Demolition of the Navajo Generating Station

Demolition of the Navajo Generating Station Authors Ms. Sunshine Pryor - United States - Tetra Tech EC, Inc. Mr. Pete Everds - United States - Tetra Tech EC, Inc. Mr. Michael O\u27Hare - United States - Tetra Tech EC, Inc. Abstract Operation of the Navajo Generating Station (NGS), a 2,250 MW coal-fired power plant, in Northern Arizona ceased in 2019 with demolition starting soon after and restoration will be completed in early 2024. Decommissioning, decontamination, demolition and restoration (DDDR) activities included closure of the CCR landfill, closure of evaporation ponds and solid waste landfill, removal and disposal of the overhead catenary lines, demolition and removal of 3 – 750 MW power units and all associated equipment and support facilities. The plant was isolated from energy sources, remaining chemicals/fuels/fluids were removed, and asbestos-containing materials abated prior to demolition. Experts mechanically demolished structures using shears and equipment and explosives were used to bring down the three 775-foot stacks, boilers, and turbine deck. Site restoration included removal of ponds wastes, grading for proper stormwater drainage and retention, and revegetation. Closure of the approximately 277-acre CCR landfill included consolidation of ash, evaporation pond waste, and inert construction debris. The waste surface was prepared for the cover system (a combination of geotextile, geomembrane, and geocomposite). Cover soil was placed over the liner and stormwater drainage and retention features were installed. Access roads were constructed for inspection, monitoring, and maintenance activities. Revegetation was with a native seed mix

A Novel Statistical Algorithm for Gene Expression Analysis Helps Differentiate Pregnane X Receptor-Dependent and Independent Mechanisms of Toxicity

Genome-wide gene expression profiling has become standard for assessing potential liabilities as well as for elucidating mechanisms of toxicity of drug candidates under development. Analysis of microarray data is often challenging due to the lack of a statistical model that is amenable to biological variation in a small number of samples. Here we present a novel non-parametric algorithm that requires minimal assumptions about the data distribution. Our method for determining differential expression consists of two steps: 1) We apply a nominal threshold on fold change and platform p-value to designate whether a gene is differentially expressed in each treated and control sample relative to the averaged control pool, and 2) We compared the number of samples satisfying criteria in step 1 between the treated and control groups to estimate the statistical significance based on a null distribution established by sample permutations. The method captures group effect without being too sensitive to anomalies as it allows tolerance for potential non-responders in the treatment group and outliers in the control group. Performance and results of this method were compared with the Significant Analysis of Microarrays (SAM) method. These two methods were applied to investigate hepatic transcriptional responses of wild-type (PXR+/+) and pregnane X receptor-knockout (PXR−/−) mice after 96 h exposure to CMP013, an inhibitor of β-secretase (β-site of amyloid precursor protein cleaving enzyme 1 or BACE1). Our results showed that CMP013 led to transcriptional changes in hallmark PXR-regulated genes and induced a cascade of gene expression changes that explained the hepatomegaly observed only in PXR+/+ animals. Comparison of concordant expression changes between PXR+/+ and PXR−/− mice also suggested a PXR-independent association between CMP013 and perturbations to cellular stress, lipid metabolism, and biliary transport

Deciphering Sources of Variability in Clinical Pathology—It’s Not Just about the Numbers

Preanalytical variables can have significant impacts on clinical pathology parameters evaluated during the conduct of a nonclinical safety or toxicity study. These preanalytical variables can be controlled by careful attention to factors such as animal dietary status (diet composition, fasted, and fed state), restraint and anesthesia, intercurrent procedures, timing of clinical pathology collections, and proficiency of animal technicians. The impact of preanalytical variables on test results can be significant enough to result in difficult interpretations and/or regulatory questions or can obfuscate the effects of a test article. Control of preanalytical variables starts with knowledge of what processes and procedures impact test results. Minimizing these effects improves the quality of results and maximizes the value of the study. </jats:p

Wilmington N.C. riverfront

Painting of sailboat passing riverfront. Reproduction

Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

Biotherapeutics are expanding the arsenal of therapeutics available for treating and preventing disease. Although initially thought to have limited side effects due to the specificity of their binding, these drugs have now been shown to have potential for adverse drug reactions including effects on peripheral blood cell counts or function. Hematotoxicity caused by a biotherapeutic can be directly related to the activity of the biotherapeutic or can be indirect and due to autoimmunity, biological cascades, antidrug antibodies, or other immune system responses. Biotherapeutics can cause hematotoxicity primarily as a result of cellular activation, cytotoxicity, drug-dependent and independent immune responses, and sequelae from initiating cytokine and complement cascades.  The underlying pathogenesis of biotherapeutic-induced hematotoxicity often is poorly understood. Nonclinical studies have generally predicted clinical hematotoxicity for recombinant cytokines and growth factors.  However, most hematologic liabilities of biotherapeutics are not based on drug class but are species specific, immune-mediated, and of low incidence. Despite the potential for unexpected hematologic toxicity, the risk–benefit profile of most biotherapeutics is favorable; hematologic effects are readily monitorable and managed by dose modification, drug withdrawal, and/or therapeutic intervention.  This article reviews examples of biotherapeutics that have unexpected hematotoxicity in nonclinical or clinical studies.  </jats:p