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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Health Effects Division of the Office of Pesticide Programs (OPP) assessed the carcinogenic potential of three structurally related chloroalkylthiodicarboximide fungicides using a consensus peer review process and EPA's 1986 guidelines for cancer risk assessment. All of the fungicides were categorized as Group B2 (probable human) carcinogens based upon findings of an increased incidence of malignant tumors, or combined malignant and benign tumors, in multiple experiments involving different strains of mice and rats. The primary sites of tumor formation with the chloroalkylthiodicarboximide fungicides in male and/or female mice (CD-1 and B6C3F1) were the gastrointestinal tract (captan, folpet, and captafol), the lymph system (folpet and captafol), and the vascular system (captafol). The main sites of tumor formation in rats of one or both sexes (CR CD, Wistar, or F344 strains) were the kidney (Captan and captafol), uterus (captan), mammary gland and liver (captafol). In addition, positive trends for thyroid, testicular, mammary gland, and lymph node tumors were observed with folpet in the same strains of rats. All three of the compounds exhibited positive mutagenic activity in a variety of in vitro short-term tests for gene mutation, DNA repair, and chromosomal aberrations in prokaryotic and eukaryotic cells, but were not genotoxic in available studies performed under in vivo conditions. The assessment of human cancer risk for captan, folpet, and captafol was made using low-dose extrapolation models.
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PMID:Evaluation of the carcinogenic potential of pesticides. 4. Chloroalkylthiodicarboximide compounds with fungicidal activity. 844 25

This study was stimulated by a recent U.S. Environmental Protection Agency (EPA, 1994) statement in draft environmental carcinogen risk assessment guidelines: "Several kinds of observations from animal studies can contribute to the judgment whether animal responses indicate a significant carcinogenic hazard to humans." We have investigated each of these kinds of observation using the cancer bioassay data system database. We obtained concordances from rat to mouse (and vice versa) for various subgroups of chemicals as follows: chemicals that induced tumors at multiple sites, chemicals that induce cancer in both sexes, chemicals that display reduced latency, and chemicals increasing the rates of rare tumors. The concordances are much higher for these chemical subgroups than the chemical groups that induce tumor at a single site, in only one sex, or without reduced latency, respectively. Thus, our findings support some of the EPA's suggested factors.
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PMID:An empirical examination of factors influencing prediction of carcinogenic hazard across species. 883 53

Chronic dietary treatment of rodents with the fungicide chlorothalonil causes an increased incidence of papillomas and carcinomas of the forestomach squamous epithelium (rats and mice, both sexes) and adenomas and carcinomas of the renal proximal tubule epithelium (rats, both sexes; mice, males only); the product elicits no tumorigenic response in dogs. As a result, chlorothalonil is classified by EPA as a Group B2 "probable human carcinogen." However, chlorothalonil is not genotoxic and there is strong evidence that both the forestomach and renal tumors observed in rodents result from cytotoxicity followed by compensatory cell proliferation and hyperplasia. In the case of the forestomach, cytotoxicity results from sustained irritation of the squamous epithelium by chlorothalonil leading to inflammation, ulceration, and restorative hyperplasia. Cytotoxicity in the renal tubular epithelium is associated with formation of di- and trithiols that arise through the action of renal beta-lyase on cysteine S-conjugates derived from the corresponding glutathione conjugates of chlorothalonil. Renal cytotoxicity and cell necrosis in rodents result from the ability of the di- and trithiols to inhibit kidney mitochondrial respiration and disrupt cellular integrity. There is strong evidence that this mechanism is not operative in other species such as dogs and monkeys. The progression from cytotoxicity to hyperplasia to neoplasia is becoming increasingly well-recognized as a threshold-based mechanism of carcinogenesis. Unless exposure is excessively prolonged or intense, the cytotoxic effects will be fully reversible. Furthermore, the effects observed in rodents are not appropriate for evaluating the potential human cancer risk from chlorothalonil. Humans do not possess an organ equivalent to the rodent forestomach and the rat is a poor model for evaluating potential human risk for the renal tumorigenicity of chlorothalonil. Humans are likely to be very much less sensitive than rats to the nephrotoxic effects of chlorothalonil. In view of the fact that the tumorigenic effects of chlorothalonil are mediated through a well-understood, nongenotoxic, threshold-based mechanism of little or no relevance to humans, chlorothalonil should be a prime candidate for re-review under EPA's new risk assessment guidelines. Expert committees in both Europe and Canada have concluded that human risks to chlorothalonil should be evaluated by means of the NOEL/safety factor approach usually employed for noncarcinogenic materials.
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PMID:A mechanistic interpretation of the oncogenicity of chlorothalonil in rodents and an assessment of human relevance. 892 47

The objective of the present study was to investigate the effect of membrane fatty acid (FA) composition on the activity of phospholipase C (PLC) in HT-29 human colon cancer cells. The membrane FA composition was altered by supplementing cultured cells with FAs of different composition. The FAs were stearic acid (18:0; SA), gamma linolenic acid (18:3 omega 6; gamma LnA); alpha linolenic acid (18:3 omega 3; alpha LnA;); eicosapentaenoic acid (20:5 omega 3; EPA) and docosahexaenoic acid (22:6 omega 3; DHA). The fatty acids were supplemented as a FA/BSA complex. Cells supplemented with SA served as the control. Tumor growth was followed by counting the number of cells in culture. The results indicate that polyunsaturated fatty acid (PUFA) supplementation had no consistent effect on tumor growth from 1 day to another throughout the 15 days of growth. The fatty acid composition of membranes indicates that cells incorporated and modified the supplemented fatty acids by desaturation, elongation and retroconversion. The unsaturation index (UI) of membranes of cells supplemented with EPA and DHA was higher than other groups. PLC activity; measured in the absence of GTP gamma(S) in the assay mixture; was not influenced by membrane FA modification. However, in the presence of GTP gamma(S) PLC of cells supplemented with 18:3(omega 6) was the lowest among the groups. It has been shown that 18:3(omega 6) accumulated the most in the phosphatidylethanolamine (PE) fraction. There was a negative correlation between the activity of PLC in the presence of G protein activation and PE 18:3 (omega 6) content without affecting UI. It was concluded that G protein may be sensitive to the level of 18:3(omega 6) content and not to the general fluidity of the membranes.
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PMID:The effect of unsaturated fatty acids on membrane composition and signal transduction in HT-29 human colon cancer cells. 895 Feb 5

Unsaturated fatty acids, including n-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (C22:6, DHA) and eicosapentaenoic acid (C20:5, EPA), and a series of n-6 PUFAs were investigated for their anti-tumour and antimetastatic effects in a subcutaneous (s.c.) implanted highly metastatic colon carcinoma 26 (Co 26Lu) model. EPA and DHA exerted significant inhibitory effects on tumour growth at the implantation site and significantly decreased the numbers of lung metastatic nodules. Oleic acid also significantly inhibited lung metastatic nodules. Treatment with arachidonic acid showed a tendency for reduction in colonization. However, treatment with high doses of fatty acids, especially linoleic acid, increased the numbers of lung metastatic nodules. DHA and EPA only inhibited lung colonizations when administered together with the tumour cells, suggesting that their incorporation is necessary for an influence to be exerted. Chromatography confirmed that contents of fatty acids in both tumour tissues and plasma were indeed affected by the treatments. Tumour cells pretreated with fatty acids in vivo, in particular DHA, also showed a low potential for lung colony formation when transferred to new hosts. Thus, DHA treatment exerted marked antimetastatic activity associated with pronounced change in the fatty acid component of tumour cells. The results indicate that uptake of DHA into tumour cells results in altered tumour cell membrane characteristics and a decreased ability to metastasize.
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PMID:Inhibitory effects of docosahexaenoic acid on colon carcinoma 26 metastasis to the lung. 904 19

Polyunsaturated fatty acids (PUFA) such as gamma-linolenic acid (GLA, 18:3n-6), eicosapentaenoic acid (EPA, 20:5n-3), and docosahexaenoic acid (DHA, 22:6n-3) have been shown to be cytotoxic to tumor cells. The objective of this work was to study the effects of PUFA on the radiation response of a 36B10 rat astrocytoma cell line. Supplementation of the astrocytoma cells with 15-45 microM GLA, EPA, or DHA produced marked changes in the fatty acid profiles of their phospholipids and neutral lipids. The methylene bridge index of these lipids increased significantly. These PUFA also exerted cytotoxic effects, as determined using the clonogenic cell survival assay. While GLA and DHA produced a moderate cell-killing effect, EPA was extremely cytotoxic, especially at a concentration of 45 microM. The monounsaturated oleic acid (OA, 18:1n-9) did not affect cell survival. Further, all three PUFA, and particularly GLA, increased the radiation-induced cell kill; OA did not enhance the effect of radiation. alpha-Tocopherol acetate blocked the enhanced radiation sensitivity of GLA- and DHA-supplemented cells. In conclusion, GLA, EPA, and DHA supplementation prior to, during, and after irradiation can enhance the radiation-induced cytotoxicity of rat astrocytoma cells. GLA and DHA supplementation post-irradiation also enhanced the radiation response of the 36B10 cells. Because GLA maximally increases the radioresponsiveness of a rat astrocytoma, this PUFA might prove useful in increasing the therapeutic efficacy of radiation in the treatment of certain gliomas.
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PMID:Polyunsaturated fatty acids increase the sensitivity of 36B10 rat astrocytoma cells to radiation-induced cell kill. 907 65

An ad hoc panel of dioxin experts convened by EPA's Science Advisory Board found the Agency's claim of cancer causation by dioxin unacceptable. This paper uses the very same two studies [Fingerhut (NIOSH) and Kociba] EPA relied upon to test the observations made in an unused third study [Bertazzi] to conclude that dioxin is (1) a promoter blocker of certain cancers, including all the cancers Agency scientists claimed dioxin promoted; (2) a promoter of some other cancers that EPA scientists failed to identify; and (3) a net anticarcinogen. Three independent total tumor reductions provide evidence of both cancer prevention and quantifiable risk reductions tied to specific dioxin levels. The author indirectly suggests a general cancer prevention treatment, even for cancers already initiated.
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PMID:Dioxin is a promoter blocker, a promoter, and a net anticarcinogen. 933 90

Acrylonitrile (ACN) is a monomer used extensively in the production of plastics, synthetic fibers, and rubber. In previous assessments conducted by IARC and the EPA, ACN was classified as a probable human carcinogen based on limited evidence in humans and sufficient evidence in laboratory animals. Specifically, EPA had determined that there was an association between ACN exposure and lung cancer based on a study by O'Berg (1980, J. Occup. Med. 22, 245-252). However, a follow-up of this cohort (O'Berg et al., 1985, J. Occup. Med. 27, 835-840) shows no statistically significant excess of lung cancer mortality or incidence. Our evaluation of the more recent human database taken as a whole shows that there is not a clear association between ACN exposure and human cancer, yet the studies have insufficient power to be able to rule out a small increase. In laboratory rats, however, ACN has been shown to be clearly carcinogenic by the oral and inhalation routes. Applying the methodology of EPA's proposed 1996 cancer risk assessment guidelines to the rat tumor data, the estimated upper bound on the excess lifetime risk at continuous exposure to 1 microgram/m3 ACN is calculated to be in the range of 8.2 x 10(-6) to 1.1 x 10(-5).
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PMID:Acrylonitrile: a reevaluation of the database to support an inhalation cancer risk assessment. 944 18

Various types of polyunsaturated fatty acids (PUFAs) have been suggested to exert different effects on the colon in terms of promotion or inhibition of tumor development. Results of in vitro and in vivo studies are, however, inconsistent and it remains unclear whether or not the cellular effects of PUFAs change along with the malignant transformation of colonic cells. In this study, we used the NIH3T3 cell line and its SIC (sigmoid colon cancer) oncogene transformants to compare the effects of PUFAs on the proliferation of non-malignant and malignant cells. We also determined the cellular utilization of fatty acids in media by a high-performance liquid chromatography method. The addition of exogenous arachidonic acid (ARA, an n-6 fatty acid), eicosapentaenoic acid (EPA, n-3), and docosahexaenoic acid (DHA, n-3) exerted different effects on NIH3T3 cells, and on SIC transformants, in which selective inhibitory effects were observed at media concentrations ranging from 10 to 20 microg/ml. In cells cultured in media supplemented with EPA or DHA at a concentration of 2 microg/ml, which had no effect on cell proliferation, the cellular utilization of linoleic acid (n-6), a precursor of n-3 fatty acids, was inhibited. This inhibition was stronger in SIC transformants than in NIH3T3 cells (P < 0.05). There was no difference in the utilization of fatty acids between the two cell lines cultured in media supplemented with ARA. We conclude that the cellular response to exogenous long-chain PUFAs is modified during the course of malignant transformation, and that EPA and DHA (n-3 PUFAs) appear to have specific inhibitory effects on cancer cells and may thus enhance the host defense against colon cancer.
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PMID:Inhibitory effects of n-3 polyunsaturated fatty acids on sigmoid colon cancer transformants. 960 50

To evaluate the effects of dietary fats on breast cancer growth and metastasis, KPL-1 human breast carcinoma cells which have a propensity for axillary lymph node metastasis when inoculated into the thoracic mammary fat pad of female nude mice were examined. The mice were fed one of three semipurified diets containing 9.5% eicosapentaenoic acid plus 0.5% linoleic acid (EPA diet), 10% linoleic acid (LA diet), or 9.5% palmitic acid plus 0.5% linoleic acid (PA diet), or commercial laboratory chow containing 8.5% fat of which 4.1% was LA, 1.1% was PA, 0.06% was EPA, and 3.24% was other (Standard diet) starting 19 days before tumor cell inoculation and continuing until the end of the experiment (43 days after tumor cell inoculation). The tumor growth was faster and at a higher incidence in the mice fed the LA diet, and much slower and at a lower incidence in the EPA diet group compared with the mice fed the PA or Standard diet; the two separate experiment demonstrated identical results. The differences in tumor weight between the LA and PA groups and between the PA and EPA groups were significant (P < 0.05, respectively) at the termination of the experiment; the differences were due to different tumor cell proliferation rates. In an in vitro MTT assay, fatty acids showed direct stimulatory or inhibitory effects on the KPL-1 cells. Lymph node metastasis was seen in the LA and Standard diet groups, whereas it was not seen in the PA or EPA groups. The body weights were significantly lighter in the LA and EPA groups compared with the PA and Standard diet groups (P < 0.05, respectively). The results indicate that the EPA diet produced a reduction in tumor cell growth and metastasis whereas the LA diet had an enhancing effect on these parameters; dietary fatty acids may thus have a direct role in the growth and metastasis of human breast carcinoma independent of their systemic effects.
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PMID:Dietary effects of fatty acids on growth and metastasis of KPL-1 human breast cancer cells in vivo and in vitro. 967 80


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