A5020495575- Carcinogens and Genotoxicity Assessment
- Effects and risks of endocrine disrupting chemicals
- DNA Repair Mechanisms
- Genetically Modified Organisms Research
- Molecular Biology Techniques and Applications
- Animal testing and alternatives
- Bat Biology and Ecology Studies
- Water Treatment and Disinfection
- Animal Ecology and Behavior Studies
- Physiological and biochemical adaptations
- Toxic Organic Pollutants Impact
- Wildlife Ecology and Conservation
- Plant Genetic and Mutation Studies
- Insect Resistance and Genetics
- Pesticide Exposure and Toxicity
- Labor Movements and Unions
- Chemical Safety and Risk Management
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- CRISPR and Genetic Engineering
- DNA and Nucleic Acid Chemistry
- Sperm and Testicular Function
- Abdominal vascular conditions and treatments
- Research on Leishmaniasis Studies
- Reproductive Biology and Fertility
Swansea University
2016-2025
Gower College Swansea
2015
Institute of Life Sciences
2014
University of Wales
2006-2007
Optics Technology (United States)
2005
Monsanto (United States)
2004
Minnesota Pollution Control Agency
1986-1987
University of North Carolina at Chapel Hill
1983
University of Saskatchewan
1977
Kansas State University
1932-1936
Abstract A mechanistic understanding of carcinogenic genotoxicity is necessary to determine consequences chemical exposure on human populations and improve health risk assessments. Currently, linear dose-responses are assumed for DNA reactive compounds, ignoring cytoprotective processes that may limit permanent damage. To investigate the biological significance low-dose exposures, lymphoblastoid cells were treated with alkylating agents have different mechanisms action targets: methylmethane...
Genetic toxicology studies are required for the safety assessment of chemicals. Data from these have historically been interpreted in a qualitative, dichotomous “yes” or “no” manner without analysis dose–response relationships. This article is based upon work an international multi-sector group that examined how quantitative relationships vitro and vivo genetic data might be used to improve human risk assessment. The three approaches analyzing curves deriving point-of-departure (POD) metrics...
Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl (MMS) dose-response (Gollapudi et al., 2013), here we present analyses 1-ethyl-1-nitrosourea (ENU) 1-methyl-1-nitrosourea (MNU) additional approaches the determination genetic toxicity point-of-departure (PoD) metrics. We previously described methods to determine...
This is the second of two reports from International Workshops on Genotoxicity Testing (IWGT) Working Group Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized discussions and recommendations QWG related need for quantitative dose-response analysis genetic toxicology data, existence appropriate evaluation threshold responses, methods analyze exposure-response relationships derive points departure (PoDs) which acceptable exposure levels could...
This report summarizes the discussion, conclusions, and points of consensus IWGT Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (QWG) based a meeting in Foz do Iguaçu, Brazil October 31–November 2, 2013. Topics addressed included (1) need for quantitative dose–response analysis, (2) methods analyze exposure–response relationships & derive point departure (PoD) metrics, (3) mechanistic threshold considerations, (4) approaches define exposure-related risks, (5)...
The demonstration and acceptance of dose response thresholds for genotoxins may have substantial implications the setting safe exposure levels. Here we test hypothesis that direct-acting DNA reactive agents exhibit thresholded responses. We examine potential mechanisms involved in such responses, particularly relation to those alkylating agents. As are representative model compounds with well characterized activities targets, they could help shed light on general responses genotoxins....
Genetic toxicity testing has traditionally been used for hazard identification, with dichotomous classification of test results serving to identify genotoxic agents. However, the utility genotoxicity data can be augmented by employing dose–response analysis and point departure determination. Via interpolation from a fitted model, benchmark dose (BMD) approach estimates that elicits specified (small) effect size. BMD metrics their confidence intervals compound potency ranking within an...
The screen‐and‐bin approach for interpretation of genotoxicity data is predicated on three false assumptions: that genotoxicants are rare, dose–response functions do not contain a low‐dose region mechanistically characterized by zero‐order kinetics, and bona fide toxicological endpoint. Consequently, there need to develop implement quantitative methods interpret risk assessment regulatory decision‐making. Standardized analyze data, determine point‐of‐departure (PoD) metrics, have been...
Mutations induced in somatic cells and germ are responsible for a variety of human diseases, mutation per se has been considered an adverse health concern since the early part 20th Century. Although vitro vivo cell data most commonly used by regulatory agencies hazard identification, that is, determining whether or not substance is potential mutagen carcinogen, quantitative mutagenicity dose–response being increasingly risk assessments. Efforts currently underway to both improve measurement...
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...
Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging suggests model methyl- and ethylmethanesulfonate methylnitrosourea (MNU) ethylnitrosourea observe nonlinear dose-response with no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand mechanism of cellular tolerance biological relevance such NOGELs. MNU is one most mutagenic simple alkylators. Therefore,...
The almost complete lack of reproduction by the several hundred ground squirrels, Citellus tridecemlineatus, in our laboratory led to experiments promote such (Johnson and Wade, 1931). Anterior pituitary implants, ultra-violet light, a diet rich vitamin E, ovarian extracts implants did not increase reproduction. During this study it became evident that sexual development different individuals varied greatly, very little was known cycle captivity.
The tumorigenic dose 50 (TD
Chemical risk assessment has historically focused on single compounds, neglecting the implications of combined exposures. To bridge this gap, several methodologies, such as concentration addition (CA) and independent action (IA), have been developed. However, a systematic, consistent, integrated approach across various legislative frameworks is still lacking. The effects genotoxicants even more challenging, genotoxicity data are typically evaluated qualitatively, without considering effect...
ABSTRACT In vitro genotoxicity has historically served a hazard identification role, with simple binary outcomes provided for each of several single endpoint assays. This will need to change, given: (i) efforts curtail animal testing, (ii) the increased use multiplexed in assays and ongoing development NAMS, (iii) desire holistically consider quantitative results from multiple biomarkers/endpoints that take potency into consideration. To help facilitate more analyses biomarkers and/or assay...
Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption that have linear non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with evaluations. For aneugens, MOA has been well characterised as disruptors mitotic machinery chromosome loss via micronuclei (MN) formation an accepted endpoint used assessment. In this study we...