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Biomedical subjects

M R Elwell

Publications and source records attributed to M R Elwell.

At least 55 records · Page 3Linked to original sources
PubMed1990

Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 1. Hydrochlorothiazide.

Toxicology and carcinogenesis studies of hydrochlorothiazide, a benzothiadiazide diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 15-day, 13-week and 2-year studies. No rats died during the 15-day or 13-week studies at dietary concentrations of up to 50,000 ppm. Deaths of male mice in the top dose group in the 13-week study were likely to be related to chemical administration. In the prechronic studies, increased nephrosis and mineralization at the kidney corticomedullary junction were the primary toxic effects of hydrochlorothiazide observed in rats. In mice, chemical-related effects included nephrosis and calculi, inflammation and epithelial hyperplasia in the urinary bladder. In 2-year studies using dietary concentrations of 0, 250, 500 and 2000 ppm in rats and 0, 2500 and 5000 ppm in mice, survival of dosed and control groups of rats and mice was similar, as were body weights of mice. Dosed groups of male and female rats were uniformly lighter than controls (up to 25%) throughout the studies. Severe chronic renal disease with secondary parathyroid hyperplasia and fibrous osteodystrophy of the bone were attributed to chemical administration in rats. No neoplasms in rats or female mice or non-neoplastic lesions in mice were associated with hydrochlorothiazide. In high-dose male mice, liver neoplasms were increased but were not considered to be related to hydrochlorothiazide administration because of an unusually low incidence in the control group relative to historical controls.

Adenofibroma↗
PubMed1990

Relative toxicity and tumor-promoting ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) in hairless mice.

2,3,7,8-Tetrachlorodibenzo-p-dixoin 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are highly toxic members of a class of environmental contaminants, the polychlorinated aromatic hydrocarbons (PCAH), which exhibit a similar and highly characteristic spectrum of toxic effects. For purposes of risk assessment, it is important to be able to make accurate estimates of the relative potency of these and related compounds. Previous investigations have indicated that, in acute exposure or in vitro studies, PCDF is approximately 0.1 times as toxic and HCDF is approximately 0.01 times as toxic as TCDD. In this study, we compared the relative toxicity and tumor-promoting abilities of TCDD, PCDF, and HCDF in hairless mouse skin. Female hairless mice (HRS/J hr/hr) were treated dermally with the initiator MNNG, then dosed twice weekly for 20 weeks with acetone, TCDD (2.5-10 ng/mouse/dose), PCDF (25-100 ng/mouse/dose), or HCDF (250-1000 ng/mouse/dose) as promoter. TCDD, PCDF, and HCDF were all potent promoters for the induction of squamous cell papillomas. There was, however, no difference in the incidence or multiplicity of papilloma formation between groups. The same doses of the three PCAH, in the absence of initiator, induced no skin papillomas. TCDD produced a significant increase in liver:body weight ratio (p less than 0.001) at all doses and a decrease in thymus:body weight ratio at a dose of 10 ng (p less than 0.001). Mice treated with PCDF and HCDF had marked thymic and splenic involution, liver hypertrophy, mucous cell hyperplasia in the fundic portion of the glandular stomach, and loss of body weight. PCDF and HCDF produced a greater incidence and severity of dermatotoxic effects than TCDD. Based on data for dermal toxicity and changes in body weight and organ weights, PCDF is estimated to be 0.2 to 0.4 times, and HCDF 0.08 to 0.16 times, as toxic as TCDD following repeated dermal exposure. Therefore, toxic equivalence factors generated using data from acute and/or in vitro studies may underestimate the risk from repeated low-dose exposures to these compounds.

Animals↗
PubMed1990

Inhalation toxicity studies of cobalt sulfate in F344/N rats and B6C3F1 mice.

Groups of 10 F344/N rats and B6C3F1 mice of each sex were exposed to cobalt sulfate heptahydrate aerosols of 0, 0.3, 1.0, 3.0, 10, or 30 mg/m3, 6 hr per day, 5 days per week, for 13 weeks. All rats and female mice and all but 2/10 male mice exposed at the top concentration survived to the end of the studies. Polycythemia was observed in exposed rats but not in mice. Sperm motility was decreased in mice exposed at 3 mg/m3 (the lowest concentration evaluated) and at higher concentrations, and increased numbers of abnormal sperm and decreased testis and epididymal weights occurred in mice exposed to 30 mg/m3. Cobalt content in the urine of rats increased with increasing atmospheric cobalt exposure. Primary histopathologic effects were limited to the respiratory tract. Lesions in rats and mice included degeneration of the olfactory epithelium, squamous metaplasia of the respiratory epithelium, and inflammation in the nose; inflammation, necrosis, squamous metaplasia, ulcers (rats), and inflammatory polyps (rats) of the larynx; metaplasia of the trachea (mice); and fibrosis, histiocytic infiltrates, bronchiolar epithelial regeneration, and epithelial hyperplasia in the alveoli of the lung. The most sensitive tissue was the larynx, with squamous metaplasia observed in rats and mice at the lowest exposure concentration of 0.3 mg/m3. Thus, a no-observed-adverse-effect level was not reached in these studies.

Administration, Inhalation↗
PubMed1990

Subchronic toxicity of tetrahydrofuran vapors in rats and mice.

Tetrahydrofuran (THF), a four-carbon, cyclic ether, is widely used as an industrial solvent. Groups of 10 rats and mice of each sex were administered THF vapor by whole body inhalation for 13 weeks at exposure concentrations of 0, 66, 200, 600, 1800, and 5000 ppm. The body weights and survival were not affected by THF exposure, except in male mice at 5000 ppm concentration which had reduced weight and three deaths. Clinical signs of central nervous system (CNS) toxicity were observed in both rats and mice at high dose levels. Rats of both sexes exposed to 5000 ppm were ataxic and mice exposed to 1800 or 5000 ppm appeared to be in a state of narcosis. There were no exposure-related gross necropsy findings in rats or mice. At 5000 ppm, decreases in thymic and spleen weights in rats and mice of both sexes and increases in liver weights in both sexes of mice and in female rats were observed. A minimal to mild centrilobular hepatocytomegaly occurred in male and female mice exposed to 5000 ppm THF. Atrophy of the uterus and degeneration of the X zone in the adrenal cortex occurred in female mice exposed to 5000 ppm THF. THF exposure of rats was associated with minimal to mild acanthosis and inflammation in the forestomach. In conclusion, these studies suggest that THF, like other commonly used organic solvents, causes narcosis in rats and mice. Although minimal exposure-related effects were seen in the liver of both species, morphologic changes were present only in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

Toxicity of 4-vinyl-1-cyclohexene diepoxide after 13 weeks of dermal or oral exposure in rats and mice.

4-Vinyl-1-cyclohexene diepoxide (VCHD) is used as a chemical intermediate and as a reactive diluent for diepoxides and epoxy resins. Toxicology studies were conducted by administering VCHD in acetone by dermal application or in corn oil by gavage to F344/N rats and B6C3F1 mice for 13 weeks. In the 13-week dermal studies, groups of 10 rats of each sex received 0.3 ml of VCHD in acetone at concentrations ranging from 6.25 to 200 mg/ml, and mice received 0.1 ml at concentrations ranging from 6.25 to 100 mg/ml. Skin lesions were observed at the site of application at the top two dose levels for both species and sexes, and consisted of acanthosis, parakeratosis, and hyperkeratosis of the epidermis and sebaceous gland hyperplasia. In mice, follicular atrophy of the ovary, characterized by decreased numbers of primary and secondary follicles, occurred at the 50- and 100-mg dose levels. In 13-week oral studies, groups of 10 rats and mice of each sex were administered VCHD at dose levels ranging from 62.5 to 1000 mg/kg in corn oil. In rats and mice, there were body weight decreases in the groups given the two highest doses. The major target organs in rats were forestomach (hyperplasia and hyperkeratosis) and kidney (tubular cell degeneration/necrosis and regeneration). In mice the target organs included forestomach (hyperplasia and hyperkeratosis), ovary (follicular atrophy), and testis (degeneration of germinal epithelium).

Administration, Oral↗
PubMed1990

Comparative toxicity of ethylene dichloride in F344/N, Sprague-Dawley and Osborne-Mendel rats.

Studies were conducted to compare the toxicity of ethylene dichloride (EDC) in F344/N rats, Sprague-Dawley rats, and Osborne-Mendel rats. Ten rats/sex/group were exposed to EDC in drinking-water at 0, 500, 1000, 2000, 4000 and 8000 ppm for 13 wk. The highest concentration was limited by the maximum solubility of EDC in water (about 9000 ppm). In addition, F344/N rats (10/sex/group) were administered EDC in corn oil by gavage to compare toxicity resulting from bolus administration with that of continuous exposure in drinking-water. Gavage doses of EDC were within the range of total daily doses (in mg/kg body weight/day) resulting from exposure in drinking-water. EDC administered by gavage resulted in greater toxicity to F344/N rats than did administration of similar doses in drinking-water. All males receiving 240 and 480 mg/kg body weight and 9/10 females receiving 300 mg/kg body weight by gavage died before the end of the study. Necrosis of the cerebellum was observed in the brains of 3 males receiving 240 mg/kg body weight and 3 females receiving 300 mg/kg body weight. Hyperplasia and inflammation of the forestomach mucosa were observed in 8 male and 3 female rats that died or were killed in moribund condition. EDC caused minimal toxicity to F344/N, Sprague-Dawley and Osborne-Mendel rats at the drinking-water concentrations used in these studies; only female F344/N rats had EDC-related renal lesions. Based on mortality and EDC-related lesions, the no-effect levels for EDC administered by gavage to F344/N rats were 120 mg/kg body weight for males and 150 mg/kg body weight for females.

Administration, Oral↗
PubMed1990

Toxicity of p-chloroaniline in rats and mice.

p-Chloroaniline (PCA) was administered as PCA hydrochloride in water by gavage to groups of ten Fischer 344 rats and ten B6C3F1 mice of each sex for 13 wk. The doses, calculated as PCA rather than the hydrochloride salt, were 0, 5, 10, 20, 40 or 80 mg PCA/kg body weight/day for rats and 0, 7.5, 15, 30, 60 or 120 mg/kg body weight/day for mice. The vehicle controls were given deionized water by gavage. All male rats survived to the end of the studies. One of the ten female rats that received 80 mg PCA/kg died from unknown causes. The final body weights of rats that received 80 mg/kg were 16% lower than those of vehicle controls in the case of males and 4% lower in females. In mice, there was no mortality related to PCA administration. The final body weights of treated mice were similar to those of vehicle controls. In both rats and mice, no treatment-related effects on organ weights were observed at autopsy, except for a dose-related increase in spleen weight. The proportion of haemoglobin in the form of methaemoglobin was increased in dosed groups in both species and resulted in a secondary anaemia, the severity of which was dose related. Compound-related lesions observed histologically in rats and mice, included pigmentation (haemosiderin) in the kidney, spleen and liver and increased haematopoiesis in the liver and spleen and in the bone marrow (in rats but not mice), reflecting the response to the haemolytic anaemia and methaemoglobinaemia induced by PCA. It is concluded that the haematopoietic system is a target of PCA toxicity.

Aniline Compounds↗
PubMed1989

Toxicity studies of amphetamine sulfate, ampicillin trihydrate, codeine, 8-methoxypsoralen, alpha-methyldopa, penicillin VK and propantheline bromide in rats and mice.

Thirteen-week toxicity studies in F344/N rats and B6C3F1 mice were conducted to determine general toxicity and target organ toxicity with amphetamine sulfate, ampicillin trihydrate, codeine, 8-methoxypsoralen, alpha-methyldopa sesquihydrate, penicillin VK, and propantheline bromide. This paper discusses the toxicity observed; use of the toxicity data to set dose levels for subsequent 2-year studies; and comparison of dose levels administered to rodents with doses used in the treatment of human disease. Drugs were administered orally in the feed or by gavage. The lowest doses in the 13-week studies were comparable to therapeutic doses in man on a mg/m2 (body surface area) basis or 5-10 times doses used in man on a mg/kg body weight basis. Little toxicity was seen at the low dose level with ampicillin, penicillin VK, 8-methoxypsoralen or propantheline bromide. At higher doses, target organ toxicity seen included the urinary bladder in male rats after propantheline bromide; the glandular stomach in rats and mice after penicillin VK; the liver and adrenals in rats after 8-methoxypsoralen; and the kidney in mice and rats after alpha-methyldopa. After amphetamine, codeine, or ampicillin administration, no target organ toxicity was seen in rats or mice, even at doses which caused body weight gain depression. The high doses chosen for subsequent 2-year studies were within 10 times human dose levels when compared on a mg/m2 body surface area.

Ampicillin↗
PubMed1989

Kidney and urinary bladder lesions in F344/N rats and B6C3F1 mice after 13 weeks of 2,2-bis(bromomethyl)-1,3-propanediol administration.

Thirteen-week toxicity studies of the flame retardant 2,2-bis(bromomethyl)-1,3-propanediol (BMP; dibromoneopentyl glycol; FR-1138; CAS No. 329690-0) were conducted in male and female F344/N rats and B6C3F1 mice. The chemical was administered by oral gavage in corn oil 5 days per week for 13 weeks to rats at doses of 0, 50, 100, 200, 400, and 800 mg/kg and to mice at doses of 0, 25, 50, 100, 200, and 400 mg/kg, or in the feed for 13 weeks at concentrations of 0, 1250, 2500, 5000, 10,000, and 20,000 ppm for rats and at 0, 625, 1250, 2500, 5000, and 10,000 ppm for mice. There was a dose-related decrease in body weight gain in rats and mice after chemical administration. Mortality attributed to toxicity of BMP was seen in the gavage study in 2/10 high-dose (800 mg/kg) male rats and 3/10 high-dose (400 mg/kg) male mice no dose-related mortality occurred in the feed study. Minimal degeneration in the renal papilla was seen in male rats at 800 mg/kg in the gavage study and at doses of 5000 ppm or more in the feed study. This was also present in one female rat at the 20,000 ppm dose. In male mice renal papillary necrosis occurred at 400 mg/kg after dosing by the gavage route and at 2500, 5000, and 10,000 ppm in the dosed-feed study. In female mice papillary necrosis occurred only at the 10,000 ppm dose in the feed study. Tubular cell regeneration of the renal cortex was also present in mice at the same dose levels at which the papillary necrosis was observed. Transitional cell hypeplasia of the urinary bladder was seen in male rats at 400 and 800 mg/kg and in both sexes of mice at 200 and 400 mg/kg. Hyperplasia of the urinary bladder was also seen when BMP was administered in the feed at doses of 20,000 ppm to male rats; at doses of 2500, 5000, and 10,000 ppm to male mice; and at doses of 5000 and 10,000 ppm to female mice. The kidney and urinary bladder are target organs when BMP is administered by gavage or the dosed-feed route; mice were more sensitive than rats for the development of kidney and bladder lesions. Male rats and mice were more sensitive than females for the development of renal papillary degeneration or necrosis.

Animals↗
PubMed1989

Lung toxicity after 13-week inhalation exposure to nickel oxide, nickel subsulfide, or nickel sulfate hexahydrate in F344/N rats and B6C3F1 mice.

The relative toxicity of nickel oxide (NiO), nickel sulfate hexahydrate (NiSO4.6H2O), and nickel subsulfide (Ni3S2) was studied in F344/N rats and B6C3F1 mice after inhalation exposure for 6 hr/day, 5 days/week, for 13 weeks. Exposure concentrations used (as mg Ni/m3) were 0.4-7.9 for NiO, 0.02-0.4 for NiSO4.6H2O, and 0.11-1.8 for Ni3S2. No exposure-related effects on mortality and only minor effects on body weight gain were seen in rats or mice. The most sensitive parameter for nickel toxicity was histopathologic change in the lungs of exposed animals were chronic active inflammation, fibrosis, and alveolar macrophage hyperplasia were associated with nickel exposure. There was an exposure-related increase in lung weight in rats and mice. Equilibrium levels of nickel in the lung were reached by 13 weeks of nickel sulfate and nickel subsulfide exposure, whereas lung levels of nickel continued to increase throughout exposure to nickel oxide. Additional exposure-related histopathologic lesions in treated animals included atrophy of the olfactory epithelium after nickel sulfate and nickel subsulfide exposure. No nasal lesions were seen after nickel oxide exposure. Lymphoid hyperplasia of the bronchial lymph nodes developed in animals exposed to all three nickel compounds. The order of toxicity corresponded to the water solubility of the nickel compounds, with nickel sulfate being most toxic, followed by nickel subsulfide and nickel oxide.

Administration, Inhalation↗
PubMed1989

Toxic responses in F344 rats and B6C3F1 mice given roxarsone in their diets for up to 13 weeks.

Thirteen-week toxicity studies were conducted in groups of 10 F344 rats and B6C3F1 mice of each sex fed roxarsone at 0, 50, 100, 200, 400, or 800 ppm in the diet. Arsenic levels in blood, urine, kidneys, and liver of rats were measured in additional animals of each sex dosed with 100 or 400 ppm roxarsone. Compound-related mortality occurred in both sexes of rats at 800 ppm and mice at 800 and 400 ppm. Significant body weight gain depression occurred in both sexes of rats at 200, 400, and 800 ppm and mice at 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats and mice at 800 ppm. Lesions associated with roxarsone administration were noted only in the kidney of rats and were characterized by tubular necrosis and mineralization at the corticomedullary junction. Arsenic levels in urine, blood, liver, and kidneys increased over time and were directly proportional to the level of roxarsone in feed. These levels were greater than 6 times higher in rats than in mice and were about 2 time higher in males than in females. The no-observable-effect level for roxarsone toxicity was estimated at 100 ppm for rats and 200 ppm for mice. No hematology or clinical chemistry effects were found in rats or mice of either sex.

Animals↗
PubMed1989

Epididymal interstitial (Leydig) cell tumors in B6C3F1 mice.

Six primary interstitial cell tumors of the epididymis were identified from 46,752 male B6C3F1 mice used in chronic toxicity and carcinogenicity studies. Five of the tumors occurred at the end of 2-year studies; none were attributed to treatment. None of the mice with epididymal tumors had a primary testicular tumor. Histologically, tumors were characterized by a nodular or diffuse proliferation of tumor cells in the epididymal interstitium. Most cells were polygonal with highly vacuolated cytoplasm (vacuolated cells) or eosinophilic cytoplasm (eosinophilic cells). Smaller hyperchromatic cells with scant basophilic cytoplasm (basophilic cells) and cells with yellow-brown pigment characteristic of lipofuscin (pigmented cells) were less common. In each tumor two or more cell types were present. Extension of these tumors through the capsule, invasion of the testis, or metastasis did not occur. By electron microscopy both eosinophilic and vacuolated cell types had a large round or oval nucleus with sparse heterochromatin, abundant mitochondria with tubulovesicular cristae, and frequent desmosome structures between cell membranes. Vacuolated cells contained numerous lipid droplets. Morphological features of the epididymal tumors are similar to those of the testicular interstitial (Leydig) cell tumor in mice and rats.

Animals↗
PubMed1988

Dioxin-like effects observed in male rats following exposure to octachlorodibenzo-p-dioxin (OCDD) during a 13-week study.

Octachlorodibenzo-p-dioxin (OCDD) is a ubiquitous environmental pollutant which has been reported to be nontoxic following acute exposure but has recently been shown to accumulate upon repeated exposure. To determine if this accumulation results in toxic effects, male Fischer 344 rats were treated with 50 micrograms/kg [14C]OCDD by gavage for 10, 20, 40, or 65 times (once a day, 5 days/week) and terminated 3 days postexposure. OCDD accumulated linearly with increasing number of doses and the liver was the major depot, while the adipose served as a secondary sink. Hepatic accumulation resulted in alteration of several biochemical parameters. In animals given 65 doses of OCDD, 7-ethoxyresorufin-O-deethylase activity was elevated 40-fold over controls. Total cytochrome P-450 content doubled and exhibited a 2-nm blue-shift in the Soret maximum for the CO-reduced complex. Treatment-related cytoplasmic fatty vacuolization in the liver was observed concomitant with the biochemical alterations. Thus, subchronic exposure to OCDD appears to cause effects similar to those observed following exposure to low levels of TCDD, but is only 1/100-1/1000 as potent. Such a potency, given the persistent environmental levels to which man may be exposed during a lifetime, suggests that OCDD may pose a potential risk to human health.

Animals↗
PubMed1988

Toxicity and disposition of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF) in the rhesus monkey (Macaca mulatta).

The toxicity and disposition of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), a ubiquitous and acutely toxic environmental contaminant, was examined in three adult male Rhesus monkeys administered a single iv dose of 34 micrograms (0.1 mumol)/kg. Within 20 min, 4PeCDF was eliminated from the blood and was distributed to the liver, skin, adipose, and muscle tissues. Excretion occurred primarily via the feces with a minimum whole body half-life approximately 38 days. Within 7-14 days after administration, the packed cell volume and serum triglyceride and bile acid concentrations were significantly increased while serum cholesterol, protein, and albumin concentrations were decreased relative to pretreatment levels. Thyroid hormone levels were also altered with an increase in TSH and a decrease in T3 and T4 concentrations. After 28 days, two monkeys began exhibiting alopecia, hyperkeratinization of the toe and finger nails, facial chloracne-like lesions, and loss of body weight. They subsequently died 40 and 48 days after treatment. Similar symptoms of toxicity were observed in the third animal 58 days after 4PeCDF administration, but this animal appeared to fully recover and was administered 4PeCDF orally and [3H]1,2,3,7,8-pentachloro-dibenzofuran (1PeCDF) dermally 238 days after the initial iv dose. In this animal, approximately 2% of an oral dose of [14C]-4PeCDF was absorbed from the stomach and small intestine in 6 hr and was distributed mainly to the muscle and skin and less than 99% of a dermal dose of 1PeCDF remained at the site of application. Pathological findings in the monkeys that died indicated hyperplastic and metaplastic changes in the gastric mucosa, the Meibomian glands of the eyelid, and the ceruminous glands of the ear. Regression of these lesions was present in the surviving animal. Therefore, 4PeCDF produces dioxin-like toxicity in the monkey similar to that reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in the same dose range.

Absorption↗
PubMed1988

Subchronic toxicity of orally administered (gavage and dosed-feed) theophylline in Fischer 344 rats and B6C3F1 mice.

Theophylline, a methylated xanthine closely resembling caffeine and theobromine, is a widely used pharmaceutical agent for the treatment of respiratory disorders and certain acute cardiovascular conditions. The National Toxicology Program has conducted 13-week subchronic toxicity studies in F344 rats and B6C3F1 mice (10 animals/group) following administration of theophylline via the diet or by gavage. Administration of theophylline in the feed (0, 1000, 2000, and 4000 ppm) resulted in no mortality or body weight effects in F344 rats, but did induce periarteritis of the arteries adjacent to mesenteric lymph nodes and the pancreas, particularly arterioles in the latter. Also observed in rats dosed with theophylline via the diet was an increased severity of chronic nephropathy in males, especially at the high dose. Administration of theophylline at the same concentrations in the feed to B6C3F1 mice resulted in no mortality, but terminal body weights were significantly decreased in all dosed groups. An increased incidence of hepatocellular glycogen depletion was observed in male and female mice, and this change is believed to represent a physiological alteration exacerbated by the administration of theophylline. Administration of theophylline by gavage to F344 rats (0, 37.5, 75, and 150 mg/kg) resulted in the early death of one high-dose male and female and significantly decreased or increased terminal body weights of high-dose males and females, respectively. Similar to the results of the dosed-feed study, male and female rats receiving theophylline by gavage demonstrated a dose-related increase in the incidence and severity of perivascular inflammation of mesenteric arteries. Gavage administration of theophylline to B6C3F1 mice (0, 75, 150, and 300 mg/kg) resulted in the early death of all high-dose females and 3/10 high-dose males and significant depression of terminal body weights in high- and mid-dose males and low-dose females. As in the dosed-feed study, the primary histopathologic change in the mouse subchronic gavage study was hepatocellular glycogen depletion, although in this case it was seen only in females. In summary, the major target organs for orally administered theophylline in 13-week subchronic toxicity studies appear to be the mesenteric arteries in F344 rats and the liver in B6C3F1 mice. On the basis of organ weight changes and/or minor histopathologic effects, many other tissues were also affected, particularly the kidneys in dosed-feed male rats and the uterus in gavage-dosed female rats.

Administration, Oral↗
PubMed1988

Chordomas in Fischer 344 rats.

Tissue sections and records of 56 rats with chordoma, identified in the National Toxicology Program's (NTP) data base of approximately 115,000 rats, were examined to determine morphological characteristics, incidence, and aspects of biological behavior. Chordomas occurred in aged rats, originated predominantly in lumbosacral vertebrae, were highly malignant, occurred three times more often in male versus female rats, and commonly produced bilateral posterior paresis, paralysis, and/or distention of the colon and rectum.

Animals↗