A5078200850- Carcinogens and Genotoxicity Assessment
- Computational Drug Discovery Methods
- Effects and risks of endocrine disrupting chemicals
- Water Treatment and Disinfection
- Pesticide Exposure and Toxicity
- Analytical Chemistry and Chromatography
- DNA Repair Mechanisms
- Genetically Modified Organisms Research
- Animal testing and alternatives
- Synthesis and Biological Evaluation
- Sulfur Compounds in Biology
- Polyamine Metabolism and Applications
- Diabetes and associated disorders
- DNA and Nucleic Acid Chemistry
- Pesticide Residue Analysis and Safety
- Birth, Development, and Health
- Radiation Effects and Dosimetry
- Pesticide and Herbicide Environmental Studies
- Cancer-related Molecular Pathways
- Pharmaceutical and Antibiotic Environmental Impacts
- Pharmacogenetics and Drug Metabolism
- Electromagnetic Fields and Biological Effects
- Cancer Genomics and Diagnostics
- Chemical Safety and Risk Management
- Biochemical and biochemical processes
Pfizer (United States)
2014-2024
University of Rochester
2015
University of California, Riverside
1994-1998
Hungarian Academy of Sciences
1980
The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates information needed for support predictions major toxicological endpoints concern (e.g., genetic toxicity, carcinogenicity, acute reproductive developmental toxicity) regulatory bodies. Such novel (IST)...
A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate mutagenic potential and carcinogenic potency in rodents. Empirical computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at α-carbon; it responsible for both activation, leading formation DNA-reactive diazonium species, deactivation denitrosation. There are competing sites CYP metabolism (e.g., β-carbon), other...
The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products limit the potential carcinogenic risk related such impurities. This paper outlines series of principles procedures consider when generating (Q)SAR assessments aligned with be included regulatory submission. In absence adequate experimental data, results from two complementary methodologies may combined support an initial hazard...
The potential for N-nitrosamine impurities in pharmaceutical products presents a challenge the quality management of medicinal products. N-Nitrosamines are considered cohort-of-concern compounds due to potent carcinogenicity many structurally simple chemicals within this structural class. In past 2 years, number drug containing certain active ingredients have been withdrawn or recalled from market presence carcinogenic low-molecular-weight N,N-dialkylnitrosamine impurities. Regulatory...
In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, as assessing chemicals under REACH well the ICH M7 guideline drug impurities. There are a number obstacles performing an IST assessment, including uncertainty how assessment associated expert review should be performed or what fit purpose, lack confidence that results will accepted by colleagues, collaborators...
Abstract A genotoxic carcinogen, N ‐nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs 2018, and other ‐nitrosamines, such ‐nitrosodiethylamine (NDEA), were later sartan products. N‐nitrosamines are pro‐mutagens that can react with DNA following metabolism to produce adducts, O 6 ‐alkyl‐guanine. The adducts result replication miscoding errors leading GC>AT mutations increased risk of genomic instability carcinogenesis. Both NDMA NDEA known rodent...
Abstract N ‐Ethyl‐ ‐nitrosourea (ENU) was evaluated as part of the Stage III trial for rat Pig‐a gene mutation assay. Groups six‐ to eight‐week‐old male Sprague Dawley (SD) or Fischer 344 (F344) rats were given 28 daily doses phosphate buffered saline vehicle, 2.5, 5, 10 mg/kg ENU, and a variety genotoxicity endpoints in peripheral blood, spleen, liver, colon. Blood sampled predose (Day‐1) at various time points up Day 57. mutant frequencies determined total red blood cells (RBCs)...
Pharmaceutical applicants conduct (Q)SAR assessments on identified and theoretical impurities to predict their mutagenic potential. Two complementary models—one rule-based one statistical-based—are used, followed by expert review. models are continuously updated improve predictions, with new versions typically released a yearly basis. Numerous releases of will occur during the typical 6–7 years drug development until registration. Therefore, it is important understand impact model updates...
Abstract Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas interest for companies health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels N ‐nitrosamine drug substance‐related impurities (NDSRIs) using SAR, however some compounds require experimental data support derivation a recommended AI. Many angiotensin‐converting enzyme inhibitors, identified by suffix...
Using a simple enrichment procedure, we isolated an R-prime derivative of plasmid R68.45 carrying 17.8-megadalton segment the Rhizobium meliloti 41 chromosome. The chromosomal carried on this (pGY1) includes markers cys-24+, cys-46+, and att16-3. Plasmid pGY1 mobilized chromosome in polarized way starting from region homology, but cannot promote transfer other sites. att16-3 site allowed integration phage 16-3 into pGY1, composite 91.8 megadaltons was formed. This vector (pGY2) is suitable...
The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process impurities that have the potential to be present in drug substance or product. In absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may used as test predict impurities' DNA reactive (mutagenic) potential. However, certain situations, software is unable generate positive negative prediction either because conflicting information impurity outside applicability domain...
The role of metabolism in genotoxicity and carcinogenicity many chemicals is well established. Accordingly, both vitro metabolic activation systems vivo assays are routinely utilized for genotoxic hazard identification drug candidates prior to clinical investigations. This should, most cases provide a high degree confidence that the potential parent associated metabolites have been characterized. However, it known significant differences can exist between human which occurs with tests. poses...