Assessment of Toxicity of o-Nitrochlorobenzene in Rats following a 4-Week Inhalation Exposure

Assessment of Toxicity of o-Nitrochlorobenzene in Rats followinga 4-Week Inhalation Exposure. NAIR, R.S., JOHANNSEN, F.R., LEVINSKAS,G.J., AND TERRILL, J.B. (1986). Fundam. Appl. Toxicol. 7, 609-614.o-Nitrochlorobenzene (ONCB) is a chemical intermediate usedfor the synthesis of various industrial chemicals. To evaluatethe subchronic toxicity of this compound, three groups of 15male and 15 female Sprague-Dawley rats were exposed to ONCBvapor 6 hr/day, 5 days/week for 4 weeks at target concentrationsof 10, 30, or 60 mg/m³. A control group of 15 animals/sex wasexposed to room air in a separate inhalation chamber. Concentrationsof ONCB in the chambers were determined at least three timesa day using a uv spectrophotometer. Parameters monitored inthis study included observation for signs of toxicity, bodyweights, ophthalmoscopic exam, hematology, and clinical chemistry.At necropsy, selected organ weights were recorded and over 35tissues/animal were examined microscopically for all controland high-exposure level animals. No mortality was observed inthis study. Mean body weights of all groups were comparableto controls. Animals exposed to the mid and high concentrationsof ONCB showed a significant increase in blood methemoglobinand a significant decrease in hemoglobin, hematocrit, and redblood cell counts. Spleen and liver weights (absolute and relativeto body weight) were significantly increased for these two groups.Microscopic changes, observed only in the spleen, included increaseddegree of extramedullary hematopoiesis and hemosiderosis. Thesedata suggest that the toxicity of ONCB is comparable to thatof its structural analog, p-nitrochlorobenzene. Thus these twocompounds should have similar workplace exposure limits.     

Nasal Toxicity of Manganese Sulfate and Manganese Phosphate in Young Male Rats Following Subchronic (13-Week) Inhalation Exposure

Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to further characterize the nasal toxicity of manganese sulfate (MnSO₄) and manganese phosphate (as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnSO₄ (0.01, 0.1, and 0.5 mg Mn/m³), or hureaulite (0.1 mg Mn/m³). Nasal pathology, brain GFAP levels, and brain manganese concentrations were assessed immediately following the end of the 90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO₄ exposure to ≥0.01, ≥0.1, and 0.5 mg Mn/m³, respectively. Exposure to MnSO₄ or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure to MnSO₄ (0.5 mg Mn/m³) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, we could not confirm that manganese inhalation would result in altered brain GFAP concentrations.     

2-Week Inhalation Study of N-Monomethylformamide in Rats

2-Week Inhalation Study of yV-Monomethylformamide in Rats. KENNEDY,G. L., JR., FERENZ, R. L., BURGESS, B. A., AND STULA, E. F.(1990). Fundam. Appl. Toxicol. 14, 810–816. N-Monomethylformamide(MMF) is a chemical intermediate with potential for inhalationexposure in humans. Human exposures to MMF have occurred incancer chemotherapy but have been limited due to liver damage.To assess the toxicity of MMF, groups of 15 male rats each wereexposed by nose-only inhalation, 6 hr/day, 5 days/week, for2 weeks to either 0 (control), 50, 130, or 400 ppm MMF. Fiverats per group were killed following the 10th exposure, fivewere killed after a 14-day postexposure recovery period, andfive rats were used to determine urinary MMF excretion. Parametersinvestigated were clinical observations and body weights, clinicalpathology, and gross and microscopic pathology including organweights. Liver damage occurred in rats exposed to either 130or 400 ppm. This was detected both by increases in serum enzymeactivity indicative of liver injury and by microscopic changesin the liver. The changes were more severe in the 400-ppm ratsand were partially reversible. Other organs were not adverselyaffected by inhalation of MMF. The amount of MMF excreted inthe urine was dependent on the exposure concentration and MMFwas present 14 days postexposure at the higher exposure levels.The no-observed-effect level under the conditions of this experimentwas 50 ppm.     

The Pulmonary Response and Clearance of Ludox Colloidal Silica after a 4-Week Inhalation Exposure in Rats

Rats were exposed to Ludox colloidal silica (CS) at concentrationsof 0, 10, 50, and 150 mg/m³ for 6 hr/day, 5 days/week for 4weeks. Rats were killed after 4 weeks of exposure and 10 daysor 3 months post exposure (PE). The exposure concentration of10 mg/m³ Ludox CS is considered to be the no-effect concentration.There were no exposure-related clinical signs in any group.After 4 weeks exposure, lung weights were increased significantlyin rats exposed to 50 and 150 mg/m³ Ludox CS, but lung weightswere similar to those of controls at 3 months PE. After 4 weeksexposure to 50 mg/m³ Ludox CS, a slight alveolar macrophageresponse, polymorphonuclear leukocytic infiltration, and TypeII pneumocyte hyperplasia in alveolar duct regions were present.After 3 months PE, these pulmonary lesions had almost disappearedwith removal of most dust-laden alveolar macrophages (AMs).The pulmonary response to 150 mg/m³ Ludox CS was similar incharacter but increased in magnitude from that seen at 50 mg/m³At 3 months PE, most particleladen AMs had disappeared and theremaining AMs were aggregated and sharply demarcated. A fewaggregates of particle-laden AMs appeared to transform intosilicotic nodules comprising macrophages, epithelioid cells,and lymphocytic infiltration in some animals. Some silicoticnodules showed reticular fiber networks with minute collagenfiber deposition. Tracheobronchial lymph nodes were enlargedwith aggregates of particle-laden AMs and hyperplastic histiocyticcells. Lung-deposited Ludox cleared rapidly from the lungs withhalf-times of approximately 40 and 50 days for the 50 and 150mg/m³ groups, respectively.     

Dimethylethanolamine: Acute, 2-Week, and 13-Week Inhalation Toxicity Studies in Rats

Dimethylethanolamine (DMEA) is a volatile, water-soluble aminethat has applications in the chemical and pharmaceutical industries.These studies evaluated the acute and subchronic inhalationtoxicity of DMEA. Acute (4-hr) exposures of Wistar rats to DMEAvapor resulted in an LC5O value (95% confidence limits) of 1641(862–3125)ppm. Clinical signs of nasal and ocular irritation, respiratorydistress, and body weight loss were observed in rats exposedto 1668 ppm DMEA and higher. In the 2-week study, F-344 ratsexposed to 98, 288, or 586 ppm DMEA for 9 days (6 hr/day) duringan 11-day period also exhibited signs of respiratory and ocularirritation (except the 98 ppm group). All animals of the 586ppm group and 4 of 15 male rats of the 288 ppm group died. Bodyweight values for the 288 ppm group were reduced to about 75%of preexposure values, while the 98 ppm group gained 35% lessweight than controls. Statistically significant differencesin clinical pathology parameters (288 ppm group) and in organweight values (288 and 98 ppm groups) probably resulted fromthe decreased food consumption and not from specific targetorgan toxicity. In the groups evaluated histologically (the98 and 288 ppm groups) the eye and nasal mucosa were the primarytarget organs. In the 13-week subchronic study, F-344 rats wereexposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/weekfor 13 weeks. The principal exposure-related changes were transientcorneal opacity in the 24 and 76 ppm groups; decreased bodyweight gain for the 76 ppm group; and histopathologic lesionsof the respiratory and olfactory epithelium of the anteriornasal cavity of the 76 ppm group and of the eye of several 76ppm group females. Rats maintained for a 5-week recovery periodonly exhibited histological lesions of the nasal tissue, withthe lesions being decreased in incidence and severity. DMEAacts primarily as an ocular and upper respiratory tract irritantand toxicant at vapor concentrations of 76 ppm, while 24 ppmor less produced no biologically significant toxicity in rats.Thus, 24 ppm was considered to be the no-observable-effect level.     

Teratogenic Evaluation of Tributyltin Chloride in Rats Following Oral Exposure

ABSTRACT

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

Lung Response to Ultrafine Kevlar Aramind Synthetic Fibrills Following 2-Year Inhalation Exposure in Rats

Lung Response to Ultrafine Kevlar Aramid Synthetic Fibrils following2-Year Inhalation Exposure in Rats. LEE K. P., KELLY D.P. O'NEALF. O., STADLER, J. C., AND KENNEDY G. L., JR (1988). Fundam.Appl. Toxicol. 11, 1-20. Four groups of 100 male and 100 femalerats were exposed to ultrafine Kevlar fibrils at concentrationsof 0, 2.5,25, and 100 fibrils/cc for 6 hr/day, 5 days/week for2 years. One group was exposed to 400 fibrils/cc for 1 yearand allowed to recover for 1 year. At 2.5 fibrils/cc, the lungshad normal alveolar architecture with a few dust-laden macrophages(dust cell response) in the alveolar airspaces. At 25 fibrils/cc,the lungs showed a dust cell response, slight Type II pneumocytehyperplasia, alveolar bronchiolariation, and a negligible amountof collagenized fibrosis in the alveolar duct region. At 100fibrils/cc, the same pulmonary responses were seen as at 25fibrilsol;cc. In addition, cystic keratinizing squa- mous cellcarcinoma (CKSCC) was found in 4 female rats, but not in malerats. Female rats had more prominent foamy alveolar macrophages,holesterol granulomas, and alveolar bronchio-larization. Thesepulmonary lesions were related to the development of CKSCC.The lung tumors were derived from metaplastic squamous cellsin areas of alveolar bronchiolarization. At 400 fibrils/cc following1 year of recovery, the lung dust content, average fiber length,and the pulmonary lesions were markedly reduced, but slightcentriacinar emphysema and minimal collagenized fibrosis werefound in the alveolar duct region. One male and 6 female ratsdeveloped CKSCC. The lung tumors were a unique type of experimentallyinduced tumors in the rats and have not been seen as spontaneoustumors in man or animals. Therefore, the relevance of this typeof lung tumor to the human situation is minimal.     

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.     

Nicotine Improves Working Memory Span Capacity in Rats Following Sub-Chronic Ketamine Exposure

Ketamine, an NMDA-receptor antagonist, produces cognitive deficits in humans in a battery of tasks involving attention and memory. Nicotine can enhance various indices of cognitive performance, including working memory span capacity measured using the odor span task (OST). This study examined the effects of a sub-chronic ketamine treatment to model cognitive deficits associated with schizophrenia, and to evaluate the effectiveness of nicotine, antipsychotic clozapine, and the novel mGlu2/3 agonist, {"type":"entrez-nucleotide","attrs":{"text":"LY404039","term_id":"1257503820","term_text":"LY404039"}}LY404039, in restoring OST performance. Male hooded Lister rats were trained in the OST, a working memory task involving detection of a novel odor from an increasing number of presented odors until they exhibited asymptotic levels of stable performance. Sub-chronic ketamine exposure (10 and 30 mg/kg i.p. for 5 consecutive days) produced a dose-dependent impairment that was stable beyond 14 days following exposure. In one cohort, administration of graded doses of nicotine (0.025–0.1 mg/kg) acutely restored the performance in ketamine-treated animals, while significant improvements in odor span were observed in control subjects. In a second cohort of rats, acute tests with clozapine (1–10 mg/kg) and {"type":"entrez-nucleotide","attrs":{"text":"LY404039","term_id":"1257503820","term_text":"LY404039"}}LY404039 (0.3–10 mg/kg) failed to reverse ketamine-induced deficits in doses that were observed to impair performance in the control groups. These data suggest that sub-chronic ketamine exposure in the OST presents a valuable method to examine novel treatments to restore cognitive impairments associated with neuropsychiatric disorders such as schizophrenia. Moreover, it highlights a central role for neuronal nicotinic receptors as viable targets for intervention that may be useful adjuncts to the currently prescribed anti-psychotics.     

Triprolidine: 104-Week Feeding Study in Rats

The antihistamine, triprolidine hydrochloride, was fed at dietaryconcentrations of 0, 250, 1000, or 2000 ppm (as the free base)to groups of 60 Fischer 344 (F344) rats of each sex for up to2 years to evaluate its potential carcinogenicity. Up to 12per sex from each group were killed at 65 weeks, and hematology,clinical chemistry, and histopathology were evaluated. A completehistopatho-logical evaluation was performed on all other animals;survivors were killed at 2 years. Survival was significantlyextended in tri-prolidine-treated males and females, particularlyat the high dose. At the close of the study high-dose malesand females had gained significantly less body weight than controls.Among rats killed at 65 weeks females in the mid- and high-dosegroups weighed significantly less than controls, but weightsof control and dosed males were not significantly different.The incidences of numerous lesions tended to decrease with increasingtriprolidine dose. In females, clitoral gland adenomas, thyroidc-cell hyperplasia and neoplasia, mammary gland hyperplasiaand fibroadenomas, and uterine stromal polyps, and in males,anterior pituitary gland adenomas, preputial gland neoplasia,thyroid c-cell hyperplasia, pancreatic islet neoplasia, mononuclearcell leukemia, and the combination of lymphocytic, histiocytic,and undifferentiated cell malignant lymphomas and mononuclearleukemia, all exhibited negative dose trends. Cytoplasmic alterationsof the parotid gland and numerous liver lesions tended to bemore frequent in treated than in control animals. Liver lesionsthat exhibited positive dose trends include chronic inflammationand centrilobular fatty change in both sexes, mixed cell foci,and the combination of mixed cell foci and eosinophilic fociin females, and in males, basophilic foci and eosinophilic foci.Triprolidine was not carcinogenic in F344 rats.     

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

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

Long-Term Pulmonary Histopathologic Changes in Rats Following Acute Experimental Exposure to Chlorine Gas

In this study, we aimed to investigate the long-term histopathologic changes in the lungs of rats exposed to a high concentration of chlorine gas. Twenty-four Sprague-Dawley rats were divided into three groups: the control group (group I) (n = 8), early-examined group (group II) (n = 8), and late-examined group (group III) (n = 8). In group II the lungs of rats were taken out just after the exposure, whereas in group III the lungs were taken out 45 days after the exposure. Eosinophilic liquid accumulation in alveoli and bronchi, diffuse intraalveolar edema, vascular congestion, severe perivascular edema, and free bleeding in intraalveolar and interstitial area were observed in the lungs of rats in group II. Interstitial fibrosis and thickening of the alveolar septa were observed in group III. These findings suggest that the people using these cleaning agents are at risk of harming themselves, and the victims of chlorine gas injury should be reexamined at a later period since they may have pulmonary damage even after 45 days of exposure.     

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

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

Pulmonary Structural and Extracellular Matrix Alterations in Fischer 344 Rats Following Subchronic Phosgene Exposure

Phosgene, an acylating agent, is a very potent inducer of pulmonaryedema. Subchronic effects of phosgene in laboratory animalsare not well characterized. The purpose of the study was toelucidate potential long-term effects on collagen and elastinmetabolism during pulmonary injury/recovery and obtain informationabout the concentration x time (C x T) behavior of low levelsof phosgene. Male Fischer 344 rats (60 days old) were exposedeither to clean air or phosgene, 6 hr/day: 0.1 ppm (5 days/week),0.2 ppm (5 days/week), 0.5 ppm (2 days/week), and 1.0 ppm (1day/week), for 4 or 12 weeks. A group of rats was allowed cleanair recovery for 4 weeks after 12 weeks of phosgene exposure.This exposure scenario was designed to provide equal C x T productfor all concentrations at one particular time point except for0.1 ppm (50% C x T). Phosgene exposure for 4 or 12 weeks increasedlung to body weight ratio and lung displacement volume in aconcentration-dependent manner. The increase in lung displacementvolume was significant even at 0.1 ppm phosgene at 4 weeks.Light microscopic level histopathology examination of lung wasconducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene following 4and 12 and 16 weeks (recovery). Small but clearly apparent terminalbronchiolar thickening and inflammation were evident with 0.1ppm phosgene at both 4 and 12 weeks. At 0.2 ppm phosgene, terminalbronchiolar thickening and inflammation appeared to be moreprominent when compared to the 0.1 ppm group and changes inalveolar parenchyma were minimal. At 1.0 ppm, extensive inflammationand thickening of terminal bronchioles as well as alveolar wallswere evident. Concentration rather than C x T seems to drivepathology response. Trichrome staining for collagen at the terminalbronchiolar sites indicated a slight increase at 4 weeks andmarked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5ppm was not examined), 1.0 ppm being more intense. Wholelungprolyl hydroxylase activity and hydroxyproline, taken as anindex of collagen synthesis, were increased following 1.0 ppmphosgene exposure at 4 as well as 12 weeks, respectively. Desmosinelevels, taken as an index of changes in elastin, were increasedin the lung after 4 or 12 weeks in the 1.0 ppm phosgene group.Following 4 weeks of air recovery, lung hydroxyproline was furtherincreased in 0.5 and 1.0 ppm phosgene groups. Lung weight alsoremained significantly higher than the controls; however, desmosineand lung displacement volume in phosgene-exposed animals weresimilar to controls. In summary, terminal bronchiolar and lungvolume displacement changes occurred at very low phosgene concentrations(0.1 ppm). Phosgene concentration, rather than C x T productappeared to drive toxic responses. The changes induced by phosgene(except of collagen) following 4 weeks were not further amplifiedat 12 weeks despite continued exposure. Phosgene-induced alterationsof matrix were only partially reversible after 4 weeks of cleanair exposure.     

Inhalation Toxicology of Decamethylcyclopentasiloxane (D5) Following a 3-Month Nose-Only Exposure in Fischer 344 Rats

D₅ is a low-molecular-weight cyclic siloxane used for industrialand consumer product applications. The objective of the presentstudy was to evaluate the subchronic toxicity of D₅ followinga 3-month nose-only inhalation exposure. In addition, animalsfrom both sexes of the control and high dose groups were alloweda 4-week recovery period to observe reversibility, persistence,or delayed occurrence of any potential adverse effects. Maleand female Fischer 344 rats were exposed for 6 h/day, 5 days/weekfor 3 months to target concentrations of 0 (30/sex/group), 26(20/sex/group), 46 (20/sex/group), 86 (20/sex/group), and 224(30/sex/ group) ppm D₅. Recovery groups (0 and 224 ppm) comprised10 rats/sex/group. Body weights and food consumption were monitoredat least twice weekly over the course of exposures. Approximately16 h preceding euthanasia, animals were transferred into metabolismcaging for urine collection and were fasted. Rats were anesthetizedwith pentobarbital and euthanized by exsanguination. Blood wascollected for hematological and clinical biochemical analyses.Selected organ weights were measured and a complete set of tissueswas taken for histopathological examination. There were severalminor changes observed in clinical biochemistry parameters;the most notable was an increase in gamma glutamyl transferase(     

Systemic Toxicity of the Heavy Fraction of a Coal Coprocessing Product in Male Rats Following Subchronic Dermal Exposure

The systemic toxicity of a coal coprocessing product [heavygas oil II (HGOII)] following subchronic, dermal exposure inmale Sprague-Dawley rats was investigated. HGOII was appliedto the dorsal skin daily at doses of 8.7, 20.8, 50.0, or 120.0mg/ kg body weight (bw) for 13 weeks. Another group of ratstreated with a medium boiling coal liquefaction product (CLP)served as positive controls. Growth suppression and decreasedfood consumption were noted in the groups exposed to HGOII at20.8 mg/kg and higher, and to CLP starting at the third weekof treatment. Relative liver, kidney, and brain weights in the20.8 mg/kg HGOII group and up were higher than those of thecontrol. Increased spleen weight was observed in all HGOII-treatedgroups. CLP treatment also caused increased relative kidneyand brain weights. Serum cholesterol was elevated in the HGOII-treatedgroups starting at 8.7 mg/kg while increased uric acid and lactatedehydrogenase were observed at 20.8 mg/kg and up. Decreasederythrocyte, hemoglobin, and platelet counts were observed at20.8 mg/kg and higher. All HGOII-treated groups had elevatedreticulocytes. These biochemical and hematological changes werenot observed in the CLP-treated group. Mild to marked histologicalchanges were observed in the thyroid, thymus, liver, spleen,and bone marrow of HGOII groups. In contrast, morphologicalchanges were relatively mild in CLP-treated animals. Data fromthe present study demonstrated that the hematological endpointswere sensitive to the liquid fuels and that HGOII was more toxicthan CLP. Based on the growth rate and biochemical, hematological,and morphological changes, the no observable adverse effectlevel for HGOII is judged to be below 8.7 mg/kg bw in the rat.     

Subacute Inhalation Exposure of Rats to 1,6-Hexamethylene Diisocyanate With Recovery Period

In this subacute inhalation toxicity study of 1,6-hexamethylene diisocyanate (HDI), groups of 10 male and 10 female Sprague-Dawley rats were exposed to 0, 0.005, 0.0175, or 0.150 ppm HDI vapor, 5 h/ /day, 5 days/ /wk for 15 exposure days and included animals sacrificed 2 wk postexposure. The purpose was to characterize the HDI-induced effects and their reversibility, and to determine a no-observed-adverse-effect level (NOAEL). No compound-related effects were found for body weights, clinical chemistry, urinalysis, hematology, and organ weights. Thus, no evidence of systemic toxicity was found in this study. The exposure-related findings were restricted to the portal of entry, the respiratory tract. Transient signs of sensory irritation were observed after the daily exposure periods, but the principal findings were the histopathologic changes of the nasal epithelium. Generally, an anterior to posterior gradient of incidence and severity was found, and the changes were characterized as acanthosis, erosion, hyperkeratosis, epithelial cell hyperplasia, chronic active inflammation, squamous metaplasia, ulceration, transitional epithelial cell degeneration, goblet-cell hyperplasia, and degeneration of the olfactory epithelium. Varying degrees of concordance between exposure concentration and incidence and/or severity of the histopathologic changes were found. During a 2-wk recovery period, a tendency toward recovery was evident for tissue changes in the nasal cavity. A NOAEL of 0.0175 ppm HDI was determined.     

Toxicokinetics of Propylene Glycol Mono-t-Butyl Ether Following Intravenous or Inhalation Exposure in Rats and Mice

Propylene glycol mono-t-butyl ether (PGMBE) is a widely used solvent in industry and in consumer products, posing a potential for human exposure via inhalation or dermal routes. Toxicokinetic studies were conducted on F344/N rats and B6C3F1 mice of both sexes to evaluate single or repeated dose, species, and/or sex differences in PGMBE elimination kinetics following intravenous or inhalation exposure. In the first study, rats and mice received a single intravenous dose of 15 or 200 mg PGMBE/kg and serial blood samples were collected and analyzed for PGMBE. In the second study, rats and mice received a single 6-h whole-body inhalation exposure to 75, 300, or 1200 ppm PGMBE and serial blood samples were collected and analyzed for PGMBE. In the third study, rats and mice received whole-body inhalation exposures to 75, 300, or 1200 ppm PGMBE for 6 h/day, 5 days/wk for 14 (rats) or 16 (mice) wk. Serial blood samples were analyzed for PGMBE after 2, 6, 14 (rats), and 16 (mice) wk on study. Urine samples were also collected for 16 h postexposure and analyzed for creatinine and PGMBE sulfate and PGMBE glucuronide conjugates. These studies revealed that: (1) PGMBE was eliminated from blood following concentration-dependent nonlinear kinetics in both species; (2) saturable Michaelis–Menten kinetics were clearly exhibited following a single inhalation exposure at 1200 ppm, but were less obvious following repeated exposures; (3) mice were more efficient in eliminating PGMBE from blood at lower exposure concentrations (i.e., ≤300 ppm), but at exposure concentrations potentially exceeding their elimination capacity, mice had a greater concentration-dependent decrease in PGMBE elimination than rats; (4) there were minimal but consistent sex differences in PGMBE elimination profiles for rats, with females having higher blood concentrations at all exposure concentrations and sampling times; and (5) sex differences in PGMBE elimination were in part associated with differences in urinary excretion of PGMBE metabolites.     

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.