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J K Haseman

Publications and source records attributed to J K Haseman.

At least 109 records · Page 6Linked to original sources
PubMed1987

Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays.

Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays.

Animals↗
PubMed1987

Liver lesions in B6C3F1 mice: the National Toxicology Program, experience and position.

The spectrum of hepatocellular proliferative lesions in B6C3F1 (C57BL/6N X C3H/HeN MTV-) mice used in National Toxicology Program (NTP) two-year carcinogenicity studies includes foci of cellular alteration, adenoma, carcinoma, and hepatoblastoma. The diagnosis of hepatocellular hyperplasia is reserved for those non-neoplastic proliferative lesions which are believed to occur secondary to necrosis or a degenerative process in the liver. Diagnostic criteria, similar to those previously published, are used during the NTP peer review of these lesions. Incidences of liver tumors in control mice have been established from the NTP database and the frequency of enhanced liver tumor responses in treated mice has been determined based on 278 two-year carcinogenicity studies. Although alternative rodent strains are being examined, at the present time there is no acceptable alternative to the B6C3F1 mouse for NTP carcinogenicity studies. Interim sacrifices and "stop" studies are incorporated into two-year studies to gain knowledge about the biological behavior of mouse liver neoplasia. Also, data are being gathered relative to the pattern of oncogene activation in spontaneous and chemically induced liver tumors in B6C3F1 mice.

Adenoma↗
PubMed1987

Differential susceptibility of immature rat testes to doxorubicin at critical stages of maturation. Biochemical and functional assessment.

The toxic effects of doxorubicin on the reproductive system of the male rat were studied at different susceptible stages of postnatal development. A multidisciplinary approach including the assessment of histopathological, functional and biochemical parameters was chosen. Groups of male rats were treated once with the compound (3 mg/kg) on postnatal day 6, 16, 24 or 45. Both the onset of reproductive capacity and fertility were determined by serially mating ten animals per group for 12 weeks beginning at the age of 45 days. Reproductive organ weights, sperm counts and epididymal androgen binding protein (ABP) were measured at intermediate (80-day-old rats) or terminal sacrifice (129-day-old rats). Age dependent differential doxorubicin toxicity was evident. Treatment of 6-day-old animals with doxorubicin severely impaired development of reproductive functions. Treatment of 16-day-old animals reduced fertility throughout the mating study, as well as body and reproductive organ weights and sperm counts. Initial toxicity was observed in the group treated at 24 days of age; particularly, low reproductive organ weights and low sperm counts were found. These findings proved reversible towards the end of the study. Neither biochemical nor functional impairment of the reproductive system could be observed in the group treated at 45 days of age.

Animals↗
PubMed1987

Comparative toxicity and carcinogenicity of two chlorinated paraffins in F344/N rats and B6C3F1 mice.

The toxicity and carcinogenicity of chlorinated paraffins containing C12 with 60% Cl, and C23 with 43% Cl, were assessed in prechronic and 2-year gavage studies using F344/N rats and B6C3F1 mice of both sexes. Single administrations of chlorinated paraffins were nonlethal in rats and mice, but repeated-dose and 2-year studies demonstrated toxic responses that differed with the paraffins. The C23,Cl43% paraffin produced a granulomatous inflammation in the liver of female rats in 13-week studies, while the C12,Cl60% paraffin caused deaths of rats and mice in 16-day studies and marked liver enlargement in 13-week studies. In 2-year studies, the C23,Cl43% paraffin caused hepatic and lymphatic granulomatous inflammation and hyperplasia in both sexes of rats, and was associated with marginal increases in adrenal medullary pheochromocytomas in female rats and hepatocellular neoplasms in female mice and with clear increases in malignant lymphomas in male mice. The C12,Cl60% paraffin caused marked liver enlargement in rats and increased the severity of nephropathy in male rats and the incidence of nephropathy in female rats. C12,Cl60% also caused hepatocellular neoplasms in both sexes of rats and mice: kidney tubular cell adenomas and adenocarcinomas in male rats, thyroid follicular cell neoplasms in female rats and female mice, and a marginal increase in mononuclear cell leukemia in male rats. Thus, the short-chain, heavily chlorinated paraffin appears to have a greater potential for chronic toxicity and carcinogenicity than the longer-chain, lightly chlorinated paraffin. Both paraffins have been reported to be nonmutagenic in bacteria. (National Toxicology Program (1986) Technical Report, NIH Publications 86-2561 and 86-2564).

Animals↗
PubMed1987

Proliferative exocrine pancreatic lesions in rats. The effect of sample size on the incidence of lesions.

Pancreatic tissue from untreated and corn oil gavage control rats in four chronic (2-year) toxicity and carcinogenicity studies was examined microscopically for the presence of acinar hyperplasia, acinar adenoma, and acinar carcinoma. Formalin-fixed pancreatic tissue that had been saved from these rats was then examined for grossly visible lesions; and all additional available pancreatic tissue was embedded, routinely processed, and sectioned at 5-7 microns for histopathological examination. There were no additional gross lesions identified in the review of the residual tissues. However, microscopic examination of this additional tissue resulted in a marked increase in the number of proliferative lesions diagnosed. The incidence of acinar cell adenomas increased from 1/188 (0.5%) to 28/193 (15%) in untreated control male rats and from 8/194 (4%) to 73/195 (37%) in corn oil gavage vehicle control male rats. There were similar increases in hyperplasia in vehicle and untreated male rats, and similar but much less dramatic increases in hyperplasia and adenoma in vehicle and untreated control female rats. The previously reported effect of increased proliferative lesions of the exocrine pancreas of male rats given corn oil vehicle was confirmed. In addition, examination of a larger tissue sample identified a similar but smaller effect of the corn oil vehicle in female F344 rats that had not been detected by routine sampling of the pancreas.

Adenoma↗
PubMed1987

Comparative results of 327 chemical carcinogenicity studies.

The National Cancer Institute (NCI) and the National Toxicology Program (NTP) have carried out a number of laboratory animal carcinogenicity studies and presented the results of these experiments in a series of Technical Reports. This paper tabulates the results of the 327 NCI/NTP studies carried out to date on 308 distinct chemicals, and discusses certain issues relevant to the evaluation of carcinogenicity in these experiments. This compilation of results from NCI/NTP carcinogenicity experiments provides a large database that can be used to study structure-activity correlations, interspecies concordance, and associations between laboratory animal carcinogenicity and other toxicological effects.

Animals↗
PubMed1987

Morphology and classification of ovarian neoplasms in F344 rats and (C57BL/6 X C3H)F1 mice.

For the updating of the National Toxicology Program (NTP) classification system for rat and mouse ovarian tumors, all the primary ovarian tumors from the archives of the National Cancer Institute and NTP Carcinogenesis Testing Programs were reviewed. The relative frequency and principal diagnostic features of 204 ovarian tumors from 39,851 female F344 rats and of 587 ovarian tumors from 41,102 female (C57BL/6 X C3H)F1 (B6C3F1) mice were described. The most frequently observed neoplasms in F344 rats were malignant granulosa cell tumors (29% of primary rat ovarian neoplasms observed), benign undifferentiated sex cord-stromal tumors (26%), benign granulosa cell tumors (16%), and benign Sertoli cell tumors (7%). The most frequent neoplasms in B6C3F1 mice were cystadenomas (24%), tubulostromal adenomas (24%), benign granulosa cell tumors (21%), and benign teratomas (8%). Ovarian neoplasms were not significantly related to treatment in rats. Tubulostromal adenomas, benign and malignant granulosa cell tumors, and benign teratomas were significantly more frequent in treated mice than in controls.

Adenocarcinoma↗
PubMed1986

Use of dual control groups to estimate false positive rates in laboratory animal carcinogenicity studies.

Tumor incidence data from 18 recently completed carcinogenicity studies utilizing male and female mice and rats were examined to determine if the frequency of significant (p less than 0.05) pairwise differences between the two concurrent control groups employed in these experiments exceeded chance expectation. Although marked study-to-study variability was observed for some tumors, no evidence of extra-binomial within-study variability between the two concurrent control groups was found. The total number of observed significant (p less than 0.05) paired-control differences was virtually identical to what would be expected from the usual binomial model assumptions; the corresponding overall observed (44%) and expected (47-50%) false positive rates were essentially the same. While one should not overgeneralize the implications of these findings, these results should lessen concerns that elevated false positive rates resulting from extra-binomial within-study variability might be adversely affecting the interpretation of long-term laboratory animal carcinogenicity studies. On the other hand, these results reaffirm the conclusions of other investigators that (particularly for commonly occurring tumors) more stringent evidence than an isolated p less than 0.05 effect should be required before an increased tumor incidence is regarded as biologically significant; otherwise, the study may have an unacceptably high false positive rate.

Analysis of Variance↗
PubMed1986

Logistic regression analysis of incidental-tumor data from animal carcinogenicity experiments.

Survival differences can have a substantial impact on the statistical comparison of tumor development in control and treated animals and thus should be taken into account routinely in the analysis of carcinogenicity data from laboratory experiments. However, the appropriate survival adjustment depends on whether the tumor of interest is fatal or incidental. The usual analysis of incidental tumors, which adjusts for survival by stratifying the animals according to age at death, has various shortcomings. Alternatively, logistic regression methods allow a continuous survival adjustment and furnish a convenient framework for solving many of the problems associated with the age-stratified approach of grouping the data into time intervals. Logistic regression substitutes modeling the prevalence function for the arbitrary choice of time intervals, providing a survival adjustment (when the model holds) even when differential mortality might increase the bias or decrease the sensitivity of interval-based methods. The logistic analysis also can incorporate covariables which, if ignored, might confound the interpretation of the data. Several examples illustrate these potential advantages of basing the analysis of incidental tumors on logistic regression techniques.

Aging↗
PubMed1986

Comparison of site-specific and overall tumor incidence analyses for 81 recent National Toxicology Program carcinogenicity studies.

Eighty-one recent carcinogenicity studies carried out by the National Toxicology Program (NTP) were evaluated to determine how the utilization of statistical analyses based on the proportion of animals with primary tumors (all sites) or the proportion of animals with malignant neoplasms (all sites) affected the interpretation of the data compared to analyses of site-specific effects. Utilizing site-specific analyses, the NTP concluded that 45 of the 81 studies (56%) showed carcinogenic responses, 7 (9%) produced equivocal effects, and 29 (36%) showed no evidence of carcinogenicity. An analysis of tumors at all sites often resulted in site-specific carcinogenic responses going undetected. Less than half of the 45 carcinogens identified as producing site-specific carcinogenic responses showed a significant increase in the incidence of primary tumors (22 chemicals) or malignant tumors (21 chemicals). Among the 29 chemicals interpreted as not carcinogenic based on site-specific effects, only two showed significant increases in overall tumor incidence. Two major problems are associated with an evaluation based on overall (all sites) tumor rates: The pooling of various tumor types reduces study sensitivity for detecting chemically related increases in site-specific tumor incidences, and the biological relevance of combining the incidences of tumors of varying morphologies and topographies is questionable. Most national and international guidelines for studying chemicals for carcinogenicity in rodents (or in humans) emphasize site-specific effects. Thus, despite purported advantages of analyses based on overall tumor rates (e.g., simplicity; reducing concerns regarding false positive results) primary emphasis should continue to be on site-specific analyses.

Animals↗
PubMed1986

Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride given in drinking water to F344/N rats and B6C3F1 mice.

Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by administering this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 wk. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1 N HCl to the pH (3.7) of the 300-ppm formulation, served as controls. Survival was comparable among groups except for male mice receiving the 300-ppm dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower than that in controls. Mean body weight was reduced in 300-ppm-dose female rats and 300-ppm-dose male and female mice compared to controls. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed. Under the conditions of these studies, there was clear evidence of carcinogenicity for F344/N rats and for B6C3F1 mice in that 4,4'-methylenedianiline dihydrochloride caused increased incidences of (1) follicular-cell carcinomas of the thyroid gland (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%; p less than or equal to 0.012) and neoplastic nodules of the liver (controls, 1/50, 2%; low dose, 12/50, 24%; high dose, 25/50, 50%; p less than or equal to 0.001) in male rats, (2) follicular-cell adenomas (controls, 0/47; low dose, 2/47, 4%; high dose, 17/48, 35%; p less than or equal to 0.001) and C-cell adenomas (controls, 0/47; low dose, 3/47, 6%; high dose, 6/48, 13% p less than or equal to 0.029) of the thyroid gland in female rats, (3) follicular-cell adenomas of the thyroid gland (controls, 0/47; low dose, 3/49, 6%; high dose, 16/49, 33%; p less than or equal to 0.001), carcinomas of the liver (controls, 10/49, 20%; low dose, 33/50, 66%; high dose, 29/50, 58%; p less than or equal to 0.001), and pheochromocytomas of the adrenal gland in male mice (controls, 2/48, 4%; low dose, 12/49, 24%; high dose, 14/49, 29%; p less than or equal to 0.001), and (4) follicular-cell adenomas of the thyroid gland (controls, 0/50; low dose, 1/47, 2%; high dose, 13/50, 26%; p less than or equal to 0.001), carcinomas (controls, 1/50, 2%; low dose, 6/50, 12%; high dose, 11/50, 22%; p less than or equal to 0.002) and adenomas (controls, 3/50, 6%; low dose, 9/50, 18%; high dose, 12/50, 24%.(ABSTRACT TRUNCATED AT 400 WORDS)

Aniline Compounds↗
PubMed1986

Chronic toxicology and carcinogenesis studies of Telone II by gavage in Fischer-344 rats and B6C3F1 mice.

Telone II (technical grade, 1,3-dichloropropene), a soil fumigant, was evaluated in chronic toxicology/carcinogenicity studies using Fischer-344 (F344) rats and B6C3F1 mice of both sexes. Doses administered were 0, 25, or 50 mg/kg to rats and 0, 50, or 100 mg/kg to mice. Telone II was given in corn oil by gavage 3 times per week for 104 wk. Ancillary studies were conducted to determine time-related effects, in which dose groups containing 5 male and 5 females rats were killed after receiving Telone II for 9, 16, 21, 24, or 27 mo. The primary organs affected were the forestomach (rats and mice), urinary bladder (mice), lung (mice), and liver (rats). Compound-related non-neoplastic lesions included basal-cell or epithelial hyperplasia of the forestomach (rats and mice), epithelial hyperplasia of the urinary bladder (mice), and hydronephrosis (mice). Neoplastic lesions associated with administration of Telone II included squamous-cell papillomas of the forestomach (male and female rats, female mice), squamous-cell carcinomas of the forestomach (Male rats, female mice), transitional-cell carcinomas of the urinary bladder (female mice), alveolar/bronchiolar adenomas (female mice), and neoplastic nodules of the liver (male rats). Although cis- and trans-1,3-dichloropropene are the principal components of Telone II, the presence of 1% epichlorohydrin, a direct-acting mutagen and carcinogen added as stabilizer, may have influenced the development of forestomach lesions. The results of the ancillary studies supported the findings of the carcinogenesis studies and demonstrated the time-dependent development of lesions in the forestomach (basal-cell hyperplasia and squamous-cell papilloma). Under the conditions of these gavage studies, Telone II was shown to be carcinogenic in male and female F344 rats and female B6C3F1 mice. Although the study in male B6C3F1 mice was considered inadequate because of the low survival resulting from suppurative inflammation of the heart (myocarditis) in the control group, there was some indication of Telone II-related increases of transitional-cell carcinomas of the urinary bladder, squamous-cell papillomas of the forestomach, and alveolar/bronchiolar adenomas and carcinomas of the lung.

Allyl Compounds↗
PubMed1986

Testing for simple independent action between two factors for dichotomous response data.

This paper compares three statistics for testing simple independent action between two dichotomous factors with respect to the occurrence of a dichotomous outcome. Sizes and powers are examined for the statistics proposed, under a variety of model parameterizations. The results suggest that a test based on the ratio of the nonresponse probability estimates [considered originally by Wahrendorf, Zentgraf, and Brown (1981, Biometrics 37, 45-54)] has proper size and acceptable power, and is recommended for use in this setting.

Animals↗
PubMed1986

Forestomach lesions in rats and mice administered 3-chloro-2-methylpropene by gavage for two years.

The carcinogenicity of 3-chloro-2-methylpropene (CMP), a chemical intermediate and insecticide, was studied because of possible human exposure and because of its structural relationship to vinyl chloride and allyl chloride. CMP in corn oil was administered by gavage to groups of 50 male and 50 female Fischer 344/N rats at 0, 75, or 150 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at 0, 100, or 200 mg/kg body weight, 5 times a week for 103 weeks. The body weights of the two CMP treated groups of rats were 3-15% lower than the controls; the survival rates were similar. The body weights and survival rates of the CMP-exposed male and female mice were not different from the respective controls throughout the study. CMP administration resulted in dose-related increases in the incidence and severity of forestomach basal cell hyperplasia and the incidence of forestomach squamous cell papillomas in both sexes of rats and mice. In the two groups of CMP-exposed male mice the incidences of squamous cell carcinoma of the forestomach were also increased. Invasion or metastasis of the squamous cell carcinomas to other organs was observed in 2 male mice treated at 100 mg/kg and in 3 male mice and one female mouse treated at 200 mg/kg. The data show that CMP is a carcinogen for the forestomach in rats and mice and acts at the tissue site of contact and support genetic toxicity findings that CMP is a direct-acting alkylating agent.

Allyl Compounds↗
PubMed1986

Lung neoplasms in rodents after chronic administration of dimethyl hydrogen phosphite.

Dimethyl hydrogen phosphite (DMHP), an intermediate in the production of insecticides or herbicides, was administered by p.o. gavage for 2 yr to male Fischer 344/N rats and male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to female Fischer 344/N rats at doses of 0, 50 or 100 mg/kg. Dose related toxicity was seen in the lungs of treated male and female rats. The lung lesions were most prevalent in the high dose male rat group which received a dose twice that given to the high dose female rats. Lung lesions included alveolar epithelial hyperplasia, chemically related pneumonia, alveolar-bronchiolar adenoma, alveolar-bronchiolar carcinoma, and squamous cell carcinoma. DMHP also caused neoplastic and nonneoplastic lesions of the forestomach in male rats; a similar but less pronounced effect was observed in female rats. Nonneoplastic lesions associated with administration of DMHP included mineralization of the cerebellum in male rat and focal calcification of the testis in male mice. Under the conditions of this study, there was clear evidence for carcinogenicity for male rats, equivocal evidence for carcinogenicity in female rats, and no evidence for carcinogenicity in either male or female mice. DMHP caused the highest incidence of lung tumors in the male rat of all chemicals studied to date in the National Cancer Institute-National Toxicology Program Carcinogenesis Testing Program.

Adenoma↗
PubMed1985

Multiple organ carcinogenicity of 1,3-butadiene in B6C3F1 mice after 60 weeks of inhalation exposure.

Groups of 50 male and 50 female B6C3F1 mice were exposed 6 hours per day, 5 days per week, for 60 to 61 weeks to air containing 0, 625, or 1250 parts per million 1,3-butadiene. These concentrations are somewhat below and slightly above the Occupational Safety and Health Administration standard of 1000 parts per million for butadiene. The study was designed for 104-week exposures but had to be ended early due to cancer-related mortality in both sexes at both exposure concentrations. There were early induction and significantly increased incidences of hemangiosarcomas of the heart, malignant lymphomas, alveolar-bronchiolar neoplasms, squamous cell neoplasms of the forestomach in males and females and acinar cell carcinomas of the mammary gland, granulosa cell neoplasms of the ovary, and hepatocellular neoplasms in females. Current workplace standards for exposure to butadiene should be reexamined in view of these findings.

Air Pollutants, Occupational↗