Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 29
Filter
Add more filters










Publication year range
1.
J Appl Toxicol ; 19(2): 101-12, 1999.
Article in English | MEDLINE | ID: mdl-10215182

ABSTRACT

The acute, subchronic and genetic toxicity of the hydrochlorofluorocarbons HCFC-225ca and HCFC-225cb were evaluated to assist in establishing proper handling guides. In acute inhalation studies, rats were exposed for 4 h to various concentrations of each isomer. Based on the mortality incidence, the LC50 value for HCFC-225cb for males and females (combined) was 36800 ppm. For HCFC-225ca, the LC50 for males and females (combined) was 37300 ppm. Narcotic-like effects, e.g. prostration, incoordination and reduced motor activity, were observed during exposure to either isomer, but these signs were not evident 15 min after termination of exposure. Histopathological examination of the liver revealed an increase in mitotic figures with vacuolation of hepatocytes and fluid-filled, congested hepatic sinusoids. In cardiac sensitization studies, HCFC-225cb induced a cardiac sensitization response at 20000 ppm, with one fatal response, whereas a blend of the two isomers (45% HCFC-225ca/55% HCFC-225cb) produced a cardiac sensitization response at 15000 ppm. In 4-week subchronic inhalation studies, male and female rats were whole-body exposed to HCFC-225cb at concentrations of 0, 1000, 5000 or 15000 ppm for 6 h a day, 5 days per week. Similarly, male and female rats were whole-body exposed to HCFC-225ca concentrations of 0, 50, 500 or 5000 ppm for 6 h a day, 5 days per week. During exposure, narcotic-like and irritant effects were observed. A dose-related decrease in cholesterol and triglycerides was observed in the treated rats, with males being affected more than females. Increases in liver weight were observed in most male and female rats exposed to either isomer. The increase in liver weight was consistent in male rats with microscopic evidence of hepatocyte hypertrophy. Although liver weight was increased in female rats, no hepatocyte enlargement was observed in treated female rats. Increases in cytochrome P-450 and beta-oxidation activities were also observed in male and female rats exposed to either isomer. Neither of the HCFC-225 isomers was mutagenic in the Ames reverse mutation assay, or clastogenic in the chromosomal aberration assay with Chinese hamster lung cells. Also, neither isomer induced unscheduled DNA synthesis in liver cells. However, both isomers were clastogenic in the chromosomal aberration assay with human lymphocytes in the absence of S-9. No increases in aberrant cells were observed in activated cells exposed to either isomer.


Subject(s)
Chlorofluorocarbons/toxicity , Hazardous Substances/toxicity , Lung/drug effects , Administration, Inhalation , Animals , Cells, Cultured , Chlorofluorocarbons/administration & dosage , Cholesterol/blood , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme System/metabolism , DNA Replication/drug effects , Dogs , Dose-Response Relationship, Drug , Female , Hazardous Substances/administration & dosage , Heart/drug effects , Humans , Lethal Dose 50 , Liver/drug effects , Liver/pathology , Lymphocytes/drug effects , Male , Mutagenicity Tests , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Triglycerides/blood
2.
Drug Chem Toxicol ; 21(4): 417-47, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9839154

ABSTRACT

The chronic toxicity, oncogenicity, and mutagenicity of chlorotetrafluoroethane (HCFC-124) were evaluated. In the chronic toxicity/oncogenicity study, male and female rats were exposed to 0, 2000, 10,000, or 50,000 ppm HCFC-124 for 6 hr/day, 5 days/week, for 2 years. Body weights were obtained weekly during the first three months of the study and every other week for the remainder of the study. Food consumption was determined weekly. Clinical signs of toxicity were monitored throughout the study. An ophthalmological examination was performed on all animals prior to study start, and all surviving rats were examined at approximately 3, 12, and 24 months after study start. Clinical pathology was evaluated at 3, 6, 12, 18, and 24 months. An interim termination was conducted at 12 months. All surviving rats were necropsied at 24 months. A complete set of tissues was collected for microscopic examination, and selected tissues were weighed. There were no compound-related, adverse effects on body weight, food consumption, survival, clinical signs of toxicity, ophthalmoscopically observable ocular lesions, serum hormone concentrations, or clinical pathology parameters at any exposure concentration in either male or female rats. Compared to controls, urine fluoride was increased in males and females at all exposure concentrations, and plasma fluoride was increased in females at all exposure concentrations. Excretion of fluoride represents conversion of the parent molecule, and as such is not considered to be an adverse effect. There were no toxicologically significant, compound-related organ weight changes or gross or microscopic findings in male or female rats at any of the exposure concentrations tested. HCFC-124 was not toxic or carcinogenic in rats of either sex after inhalation exposure at concentrations of up to 50,000 ppm in this two-year chronic toxicity/oncogenicity study. After exposure to HCFC-124 for six hours per day, five days per week, for 24 months, the no-observed-adverse-effect level for male and female rats was 50,000 ppm. HCFC-124 was not mutagenic in Salmonella typhimurium strains TA1535, TA97, TA98, and TA100 with and without activation when evaluated at concentrations up to 60% HCFC-124 for 48 hours. No evidence of clastogenic activity was observed in cultured human lymphocytes at atmospheric concentrations up to 100% HCFC-124 for 3 hours, with and without metabolic activation. In vivo, no micronuclei were induced in mouse bone marrow cells following exposure of mice to concentrations of 99,000 ppm HCFC-124 6 hours/day for 2 days.


Subject(s)
Chlorofluorocarbons, Methane/toxicity , Administration, Inhalation , Animals , Body Weight/drug effects , Bone Marrow Cells/drug effects , Cells, Cultured , Chlorofluorocarbons, Ethane , Chlorofluorocarbons, Methane/metabolism , Chromosome Aberrations , Dose-Response Relationship, Drug , Eating/drug effects , Female , Fibroadenoma/epidemiology , Fluorides/blood , Fluorides/urine , Gonadal Steroid Hormones/blood , Humans , Leukocytes/drug effects , Liver/drug effects , Male , Mice , Mice, Inbred ICR , Rats , Salmonella typhimurium/drug effects , Survival Rate , Time Factors , Toxicity Tests , Triglycerides/blood
3.
Toxicol Lett ; 92(3): 209-19, 1997 Aug 22.
Article in English | MEDLINE | ID: mdl-9334832

ABSTRACT

Four male and three female marmosets in each group were exposed to air only, 1000 ppm of HCFC 225ca or 5000 ppm of HCFC 225cb, for 6 h per day for 28 consecutive days. HCFC 225ca caused a slight reduction in body weight. HCFC 225cb occasionally caused somnolence during exposure and vomiting on the first day of exposure. Clinical chemistry findings included a mild reduction of triglyceride, cholesterol and phospholipid levels and increased GOT level in the HCFC 225ca exposure group. HCFC 225cb also caused a reduction of triglyceride levels in some animals. HCFC 225ca caused a slight increase of hepatic carnitine palmitoyltransferase (CPT) activity while HCFC 225cb slightly increased cyanide-insensitive palmitoyl CoA beta-oxidation (FAOS) activity. In the HCFC 225cb exposure group, an increase in cytochrome P-450 content was also observed. HCFC 225ca caused a fatty change in the hepatic cells. Increased incidence of lipid droplets in the hepatic cells and myelin-like bodies in hepatic cells, Kupffer's cells and hepatic blood vessels were observed electron microscopically in the HCFC 225ca exposure group. A proliferation of smooth endoplasmic reticulum was observed in the HCFC 225cb exposure group. Decreased peroxisome volume density in the HCFC 225ca group, and increased volume density in the HCFC 225cb exposed females were seen. However, organ weight measurement and histopathological examination did not reveal hepatomegaly or hypertrophy with either substance. Although slight changes were noticed in peroxisome volume density and in some of the peroxisomal enzyme activities, the changes related to peroxisome proliferation with HCFC 225ca and 225cb were minimal in marmosets compared to those seen in rats. Histopathological examination and hormonal analysis did not reveal any abnormalities in the pancreas or testes.


Subject(s)
Chlorofluorocarbons/toxicity , Liver/drug effects , Administration, Inhalation , Animals , Body Weight/drug effects , Callithrix , Chlorofluorocarbons/administration & dosage , Female , Liver/pathology , Liver/ultrastructure , Male , Microbodies/drug effects
4.
Fundam Appl Toxicol ; 32(1): 11-22, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8812205

ABSTRACT

Inhalation studies were conducted to determine the potential toxicity of HCFC-124. Groups of rats and mice were exposed to HCFC-124 6 hr/day, 5 days/week for 13 weeks at 0, 5000, 15,000, and 50,000 ppm. Subgroups of rats and mice were held for a 1-month recovery period. A functional observational battery (FOB) was conducted on rats at 0, 4, 13, and 16 weeks. Clinical pathology evaluations were conducted at 7, 13, and 17 weeks. Thirteen or 17 weeks after study initiation, rats and mice underwent gross and microscopic evaluation, and livers were evaluated for hepatic beta-oxidation activity. In addition, groups of female rats and rabbits were exposed to HCFC-124 by inhalation during gestation to 0, 5000, 15,000, or 50,000 ppm. Exposure of rats and mice to HCFC-124 caused minimal compound-related effects. Compound-related changes occurred in several clinical pathology parameters in rats and mice. Hepatic beta-oxidation activity was significantly higher in 5000, 15,000, and 50,000 ppm male mice; however, there were no compound-related effects on beta-oxidation activity in rats. During the daily exposures, rats, mice, and rabbits exposed to 50,000 ppm were less responsive to auditory stimuli or less active compared to controls. At the 13-week FOB, male rats exposed to 15,000 or 50,000 ppm had decreased arousal. There were no compound-related effects on mortality, clinical signs, ocular tissues, hematology parameters, organ weights, and tissue morphology at any concentration in rats or mice. Maternal toxicity in rats was evident by a significant decrease in weight gain and food consumption at 50,000 ppm. Similarly, 50,000 ppm pregnant rabbits had lower food consumption. However, for both rats and rabbits, there was no evidence of fetal toxicity at any concentration.


Subject(s)
Chlorofluorocarbons, Methane/toxicity , Teratogens/toxicity , Administration, Inhalation , Animals , Chlorofluorocarbons, Ethane , Dose-Response Relationship, Drug , Female , Liver/drug effects , Liver/metabolism , Male , Mice , Microbodies/metabolism , Pregnancy , Rabbits , Rats
5.
Fundam Appl Toxicol ; 31(2): 200-9, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8789786

ABSTRACT

The toxicity potential of 1,1,1-trifluoroethane (HFC-143a), a CFC alternative, was evaluated in several acute, subchronic, and developmental toxicity studies by the inhalation route and in genotoxicity studies. HFC-143a has a very low acute inhalation toxicity potential as shown by a 4-hr LC50 of > 540,000 ppm in rats. HFC-143A has a low potential to induce cardiac sensitization in experimental screening studies in dogs; only the highest concentration tested--300,000 ppm--elicited a cardiac sensitization response. In an initial 4-week nose-only inhalation study, male and female rats were exposed 6 hr/day, 5 days/week at concentrations of 0, 2000, 10,000, or 40,000 ppm. Females showed no evidence of toxicity at any exposure level; male rats did exhibit degenerative changes only in the tests at all exposure levels. However, because of exposure system irregularities, which resulted in excessive temperature conditions and stress in the HFC-143a-exposed groups, the study was repeated in male rats exposed by whole-body inhalation. In this repeat study no toxicity was observed at < or = 40,000 ppm. Moreover, a subsequent 90-day whole-body inhalation study in rats exposed 6 hr/day, 5 days/week at 0, 2000, 10,000, or 40,000 ppm resulted in no evidence of toxicity at any exposure concentration. The results of the second 4-week and the 90-day studies using whole-body exposures indicate that the findings from the first 4-week study were related to the stress induced by excessive temperatures and nose-only restraint. Therefore, the no-observed-effect level (NOEL) for rats repeatedly exposed up to 90 days was considered to be 40,000 ppm. In developmental toxicity studies with rats and rabbits, an increase in visceral variations or skeletal malformations was observed, respectively, at HFC-143a concentrations of 2000, 10,000 or 40,000 ppm (rat) or at the low and high concentrations (rabbit). Because of the unusually low control incidence of variations (1.6% per litter in the control versus 6.8-16.8% for historical control values), the lack of a clear dose-response relationship, and the lack of other developmental effects, these findings were not considered related to HFC-143a exposure. In addition, results from genotoxicity studies (Ames, chromosomal aberration with human lymphocytes, mouse micronucleus) demonstrated that HFC-143a was not mutagenic.


Subject(s)
Abnormalities, Drug-Induced , Heart/drug effects , Hydrocarbons, Fluorinated/toxicity , Mutagens/toxicity , Animals , Dogs , Dose-Response Relationship, Drug , Escherichia coli/drug effects , Escherichia coli/genetics , Female , Humans , Lymphocytes/drug effects , Male , Mice , Mutagenicity Tests , Rabbits , Rats , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Toxicity Tests
6.
Fundam Appl Toxicol ; 28(2): 223-31, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8835232

ABSTRACT

Acute, subacute, and subchronic inhalation toxicity studies, developmental toxicity studies, a cardiac sensitization evaluation, and mutagenicity assays were conducted with pentafluoroethane (HFC-125). In the acute study, rats were exposed to a single concentration of 800,000 ppm for 4 hr. Ataxic gait and abnormal respiration were observed during exposure but not after exposure. There was no mortality or other signs of toxicity. Repeated exposures of rats to 50,000 ppm, 6 hr/day, 5 days/week for either 4 or 13 weeks elicited no effects on body weight, food consumption, clinical signs, hematology, biochemistry, urinalysis, organ weight, or tissue morphology. Positive evidence of cardiac sensitization in response to an intravenous epinephrine challenge in dogs was seen at 100,000 ppm and above, but not at 75,000 ppm. HFC-125 was not mutagenic in Salmonella typhimurium and Escherichia coli strains at concentrations of 20 to 100% (v/v) with and without activation. No evidence of clastogenic activity was observed in cultured Chinese hamster ovary (CHO) cells or human lymphocytes at < or = 70% HFC-125 when treatments were conducted for 3-4 hr with activation or for 24 and 48 hr (human lymphocytes only) without activation. However, a statistically significant increase in chromosomally aberrant cells was observed in CHO cells at 60% HFC-125 when treatment without activation was extended to 48 hr. The biological significance of this effect is questionable since signs of severe toxicity were also present. In vivo, no micronuclei were induced in mouse bone marrow at concentrations as high as 600,000 ppm HFC-125 for a 6-hr exposure. In addition, HFC-125 did not induce embryotoxic or teratogenic effects in either the rat or the rabbit at exposure concentrations as high as 50,000 ppm.


Subject(s)
Fluorocarbons/toxicity , Toxicity Tests , Abnormalities, Drug-Induced , Administration, Inhalation , Animals , Body Weight/drug effects , Bone Marrow , CHO Cells/drug effects , Cricetinae , Dogs , Embryonic and Fetal Development/drug effects , Escherichia coli/drug effects , Female , Fluorocarbons/administration & dosage , Heart/drug effects , Humans , Lymphocytes/drug effects , Male , Micronucleus Tests , Mutagenicity Tests , Pregnancy , Rabbits , Rats , Rats, Sprague-Dawley , Salmonella typhimurium/drug effects
7.
Food Chem Toxicol ; 33(6): 483-90, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7797175

ABSTRACT

The acute and subchronic toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b), a CFC alternative, was evaluated in several acute and subchronic studies to assist in establishing proper handling guides. Data from acute toxicity studies in rats and rabbits demonstrated that HCFC-141b has very low acute toxicity. HCFC-141b was not a skin irritant, but was a mild eye irritant, in rabbits and was not a skin sensitizer in guinea pigs. Skin application of HCFC-141b to rabbits at 2000 mg/kg body weight produced no adverse effects. Oral administration at 5000 mg/kg body weight did not cause any deaths or clinical signs of toxicity in rats. The 4-hr LC50 for HCFC-141b was about 62,000 ppm in rats. Repeated exposures of rats for 6 hr/day, 5 days/wk for up to 90 days at concentrations of 2000, 8000 or 20,000 ppm did not result in significant adverse effects. Minor, but dose-dependent, reductions in body weight were observed in male and female rats during the 90-day study. Decreased responsiveness was also observed in rats but only at 20,000 ppm. An increase in serum cholesterol or triglycerides was observed in male and female rats at 20,000 ppm, and in males at 8000 ppm. No specific organ pathology was noted in these subchronic inhalation studies. The no-observable-adverse-effect level (NOAEL) from these studies was 8000 ppm. Results from other studies demonstrate that HCFC-141b was not neurotoxic in rats. As with trichlorofluoroethane (CFC-11), a cardiac sensitization response to an intravenous epinephrine challenge occurred in dogs with HCFC-141b at 5000 ppm and higher concentrations in experimental screening studies.


Subject(s)
Chlorofluorocarbons/toxicity , Administration, Inhalation , Administration, Oral , Administration, Topical , Animals , Chlorofluorocarbons/administration & dosage , Chlorofluorocarbons, Ethane , Dermatitis, Contact , Eye/drug effects , Female , Male , Rats , Rats, Wistar , Skin Tests , Time Factors
8.
Fundam Appl Toxicol ; 25(1): 101-14, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7601319

ABSTRACT

The potential chronic toxicity and oncogenicity of hydrochlorofluorocarbon 123 (HCFC-123) was evaluated by exposing male and female rats to 0, 300, 1000, or 5000 ppm HCFC-123 for 6 hr/day, 5 days/week, for 2 years. Clinical pathology was evaluated at 6, 12, 18, and 24 months. An interim termination and measurements of hepatic cell proliferation and beta-oxidation activity were conducted at 12 months. The terminal euthanization occurred at 24 months. Males and females exposed to 5000 ppm and females exposed to 300 or 1000 ppm had lower body weights and body weight gains. Serum triglyceride and glucose concentrations were significantly decreased at all exposure concentrations in both sexes. Serum cholesterol was also lower in 300, 1000, and 5000 ppm females and in 5000 ppm males. Alterations in serum protein concentrations occurred at 300, 1000, and 5000 ppm. Survival was higher in 1000 and 5000 ppm males and females. At 24 months, increased relative liver weight occurred in 5000 ppm males, and decreased absolute kidney weight occurred in 5000 ppm males and in 1000 and 5000 ppm females. Benign hepatocellular adenomas were increased in 5000 ppm males and in all test groups of females. Hepatic cholangiofibromas were also increased in 5000 ppm females. Pancreatic acinar cell adenomas were increased in all test groups of males, and acinar cell hyperplasia was increased in the 1000 and 5000 ppm males and females. Benign testicular interstitial adenomas and focal interstitial cell hyperplasia were also increased in all male test groups compared to controls. Diffuse retinal atrophy was increased in all male and female test groups, but it was considered to be an indirect compound-related effect. Hepatic beta-oxidation activity (peroxisome proliferation) was higher in 300, 1000 and 5000 ppm males and 1000 and 5000 ppm females. Compound-related differences in the rate of hepatic cell proliferation were not observed at any exposure concentration. Decreased incidences of a variety of age-related lesions occurred at 1000 and 5000 ppm.


Subject(s)
Carcinogens/toxicity , Chlorofluorocarbons/toxicity , Liver/drug effects , Pancreas/drug effects , Testis/drug effects , Administration, Inhalation , Animals , Blood Proteins/analysis , Body Weight/drug effects , Carcinogens/administration & dosage , Chlorofluorocarbons/administration & dosage , Chlorofluorocarbons, Ethane , Female , Liver/pathology , Liver Neoplasms, Experimental/chemically induced , Male , Organ Size/drug effects , Pancreas/pathology , Pancreatic Neoplasms/chemically induced , Rats , Testicular Neoplasms/chemically induced , Testis/pathology , Toxicity Tests
9.
Fundam Appl Toxicol ; 23(2): 169-78, 1994 Aug.
Article in English | MEDLINE | ID: mdl-7982525

ABSTRACT

Hydrochlorofluorocarbon 123 (HCFC 123) is one of the chemicals being considered as a replacement for the chlorofluorocarbons. Four subchronic inhalation toxicity studies from 1 to 3 months in duration have been conducted with HCFC 123. One study utilized rats and dogs, while the others were limited to rats only. The exposure levels have ranged from 300 ppm up to 20,000 ppm. Although the studies were conducted over a 14-year period, the results were consistent. In all studies, increases in liver weights were seen at 1000 ppm and above; additionally, one showed this effect at 500 ppm. Histopathological findings were minimal, consisting primarily of focal necrosis in the liver of the dogs at 10,000 ppm. Induction of peroxisomal activity, lowering of serum cholesterol and triglyceride levels, and an increase in urinary fluoride levels were also seen. The 4-hr LC50 in the rat has been reported as 35,000 ppm. At 20,000 ppm for 6 hr, the total daily dose on a concentration times time basis is almost equal to the LC50, yet, in the 4-week study, with 20 exposures at this level, there was no mortality or even marked signs of toxicity. There appeared to be no evidence for cumulative toxicity from multiple exposures in these studies. Overall, HCFC 123 appears to have a low level of toxicity by the inhalation route.


Subject(s)
Chlorofluorocarbons/administration & dosage , Chlorofluorocarbons/toxicity , Administration, Inhalation , Animals , Atmosphere Exposure Chambers , Blood/drug effects , Body Weight/drug effects , Chlorofluorocarbons, Ethane , Dogs , Female , Male , Organ Size/drug effects , Rats , Toxicology/methods
10.
Toxicol Lett ; 68(1-2): 25-30, 1993 May.
Article in English | MEDLINE | ID: mdl-8516770

ABSTRACT

Fluorocarbons containing chlorine or bromine have been associated with stratospheric ozone depletion and the search for suitable alternatives is progressing at an accelerated pace. The Program for Alternative Fluorocarbon Toxicity Testing (PAFT), an international group representing most of the world's CFC producers, has been conducting comprehensive toxicological evaluations on several possible replacements for current fire-extinguishing agents--1,1-dichloro-2,2,2-trifluoroethane (HCFC-123), 1-chloro-1,2,2,2-tetrafluoroethane (HCFC-124), pentafluoroethane (HFC-125), and 1-fluoro-2,2,2-trifluoroethane (HFC-134a). Results from short-term experimental studies showing a low order of acute toxicity, as well as results from longer-term toxicity studies on these replacements, will be discussed.


Subject(s)
Flame Retardants/toxicity , Fluorocarbons/toxicity , Animals , Program Development , Toxicology
11.
Sci Total Environ ; 86(1-2): 83-108, 1989 Oct 01.
Article in English | MEDLINE | ID: mdl-2602942

ABSTRACT

Rats were exposed by inhalation to chromium dioxide (CrO2) dust at design concentrations of 0, 0.5 (stabilized and unstabilized, respectively) or 25 mg m-3 (stabilized) for 6 h day-1, 5 days week-1 for 2 years. No dust-exposure-related pathological changes were observed, other than lung lesions, in all exposed rats. There were no significant differences in pulmonary response between unstabilized and stabilized CrO2 at the 0.5 mg m-3 exposure level. The lungs showed minute dust deposition in the alveoli adjacent to the alveolar ducts, but maintained an intact general architecture. The pulmonary responses satisfied the biological criteria for a nuisance dust. At 25 mg m-3, dust deposition was sharply confined to the alveoli in the alveolar duct region. Alveolar walls enclosing dust-laden macrophage (dust cell) aggregates were thickened with hyperplastic Type II pneumocytes and slightly collagenized fibrosis. Alveoli adjacent to the terminal bronchioles were lined with bronchiolar epithelium (alveolar bronchiolarization). In addition, lungs showed foamy macrophage response, cholesterol granulomas, alveolar proteinosis, and minute fibrotic pleurisy. These pulmonary lesions occurred predominantly in female rats. Of 108 female rats, six developed keratin cysts and two had cystic keratinizing squamous cell carcinoma (CKSCC). None of 106 male rats had either a keratin cyst or a CKSCC. The lung tumors developed from metaplastic squamous cells in the areas of alveolar bronchiolarization in the alveolar duct region. The lung tumors were well differentiated and devoid of characteristics of true malignancy. The CKSCC is an experimentally-induced, unique tumor type and is different from the type of spontaneous lung tumor seen in man or animals. The relevance to man of ths type of lung tumor appears to be negligible.


Subject(s)
Chromium Compounds , Chromium/toxicity , Dust , Lung/pathology , Administration, Inhalation , Aerosols , Animals , Chromium/administration & dosage , Chromium/urine , Female , Lung/drug effects , Male , Rats , Rats, Inbred Strains , Time Factors
13.
Fundam Appl Toxicol ; 11(1): 68-75, 1988 Jul.
Article in English | MEDLINE | ID: mdl-2850254

ABSTRACT

Groups of 100 male and 100 female Crl:CDBR rats were exposed by whole-body inhalation to FC-113 (1,1,2-trichloro-1,2,2-trifluoroethane) for 6 hr a day, 5 days a week for 24 months. Average exposure concentrations (+/- 1 SD) were 0.0 (control), 2000 +/- 100, 10,000 +/- 500, and 20,000 +/- 1000 ppm (v/v), respectively. Body weights were consistently lower in both male and female rats in the 20,000 ppm exposure group after approximately 1 and 4 months' exposure, respectively, and in female rats after 12 months' exposure at 10,000 ppm. Observations of appearance and behavior, mortality, and clinical laboratory measurements were unremarkable during the 24-month exposure period. Despite exposure levels as high as 20,000 ppm, only occasional slight increases in urinary fluoride were seen. Microscopic examination of tissues from rats examined during and at the end of the 24-month study revealed no evidence of compound-related toxicity or carcinogenicity. Based mainly on a 5 to 10% decrease in body weight gain at the 10,000 and 20,000 ppm exposure levels, the no-observed-effect level for FC-113 in this study was 2000 ppm.


Subject(s)
Carcinogens , Chlorofluorocarbons, Methane/toxicity , Adenoma/chemically induced , Adenoma, Islet Cell/chemically induced , Administration, Inhalation , Air Pollutants/toxicity , Animals , Body Weight/drug effects , Chlorofluorocarbons, Ethane , Female , Fluorides/urine , Male , Organ Size/drug effects , Rats , Rats, Inbred Strains , Sex Factors , Time Factors
14.
Fundam Appl Toxicol ; 10(1): 125-45, 1988 Jan.
Article in English | MEDLINE | ID: mdl-3350223

ABSTRACT

Rats were exposed by inhalation to chromium dioxide (CrO2) dust at design concentrations of 0, 0.5 mg/m3 (stabilized and unstabilized, respectively), or 25 mg/m3 (stabilized) for 6 hr/day, 5 days/week for 2 years. No dust-exposure-related pathological changes other than lung lesions were observed in all exposed rats. There were no significant differences in pulmonary responses between unstabilized and stabilized CrO2 at the 0.5 mg/m3 exposure level. The lungs showed minute dust deposition in the alveoli adjacent to the alveolar ducts, but maintained an intact general architecture. The pulmonary responses satisfied the biological criteria for a nuisance dust. At 25 mg/m3, dust deposition was sharply confined to the alveoli in the alveolar duct region. Alveolar walls enclosing dust-laden macrophage (dust cell) aggregates were thickened with hyperplastic Type II pneumocytes and slightly collagenized fibrosis. Alveoli adjacent to the terminal bronchioles were lined with bronchiolar epithelium (alveolar bronchiolarization). In addition, lungs showed foamy macrophage response, cholesterol granulomas, alveolar proteinosis, and minute fibrotic pleurisy. These pulmonary lesions occurred predominantly in female rats. Of 108 female rats, 6 developed keratin cysts and 2 had cystic keratinizing squamous cell carcinoma (CKSCC). None of 106 male rats had either a keratin cyst or a CKSCC. The lung tumors developed from metaplastic squamous cells in the areas of alveolar bronchiolarization at the alveolar duct region. The lung tumors were well differentiated and devoid of characteristics of true malignancy. The CKSCC is an experimentally induced, unique tumor type and is different from the type of spontaneous lung tumor seen in man or animals. The relevance to man of this type of lung tumor appears to be negligible.


Subject(s)
Chromium Compounds , Chromium/toxicity , Dust/adverse effects , Aerosols , Animals , Body Weight/drug effects , Chromium/urine , Female , Lung/pathology , Lung Diseases/chemically induced , Lung Diseases/pathology , Male , Organ Size/drug effects , Particle Size , Rats , Rats, Inbred Strains
15.
Environ Res ; 41(1): 144-67, 1986 Oct.
Article in English | MEDLINE | ID: mdl-3757966

ABSTRACT

Rats were exposed to TiO2 by the inhalation route at concentrations of 0, 10, 50, or 250 mg/m3 for 6 hr/day, 5 days/week for 2 years. Lung weights of rats at 10 mg/m3 were within normal limits after 2 years exposure. Lung weights increased significantly after 6 months at 50 mg/m3 and after 3 months at 250 mg/m3. After 2 years exposure, TiO2 retention in dried lung was 3.1% (26.5 mg per lung) at 10 mg/m3, 16.9% (124 mg per lung) at 50 mg/m3, and 28% (665 mg per lung) at 250 mg/m3. Lung clearance mechanisms appeared to be overloaded at 250 mg/m3. Dust particles were retained in the lung in a dose-related fashion, but there was no significant difference in lung clearance rate between 10 and 50 mg/m3. Lung response at 10 mg/m3 satisfied the biological criteria for a "nuisance dust," while adverse effects resulting from gradually accumulated particles (8.1%, 67.7 mg per lung) were found after 1 year of exposure to 50 mg/m3. An early pulmonary response indicating an overloaded lung clearance mechanism was manifested by massive accumulation of dust-laden macrophages (dust cells), foamy dust cells, free particles, or cellular debris derived from disintegrated foamy dust cells in the alveoli adjacent to the alveolar ducts. Alveolar proteinosis also appeared to be an important marker of an overloaded lung clearance mechanism and was observed at 50 and 250 mg/m3 after 1 year of exposure. Cholesterol granulomas were developed with degenerative foamy dust cells at 50 and 250 mg/m3 after 1 year of exposure. After 2 years exposure at 250 mg/m3, bronchioalveolar adenomas occurred in the alveoli showing type II pneumocyte hyperplasia, while cystic keratinizing squamous carcinomas were developed from squamous metaplasia of alveoli showing bronchiolarization in the alveolar duct region. Since the lung tumors were a unique type of experimentally induced tumors under exaggerated exposure conditions and have not usually been seen in man or animals, their relevance to man is questionable.


Subject(s)
Dust/adverse effects , Lung/drug effects , Titanium/toxicity , Animals , Carcinoma, Squamous Cell/etiology , Cholesterol/metabolism , Dose-Response Relationship, Drug , Female , Granuloma/etiology , Lung/metabolism , Lung/pathology , Lung Neoplasms/etiology , Macrophages/drug effects , Male , Metabolic Clearance Rate/drug effects , Organ Size/drug effects , Phagocytosis , Proteins/metabolism , Rats , Titanium/metabolism
16.
Toxicol Appl Pharmacol ; 83(1): 30-45, 1986 Mar 30.
Article in English | MEDLINE | ID: mdl-3952749

ABSTRACT

Rats were exposed to TiCl4 hydrolysis products by inhalation exposure at aerosol concentrations of 0, 0.1, 1.0, and 10 mg/m3 for 6 hr/day, 5 days/week for 2 years. There were no abnormal clinical signs, body weight changes, or excess mortality in any exposed groups. No pathological changes other than a mild rhinitis were observed at 0.1 mg/m3. At 1.0 mg/m3, the incidence of mild rhinitis and tracheitis was increased. The lungs showed a minute dust-laden macrophage (dust cell) reaction with slight Type II pneumocyte hyperplasia in alveoli adjacent to the alveolar ducts. The pulmonary response at the 1.0 mg/m3 satisfied the biological criteria for a nuisance dust. At 10 mg/m3, extrapulmonary particle deposition occurred in the tracheobronchial lymph nodes, liver, and spleen without any tissue response. An increased incidence of rhinitis, tracheitis, and dust cell response with Type II pneumocyte hyperplasia, alveolar bronchiolarization, foamy dust cell accumulation, alveolar proteinosis, cholesterol granuloma, and focal pleurisy was also observed. The pulmonary lesions developed in the alveolar duct region where dust cells had accumulated and had provoked a chronic tissue response. In addition, a few well-differentiated, cystic keratinizing squamous carcinomas were developed from alveoli showing bronchiolarization with squamous metaplasia in the alveolar duct region. No tumor metastasis was found in other organs. The lung tumors were a unique type of experimentally induced tumor and have not been seen usually in man or animals. Therefore, the relevance to man of this type of lung tumor is highly questionable.


Subject(s)
Respiratory System/pathology , Respiratory Tract Neoplasms/chemically induced , Titanium/toxicity , Animals , Dose-Response Relationship, Drug , Female , Hydrolysis , Lung/drug effects , Lung/pathology , Male , Rats , Respiration , Respiratory System/drug effects , Respiratory Tract Neoplasms/pathology , Time Factors
17.
Food Chem Toxicol ; 24(3): 237-40, 1986 Mar.
Article in English | MEDLINE | ID: mdl-3957176

ABSTRACT

Groups of 110 rats of each sex were exposed by whole-body inhalation to 0, 1000, 10,000 or 20,000 ppm (v/v) of hydrochlorofluorocarbon 142b (CFC 142b or 1-chloro-1, 1-difluoroethane) for 6 hr/day, 5 days/wk for 104 wk (ten rats from each group were killed after 52 wk) in a combined chronic toxicity and oncogenicity study. Concurrently, ten male rats per group were exposed to the same concentrations for 13 wk in a bone-marrow cytogenicity study and another ten male rats per group were exposed for 15 wk in a dominant lethal study. No toxicologically significant compound-related effects were observed in behaviour, appearance, growth, clinical pathology, or gross and microscopic pathology. Respiratory infection and consequently higher than expected mortality during the first year did not compromise the studies or conclusions but may have contributed to the intergroup differences in the numbers of chromosome breaks and acentric fragments. No evidence for mutagenic potential was seen in either the dominant lethal or the cytogenetic assays. These data indicate the very low toxicity of CFC 142b with respect to chronic effects and genotoxic and oncogenic potential. The toxicological profile of CFC 142b is similar to that of other chlorofluorocarbons that have been assigned a threshold limit value (TLV) of 1000 ppm as a workplace 8-hr time-weighted average by the American Conference of Governmental Industrial Hygienists.


Subject(s)
Carcinogens , Chlorofluorocarbons, Methane/toxicity , Animals , Chromosome Aberrations , Dose-Response Relationship, Drug , Female , Male , Mutagens , Neoplasms, Experimental/chemically induced , Rats , Rats, Inbred Strains
18.
Exp Mol Pathol ; 42(3): 331-43, 1985 Jun.
Article in English | MEDLINE | ID: mdl-3996554

ABSTRACT

Titanium dioxide (TiO2) has been used extensively in the manufacturing of white pigment and has generally been regarded as a nuisance dust in animals and man. After inhalation exposure, little is known about transmigration routes and potential toxic effects of translocated particles in other organs. In order to answer these questions, rats were exposed to TiO2 by inhalation exposure at concentrations of 0, 10, 50, and 250 mg/m3 for 2 years. A few free particles were retained in the nasal and tracheobronchial epithelium without any cellular damage, but aggregates of dust-laden macrophages (dust cells) were found in the lymphoid tissue of the submucosa. Inhaled particles were mostly engulfed by alveolar macrophages and confined sharply to the alveolar duct region at 10 and 50 mg/m3, while dust cells were scattered throughout alveoli at 250 mg/m3. A fraction of the inhaled particles was retained in the membranous pneumocytes and interstitial macrophages. A dense accumulation of dust cells was found in the perivascular and peribronchial lymphoid tissue. Some dust cells entered peribronchial lymphatics or pulmonary blood vessels and the general circulation. Dust cells in the hyperplastic peribronchial lymphoid tissue were exposed directly in the luminal surface of the airways and were subsequently eliminated via airways. Massive dust deposition was observed in the tracheobronchial lymph nodes. Dust transmigration was markedly reduced in the cervical lymph nodes, and only a trace amount of dust particles was found in the mesenteric lymph nodes. Some dust cells entered either blood or lymphatic vessels in the lymph nodes and then migrated into the general circulation. The incidence of extrapulmonary dust deposition in the liver or spleen was increased in a dose-related fashion similar to the lung dust burden. Since there was no tissue response to translocated particles in the lymph nodes, spleen, or liver, potential adverse health effects appear to be negligible.


Subject(s)
Dust/analysis , Lung/analysis , Titanium/analysis , Administration, Intranasal , Animals , Cell Aggregation , Cell Movement , Female , Liver/analysis , Liver/physiopathology , Lung/blood supply , Lung/physiopathology , Lymph Nodes/analysis , Lymph Nodes/physiopathology , Male , Microscopy, Electron, Scanning , Particle Size , Rats , Spleen/analysis , Spleen/physiopathology , Titanium/administration & dosage
19.
Toxicol Appl Pharmacol ; 79(2): 179-92, 1985 Jun 30.
Article in English | MEDLINE | ID: mdl-4002222

ABSTRACT

Rats were exposed to TiO2 by inhalation exposure to concentrations of 0, 10, 50, and 250 mg/m3 for 6 hr/day, 5 days/week for 2 years. There were no abnormal clinical signs, body weight changes, or excess mortality in any exposed group. Exposed groups showed slight increases in the incidence of pneumonia, tracheitis, and rhinitis with squamous metaplasia in the anterior nasal cavity. The pulmonary response at 10 mg/m3 satisfied the biological criteria for a "nuisance dust." The lung reaction was characterized by dust-laden macrophage (dust cell) infiltration in the alveolar ducts and adjoining alveoli with hyperplasia of Type II pneumocytes. Rats at 50 and 250 mg/m3 exposure concentrations revealed a dose-dependent dust cell accumulation, a foamy macrophage response, Type II pneumocyte hyperplasia, alveolar proteinosis, alveolar bronchiolarization, cholesterol granulomas, focal pleurisy, and dust deposition in the tracheobronchial lymph nodes. Minute collagenized fibrosis occurred in the alveolar walls enclosing large dust cell aggregates. The pulmonary lesions with massive dust accumulation appeared to be the result of an overwhelmed lung clearance mechanism at 250 mg/m3 exposure. Bronchioloalveolar adenomas and cystic keratinizing squamous cell carcinomas occurred at 250 mg/m3 exposure, while no compound-related lung tumors were found in rats exposed to either 10 or 50 mg/m3. In addition to excessive dust loading in the lungs of rats exposed chronically at 250 mg/m3, the lung tumors were different from common human lung cancers in terms of tumor type, anatomic location, tumorigenesis, and were devoid of tumor metastasis. Therefore, the biological relevance of these lung tumors and other pulmonary lesions for man is negligible.


Subject(s)
Dust , Lung Neoplasms/chemically induced , Pulmonary Alveoli/drug effects , Titanium/toxicity , Animals , Atmosphere Exposure Chambers , Body Weight/drug effects , Female , Lung Neoplasms/pathology , Male , Microscopy, Electron, Scanning , Nasal Cavity/drug effects , Organ Size/drug effects , Pulmonary Alveoli/ultrastructure , Rats , Tracheitis/chemically induced
SELECTION OF CITATIONS
SEARCH DETAIL
...