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Biomedical subjects

F R Johannsen

Publications and source records attributed to F R Johannsen.

At least 19 recordsLinked to original sources
PubMed1992

Toxicity of calcium sodium metaphosphate fiber. II. Chronic inhalation and oncogenicity study.

Male and female Fischer 344 rats (80/sex/group) were exposed to CSM fiber 6 hr/day, 5 days/week at target-exposure levels of 0, 1, 5, or 25 mg/m3 for 24 months, corresponding to 0, 27, 80, and 513 fibers/cc, respectively. Number and size of the airborne fibers were determined during the course of the study. At 3 and 12 months, 10 rats/sex/group were euthanized and at 18 and 24 months 5 rats/sex/group were euthanized. In addition, 5 rats/sex/group were removed from exposure at 18 months and maintained for a 6-month recovery period. All animals surviving at the completion of the exposure period were maintained in a clean environment for up to 5 additional months. Clinical laboratory examinations were performed on 10 animals/sex/group at 3, 12, and 24 months. The number of fibers in the lung were also determined at 3, 12, 18, and 24 months. Body weight and survival did not appear to be affected by treatment. There were no biologically significant effects on clinical parameters. There was a dose-related increase in lung weight during the exposure period which was generally reversible during the recovery periods. There also was a dose-related increase in the number of fibers/milligram of lung, but no increase in lung fiber burden after the first 3 months. The number of fibers in the lungs of animals exposed to CSM fiber for 18 months and allowed 6-month recovery period showed a decrease especially at the high dose. No increase in tumors (benign or malignant) was observed in this study. Microscopic changes considered reflective of an irritant response were observed in the nasal turbinates notably at the 5 and 25 mg/m3 levels. Histological changes were also observed in the lungs at the 5 and 25 mg/m3 levels. The incidence and/or severity of histopathological changes in the 1 mg/m3 group was considered to be essentially comparable to controls.

Administration, Inhalation↗
PubMed1992

Evaluation of teratogenic potential of N-formylpiperidine in rats.

The teratogenic potential of a versatile solvent, N-formylpiperidine (NFP), was evaluated in the rat. Three groups of 25 mated female Sprague-Dawley rats were given 110, 220, or 440 mg/kg/day NFP in distilled water by gavage on Days 6 through 20 of gestation. A control group of 25 animals received distilled water on a comparable regimen. Maternal animals were observed daily for signs of toxicity; body weights and food consumption were measured at regular intervals throughout the study. All animals were euthanized on Gestation Day 21 and the fetuses examined for cleft palate and external abnormalities. One-half of the fetuses in each litter were examined for visceral anomalies while the remaining fetuses were examined for skeletal malformations after appropriate staining. One female in the high dosage group died on Gestation Day 12. Clinical signs of toxicity, observed in 6 females in the high dosage group, included tremors, convulsive movements, and an apparent weakness of the legs. Maternal toxicity, in terms of significantly decreased body weight and food consumption, was observed in the mid and high dosage groups. Food consumption was also significantly depressed for the first 4 days of dosing in the low dosage group. There was a significant increase in number of resorptions in the high dosage group when compared to controls. No effects were observed on other reproductive parameters. Mean fetal body weight was significantly lower in the high dosage group when compared to controls. While the incidence of fetal malformations on a litter basis was higher in the high dosage group, this change was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A two-generation reproduction study in rats receiving diets containing hexamethylenediamine.

Rats received diets containing average daily doses of 0, 50, 150, and 500 mg/kg/day of hexamethylenediamine over two generations. Although no treatment-related mortality was observed in any of the groups, the weight gain of adults and pups was slightly reduced in the high dose group. While the litter size was also slightly reduced at birth in the high dose group, there was no adverse effect on survival during lactation in any of the treated groups. Thus, the dietary administration of up to 150 mg/kg/day of hexamethylenediamine over two generations did not adversely affect reproduction or fertility in rats.

Animals↗
PubMed1991

Subchronic and reproduction studies with dibutyl phenyl phosphate in Sprague-Dawley rats.

Dibutyl phenyl phosphate (DBPP) was administered to male and female Sprague-Dawley rats in their diets in separate subchronic (91-day) and two-generation reproduction studies. Dose levels of DBPP were 5, 50, and 250 mg/kg/day in both studies. In the reproduction study, cross-fostering was performed between some high-exposure and control litter offspring and dams following a second mating of F0 animals. Compared to control animals, body weights were consistently lower in high-exposure adult animals in both studies; this observation was less consistent in mid-exposure adult rats. High-exposure rats in the subchronic study had decreased erythrocyte counts and hematocrit and hemoglobin levels. They also had increased absolute and/or relative liver weights with concomitant decreased hepatocytic vacuolation and increased fatty accumulation. In the reproduction study, mating and fertility indices were comparable among the parental animals in both generations, but survivability among high-exposure pups reared by control dams appeared to be decreased. Urinary bladder histopathologic changes, consisting of mononuclear cell infiltration and transitional epithelial hyperplasia, were noted in mid- and high-exposure rats from both studies. The no observable adverse effect level in both of these studies was 5 mg/kg/day.

Animals↗
PubMed1991

Hepatic involvement of two chlorinated propenes following repeated oral exposure in the rat.

The comparative toxicity of two chlorinated propene isomers, 1,2,3-trichloropropene (TRCP) and 1,1,2,3-tetrachloropropene (TECP), was investigated via subchronic oral administration to rats for 4 weeks. Test groups, each consisting of 5 male and 5 female rats, were exposed to 0, 3, 10, 30, 100 or 300 mg/kg/d TRCP or TECP by gavage. A separate corn oil control group was used for each chloropropene. While all rats of both sexes given 300 mg/kg/d TRCP died, only 1 female exposed to 300 mg/kg TECP died. Mean body weights were reduced in male rats given 100 mg/kg/d TRCP. With TECP, dose-related reductions in mean body weight and food consumption were seen at 100 and 300 mg/kg/d. Moderate fatty changes in the livers of high-dose TRCP-treated rats which died during the first study week were probably related to chloropropene exposure. Treatment-related necrotic/degenerative lesions of the liver were seen in both male and female rats administered 300 mg/kg/d TECP.

Administration, Oral↗
PubMed1991

Subchronic inhalation toxicity and reproductive assessment in rats of three chlorinated propenes.

Groups of 15 male and 15 female Sprague-Dawley rats were exposed to 1 of 3 chloropropene (2,3-Di = DCP; 1,2,3-Tri = TRCP; and 1,1,2,3-Tetra = TECP) vapors to provide information on repeated exposures and the potential for reproductive impairment by the most likely route of occupational exposure. Target exposure concentrations were 0, 1, 5, and 15 ppm, 6 h/d, 5 d/wk for 13 wk. The following parameters were evaluated: pharmacotoxic signs, survival, body weights, hematology, clinical blood chemistry, urine analysis, gross and histopathology (over 40 tissues/rat), organ weights, and selected weight ratios. Signs of nasal irritation were noted in rats exposed to 15 ppm of either DCP or TRCP but not TECP. Small decreases in overall body weight were observed in female rats exposed to 15 ppm TCP. An increase (approximately 15%) in spleen weight, with no corresponding histopathological or clinical findings, was observed in 15 ppm DCP-treated male rats. No other effects considered related to treatment were observed following exposure to any of the three chlorinated propenes. Additional groups of 10 male and 20 female Sprague-Dawley rats were exposed to DCP, TRCP, or TECP vapors at target concentrations of 0, 1, or 5 ppm for 6 h/d, 5 d/wk for a 10-wk premating period, a mating period, and the first 14 d (females only) of gestation. Females were allowed to deliver litters and the offspring were evaluated during a 21-d lactation period. Mating, pregnancy, and fertility indices were generally comparable among all test groups, although female mating and pregnancy indices of both DCP-treated females were lower than expected in the regular and postrecovery reproduction phase. No effects were seen on pup survival, sex distribution, body weights, organ weights, and ratios. A modest reduction in pup body weights was observed following TECP exposure but was attributed to large litter size. No treatment-related effects were seen following necropsy of adults or weanlings, nor were such effects noted following microscopic evaluation of gonads from parental animals.

Administration, Inhalation↗
PubMed1990

Chronic toxicity, oncogenic potential, and reproductive toxicity of p-nitroaniline in rats.

Dose levels for these studies were selected mainly on the basis of subchronic studies, although consideration was also given to workplace exposure levels and proposed mechanism of tumor formation with structurally similar compounds. For the chronic study, groups of 60 male and 60 female Sprague-Dawley CD (Registered Trademark of Charles River Breeding Laboratories, Portage, MI) rats were given 0, 0.25, 1.5, or 9.0 mg/kg/day paranitroaniline (PNA) by gavage in corn oil for a period of 2 years. Parameters monitored included clinical observations, ophthalmoscopic exams, body weights, food consumption, hematology, clinical chemistry, and urinalysis at regular intervals throughout the study. All gross lesions and over 40 tissues were examined histologically for all control and high-dosage-level animals. Gross lesions, spleens, and livers of low- and mid-dosage groups were also examined histologically. For the reproduction study, groups of 15 male and 30 female rats, designated as F0 generation, were given PNA at the same levels as the chronic study for 14 weeks prior to mating and during mating, gestation, and lactation. Selected groups of 15 male and 30 female rats of the F1 generation received the same dose of PNA for 18 weeks prior to mating and during mating, gestation, and lactation. F2 pups were observed through weaning at which time they were euthanized. Observations made during the study included body weights, food consumption, mating and fertility indices, pup and litter survival indices, and histopathology of selected tissues. In the chronic study, except for a slight decrease in survival of high-dose male rats late in the study, survival in all treated groups was comparable to controls. Blood methemoglobin levels were elevated in the mid- and high-dosage groups, while slight anemia was observed in the high-dosage group also. Spleen weights were significantly increased in the high-dosage groups. An accumulation of brown pigment was observed in the cytoplasm of the sinusoidal macrophages or littoral cells of the liver and in the reticuloendothelial cells of the spleen. No treatment-related increase in tumor incidence was observed. In the reproduction study, no consistent pattern of effect from treatment between the F0 and F1 generation was seen in mating, pregnancy, or fertility indices. Thus, administration of PNA at levels which produced significant methemoglobinemia and low-level anemia in the rat and histological changes in the spleen produced no tumors or reproducible effects on reproductive performance.

Aniline Compounds↗
PubMed1990

A scheme for classifying carcinogens.

We present a scheme for classifying chemical carcinogens according to the weight of the evidence that each substance poses a human cancer hazard. The approach represents a logical extension of and builds upon those previously developed by the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, and the so-called Tripartite Group of industrial scientists. It takes into account new scientific knowledge about chemical carcinogenesis and animal models. Eight categories are presented: known human carcinogen (Category 1), carcinogenic activity in animals, probable human carcinogen (Category 2), possible human carcinogen (Category 3), equivocal evidence for carcinogenic activity (Category 4), evidence inadequate for classification (Category 5), carcinogenic activity in animals; probably not a human cancer hazard (Category 6), carcinogenic activity in animals; considered not a human cancer hazard (Category 7), evidence of noncarcinogenicity (Category 8). Evidence useful for categorization includes human studies, animal bioassays, corroborative evidence from bioassays, and mechanistic studies relevant to determining the predictivity of animal responses for human hazard. Weighing this evidence to derive a conclusion about classification is a process that requires expert judgment; it cannot now be reduced to a simple set of decision rules. However, we identify the kinds of information that can be useful in this process, and indicate how each might most appropriately be used.

Animals↗
PubMed1990

Risk assessment of carcinogenic and noncarcinogenic chemicals.

"Risk Assessment" is a general term used with increasing frequency by both scientists and regulators. Scientifically based risk assessments consider available toxicologic data when judging which agents pose a significant risk to the human population. The science of toxicology focuses on identifying potential hazards to human health using surrogate animal studies. Margins of Safety and establishment of ADIs (Acceptable Daily Intakes) are methods applied to animal test data to set "safe" levels of potential exposure. While the use of Safety Factors in development of the ADI can support a pragmatic conclusion of safety, this approach cannot provide estimates of the probability of harm or the degree of safety. Therefore, Quantitative Risk Assessment (QRA) methods using mathematical models have been advanced to extrapolate from animal exposures which are usually high to much lower human exposure levels where experimental response is absent. Such methodology has been applied primarily by U.S. regulatory agencies to experimental oncogenic responses to estimate the risks of chemical exposure. The present manuscript considers both methods for evaluation of chemical safety and focuses on the scientific merits and limitations of each.

Animals↗
PubMed1989

Subchronic inhalation and oral toxicity of hydrogenated terphenyls in rats.

The subchronic toxicity of a commercial blend of partially hydrogenated terphenyl was evaluated in rats by inhalation and oral routes of exposure. Animals were exposed to target concentrations of 0, 10, 100, or 500 mg/m3 for 6 hr/day, 5 days/week or were offered diets daily with concentrations of 0, 50, 200, or 2000 ppm. Each study lasted approximately 14 weeks. The study designs included observations for clinical signs, body weights, ophthalmic exams, hematology and clinical chemistry, major organ weights, and gross and histopathology. No treatment-related effects were noted in the ophthalmic exams. Body weights were slightly depressed in high-dose males from the inhalation study and high-dose females in the dietary study. Liver and liver/body weights were increased in high-dose animals of both sexes and high- and mid-dose males in the dietary and inhalation studies, respectively. In the high-dose females of the dietary study, kidney and kidney/body weights were increased with increased adrenal and adrenal/body weights were also observed. No compound-related gross lesions nor pathological correlates to the organ weight changes were observed in either study. The no-adverse effect levels were considered to be 100 mg/m3 and 200 ppm (15.9 mg/kg) for the inhalation and dietary studies, respectively. These data indicate that a wide margin of safety exists for hydrogenated terphenyl workplace exposure.

Administration, Inhalation↗
PubMed1988

A 6-month multispecies inhalation study with maleic anhydride.

This study was initiated to assess the safety of atmospheres containing maleic anhydride. Accordingly, rats (15/sex/group), hamsters (15/sex/group), and monkeys (3/sex/group) were treated 6 hr a day 5 days a week for 6 months. Atmospheres were generated by subliming maleic anhydride and were monitored using Tenax collection columns and gas chromatography to detect total maleic; i.e., maleic anhydride plus maleic acid. The mean analytical concentrations were 0, 1.1, 3.3, and 9.8 mg/m3 of total maleic. Dose-related signs of nasal and ocular irritation were observed at each test level in all three species; signs included discharge, sneezing, gasping, and coughing. No significant treatment-related mortality was observed in any species. While reduced weight gains were observed only in mid- and high-dose rats, their terminal body weights were greater than 90% of control values. No treatment-related effects were observed in hematology, clinical chemistry, urinalysis, and pulmonary function tests. Although microscopic evaluation of tissue revealed evidence of nasal irritation in all species, there was no evidence of systemic toxicity which was directly attributed to maleic anhydride. While the results of this study support the current ACGIH TLV and OSHA PEL of 1 mg/m3 regarding systemic toxicity, continuous exposure at this level during the day may produce some signs of irritation.

Administration, Inhalation↗
PubMed1988

Evaluation of the subchronic and reproductive effects of a series of chlorinated propanes in the rat. I. Toxicity of 1,2,3-trichloropropane.

Repeated inhalation exposure and 1-generation reproduction studies have been conducted in the rat to address the adequacy of the 10 ppm occupational exposure limit established for 1,2,3-trichloropropane (TriCP). Groups of 5 rats per sex were exposed for 6 h/d, 5 d/wk up to 4 wk to target TriCP concentrations of 0-900 ppm. Nine of 10 rats died after a single exposure at 900 ppm. Additional deaths were seen in the 300 (1 death) and 600 (3 deaths) ppm test groups. Mean body weights for all TriCP-treated groups were lower than control values. Liver weights were increased in animals of both sexes at 600 ppm and lower. For females ovary weights for the 300 and 600 ppm groups and spleen weights for the 300 ppm group were lower than those of controls. Males exhibited decreased testes weights only at the 600 ppm TriCP level (not evaluated at 900 ppm). Results of a 13-wk exposure, 6 h/d, 5 d/wk of 15 rats/sex.group to TriCP target vapor concentrations of 5, 15, or 50 ppm also resulted in liver weight increases at all test levels. Histopathologic examination showed hepatocellular hypertrophy in male rats at all TriCP levels. Other microscopic findings related to treatment in rats exposed to 15 ppm and to 5 ppm TriCP included lung hyperplasia (both sexes) and splenic extramedullary hematopoiesis (females only) and parallel observed organ weight increases. No treatment-related deaths were observed in this study, nor were there apparent effects on the hematology or clinical chemistries. Group mean body weights at 50 ppm (both sexes) and 15 ppm (females only) TriCP were reduced when compared to controls. In a 13-wk follow-up study in rats at 0, 0.5, and 1.5 ppm TriCP, no gross or microscopic findings related to treatment were found. Groups of 10 male and 20 female rats were exposed 6 h/d, 5 d/wk to 0, 5, or 15 ppm TriCP vapor during premating and mating. Females also were exposed during gestation. Low mating performance was observed in all groups of female rats including the controls, although fewer females in the 15-ppm group mated than in other study groups. Mating and fertility indices of male rats in both treated and control groups were generally low. All measured progeny indices appeared unaffected by treatment. A follow-up study of the same design was conducted at levels of 0, 0.5, and 1.5 ppm TriCP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Evaluation of the subchronic and reproductive effects of a series of chlorinated propanes in the rat. II. Toxicity of 1,2,2,3-tetrachloropropane and 1,1,2,2,3-pentachloropropane.

Comparative subchronic and reproductive toxicity studies by inhalation exposure were conducted with 1,2,2,3-tetrachloropropane (TECP) and 1,1,2,2,3-pentachloropropane (PCP). Groups of 5 male and 5 female CD rats were exposed 6 h/d, 5 d/wk for 4 wk to either TECP or PCP at target concentrations of 0, 100, 300, 600, or 900 ppm (single exposure only). Deaths occurred at and above 300 ppm PCP and 600 ppm TECP. Significant irritation of mucosal tissue was attributed to vapors of TECP and PCP. Lower group mean body weights of surviving male rats of all groups were observed after 4 wk of exposure to TECP. Liver, kidney, and ovary weights were affected by PCP treatment. Groups of 15 male and 15 female CD rats were exposed to target vapors of 0-50 ppm TECP or PCP for 6 h/d, 5 d/wk for 13 wk. Irritation about the nose and eyes was observed at all TECP, but not with PCP, test levels. Liver weights were increased at and above 5 ppm in all groups of TECP-treated males. Kidney weights were also elevated in male rats at 15 and 50 ppm PCP and females from the 50 ppm PCP group. Degenerative changes in these two corresponding tissues were seen at and above 5 ppm TECP and PCP. A treatment level of 1.5 ppm TECP or PCP was without systemic effect clinically or pathologically. Groups of 10 male and 20 female CD rats were exposed 6 h/d, 5 d/wk for a premating, mating, or gestation (F only) period to target levels of 0, 5, or 15 ppm TECP or PCP. No treatment-related effects were seen in the PCP study. While mating performance overall was poor in the TECP study, female mating performance of the 15 ppm TECP-exposed group appeared lower than control. In a follow-up study with TECP using the same study design, no effects on female or male fertility or fecundity or on offspring were seen up to 1.5 ppm TECP.

Animals↗
PubMed1987

Oral toxicity of trichlorobenzyl chloride and its acid derivative.

The acute rat oral LD50 of 2,4,6-Trichlorobenzyl chloride (TCBC) was determined to be 3075 mg/kg. When male and female rats were administered 1500 and 3000 ppm TCBC in the diet for 3 weeks, marked retardation in weight gain was observed. Reductions in food consumption were noted in both groups of treated male, but not female, rats. All blood chemistry and urinalysis parameters including those indicative of liver injury, were within the range of normal limits. Gross necropsy revealed pale livers in all high-dose rats and the majority of low-dose animals. Gross observations correlated with observation of degenerative hepatic changes (irregularity of cell and nuclear size, cord pattern, edema and cytoplasmic alterations) following microscopic evaluation. Rats and dogs administered up to 100 ppm trichlorobenzoic acid (TCBA) in the diet for 90 days exhibited no effects considered related to treatment.

Animals↗
PubMed1987

Acute and subchronic toxicity of tetramethylcyclohexanes.

The acute oral toxicity in rats was estimated for seven isomers or isomeric ratios of tetramethylcyclohexane (TMCH). Lack of sufficient mortality at the highest dosage test (15.8 g/kg) precluded evaluation of an LD50 for mixed cis, trans-isomers of 1,2,3,4-TMCH, 1,2,3,5-TMCH, 1,2,4,5-TMCH and 1,1,2,3-TMCH, for the separate cis- or trans-forms of 1,1,3,5-TMCH or a 1:1 mixture of c,t-1,1,3,5-TMCH and c,t-1,2,3,4-TMCH. Mixed (c,t-combined) isometric TMCH was administered orally to rats (30/group) and dogs (8/group) for 90 days at dietary levels of 0, 3000, 10,000 and 30,000 ppm TMCH and 0, 100, 300 and 1000 ppm TMCH, respectively. Administration of up to 30,000 TMCH to rats produced no discernible effects on survival, behavior, growth, food consumption, clinical blood picture or urine analysis. Absolute kidney weights of male but not female rats were elevated at all test levels. TMCH-related microscopic lesions were confined to the kidney of male rats in all treated groups. These histopathologic changes were characteristic of tubular nephrosis. No treatment-related effects were observed in groups of dogs fed up to 1000 ppm TMCH for 90 days.

Animals↗
PubMed1987

Toxicological profile of orally administered 1,6-hexane diamine in the rat.

The industrial chemical 1,6-Hexane Diamine, or hexamethylenediamine (HMD), has an acute oral LD50 of 980 mg kg-1 in rats. Dietary administration of HMD to groups of rats for 3 months at dosages of 0, 50, 150, and 500 mg kg-1 resulted in a modest retardation in weight gain at the two higher test levels. No other obvious signs of toxicity or changes in the peripheral blood picture or selected clinical pathology parameters were found at any test level throughout the study. Evaluation of absolute and relative weights of 10 selected organs, as well as complete necropsies and microscopic evaluation of over 30 selected tissues and organs, revealed no changes considered related to treatment. The administration of HMD by gavage to pregnant rats at 0, 112, 184 and 300 mg kg-1 day-1 on days 6-15 of pregnancy (day 1 = day sperm detected) did not induce any teratogenic effects. Signs of maternal toxicity were observed only at 300 mg kg-1 day-1. Embryotoxicity was observed at both the 300 and 184 mg HMD kg-1 day-1 dosage levels. No treatment-related effects were observed at 112 mg HMD kg-1 day-1.

Abnormalities, Drug-Induced↗
PubMed1987

Subchronic inhalation toxicity of hexamethylenediamine in rats.

Four groups of 15 male and 15 female Sprague-Dawley-derived (CD) rats each were exposed to aqueous hexamethylenediamine (HMD) aerosols for 6 hr/day, 5 days/week for 13 weeks at mean analytical concentrations of 0, 12.8, or 51 mg/m3. Because of exposure-related deaths in a group of male and female rats similarly exposed to 215 mg/m3 HMD, this group was terminated during the seventh week of the study. Signs of respiratory and conjunctival irritation were observed in rats at both the 51 and 215 mg/m3 HMD test levels. Body weight gain was significantly reduced in both sexes exposed to 215 mg/m3 HMD. At the 5-week study interval, slight hemopoietic stimulation of peripheral blood parameters was observed in rats of both sexes exposed to 215 mg/m3 HMD. Treatment-related microscopic lesions were seen only in rats exposed to 215 mg/m3 MD and were confined to the trachea, nasal passages, and lungs. The no-effect level in this study is considered to be 12.8 mg/m3 HMD.

Administration, Inhalation↗