Risk Assessment for Developmental Toxicity: Airborne Occupational Exposure to Ethanol and Iodine

Dean Mattison explains hazard identification, hazard characterization and exposure characterization as furnishing a foundation for Risk assessment generally. He then illustrates their application in assessing the fetal Risk posed by two common substances. Ultimately, he argues that only after Risks have been so examined can women of child bearing age (or anyone) decide what if any measures are appropriate to avoid them

Daganatos sejtek rezisztenciáját gátló vegyületek fejlesztése = Development of compounds targeting multidrug resistant cancer

A korszerű daganatellenes terápia jelentős sikerei ellenére a kemoterápiával szemben fellépő rezisztencia (multidrog rezisztencia, MDR) továbbra is megoldásra váró klinikai kihívás. Számos rosszindulatú megbetegedés, valamint az áttétet adó daganatok hatékony kezelése a terápia során rendszerint kialakuló MDR hatás miatt a mai napig nem megoldott. A rezisztens fenotípus gyakran társul az ABC-transzporterek családjába tartozó fehérjék emelkedett expressziójával. E család legismertebb képviselője a Pgp (ABCB1) membránfehérje, mely az ATP energiáját felhasználva megakadályozza a citosztatikus vegyületek sejten belüli felhalmozódását. A farmakogenomikai megközelítés révén lehetővé válik a személyre szabott gyógyítás, a daganatos megbetegedések molekuláris profiljához igazított kemoterápiás kezelés. A kutatás fő célja az volt, hogy a korábban kidolgozott farmakogenomikai módszer segítségével olyan ?MDR-inverz? vegyületeket fedezzünk fel, melyek szelektíven elpusztítják az egyébként multidrog rezisztens sejteket. Fontosabb eredményeink a következő pontokban összegezhetők: (i) módszerünk számos további MDR-inverz vegyületet azonosított; (ii) a szerkezetek analízise lehetővé tette QSAR modellek felállítását; (iii) javaslatot tettünk a vegyületek hatásmechanizmusára. Távlati tervünk, hogy a megismert MDR-inverz vegyületekből kiindulva originális gyógyszerkutatást folytassunk a rákos sejteket szelektíven pusztító molekulák preklinikai fejlesztése céljából. | Despite considerable advances in drug discovery, resistance to chemotherapy confounds the effective treatment of cancer patients. Cancer cells can become resistant to a single drug or they may acquire broad cross-resistance to mechanistically and structurally unrelated drugs (multidrug resistance (MDR)). ATP-Binding Cassette (ABC) proteins comprise the largest protein family, many members of which are of immediate medical importance and relevant to human health. The application of pharmacogenetics has the potential to improve the management of patients, particularly by providing the molecular basis for choosing among the increasing number of chemotherapeutic agents available for the treatment. The major aim of this project was to apply a pharmacogenomic approach to discover ?MDR-inverse? compounds that selectively kill multidrug resistant cancer cells. The results can be summarized as follows: (i) we identified a series of MDR-inverse compounds; (ii) we delineated structural features associated with their cytotoxic activity; (iii) we proposed a mechanism of action for the toxicity of newly identified MDR1-inverse compounds. Our future aim is to establish the framework for the preclinical development of the most promising MDR-inverse molecules, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care

Unexpected transformation of dissolved phenols to toxic dicarbonyls by hydroxyl radicals and UV light.

Water treatment systems frequently use strong oxidants or UV light to degrade chemicals that pose human health risks. Unfortunately, these treatments can result in the unintended transformation of organic contaminants into toxic products. We report an unexpected reaction through which exposure of phenolic compounds to hydroxyl radicals (•OH) or UV light results in the formation of toxic α,β-unsaturated enedials and oxoenals. We show that these transformation products damage proteins by reacting with lysine and cysteine moieties. We demonstrate that phenolic compounds react with •OH produced by the increasingly popular UV/hydrogen peroxide (H2O2) water treatment process or UV light to form toxic enedials and oxoenals. In addition to raising concerns about potential health risks of oxidative water treatment, our findings suggest the potential for formation of these toxic compounds in sunlit surface waters, atmospheric water, and living cells. For the latter, our findings may be particularly relevant to efforts to understand cellular damage caused by in vivo production of reactive oxygen species. In particular, we demonstrate that exposure of the amino acid tyrosine to •OH yields an electrophilic enedial product that undergoes cross-linking reaction with both lysine and cysteine residues

Challenges for the development of a biotic ligand model predicting copper toxicity in estuaries and seas

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2011 SETAC.An effort is ongoing to develop a biotic ligand model (BLM) that predicts copper (Cu) toxicity in estuarine and marine environments. At present, the BLM accounts for the effects of water chemistry on Cu speciation, but it does not consider the influence of water chemistry on the physiology of the organisms. We discuss how chemistry affects Cu toxicity not only by controlling its speciation, but also by affecting the osmoregulatory physiology of the organism, which varies according to salinity. In an attempt to understand the mechanisms of Cu toxicity and predict its impacts, we explore the hypothesis that the common factor linking the main toxic effects of Cu is the enzyme carbonic anhydrase (CA), because it is a Cu target with multiple functions and salinity-dependent expression and activity. According to this hypothesis, the site of action of Cu in marine fish may be not only the gill, but also the intestine, because in this tissue CA plays an important role in ion transport and water adsorption. Therefore, the BLM of Cu toxicity to marine fish should also consider the intestine as a biotic ligand. Finally, we underline the need to incorporate the osmotic gradient into the BLM calculations to account for the influence of physiology on Cu toxicity.Brunel Universit

Epigenetic Effects of Polybrominated Diphenyl Ethers on Human Health.

Disruption of epigenetic regulation by environmental toxins is an emerging area of focus for understanding the latter's impact on human health. Polybrominated diphenyl ethers (PBDEs), one such group of toxins, are an environmentally pervasive class of brominated flame retardants that have been extensively used as coatings on a wide range of consumer products. Their environmental stability, propensity for bioaccumulation, and known links to adverse health effects have evoked extensive research to characterize underlying biological mechanisms of toxicity. Of particular concern is the growing body of evidence correlating human exposure levels to behavioral deficits related to neurodevelopmental disorders. The developing nervous system is particularly sensitive to influence by environmental signals, including dysregulation by toxins. Several major modes of actions have been identified, but a clear understanding of how observed effects relate to negative impacts on human health has not been established. Here, we review the current body of evidence for PBDE-induced epigenetic disruptions, including DNA methylation, chromatin dynamics, and non-coding RNA expression while discussing the potential relationship between PBDEs and neurodevelopmental disorders

Superior removal of arsenic from water with zirconium metal-organic framework UiO-66

10.1038/srep16613Scientific Reports51661

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

An evaluation of metal removal during wastewater treatment: The potential to achieve more stringent final effluent standards

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2011 Taylor & Francis.Metals are of particular importance in relation to water quality, and concern regarding the impact of these contaminants on biodiversity is being encapsulated within the latest water-related legislation such as the Water Framework Directive in Europe and criteria revisions to the Clean Water Act in the United States. This review undertakes an evaluation of the potential of 2-stage wastewater treatment consisting of primary sedimentation and biological treatment in the form of activated sludge processes, to meet more stringent discharge consents that are likely to be introduced as a consequence. The legislation, sources of metals, and mechanisms responsible for their removal are discussed, to elucidate possible pathways by which the performance of conventional processes may be optimized or enhanced. Improvements in effluent quality, achievable by reducing concentrations of suspended solids or biochemical oxygen demand, may also reduce metal concentrations although meeting possible requirements for the removal of copper my be challenging