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Kerger B.D.,Cardno ChemRisk LLC | James R.C.,ToxStrategies | Galbraith D.A.,Cardno ChemRisk LLC
Frontiers in Genetics | Year: 2014

The diagnosis of mesothelioma is not always straightforward, despite known immunohistochemical markers and other diagnostic techniques. One reason for the difficulty is that extrapleural tumors resembling mesothelioma may have several possible etiologies, especially in cases with no meaningful history of amphibole asbestos exposure. When the diagnosis of mesothelioma is based on histologic features alone, primary mesotheliomas may resemble various primary or metastatic cancers that have directly invaded the serosal membranes. Some of these metastatic malignancies, particularly carcinomas and sarcomas of the pleura, pericardium and peritoneum, may undergo desmoplastic reaction in the pleura, thereby mimicking mesothelioma, rather than the primary tumor. Encasement of the lung by direct spread or metastasis, termed pseudomesotheliomatous spread, occurs with several other primary cancer types, including certain late-stage tumors from genetic cancer syndromes exhibiting chromosomal instability. Although immunohistochemical staining patterns differentiate most carcinomas, lymphomas, and mestastatic sarcomas from mesotheliomas, specific genetic markers in tumor or somatic tissues have been recently identified that may also distinguish these tumor types from asbestos-related mesothelioma. A registry for genetic screening of mesothelioma cases would help lead to improvements in diagnostic criteria, prognostic accuracy and treatment efficacy, as well as improved estimates of primary mesothelioma incidence and of background rates of cancers unrelated to asbestos that might be otherwise mistaken for mesothelioma. This information would also help better define the dose-response relationships for mesothelioma and asbestos exposure, as well as other risk factors for mesothelioma and other mesenchymal or advanced metastatic tumors that may be indistinguishable by histology and staining characteristics. © 2014 Kerger, James and Galbraith.

PubMed | American Chemistry Council, ToxStrategies, Royal Dutch Shell, Sasol Limited and 2 more.
Type: | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2016

In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F

PubMed | University of Genoa and ToxStrategies
Type: | Journal: Toxicology and applied pharmacology | Year: 2016

Evaluation of the reducing capacity of human gastric fluid from healthy individuals, under fasted and fed conditions, is critical for assessing the cancer hazard posed by ingested hexavalent chromium [Cr(VI)] and for developing quantitative physiologically-based pharmacokinetic models used in risk assessment. In the present study, the patterns of Cr(VI) reduction were evaluated in 16 paired pre- and post-meal gastric fluid samples collected from 8 healthy volunteers. Human gastric fluid was effective both in reducing Cr(VI), as measured by using the s-diphenylcarbazide colorimetric method, and in attenuating mutagenicity in the Ames test. The mean (SE) Cr(VI)-reducing ability of post-meal samples (20.42.6gCr(VI)/mL gastric fluid) was significantly higher than that of pre-meal samples (10.22.3gCr(VI)/mL gastric fluid). When using the mutagenicity assay, the decrease of mutagenicity produced by pre-meal and post-meal samples corresponded to reduction of 13.31.9 and 25.62.8gCr(VI)/mL gastric fluid, respectively. These data are comparable to parallel results conducted by using speciated isotope dilution mass spectrometry. Cr(VI) reduction was rapid, with >70% of total reduction occurring within 1min and 98% of reduction is achieved within 30min with post-meal gastric fluid at pH2.0. pH dependence was observed with decreasing Cr(VI) reducing capacity at higher pH. Attenuation of the mutagenic response is consistent with the lack of DNA damage observed in the gastrointestinal tract of rodents following administration of 180ppm Cr(VI) for up to 90days in drinking water. Quantifying Cr(VI) reduction kinetics in the human gastrointestinal tract is necessary for assessing the potential hazards posed by Cr(VI) in drinking water.

Craig Rowlands J.,Dow Chemical Company | Urban J.D.,ToxStrategies | Wikoff D.S.,ToxStrategies | Budinsky R.A.,Dow Chemical Company
Drug Metabolism and Pharmacokinetics | Year: 2011

The human aryl hydrocarbon receptor (AHR) is a protein for which there is little evidence of polymorphic variability of functional consequence. It has been hypothesized that potential variability in dioxin sensitivity may be due to polymorphisms in AHR-associated proteins, such as the human AHRinteracting protein (AIP). There are limited data on AIP single nucleotide polymorphisms (SNPs) with potential functional consequences. We sequenced 103 human DNA samples within the open reading frames of the AIP locus using samples from six ethnic populations to further characterize AIP SNPs. Eight exonic SNPs were identified at the AIP locus, including three novel SNPs: T48T, L212L, and V302V. Combined with prior reports, there are now a total of 14 exonic SNPs that have been identified within AIP. Of these, six are non-synonymous and are therefore of potential functional importance, though only two of these (Q228K and A276V) were detected in the current study. The functional consequences of Q228K and A276V are unknown, although functional evidence from AIP SNPs associated with congenital pituitary tumors suggests that such amino acid changes are likely to have no effect or to decrease, rather than increase, sensitivity to dioxins. To date, no non-synonymous SNPs have been detected in the AHR-binding region of AIP. © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX).

Thompson C.M.,ToxStrategies | Fedorov Y.,Thermo Fisher Scientific | Brown D.D.,Thermo Fisher Scientific | Suh M.,ToxStrategies | And 4 more authors.
PLoS ONE | Year: 2012

Oral exposure to high concentrations of hexavalent chromium [Cr(VI)] induces intestinal redox changes, villus cytotoxicity, crypt hyperplasia, and intestinal tumors in mice. To assess the effects of Cr(VI) in a cell model relevant to the intestine, undifferentiated (proliferating) and differentiated (confluent) Caco-2 cells were treated with Cr(VI), hydrogen peroxide or rotenone for 2-24 hours. DNA damage was then assessed by nuclear staining intensity of 8-hydroxydeoxyguanosine (8-OHdG) and phosphorylated histone variant H2AX (γ-H2AX) measured by high content analysis methods. In undifferentiated Caco-2, all three chemicals increased 8-OHdG and γ-H2AX staining at cytotoxic concentrations, whereas only 8-OHdG was elevated at non-cytotoxic concentrations at 24 hr. Differentiated Caco-2 were more resistant to cytotoxicity and DNA damage than undifferentiated cells, and there were no changes in apoptotic markers p53 or annexin-V. However, Cr(VI) induced a dose-dependent translocation of the unfolded protein response transcription factor ATF6 into the nucleus. Micronucleus (MN) formation was assessed in CHO-K1 and A549 cell lines. Cr(VI) increased MN frequency in CHO-K1 only at highly cytotoxic concentrations. Relative to the positive control Mitomycin-C, Cr(VI) only slightly increased MN frequency in A549 at mildly cytotoxic concentrations. The results demonstrate that Cr(VI) genotoxicity correlates with cytotoxic concentrations, and that H2AX phosphorylation occurs at higher concentrations than oxidative DNA damage in proliferating Caco-2 cells. The findings suggest that in vitro genotoxicity of Cr(VI) is primarily oxidative in nature at low concentrations. Implications for in vivo intestinal toxicity of Cr(VI) will be discussed. © 2012 Thompson et al.

Urban J.D.,ToxStrategies | Budinsky R.A.,Dow Chemical Company | Craig Rowlands J.,Dow Chemical Company
Drug Metabolism and Pharmacokinetics | Year: 2012

Single nucleotide polymorphisms (SNPs) in genes coding for proteins that maintain the cytosolic aryl hydrocarbon receptor (AHR) complex may affect individual susceptibility to dioxin-like compound (DLC)-induced toxicity. The cytosolic 90 kDa heat shock proteins (HSP90s) are ubiquitous chaperone proteins that bind to and stabilize numerous client proteins, including non-ligand-bound AHR. The objective of this study was to characterize SNPs in the human cytosolic HSP90 genes (HSP90AA1 and HSP90AB1). DNA sequencing of 101 human samples detected eight and seven unique SNPs at the HSP90AA1 and HSP90AB1 loci, respectively. For HSP90AA1, two non-synonymous (L71M and E554D) and one rare early termination (Q107X) SNP were observed. One SNP (E554D) was a rare novel polymorphism located in the middle substrate binding region. All SNPs detected in the HSP90AB1 gene were synonymous. With the exception of Q107X, in silico analyses predicted all HSP90 SNPs would have very low to medium risk of affecting the regulation of alternative splicing in gene transcription or protein function. Overall, a very limited presence of SNPs with predicted functional consequence in key domains of the human HSP90 proteins was observed in this study. © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX).

Rowlands C.J.,Dow Chemical Company | Staskal D.F.,ToxStrategies | Gollapudi B.,Dow Chemical Company | Budinsky R.,Dow Chemical Company
Pharmacogenetics and Genomics | Year: 2010

BACKGROUND: The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like chemicals are mediated through binding-dependent activation of the cytosolic aryl hydrocarbon receptor (AHR). The human AHR is a low-affinity receptor relative to most rodents, but some reports suggest that there may be individuals with polymorphic high-affinity receptors, thereby possibly increasing the sensitivity to dioxins in such people. METHODS: Although no polymorphisms have been reported in the ligand binding region of the AHR in the over 100 reported sequences, we sequenced 108 additional human AHR genes in an effort to further identify single single nucleotide polymorphisms (SNPs) within the open reading frames of the AHR locus. The DNA was sequenced from six ethnic populations that included Japanese, Chinese, European/Caucasian, African-American, South East Asian, and Hispanic. RESULTS: Six exonic SNPs were identified; four had been described as previously reported and two seem to be novel. Four of the SNPs identified lead to amino acid changes in the AHR protein and two of the SNPs lead to synonymous substitutions. An additional four SNPs have been reported elsewhere that were not identified in the current analysis. With these new sequences, more than 200 human AHR gene sequences have been analyzed for SNPs. CONCLUSION: The results indicate a very limited presence of polymorphisms in the core ligand binding region of the human AHR. Other regions, such as the transactivation domain, seem to be slightly more polymorphic in the human population and the impact on functionality should be further examined. © 2010 Lippincott Williams & Wilkins, Inc.

Urban J.D.,ToxStrategies | Budinsky R.A.,Dow Chemical Company | Rowlands J.C.,Dow Chemical Company
Drug Metabolism and Pharmacokinetics | Year: 2011

Species' variation(s) in gene homologues can result in differences among species in their quantitative and qualitative susceptibility and responsiveness to environmental contaminants. In the case of dioxin-like compounds (DLCs), it has been hypothesized that single nucleotide polymorphisms (SNPs) in genes associated with aryl hydrocarbon receptor (AHR)-regulated pathways may result in greater susceptibility to DLC toxicity. A key step in the activation of AHR involves heterodimerization with the AHR nuclear translocator (ARNT) protein before binding to its DNA response element. The objective of this study was to identify SNPs in the human ARNT gene that could potentially affect the sensitivity of AHRdependent gene transcription. Results from DNA sequencing of 101 human samples demonstrated the presence of five unique SNPs at the ARNT locus, including three non-synonymous SNPs, of which two were novel: V304M and T462A. The genetic frequencies of the non-synonymous SNPs were very low (≤0.02), and the novel SNPs occurred in the Per-ARNT-Sim (PAS) functional domain. In silico analysis indicated that V304M was the only SNP identified in the current population with the potential to significantly alter ARNT protein function. Our findings indicated a very limited occurrence of SNPs with predicted functional consequence in key domains of human ARNT. © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX).

Bunch A.G.,ToxStrategies | Perry C.S.,ToxStrategies | Abraham L.,ToxStrategies | Wikoff D.S.,ToxStrategies | And 5 more authors.
Science of the Total Environment | Year: 2013

Shale gas exploration and production (E&P) has experienced substantial growth across the U.S. over the last decade. The Barnett Shale, in north-central Texas, contains one of the largest, most active onshore gas fields in North America, stretching across 5000. square miles and having an estimated 15,870 producing wells as of 2011. Given that these operations may occur in relatively close proximity to populated/urban areas, concerns have been expressed about potential impacts on human health. In response to these concerns, the Texas Commission on Environmental Quality established an extensive air monitoring network in the region. This network provides a unique data set for evaluating the potential impact of shale gas E&P activities on human health. As such, the objective of this study was to evaluate community-wide exposures to volatile organic compounds (VOCs) in the Barnett Shale region. In this current study, more than 4.6. million data points (representing data from seven monitors at six locations, up to 105 VOCs/monitor, and periods of record dating back to 2000) were evaluated. Measured air concentrations were compared to federal and state health-based air comparison values (HBACVs) to assess potential acute and chronic health effects. None of the measured VOC concentrations exceeded applicable acute HBACVs. Only one chemical (1,2-dibromoethane) exceeded its applicable chronic HBACV, but it is not known to be associated with shale gas production activities. Annual average concentrations were also evaluated in deterministic and probabilistic risk assessments and all risks/hazards were below levels of concern. The analyses demonstrate that, for the extensive number of VOCs measured, shale gas production activities have not resulted in community-wide exposures to those VOCs at levels that would pose a health concern. With the high density of active wells in this region, these findings may be useful for understanding potential health risks in other shale play regions. © 2013 The Authors.

TBBPA is a non-genotoxic flame retardant used to improve fire safety in a wide variety of consumer products. Estimated human exposures to TBBPA are very low (<0.000084mg/kg-day), relative to the doses (500 and 1000mg/kg-day of TBBPA) administered in a recent bioassay that resulted in uterine tumors in Wistar Han rats following chronic exposure. As part of an effort to characterize the relevance of the uterine tumors to humans, data and biological knowledge relevant to the progression of events associated with TBBPA-induced uterine tumors in female rats were organized in an adverse outcome pathway (AOP) framework. Based on a review of possible MOAs for chemically induced uterine tumors and available TBBPA data sets, a plausible molecular initiating event (MIE) was the ability of TBBPA to bind to and inhibit estrogen sulfotransferases, the enzymes responsible for sulfation of estradiol. Subsequent key events in the AOP, including increased bioavailability of unconjugated estrogens in uterine tissue, would occur as a result of decreased sulfation, leading to a disruption in estrogen homeostasis, increased expression of estrogen responsive genes, cell proliferation, and hyperplasia. Available data support subsequent key events, including generation of reactive quinones from the metabolism of estrogens, followed by DNA damage that could contribute to the development of uterine tumors. Uncertainties associated with human relevance are highlighted by potential strain/species sensitivities to development of uterine tumors, as well as the characterization of a dose-dependent MIE. For the latter, it was determined that the TBBPA metabolic profile is altered at high doses (such as those used in the cancer bioassay), and thus an MIE that is only operative under repeated high dose, administration. The MIE and subsequent key events for the development of TBBPA-induced uterine tumors are not feasible in humans given differences in the kinetic and dynamic factors associated with high dose exposures in rats relative to human exposure levels to TBBPA.

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