National Toxicology Program technical report series
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Natl Toxicol Program Tech Rep Ser · Sep 2007
Photocarcinogenesis study of glycolic acid and salicylic acid (CAS Nos. 79-14-1 and 69-72-7) in SKH-1 mice (simulated solar light and topical application study).
Acidic solutions have been used for decades to treat a variety of skin conditions. Many of these solutions consist of organic acids with a hydroxy group on a carbon adjacent to the carbonyl carbon and are referred to as alpha-hydroxy acids (AHA). Organic acids with hydroxy groups on the second carbon from the carbonyl carbon are referred to as beta-hydroxy acids (BHA). Both AHA and BHA are used to treat various skin conditions. One of the most widely used AHA is glycolic acid, while salicylic acid is a commonly used BHA. Chemical peels containing 20% to 70% glycolic acid have been used by dermatologists to treat ichthyosis, acne, xerosis, actinic keratosis, seborrheic keratoses, warts, and psoriasis. AHA have recently been used to treat photoaged skin and are now included in many commercially available cosmetic skin treatments. When used in a formulation for a chemical peel, topical treatment of skin with AHA and BHA can result in removal of the stratum corneum, alteration of the skin's histology, and increased cell proliferation in the basal layer of the epidermis. Since AHA and BHA are used to correct photoaged skin, and since exposure to sunlight of skin treated with AHA or BHA is likely, studies were designed to determine the effects of topical application of creams containing AHA (0%, 4%, or 10% glycolic acid, pH 3.5) or BHA (0%, 2%, or 4% salicylic acid, pH 4.0) on the photocarcinogenesis of simulated solar radiation using a filtered 6.5 kW xenon arc light source [simulated solar light (SSL)]. Male and female Crl:SKH-1 (hr-/hr-) hairless mice were exposed to glycolic acid or salicylic acid alone or in combination with SSL for 40 weeks, and the mice were followed for an additional 12 weeks. 1-YEAR STUDY IN MICE: Groups of 36 male and 36 female mice were exposed to 0.0, 0.3, 0.6, or 0.9 minimal erythema dose (MED) of SSL during the afternoon (1200 to 1600 hours) 5 days per week for 40 weeks. Groups of 18 male and 18 female mice were treated in the morning (0800 to 1100 hours) with 2 mg/cm2 control cream, 4% glycolic acid cream, 10% glycolic acid cream, 2% salicylic acid cream, or 4% salicylic acid cream on the dorsal skin, and in the afternoon (1200 to 1600 hours) with 0.3 MED of SSL 5 days per week for 40 weeks. Additional groups of 18 male and 18 female mice were treated in the morning (0800 to 1100 hours) with 2 mg/cm2 control cream, 4% glycolic acid cream, 10% glycolic acid cream, 2% salicylic acid cream, or 4% salicylic acid cream on the dorsal skin, and in the afternoon (1200 to 1600 hours) with 0.6 MED of SSL 5 days per week for 40 weeks. All mice were held an additional 12 weeks following the end of treatment. There were no effects of SSL exposure or topical treatment on the body weights of the mice. Increasing doses of SSL resulted in an SSL-dose trend in survival, with the greatest dose of SSL causing the earliest removal. This effect was present in both the untreated and control cream treated mice. The only consistent effect of glycolic acid on survival was a dose-dependent increase in survival of females at 0.3 MED SSL. Survival was increased in mice exposed to 0.6 MED of SSL and treated with 2% and 4% salicylic acid compared to mice treated with 0.6 MED and treated only with the vehicle. This effect was not observed in the mice treated with 0.0 and 0.3 MED of SSL and salicylic acid compared to the control groups. The mean or median time to first skin tumor of at least 1 mm decreased with increasing SSL exposure concentration in mice that were not treated with cream. Addition of the control cream resulted in a decrease in the time to tumor at 0.3 and 0.6 MED of SSL in male and female mice. The addition of glycolic acid (4% or 10%) did not affect the time to tumor in male or female mice at either SSL dose when compared to mice receiving the control cream. When compared to mice receiving control cream, the inclusion of 4% salicylic acid in the cream increased the time to tumor for male mice receiving 0.3 or 0.6 MED of SSL and female mice receiving 0.3 MED of SSL. The results indicate that inclusion of glycolic acid in the topical cream had no effect on the time required to induce tumors by SSL; however, inclusion of salicylic acid at 4% in the cream was photoprotective, increasing the time required to achieve median tumor incidence at a corresponding dose of SSL and control cream. The skin tumors induced by SSL in mice were squamous cell papilloma, carcinoma in situ, and squamous cell carcinoma. Except for papilloma in male mice, the tumors were induced in a dose-dependent manner by SSL in male and female mice. In male and female mice treated with control cream, the exposure to SSL caused significant increases in the incidences of carcinoma in situ, squamous cell carcinoma, and the combined incidence of carcinoma in situ and squamous cell carcinoma. When male or female mice were exposed to 0.3 or 0.6 MED SSL, the inclusion of 4% or 10% glycolic acid did not affect the induction of skin neoplasms over the incidence detected when the control cream was used, with the single exception of a glycolic acid dose-trend in squamous cell carcinoma incidence in male mice receiving 0.3 MED SSL. The inclusion of salicylic acid in the cream that was topically applied to female mice did not affect squamous cell papilloma formation at either SSL dose. The incidence of carcinoma in situ was decreased in male and female mice at 0.3 MED SSL when treated with 4% salicylic acid. A salicylic acid dose-trend was also observed in both sexes at 0.3 MED SSL. ⋯ These experiments investigated the impact of topical application of a cosmetic formulation containing 4% or 10% glycolic acid (pH 3.5) or 2% or 4% salicylic acid (pH 4) on the photocarcinogenesis of filtered 6.5 kW xenon arc simulated solar light (SSL) in SKH-1 hairless mice. Taking into consideration the survival data, time to tumor data, and the pathology results, glycolic acid did not alter the photocarcinogenesis of SSL, and salicylic acid was photoprotective, reducing the carcinogenicity of 0.3 MED SSL.
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Natl Toxicol Program Tech Rep Ser · Feb 2007
Toxicology and carcinogenesis studies of diisopropylcarbodiimide (Cas No. 693-13-0) in F344/N rats and B6C3F1 mice (dermal studies).
Diisopropylcarbodiimide is used as a reagent for peptide syntheses and as a chemical intermediate. The National Cancer Institute nominated diisopropylcarbodiimide for study as a representative chemical in the alkylcarbodiimide class because of its acute toxicity; its use in chemical, pharmaceutical, and recombinant DNA industries; and the absence of data on potential health effects. Male and female F344/N rats and B6C3F1 mice were administered diisopropylcarbodiimide (greater than 99% pure) dermally for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female F344/N rats were dermally administered 0.3 mL ethanol containing 0, 3, 9, 27, or 81 mg diisopropylcarbodiimide or 0.3 mL of the neat chemical containing 242 mg per animal, 5 days a week for 2 weeks. All rats in the 27, 81, and 242 mg groups died before the end of the study. Of the surviving groups, final body weights were similar to those of the vehicle controls. Clinical findings included convulsions/seizures, nasal/eye discharge, tremors, and comatose conditions in 81 and 242 mg rats and lethargy, ataxia, and abnormal breathing in 27 mg rats. The incidences of epidermal hyperplasia at the site of application in 9 and 27 mg males and 27 mg females were significantly greater than those in the vehicle controls; the incidences of hyperkeratosis in 3 and 9 mg males and 9 mg females were also significantly increased. 2-WEEK STUDY IN MICE: Groups of five male and five female B6C3F1 mice were dermally administered 0.1 mL ethanol containing 0, 1, 3, 9, or 27 mg diisopropylcarbodiimide or 0.1 mL of the neat chemical containing 81 mg per animal, 5 days a week for 2 weeks. All 9, 27, and 81 mg mice died before the end of the study. Final body weights of the surviving groups were similar to those of the vehicle controls. Clinical findings in 9, 27, and 81 mg mice included comatose conditions, convulsions/seizures, tremors, abnormal breathing, nasal/eye discharge, lethargy, and irritation at the site of application. Incidences of chronic active inflammation at the site of application in 9 mg males and females were significantly greater than those in the vehicle control groups. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female core study F344/N rats were dermally administered 0, 10, 20, 40, 80, or 160 mg diisopropylcarbodiimide/kg body weight in ethanol, 5 days per week for 3 months. Groups of 10 male and 10 female clinical pathology rats were administered the same doses for 22 days. All 160 mg/kg core study rats were sacrificed moribund or died within the first week of the study. All 80 mg/kg rats died or were found moribund by day 59. Significant decreases in body weight gain occurred in 40 mg/kg males and females, and a significant decrease in final mean body weight occurred in 40 mg/kg females. Clinical findings in groups administered 40 mg/kg or more generally included irritation of the skin at the site of application, seizures, ataxia, abnormal breathing, ruffled fur, thinness, and lethargy. Significantly increased incidences of skin lesions at the site of application included epidermal hyperplasia in all dosed groups of males (except 160 mg/kg) and 40 mg/kg or greater females, epidermal necrosis in 160 mg/kg males and females, and chronic active inflammation in 80 and 160 mg/kg males and females. Significantly increased incidences of nonneoplastic lesions occurred in the brain, lung, and liver (males only) of rats administered 80 or 160 mg/kg. 3-MONTH STUDY IN MICE Groups of 10 male and 10 female B6C3F1 mice were dermally administered 0, 17.5, 35, 70, 140, or 280 mg/kg diisopropylcarbodiimide in ethanol, 5 days per week for 3 months. All mice in the 280 mg/kg group and nine males and nine females in the 140 mg/kg group died before the end of the study. The final mean body weight gain of 70 mg/kg males was significantly less than that of the vehicle control group. Clinical findings observed in 140 and 280 mg/kg mice included abnormal breathing, ataxia, comatose conditions, convulsions/seizures, irritation at the site of application, lethargy, ruffled fur, and thinness. Significant increases in kidney weights occurred in 17.5 and 35 mg/kg males. Significant decreases in total spermatid heads per testis and average spermatid count occurred in 17.5 mg/kg males. At the site of application, the incidences of epidermal hyperplasia in males and females administered 70 mg/kg or greater, chronic inflammation in 140 and 280 mg/kg males and 70 mg/kg or greater females, and sebaceous gland hyperplasia in 140 mg/kg males were significantly increased. Thymic atrophy was significantly increased in 140 and 280 mg/kg males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were dermally administered 0, 10, 20, or 40 mg/kg diisopropylcarbodiimide in anhydrous ethanol 5 days per week for 2 years. Survival of 20 mg/kg males was significantly greater than that of the vehicle controls; survival of all dosed groups of females was similar to that of the vehicle controls. Body weights of 40 mg/kg rats were generally less than those of the vehicle controls after week 13. Clinical findings frequently observed in 40 mg/kg males included ataxia, excitability, impaired gait, low muscle tone, abnormal breathing, lethargy, vocalization, and seizures. Because of severe neurological signs exhibited by the 40 mg/kg males, a neuropathological review of these animals was performed. The principal pathological findings of the brain included neuronal necrosis, hemorrhage, and/or fibrinoid arteriole necrosis. Incidences of hemorrhage in the lung of 40 mg/kg males, chronic lung inflammation in 10 and 20 mg/kg females, and alveolar epithelium hyperplasia in 20 mg/kg females were significantly greater than those of the vehicle controls. At the site of application, the incidences of epidermal hyperplasia in all dosed groups of males and 20 and 40 mg/kg females and chronic inflammation in all dosed groups of males and 40 mg/kg females were significantly increased. There was no increased incidences of neoplasms related to diisopropylcarbodiimide administration. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were dermally administered 0, 10, 20, or 40 mg/kg diisopropylcarbodiimide in anhydrous ethanol, 5 days per week for 2 years. Survival of all dosed groups was similar to that of the vehicle control groups. Mean body weights of dosed groups of mice were generally similar to those of the vehicle control groups throughout the study. There were no increased incidences of neoplasms that were attributed to the administration of diisopropylcarbodiimide. Significantly increased incidences of epidermal hyperplasia and focal dermal inflammation of the skin at the site of application occurred in 20 mg/kg male mice. ⋯ Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of diisopropylcarbodiimide in male or female F344/N rats or B6C3F1 mice administered 10, 20, or 40 mg/kg. Clinical and histological signs of neurotoxicity in male rats were associated with diisopropylcarbodiimide administration.
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Natl Toxicol Program Tech Rep Ser · Jan 2006
NTP toxicology and carcinogenesis studies of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage Studies).
DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. ⋯ Gingival squamous cell carcinoma, although reduced in incidence as compared to the 1,000 ng/kg core study group, was still present in the 1,000 ng/kg stop-exposure group. At 2 years, adenomas and/or carcinomas were present in the adrenal cortex of most core study groups and in the 1,000 ng/kg stop-exposure group. Dose-related effects on the incidences of adrenal cortex atrophy and cytoplasmic vacuolization were also seen. (ABSTRACT TRUNCATED)
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Natl Toxicol Program Tech Rep Ser · Dec 2002
NTP toxicology and carcinogensis studies of vanadium pentoxide (CAS No. 1314-62-1) in F344/N rats and B6C3F1 mice (inhalation).
Vanadium pentoxide, commercially the most important compound of vanadium, presents a potential occupational hazard during the cleaning of oil-fired boilers and furnaces, the handling of catalysts, and during the refining, processing, or burning of vanadium-rich mineral ores or fossil fuels. Vanadium pentoxide was nominated for study by the National Cancer Institute as a representative of the metals class study. Male and female F344/N rats and B6C3F1 mice were exposed to vanadium pentoxide (99% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, 4, 8, 16, or 32 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Three males in the 32 mg/m(3) group died before the end of the study. Mean body weights of males and females exposed to 8 mg/m(3) or greater were less than those of the chamber controls. Clinical findings included rapid respiration and hypoactivity in rats exposed to 16 or 32 mg/m(3). Relative lung weights of 4 mg/m(3) or greater males and 2 mg/m(3) or greater females were significantly greater than those of the chamber controls. Lavage fluid analysis indicated an inflammatory response in the lung that was either directly mediated by vanadium pentoxide or was secondary to lung damage induced by vanadium pentoxide exposure. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, 4, 8, 16, or 32 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. All males exposed to 32 mg/m(3) and one 8 mg/m(3) male died or were killed moribund before the end of the study. Mean body weights of 16 mg/m(3) males and 8 mg/m(3) or greater females were significantly less than those of the chamber controls, and the 32 mg/m(3) females lost weight during the study. Absolute and relative lung weights of 4 mg/m(3) or greater males and all exposed groups of females and liver weights of 16 mg/m(3) males were significantly greater than those of the chamber controls. The mediastinal lymph nodes were enlarged in 4, 8, and 16 mg/m(3) males and females, and lymphoid hyperplasia was confirmed histologically. Lavage fluid analysis indicated an inflammatory response in the lung that was either directly mediated by vanadium pentoxide or was secondary to lung damage induced by vanadium pentoxide exposure. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8, or 16 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 3 months. Seven males and three females exposed to 16 mg/m(3) died during the study. Mean body weights were significantly less in males exposed to 4 mg/m(3) or greater and in females exposed to 16 mg/m(3). Abnormal breathing, thinness, lethargy, abnormal posture, and ruffled fur were observed in rats exposed to 16 mg/m(3). Hematology results indicated that exposure of rats to vanadium pentoxide induced a microcytic erythrocytosis in males and females. Absolute and relative lung weights were significantly greater for 4 mg/m(3) or greater males and females than for the chamber controls as were the relative lung weights of 2 mg/m(3) males. The estrous cycle of females exposed to 8 mg/m(3) was significantly longer than that of the chamber control group, and the number of cycling females in the 16 mg/m(3) group was reduced. The incidences of several nonneoplastic lesions of the lung and nose were significantly increased in males and females exposed to 2 mg/m(3) or greater. Data from pulmonary function analyses indicated that a restrictive lung disease was present in male and female rats exposed to 4 mg/m(3) or greater, while an obstructive lung disease was present only in the 16 mg/m(3) groups. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8, or 16 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 3 months. One male exposed to 16 mg/m(3) died before the end of the study. Mean body weights of 8 and 16 mg/m(3) males and 4 mg/m(3) or greater females were significantly less than those of the chamber controls. Absolute and relative lung weights of males and females exposed to 4 mg/m(3) or greater were significantly greater than those of the chamber controls. The epididymal spermatozoal motility of males exposed to 8 or 16 mg/m(3) was significantly decreased. Some mice exposed to 2 or 4 mg/m(3) had inflammation of the lung, and all mice exposed to 8 or 16 mg/m(3) had inflammation and epithelial hyperplasia of the lung. 16-DAY SPECIAL STUDY IN RATS: Groups of 60 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, or 2 mg/m(3) and groups of 40 female rats were exposed to 4 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Alveolar and bronchiolar epithelial hyperplasia was observed in most rats exposed to 2 or 4 mg/m(3) on days 6 and 13. Histiocytic infiltration and inflammation occurred in a time- and concentration-related manner. Cell turnover rates were increased in the terminal bronchioles on days 6 and 13 and in the alveoli in the 4 mg/m(3) group on day 6 and in all exposed groups on day 13. Assessment of lung vanadium concentrations suggested deposition and clearance exhibited linear kinetics over the exposure range studied. Lung clearance half-times ranged from 4.42 to 4.96 days. 16-DAY SPECIAL STUDY IN MICE: Groups of 60 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, or 4 mg/m(3) and groups of 40 female mice were exposed to 8 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Alveolar and bronchiolar epithelial hyperplasia occurred with similar incidences and severities among the exposed groups on days 6 and 13, and time- and concentration-related increases in the incidences of interstitial inflammation and histiocytic infiltration also occurred in these groups. Cell turnover rates were increased in the terminal bronchioles on day 6 and remained greater than those of the chamber controls on day 13. In the alveoli, cell turnover rates were increased in an exposure concentration-related manner on day 13; cell turnover rates were increased only in the 8 mg/m(3) group on day 6. Assessment of lung vanadium concentrations suggested deposition and clearance exhibited linear kinetics over the exposure range studied. Lung clearance half-times ranged from 2.40 to 2.55 days. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 0.5, 1, or 2 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 104 weeks. Survival and body weights of males and females were generally similar to those of the chamber controls. Mean body weights of females exposed to 2 mg/m(3) were less than those of the chamber controls throughout the study. Alveolar/bronchiolar neoplasms were present in exposed groups of male rats, and the incidences often exceeded the historical control ranges. Alveolar/bronchiolar adenomas were present in 0.5 and 1 mg/m(3) females; one 2 mg/m(3) female also had an alveolar/bronchiolar carcinoma. The incidence of alveolar/bronchiolar adenoma in the 0.5 mg/m(3) group was at the upper end of the historical control ranges. Nonneoplastic lesions related to vanadium pentoxide exposure occurred in the respiratory system (lung, larynx, and nose) of male and female rats, and the severities of these lesions generally increased with increasing exposure concentration. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, or 4 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 104 weeks. Survival of 4 mg/m(3) males was significantly less than that of the chamber controls. Mean body weights of 4 mg/m(3) males and all exposed groups of females were generally less than those of the chamber controls throughout the study, and those of males exposed to 2 mg/m(3) were less from week 85 to the end of the study. Many mice exposed to vanadium pentoxide were thin, and abnormal breathing was observed in some mice, particularly those exposed to 2 or 4 mg/m(3). The incidences of alveolar/bronchiolar neoplasms were significantly increased in all groups of exposed males and females. Nonneoplastic lesions related to vanadium pentoxide exposure occurred in the respiratory system (lung, larynx, and nose) of male and female mice, and the severities of these lesions generally increased with increasing exposure concentration. Bronchial lymph node hyperplasia was present in many exposed females. ⋯ Under the conditions of this 2-year inhalation study, there was some evidence of carcinogenic activity of vanadium pentoxide in male F344/N rats and equivocal evidence of carcinogenic activity of vanadium pentoxide in female F344/Nrats based on the occurrence of alveolar/bronchiolar neoplasms. There was clear evidence of carcinogenic activity of vanadium pentoxide in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. (ABSTRACT TRUNCATED)
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Natl Toxicol Program Tech Rep Ser · Jul 2001
Toxicology and carcinogenesis studies of indium phosphide (CAS No. 22398-90-7) in F344/N rats and B6C3F1 mice (inhalation studies).
Indium phosphide is used to make semiconductors,injection lasers, solar cells, photodiodes, and light-emittingdiodes. Indium phosphide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure,and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to indium phosphide (greater than 99% pure) by inhalation for 14 weeks or 2 years. ⋯ Mice exhibited clearance half-times of 144 and 163 days for the 0.1 and 0.3 mg/m3 groups, respectively, as compared to 262 and 291 days for rats exposed to the same concentrations. The lung deposition and clearance model was used to estimate the total amount of indium deposited in the lungs of rats and mice after exposure to 0.03 mg/m3 for 2 years or to 0.1 or 0.3 mg/m3 for 21 or 22 weeks, the lung burdens at the end of the 2-year study, and the area under lung burden curves (AUC). For both species, estimates at the end of 2 years indicated that the lung burdens in the continuously exposed 0.03 mg/m3 groups were greater than those in the 0.1 or 0.3 mg/m3 groups. (ABSTRACT TRUNCATED)