Pharmacokinetic Characteristics of Ursolic Acid in Rats Following Intratracheal Instillation and Nose-Only Inhalation Exposure

Ursolic acid (UA) is a common pentacyclic triterpene phytochemical with various pharmacological activities. However, UA is classified as a class IV drug in BCS system and its development as an oral drug is limited. Pulmonary delivery is an effective way to improve the bioavailability of drugs with low absorption. In this study, the differences in pharmacokinetic behaviors of UA after pulmonary and oral administration was explored in rats. Compared with oral administration, the plasma concentration of UA increased rapidly after pulmonary administration, and the bioavailability increased about 80 times. UA instantly accumulated in the lungs after pulmonary administration, and the pulmonary AUC_0-t/dose increased by 114 times compared to oral dosing. Incubation experiments showed that the metabolism of UA in rat lung microsomes was significantly reduced compared with that in liver microsomes, in which the clearance rate of phase I and phase II metabolism was reduced by 14.7 times and 1.4 times respectively. These results indicated that pulmonary administration could improve the bioavailability of UA and reduce its metabolism. This study not only provides a preferable route of administration for the application of UA but also offers new insights for the development of phytochemical drug candidates with poor pharmacokinetic properties.     

Propolis Attenuates Doxorubicin-Induced Testicular Toxicity in Rats

Doxorubicin (Dox), an effective anticancer agent, can impair testicular function leading to infertility. The present study aimed to explore the protective effect of propolis extract on Dox-induced testicular injury. Rats were divided into four groups (n = 10). Group I (normal control), group II received propolis extract (200 mg kg⁻¹; p.o.), for 3 weeks. Group III received 18 mg kg⁻¹ total cumulative dose of Dox i.p. Group IV received Dox and propolis extract. Serum and testicular samples were collected 48 h after the last treatment. In addition, the effects of propolis extract and Dox on the growth of solid Ehrlich carcinoma in mice were investigated. Dox reduced sperm count, markers of testicular function, steroidogenesis and gene expression of testicular 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) and steroidogenic acute regulatory protein (StAR). In addition, it increased testicular oxidative stress, inflammatory and apoptotic markers. Morphometric and histopathologic studies supported the biochemical findings. Treatment with propolis extract prevented Dox-induced changes without reducing its antitumor activity. Besides, administration of propolis extract to normal rats increased serum testosterone level coupled by increased activities and gene expression of 3ß-HSD and 17ß-HSD. Propolis extract may protect the testis from Dox-induced toxicity without reducing its anticancer potential.     

Acute Functional Enhancement of Circulatory Neutrophils After Intratracheal Instillation with Diesel Exhaust Particles in Rats

Abstract

We have previously demonstrated that intratracheal instillation (IT) with diesel exhaust particles (DEP) exacerbates myocardial ischemia/reperfusion-induced arrhythmia in rats. Since activated neutrophils play a pivotal role in ischemia/reperfusion arrhythmia, in the present study we investigated the effects of DEP on peripheral neutrophil count and on the oxyradical production (ORP) of neutrophils in rats. We also determined the production of cytokines for better understanding of the relationship between pulmonary inflammation and neutrophil function. Instillation with 5 mg DEP elevated circulatory neutrophil counts (CNC) at 12 and 24 h post-instillation to levels approximately 2.1- and 2.3-fold those in the vehicle-treated animals, respectively. On the other hand, 1-mg DEP caused an approximately 0.4-fold increase in CNC at 6 h. 12-O-Tetradecanoylphorbol 13-acetate-induced ORP in the isolated neutrophil was enhanced at 12 and 24 h after instillation with 5 mg DEP. Cytokine-induced neutrophil chemoattractant-1 (CINC-1), tumor necrosis factor-α (TNFα) and macrophage inflammatory protein-2 (MIP-2) levels were increased in the bronchoalveolar lavage fluid (BALF) collected from animals that received 5 mg DEP. In serum, a marked elevation of CINC-1 and a slight elevation of MIP-2 were also observed, while TNFα was not detected. Granulocyte–macrophage colony-stimulating factor (GM-CSF) was detected in neither BALF nor serum for 24 h after the instillation. These results suggest that IT instillation of DEP enhances systemic oxidative stress by increasing neutrophil count and ORP in the acute period.     

Pulmonary Uptake of Liposome-associated α-Tocopherol Following Intratracheal Instillation in Rats

Abstract— This study examined the uptake and subcellular distribution of α-tocopherol in the lung following intratracheal instillation of liposome-associated α-tocopherol in rats. The liposomal suspension was composed of dipalmitoylphosphatidylcholine (DPPC) and α-tocopherol (molar ratio 7:3), labelled with [³H]α-tocopherol and [¹⁴C]cholesterol. Following intratracheal administration of the liposomal preparation (2 mg α-tocopherol/animal), the recovery of [³H]α-tocopherol in the lung was maximal (87% of initial dose) 1 h after treatment; thereafter, α-tocopherol levels remained relatively high (no less than 73% of initial dose) for the rest of the 72-h experimental period. This treatment effect resulted in a 16-fold increase in pulmonary total α-tocopherol concentration 72 h post-instillation. No radioactivity was detected in the blood, liver, kidney, pancreas, spleen and heart of animals during the 72-h experimental period. [³H]α-Tocopherol was recovered largely from cytosolic (45%) and nuclear (36%) fractions of lung and to a lesser extent, from microsomal (11%) and mitochondrial (9%) fractions. Chromatographic analysis of the subcellular fractions revealed that [³H]α-tocopherol was co-eluted with ¹⁴C-labelled liposomal lipids. Our in-vitro study, involving the incubation of Fe³⁺-ADP (a pro-oxidant) with mitochondrial or microsomal fractions isolated from lung tissues of animals treated with liposome-associated α-tocopherol, provided evidence that α-tocopherol levels present in the membranes of these subcellular fractions were sufficient to protect against oxidant-induced lipid peroxidation. α-Tocopherol in the rat lung can be greatly increased by the intratracheal instillation of α-tocopherol entrapped in DPPC-liposomes, suggesting that this liposomal preparation may be used as an effective prophylactic agent against oxidant-induced lung injury.     

Physicochemical and Mineralogical Characterization of Test Materials used in 28-Day and 90-Day Intratracheal Instillation Toxicology Studies in Rats

Two recent intratracheal instillation toxicology studies in rats clearly show that a naturally occurring quartz, with occluded crystal surfaces (quartz isolate), produced significantly less inflammatory response than a crushed reference quartz (DQ12). Respirable-size quartz isolate was isolated from bentonite parent rock, without crushing or the use of chemicals, to ensure that the surface properties of the quartz particles were unaltered. The isolation technique utilized gentle mechanical dispersion followed by sedimentation in an aqueous medium. Extensive mineralogical and chemical characterizations were undertaken to define the physicochemical properties of the test materials. The characterizations showed significant, measurable physicochemical differences between the two quartz types. These differences may help to explain the difference in toxicological response associated with these materials. The evaluation methods and resulting data that characterized the chemical and physical properties of the instillation test materials are discussed. The data presented show that such characterizations are essential if meaningful correlations are to be made between test materials and their toxicological profiles.     

Metabolism and Testicular Toxicity of 1,3-Dinitrobenzene in Rats of Different Ages

Susceptibility to 1,3-dinitrobenzene (l,3-DNB)-induced testiculardamage is known to increase with age. The present study investigatedthe possibility that age-dependent differences in metabolismand disposition could account for differences in toxicity. [¹⁴C]1,3-DNB(25 mg/kg, ip) was administered to Sprague-Dawley rats whichwere 31, 75, or 120 days of age. Levels of 1,3-DNB and 1,3-DNBmetabolites were determined in blood and urine. As animal ageincreased, peak blood concentrations of 1,3-DNB were lower anddeclined more slowly indicating an age-dependent decrease inrate of metabolism and a possible increase in volume of distribution.In younger animals, faster elimination rates were associatedwith higher blood levels of metabolites. Urinary metaboliteswere generally similar for all age groups with the exceptionof the diacetamidobenzene metabolite which was significantlylower in the urine of 31 day old rats. There were clear differencesin the toxicokinetic profile for 1,3-DNB between the 31 dayold rats and the other two age groups. However, differencesbetween the 75 and 120 day old animals were less marked. Testiculardamage induced by 1,3-DNB (25 mg/kg, ip) was hardly detectablein the youngest animals, while the intermediate age group showeda moderate lesion particularly in later stages of spermatogenesis.For the oldest animals, testicular damage was more severe, particularlyin the earlier stages of spermatogenesis. Overall, the rapidelimination rate could account for the lack of 1,3-DNB toxicityin very young animals. However, simple metabolic differenceswere less likely to adequately explain the increase in testiculardamage found as animal age increased from 75 to 120 days.     

Pulmonary Delivery of Detirelix by Intratracheal Instillation and Aerosol Inhalation in the Briefly Anesthetized Dog

Pulmonary delivery of the decapeptide detirelix was studied in briefly anesthetized dogs and the pharmacokinetics were examined following intravenous administration, intratracheal instillation, and aerosol inhalation. Detirelix administrations to the lung gave plasma profiles that were extended over two days, and that differed markedly from those of similarly sized peptides. Absorption from the lung after instillation was slow (T_max= 6.5 ± 3.6 h) with a relative bioavailability of 29 ± 10%. Administration of detirelix-containing aerosols resulted in similar plasma profiles as for administration by instillation. Compartmental and non-compartmental methods of pharmacokinetic analysis indicated no faster absorption from aerosols than from instilled solutions; an absorption rate limiting process may be an explanation. Plasma profiles were not affected by the use of detirelix liquid crystal favoring formulations or destabilizing formulations, and suggested that in situ liquid crystal formation was not an explanation for the slow absorption. No significant changes in pharmacokinetics or systemic uptake were observed during the five-month period of repeated pulmonary administrations. Histopathologic examination revealed the lungs to be essentially normal.     

Pulmonary Toxicity to Intratracheally Administered Indium Trichloride in Fischer 344 Rats

The use of indium by the semiconductor industry has risen sharplyin recent years with the discovery that the electrical propertiesof compounds such as indium phosphide and indium arsenide arebetter than those of silicon. However, relatively little isknown about its potential to induce lung damage. These studiesexamined the effect of indium trichloride (InCl₃) on the lung.To examine the disposition and removal of InCl₃ from the lung,groups of female Fischer 344 rats received a single intratrachealdose of 1.3 mg In/kg as InCl₃ and were euthanized after 1, 2,4, 7, 14, 28, and 56 days at which time lung samples were analyzedfor metal content. Furthermore, the histology, hydroxyprolinelevels, and bronchoalveolar lavage (BAL) fluid cellularity ofthe lung were studied. In addition, the effect of 0.00016, 0.00325,0.065, and 1.3 mg In/kg on inflammatory response and BAL fluidcellularity was compared. While a dose as low as 0.00325 mgIn/kg was capable of initiating an influx of inflammatory cells,instillation of 1.3 mg In/kg resulted in an inflammatory responsethat was still evident 56 days later. After 28 days, the lungweight of the InCl₃ animals was 2.5 times greater than thatof the controls. The total cell number in the BAL fluid of thetreated animals after 28 days was 32 times higher than thatin the control rats. Sixty-seven percent of these cells weregranulocytes. Compared to the controls, the hydroxyproline contentof the lungs from the InCl₃ animals were two fold greater after28 and 56 days. Furthermore, the levels of fibronectin and TNFpresent in the BAL fluid of InCl₃ rats increased sharply duringthe first 24 hr and remained elevated 56 days later. These dataand the histological examination of the lung following InCl₃treatment suggest that InCl₃ is capable of causing severe lungdamage and the development of fibrosis.     

Pharmacokinetics of Detirelix Following Intratracheal Instillation and Aerosol Inhalation in the Unanesthetized Awake Sheep

The unanesthetized awake sheep was employed as large animal model for the determination of bioavailability and pharmacokinetics following the pulmonary instillation of the decapeptide detirelix. After intratracheal administration of a 80 µg/kg dose, the average t_1/2 of elimination was 9.8 ± 1.3 hours (n = 5) which was similar to the elimination kinetics of a 30 µg/kg i.v. dose (7.2 ± 2.9 hours). Mean residence time (MRT) was prolonged to 10.3 ± 2.0 hours vs. 2.7 ± 0.8 hours i.v., and mean absorption time (MAT) was calculated to be 7.5 ± 1.8 hours. Maximum plasma levels c_max) of 9.2 ng/ml were reached after 2 hours. The average bioavailability was 9.8 ± 3.9% of the dose. The pharmacokinetic profile was found to be similar after aerosol administration. It was concluded that detirelix was absorbed systemically when administered by pulmonary instillation or aerosolization and that the unanesthetized awake sheep is a suitable model to study resulting drug profiles.     

Inhalation Developmental Toxicity Study of Propylene Oxide in Fischer 344 Rats

The developmental toxicity potential of propylene oxide (PO)was evaluated in Fischer 344 rats following inhalation exposure.Four groups of 25 mated female rats were exposed to 0, 100,300, and 500 ppm of PO for 6 hr per day on Gestation Days 6through 15, inclusive. Cesarean sections were performed on allfemales on Gestation Day 20 and the fetuses removed for morphologicalevaluation. Exposure to propylene oxide did not adversely affectsurvival, appearance, or behavior at any of the exposure levelstested. Maternal body weight gain and food consumption werereduced significantly among the females at the 500 ppm levelduring the exposure period. No exposure-related effects werenoted with respect to maternal water consumption, organ weights,cesarean section, or fetal morphological observations with thesole exception of increased frequency of seventh cervical ribsin fetuses at the maternally toxic exposure level of 500 ppm.In summation, the no-observable-adverse-effect level (NOAEL)of propylene oxide. when administered to Fischer 344 rats viawhole-body inhalation exposure, was considered to be 300 ppm.     

Development Toxicity of Inhaled Ethylene Oxide in Rats Following Short-Duration Exposure

The developmental toxicity of ethylene oxide (EtO) was examinedin Sprague-Dawley rats following inhalation exposure duringDays 6 to 15 of gestation. Two different exposure regimens wereused: (1) exposure for 0.5 hr once a day to 0, 400, 800, or1200 ppm EtO; or (2) exposure for 0.5 hr three times a day to0, 200, or 400 ppm EtO or 0, 800, or 1200 ppm EtO. Repeatedbrief exposures (3x0.5 hr/day) to EtO caused fetal toxicityindicated by reduced fetal weight at 800 and 1200 ppm, and overtmaternal toxicity manifested as reduced body weight gain at1200 ppm. Neither embryolethality nor teratogenicity occurredfollowing any exposure regimen.     

Local and Systemic Immune Responses to Intratracheal Instillation of Antigen and DNA Vaccines in Mice

PURPOSE: The purpose of this study was to determine the immunization efficacy of antigen and DNA vaccines after delivery to the lung, to assess the integrity of the pulmonary tissue after vaccination, and to elucidate mechanisms involved in the induction of immunity. METHODS: Ovalbumin, the plasmid encoding ovalbumin, the hepatitis B surface antigen (HBsAg), or plasmid encoding HBsAg were intratracheally instilled or injected in quadriceps in mice. The immune response and its Th polarization were analyzed over time. Markers of inflammation were measured in bronchoalveolar lavage, and lung histology was performed. The fate of ovalbumin following intratracheal instillation was studied. RESULTS: According to the vaccine, the pulmonary route produced stronger or equivalent humoral and cellular responses systemically and locally in the lung as compared to injection. The IgG subclasses and cytokine pattern indicate that the immunity was preferentially polarized toward the Th2 and Th1 type for antigen and DNA immunization, respectively. Ovalbumin penetrated the respiratory tissue and blood poorly after intratracheal instillation, suggesting that the immune response was triggered at airway surfaces. Overall, vaccines delivered to the lung did not induce any local sign of inflammation. CONCLUSIONS: Pulmonary administration of vaccines might be a promising alternative to conventional vaccination by injection.     

Systemic Absorption and Activity of Recombinant Consensus Interferons After Intratracheal Instillation and Aerosol Administration

Purpose. The pulmonary pharmacokinetics and bioactivity of E. coli derived recombinant consensus interferon (CIFN) and a modified lactose-conjugated consensus interferon (LacCIFN) were evaluated in animals. Methods. Estimated doses of 20 and 100 µg/kg of the interferons were administered to anesthetized rats by aerosol via ultrasonic nebulizer as well as intravenous injection. Rats also received nominal doses of 50 and 200 µg/kg via intratracheal instillation (IT). Hamsters were treated with interferon via various routes including IT. The effectiveness of treatment was assessed by the resistance to development of hind leg paralysis following infection with encephalomyocarditis virus. Results. Significant amounts of CIFN and LacCIFN were found in rat plasma after aerosol administration. Peak plasma levels occurred 25–30 minutes with estimated bioavailabilities approaching 70%. Absorption of CIFN was rate limiting and plasma levels were detectable 12 hr post-dose. The CIFN at IT doses as low as 5 µg/kg was effective at reducing paralysis in hamsters but protection was variable and doses of up to 100 µg/kg were not 100% effective. Conclusions. Despite the incomplete protection, the results demonstrate the feasibility of treating systemic viral infections with interferon administered directly to the lungs.     

维生素E对多柔比星所致生殖毒性雄性大鼠的保护作用

目的探讨维生素E对多柔比星致生殖毒性雄性大鼠的保护作用。方法通过一次性静脉注射多柔比星7.5 mg.kg-1制备多柔比星致雄性大鼠生殖毒性损伤模型。维生素E组(n=8)从造模前1 d起,灌服维生素E 100mg.d-1连续14 d。模型组(n=8)造模后,每日经腹腔注射0.9%氯化钠溶液1 mL。对照组(n=8)不造模,每日经腹腔注射0.9%氯化钠溶液1 mL。通过观察大鼠血清超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量和睾丸病理组织学变化评估多柔比星对雄性大鼠生殖毒性作用。结果与对照组比较,模型组大鼠血清SOD活性降低,MDA含量升高(P<0.05),睾丸重量和睾丸系数降低(P<0.05),精曲小管生精细胞明显减少,精母细胞和精子细胞退变,部分坏死、脱落。维生素E组大鼠血清SOD活性和MDA含量与对照组比较差异无显著性(P>0.05),睾丸重量和睾丸系数的变化和睾丸病理损伤程度轻于模型组。结论维生素E对多柔比星所致生殖毒性雄性大鼠具有保护作用,其药理作用机制与提高机体抗氧化能力、抑制脂质过氧化反应有关。     

Role of Testis Exposure Levels in the Insensitivity of Prepubertal Rats to Carbendazim-Induced Testicular Toxicity

Our recent studies have indicated that benomyl (BNL)-inducedtesticular toxicity is mediated by its major metabolite carbendazim(CBZ). The present study has used CBZ to investigate hypothesesthat could explain prepubertal insensitivity to BNL. When CBZ(164 mg/kg intraperitoneally) was administered to postpubertaland prepubertal rats, it caused little testicular damage inprepubertal rats, but in adult rats, sloughing of the seminiferousepithelium resulted. When the inhibitory effect of CBZ on prepubertaltesticular microtubule assembly was compared with that on postpubertalassembly, the IC50 values were very similar. Pharmacokineticstudies revealed that blood levels of CBZ were comparable inthe two age groups; however, higher levels of CBZ were foundin the adult testes (210.52 nmol/g wet wt) in comparison withyoung testes (67.77 nmol/g wet wt). These data suggest thatdelivery to and/or retention of CBZ in the testis may play arole in the age-dependent differences in susceptibility to CBZtoxicity. When CBZ was administered intratesticularly to reachlevels sufficient to cause damage, the young animals did showan increased incidence of vacuolization and detachment of theseminiferous epithelium; however, in contrast to the older animals,sloughing of the seminiferous epithelium was not observed inthe prepubertal animals. Overall, the low levels of CBZ measuredin the testes of prepubertal animals offer a partial explanationfor the insensitivity of young animals to CBZ-induced testiculartoxicity following intraperitoneal administration. A differentialresponsiveness between the two age groups is also likely, however,since prepubertal animals lack elongated spermatids and it issloughing of this cell type that characterizes CBZ-induced testiculartoxicity in the adult.     

Histopathological Changes in Rat Lung Following Intratracheal Instillation of Silicon Carbide Whiskers and Potassium Octatitanate Whiskers

Abstract

We evaluated the pattern of pulmonary inflammation for the assessment of the biological hazards of two man-made mineral fibers. Rats were exposed by intratracheal instillation to a 2 mg dose of each of two kinds of man-made mineral fibers (PT1, potassium octatitanate whisker; and SiCW, silicon carbide whisker), or three kinds of comparable respirable particles (crystalline silica, crocidolite asbestos, and titanium dioxide, TiO₂). The lung tissue was evaluated at 3 day, 1 wk, and 1, 3 and 6 mo after exposure. Digital images taken of the lung sections were examined by morphometric point counting method (PCM). PT1 and SiCW showed a similar inflammatory pattern, which contains temporal inflammation such as moderate alveolitis within 1 wk after the exposure, and in later phase aggregation foci of instilled fibers. Differences in repair patterns of these two man-made mineral fibers showed that the toxicity of these two fibers is less toxic than for crocidolite or crystalline silica. Although SiCW showed a higher inflammation score than TiO₂ within 1 mo after instillation, the inflammation scores and fibrotic changes of PT1 and SiCW were not significant as TiO₂ at 3 mo and 6 mo in this study. Careful use should be recommended when these materials are used in the workplace.