Toxicology Consultant

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Toxicology Consultant

United Kingdom

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Arnich N.,AFSSA | Canivenc-Lavier M.-C.,French National Institute for Agricultural Research | Kolf-Clauw M.,National Veterinary School of Toulouse | Coffigny H.,CEA Fontenay-aux-roses | And 9 more authors.
International Journal of Hygiene and Environmental Health | Year: 2011

Since more than 10 years, risk assessment of bisphenol A (BPA) is debated at the international level. In 2008, the U.S. National Toxicology Program (NTP) expressed some concern for adverse effects, at current level of exposure to BPA, on developmental toxicity. In this context, the French Food Safety Agency (AFSSA) decided to review the toxicity data on BPA with a special focus on this endpoint at doses below 5. mg/kg bw/day (the no observed adverse effect level set by different regulatory bodies). This paper summarizes the conclusions of a collective assessment conducted by an expert Working Group from AFSSA. Studies were classified into 3 groups: (i) finding no toxicity, (ii) reporting results not considered to be of concern and (iii) indicating warning signals. The term " warning signal" means that no formal conclusion can be drawn regarding the establishment of a health based guidance value but the study raises some questions about the toxicity of BPA at low doses. It was concluded that studies are needed to ascertain the significance for human health of these warning signals and to be able to propose new methodologies for assessing the risks associated with low doses of BPA and more generally of endocrine disruptors. © 2011 Elsevier GmbH.

PubMed | University of Groningen and Toxicology Consultant
Type: Journal Article | Journal: Toxicology in vitro : an international journal published in association with BIBRA | Year: 2015

In rat in vivo, both paracetamol (APAP) and carbon tetrachloride (CCl4) induce liver necrosis, but long-term treatment with CCl4, in contrast to paracetamol, causes liver fibrosis. The aim of this study was to perform transcriptomic analysis to compare the early changes in mRNA expression profiles induced by APAP and CCl4 in the rat precision-cut liver slice model (PCLS) and to identify early markers that could predict fibrosis-inducing potential. Microarray data of rat PCLS exposed to APAP andCCl4was generated using a toxic dose based on decrease in ATP levels. Toxicity pathway analysis using a custom made fibrosis-related gene list showed fibrosis as one of the predominant toxic endpoints in CCl4-treated, but not in APAP-treated PCLS. Moreover, genes which have a role in fibrosis such as alpha-B crystallin, jun proto-oncogene, mitogen-activated protein kinase 6, serpin peptidase inhibitor and also the transcription factor Kruppel-like-factor-6 were up-regulated by CCl4, but not by APAP. Predicted activation or inhibition of several upstream regulators due to CCl4 is in accordance with their role in fibrosis. In conclusion, transcriptomic analysis of PCLS successfully identified the fibrotic potential of CCl4 as opposed to APAP. The application of PCLS as an ex vivo model to identify early biomarkers to predict the fibrogenic potential of toxic compounds should be further explored.

Landsiedel R.,BASF | Ma-Hock L.,BASF | Haussmann H.-J.,Toxicology Consultant | van Ravenzwaay B.,BASF | And 2 more authors.
Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology | Year: 2012

While technical and medical potential offered by nanotechnologies increase, the safety assessment of engineered nanomaterials (NMs) needs to follow this pace. Inhalation is a major route of occupational and environmental exposure, and is most relevant for most of the respective safety assessment studies. Control and generation of aerosol from the test materials for this route of administration are technically demanding, and not surprisingly, there are relatively few NMs tested in toxicokinetic, short-term, and subchronic inhalation studies. These studies were in part adapted to the peculiarities of inhaled NMs, but few were also conducted according to organization for economic co-operation and development (OECD) test guidelines. Inhalation studies on the potential to develop chronic diseases, or studies to check the potential analogy to cardiovascular diseases associated with adverse health effects from ambient air pollution, are largely missing. On the way forward, appropriate inhalation studies need to be performed on a number of NMs to assess their hazards and to provide a sound database for correlation and validation of alternative in vitro methods. Moreover, these studies can potentially aid in the grouping of different NMs based on their biokinetics or biological effects. For carcinogenic and cardiovascular effects, research studies are needed to verify-or disprove-the relevance and the mechanisms by which NMs contribute to these effects. © 2012 Wiley Periodicals, Inc.

Brusick D.,Toxicology Consultant | Grotz V.L.,McNeil Nutritionals LLC | Slesinski R.,Spherix | Kruger C.L.,Spherix | And 2 more authors.
Food and Chemical Toxicology | Year: 2010

Sucralose is a non-nutritive sweetener that is approximately 600 times sweeter than table sugar. It is currently approved for use in over 80 countries. Evidence from chronic studies demonstrates that this compound is not carcinogenic. This report summarizes the results of genotoxicity studies that were part of the original safety assessment of sucralose-conducted early in the safety investigation and shared with regulatory agencies around the world. Studies included the Ames (Salmonella typhimurium) reverse mutation test, the Escherichia coli pol A+/A- test, an in vitro chromosome damage assay in human lymphocytes. , mutation in TK +/- mouse lymphoma cells, an in vivo chromosome aberration test in rats and two separate micronucleus tests in mice. All results were evaluated as negative. These results support the overall conclusion by regulatory and heath agencies that sucralose is safe for its intended use. © 2010 Elsevier Ltd.

Winkelmann B.R.,ClinPhenomics GmbH | Winkelmann B.R.,Cardiology Group Frankfurt Sachsenhausen | Von Holt K.,Toxicology Consultant | Unverdorben M.,Clinical Research Institute
Biomarkers in Medicine | Year: 2010

Genes influence smoking behavior, affect the metabolism of nicotine and specific chemicals produced during combustion, and enhance (or diminish) pathomechanistic pathways associated with the atherogenic potential of smoking, including oxidative stress, its inflammatory burden or procoagulant potential. Genome-wide association studies have revolutionized the search for new functional genetic markers with ever increasing marker density and the precision in identifying new genetic loci without the need for prior knowledge of functional pathways. Nevertheless, the satistical challenge remains to identify the few true positives, the need for replication of findings and the tedious work of identifying functional genetic variants and their mode of action. Genetic variation within a gene or in areas of the genetic code that control the expression of such a gene is far from being understood. Major advances include the detection of large-scale copy-number variants in the human genome and the demonstration of the decisive role of 'miRNA in controlling gene expression. The role of the genomic methylation pattern in controlling the transcription of the underlying genetic sequence and its role in interacting with environmental influences have yet to be explored in depth. Although candidate genes and their genetic variants have been associated with atherosclerosis and cigarette smoking, a major breakthrough has still to be made. © 2010 Future Medicine Ltd.

Shiotsuka R.N.,Bayer Material Science | Stuart B.P.,Stonehedge Pathology Services | Charles J.M.,Toxicology Consultant | Simon G.S.,Rhodia | And 2 more authors.
Inhalation Toxicology | Year: 2010

The polyisocyanates of 1,6-hexamethylene diisocyanate (HDI) find widespread commercial use as components of paints and in the formulation of light-stable polyurethane coating materials. This 2-year study assessed the oncogenicity of the diisocyanate monomer HDI in male and female Fischer-344 rats exposed 6h/day, 5 days/week to mean analytical air concentrations of 0, 0.005, 0.025, and 0.164ppm HDI. During the in-life phase, transient eye irritation was observed in 0.164ppm males, and a slight body weight decrease (5%) in the 0.164ppm females during the second year of exposure. There were no exposure-related effects on mortality. Compound-related, non-neoplastic histopathologic changes were limited to the respiratory tract and changes were characterized by epithelial tissue reaction to the acute irritant properties of HDI vapor. For tissues of the nasal cavity, the major histopathologic findings were degeneration of the olfactory epithelium characterized by destruction of the epithelial architecture often with narrowing or atrophy and occasional focal erosion or ulceration. In addition, there was variable degeneration of the respiratory epithelium with hyperkeratosis of the epithelium, epithelial and mucus secretory cell hyperplasia, squamous metaplasia, chronic-active inflammation, and errosive or ulcerative changes. These tissue effects along with a statistically significant decrease in body weight of female rats demonstrated attainment of a maximum tolerated dose. There was no evidence of progression of these changes in the nasal epithelium to neoplasia nor evidence of any compound-related neoplastic lesions for any of the other tissues examined. Therefore, it is concluded that HDI did not show a carcinogenic potential in this study. © 2010 Informa Healthcare USA, Inc.

Butenhoff J.L.,3M | Kennedy G.L.,DuPont Company | Jung R.,Toxicology Consultant | Chang S.-C.,3M
Toxicology Reports | Year: 2014

Perfluorooctanoate (PFOA) is a fully fluorinated eight-carbon fatty acid analog with exceptional stability toward degradation that has been used as an industrial surfactant and has been detected in environmental and biological matrices. Exposures to PFOA in the workplace and in the environment have continuously stimulated investigations into its potential human health hazards. In this article, the results of fifteen unpublished genotoxicity assays conducted with perfluorooctanoate (as either the linear or linear/branched ammonium salt (APFO) or the linear/branched sodium salt) are reported and include: seven mutation assays (three in vitro reverse mutation assays with histidine auxotrophic strains of Salmonella typhimurium, two in vitro reverse mutation assays with the tryptophan auxotrophic Escherichia coli WP2uvr strain, one in vitro mitotic recombination (gene conversion) assay with Saccharomyces cerevisiae D4, and an in vitro Chinese hamster ovary (CHO) HGPRT forward mutation assay); seven studies to assess potential for chromosomal damage (three in vitro CHO chromosomal aberration studies, an in vitro human whole blood lymphocyte chromosomal aberration study, and three in vivo mouse micronucleus assays); and an in vitro C3H 10T1/2 cell transformation assay. Although PFOA has not been demonstrated to be metabolized, all in vitro assays were conducted both in the presence and in the absence of a mammalian hepatic microsomal activation system. These assays were originally described in twelve contract laboratory reports which have been available via the United States Environmental Protection Agency public docket (Administrative Record 226) for over a decade; however, the details of these assays have not been published previously in the open scientific literature. With the exception of limited positive findings at high and cytotoxic concentrations in some assay trials which reflected the likely consequence of cytotoxic disruption of normal cellular processes and not a specific genotoxic effect, the results of the studies presented in this paper and other published results clearly demonstrate the absence of direct mutagenic or genotoxic risk associated with PFOA. This finding is consistent with the physical/chemical characteristics of PFOA and is supported by other published genotoxicity studies. © 2014 he Authors.

Croom E.,Toxicology Consultant
Progress in Molecular Biology and Translational Science | Year: 2012

Xenobiotics have been defined as chemicals to which an organism is exposed that are extrinsic to the normal metabolism of that organism. Without metabolism, many xenobiotics would reach toxic concentrations. Most metabolic activity inside the cell requires energy, cofactors, and enzymes in order to occur. Xenobiotic-metabolizing enzymes can be divided into phase I, phase II, and transporter enzymes. Lipophilic xenobiotics are often first metabolized by phase I enzymes, which function to make xenobiotics more polar and provide sites for conjugation reactions. Phase II enzymes are conjugating enzymes and can directly interact with xenobiotics but more commonly interact with metabolites produced by phase I enzymes. Through both passive and active transport, these more polar metabolites are eliminated. Most xenobiotics are cleared through multiple enzymes and pathways. The relationship between chemical concentrations, enzyme affinity and quantity, and cofactor availability often determine which metabolic reactions dominate in a given individual. © 2012 Elsevier Inc. All rights reserved.

Context The silencing or activation of cancer-associated genes by epigenetic mechanisms can ultimately lead to the clonal expansion of cancer cells. Objective The aim of this review is to summarize all relevant epigenetic biomarkers that have been proposed to date for the diagnosis of some prevalent human cancers. Methods A Medline search for the terms epigenetic biomarkers, human cancers, DNA methylation, histone modifications and microRNAs was performed. Results One hundred fifty-seven relevant publications were found and reviewed. Conclusion To date, a significant number of potential epigenetic cancer biomarkers of human cancer have been investigated, and some have advanced to clinical implementation. © 2016 Taylor & Francis

PubMed | Toxicology Consultant
Type: Journal Article | Journal: Chemical research in toxicology | Year: 2012

The chemical composition of cigarette mainstream smoke (MS) has been quantitatively analyzed in multiple studies, often with the objective to toxicologically evaluate and compare various types of MS. Increases and decreases in yields of constituents between MS types can only be consolidated if these yields are compared on the basis of toxicological properties of the individual constituents. For the risk assessment of various complex mixtures including MS, a hazard index (HI) approach has been used that requires weighing of the exposure to individual MS constituents by cancer and noncancer potency values. The objective of the current study is to review the past uses of the HI concept for MS and smokeless tobacco and discuss strengths and limitations of using this concept. Published information as well as information made available on the Web was used. The HI concept has been applied to MS for determining and comparing theoretical lifetime risks, for consumer communication, for the prioritization of constituents for reduction, for ingredient assessment, and for the selection of constituents for regulation. The limitations of this approach are associated with the limited number of MS constituents with available yield data, the gaps and uncertainties in available potency values, the application to relatively high exposure concentrations, and the default assumption of additivity. The derived theoretical noncancer index is dominated by acrolein to an extent that there seems to be not much advantage in using the HI concept for noncancer assessments. The derived theoretical cancer index is dominated by genotoxic carcinogens of the MS vapor phase and may thus complement currently used toxicological assays in a tiered evaluation approach. As is the case for every other assay and interpretation model, the HI concept needs to be applied with its limitations and weaknesses in mind. Its best application is for comparative purposes. It should be kept in mind that the HI concept is a theoretical concept and does not provide actual risk information.

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