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Biomedical subjects

E J Gralla

Publications and source records attributed to E J Gralla.

At least 19 recordsLinked to original sources
PubMed1984

A 13-week vapor inhalation study of n-hexane in rats with emphasis on neurotoxic effects.

Male and female Fischer 344 rats were exposed to 0-, 3000-, 6500-, or 10,000-ppm n-hexane vapors 6 hr per day, 5 days per week, for 13 weeks. The 13-week exposures had no adverse effect on the growth of female rats. However, the mean body weight gain of male rats in the 10,000-ppm group was significantly lower than for controls at 4 weeks of exposure and thereafter. In addition to the depression of body weight gain, the male exposed to 10,000 ppm had slightly but significantly lower brain weights at necropsy. No adverse testicular effects were noted. Axonopathy was observed in the tibial nerve in four of five male rats from the 10,000-ppm group and one of five male rats in the 6500-ppm group and in the medulla from one male rat in the 10,000-ppm group. These axonal changes were detectable only in teased nerve fiber preparations or in Epon embedded specimens. Histopathologic studies on Formalin fixed tissues did not reveal any lesions that were attributed to n-hexane exposure.

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PubMed1983

Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure.

Groups of approximately 120 male and 120 female Fischer 344 rats and C57BL/6 X C3H F1 mice were exposed by inhalation to 0, 2.0, 5.6, and 14.3 ppm of formaldehyde gas 6 hr/day, 5 days/week, for 24 months. This exposure period was followed by up to 6 months of nonexposure. Interim sacrifices were conducted at 6, 12, 18, 24, 27, and 30 months. Significant formaldehyde-induced lesions were restricted to the nasal cavity and proximal trachea. The distribution and severity of these lesions were concentration dependent. Rhinitis, epithelial dysplasia, and squamous metaplasia occurred in all exposure groups of rats and in the intermediate and high exposure groups of mice. There was regression of rhinitis, dysplasia, and metaplasia at 27 months (3 months postexposure) in the 14.3- and 5.6-ppm groups of mice and in the 2.0- and 5.6-ppm groups of rats. Squamous cell carcinomas were observed in the nasal cavities of 103 rats (52 females and 51 males) and 2 male mice exposed to 14.3 ppm and in 2 rats (one male and one female) exposed to 5.6 ppm of formaldehyde gas. Formaldehyde inhalation was also weakly associated with an increase in the frequency of polypoid adenomas in the nasal cavity of male rats.

Animals↗
PubMed1982

Iron retention and excretion in mice transfused with homologous or heterologous blood and treated with chelators.

The studies in this report characterized an animal model for detecting chemicals that are capable of depleting elevated tissue iron. Male mice were transfused with heated, washed erythrocytes and the iron uptake by liver and spleen plus urinary iron excretion were measured. After the time and transfusion iron accumulations and excretion patterns were established, the influence of the following experimental variables was examined and compared: homologous vs heterologous blood transfusion, dose related responses, the efficacy of a chelator against iron buildup from long-term transfusion, and organ iron responses to an agent with combined chelation and hemolytic potentials. Both the liver and the spleen accumulated iron from transfused blood; however, the spleen appeared to have a limited capacity compared to the liver. Drugs having lower potencies or given at lower dose levels enhanced urinary iron excretion. Higher potencies or higher dose levels induced the same response and depleted liver iron. At still higher doses or with more potent drugs, the two responses mentioned occurred accompanied by spleen iron reduction. An increased urine iron alone was equivocal since drug-induced hemolytic anemia caused a ferricosuria accompanied by elevated liver and spleen iron. Heterologous or homologous transfusions produced similar organ iron elevations and urine iron excretion in untreated mice. A higher level of drug potency was required to deplete tissue iron whenever the drug treatment was administered following transfusion.

Animals↗
PubMed1980

Induction of squamous cell carcinomas of the rat nasal cavity by inhalation exposure to formaldehyde vapor.

Groups of 120 male and 120 female rats were exposed by inhalation to 0, 2, 6, or 15 ppm formaldehyde vapor 6 hr/day, 5 days/week, for 18 months of a 24-month study. The present communication describes interim findings based on data available after 18 months of exposure. Squamous cell carcinomas occurred in the nasal cavities of 36 rats exposed to 15 ppm formaldehyde. The tumors ranged from small early carcinomas of the nasal turbinate to large invasive osteolytic neoplasms which extended into the subcutis of the premaxilla. Similar tumors were not detected in rats exposed for 18 months to 2 or 6 ppm or in mice exposed to 2, 6, or 15 ppm formaldehyde. Rhinitis, epithelial dysplasia, and squamous metaplasia occurred in rats from all exposure levels of formaldehyde; however, the severity and extent of the lesions were dose related. In contrast, papillary hyperplasia and squamous atypia occurred only in animals exposed to 15 ppm formaldehyde.

Animals↗
PubMed1979

Toxicology studies in mice, beagle dogs and rhesus monkeys given chlorozotocin (NSC 178, 248).

Chlorozotocin was studied for toxic effects in beagle dogs and rhesus monkeys. The results are the subject of this report. The compound was administered i.v. as single and 5 daily doses in dogs and monkeys; and, in dogs, as 10 consecutive daily doses, once weekly for 6 weeks and for 5 daily doses followed by 9 days rest repeated 3 times. The most prominent toxicities in both species were dose-related renal tubular lesions. These appeared as a necrosis at the most toxic levels and a nephrosis at lower doses. The latter change was also seen in animals surviving higher doses but only after a 6-week posttreatment period. Bone marrow hypoplasia and lymphoid atrophy were other common findings at the highest doses in both species. The same general pattern of toxicity appeared in extended treatment studies in dogs, but also included aspermatogenesis. Signs of hepatotoxicity were seen in dogs at the highest dose levels, while monkeys receiving lethal doses also evidenced a toxic gastroenteritis. A single monkey had a diabetic response following 1 treatment with a high non-lethal dose. Renal lesions found in mice following acute, single dose administration were similar to those described for the larger laboratory animals.

Animals↗
PubMed1979

The dosing schedule dependent toxicities of adriamycin in beagle dogs and rhesus monkeys.

The toxic effects of Adriamycin were studied following i.v. administration of from 10.0 mg/kg to 0.039 mg/kg (200--0.780 mg/m2) to beagle dogs, and from 5.83 mg/kg to 0.625 mg/kg (49.9--7.5 mg/m2) in rhesus monkeys by a variety of short and long term treatment schedules. 5 daily doses and 1 dose every 3 weeks were given for both species and, only in dogs, as single injections, 10 daily treatments and 5 daily doses followed by 9 days rest, repeated 3 times. In both species, short term administration of toxic doses caused weight losses, anorexia, diarrhea, atypical oesophageal and intestinal mucosa, bone marrow hypoplasia, lymphoid atrophy and alopecia. Specific adverse responses seen only in monkeys were hypocalcemia, hypomagnesemia, atypical buccal mucosa and reddish urinary pigmentation. Testicular degeneration and prostatic atrophy were produced in dogs. The triweekly treatment schedule caused an additional toxicity at lower doses. In both species a cardiotoxicity syndrome developed with pulmonary oedema and centrolobular hepatic necrosis, plus focal necrosis and vacuolization in cardiac myocytes. Clinical signs of cardiac dysfunction were EKG arrhythmias in dogs, and peripheral oedema, ascites and hydrothorax in monkeys.

Animals↗
PubMed1977

Animal model of spontaneous neoplasia based on lymph and cells collected from thoracic duct of normal dogs and dogs with malignant lymphoma.

Peripheral blood and thoracic duct lymph from normal dogs and dogs with a leukemic malignant lymphoma were compared for total and differential leukocyte count and lymph flow rate. Except for higher numbers of circulating atypical lymphocytes, the blood leukocyte count as well as the lymph cell count and flow rate were similar in both groups. Lymph cell differential pattersn in lymphoma dogs had higher numbers of lymphoblasts and minor cell types, plasmacytes, monocytes, and reticulum cells, plus degenerating and mitotic cells. There was a five-fold increase in the lymph leukocyte count shortly after irradiation in two lymphomatous dosg. Stained preparations of this lymph showed signs of 100% cell mortality. It was concluded that the thoracic duct lymph is a practical source of normal and cancerous lymphoid cells, and that the lymph and cells collected from dogs with malignant lymphoma are excellent models for certain studies of spontaneous neoplasia.

Animals↗
PubMed1976

Teaching toxicology as a basic medical science.

In this report the author describes a four-year effort at the Yale University School of Medicine to teach toxicology as an elective basic medical science from the standpoint of organ-specific toxic effects. The primary objective is to prepare physicians to understand, recognize, and manage adverse effects from drugs and other environmental chemicals. It is a multidisciplinary program which integrates easily into the medical school curriculum in a manner that is appealing to the students.

Curriculum↗
PubMed1975

Pharmacology of a new triazine antifolate in mice, rats, dogs, and monkeys.

Triazinate (TZT), a potent inhibitor of dihydrofolate reductase, was selected for detailed investigation to determine its mechanism of selective action as well as its metabolic fate in mice, rats, dogs, and monkeys. The serum disappearance of TZT in normal and tumor-bearing mice was similar, with a rapid tissue equilibration phase and a slower elimination phase. Serum disappearance in normal and tumor-bearing rats was 1.5 to 2.2 hr. Serum disappearance in dogs and monkeys was similar, with half-lives of 3 to 4 and 2 to 4 hr, respectively. Urinary excretion of TZT at 24 hr was only 5 to 6% of the injected dose in mice and rats; in contrast, the dogs excreted 60% of the injected dose in 8 hr. TZT accumulated to comparable degrees in the organs of rats and mice, with progressively lesser concentrations in liver, kidney, spleen, and brain. Dihydrofolate reductase activity became almost undectectable in all tissues studied within 15 min after drug adminsitration. An important difference in drug accumulation was in the ascites cells of tumor-bearing animals: in mice, the drug level was consistently lower in the L1210 cells than in the ascites fluid; in contrast, by 30 min after treatment with TZT the drug level in Walker 256 cells was 10-fold higher than the level in the ascites fluid. No evidence for drug metabolism was found in extracts of urine, feces, or organ tissues from either mice or rats. TZT and two related triazines were studied for their ability to accumulate in the cerbrospinal fluid of dogs after i.v. administration. TZT achieved a cerebrospinal fluid level of approximately 15% of the serum concentration at 1 hr; in contrast, the other two triazines reached maximum cerebrospinal fluid values of 1% at 1 hr.

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