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

Although it cannot be said that "everything causes cancer," our environment will never be carcinogen-free. As a result, there are many substances we come in contact with daily that could be potentially harmful to our health. Even with the growing knowledge of the mechanisms of carcinogenesis, it is difficult to single out the exact cancer-causing or -promoting effects of single substances. The confusion that exists about the environment, lifestyle, and cancer can be overwhelming for everyone. Garfinkel offered the following suggestions for health care providers to use in putting this issue into better perspective for consumers: (1) no single study of cancer risk factors should be used as a basis for writing or changing public health policy; (2) animal studies should be supportive of findings in epidemiological studies; (3) any environmental factor-cancer effect relationship should be demonstrated biologically; (4) regulatory agencies such as the EPA tend to be conservative in their interpretation of study results, and may suggest caution even when the risk of developing cancer is low; (5) regulatory agencies have been known to extrapolate future effects of carcinogen exposure from current incomplete or limited information about the carcinogen in question. With the knowledge that we do have, we must strive to take personal control over life-style factors that may cause cancer.
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PMID:Professional and consumer concerns about the environment, lifestyle, and cancer. 154 15

The Moolgavkar-Venzon-Knudson (M-V-K) two-stage model for carcinogenesis was used to estimate the risk-specific dose (RsD) based on the incidence of tumors reported by Kociba et al. (1978) for Sprague-Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; dioxin). The results from the recently completed (1990) reevaluation of the Kociba et al. study, which used the current National Toxicology Program (NTP) pathology criteria, were also evaluated. Time-to-tumor information for each rat was incorporated into the analysis. Model parameters for the approximate form of the hazard function of the two-stage M-V-K model were determined by maximum likelihood estimation. This simplification was significant but necessary, because laboratory data on the intermediate cell growth rate and the transition rates have not been determined. Estimates of the RsD (10(-6) risk) (based on the original 1978 histopathology results) were 10 fg/kg/d when carcinomas and hyperplastic nodules were combined and 150 fg/kg/d when only carcinomas were considered. In contrast, using the 1990 histopathology data, the RsD (10(-6) risk) was 80 fg/kg/d when adenomas and carcinomas were combined and 25,000 fg/kg/d when only hepatocellular carcinomas were considered. Since the two-stage M-V-K model is intended to predict the occurrence of malignant tumors, the mathematically appropriate RsD is 25,000 fg/kg/d (10(-6) risk). Because the model does not account for pharmacokinetics or the possibility of other toxic effects, the appropriate RsD (10(-6) risk) for humans should be much smaller. Using the carcinoma data only, a sensitivity analysis of key parameters in the model was conducted. Results indicated that the ranges of plausible values for the RsD (10(-6) risk) for the original 1978 and the 1990 reevaluation data were 70-2600 fg/kg/d and 120-50,000 fg/kg/d, respectively. The lowest plausible RsD is, therefore, approximately 10-fold greater than the current U.S. EPA RsD (10(-6) risk) of 6.4 fg/kg/d [which is based on the linearized multistage (LMS) model]. Even though these results must be considered preliminary until some of the values for the model parameters are experimentally determined and a complete physiologically based or receptor-based model is developed, this analysis shows that nearly any plausible laboratory data on tumor progression will yield a much higher RsD than currently embraced by the U.S. EPA.
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PMID:Risk assessment of 2,3,7,8-TCDD using a biologically based cancer model: a reevaluation of the Kociba et al. bioassay using 1978 and 1990 histopathology criteria. 165 56

Considering that nowadays there is no unanimity about the possibility of adopting environmental and/or biological limit values in occupational exposure to carcinogens, some aspects are discussed about the mechanism of action of carcinogens, their metabolism and problems deriving from the possible multiple exposures, interactions and speciation of the different compounds. After the analysis of the results obtained by means of two different approaches by the American Conference of Governmental Industrial Hygienist and the Environmental Protection Agency of the United States, the authors examine some aspects of the qualitative and as far as possible quantitative comparison for the 16 substances included in both lists and they discuss how the mathematical models are used in the process of carcinogenic risk evaluation. Finally, it is considered the possible application even in occupational carcinogenesis of a model such as the one of the EPA.
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PMID:[The evaluation of occupational exposure to carcinogenic substances: limit values and risk assessments]. 215 17

The effects of eicosapentaenoic acid (EPA, n-3 polyunsaturated fatty acid) and linoleic acid (n-6 polyunsaturated fatty acid) on azoxymethane-induced colon carcinogenesis in rats were studied. Male Donryu rats were given two types of semipurified diet containing 4.7% EPA plus 0.3% linoleic acid and 5% linoleic acid. The rats were given s.c. injection of azoxymethane (7.4 mg/kg body weight once a week for 11 weeks) and sacrificed 15 weeks after the last injection of azoxymethane. The tumor incidence and tumor yields (tumors per rat) of the colon were significantly lower in rats on the EPA diet compared to those on the linoleic acid diet; i.e., 33%, 0.41 +/- 0.61 and 69%, 1.66 +/- 1.69, respectively. In the analysis of phospholipid fatty acid composition, the colon tumor showed higher levels of arachidonic acid and lower levels of linoleic acid than those in the normal colon mucosa in both diet groups. Despite the increase of arachidonic acid in colon tumor, the EPA diet suppressed the excessive production of prostaglandin E2, which may be accompanied with neoplastic formation, whereas linoleic acid diet caused a marked increase in the tumor content of prostaglandin E2 compared to normal colon mucosa. These results suggest that EPA exerts its inhibitory effect on colon carcinogenesis by modulating lipid metabolism and inhibiting prostaglandin E2 synthesis in tumor cells.
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PMID:Effect of dietary eicosapentaenoic acid on azoxymethane-induced colon carcinogenesis in rats. 284 39

The skin and lung tissues from SENCAR mice used as part of the Environmental Protection Agency's (EPA's) Carcinogenesis Testing Matrix were examined. This study included SENCAR mice used in three different short-term bioassay protocols in which the skin papilloma assay was used to identify initiators, promoters, and complete carcinogens. Also included were the pathology findings from SENCAR mice used in the combined bioassay in which the skin assay and the lung adenoma assay were conducted simultaneously. The gross and microscopic features of treatment-associated and spontaneous lesions of the skin and lung of the SENCAR mouse used in these studies are defined and the lesions most commonly observed are described. Generally, gross observations and microscopic findings in both the skin and lung tissues were poorly correlated. Although there are several definite criteria on which gross interpretations of the various skin and lung lesions can be made, with the exception of pedunculated squamous cell papillomas and the classic squamous cell carcinomas, the various lesion types had a wide variety of clinical presentations that severely compromised the accuracy of gross diagnosis. Further, in the case of benign skin neoplasms, malignant transformation of these tumors most often occurred at the base of the lesion and was initially hidden from gross observation. As a result, approximately 50% of the neoplasms interpreted clinically as benign tumors (papillomas and keratoacanthomas) were actually malignant neoplasms. Moreover, many lesions determined grossly to be nontumorous were in fact found to be neoplastic when examined microscopically. The SENCAR mouse was found to be more responsive in the lung adenoma assay than other strains examined with exception of the Strain A. Although accurate interpretation of the lung lesions in the SENCAR was compromised by nonneoplastic treatment-associated and/or spontaneous lesions, the feasibility of using the SENCAR skin and lung as target tissues in two-stage combined carcinogenesis studies merits further consideration.
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PMID:Gross and microscopic lesions in the female SENCAR mouse skin and lung in tumor initiation and promotion studies. 378 Jun 37

Methylene chloride (dichloromethane, DCM) is metabolized by two pathways: one dependent on oxidation by mixed function oxidases (MFO) and the other dependent on glutathione S-transferases (GST). A physiologically based pharmacokinetic (PB-PK) model based on knowledge of these pathways was used to describe the metabolism of DCM in four mammalian species (mouse, rat, hamster, and humans). Kinetic constants for the model were derived from in vivo experiments or the literature. The model was constructed to distinguish contributions from the two pathways of metabolism in lung and liver tissue, and to permit extrapolation from rodents to humans. Model validation was conducted by comparing predicted blood concentration time-course data in rats, mice, and humans with experimental data from these species. The tumor incidence in two chronic studies of DCM toxicity in mice was correlated with various measures of target tissue dose calculated with the PB-PK model. Tumor incidence correlated well with tissue AUC (area under the concentration/time curve) and amount of DCM metabolized by the GST pathway. However, tumor incidence did not correlate with the amount of DCM metabolized by the MFO pathway. Because of its low chemical reactivity, DCM is unlikely to be directly involved in carcinogenesis. Consequently, metabolism of DCM by GST appears to be important in carcinogenesis. The PB-PK model was used to estimate target doses of presumed toxic chemical species in humans exposed to DCM by inhalation or by drinking water. Target tissue doses in humans exposed to low concentrations of DCM are 140- to 170-fold lower (inhalation) or 50- to 210-fold lower (drinking water) than would be expected from the linear extrapolation and body surface area factors which have been used in conventional risk assessment methods (D. V. Singh, H. L. Spitzer, and P. D. White (1985). Addendum to the Health Assessment Document for Dichloromethane (Methylene Chloride). EPA/600/8-82/004F). The PB-BK analysis thus suggests that conventional risk analyses greatly overestimate the risk in humans exposed to low concentrations of DCM. PB-PK considerations provide a scientific basis for risk assessment, improve experimental design in chronic studies, and structure collection of quantitative metabolic constants required for risk assessment.
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PMID:Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. 382 80

The literature on cell transformation by chemical carcinogens has been critically reviewed. This subject is highly relevant to carcinogenesis in vivo, because the phenotypic changes that are collectively referred to as cell transformation usually involve the acquisition of tumorigenicity on inoculation into suitable rodent hosts. The systems chosen for review fall into 3 categories: cell strains (cells with a limited lifespan); cell lines (cells with an unlimited lifespan); and oncogenic viral-chemical interactions involving cells (Fischer rat embryo cells expressing an endogenous retrovirus, mouse embryo cells expressing the AKR leukemia virus, chemical enhancement of a simian adenovirus, SA7 transformation of Syrian hamster or rat embryo cells). Of the entire literature reviewed, 117 papers have been accepted for data abstraction by pre-defined criteria; these include 41 references to cell strains, 40 in cell lines, and 38 in viral-chemical interactions including cells. Because different systems have been reviewed, it would be meaningless to group all the compounds. The overall summary of the systems is as follows (many compounds have been tested in more than one system and, hence, are duplicated in these totals). (Chart: see text) In general, there is a reasonably good correlation between the results of the cell transformation systems and in vivo carcinogenesis. However, the many deficiencies of the EPA Merged Carcinogen List preclude definitive comparisons. Moreover, a number of 'false negatives' were obtained in systems that did not employ external metabolic activation. Further validation of all systems is required, but it seems very probable that several cell transformation systems will become valuable in assaying (with reasonable time and cost) the carcinogenic potential of environmental chemicals.
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PMID:Cell transformation by chemical agents--a review and analysis of the literature. A report of the U.S. Environmental Protection Agency Gene-Tox Program. 633 91

After 30 years of experience with human exposure to dichlorvos (DDVP) in the home, workplace, and sickroom, the U.S. EPA has published its intent to revoke the food additive registration of this cholinesterase-inhibiting insecticide. The basis for the Agency action is the result of the National Toxicology Program (NTP) toxicology and carcinogenesis study of DDVP in rats and mice (NTP Technical Report No. 342, September 1989). In those experiments the NTP considered the result in the female mouse portion of the study to afford unequivocal evidence of carcinogenicity. The NTP considered the interpretations of the male and female rat and the male mouse studies to be less than clear. Despite the NTP interpretation, the EPA considers the male rat data (increased incidence of mononuclear cell leukemia) to be sufficient to warrant the regulatory change. The purpose of this report is to summarize a review of the interpretation of the NTP data and to assess the predictive validity of the results relative to potential human health impact. Critical review of experimental data indicates that the evidence for a carcinogenic effect of DDVP in animals is equivocal. Further, DDVP possess no in vivo mutagenic activity in mammalian assay systems and it bears no significant structural similarity to known carcinogens. Therefore, a weight-of-the-evidence analysis leads to the conclusion that DDVP poses neither mutagenic nor carcinogenic risks to humans exposed under normal conditions of use of foreseeable conditions of misuse.
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PMID:Dichlorvos carcinogenicity: an assessment of the weight of experimental evidence. 772 38

The type rather than the amount of dietary fat may be more important in breast carcinogenesis. While animal studies support this view, little is known about the effects of essential fatty acids (EFAs) at the cellular level. The MCF-7 breast cancer and the MCF-10A non-cancerous human mammary epithelial cell lines are compared in terms of growth response to EFAs and ability to incorporate and process the EFAs. Eicosapentaenoic (EPA, n-3) and docosahexaenoic (DHA, n-3) acids, presented bound to albumin, inhibited the growth of MCF-7 cells by as much as 50% in a dose-dependent manner (6-30 microM) in medium containing 0.5% serum. alpha-Linolenic (LNA, n-3) and arachidonic (AA, n-6) acids inhibited growth less extensively, while linoleic acid (LA, n-6) had no effect. In contrast, MCF-10A cells were not inhibited by any of the EFAs at levels below 24 microM. The differential effects of AA, EPA and DHA on MCF-7 and MCF-10A cells support a protective role of highly unsaturated essential fatty acids against breast cancer. The EFAs were primarily incorporated into phosphoglycerides. MCF-7 cells showed chain elongations and possibly delta 8 desaturation, but no AA was formed from LA, nor EPA or DHA from LNA. In contrast, MCF-10A cells desaturated and elongated the exogenous EFAs via all the known pathways. These findings suggest defects in the desaturating enzymes of MCF-7 cells. LNA, DHA and AA presented to MCF-7 cells in phospholipid liposomes inhibited growth as extensively as albumin-bound free acids, but were less extensively incorporated, suggesting different mechanisms of inhibition for the two methods.
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PMID:n-3 and n-6 fatty acid processing and growth effects in neoplastic and non-cancerous human mammary epithelial cell lines. 805 69

This is a narrative account of the origins and development of carcinogen risk assessment in the U.S. EPA, which pioneered the field. It began in an era of high hopes that the regulation of carcinogens in the environment would make a major reduction in the heavy public health burden of cancer. The immediate cause for the development of carcinogen risk assessment was the need to respond to heavy criticism that the EPA was not using science in an unbiased way to defend its regulation of important pesticides as carcinogens. The formulation of the initial assessment guidelines is described as well as the rationale behind the assessment procedures that were developed by the EPA's Carcinogen Assessment Group. The issue of whether the original hopes of reducing cancer has been realized is discussed. Recent developments in molecular carcinogenesis point to the possibility of a revised view of the role of environmental carcinogens at low levels of exposure from that of causing cancer de novo to an acceleration of the development of cancer that results from heritable genetic defects. It is suggested that advances in carcinogen risk assessment will mainly depend on a better understanding of the causes and mechanisms of cancer in humans at the molecular level.
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PMID:Carcinogen risk assessment in the U.S. Environmental Protection Agency. 817 52


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