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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The known aneuploidogens, benomyl and its metabolite, carbendazim (methyl 2-benzimidazole carbamate (MBC)), were selected for the third in a series of ongoing projects with selected pesticides. Mutagenicity and carcinogenicity data submitted to the US Environmental Protection Agency's (US EPA's) Office of Pesticide Programs (OPP) as part of the registration process are examined along with data from the open literature. Mutagenicity and carcinogenicity profiles are developed to provide a complete overview and to determine whether an association can be made between benomyl- and MBC-induced mouse liver tumors and aneuploidy. Since aneuploidogens are considered to indirectly affect DNA, the framework adopted by the Agency for evaluating any mode of action (MOA) for carcinogenesis is applied to the benomyl/MBC data. Both agents displayed consistent, positive results for aneuploidy induction but mostly negative results for gene mutations. Non-linear dose responses were seen both in vitro and in vivo for aneuploidy endpoints. No evidence was found suggesting that an alternative MOA other than aneuploidy may be operative. The data show that by 14 days of benomyl treatment, events associated with liver toxicity appear to set in motion the sequence of actions that leads to neoplasms. Genetic changes (as indicated by spindle impairment leading to missegregation of chromosomes, micronucleus induction and subsequent aneuploidy in bone marrow cells) can commence within 1-24h after dosing, well within the time frame for early key events. Critical steps associated with frank tumor formation in the mouse liver include hepatotoxicity, increased liver weights, cell proliferation, hypertrophy, and other steps involving hepatocellular alteration and eventual progression to neoplasms. The analysis, however, reveals weaknesses in the data base for both agents (i.e. no studies on mouse tubulin binding, no in vivo assays of aneuploidy on the target tissue (liver), and no clear data on cell proliferation relative to dose response and time dependency). The deficiencies in defining the MOA for benomyl/MBC introduce uncertainties into the analysis; consequently, benomyl/MBC induction of aneuploidy cannot be definitively linked to mouse liver carcinogenicity at this time.
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PMID:A survey of EPA/OPP and open literature on selected pesticide chemicals. III. Mutagenicity and carcinogenicity of benomyl and carbendazim. 1222 May 88

Specialty acrylates and methacrylates (SAM) comprise a large family of industrial monomers. In the late 1980s, the United States EPA and the industry SAM Panel collaborated to evaluate the potential effects, particularly carcinogenesis, of this family of chemicals. As part of this arrangement, the SAM Panel, with EPA input and approval, conducted four studies with a representative acrylate, triethyleneglycol diacrylate (TREGDA), and methacrylate, triethyleneglycol dimethacrylate (TREGDMA). All studies used unoccluded skin application to male mice as follows: Study 1, evaluation of skin irritation compared to cell proliferation in the basal epithelium (BE) following 7 or 14 days of treatment; Study 2, 14-day dose range-finding study; Study 3, 90-day subchronic toxicity study; and Study 4, chronic bioassays employing the EPAs draft guidelines for dermal chronic bioassays. BE cell proliferation was determined in subchronic and carcinogenicity studies (Studies 1, 3, and 4). Organ weight changes (Studies 3 and 4) and increased mortality (Study 4) were observed for the highest dose of TREGDMA. However, there was no related histopathology. Both chemicals induced cell proliferation (7 days through 78 weeks) that correlated with acute and chronic inflammation of the skin. No skin tumors were observed in this study. TREGDA resulted in skin lesions at doses approximately 20-fold lower than TREGDMA. Most of the skin lesions showed similar patterns of microscopic cutaneous alteration suggestive of nonspecific irritation for both chemicals. However, the high concentration TREGDA group in the 78-week study also had evidence of epidermal cell necrosis. In contrast to earlier studies with acrylates, dose selection was based on careful examination of skin irritation and cell proliferation to avoid excessive skin damage. Under these conditions, TREGDA and TREGDMA were not carcinogenic.
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PMID:Skin irritation, basal epithelial cell proliferation, and carcinogenicity evaluations of a representative specialty acrylate and methacrylate. 1266 9

This study was conducted to investigate the role of the enzyme cyclooxygenase (COX) and its prostaglandin product PGE(2) in n-6 and n-3 polyunsaturated fatty acid (PUFA)-mediated effects on cellular proliferation of two human colorectal carcinoma cell lines. The long chain PUFAs eicosapentaenoic acid (EPA; 20:5n-3) and arachidonic acid (AA; 20:4n-6) both inhibited cell proliferation of Caco-2 cells compared with the long chain fatty acids alpha-linolenic acid (ALA; 18:3n-3) and linoleic acid (LA; 18:2n-6). Neither incubation with PGE(2) nor reduction in PGE(2) synthesis by EPA compared with AA led to differential effects on cell proliferation in Caco-2 cells. This suggests that n-6 and n-3 PUFA-mediated cell proliferation in Caco-2 cells is not regulated via PGE(2) levels. AA and EPA had no effect on growth of HT-29 colon cancer cells with a low COX activity. However, stimulation of COX-2 activity by IL-1 beta resulted in a decrease in cell proliferation and an induction of cytotoxicity by AA as well as by EPA. Both inhibition of the COX pathway by indomethacin as well as inhibition of direct lipid peroxidation by antioxidants such as vitamin E and C diminished the anti-proliferative effects of AA as well as EPA. Also, malondialdehyde, a product of lipid peroxidation and COX-activity was decreased by addition of vitamin E and partially decreased by indomethacin. These data support the hypothesis that growth inhibitory and cytotoxic effects of PUFAs with methylene-interrupted double bonds such as AA and EPA are due to peroxidation products that are generated during lipid peroxidation and COX activity.
Carcinogenesis 2003 Mar
PMID:The role of cyclooxygenase in n-6 and n-3 polyunsaturated fatty acid mediated effects on cell proliferation, PGE(2) synthesis and cytotoxicity in human colorectal carcinoma cell lines. 1266 96

The term "asbestos" has a commercial/industrial derivation limited to naturally occurring fibrous minerals of the serpentine or amphibole series. Chrysotile is the only type of asbestos in the serpentine series, whereas the amphibole series is represented by actinolite, amosite, anthophyllite, crocidolite, and tremolite. The essential characteristic of asbestos minerals is their fibrous nature. Large portions of the population ingest asbestos through consumption of food and water. Asbestos or asbestos-like fibers may gain access to water supplies as a result of mining (Lake Superior), from the presence of natural serpentine or amphibole deposits in watersheds (Seattle, WA, and San Francisco, CA) or, under certain conditions, through the use of asbestos-cement pipes for municipal water supplies. For the latter, erosion of the pipe with release of fibers is associated with the "aggressiveness" of the water, a term representing a mathematical expression of pH, alkalinity, and calcium content. The EPA estimated that 68.5% of water systems in the United States utilize water that is potentially capable of eroding asbestos-cement pipe. Carcinogenesis studies of amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted in male and female rats. Amosite asbestos was administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats, starting with the dams of the study animals. One group of amosite asbestos-exposed rats (amosite preweaning gavage) also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. Litter size was the same, but the offspring from mothers exposed to amosite asbestos were smaller at weaning than those from nonexposed mothers and remained smaller throughout their life. The DMH was administered by gavage at a dose of 7.5 mg/kg for males and 15 mg/kg for females every 14 days, starting at 8 weeks of age, for a total of five doses. The administration of DMH did not affect body weight gain either in amosite-exposed or nonexposed animals. The amosite-exposed rats showed enhanced survival compared with that of the nonexposed rats. DMH exposure reduced survival by approximately 1 year, although the survival of the amosite plus DMH groups was slightly greater than that of the DMH group alone. Significant increases in the incidences of C-cell carcinomas of the thyroid gland (untreated control, 11/117; amosite, 50/246, P<0.05; amosite preweaning gavage, 14/100) and of leukemia (38/117; 106/249, P<0.05; 49/100, P<0.01) in male rats were observed in amosite-exposed groups. However, the biologic significance of the C-cell carcinomas in relation to amosite asbestos exposure is discounted because of a lack of significance when C-cell adenomas and carcinomas were combined and because the positive effect was not observed in the amosite preweaning gavage group. The biologic significance of an increased incidence of leukemia is questionable because of a lack of statistical significance in the amosite group when evaluated by life table analysis and because no toxic lesions were observed in the target organs, i.e., gastrointestinal tract and mesothelium. DMH caused a high incidence (62%-74%) of intestinal neoplasia in amosite-exposed and nonexposed groups. Neither an enhanced carcinogenic nor a protective effect was demonstrated by exposure to amosite asbestos. Conclusions: Under the conditions of these feed studies, amosite asbestos was not overtly toxic, did not affect survival, and was not carcinogenic when ingested at a concentration of 1% in the diet by male or female F344/N rats. The cocarcinogenic studies using DMH were considered inadequate because of the high incidence of DMH-induced intestinal neoplasia in both the amosite asbestos-exposed and nonexposed groups. Levels of Evidence of Carcinogenicity: Amosite Asbestos: Male Rats: Negative. Female Rats: Negative. Amosite Asbestos + DMH: Male Rats: Inadequate. Female Rats: Inadequate. Note: Amosite Asbestos was previously tested in Syrmosite Asbestos was previously tested in Syrian Golden Hamsters administered in feed (See TR-249, reported 1983).
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PMID:NTP Toxicology and Carcinogenesis Studies of Amosite Asbestos (CAS No. 12172-73-5) in F344/N Rats (Feed Studies). 1274

It is widely reported that an association exists between dietary fat intake and the incidence of prostate cancer in humans. To study this association, there is a need for an animal model where prostate carcinogenesis occurs spontaneously. The canine prostate is considered a suitable experimental model for prostate cancer in humans since it is morphologically similar to the human prostate and both humans and dogs have a predisposition to benign and malignant prostate disease. In this study, the FA and lipids profiles of the normal canine prostate tissue from nine dogs were examined. The total lipid content of the canine prostate tissue was 1.7 +/- 0.5% (wet weight). The lipid composition analysis using TLC-FID showed that the two major lipid classes were phospholipids and TAG. Total FA, phospholipid, and TAG FA analysis showed that the major FA were palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2n-6), and arachidonic acid (20:4n-6). The n-3 FA were present at <3% of total FA and included alpha-linolenic acid (18:3n-3) (in total and TAG tissue FA), EPA (20:5n-3) (not in TAG), and DHA (22:6n-3) (not in TAG). The n-3/n-6 ratio was 1:11, 1:13, and 1:8 in total, phospholipid, and TAG FA, respectively. This study shows the canine prostate has a low level of n-3 FA and a low n-3/n-6 ratio. This is perhaps due to low n-3 content of the diet of the dogs. FA analysis of dogfoods available in Australia showed that the n-3 content in both supermarket and premium brand dogfoods was <3% (wet weight), and the n-3/n-6 ratio was low.
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PMID:Lipids and FA analysis of canine prostate tissue. 1293 77

Several national and international health agencies worldwide have established carcinogen identification programs with the aim of identifying the agents and exposures that contribute to the global burden of cancer. These programs have many features in common. IARC's program is described in some detail, with an emphasis on how evaluations can be changed by mechanistic data. Recently, several programs have expanded on the guidance they provide in assessing mechanistic data. The most comprehensive example is EPA's recent draft final Guidelines for Carcinogen Risk Assessment. In all programs, however, the principal role of mechanistic information has been to support the positive results observed in epidemiological studies or to discount the relevance of positive results observed in experimental animal bioassays. An alternative paradigm for carcinogen identification is proposed, one where mechanistic studies have a central role, rather than a supporting one. Under this paradigm, potentially carcinogenic agents would be identified by (1) identifying the key precursor events and processes involved in human cancer and (2) testing to see whether an agent can affect these events and processes. Under this paradigm, which is consistent with a multi-factorial view of carcinogenesis, it might be possible to identify carcinogens through mechanistic understanding alone, without waiting for epidemiological studies or 2-year carcinogenesis bioassays in rats and mice. This paradigm asks the question, "What is a human carcinogen? Is it an agent that we observe to induce tumors, or more generally, an agent with a clear role in tumor development?"
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PMID:Current criteria to establish human carcinogens. 1548 33

U.S. EPA's integrated risk information system (IRIS) assessment of 2-butoxyethanol (EGBE) indicates that the human carcinogenic potential of EGBE cannot be determined at this time, but that "suggestive evidence" for cancer exists from laboratory animal studies (hemangiosarcoma of the liver in male mice and forestomach squamous cell papilloma or carcinoma in female mice [National Toxicology Program (NTP), 2000a. Toxicology and carcinogenesis studies of 2-butoxyethanol (CAS no. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program Technical Report Series No. 484. U.S. Department of Health and Human Services, National Institutes of Health, Washington, DC]). Since the last EGBE IRIS assessment, a number of studies have provided evidence that the carcinogenic effects observed in mice are nonlinear in their mode of action and may be dependent on threshold events such as EGBE-induced hemolytic effects. EPA is in the process of considering several questions relating to this issue. First, can a plausible mode of action be determined for the two types of tumors observed in mice? Second, are the mechanisms involved applicable to humans? If so, should the mode of action be considered to result in a linear or nonlinear dose-response? These questions will be addressed within the context of the agency's new cancer guidelines and with regard to how the answers might affect a revised IRIS assessment for EGBE.
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PMID:U.S. EPA's IRIS assessment of 2-butoxyethanol: the relationship of noncancer to cancer effects. 1570 94

Under the 2005 U.S. EPA Guidelines for Carcinogen Risk Assessment (1), evaluations of carcinogens rely on mode of action data to better inform dose response assessments. A reassessment of carbon tetrachloride, a model hepatotoxicant and carcinogen, provides an opportunity to incorporate into the assessment biologically relevant mode of action data on its carcinogenesis. Mechanistic studies provide evidence that metabolism of carbon tetrachloride via CYP2E1 to highly reactive free radical metabolites plays a critical role in the postulated mode of action. The primary metabolites, trichloromethyl and trichloromethyl peroxy free radicals, are highly reactive and are capable of covalently binding locally to cellular macromolecules, with preference for fatty acids from membrane phospholipids. The free radicals initiate lipid peroxidation by attacking polyunsaturated fatty acids in membranes, setting off a free radical chain reaction sequence. Lipid peroxidation is known to cause membrane disruption, resulting in the loss of membrane integrity and leakage of microsomal enzymes. By-products of lipid peroxidation include reactive aldehydes that can form protein and DNA adducts and may contribute to hepatotoxicity and carcinogenicity, respectively. Natural antioxidants, including glutathione, are capable of quenching the lipid peroxidation reaction. When glutathione and other antioxidants are depleted, however, opportunities for lipid peroxidation are enhanced. Weakened cellular membranes allow sufficient leakage of calcium into the cytosol to disrupt intracellular calcium homeostasis. High calcium levels in the cytosol activate calcium-dependent proteases and phospholipases that further increase the breakdown of the membranes. Similarly, the increase in intracellular calcium can activate endonucleases that can cause chromosomal damage and also contribute to cell death. Sustained cell regeneration and proliferation following cell death may increase the likelihood of unrepaired spontaneous, lipid peroxidation- or endonuclease-derived mutations that can lead to cancer. Based on this body of scientific evidence, doses that do not cause sustained cytotoxicity and regenerative cell proliferation would subsequently be protective of liver tumors if this is the primary mode of action. To fulfill the mode of action framework, additional research may be necessary to determine alternative mode(s) of action for liver tumors formed via carbon tetrachloride exposure.
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PMID:Postulated carbon tetrachloride mode of action: a review. 1776 46

Assessment of human cancer risk from animal carcinogen studies is severely limited by inadequate experimental data at environmentally relevant exposures and by procedures requiring modeled extrapolations many orders of magnitude below observable data. We used rainbow trout, an animal model well-suited to ultralow-dose carcinogenesis research, to explore dose-response down to a targeted 10 excess liver tumors per 10000 animals (ED(001)). A total of 40800 trout were fed 0-225 ppm dibenzo[a,l]pyrene (DBP) for 4 weeks, sampled for biomarker analyses, and returned to control diet for 9 months prior to gross and histologic examination. Suspect tumors were confirmed by pathology, and resulting incidences were modeled and compared to the default EPA LED(10) linear extrapolation method. The study provided observed incidence data down to two above-background liver tumors per 10000 animals at the lowest dose (that is, an unmodeled ED(0002) measurement). Among nine statistical models explored, three were determined to fit the liver data well-linear probit, quadratic logit, and Ryzin-Rai. None of these fitted models is compatible with the LED(10) default assumption, and all fell increasingly below the default extrapolation with decreasing DBP dose. Low-dose tumor response was also not predictable from hepatic DBP-DNA adduct biomarkers, which accumulated as a power function of dose (adducts = 100 x DBP(1.31)). Two-order extrapolations below the modeled tumor data predicted DBP doses producing one excess cancer per million individuals (ED(10)(-6)) that were 500-1500-fold higher than that predicted by the five-order LED(10) extrapolation. These results are considered specific to the animal model, carcinogen, and protocol used. They provide the first experimental estimation in any model of the degree of conservatism that may exist for the EPA default linear assumption for a genotoxic carcinogen.
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PMID:Nonlinear cancer response at ultralow dose: a 40800-animal ED(001) tumor and biomarker study. 2379 19

The present study demonstrates the anti-tumor effects of combined supplementations of dietary fish oil (Maxepa) and 1alpha,25-dihydroxyvitamin D(3) (vitamin D(3)) on 7,12-dimethylbenz(alpha)anthracene (DMBA)-induced rat mammary carcinogenesis. Female Sprague-Dawley rats at 50 days of age were treated with 7,12-dimethylbenz(alpha)anthracene (DMBA; 0.5mg/100g body weight) by a single tail vein injection in an oil emulsion. Both fish oil (rich in EPA and DHA) and vitamin D(3) were administered orally at a dose of 0.5 ml/day/rat and 0.3 microg/100 microL propylene glycol twice a week respectively and continued to 35 weeks after DMBA administration. Fish oil in combination with vitamin D(3) resulted in a significant reduction in incidence, multiplicity and volume of mammary tumors. These supplementation also inhibited DMBA-induced mammary 7-methylguanine DNA adducts formation, which was measured by HPLC-fluorescence assay (at four sequential time points; ANOVA, F=42.56, P<0.0001). Immunohistochemical analysis revealed that the effect of fish oil and vitamin D(3) occurred through suppression of cell proliferation (BrdU-LI: P<0.0001). Fish oil and vitamin D(3) together also reduced the mRNA expression of iNOS (84%, P<0.05). In view of their natural availability, non-toxicity and acceptability; combined supplementation of fish oil and vitamin D(3) might be effective for chemoprevention of mammary carcinogenesis.
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PMID:Combinatorial effect of fish oil (Maxepa) and 1alpha,25-dihydroxyvitamin D(3) in the chemoprevention of DMBA-induced mammary carcinogenesis in rats. 2059 47


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