The Experts below are selected from a list of 123588 Experts worldwide ranked by ideXlab platform
Melvin E. Andersen - One of the best experts on this subject based on the ideXlab platform.
-
identifying qualitative differences in pparα signaling networks in human and rat hepatocytes and their significance for next generation Chemical Risk assessment methods
Toxicology in Vitro, 2020Co-Authors: Patrick D Mcmullen, Sudin Bhattacharya, Courtney G Woods, Salil N Pendse, Mary Mcbride, Valerie Y Soldatow, Chad Deisenroth, Edward L Lecluyse, Rebecca A Clewell, Melvin E. AndersenAbstract:Abstract In this paper, we evaluate the PPARα signaling network in rats, examining transcriptional responses in primary hepatocytes exposed to a PPARα specific ligand, GW7647. These transcriptomic studies were complemented with ChIP-seq studies of PPARα binding and transcription binding motif identification for PPARα responsive genes. We also conducted a limited study of GW7647 dosing the in intact rat to examine differences in transcriptional responses for primary hepatocytes in vitro and in the intact liver. The rat network has a much larger number of down-regulated genes and pathways than we had found in the human and the PPARα binding motifs in rat differed for upregulated and down regulated genes. Based on these results and comparison with our previous work with the human PPARα signaling network, we identified qualitative differences in the transcriptional networks controlled by PPARα activation in the two species that provide an explanation of the interspecies differences in the responses of humans and rodents to GW7647 and likely to other PPARα agonists. These studies also allow some observations on the manner in which in vitro, fit-for-purpose assays in human hepatocytes could form the basis for Risk assessment without recourse to in-life studies in rodents or other test species.
-
integrating pathway based transcriptomic data into quantitative Chemical Risk assessment a five Chemical case study
Mutation Research, 2012Co-Authors: Russell S Thomas, Harvey J Clewell, Bruce C Allen, Longlong Yang, Eric Healy, Melvin E. AndersenAbstract:The traditional approach for performing a Chemical Risk assessment is time and resource intensive leading to a limited number of published assessments on which to base human health decisions. In comparison, most contaminated sites contain Chemicals without published reference values or cancer slope factors that are not considered quantitatively in the overall hazard index calculation. The integration of transcriptomic technology into the Risk assessment process may provide an efficient means to evaluate quantitatively the health Risks associated with data poor Chemicals. In a previous study, female B6C3F1 mice were exposed to multiple concentrations of five Chemicals that were positive for lung and/or liver tumor formation in a two-year rodent cancer bioassay. The mice were exposed for a period of 13 weeks and the target tissues were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. In this study, the dose-response changes in gene expression were analyzed using a benchmark dose (BMD) approach and the responses grouped based on pathways. A comparison of the transcriptional BMD values with those for the traditional non-cancer and cancer apical endpoints showed a high degree of correlation for specific pathways. Many of the correlated pathways have been implicated in non-cancer and cancer disease pathogenesis. The results demonstrate that transcriptomic changes in pathways can be used to estimate non-cancer and cancer points-of-departure for use in quantitative Risk assessments and have identified potential toxicity pathways involved in Chemically induced mouse lung and liver responses.
-
Toxicokinetic modeling and its applications in Chemical Risk assessment.
Toxicology letters, 2003Co-Authors: Melvin E. AndersenAbstract:In recent years physiologically based pharmacokinetic (PBPK) modeling has found frequent application in Risk assessments where PBPK models serve as important adjuncts to studies on modes of action of xenobiotics. In this regard, studies on mode of action provide insight into both the sites/mechanisms of action and the form of the xenobiotic associated with toxic responses. Validated PBPK models permit calculation of tissue doses of xenobiotics and metabolites for a variety of conditions, i.e. at low-doses, in different animal species, and in different members of a human population. In this manner, these PBPK models support the low-dose and interspecies extrapolations that are important components of current Risk assessment methodologies. PBPK models are sometimes referred to as physiological toxicokinetic (PT) models to emphasize their application with compounds causing toxic responses. Pharmacokinetic (PK) modeling in general has a rich history. Data-based PK compartmental models were developed in the 1930's when only primitive tools were available for solving sets of differential equations. These models were expanded in the 1960's and 1970's to accommodate new observations on dose-dependent elimination and flow-limited metabolism. The application of clearance concepts brought many new insights about the disposition of drugs in the body. In the 1970's PBPK/PT models were developed to evaluate metabolism of volatile compounds of occupational importance, and, for the first time, dose-dependent processes in toxicology were included in PBPK models in order to assess the conditions under which saturation of metabolic and elimination processes lead to non-linear dose response relationships. In the 1980's insights from Chemical engineers and occupational toxicology were combined to develop PBPK/PT models to support Risk assessment with methylene chloride and other solvents. The 1990's witnessed explosive growth in Risk assessment applications of PBPK/PT models and in applying sensitivity and variability methods to evaluate model performance. Some of the compounds examined in detail include butadiene, styrene, glycol ethers, dioxins and organic esters/aids. This paper outlines the history of PBPK/PT modeling, emphasizes more recent applications of PBPK/TK models in health Risk assessment, and discusses the Risk assessment perspective provided by modern uses of these modeling approaches.
Russell S Thomas - One of the best experts on this subject based on the ideXlab platform.
-
accelerating the pace of Chemical Risk assessment
Chemical Research in Toxicology, 2018Co-Authors: Robert J Kavlock, Maureen R Gwinn, Tina Bahadori, Tara S Bartonmaclaren, Mike Rasenberg, Russell S ThomasAbstract:Changes in Chemical regulations worldwide have increased the demand for new data on Chemical safety. New approach methodologies (NAMs) are defined broadly here as including in silico approaches and in chemico and in vitro assays, as well as the inclusion of information from the exposure of Chemicals in the context of hazard [European Chemicals Agency, “New Approach Methodologies in Regulatory Science”, 2016]. NAMs for toxicity testing, including alternatives to animal testing approaches, have shown promise to provide a large amount of data to fill information gaps in both hazard and exposure. In order to increase experience with the new data and to advance the applications of NAM data to evaluate the safety of data-poor Chemicals, demonstration case studies have to be developed to build confidence in their usability. Case studies can be used to explore the domains of applicability of the NAM data and identify areas that would benefit from further research, development, and application. To ensure that this...
-
Chemical Risk assessment traditional vs public health perspectives
American Journal of Public Health, 2017Co-Authors: Maureen R Gwinn, Daniel A Axelrad, Tina Bahadori, David Bussard, Wayne E Cascio, Kacee Deener, David J Dix, Russell S Thomas, Robert J Kavlock, Thomas A BurkeAbstract:Preventing adverse health effects of environmental Chemical exposure is fundamental to protecting individual and public health. When done efficiently and properly, Chemical Risk assessment enables Risk management actions that minimize the incidence and effects of environmentally induced diseases related to Chemical exposure. However, traditional Chemical Risk assessment is faced with multiple challenges with respect to predicting and preventing disease in human populations, and epidemiological studies increasingly report observations of adverse health effects at exposure levels predicted from animal studies to be safe for humans. This discordance reinforces concerns about the adequacy of contemporary Risk assessment practices for protecting public health.It is becoming clear that to protect public health more effectively, future Risk assessments will need to use the full range of available data, draw on innovative methods to integrate diverse data streams, and consider health endpoints that also reflect t...
-
Recommended approaches in the application of toxicogenomics to derive points of departure for Chemical Risk assessment
Archives of Toxicology, 2017Co-Authors: Reza Farmahin, Nikolai L. Chepelev, Andrew Williams, Russell S Thomas, Byron Kuo, Tara S. Barton-maclaren, Ivan H. Curran, Andy Nong, Michael G. Wade, Carole L YaukAbstract:There is increasing interest in the use of quantitative transcriptomic data to determine benchmark dose (BMD) and estimate a point of departure (POD) for human health Risk assessment. Although studies have shown that transcriptional PODs correlate with those derived from apical endpoint changes, there is no consensus on the process used to derive a transcriptional POD. Specifically, the subsets of informative genes that produce BMDs that best approximate the doses at which adverse apical effects occur have not been defined. To determine the best way to select predictive groups of genes, we used published microarray data from dose–response studies on six Chemicals in rats exposed orally for 5, 14, 28, and 90 days. We evaluated eight approaches for selecting genes for POD derivation and three previously proposed approaches (the lowest pathway BMD, and the mean and median BMD of all genes). The relationship between transcriptional BMDs derived using these 11 approaches and PODs derived from apical data that might be used in Chemical Risk assessment was examined. Transcriptional BMD values for all 11 approaches were remarkably aligned with corresponding apical PODs, with the vast majority of toxicogenomics PODs being within tenfold of those derived from apical endpoints. We identified at least four approaches that produce BMDs that are effective estimates of apical PODs across multiple sampling time points. Our results support that a variety of approaches can be used to derive reproducible transcriptional PODs that are consistent with PODs produced from traditional methods for Chemical Risk assessment.
-
temporal concordance between apical and transcriptional points of departure for Chemical Risk assessment
Toxicological Sciences, 2013Co-Authors: Russell S Thomas, Longlong Yang, Eric Healy, Scott C Wesselkamper, Nina Ching Y Wang, Jay Q Zhao, Dan D Petersen, Jason C Lambert, Ila Cote, Michael B BlackAbstract:The number of legacy Chemicals without toxicity reference values combined with the rate of new Chemical development is overwhelming the capacity of the traditional Risk assessment paradigm. More efficient approaches are needed to quantitatively estimate Chemical Risks. In this study, rats were dosed orally with multiple doses of six Chemicals for 5 days and 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points of departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with eight additional Chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.827, p = 0.0031) and cancer-related (r = 0.940, p = 0.0002) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two, suggesting that for the current Chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a
-
integrating pathway based transcriptomic data into quantitative Chemical Risk assessment a five Chemical case study
Mutation Research, 2012Co-Authors: Russell S Thomas, Harvey J Clewell, Bruce C Allen, Longlong Yang, Eric Healy, Melvin E. AndersenAbstract:The traditional approach for performing a Chemical Risk assessment is time and resource intensive leading to a limited number of published assessments on which to base human health decisions. In comparison, most contaminated sites contain Chemicals without published reference values or cancer slope factors that are not considered quantitatively in the overall hazard index calculation. The integration of transcriptomic technology into the Risk assessment process may provide an efficient means to evaluate quantitatively the health Risks associated with data poor Chemicals. In a previous study, female B6C3F1 mice were exposed to multiple concentrations of five Chemicals that were positive for lung and/or liver tumor formation in a two-year rodent cancer bioassay. The mice were exposed for a period of 13 weeks and the target tissues were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. In this study, the dose-response changes in gene expression were analyzed using a benchmark dose (BMD) approach and the responses grouped based on pathways. A comparison of the transcriptional BMD values with those for the traditional non-cancer and cancer apical endpoints showed a high degree of correlation for specific pathways. Many of the correlated pathways have been implicated in non-cancer and cancer disease pathogenesis. The results demonstrate that transcriptomic changes in pathways can be used to estimate non-cancer and cancer points-of-departure for use in quantitative Risk assessments and have identified potential toxicity pathways involved in Chemically induced mouse lung and liver responses.
Paul Whaley - One of the best experts on this subject based on the ideXlab platform.
-
systematic evidence maps as a novel tool to support evidence based decision making in Chemicals policy and Risk management
Environment International, 2019Co-Authors: Taylor A M Wolffe, Paul Whaley, Crispin J Halsall, Andrew A Rooney, Vickie R WalkerAbstract:Abstract Background While systematic review (SR) methods are gaining traction as a method for providing a reliable summary of existing evidence for health Risks posed by exposure to Chemical substances, it is becoming clear that their value is restricted to a specific range of Risk management scenarios - in particular, those which can be addressed with tightly focused questions and can accommodate the time and resource requirements of a systematic evidence synthesis. Methods The concept of a systematic evidence map (SEM) is defined and contrasted to the function and limitations of systematic review (SR) in the context of Risk management decision-making. The potential for SEMs to facilitate evidence-based decision-making are explored using a hypothetical example in Risk management priority-setting. The potential role of SEMs in reference to broader Risk management workflows is characterised. Results SEMs are databases of systematically gathered research which characterise broad features of the evidence base. Although not intended to substitute for the evidence synthesis element of systematic reviews, SEMs provide a comprehensive, queryable summary of a large body of policy relevant research. They provide an evidence-based approach to characterising the extent of available evidence and support forward looking predictions or trendspotting in the Chemical Risk sciences. In particular, SEMs facilitate the identification of related bodies of decision critical Chemical Risk information which could be further analysed using SR methods, and highlight gaps in the evidence which could be addressed with additional primary studies to reduce uncertainties in decision-making. Conclusions SEMs have strong and growing potential as a high value tool in resource efficient use of existing research in Chemical Risk management. They can be used as a critical precursor to efficient deployment of high quality SR methods for characterising Chemical health Risks. Furthermore, SEMs have potential, at a large scale, to support the sort of evidence summarisation and surveillance methods which would greatly increase the resource efficiency, transparency and effectiveness of regulatory initiatives such as EU REACH and US TSCA.
-
implementing systematic review techniques in Chemical Risk assessment challenges opportunities and recommendations
Environment International, 2016Co-Authors: Paul Whaley, Chris D. Collins, Marlene Agerstrand, Crispin J Halsall, Elisa Aiassa, Diane Benford, Gary Bilotta, David Coggon, Ciara Dempsey, Raquel DuartedavidsonAbstract:Systematic review (SR) is a rigorous, protocol-driven approach designed to minimise error and bias when summarising the body of research evidence relevant to a specific scientific question. Taking as a comparator the use of SR in synthesising research in healthcare, we argue that SR methods could also pave the way for a “step change” in the transparency, objectivity and communication of Chemical Risk assessments (CRA) in Europe and elsewhere. We suggest that current controversies around the safety of certain Chemicals are partly due to limitations in current CRA procedures which have contributed to ambiguity about the health Risks posed by these substances. We present an overview of how SR methods can be applied to the assessment of Risks from Chemicals, and indicate how challenges in adapting SR methods from healthcare research to the CRA context might be overcome. Regarding the latter, we report the outcomes from a workshop exploring how to increase uptake of SR methods, attended by experts representing a wide range of fields related to Chemical toxicology, Risk analysis and SR. Priorities which were identified include: the conduct of CRA-focused prototype SRs; the development of a recognised standard of reporting and conduct for SRs in toxicology and CRA; and establishing a network to facilitate research, communication and training in SR methods. We see this paper as a milestone in the creation of a research climate that fosters communication between experts in CRA and SR and facilitates wider uptake of SR methods into CRA.
Robert J Kavlock - One of the best experts on this subject based on the ideXlab platform.
-
accelerating the pace of Chemical Risk assessment
Chemical Research in Toxicology, 2018Co-Authors: Robert J Kavlock, Maureen R Gwinn, Tina Bahadori, Tara S Bartonmaclaren, Mike Rasenberg, Russell S ThomasAbstract:Changes in Chemical regulations worldwide have increased the demand for new data on Chemical safety. New approach methodologies (NAMs) are defined broadly here as including in silico approaches and in chemico and in vitro assays, as well as the inclusion of information from the exposure of Chemicals in the context of hazard [European Chemicals Agency, “New Approach Methodologies in Regulatory Science”, 2016]. NAMs for toxicity testing, including alternatives to animal testing approaches, have shown promise to provide a large amount of data to fill information gaps in both hazard and exposure. In order to increase experience with the new data and to advance the applications of NAM data to evaluate the safety of data-poor Chemicals, demonstration case studies have to be developed to build confidence in their usability. Case studies can be used to explore the domains of applicability of the NAM data and identify areas that would benefit from further research, development, and application. To ensure that this...
-
Chemical Risk assessment traditional vs public health perspectives
American Journal of Public Health, 2017Co-Authors: Maureen R Gwinn, Daniel A Axelrad, Tina Bahadori, David Bussard, Wayne E Cascio, Kacee Deener, David J Dix, Russell S Thomas, Robert J Kavlock, Thomas A BurkeAbstract:Preventing adverse health effects of environmental Chemical exposure is fundamental to protecting individual and public health. When done efficiently and properly, Chemical Risk assessment enables Risk management actions that minimize the incidence and effects of environmentally induced diseases related to Chemical exposure. However, traditional Chemical Risk assessment is faced with multiple challenges with respect to predicting and preventing disease in human populations, and epidemiological studies increasingly report observations of adverse health effects at exposure levels predicted from animal studies to be safe for humans. This discordance reinforces concerns about the adequacy of contemporary Risk assessment practices for protecting public health.It is becoming clear that to protect public health more effectively, future Risk assessments will need to use the full range of available data, draw on innovative methods to integrate diverse data streams, and consider health endpoints that also reflect t...
-
update on epa s toxcast program providing high throughput decision support tools for Chemical Risk management
Chemical Research in Toxicology, 2012Co-Authors: Robert J Kavlock, Richard S Judson, Matthew T Martin, Thomas B Knudsen, Keith A Houck, Kelly J Chandler, Sid Hunter, Nicole Kleinstreuer, Stephanie Padilla, David M ReifAbstract:The field of toxicology is on the cusp of a major transformation in how the safety and hazard of Chemicals are evaluated for potential effects on human health and the environment. Brought on by the recognition of the limitations of the current paradigm in terms of cost, time, and throughput, combined with the ever increasing power of modern biological tools to probe mechanisms of Chemical–biological interactions at finer and finer resolutions, 21st century toxicology is rapidly taking shape. A key element of the new approach is a focus on the molecular and cellular pathways that are the targets of Chemical interactions. By understanding toxicity in this manner, we begin to learn how Chemicals cause toxicity, as opposed to merely what diseases or health effects they might cause. This deeper understanding leads to increasing confidence in identifying which populations might be at Risk, significant susceptibility factors, and key influences on the shape of the dose–response curve. The U. S. Environmental Pro...
-
estimating toxicity related biological pathway altering doses for high throughput Chemical Risk assessment
Chemical Research in Toxicology, 2011Co-Authors: Richard S Judson, Russell S Thomas, Robert J Kavlock, Woodrow R Setzer, Elaine Cohen A Hubal, Matthew T Martin, Thomas B Knudsen, Keith A Houck, Barbara A Wetmore, David J DixAbstract:We describe a framework for estimating the human dose at which a Chemical significantly alters a biological pathway in vivo, making use of in vitro assay data and an in vitro-derived pharmacokinetic model, coupled with estimates of population variability and uncertainty. The quantity we calculate, the biological pathway altering dose (BPAD), is analogous to current Risk assessment metrics in that it combines dose-response data with analysis of uncertainty and population variability to arrive at conservative exposure limits. The analogy is closest when perturbation of a pathway is a key event in the mode of action (MOA) leading to a specified adverse outcome. Because BPADs are derived from relatively inexpensive, high-throughput screening (HTS) in vitro data, this approach can be applied to high-throughput Risk assessments (HTRA) for thousands of data-poor environmental Chemicals. We envisage the first step of HTRA to be an assessment of in vitro concentration-response relationships across biologically important pathways to derive biological pathway altering concentrations (BPAC). Pharmacokinetic (PK) modeling is then used to estimate the in vivo doses required to achieve the BPACs in the blood at steady state. Uncertainty and variability are incorporated in both the BPAC and the PK parameters and then combined to yield a probability distribution for the dose required to perturb the critical pathway. We finally define the BPADL as the lower confidence bound of this pathway-altering dose. This perspective outlines a framework for using HTRA to estimate BPAD values; provides examples of the use of this approach, including a comparison of BPAD values with published dose-response data from in vivo studies; and discusses challenges and alternative formulations.
Yumei Tan - One of the best experts on this subject based on the ideXlab platform.
-
pbpk model reporting template for Chemical Risk assessment applications
Regulatory Toxicology and Pharmacology, 2020Co-Authors: Yumei Tan, Melissa Chan, Amechi Chukwudebe, Jeanne Y Domoradzki, Jeffrey W Fisher, Eric C Hack, Paul M Hinderliter, Kota Hirasawa, Jeremy A Leonard, Annie LumenAbstract:Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/Chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental Chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and Risk assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.
-
uses of nhanes biomarker data for Chemical Risk assessment trends challenges and opportunities
Environmental Health Perspectives, 2015Co-Authors: Jon R Sobus, Yumei Tan, Robert S Dewoskin, Joachim D Pleil, Martin B Phillips, Barbara Jane George, Krista Y Christensen, Dina M Schreinemachers, Marc A Williams, Elaine Cohen A HubalAbstract:BackgroundEach year, the U.S. NHANES measures hundreds of Chemical biomarkers in samples from thousands of study participants. These biomarker measurements are used to establish population referenc...