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Biomedical subjects

J Huff

Publications and source records attributed to J Huff.

At least 55 records · Page 3Linked to original sources
PubMed1995

Chemically induced mammary gland cancer in the National Toxicology Program's carcinogenesis bioassay.

Incidences of breast cancer change in populations as people migrate from one area of the world to another, suggesting that environmental factors contribute to this disease. There is a continuing effort to identify these environmental factors and the role that exposures to specific chemicals play in this disease. Results from experimental studies show that chemicals identified to cause mammary gland cancer in rodents are frequently mutagenic chemicals, suggesting that genetic damage is an important mechanism for the induction of this cancer. Prevalent classes of chemicals that were identified to cause mammary gland cancer in rodents in studies by the National Toxicology Program include halogenated hydrocarbons, aromatic amino/nitro compounds and epoxide-forming chemicals. Results from these experimental studies will help to elucidate mechanisms and possible causes of breast cancer in humans.

Animals↗
PubMed1995

Effects of testosterone, testosterone propionate, 17 beta-trenbolone and progesterone on cell transformation and mutagenesis in Syrian hamster embryo cells.

Testosterone, testosterone propionate, 17 beta-trenbolone and progesterone, which represent the main endogenous and synthetic androgens and a progestin, were evaluated for possible cell transformation and genetic effects in Syrian hamster embryo (SHE) cells. Cell growth was reduced by treatment with the steroids at 10-30 micrograms/ml in a dose-related manner. Testosterone and testosterone propionate were less toxic than the other two steroids. Testosterone, testosterone propionate and progesterone induced morphological transformation of SHE cells with similar transformation frequencies. The most potent effects were observed with testosterone propionate, which induced cell transformation at 1-30 micrograms/ml in a dose-related manner. Testosterone and progesterone transformed cells only at the highest dose (30 micrograms/ml). 17 beta-Trenbolone did not induce a statistically significant level of cell transformations at any dose tested (up to 30 micrograms/ml). The transformation frequencies induced by testosterone, testosterone propionate and progesterone were less than one-half that induced by benzo[a]pyrene at 1 microgram/ml. None of these steroids induced significant increases in frequencies of chromosome aberrations or aneuploidy. Gene mutations were not observed for testosterone at the HPRT or Na+/K+ ATPase locus. Because these steroids are also associated with carcinogenic activity in vivo, these in vitro findings provide a model and new insights into the study of the mechanisms of androgen- and progestin-induced cell transformation.

Animals↗
PubMed1995

Long-term exposure to the anti-inflammatory agent phenylbutazone induces kidney tumors in rats and liver tumors in mice.

Long-term toxicity and carcinogenicity of phenylbutazone, a nonsteroidal anti-inflammatory drug, were evaluated in F344/N rats and B6C3F1 mice. In 2-year studies, phenylbutazone was given in corn oil by gavage 5 days per week to groups of 50 rats of each sex at doses of 0, 50, or 100 mg/kg body weight, and to groups of 50 mice at doses of 0, 150, or 300 mg/kg body weight. Body weights and survival were similar among groups. Major target organs are kidneys in rats and liver in mice. Kidney: inflammation, papillary necrosis, and mineralization in both sexes of rats, and hyperplasia and dilatation of the pelvis epithelium, and cysts in female rats. Uncommon tubular cell tumors of the kidney were found in 13 exposed rats: 5 in the 50 mg group and 4 in the 100 mg group of males; 4 in dosed female rats; none in controls. In female rats, dose-related increases in hyperplasia of the pelvis transitional epithelium, and 2 carcinomas were discovered. Urinary bladder: papillomas of the transitional epithelium were seen in 2 low-dose male and in 1 low-dose female rats. Forestomach: ulcers in rats, with acanthosis, hyperkeratosis, and basal cell hyperplasia in female rats; however, no neoplasms were associated with these lesions. Liver: primarily in male mice exposed to phenylbutazone, hemorrhage, centrilobular cytomegaly and karyomegaly, fatty metamorphosis, cellular degeneration, and coagulative necrosis were seen; clear cell foci were observed in male mice. In summary, under the conditions of these 2-year oral intubation studies, phenylbutazone is associated with renal carcinogenicity in rats, as evidenced by increases in tubular cell neoplasms in both sexes. Evidence of carcinogenicity for male mice was shown by increased incidences and multiplicity of liver tumors. No carcinogenic activity was found for female mice.

Adenoma↗
PubMed1994

Leukemia induced in rats but not mice by dimethyl morpholinophosphoramidate, a simulant anticholinesterase agent.

Dimethyl morpholinophosphoramidate (DMMPA), an organophosphate, caused leukemia in male and female Fischer 344/N rats. DMMPA was administered in corn oil by oral intubation to groups of 50 male and 50 female rats at 0, 150, 300, or 600 mg/kg body weight, five times per week for 2 years. B6C3F1 mice were given 0, 150 (males only), 300, and 600 (females only) mg/kg body weight under the same schedule. DMMPA induced a dose-related enhancement in the incidence of mononuclear cell leukemia in rats--males: controls = 14/50, 150 mg group = 21/50; 300 mg group = 19/50; 600 mg group = 25/50; females: controls = 9/50, 150 mg group = 13/50; 300 mg group = 12/49; 600 mg group = 18/50. Survival-adjusted rates strengthen the DMMPA effect: males--31%, 50%, 47%, and 63%; females--20%, 32%, 30%, 50%. Latent periods for mononuclear cell leukemia development in exposed rats were not shortened compared to controls. No carcinogenic effects in mice were detected. DMMPA was not mutagenic in Salmonella, was mutagenic for mouse lymphoma cells, and induced both chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells.

Administration, Oral↗
PubMed1994

Fibrous glass and cancer.

Some argue that fibrous glass (glass wool) should not be considered as a likely human carcinogen and hence should not be listed in the Seventh Annual Report on Carcinogens (ARC) prepared by the National Toxicology Program (NTP) and mandated by the U.S. Congress. In examining this issue, data from both laboratory experiments (animal studies) and epidemiologic studies (human data) are reviewed with the results evaluated according to the criteria established by the International Agency for Research on Cancer (IARC) and adopted in slightly modified form by the NTP for classifying substances as human carcinogens or likely human carcinogens. From our comprehensive review of the available information, we conclude that fibrous glass materials are carcinogenic, and in view of the NTP and IARC definitions should be listed in the ARC. Our review then examines the carcinogenic potency of glass fibers to humans in comparison with asbestos fibers and concludes that on a fiber-per-fiber basis, glass fibers may be as potent or even more potent than asbestos. The implications of these findings are then presented for regulatory purposes in the occupational setting.

Administration, Inhalation↗
PubMed1994

Reserpine-induced cell transformation without detectable genetic effects in Syrian hamster embryo cells in culture.

Reserpine, a naturally occurring rauwolfia alkaloid, used mainly as an antihypertensive drug, was examined for its ability to induce cell transformation and genetic effects in Syrian hamster embryo (SHE) cells in culture. Treatment of SHE cells with 2 micrograms/ml of reserpine had no effect on cell growth, while 4 micrograms/ml of reserpine reduced the growth rate slightly and 8 micrograms/ml resulted in a significant inhibition of cell growth. Reserpine at doses of 4-8 micrograms/ml for 48 h induced a dose-related increase in morphological transformation of the cells. Reserpine-transformed colonies were morphologically indistinguishable from colonies transformed with benzo[a]pyrene (B[a]P) or other chemical carcinogens. Over the dose range that resulted in cell transformation, treatment of SHE cells with reserpine failed to induce any detectable gene mutations at two genetic loci, chromosomal abnormalities including structural and numerical changes, or DNA adduct formation. These findings indicate that reserpine may have carcinogenic potential by unknown mechanisms that do not include direct induction of gene and/or chromosome mutations.

Aneuploidy↗
PubMed1993

Predictive strategies for selecting 379 NCI/NTP chemicals evaluated for carcinogenic potential: scientific and public health impact.

The a priori criteria used by the National Cancer Institute/National Toxicology Program (NCI/NTP) are described for 379 chemicals selected and evaluated for carcinogenic potential. We classified the chemicals according to exposure and structural categories and evaluated the predictive ability of the scientific selection criteria of chemicals suspected of being carcinogenic in advance of any study. Of the 379 chemicals, 253 (67%) were selected with a suspicion of carcinogenicity; 171 (68%) of these 253 chemicals induced cancer in at least one of the sex-species experiments. The other 126 (33%) chemicals were selected mainly, but not exclusively, on the basis of exposure considerations and production volumes; only 27 (21%) of these were judged to be positive. Overall, 198 (52%) of the 379 chemicals studied induced tumors in at least one organ of one sex of one species, but only 87 (23%) of these 379 chemicals were positive in both species and are considered most likely to present carcinogenic hazards to humans. Importantly, 78 (90%) of these 87 chemicals were selected with a prospective suspicion of carcinogenicity. Although the program has studied only a part of the "Universe of Chemicals" (defined as chemicals to which humans are exposed), the scientific data generated are essential for developing structure activity data bases of potentially hazardous chemical classes and for predicting the carcinogenicity of chemicals not yet studied. Thus, the bioassay program has had beneficial and crucial impacts on public health, as demonstrated by the use of these data by international, Federal, and State regulatory agencies to reduce or eliminate exposures to chemicals shown to be unequivocally carcinogenic in laboratory animals.

Animals↗
PubMed1993

Issues and controversies surrounding qualitative strategies for identifying and forecasting cancer causing agents in the human environment.

Certain chemicals, mixtures of chemicals, exposure circumstances, life-styles and personal or cultural habits, occupations, viruses, living conditions, and physical agents have been causally associated with cancers in humans. Most however are not considered potentially carcinogenic, and the proportion of 'agents' eventually identified to cause cancer is projected to be relatively low. Current methods to identify carcinogenic potential of chemicals rely largely on short-term in vitro and in vivo tests, mid- & long-term in vivo assays, molecular mechanisms, epidemiological investigations, and structural-activity-effect-relationships. Thus, the scientific and public health communities must continue to utilize available means and concomitantly strive to develop newer methods and tools to more easily, quickly, cheaply, and reliably identify carcinogens in the human milieu. Since adequate human studies are typically absent, the most useful method for identifying potential human carcinogens continues to be long-term carcinogenesis experiments. Agents identified as causing cancers in humans have been shown to cause cancer in animals, and this knowledge, together with similarities in mechanisms of carcinogenesis across species, led to the scientific logic and public health strategy that chemicals shown clearly to be carcinogenic in animals should be considered as being likely and anticipated to present cancer risks to humans. The quest of hazard identification efforts is cancer prevention, largely by reducing or eliminating exposures to chemicals that cause cancer and other diseases.

Animals↗
PubMed1993

Chemicals and cancer in humans: first evidence in experimental animals.

Certain human diseases have been traced to exposure to environmental and occupational chemicals. In many instances the first evidence of potential adverse effects came from experimental studies and were subsequently discovered in humans. Associations of human cancers, as a diverse group of diseases, and chemicals have been made since the middle 1700s. Since then, nearly 100 chemicals, mixtures of chemicals, or exposure circumstances are now recognized as being or strongly implicated as being carcinogenic to humans. Of the less than 1000 agents evaluated adequately for carcinogenicity in laboratory animals, a varying spectrum of data from studies on humans are available for only about 20-25%. So far, more than 60 agents are linked unequivocally as causing cancer in humans, and another 50 or so are strongly suspected of being carcinogenic to humans. Not all of these have been or can be evaluated in animals because some are industrial processes or "occupations," some are environmental and cultural risk factors, and some are mixtures of agents. For those that can be studied experimentally, the qualitative concordance between humans and animals approaches unity, and in every case there is at least one common organ site of cancer in both species. The evidence of carcinogenicity in experimental animals preceded that observed in humans for nearly 30 agents and is the subject of this paper.

Animals↗
PubMed1993

Carcinogenicity of 1,3-butadiene.

1,3-Butadiene, a high-production volume chemical used largely in the manufacture of synthetic rubber, is a multiple organ carcinogen in rats and mice. In inhalation studies conducted in mice by the National Toxicology Program, high rates of early lethal lymphomas occurring at exposure levels of 625 ppm or higher reduced the development and expression of later developing tumors at other sites. Use of survival-adjusted tumor rates to account for competing risk factors provided a clearer indication of the dose responses for 1,3-butadiene-induced neoplasms. An increase in lung tumors in female mice was observed at exposure concentrations as low as 6.25 ppm, the lowest concentration ever used in a long-term carcinogenicity study of this gas. Human exposures to 1,3-butadiene by workers employed at facilities that produce this chemical and at facilities that produce styrene-butadiene rubber have been measured at levels higher than those that cause cancer in animals. Furthermore, epidemiology studies have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers. In response to the carcinogenicity findings for 1,3-butadiene in animals and in humans, the Occupational Safety and Health Administration has proposed lowering the occupational exposure standard for this chemical from 1000 ppm to 2 ppm. Future work is needed to understand the mechanisms of tumor induction by 1,3-butadiene; however, the pursuit of this research should not delay the reduction of human exposure to this chemical.

Air Pollutants, Occupational↗
PubMed1993

Cell proliferation and chemical carcinogenesis: symposium overview.

Cancer, by definition, is a proliferative disease. The fundamental scientific issue explored at the international symposium "Cell Proliferation and Chemical Carcinogenesis" was the impact of chemically enhanced cell proliferation on the dynamic carcinogenic processes. This conference, held at the National Institute of Environmental Health Sciences January 14-16, 1992, provided an open forum for the exchange of new results, information, and ideas in four areas: a) general principles of cell division and carcinogenesis, b) critical evaluation of cell proliferation methodologies, c) cell proliferation and modeling of organ-specific carcinogenesis, and d) cell proliferation and human carcinogenesis. This overview summarizes key findings from that symposium. The general view expressed was that although cell proliferation is involved inextricably in the development of cancers, chemically enhanced cell division does not reliably predict carcinogenicity. Our knowledge of the multistep nature of carcinogenesis has advanced substantially during recent years; however, much still needs to be learned. A greater understanding of the cellular and molecular events in chemical carcinogenesis should improve all aspects of the overall risk assessment process, including extrapolations based on dose, species, and interindividual differences.

Animals↗
PubMed1993

Absence of morphologic correlation between chemical toxicity and chemical carcinogenesis.

The experimental data set used to evaluate site-specific histopathologic correspondence between the morphologic end points of toxicity and carcinogenicity comprises 130 chemical carcinogenesis studies. Nearly 1500 sex-species-exposure-group experiments were evaluated for a) evidence of toxicity or/and carcinogenicity, b) dose-response relationships, c) site-specific correlations of toxicity and carcinogenicity, and d) correspondence with Salmonella mutagenicity. The major conclusions are that chemicals evaluated for long-term toxicity and carcinogenicity in experimental animals divide typically and consistently into three categories: a) chemicals causing organ toxicity without cancer, b) chemicals causing site-specific cancer with no associated toxicity, and c) chemicals causing both toxicity and cancer in the same organ. Few chemicals overall (and none in this data set) fit the remaining group that cause neither toxicity nor carcinogenicity under these protocol conditions. Mutagenicity exhibited no consistent pattern with any of these groupings. Only 7 of 53 "positive" chemicals had target organ toxicity at all sites of carcinogenicity. Just three chemicals showed carcinogenic effects at the highest exposure concentrations without supporting evidence of tumors at the lower levels. From these comparative morphological analyses, and for almost all cases, available data do not support a correlation between chemically induced toxicity or regenerative phenomena and carcinogenicity. Consequently, until scientific knowledge about molecular mechanisms of chemical carcinogenesis becomes better understood and generally accepted, attempts to use toxicity findings to modify risk assessment processes will be fraught with uncertainty and thus could have a negative impact on public health.

Animals↗
PubMed1992

1,3-Butadiene: toxicity and carcinogenicity in laboratory animals and in humans.

1,3-Butadiene is a high production volume chemical used largely in the manufacture of synthetic rubber. The production and use of 1,3-butadiene increased dramatically during World War II with the development of the synthetic rubber industry. Before the 1980s, 1,3-butadiene was not considered to be particularly hazardous to human health; therefore, OSHA established a permissible limit of 1,000 ppm for occupational exposure to this chemical. Results of recent inhalation carcinogenicity studies have demonstrated clearly that 1,3-butadiene is a multiple-organ carcinogen in Sprague-Dawley rats and in B6C3F1 mice. Particularly noteworthy in mice were the early occurrences and extensive development of lymphomas, the induction of uncommon hemangiosarcomas of the heart, and the development of malignant lung tumors at exposure concentrations as low as 6.25 ppm. Because 6.25 ppm was the lowest concentration ever used in a long-term carcinogenicity of this gas, it is likely that lower exposure levels would also cause cancers in laboratory animals. In addition, multiple organ site neoplasia was induced in mice after only 13 weeks of exposure. Two reactive epoxides, 1,2-epoxy-3-butene and diepoxybutane, have been identified as intermediates in the biotransformation of 1,3-butadiene in rats and mice. Metabolism is probably an important factor in the carcinogenicity of 1,3-butadiene, because in vitro mutagenicity of 1,3-butadiene requires metabolic activation, whereas these epoxide intermediates are direct acting mutagens in bacteria and are carcinogens in rats and mice. The metabolism of 1,3-butadiene in rats and mice is linear up to concentrations of at least 1000 ppm. Pharmacokinetic studies on 1,3-butadiene and on 1,2-epoxy-3-butene have revealed certain quantitative differences in metabolic rates between Sprague-Dawley rats and B6C3F1 mice; however, these differences were not of sufficient magnitude to account for the reported different target site carcinogenic responses in these two strains of animals. Thus, additional factors must be involved in distinguishing site specificity in the carcinogenicity of 1,3-butadiene between species. In addition to its carcinogenic effects, 1,3-butadiene is a potent in vivo genotoxic agent to mouse bone marrow cells. Hematologic changes indicative of a partially regenerative anemia were induced in mice at 62.5 and higher concentrations. 1,3-Butadiene is also a reproductive and developmental toxicant. Epidemiology studies of workers employed in the production of 1,3-butadiene or of styrene-butadiene rubber have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed1992

Liver carcinogenesis by methyl carbamate in F344 rats and not in B6C3F1 mice.

Short-term and long-term carcinogenicity of methyl carbamate (MCB) was evaluated in F344 rats and B6C3F1 mice. In experiments lasting 6, 12, and 18 months, MCB was given in water by gavage to groups of 10 male and 10 female rats at 0 or 400 mg/kg body weight, 5 days per week, and to similar groups of mice at 0 or 1,000 mg/kg. At 6 months, MCB induced atypical mitoses, cytologic alterations, cytomegaly, pigmentation, necrosis, and neoplastic nodules of the liver in rats. At 12 and 18 months, carcinomas of the liver were induced by MCB in 80-90% of male rats and in 60-80% of female rats. None was observed in control rats or in mice. In the 2-year studies, MCB was given to groups of 50 male and 50 female rats at 0, 100, or 200 mg/kg and to similar groups of mice at 0, 500, or 1,000 mg/kg, 5 days/week. Chronic focal inflammation, cytologic alteration, hyperplasia, and neoplastic nodules and carcinomas (200 mg/kg groups only) of the liver were induced by MCB in rats. Liver tumor incidence data for combined experiments in rats were: males--5% in controls, 0% in 100 mg/kg group, 14% in 200 mg/kg group, and 77% in 400 mg/kg group; females--5% in controls, 0% in controls, 0% in 100 mg/kg group, 12% in 200 mg/kg group, and 63% in 400 mg/kg group. MCB was not shown to be carcinogenic in mice.

Animals↗