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Non-genotoxic carcinogens act by promoting the clonal expansion of preneoplastic cells by directly or indirectly stimulating cell division or inhibiting cell loss in the target organ. The specific mode-of-action (MoA) by which some non-genotoxic carcinogens ultimately cause cancer is not completely understood. To date, there are several proposed MoAs for non-genotoxic carcinogens, and some of these propose inhibition of apoptosis as one of the key events. In general, inhibition of apoptosis is considered a necessary step for cell survival and in theory can occur in combination or in association with other key promotional events, such as cell proliferation, oxidative stress and inhibition of intercellular communication to promote carcinogenesis. However, the evidence supporting the role of inhibition of apoptosis as a necessary step in promoting specific chemically induced tumors is often debated. To address this evidence, we reviewed studies that utilized prototypical nuclear receptor-mediated hepatocarcinogens. Based on this review, it is proposed that the ability to determine the importance of inhibition of apoptosis as a key event in the MoA for tumor promotion is hampered by the limitations of the methods utilized for its detection. This review provides an assessment of the strengths and limitations of the current methodology used for detection of apoptosis and provides suggestions for improving its detection, thereby strengthening the weight of evidence supporting inhibition of apoptosis as a key event in a MoA for tumor promotion. [ABSTRACT FROM PUBLISHER]

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data ( in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs. [ABSTRACT FROM AUTHOR]

The Health and Environmental Sciences Institute (HESI)-coordinated Risk Assessment in the 21st Century (RISK21) project was initiated to develop a scientific, transparent, and efficient approach to the evolving world of human health risk assessment, and involved over 120 participants from 12 countries, 15 government institutions, 20 universities, 2 non-governmental organizations, and 12 corporations. This paper provides a brief overview of the tiered RISK21 framework called the roadmap and risk visualization matrix, and articulates the core principles derived by RISK21 participants that guided its development. Subsequent papers describe the roadmap and matrix in greater detail. RISK21 principles include focusing on problem formulation, utilizing existing information, starting with exposure assessment (rather than toxicity), and using a tiered process for data development. Bringing estimates of exposure and toxicity together on a two-dimensional matrix provides a clear rendition of human safety and risk. The value of the roadmap is its capacity to chronicle the stepwise acquisition of scientific information and display it in a clear and concise fashion. Furthermore, the tiered approach and transparent display of information will contribute to greater efficiencies by calling for data only as needed (enough precision to make a decision), thus conserving animals and other resources. [ABSTRACT FROM AUTHOR]

The RISK21 integrated evaluation strategy is a problem formulation-based exposure-driven risk assessment roadmap that takes advantage of existing information to graphically represent the intersection of exposure and toxicity data on a highly visual matrix. This paper describes in detail the process for using the roadmap and matrix. The purpose of this methodology is to optimize the use of prior information and testing resources (animals, time, facilities, and personnel) to efficiently and transparently reach a risk and/or safety determination. Based on the particular problem, exposure and toxicity data should have sufficient precision to make such a decision. Estimates of exposure and toxicity, bounded by variability and/or uncertainty, are plotted on the X- and Y-axes of the RISK21 matrix, respectively. The resulting intersection is a highly visual representation of estimated risk. Decisions can then be made to increase precision in the exposure or toxicity estimates or declare that the available information is sufficient. RISK21 represents a step forward in the goal to introduce new methodologies into 21st century risk assessment. Indeed, because of its transparent and visual process, RISK21 has the potential to widen the scope of risk communication beyond those with technical expertise. [ABSTRACT FROM AUTHOR]

Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose-response behavior of key events, alteration of the dose-response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure. [ABSTRACT FROM AUTHOR]

A screening-level risk assessment was conducted for styrene-acrylonitrile (SAN) Trimer detected at the Reich Farm Superfund site in Toms River, NJ. Consistent with a screening-level approach, on-site and off-site exposure scenarios were evaluated using assumptions that are expected to overestimate actual exposures and hazards at the site. Environmental sampling data collected for soil and groundwater were used to estimate exposure point concentrations. Several exposure scenarios were evaluated to assess potential on-site and off-site exposures, using parameter values for exposures to soil (oral, inhalation of particulates, and dermal contact) and groundwater (oral, dermal contact) to reflect central tendency exposure (CTE) and reasonable maximum exposure (RME) conditions. Three reference dose (RfD) values were derived for SAN Trimer for short-term, subchronic, and chronic exposures, based upon its effects on the liver in exposed rats. Benchmark (BMD) methods were used to assess the relationship between exposure and response, and to characterize appropriate points of departure (POD) for each RfD. An uncertainty factor of 300 was applied to each POD to yield RfD values of 0.1, 0.04, and 0.03 mg/kg-d for short-term, subchronic, and chronic exposures, respectively. Because a chronic cancer bioassay for SAN Trimer in rats (NTP 2011a) does not provide evidence of carcinogenicity, a cancer risk assessment is not appropriate for this chemical. Potential health hazards to human health were assessed using a hazard index (HI) approach, which considers the ratio of exposure dose (i.e., average daily dose, mg/kg-d) to toxicity dose (RfD, mg/kg-d) for each scenario. All CTE and RME HI values are well below 1 (where the average daily dose is equivalent to the RfD), indicating that there is no concern for potential noncancer effects in exposed populations even under the conservative assumptions of this screening-level assessment. [ABSTRACT FROM AUTHOR]

While risk assessments are extensively used for guiding critical and resource intensive decisions, assessments that rigorously integrate key exposure and toxicity terms are less often published. This article derives residential soil clean-up levels accounting for ingestion and dermal contact (direct contact criteria [DCC]) for a chlorinated dibenzo-p-dioxin and furan (PCDD/F as toxicity equivalence TEQD/F) impacted site using site-specific information and deterministic and probabilistic methods. In addition, TEQD/F risk assessment has been the subject of extensive scientific and regulatory debate including in-depth comments from two USEPA Science Advisory Boards and the National Academy of Sciences (NAS) on the proposed USEPA Draft Dioxin Risk Assessment. This article presents and applies toxicity values seeking to address the NAS recommendations regarding cancer risk assessment. Deterministic DCC estimates ranged from 19 to 250 ppb through application of linear and nonlinear cancer toxicity values, and a DCC of 5.3 ppb was estimated based on the World Health Organization's Joint Exposure Committee on Food Additive's assessment value for noncancer and cancer endpoints. A wide range of DCC estimates were calculated using probabilistic methods, with the prior USEPA 1 ppb clean-up value falling below the first percentile of estimates, suggesting that the 1 ppb value is health protective. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor is a ligand-activated transcription factor responsive to both natural and synthetic environmental compounds, with the most potent agonist being 2,3,7,8-tetrachlotrodibenzo-p-dioxin. The aim of this work was to develop a categorical COmmon REactivity PAttern (COREPA)-based structure-activity relationship model for predicting aryl hydrocarbon receptor ligands within different binding ranges. The COREPA analysis suggested two different binding mechanisms called dioxin- and biphenyl-like, respectively. The dioxin-like model predicts a mechanism that requires a favourable interaction with a receptor nucleophilic site in the central part of the ligand and with electrophilic sites at both sides of the principal molecular axis, whereas the biphenyl-like model predicted a stacking-type interaction with the aryl hydrocarbon receptor allowing electron charge transfer from the receptor to the ligand. The current model was also adjusted to predict agonistic/antagonistic properties of chemicals. The mechanism of antagonistic properties was related to the possibility that these chemicals have a localized negative charge at the molecule's axis and ultimately bind with the receptor surface through the electron-donating properties of electron-rich groups. The categorization of chemicals as agonists/antagonists was found to correlate with their gene expression. The highest increase in gene expression was elicited by strong agonists, followed by weak agonists producing lower increases in gene expression, whereas all antagonists (and non-aryl hydrocarbon receptor binders) were found to have no effect on gene expression. However, this relationship was found to be quantitative for the chemicals populating the areas with extreme gene expression values only, leaving a wide fuzzy area where the quantitative relationship was unclear. The total concordance of the derived aryl hydrocarbon receptor binding categorical structure-activity relationship model was 82% whereas the Pearson's coefficient was 0.88. [ABSTRACT FROM AUTHOR]

Carbonyl gold iodide, OCAuI, is generated in the gas phase through synchronizing the laser ablation of a gold sample with the pulsed, supersonic expansion of gas containing carbon monoxide and an iodine precursor. Fourier Transform microwave (FT-MW) spectroscopy has been used to detect and assign lines in the pure rotational spectrum of the molecule. The frequencies of lines in the spectra of three isotopomers are presented and used to determine rotational, centrifugal distortion and hyperfine coupling constants through iterative least-squares fitting. Rotational constants B0 of the three isotopomers allow determination of the r0 molecular geometry. The structure is linear. The bond lengths are consistent with previous studies of OCMX complexes (M = Cu, Ag, Au; X = F, Cl, Br, I). The frequency of the lowest energy vibrational stretching mode is estimated from the centrifugal distortion constant of the 16O12CAuI isotopomer. The nuclear quadrupole coupling constants of both iodine, [image omitted], and gold, [image omitted], have been determined. The ionic character of the Au-I bond is calculated using [image omitted]. Nuclear shielding parameters for OCAuI and other OCAuX species are determined from the measured nuclear spin-rotation constants, [image omitted] and [image omitted]. [ABSTRACT FROM AUTHOR]

WITHDRAWN TO APPEAR IN SPECIAL ISSUE IN 2007 [ABSTRACT FROM AUTHOR]

1. Rats fed intragastrically with ethanol-containing diets made with low levels of carbohydrates have greater CYP2E1 induction than rats fed similar diets made with high carbohydrate levels. 2. FGC-4 rat hepatoma cells were used to test the hypothesis that carbohydrates could down-regulate ethanol-induced CYP2E1 induction. 3. FGC-4 cells grown in a glucose-free media and treated with 1-100 mM ethanol for 24 h exhibited a dose-dependent increase ( p < 0.05) in CYP2E1, with maximum mRNA steady-state (3.8-fold) or protein (3.1-fold) levels measured at 30 or 100 mM ethanol, respectively. 4. In cells treated with 30 mM ethanol, a glucose concentration-dependent inhibition ( p < 0.05) of CYP2E1 mRNA was observed between 2.5 and 10 mM glucose. 5. Induction by 30 mM ethanol of CYP2E1 protein was reduced in cells co-treated with 1 mM or greater glucose concentration and complete inhibition was measured with 5 mM glucose co-treatment. 6. These data demonstrate that under culture conditions of extremely low carbohydrate concentrations: (1) ethanol treatment of FGC-4 cells results in elevated steady-state levels of CYP2E1 mRNA and protein; and (2) glucose inhibits this increase. 7. It is concluded that glucose can negatively regulate CYP2E1 expression and could at least partially explain the greater induction of hepatic CYP2E1 in rats fed low carbohydrate ethanol-containing diets compared with high carbohydrate diets at the same ethanol level. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon (or dioxin) receptor (AhR) is a ligand-activated basic helix-loop-helix (bHLH) protein that heterodimerizes with thebHLH protein ARNT (aryl hydrocarbon nuclear translocator) forming a complex that binds to xenobiotic regulatory elements in target gene enhancers. Genetic, biochemical, and molecular biology studies have revealed that the AhR mediates the toxic and biological effects of environmentally persistent dioxins and related compounds. Cloning of the receptor and its DNA-binding partner, ARNT, has facilitated detailed efforts to understand the mechanisms of AhR-mediated signal transduction. These studies have determined that this unique receptor consistsof several functional domains and belongs to a subfamily of bHLH proteins that share a conserved motif termed the PAS domain. In addition, recent genetic studies have revealed that expression of the AhR is a requirement for proper embryonal development, which appears to be acommon function shared by many other bHLH proteins. This review is asummary of recent molecular studies of AhR-mediated gene regulation. [ABSTRACT FROM AUTHOR]