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Biomedical subjects

J E Huff

Publications and source records attributed to J E Huff.

At least 37 records · Page 2Linked to original sources
PubMed1989

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3F1 mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals. For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3F1 mice, and female B6C3F1 mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Two-year inhalation carcinogenesis studies of methyl methacrylate in rats and mice: inflammation and degeneration of nasal epithelium.

Methyl methacrylate (MMA), a liquid monomer, is used as a chemical intermediate in the manufacture of plexiglass and other acrylic products and as "bone cement" in orthopedic and dental surgery. Toxicology and carcinogenesis inhalation studies of MMA were conducted because of: (1) widespread human exposure; (2) evidence of mutagenicity; and (3) inadequacy of previously conducted long-term oral, dermal, and inhalation studies. Groups of 50 male F344/N rats were exposed to MMA by inhalation at 0, 500, or 1000 ppm, female F344/N rats at 0, 250, or 500 ppm, and male and female B6C3F1 mice at 0, 500, or 1000 ppm, 6 h a day, 5 days a week for 102 weeks. Survival rates of male and female rats and mice exposed to MMA were similar to those of their respective controls. Body weights were reduced in the low and high dose male (3-6% and 5-10%, respectively) and female (5-7% and 8-10%) rats exposed to MMA for more than 80 weeks and in male (7-19% and 6-17%) and female (0-13% and 0-17%) mice for more than 20 weeks. Inhalation exposure of MMA for 102 weeks did not induce any increased incidences of neoplasms in male or female rats or mice. Non-neoplastic lesions in the nasal cavity of MMA-exposed rats and mice were significantly increased and these included inflammation and degeneration of the olfactory epithelium of MMA-exposed male and female rats and inflammation, hyperplasia, cytoplasmic inclusions in the respiratory epithelium, and degeneration of the olfactory epithelium in male and female mice.

Administration, Inhalation↗
PubMed1988

Inhibition of some spontaneous tumors by 4-hexylresorcinol in F344/N rats and B6C3F1 mice.

4-Hexylresorcinol (4-HR) is used as an anthelmintic and antiseptic in human and veterinary medicine. Toxicology and carcinogenesis studies were conducted by administering 4-HR in corn oil by gavage at 0, 62.5, or 125 mg/kg to F344 rats and B6C3F1 mice of each sex for 2 years. The nonneoplastic lesions associated with 4-HR exposure were nephropathy and osteosclerosis in dosed male and female mice. The only evidence of neoplasia associated with 4-HR was marginally increased incidences of adrenal gland pheochromocytomas and harderian gland tumors in male mice. Decreases were observed in the incidences of mononuclear cell leukemia in dosed male and female rats, hepatocellular adenomas or carcinomas in dosed male mice, and circulatory system tumors in high-dose male and female mice. These negative tumor trends in rats and mice, along with an indication of reduced overall incidences of benign and malignant tumors in treated groups compared to controls, suggest that 4-HR may deserve further study as a possible antineoplastic agent.

Animals↗
PubMed1988

The effects of allyl isovalerate on the hematopoietic and immunologic systems in rodents.

Female B6C3F1 mice plus male and female Fischer 344/N rats were gavaged with allyl isovalerate (AIV) in corn oil at 0, 31, 62, or 125 (mice) and 0, 31, 62, 125, or 250 (rats) mg/kg body weight for five daily exposures per week for a 2-week period. Hematologic, immunologic, and histopathologic studies were performed 48 to 72 hr following the final treatment. AIV exposure had no effect on hematology or bone marrow cellularity in mice or rats. AIV exposure at 250 mg/kg was toxic to rats causing reduced weight gain and hepatotoxicity. In vivo and in vitro studies revealed that pluripotent hematopoietic stem cells (CFU-S) and granulocyte-macrophage progenitors (CFU-GM) in the bone marrow were decreased in the treated mice. Hematopoietic suppression was correlated with the reduction in the hexose monophosphate shunt metabolism of bone marrow cells but the Embden-Meyerhof pathway and tricarboxylic acid pathway enzymes did not appear to be affected. Examination of host resistance following Plasmodium and Listeria challenge did not demonstrate significant differences between treated and control mice, nor were there other effects on the immune system. This suggests that the myelotoxic effects were minimal and of a degree that would not alter host resistance.

Animals↗
PubMed1988

Toxicity and carcinogenicity of rotenone given in the feed to F344/N rats and B6C3F1 mice for up to two years.

Toxicity and carcinogenicity studies of rotenone were conducted in F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were given rotenone in their diet for up to 103 weeks. The doses were 0, 38, and 75 ppm for rats and 0, 600, and 1,200 ppm for mice. Reduction in body weight gain occurred in male and female mice given rotenone. No effects on survival were observed for rats of either sex or female mice. Survival of male mice at 1,200 ppm was significantly greater than that of controls (47/50 vs. 29/50). There were no observed nonneoplastic effects due to rotenone, and for male and female mice no neoplasms were induced by rotenone. Parathyroid adenomas occurred at a higher incidence (4/44) in male rats at 75 ppm than in the controls (1/41). Because these tumors are rare (historical rate in NTP studies is 0.3%), the increase in the incidence of these benign tumors may have been related to rotenone administration. Hepatocellular neoplasms were reduced (p less than 0.01) in males receiving 1,200 ppm 1/50 relative to controls 12/47. Because this low rate of liver tumors is unusual in male B6C3F1 mice, this decrease was considered to be related to rotenone administration.

Animals↗
PubMed1987

Species correlation in long-term carcinogenicity studies.

Species correlation in neoplastic response was examined for 266 long-term toxicology and carcinogenicity studies. The overall concordance between rats and mice exposed to the same chemical was 74% (198/266). Within a species, the results for males and females were also highly correlated (87% concordance for rats and 89% for mice). Had only male rats and female mice been utilized in these experiments, the same conclusions regarding carcinogenicity would have been reached in 96% of the studies (255/266). The high interspecies correlation shown in these studies supports the view that extrapolation of carcinogenicity outcomes to other species, including humans, is appropriate.

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

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↗
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↗
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↗