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

Formaldehyde induced squamous-cell carcinomas in the nasal passages of F344 rats in two inhalation bioassays at exposure levels of 6 ppm and above. Increases in rates of cell proliferation were measured by T. M. Monticello and colleagues at exposure levels of 0.7 ppm and above in the same tissues from which tumors arose. A risk assessment for formaldehyde was conducted at the CIIT Centers for Health Research, in collaboration with investigators from Toxicological Excellence in Risk Assessment (TERA) and the U.S. Environmental Protection Agency (U.S. EPA) in 1999. Two methods for dose-response assessment were used: a full biologically based modeling approach and a statistically oriented analysis by benchmark dose (BMD) method. This article presents the later approach, the purpose of which is to combine BMD and pharmacokinetic modeling to estimate human cancer risks from formaldehyde exposure. BMD analysis was used to identify points of departure (exposure levels) for low-dose extrapolation in rats for both tumor and the cell proliferation endpoints. The benchmark concentrations for induced cell proliferation were lower than for tumors. These concentrations were extrapolated to humans using two mechanistic models. One model used computational fluid dynamics (CFD) alone to determine rates of delivery of inhaled formaldehyde to the nasal lining. The second model combined the CFD method with a pharmacokinetic model to predict tissue dose with formaldehyde-induced DNA-protein cross-links (DPX) as a dose metric. Both extrapolation methods gave similar results, and the predicted cancer risk in humans at low exposure levels was found to be similar to that from a risk assessment conducted by the U.S. EPA in 1991. Use of the mechanistically based extrapolation models lends greater certainty to these risk estimates than previous approaches and also identifies the uncertainty in the measured dose-response relationship for cell proliferation at low exposure levels, the dose-response relationship for DPX in monkeys, and the choice between linear and nonlinear methods of extrapolation as key remaining sources of uncertainty.
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PMID:Benchmark dose risk assessment for formaldehyde using airflow modeling and a single-compartment, DNA-protein cross-link dosimetry model to estimate human equivalent doses. 1283 40

The immune system is involved in host defense against infectious agents, tumor cells, and environmental insults. Inflammation is an important component of the early immunologic response. Inappropriate or dysfunctional immune responses underlie acute and chronic inflammatory diseases. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds that have important roles in inflammation and in the regulation of immunity. Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators, through several mechanisms, including decreased availability of AA, competition for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, and decreased expression of COX-2 and 5-LOX. This alone is a potentially beneficial anti-inflammatory effect of n-3 FA. However, n-3 FA have a number of other effects that might occur downstream of altered eicosanoid production or might be independent of this effect. For example, dietary fish oil results in suppressed production of proinflammatory cytokines and can modulate adhesion molecule expression. These effects occur at the level of altered gene expression. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease and to protect against the effects of endotoxin. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some asthmatics, supporting the idea that the n-3 FA in fish oil are anti-inflammatory. There are indications that the inclusion of fish oil in enteral and parenteral formulae is beneficial to patients.
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PMID:N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. 1284 78

Inflammation of the synovial membrane in rheumatoid arthritis is mediated by specialized cells necessary for immune response. The most prominent features are the accumulation of mononuclear phagocytes, lymphocytes and leukocytes in the proliferating tissue. Pro-inflammatory and proliferative signals are transmitted to the bone marrow and to the synovial membrane. The result is a monoclonal stimulation of specific cell lines, and synovial proliferation in the inflamed joint. Angiogenesis, synovial hypertrophy, and increased perfusion facilitate the accumulation of inflammatory cells. Components of the autoimmune reaction are described in the international system of classification, the CD-System (cluster of differentiation). Pro-inflammatory signals are mediated by metabolites of arachidonic acid. Prostaglandins, leukotrienes, lipoxines and hydroxy fatty acids, derived from this PUFA, stimulate the formation and the activity of adhesion molecules (integrines), cytokines (gamma-interferon, interleukin-1, interleukin-6, tumor-necrosis factor), chemokines (interleukine-8, macrophage-chemotactic peptide, RANTES and colony -stimulating factors ((CSF, granulocytes/ monocytes-CSF, Multi-CSF (= IL-3)). Dietary means to mitigate inflammation comprise reduction of arachidonic acid, and increased intake of eicosapentaenoic acid and antioxidants. In the literature 12 randomized, placebo-controlled double-blind studies, fulfilling GCP-criteria, demonstrate a moderate but consistent improvement of clinical findings and laboratory parameters in patients with RA. A dose-response relationship was established up to an daily dose of 2.6 gram fish oil, equivalent to about 1.6 gram EPA. In these experiments EPA was the omega-3 fatty acid responsible for improvement, with distinct effects on inhibition of cytokines formation (IL-1 to IL-6, IL-8, TFN-alpha, GM-CSF), decreased induction of proinflammatory adhesion molecules (selectines, intercellular adhesions molecule-1 (ICAM-1)), and degrading enzymes (e.g. phospholipase A2, cyclooxygenase-2, inducible NO-synthetase). Only one study reports the relevance of the background diet. From this study it became apparent that reduction of dietary arachidonic acid improves the incorporation and the clinical benefit of EPA.
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PMID:Dietary fatty acids and immune reactions in synovial tissue. 1291 34

The human relevance framework (HRF) outlines a four-part process, beginning with data on the mode of action (MOA) in laboratory animals, for evaluating the human relevance of animal tumors. Drawing on U.S. EPA and IPCS proposals for animal MOA analysis, the HRF expands those analyses to include a systematic evaluation of comparability, or lack of comparability, between the postulated animal MOA and related information from human data sources. The HRF evolved through a series of case studies representing several different MOAs. HRF analyses produced divergent outcomes, some leading to complete risk assessment and others discontinuing the process, according to the data available from animal and human sources. Two case examples call for complete risk assessments. One is the default: When data are insufficient to confidently postulate a MOA for test animals, the animal tumor data are presumed to be relevant for risk assessment and a complete risk assessment is necessary. The other is the product of a data-based finding that the animal MOA is relevant to humans. For the specific MOA and endpoint combinations studied for this article, full risk assessments are necessary for potentially relevant MOAs involving cytotoxicity and cell proliferation in animals and humans (Case Study 6, chloroform) and formation of urinary-tract calculi (Case Study 7, melamine). In other circumstances, when data-based findings for the chemical and endpoint combination studied indicate that the tumor-related animal MOA is unlikely to have a human counterpart, there is little reason to continue the risk assessment for that combination. Similarly, when qualitative considerations identify MOAs specific to the test species or quantitative considerations indicate that the animal MOA is unlikely to occur in humans, such hazard findings are generally conclusive and further risk assessment is not necessary for the endpoint-MOA combination under study. Case examples include a tumor-related protein specific to test animals (Case Study 3, d-limonene), the tumor consequences of hormone suppression typical of laboratory animals but not humans (Case Study 4, atrazine), and chemical-related enhanced hormone clearance rates in animals relative to humans (Case Study 5, phenobarbital). The human relevance analysis is highly specific for the chemical-MOA-tissue-endpoint combination under analysis in any particular case: different tissues, different endpoints, or alternative MOAs for a given chemical may result in different human relevance findings. By providing a systematic approach to using MOA data, the HRF offers a new tool for the scientific community's overall effort to enhance the predictive power, reliability and transparency of cancer risk assessment.
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PMID:A framework for human relevance analysis of information on carcinogenic modes of action. 1472 33

Defining the mode(s) of action by which chemicals induce tumors in laboratory animals has become a key to judgments about the relevance of such tumor data for human risk assessment. Frameworks for analyzing mode of action information appear in recent U.S. EPA and IPCS publications relating to cancer risk assessment. This FORUM paper emphasizes that mode of action analytical frameworks depend on both qualitative and quantitative evaluations of relevant data and information: (1) presenting key events in the animal mode of action, (2) developing a "concordance" table for side-by-side comparison of key events as defined in animal studies with comparable information from human systems, and (3) using data and information from mode of action analyses, as well as information on relative sensitivity and exposure, to make weight-of-evidence judgments about the relevance of animal tumors for human cancer assessments. The paper features a systematic analysis for using mode of action information from animal and human studies, based in part on case examples involving environmental chemicals and pharmaceuticals.
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PMID:Evaluating the human relevance of chemically induced animal tumors. 1501 6

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

The objective of this study was to determine the concentrations of an extended series of polycyclic aromatic hydrocarbons (PAHs) and nitrated PAHs in outdoor air samples collected in low-contaminated urban areas, affected mainly by traffic emissions, and to estimate in vitro mutagenic and dioxin-like toxicity of extracts from these samples. Data on concentrations of PAHs and toxic in vitro potencies were compared in extracts obtained by different sampling methods. PAHs and their derivatives were analysed by high performance liquid chromatography with diode array and fluorescence detection, as well as gas chromatography with mass spectrometry. The total sum of 39 PAHs under study ranged from 6.7 to 62.7 ng.m(-3); of this, the sum of 16 U.S. EPA priority PAHs in urban air samples ranged from 3.2 to 6.2 ng.m(-3). Phenanthrene was the prevalent PAH in all air samples tested, with concentrations up to 17.6 ng.m(-3), followed by fluorene, fluoranthene and pyrene present mostly in the gaseous phase. Also, other low molecular weight PAHs (with MW up to 228) were distributed mostly in gaseous phase. The particulate phase contained mostly carcinogenic PAHs, among which, benzo[a]pyrene, indeno[1,2,3-cd]pyrene and benzofluoranthenes were predominant compounds (with benzo[a]pyrene reaching levels up to 1.57 ng.m(-3)). Traffic emissions were confirmed as the major source of PAHs in the airborne samples due to the presence of elevated concentrations of benzo[ghi]perylene and coronene. The most abundant nitrated PAH derivatives were nitronaphthalenes, which were present exclusively in the vapor phase; 9-nitroanthracene, 9-nitrophenantrene and 3-nitrofluoranthene were associated mostly with particulate matter (PM(10)). Bioassays for detection of the Ah receptor-mediated activity and mutagenicity in vitro were used as a screen of potential adverse effects of air pollutants emitted from traffic. The major part of mutagenic and aryl hydrocarbon receptor (AhR)-mediated activities was found to be present in the PM(10) fraction. Although the PM(10) sampling technique was found to be a suitable method regarding the subsequent determination of mutagenic and AhR-mediated activities in vitro, relative toxic potencies, associated with low molecular weight PAHs (such as tumor promotion and other adverse effects), could be underestimated.
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PMID:A combined chemical and bioassay analysis of traffic-emitted polycyclic aromatic hydrocarbons. 1550

The guidelines for carcinogen risk assessment recently proposed by the U.S. Environmental Protection Agency (U.S. EPA) provide an increased opportunity for the consideration of pharmacokinetic and mechanistic data in the risk assessment process. However, the greater flexibility of the new guidelines can also make their actual implementation for a particular chemical highly problematic. To illuminate the process of performing a cancer risk assessment under the new guidelines, the rationale for a state-of-the-science risk assessment for trichloroethylene (TCE) is presented. For TCE, there is evidence of increased cell proliferation due to receptor interaction or cytotoxicity in every instance in which tumors are observed, and most tumors represent an increase in the incidence of a commonly observed, species-specific lesion. A physiologically based pharmacokinetic (PBPK) model was applied to estimate target tissue doses for the three principal animal tumors associated with TCE exposure: liver, lung, and kidney. The lowest points of departure (lower bound estimates of the exposure associated with 10% tumor incidence) for lifetime human exposure to TCE were obtained for mouse liver tumors, assuming a mode of action primarily involving the mitogenicity of the metabolite trichloroacetic acid (TCA). The associated linear unit risk estimates for mouse liver tumors are 1.5 x 10(-6) for lifetime exposure to 1 microg TCE per cubic meter in air and 0.4 x 10(-6) for lifetime exposure to 1 microg TCE per liter in drinking water. However, these risk estimates ignore the evidence that the human is likely to be much less responsive than the mouse to the carcinogenic effects of TCA in the liver and that the carcinogenic effects of TCE are unlikely to occur at low environmental exposures. Based on consideration of the most plausible carcinogenic modes of action of TCE, a margin-of-exposure (MOE) approach would appear to be more appropriate. Applying an MOE of 1000, environmental exposures below 66 microg TCE per cubic meter in air and 265 microg TCE per liter in drinking water are considered unlikely to present a carcinogenic hazard to human health.
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PMID:Applying mode-of-action and pharmacokinetic considerations in contemporary cancer risk assessments: an example with trichloroethylene. 1668 25

During the course of our recent study on the anti-tumor effect of conjugated eicosapentaenoic acids (CEPA), we found that acid mixtures prepared by treating EPA with KOH in ethylene glycol induced potent apoptotic cell death in human tumor cells via membrane phospholipid peroxidation. Interestingly, the KOH-treated CEPA mixtures were more cytotoxic than EPA and CLA and had no effect on normal human fibroblast cells. To identify the specific cytotoxic FA in the CEPA mixture, we synthesized possible candidates for the active species. Here, we report the synthesis of (5E,7E,9E, 14Z, 17Z)-5,7,9,14,1 7-eicosapentaenoic acid (E-CEPA) and its 5-(Z) isomer (Z-CEPA), both of which are conjugated trienes that exist naturally in red algae (Ptilota filicina J. Agardh). E-CEPA and Z-CEPA were synthesized from methyl 5-oxopentanoate in six steps, using three types of Wittig reactions as the key steps. Next, we examined the cytotoxicity of E-CEPA and Z-CEPA in human tumor cells and confirmed their bioactivity. Both E-CEPA and Z-CEPA had a strong cytotoxic reaction in tumor cells, and this effect occurred through induction of apoptosis.
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PMID:Synthesis of the conjugated trienes 5E,7E,9E,14Z,17Z-eicosapentaenoic acid and 5Z,7E,9E,14Z,17Z-eicosapentaenoic acid, and their induction of apoptosis in DLD-1 colorectal adenocarcinoma cells. 1588 62

Trivalent inorganic arsenic (arsenite, arsenic trioxide, As(III)) is a primary contaminant of groundwater supplies worldwide. As(III), marketed as trisenox, is also an FDA-approved agent to treat cancer It has been previously shown by our laboratory that As(III) administered at doses lower than a therapeutic anticancer dose results in an increase in tumor formation and blood vessel density of tumors. In this work it was found that chronic administration of As(III) approaching the EPA action level of 10 ppb, given in the drinking water of mice 5 weeks prior to B16-F10 melanoma implantation, increased the growth rate of primary tumors and the number of metastases to the lung. Further, levels of arsenic in the tumor and lung were found to be much greater than those in the blood and similar to pro-angiogenic As(III) doses. Levels of hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) surrounding the blood vessels in the tumors of the As(III)-treated mice were also found to be increased. Exposure of isolated B16-F10 tumor cells to chronic (3 or 7 day) but not acute (4 h) low-dose As(III) was found to increase HIF-1alpha expression and secretion of VEGF. Finally, coadministration of an inhibitor of HIF (YC-1) or a VEGFR-2 kinase inhibitor (SU5416) was found to antagonize the pro-angiogenic effects of low-dose As(III). Together, these results suggest that chronic exposure to low-dose As(III) could stimulate growth of tumors through a HIF-dependent stimulation of angiogenesis.
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PMID:Role of HIF signaling on tumorigenesis in response to chronic low-dose arsenic administration. 1588 69


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