Pharmacology, Toxicology and Environmental Health Commons^™

Can Acute Dermal Systemic Toxicity Tests Be Replaced With Oral Tests? A Comparison Of Route-Specific Systemic Toxicity And Hazard Classifications Under The Globally Harmonized System Of Classification And Labelling Of Chemicals (Ghs), Nigel P. Moore, David J. Andrew, Donald L. Bjerke, Stuart Creton, David Dreher, Thomas Holmes, Pilar Prieto, Troy Seidle, Tim G. Rowan

Troy Seidle, PhD

Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification …

The Development Of New Concepts For Assessing Reproductive Toxicity Applicable To Large Scale Toxicological Programmes, S. Bremer, C. Pellizzer, S. Hoffmann, T. Seidle, T. Hartung

Troy Seidle, PhD

Large scale toxicological testing programmes which are currently ongoing such as the new European chemical legislation REACH require the development of new integrated testing strategies rather than applying traditional testing schemes to thousands of chemicals. The current practice of requiring in vivo testing for every possible adverse effect endanger the success of these programmes due (i) to limited testing facilities and sufficient capacity of scientific/technical knowledge for reproductive toxicity; (ii) an unacceptable number of laboratory animals involved (iii) an intolerable number of chemicals classified as false positive.

A key aspect of the implementation of new testing strategies is the determination …

Discovery Of Thienoquinolone Derivatives As Selective And Atp Non-Competitive Cdk5/P25 Inhibitors By Structure-Based Virtual Screening, Arindam Chatterjee, Stephen J. Cutler, Robert J. Doerksen, Ikhlas A. Khan, John S. Williamson

Office for Research Publications and Presentations

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2- …

Inhalable Constituents Of Thirdhand Tobacco Smoke: Chemical Characterization And Health Impact Considerations, Mohamad Sleiman, Jennifer M. Logue, Wentai Luo, James F. Pankow, Lara A. Gundel, Hugo Destaillats

Chemistry Faculty Publications and Presentations

Tobacco smoke residues lingering in the indoor environment, also termed thirdhand smoke (THS), can be a source of long-term exposure to harmful pollutants. THS composition is affected by chemical transformations and by air–surface partitioning over time scales of minutes to months. This study identified and quantified airborne THS pollutants available for respiratory exposure, identified potential environmental tracers, and estimated health impacts to nonsmokers. In a ventilated 18 m3 laboratory chamber, six cigarettes were machine-smoked, and levels of particulate matter (PM2.5) and 58 volatile organic compounds (VOCs) were monitored during an aging period of 18 h. Results were compared with field …

Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego Amado Torres

Doctoral Dissertations

Proteins have the capacity to bind specific sets of compounds known as ligands, these are small molecules with a recurrent theme in their molecular design that is a characteristic exploited here to (i) identify particular affinities of small molecules for proteins with the aim of using them as ligands, inhibitors, or targeting moieties in more complex systems by means of a methodology that screens small molecules based on protein affinity; (ii) decorate a self-assembling supramolecular system at different positions, making it responsive to a complementary protein with the aim of exploring differences in disassembly and sensitivity of the release of …

Investigation Into The Control Of Melittin Secondary Structure And Antimicrobial Activity, Zachary B. Molinets

Open Access Theses

Antimicrobial resistance has been an exponentially growing problem since the discovery of antibiotics. Antibiotics have been misused for many years and this misuse has grown into a real problem for the medical community. While there are countless safeguards to prevent infection by a resistant strain of bacteria, there are still many plagued by it and must be treated with sometimes dangerous antibiotics. Melittin, along with many other peptides, contain potent antimicrobial properties, but are also toxic toward enthrocytes. The control of the secondary structure of peptides provides the key to adjusting their activity.

Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego F. Amado Torres

Diego Amado Torres

Proteins have the capacity to bind specific sets of compounds known as ligands, these are small molecules with a recurrent theme in their molecular design that is a characteristic exploited here to (i) identify particular affinities of small molecules for proteins with the aim of using them as ligands, inhibitors, or targeting moieties in more complex systems by means of a methodology that screens small molecules based on protein affinity; (ii) decorate a self-assembling supramolecular system at different positions, making it responsive to a complementary protein with the aim of exploring differences in disassembly and sensitivity of the release of …

Candy Flavorings In Tobacco, Jessica E. Brown, Wentai Luo, Lorne M. Isabelle, James F. Pankow

Chemistry Faculty Publications and Presentations

Professor James F. Pankow reveals striking similarities between the patterns in the flavoring chemicals used in flavored tobacco products and those in popular candy and Kool-Aid products. The authors analyzed 12 artificially flavored candy and fruit drink products and compared them to 15 widely-available flavored tobacco products. They found significant overlap in the chemical signatures of the flavor chemicals. Several of the tobacco products contained flavor chemicals at much higher concentrations than in the non-tobacco products.

Speciation, Metabolism, Toxicity, And Protein-Binding Of Different Arsenic Species In Human Cells, Szabina A. Stice

FIU Electronic Theses and Dissertations

Despite of its known toxicity and potential to cause cancer, arsenic has been proven to be a very important tool for the treatment of various refractory neoplasms. One of the promising arsenic-containing chemotherapeutic agents in clinical trials is Darinaparsin (dimethylarsinous glutathione, DMA^III(GS)). In order to understand its toxicity and therapeutic efficacy, the metabolism of Darinaparsin in human cancer cells was evaluated. With the aim of detecting all potential intermediates and final products of the biotransformation of Darinaparsin and other arsenicals, an analytical method employing high performance liquid chromatography inductively coupled mass spectrometry (HPLC-ICP-MS) was developed. This method was …

Synthesis And Characterization Of Brain Penetrant Prodrug Of Neuroprotective D264: Potential Disease Modifying Treatment Agent For Parkinson's Disease, Fahd Shamoon Dholkawala

Wayne State University Theses

Parkinson's disease (PD) is a complex neurodegenerative disorder with progressive loss of dopamanergic neurons in the substantia nigra region of the brain and accumulation of intracytoplasmic inclusions called `Lewy bodies'. PD is characterized by tremors, rigidity, slowness of movement, bradykinesia and postural imbalances. Although the etiology of PD is not well understood, it is well established that oxidative stress, mitochondrial dysfunction, alpha-synuclein aggregation play a central role in the pathogenesis of PD. Current treatment methods are based on symptomatic relief without addressing the underlying pathophysiological factors responsible for the disease. It is important to develop therapies which can address these …

Dj-1 And Atp13a2: Two Proteins Involved In Parkinson’S Disease, Josephat M Asiago

Open Access Dissertations

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting approximately 0.3% of the total U.S. population, and its prevalence increases with age. Two neuropathological hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta, a region in the midbrain involved in initiating and sustaining movement, and the presence of cytosolic inclusions called Lewy bodies (LBs) in various brain regions. LBs are enriched with fibrillar forms of the presynaptic protein &agr;-synuclein (aSyn). Two autosomal recessive genes implicated in familial PD are PARK9, encoding the P-type ATPase ATP13A2, a lysosomal ATPase; and …

The Development Of Liquid Chromatography Mass Spectrometry Methods For The Analysis Of Cyanobacterial Toxins In Environmental Freshwaters, Brian Anthony Dineen

Theses

Cyanobacteria, also known as blue-green algae, are a common component of many freshwater and marine ecosystems and have a potential to produce several different classes of biotoxins. The most common class of cyanobacterial toxins are the microcystins (MCs) and cylindrospermopsins (CYLs). MCs are cyclic heptapeptides that display potent hepatotoxicity and are tumour promoters. CYLs are alkaloids that are cytotoxic and can cause illness and display hepatotoxic effects in animals and humans. Worldwide, these toxins have caused fatal poisonings to animals, birds and fish. Several incidents of human intoxications have been reported and the presence of these toxins in environmental waters …

Investigation Of Pyrrolizidine Alkaloids In Foods Using Liquid Chromatography Mass Spectrometry, Caroline Griffin

Theses

Pyrrolizidine Alkaloids (PAs) are known plant toxins which can cause hepatic veno-occlusive disease (HVOD) in both humans and livestock when ingested. Although PAs are primarily known for their hepatotoxicity they also induce genotoxicity, carcinogenicity and pneumotoxicity. PAs are consumed through plants as food, for medicinal purposes, or as contaminants of agricultural crops. Aside from ingesting the plants directly PA exposure may occur through the consumption of honey produced by bees that visit PA-containing plants or by drinking milk produced by animals that have consumed PA-containing plants. Possible PA contamination in our food chain is a potential health risk.

To assess …

Concern-Driven Integrated Toxicity Testing Strategies For Nanomaterials - Report Of The Nanosafety Cluster Working Group 10, Hugh Byrne, Agnes G. Oomen, Peter M.J. Bos, Teresa F. Fernandes, Kerstin Hund-Rinke, Diana Boraschi, Karin Aschberger, Stefania Gottardo, Frank Von Der Kammer, Dana Kühnel, Danail Hristozov, Antonio Marcomini, Lucia Migliore

Articles

Bringing together topic-related European Union-(EU)-funded projects, the so-called “NanoSafety Cluster” aims at identifying key areas for further research on risk assessment procedures for nanomaterials (NM). The outcome of NanoSafety Cluster Working Group 10, this commentary presents a vision for concern-driven integrated approaches for the (eco-)toxicological testing and assessment (IATA) of NM. Such approaches should start out by determining concerns, i.e. specific information needs for a given NM based on realistic exposure scenarios. Recognized concerns can be addressed in a set of tiers using standardized protocols for NM preparation and testing. Tier 1 includes determining physico-chemical properties, non-testing (e.g. structure …

Improving The Microbial Source Tracking Toolbox : Evaluating The Use Of Selective Enrichments And Artificial Sweeteners In A Multi-Tiered Approach, Stacey A. Helming

Legacy Theses & Dissertations (2009 - 2024)

Microbial contamination of surface waters is a public health concern world-wide, with non-point source fecal input contributing to millions of cases of waterborne illness annually. Numerous techniques have been proposed to monitor for non-point source fecal contamination, but few studies have explored the correlation of multiple chemical and microbial fecal source tracking markers in ambient waters. Therefore, the purpose of these studies was to evaluate the use of multiple "ideal" markers of fecal contamination and improve upon any analytical techniques required to identify species-specific fecal contamination in surface waters. The use of selective enrichments to improve the sensitivity of end-point …

Impact Of Zinc Oxide Nanoparticles On Green Pea Plant & Seed Quality And Effects On Physiological Traits Of Green Peas, Corn, And Zucchini By Silver Nanoparticles, Arnab Mukherjee

Open Access Theses & Dissertations

The production and use of numerous engineered nanomaterials (ENMs) have increased exponentially over the past decade. Nanoparticles (NPs), ENMs possessing diameter between 1-100 nm, (NPs), are widely used in many applications. Worldwide consumption of NPs has increased their possible release into the environment. This, in turn, has elevated the extent of the potential impacts of NP exposure to living and non-living organisms. This is why the assessment of the impact of NPs on different environmental components, especially on plants, the producer in the food web, has become a very important aspect of nano-ecotoxicology. However, studies focusing on phytotoxicity and effects …

Addressing Public Health Risks Of Persistent Pollutants Through Nutritional Modulation And Biomimetic Nanocomposite Remediation Platforms, Bradley J. Newsome

Theses and Dissertations--Chemistry

Due to their relative chemical stability and ubiquity in the environment, chlorinated organic contaminants such as polychlorinated biphenyls (PCBs) pose significant health risks and enduring remediation challenges. Engineered nanoparticles (NPs) provide a novel platform for sensing/remediation of these toxicants, in addition to the growing use of NPs in many industrial and biomedical applications, but there remains concern for their potential long-term health effects. Research highlighted herein also represents a transdisciplinary approach to address human health challenges associated with exposure to PCBs and NPs. The objectives of this dissertation research are two-fold, 1) to develop effective methods for capture/sensing and remediation …