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Biomedical subjects

J K Haseman

Publications and source records attributed to J K Haseman.

At least 73 records · Page 4Linked to original sources
PubMed1992

Effects of corn oil, time-related changes, and inter-laboratory variability on tumor occurrence in control Fischer 344 (F344/N) rats.

Survival, body weight, and site-specific tumor rates in untreated, corn oil gavage, and water gavage control Fischer 344 (F344/N) rats from 88 National Toxicology Program (NTP) long term carcinogenicity studies were evaluated to determine which factors were primarily responsible for inter-study variability. For male rats, previously-reported decreases in leukemia and increases in body weight, survival, and pancreatic acinar cell tumors attributable to corn oil gavage were confirmed. Corn oil did not appear to affect tumor rates in female rats. The gavage technique per se did not appear to influence tumor rates in rats of either sex. Previously reported time-related increases in certain site-specific neoplasia in control rats appeared to have stabilized in recent years, but control tumor rates are still much greater than those seen a decade ago. More recent studies continue to show increasing rates of leukemia and mammary gland tumors and decreasing survival. Female rats also continue to show time-related increases in maximum mean body weight. Inter-laboratory variability in body weight and in the rates of a number of site-specific neoplasms were also significant. High mean body weights in control groups were found to be associated with increased rates of mammary and pituitary tumors. Our evaluation supports the view that if historical control data are to be utilized in the interpretation of experimental results, primary emphasis should be given to lab and route of administration-specific tumor rates for studies that are contemporary to the study under evaluation. It also suggests that certain experimental design changes (e.g., dietary modifications) may be needed to reduce tumor rates and to increase survival.

Animals↗
PubMed1991

Results and conclusions of the National Toxicology Program's rodent carcinogenicity studies with sodium fluoride.

The US National Toxicology Program (NTP) has conducted toxicity and carcinogenicity studies with sodium fluoride administered in the drinking water to F344/N rats and B6C3F1 mice. The drinking water concentrations used in the 2-year studies were 0, 25, 100, or 175 ppm sodium fluoride (equivalent to 0, 11, 45 or 79 ppm fluoride). Survival and weight gains of rats and mice were not affected by fluoride treatment. Animals receiving sodium fluoride developed effects typical of dental fluorosis, and female rats given 175 ppm had increased osteosclerosis. There were no increases in neoplasms in female rats or in male or female mice that were attributed to sodium fluoride administration. There was equivocal evidence of carcinogenic activity of sodium fluoride in male rats based on the occurrence of a small number of osteosarcomas in treated animals.

Animals↗
PubMed1991

Inhalation of tetranitromethane causes nasal passage irritation and pulmonary carcinogenesis in rodents.

Fischer 344 rats and B6C3F1 mice were exposed for 2 years to vapors of tetranitromethane at concentrations below (0.5 ppm) and slightly above (2 or 5 ppm) the current U.S. recommended occupational exposure limit. Under the conditions of exposure of 6 h/day, 5 days/week, tetranitromethane was found to cause mild irritation and hyperplastic lesions in the nasal passages, but not nasal cavity neoplasms were observed. In contrast, nearly all animals exposed to the higher TNM concentrations, and the majority of animals exposed to the lower concentrations developed alveolar/bronchiolar adenoma or carcinoma; squamous cell neoplasms of the lung also occurred in exposed rats. The extent of the lung tumor response, and the low concentrations of tetranitromethane required for this response, are unprecedented in National Toxicology Program (NTP) studies.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1991

Statistical methods for analyzing developmental toxicity data.

A description and review of methods for performing per-litter analyses involving extrabinomial proportion response is provided. It is stressed that the litter should be regarded as the appropriate experimental unit for quantitative analysis in studies for teratogenic or heritable mutagenic effects. Attention is directed at statistical identification of possible treatment effects, such as a positive dose response to a chemical stimulus. The methods range from distribution-free, nonparametric analyses to models involving parametric distributions such as the beta-binomial density. It is seen that most current methods require computer implementation. When concern is raised over misspecification of assumptions critical to the statistical analysis, it is argued that relatively parameter-free methods are appropriate for use. These include statistical bootstrapping and rank-based analyses.

Models, Statistical↗
PubMed1991

Comparative toxicity and carcinogenicity studies of tetracycline and oxytetracycline in rats and mice.

Two-year toxicity and carcinogenicity studies of oxytetracycline hydrochloride and tetracycline hydrochloride, two structurally similar and widely used antibiotics, were performed in F344/N rats and B6C3F1 mice. Rats and mice were continuously exposed via their diet to the following levels of antibiotic: oxytetracycline HCl--rats 0, 25,000, or 50,000 ppm; mice 0,6,300, or 12,500 ppm; tetracycline HCl--rats and mice 0, 12,500, or 25,000 ppm. On a milligram per kilogram of body weight basis these exposures represent doses that are 20 to 140 times daily human therapeutic doses. Dose-related increased survival was noted among oxytetracycline-treated male rats and tetracycline-treated female rats and male mice, while treatment-related reduced body weight gain occurred in oxytetracycline- and tetracycline-treated mice. Microscopic changes included fatty metamorphosis and focal cellular change in livers of oxytetracycline-treated male rats and basophilic cytoplasmic and clear cell change in livers of tetracycline-treated male rats. The only neoplastic changes were a marginally increased trend in pheochromocytoma of the adrenal medulla (equivocal evidence only) among oxytetracycline-exposed male rats (12/50 controls, 19/50 low dose, 24/50 high dose) and an increased incidence of pituitary adenoma or adenocarcinoma among high-dose oxytetracycline-treated female rats (20/50 controls, 32/50 high dose). Although oxytetracycline and tetracycline appeared to increase the incidence of pituitary hyperplasia in high-dose male and female rats, respectively, the total incidence of proliferative changes (hyperplasia, adenoma, and adenocarcinoma) was not affected by antibiotic exposure. The results from these studies therefore support the notion that neither antibiotic is carcinogenic in rodents. There were several negative trends suggesting possible protective effects by both these tetracycline analogs against certain spontaneous neoplastic and non-neoplastic changes.

Animals↗
PubMed1991

Carcinogenicity of p-chloroaniline in rats and mice.

p-Chloroaniline (PCA), a dye intermediate, was evaluated for potential long-term toxicity and carcinogenicity. Groups of 50 F344/N rats of each sex were given by gavage PCA hydrochloride in deionized water at doses of 0, 2, 6 or 18 mg/kg body weight, 5 days/wk for 103 wk. Groups of 50 male and female B6C3F1 mice of each sex were given 0, 3, 10 or 30 mg/kg on the same schedule. In general, body weights and survival were unaffected by PCA administration. In rats the group given 18 mg/kg had mild haemolytic anaemia and slight increases in methaemoglobin at various times during the study. Fibrosis of the spleen was significantly increased in all PCA-treated groups of male rats and in the 18-mg/kg group of female rats. Sarcomas of the spleen occurred in male rats, their incidence being 0/49, 1/50, 3/50 and 38/50 in control low-, mid- and high-dose groups, respectively. There was a slightly increased incidence of pheochromocytomas of the adrenal gland in both male and female rats. Dosed groups of male mice had increased incidences of hepatocellular adenomas or carcinomas (11/50, 21/49, 20/50 and 21/50 in controls, low- mid- and high-dose groups, respectively). Haemangiosarcomas of the liver or spleen were also increased in the high-dose group (incidences of 4/50, 4/49, 1/50 and 10/50 in controls, low-, mid- and high-dose groups, respectively). In conclusion, PCA was carcinogenic in male rats and male mice.

Adenoma↗
PubMed1991

Carcinogenesis studies of dichlorvos in Fischer rats and B6C3F1 mice.

Dichlorvos (dichlorovinyl dimethyl phosphoric acid ester) is a cholinesterase inhibitor used widely as a contact and stomach insecticide for control of internal and external parasites. Carcinogenesis studies were conducted by administering dichlorvos in corn oil by gavage 5 times a week for 103 weeks to groups of 50 male and 50 female Fischer rats at 0, 4, or 8 mg/kg body weight, to groups of 50 male B6C3F1 mice at 0, 10, or 20 mg/kg, and to groups of 50 female B6C3F1 mice at 0, 20, or 40 mg/kg. During the course of the studies, body weights and survival rates of the male and female rats and mice were not different from those of their respective controls; females of both species appeared to gain more weight than controls. Neoplasms induced by dichlorvos included adenomas of the exocrine pancreas (male rats), mononuclear cell leukemia (male rats), and squamous cell papilloma of the forestomach (male and female mice; two other female mice had squamous cell carcinomas). Lesions observed in female rats that may have been due to dichlorvos administration included adenomas of the exocrine pancreas and fibroadenomas of the mammary gland. The results demonstrated that dichlorvos is carcinogenic for Fischer rats and B6C3F1 mice.

Adenoma↗
PubMed1991

Toxicity and carcinogenicity studies of nalidixic acid in rodents.

Toxicity and carcinogenicity studies of nalidixic acid, an antimicrobial agent used to treat bacterial infections of the urinary tract, were conducted in F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. In the 13-week studies, nalidixic acid was administered at dietary concentrations ranging from 1,000 to 16,000 ppm. Body weights of both rats and mice were reduced in the groups receiving diet containing 8,000 and 16,000 ppm, and feed consumption of rats in the highest treatment groups was approximately two-thirds that of controls. Degeneration of the germinal epithelium in the seminiferous tubules of the testis was observed in male rats that received 16,000 ppm; no other compound-related histopathologic effects were observed in either species. Two-year studies were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 rats and mice/sex/group. The average daily feed consumption was slightly reduced compared to control groups and resulted in approximate daily doses of 82 or 175 mg nalidixic acid/kg for low dose and high dose rats, and 220 or 475 mg/kg for low dose and high dose mice. Mean body weights of dosed rats and mice were lower than those of controls, except for groups of low dose female rats and male mice. The incidences of preputial gland neoplasms in dosed male rats and of clitoral gland neoplasms in dosed female rats were significantly increased compared to those in controls; responses in low dose groups were similar to those in high dose groups. There were decreased incidences of leukemia and mammary gland neoplasms in dosed female rats and of pituitary gland neoplasms in dosed male rats. Subcutaneous tissue fibrosarcomas were marginally increased in dosed male mice. There were no increased incidences of neoplasms in dosed female mice. Under the conditions of these studies, the dietary administration of nalidixic acid was carcinogenic for rats, causing preputial gland or clitoral gland neoplasms in males and females, respectively. The association of subcutaneous neoplasms with administration of nalidixic acid to male mice was equivocal.

Animals↗
PubMed1990

Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: confirmation of earlier results with 41 additional chemicals.

The effectiveness of four in vitro short-term tests (STT) for genetic toxicity, induction of mutations in Salmonella (SAL) and mouse lymphoma L5178Y cells (MLA), and induction of sister chromatid exchanges (SCE) and chromosome aberrations (ABS) in Chinese hamster ovary cells that are used for predicting rodent carcinogenicity were examined. The in vitro results were compared with the results from 41 rodent carcinogenicity studies performed by the National Toxicology Program. The predictive values of, and interrelationships among, the STT for these 41 chemicals were similar to those previously reported for 73 chemicals and confirm those earlier results [Tennant RW, Margolin BH, Shelby MD, Zeiger E, Haseman JK, Spalding J, Caspary W, Resnick M, Stasiewicz S, Anderson B, Minor R (1987): Science 236:933-941]. Because of this similarity among the two datasets, the chemicals were combined into a single dataset of 114. The results with 114 chemicals show that SAL had the lowest sensitivity (.48) and the highest specificity (.91), whereas MLA had the highest sensitivity (.72) and the lowest specificity (.40). The concordances of the test results with rodent carcinogenicity were .66, .61, .59, and .59, for SAL, ABS, SCE, and MLA, respectively. Salmonella was the most predictive for carcinogenicity; 89% of the chemicals mutagenic in SAL were carcinogenic in rodents, however a negative result in any or all of the STT was not indicative of noncarcinogenicity. The STT results reported here show good agreement with the potential electrophilicity of the chemicals, and the majority of carcinogens that are undetected by the STT do not have an electrophilic structure. There was no complementarity among the tests and no combination of the four tests was more effective than any single test for predicting carcinogenicity.

Animals↗
PubMed1990

Carcinogenicity results for 114 laboratory animal studies used to assess the predictivity of four in vitro genetic toxicity assays for rodent carcinogenicity.

Carcinogenicity results are presented for 114 long-term rodent studies carried out by the National Toxicology Program. Tumor rates are given for each positive or equivocal effect observed in 67 studies judged to show carcinogenic effects and in the 17 studies that show equivocal effects. The liver was found to be the most common site of carcinogenicity for both mice and rats; other frequent target sites included the lung, kidney, hematopoietic system, forestomach, thyroid gland, and mammary gland. The evaluative approach used in reaching decisions regarding the carcinogenicity of chemicals is discussed. No rigid statistical decision rules were employed, and biological as well as statistical factors were considered in the overall evaluation of the data. These long-term studies were utilized in a comprehensive evaluation of the ability of four in vitro genetic toxicity tests to predict rodent carcinogenicity. Details concerning these procedures and the results of this investigation are given elsewhere [Zeiger E, Haseman JK, Shelby MD, Margolin BH, Tennant RW 1990: Environ Mol Mutagen 16 (Supp. 18):1-14]. Interestingly, those chemicals evaluated at relatively low doses in the rodent experiments (because of the underlying toxicity of the chemicals) were far more likely to be positive in each of the four genetic toxicity assays than were "less toxic" chemicals evaluated in higher doses in the rodent studies.

Animals↗
PubMed1990

No evidence of toxicity or carcinogenicity of pentaerythritol tetranitrate given in the diet to F344 rats and B6C3F1 mice for up to two years.

Toxicology and carcinogenesis studies of pentaerythritol tetranitrate (PETN), an organic nitrate used in explosives and as a therapeutic agent for angina pectoris, were conducted by administering diets containing PETN,NF (National Formulary Grade, a 1:4 mixture of PETN and lactose) to both sexes of F344 rats and B6C3F1 mice in 14-day, 13-week and 2-year studies. PETN was found to be essentially non-toxic in 14-day and 13-week studies at dietary concentrations as high as 10,000 ppm; the weight gain of female rats was lower than that of controls at 5000 and 10,000 ppm in the 13-week study. In the 13-week studies, one in ten high-dose female rats had an adenoma of the Zymbal gland and one in ten high-dose female mice had a hepatocellular adenoma. Dietary concentrations chosen for the 2-year studies were 5000 and 10,000 ppm for male rats and male and female mice, and 1240 and 2500 ppm for female rats. In the 2-year studies, there were no adverse effects on survival or body weight gains in either sex of rats or mice. No neoplastic or non-neoplastic lesions were considered to be related clearly to PETN administration. Neoplasms of the Zymbal gland occurred at low incidences in PETN-exposed groups of both sexes of rats in the 2-year study.

Animals↗
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

Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 2. Furosemide.

Toxicology and carcinogenesis studies of furosemide, a widely used diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 14-day, 13-week and 2-year studies. Deaths occurred among rats and mice receiving diets containing 46,000 ppm furosemide in 14-day studies, and animals given diets containing lower concentrations lost weight. No deaths were seen in 13-week studies using top concentrations ranging from 10,000 to 20,000 ppm, but animals at higher concentrations had lower weight gains than controls. Nephrosis in rats and mice was the only significant compound-related lesion observed in the prechronic studies. In 2-year studies, rats received diets containing 0, 350 or 700 ppm furosemide and mice received diets containing 0, 700 or 1400 ppm furosemide. Survival of dosed and control rats of both sexes and male mice was similar; survival of high-dose female mice was lower than controls. Nephropathy was increased in male rats and in male and female mice. In female mice, increased malignant tumors of the mammary gland were associated with furosemide administration. In male rats, marginal increases in tubular cell neoplasms of the kidney and in meningiomas of the brain were observed in dosed animals, but these were not considered to be related clearly to exposure to furosemide.

Adenoma↗
PubMed1990

Use of statistical decision rules for evaluating laboratory animal carcinogenicity studies.

In the evaluation of long-term rodent carcinogenicity studies, many different tumor sites and types are evaluated, which may increase the likelihood of a statistical false positive. To deal with this issue, a number of statistical decision rules have been proposed that take into account multiple comparisons. This paper discusses the various types of decision rules and evaluates the factors that may lead to different interpretations of experimental results. These concepts are illustrated by examining the statistical decision procedures used by three analysts to evaluate the results of 25 long-term rodent carcinogenicity studies carried out by the National Cancer Institute. Agreement among these decision rules is shown to be greater than originally reported. It is also concluded that while the application of statistical decision rules may be of value in some instances to guard against statistical false positives, the final interpretation of the data should be based on biological as well as statistical considerations. Thus, statistical decision rules should not be employed as a substitute for sound scientific judgment in the overall evaluation of these experiments.

Animals↗
PubMed1990

Neurotoxicity and carcinogenicity of N-methylolacrylamide in F344 rats and B6C3F1 mice.

Toxicology and carcinogenicity studies of N-methylolacrylamide were conducted by administering the chemical by gavage in water to both sexes of F344/N rats and B6C3F1 mice 5 times per week for 16 d, 13 wk, or 2 yr. In 16-d studies, rats receiving doses of 200 mg/kg or higher and mice receiving 400 mg/kg died. In 13-wk studies, all rats given 100 mg/kg or higher doses died. Rats receiving 50 mg/kg or higher doses developed hindlimb ataxia progressing to paralysis. In neurobehavioral assessments, decreased forelimb and hindlimb grip strength occurred in rats at doses as low as 12.5 mg/kg. Landing footspread was also increased in dosed rats compared to controls. Axon filament and myelin sheath degeneration in the spinal cord and/or peripheral nerves occurred in rats receiving doses of 25 mg/kg or higher. Necrosis in the granular cell layer of the cerebellum was seen in rats given 200 mg/kg. Mice receiving 200 mg/kg in 13-wk studies died. Decreased grip strength was noted in mice at doses as low as 25 mg/kg, and rotarod performance was also affected by N-methylolacrylamide administration, but no neuropathology was seen microscopically. Testicular weights were decreased at doses as low as 12.5 mg/kg, and hepatocellular necrosis, thymic lymphocyte necrosis, and hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were seen in mice that died (200 mg/kg). In 2-yr studies, survival and weight gains in male and female rats receiving doses of 6 or 12 mg/kg/d were minimally affected. No biologically important clinical signs or neoplastic or nonneoplastic lesions were attributed to N-methylolacrylamide administration to rats, suggesting that higher doses could have been tolerated. In mice, survival was not different between dosed and control groups (0, 25, or 50 mg/kg/d). Body weights were higher by as much as 25% in dosed compared to control groups. No compound-related clinical signs were observed, but increases in neoplasms of the harderian gland, liver, and lung were clearly related to chemical administration in both sexes of mice. Benign granulosa-cell neoplasms of the ovary were also increased in dosed female mice.

Acrylamides↗
PubMed1990

Growth, body weight, survival, and tumor trends in F344/N rats during an eleven-year period.

Time trends for growth, body weight, survival and tumor prevalences in 144 diet control groups with a total of 5,184 male F344/N rats and 146 diet control groups with a total of 5,289 female rats of NCI-NTP 2-yr chemical carcinogenicity studies started during an 11-yr period (1971 to 1981) in 11 toxicology testing laboratories were evaluated. Male and female rats in more recent studies grew faster and attained a higher body weight than rats from earlier studies. Survival of males showed a significantly decreasing trend over time, which may have been related to diseases associated with increasing body weight, prevalence of leukemia and changes in criteria for euthanasia of moribund animals. The time trend for survival of females was not significant. There were highly significant (p less than 0.001) positive time trends for prevalences of leukemia, anterior pituitary tumors and thyroid C-cell tumors in both sexes, adrenal pheochromocytomas in males and mammary tumors and endometrial stromal polyps in females. The prevalence of mammary tumors in females and pituitary tumors in males had a highly significant (p less than 0.01) positive association with body weight. Histological reevaluation of tumor prevalences in approximately 250 rats of each sex at each of 4 different time periods indicated that changes in diagnostic criteria may have contributed to but could not totally explain the increased prevalence of leukemia. Changes in diagnostic criteria and the amount of tissue examined may have contributed to the increased prevalence of anterior pituitary tumors in both sexes and adrenal pheochromocytomas in males. Interlaboratory variability and changes in diet may also have contributed to the time-related trends.

Adrenal Gland Neoplasms↗
PubMed1990

Growth, body weight, survival, and tumor trends in (C57BL/6 X C3H/HeN) F1 (B6C3F1) mice during a nine-year period.

Time trends for growth, body weight, survival and tumor prevalences in 121 diet control groups with a total of 4,636 male B6C3F1 mice and 123 diet control groups with a total of 4,758 female mice of NCI-NTP 2-yr chemical carcinogenicity studies started during a 9-yr period (1973 to 1981) in 11 laboratories were evaluated. Male and female mice did not show substantial changes in growth patterns. Both sexes had highly significant time trends with decreasing body weights in the more recent studies. This apparent trend was due to high body weights during the first 3 yr and highly significant interlaboratory variability. Time trends for survival of both sexes were not significant. Prevalences of liver tumors, lung tumors, and lymphoma in males and lung tumors in females did not show significant time trends. There were significant positive time trends for prevalences of liver tumors and lymphoma in female mice, but the trends were not significant when adjusted for interlaboratory variability. The positive time trend for anterior pituitary tumors of females was highly significant and may be due in part to an increase in the amount of pituitary tissue examined in the more recent studies. Histological reevaluation of liver and anterior pituitary tissue in 208-249 female mice at each of 4 different times periods did not substantially change the prevalences or the time trends. The major factor influencing time trends in mice appeared to be interlaboratory variability.

Animals↗