Error-corrected next generation sequencing - Promises and challenges for genotoxicity and cancer risk assessment.

Error-corrected Next Generation Sequencing (ecNGS) is rapidly emerging as a valuable, highly sensitive and accurate method for detecting and characterizing mutations in any cell type, tissue or organism from which DNA can be isolated. Recent mutagenicity and carcinogenicity studies have used ecNGS to quantify drug-/chemical-induced mutations and mutational spectra associated with cancer risk. ecNGS has potential applications in genotoxicity assessment as a new readout for traditional models, for mutagenesis studies in 3D organotypic cultures, and for detecting off-target effects of gene editing tools.

Considerations towards the better integration of epidemiology into quantitative risk assessment.

Environmental epidemiology has proven critical to study various associations between environmental exposures and adverse human health effects. However, there is a perception that it often does not sufficiently inform quantitative risk assessment. To help address this concern, in 2017, the Health and Environmental Sciences Institute initiated a project engaging the epidemiology, exposure science, and risk assessment communities with tripartite representation from government agencies, industry, and academia, in a dialogue on the use of environmental epidemiology for quantitative risk assessment and public health decision making.

International evaluation study of a highly efficient culture assay for detection of residual human pluripotent stem cells in cell therapies.

The Health and Environmental Sciences Institute Cell Therapy-TRAcking, Circulation & Safety Technical Committee launched an international, multisite study to evaluate the sensitivity and reproducibility of the highly efficient culture (HEC) assay, an assay to detect residual undifferentiated human pluripotent stem cells (hPSCs) in cell therapy products. All facilities detected colonies of human induced pluripotent stem cells (hiPSCs) when five hiPSCs were spiked into 1 million hiPSC-derived cardiomyocytes. Spiking with a trace amount of hiPSCs revealed that repeatability accounts for the majority of reproducibility while the true positive rate was high.

Common Considerations for Genotoxicity Assessment of Nanomaterials.

Genotoxicity testing is performed to determine potential hazard of a chemical or agent for direct or indirect DNA interaction. Testing may be a surrogate for assessment of heritable genetic risk or carcinogenic risk. Testing of nanomaterials (NM) for hazard identification is generally understood to require a departure from normal testing procedures found in international standards and guidelines.

Environmental epidemiology and risk assessment: Exploring a path to increased confidence in public health decision-making.

Throughout history, environmental epidemiology has proven crucial to identify certain threats to human health and to provide a basis for the development of life-saving public health policies. However, epidemiologists are facing challenges when studying tenuous threats such as environmental exposure to chemicals, whose association with adverse health effects may be difficult to characterize. As a result, epidemiological data can seldom be fully leveraged for quantitative risk assessment and decision-making.

Urinary miRNA Biomarkers of Drug-Induced Kidney Injury and Their Site Specificity Within the Nephron.

Drug-induced kidney injury (DIKI) is a major concern in both drug development and clinical practice. There is an unmet need for biomarkers of glomerular damage and more distal renal injury in the loop of Henle and the collecting duct (CD). A cross-laboratory program to identify and characterize urinary microRNA (miRNA) patterns reflecting tissue- or pathology-specific DIKI was conducted.

Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects.

Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings.

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (C) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and C exposures. For 13.

Developing a framework for assessing chemical respiratory sensitization: A workshop report.

Respiratory tract sensitization can have significant acute and chronic health implications. While induction of respiratory sensitization is widely recognized for some chemicals, validated standard methods or frameworks for identifying and characterizing the hazard are not available. A workshop on assessment of respiratory sensitization was held to discuss the current state of science for identification and characterization of respiratory sensitizer hazard, identify information facilitating development of validated standard methods and frameworks, and consider the regulatory and practical risk management needs.

Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report.

During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies.

Reprint of "Potential seminal transport of pharmaceuticals to the conceptus".

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins.

Potential seminal transport of pharmaceuticals to the conceptus.

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins.