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 …

An Evaluation Of The Us High Production Volume (Hpv) Chemical-Testing Programme: A Study In (Ir)Relevance, Redundancy And Retro Thinking, Andrew Nicholson, Jessica Sandler, Troy Seidle

Troy Seidle, PhD

Under the US Environmental Protection Agency (EPA) High Production Volume (HPV) Challenge Programme, chemical companies have volunteered to conduct screening-level toxicity tests on approximately 2800 widely-used industrial chemicals. Participating companies are committed to providing available toxicity information to the EPA and presenting testing proposals for review by the EPA and posting on the EPA Web site as public information. People for the Ethical Treatment of Animals (PETA) and a coalition of animal protection organisations have reviewed all the test plans submitted by the participating chemical companies for compliance with the original HPV framework, as well as with animal welfare guidelines …

Cross-Sector Review Of Drivers And Available 3rs Approaches For Acute Systemic Toxicity Testing, Troy Seidle, Sally Robinson, Tom Holmes, Stuart Creton, Pilar Prieto, Julia Scheel, Magda Chlebus

Troy Seidle, PhD

Acute systemic toxicity studies are carried out in many sectors in which synthetic chemicals are manufactured or used and are among the most criticized of all toxicology tests on both scientific and ethical grounds. A review of the drivers for acute toxicity testing within the pharmaceutical industry led to a paradigm shift whereby in vivo acute toxicity data are no longer routinely required in advance of human clinical trials. Based on this experience, the following review was undertaken to identify (1) regulatory and scientific drivers for acute toxicity testing in other industrial sectors, (2) activities aimed at replacing, reducing, or …

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 …

Bringing Toxicology Into The 21st Century: A Global Call To Action, Troy Seidle, Martin Stephens

Troy Seidle, PhD

Conventional toxicological testing methods are often decades old, costly and low-throughput, with questionable relevance to the human condition. Several of these factors have contributed to a backlog of chemicals that have been inadequately assessed for toxicity. Some authorities have responded to this challenge by implementing large-scale testing programmes. Others have concluded that a paradigm shift in toxicology is warranted. One such call came in 2007 from the United States National Research Council (NRC), which articulated a vision of ‘‘21st century toxicology” based predominantly on non-animal techniques. Potential advantages of such an approach include the capacity to examine a far greater …

A Modular One-Generation Reproduction Study As A Flexible Testing System For Regulatory Safety Assessment, Richard Vogel, Troy Seidle, Horst Spielmann

Troy Seidle, PhD

The European Union’s Registration, Evaluation and Authorisation of Chemicals (REACH) legislation mandates testing and evaluation of approximately 30,000 existing substances within a short period of time, beginning with the most widely used “high production volume” (HPV) chemicals. REACH testing requirements for the roughly 3000 HPV chemicals specify three separate tests for reproductive toxicity: two developmental toxicity studies on different animal species (OECD Test Guideline 414) and a two-generation reproduction toxicity study (OECD TG 416). These studies are highly costly in both economic and animal welfare terms. OECD TG 416 is a fertility study intended to evaluate reproductive performance of animals …

Biological And Physiological Condition Of Juvenile California Halibut (Paralichthys Californicus) Exposed To A Contamination Gradient In Mission Bay, Ca, Kevin Stolzenbach

Theses

Contaminated sediments in marine environments have been shown to be good indicators of ecological risk and a means to assess anthropogenic impacts on marine habitats and the animals that inhabit them (Long et al. 1995, Rattner 2009). Estuarine sediments are especially complex media with regard to physical, chemical, and biological characteristics that trap, store, modify and sometimes release contaminants to the biota (Long et al. 1995). Especially vulnerable are animals that are in constant contact with the sediments, such as flatfishes that partially bury themselves for camouflage (Costa et al. 2011). Impacts can be assessed in a number of ways, …

Response Of Soil Nitrification To The Veterinary Pharmaceuticals Monensin, Ivermectin And Zinc Bacitracin, Magda A. Konopka

Electronic Thesis and Dissertation Repository

Pharmaceutical residues can reach agricultural land through amendment with animal or human waste. Since 2010, a series of replicated plots received annual applications of ivermectin, monensin and zinc bacitracin, either singly or in a mixture, at 0.1 mg/kg and 10 mg/kg concentrations. I collected soil samples before and after the fourth annual application of pharmaceuticals and assayed them for functional changes and amoA gene abundance, a gene needed for ammonia oxidation. In 2013, I exposed the soils to 100 mg/kg in a laboratory experiment which resulted in acceleration of nitrification. Under 10 mg/kg treatments in the field the abundance of …

Cd151-Α3Β1 Integrin Complexes Suppress Ovarian Tumor Growth By Repressing Slug-Mediated Emt And Canonical Wnt Signaling, Lauren A. Baldwin, John T. Hoff, Jason Lefringhouse, Michael Zhang, Changhe Jia, Zeyi Liu, Sonia Erfani, Hongyan Jin, Mei Xu, Qing-Bai She, John R. Van Nagell Jr., Chi Wang, Li Chen, Rina Plattner, David M. Kaetzel, Jia Luo, Michael Lu, Dava West, Chunming Liu, Fred R. Ueland, Ronny Drapkin, Binhua P. Zhou, Xiuwei H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by …

Impacts Of Land-Cover Change And High Rainfall On Soil Erosion Among Three Farms In Cerro Punta, Chiriquí, Panamá., Madeline Happ

Independent Study Project (ISP) Collection

Soil erosion is a key source leading to the depletion of Earth’s natural resources. Beginning with deforestation, soils are stripped of their rich vegetation cover, leaving them vulnerable to wind, water, and sometimes total exhaustion. One of the major causes of deforestation, if not the primary cause, is for agricultural purposes. Extensive agricultural fields, steep slopes, and heavy rains characterize the highlands of Chiriquí; thus, the land displays potential for severe loss of soil. This paper illustrates and discusses the extent of soil erosion in Cerro Punta, Chiriquí, specifically considering the steep terrains and very wet environment that impact the …

A Quantitative Analysis Of The Value-Enhancing Effects Of Nicotine, Bupropion, And Varenicline In Male And Female Rats, Scott Barrett

Department of Psychology: Dissertations, Theses, and Student Research

Smoking and tobacco dependence are serious health concerns in the United States and globally. Reward via the pharmacological effects of nicotine are believed to be the principal motivating factor that drive tobacco dependence. Research reveals differences in sensitivity between males and females to the motivational effects of nicotine in tobacco use. Enhancement of reinforcement value of non-nicotine rewards contributes to overall nicotine reward. Similar value-enhancing effects have been observed by the two most commonly prescribed smoking cessation aids, bupropion and varenicline. The present dissertation investigated the value-enhancing effects of nicotine, bupropion and varenicline in both male and female rats using …

Impact Of Gestational Exposure To 2,3,7,8-Tetrachlorodibenzo-P-Dioxin On T Lymphocyte Development, Lori S. Ahrenhoerster

Theses and Dissertations

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant and the best characterized agonist of the arylhydrocarbon receptor (AHR), a transcription factor crucial to the detoxification of numerous xenobiotics. Studies in animals show that TCDD is immunosuppressive in adult exposures, and epidemiological studies have found an association between TCDD exposure and hematologic cancers. Additionally, developmental exposure to TCDD has been shown to increase the likelihood of autoimmunity and to impair immune response to later-life infections. The cells of the immune system are all descended from multipotent hematopoietic stem cells (HSCs) that originate in the fetus. This multipotency, defined as the ability to …

Numerical Simulations Of In Vitro Nanoparticle Toxicity – The Case Of Poly(Amido Amine) Dendrimers., Marcus Maher, Pratap Naha, Sourav Prasanna Mukherjee, Hugh Byrne

Articles

A phenomenological rate equation model is constructed to numerically simulate nanoparticle uptake and subsequent cellular response. Polyamidoamine dendrimers (generations 4-6) are modelled and the temporal evolution of the intracellular cascade of; increased levels of reactive oxygen species, intracellular antioxidant species, caspase activation, mitochondrial membrane potential decay, tumour necrosis factor and interleukin generation is simulated, based on experimental observations.

The dose and generation dependence of several of these response factors are seen to well represent experimental observations at a range of time points. The model indicates that variations between responses of different cell-lines, including murine macrophages, human keratinocytes and colon cells, …

Interactive Effects Of Climate Change With Nutrients, Mercury, And Freshwater Acidification On Key Taxa In The North Atlantic Landscape Conservation Cooperative Region, Alfred E. Pinkey, Charles T. Driscoll, David C. Evers, Michael J. Hooper, Jeffrey Horan, Jess W. Jones, Rebecca S. Lazarus, Harold G. Marshall, Andrew Milliken, Barnett A. Rattner, John Schmerfold, Donald W. Sparling

Biological Sciences Faculty Publications

The North Atlantic Landscape Conservation Cooperative LCC (NA LCC) is a public-private partnership that provides information to support conservation decisions that may be affected by global climate change (GCC) and other threats. The NA LCC region extends from southeast Virginia to the Canadian Maritime Provinces. Within this region, the US National Climate Assessment documented increases in air temperature, total precipitation, frequency of heavy precipitation events, and rising sea level, and predicted more drastic changes. Here, we synthesize literature on the effects of GCC interacting with selected contaminant, nutrient, and environmental processes to adversely affect natural resources within this region. Using …

Aminoglycoside-Induced Otoneurotoxicity: Analysis Of Inner Hair Cell Synaptic Plasticity Following Drug Exposure, Matthew M. Abernathy

Dissertations

Aminoglycoside antibiotics are powerful drugs for combating bacterial infections, but are limited in use due to their ototoxicity. This class of drug targets the auditory hair cells of the cochlea, causing cell death, which leads to a decline in auditory function. In spite of much research aimed at revealing a mechanism of damage, there are no co-therapies available to diminish the ototoxic liability of aminoglycosides. Existing research does show that there may be a neurodegenerative process that contributes to the observed toxicity. In an effort towards clarifying present understanding of issue, this dissertation project was conducted to characterize the neurodegenerative …

Development And Characterization Of An Autologous Whole Cell Breast Cancer Vaccine, Samantha Leigh Kurtz

Graduate Theses and Dissertations

Approximately 40,000 women will die from breast cancer in the United States in 2014. About 90% of these deaths will be due to metastases, rather than the primary tumor and majority of metastases are due to the recurrence and progression of non-metastatic disease. Current adjuvant treatments, such as chemotherapy and radiation, have severe side effects and may result in overtreatment and drug resistance.

Since greater than 90% of patients are diagnosed between stages I-III and have minimal residual disease after treatment, there is an opportunity to treat patients with an autologous breast cancer vaccine. Autologous vaccines under development have a …

Evaluating The Effects Of Aroclor 1260 In Non-Alcoholic Fatty Liver Disease : The Role Of Xenobiotic Receptors., Banrida Wahlang

Electronic Theses and Dissertations

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants, present in 100% of US adults and dose-dependently associated with nonalcoholic fatty liver disease (NAFLD) in epidemiologic studies. PCBs are predicted to interact with receptors previously implicated in xenobiotic/energy metabolism and NAFLD. These receptors include the aryl hydrocarbon receptor (AhR), pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptors (PPARs), liver-X-receptor and farnesoid-X-receptor. This study evaluated the hepatic effects of the PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity. Male C57Bl/6J mice were fed a control or 42% high fat diet (HFD) …

Molecular Characterization Of Hemoglobin Protein In Larvae Of 4th Instar Chironomidae For Evaluating Environmental Quality, Jun Taek Oh

Seton Hall University Dissertations and Theses (ETDs)

Studying environmental quality is a challenging task. It is a complicated exercise since the environment is constantly influenced by numerous variables such as climate change, anthropogenic activities, and unexpected natural disasters. Traditionally, exposure to chemical pollutants depended on chemical and physical analysis of environmental media. Unfortunately, this approach has not taken into consideration bioavailability of the chemical(s) of interest to exposed organisms and/or modification of the chemical (bioactivation/detoxification) by the organism. Benthic macroinvertebrates (BMIs) have been chosen as bioindicators for numerous environmental biomonitoring programs geared towards the assessment of aquatic ecosystems. Biomonitoring requires a more subtle measure – a biomarker …

Considering A New Paradigm For Alzheimer’S Disease Research, Gillian R. Langley

Gill Langley, PhD

Using Alzheimer’s disease as a case study, this review argues that it might be time to consider a new paradigm in medical research and drug discovery. The existing framework is overly dependent on often unvalidated animal models, particularly transgenic mice. Translational success remains elusive and costly late-stage drug failure is common. The conventional paradigm tends to overlook species differences and assumes that animal-based findings are generally applicable to humans. Could pathways-based research using advanced human-specific models probed with new tools, including those of systems biology, take centre stage? The current transition in chemical toxicology to a 21st-century paradigm could be …

Engaging Communities To Identify And Address Environmental Health Literacy Gaps, Anna G. Hoover

Anna G. Hoover

Frequently, decisions about the informational components and delivery mechanisms required to promote effective environmental health literacy are made by such technical experts as toxicologists, chemists, and communication scientists. However, because sensemaking processes are both retrospective and collective, context must be a central component for understanding the particular information needs of communities and stakeholder groups. Individual assessments of and tolerance for environmental health risks are rooted in past and present experiences that are understood, refined, and reinforced through dialogue with others who have shared similar experiences. Thus, the promotion of environmental health literacy requires formative engagement with communities and stakeholders to …