Grace Patlewicz

Grace Patlewicz

About

174
Publications
33,119
Reads
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10,079
Citations
Citations since 2017
59 Research Items
5376 Citations
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201720182019202020212022202302004006008001,0001,200
201720182019202020212022202302004006008001,0001,200
Introduction

Publications

Publications (174)
Article
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Understanding the metabolic fate of a xenobiotic substance can help inform its potential health risks and allow for the identification of signature metabolites associated with exposure. The need to characterize metabolites of poorly studied or novel substances has shifted exposure studies towards non-targeted analysis (NTA), which often aims to pro...
Article
The Analog Identification Methodology (AIM) was developed over 20 years ago to identify analogues to support read-across at the US Environmental Protection Agency. However, the current public version of the standalone tool, released in 2012, is no longer usable on Windows operating systems supported by Microsoft. Additionally, the structural logic...
Article
Full-text available
The assessment of human health hazards posed by chemicals traditionally relies on toxicity studies in experimental animals. However, most chemicals currently in commerce do not meet the minimum data requirements for hazard identification and dose-response analysis in human health risk assessment. Previously, we introduced a read-across framework de...
Article
Screening new compounds for potential bioactivities against cellular targets is vital for drug discovery and chemical safety. Transcriptomics offers an efficient approach for assessing global gene expression changes, but interpreting chemical mechanisms from these data is often challenging. Connectivity mapping is a potential data-driven avenue for...
Article
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Current computational technologies hold promise for prioritizing the testing of the thousands of chemicals in commerce. Here, a case study is presented demonstrating comparative risk-prioritization approaches based on the ratio of surrogate hazard and exposure data, called margins of exposure (MoEs). Exposures were estimated using a U.S. EPA’s Expo...
Article
Per- and Polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals that are in widespread use and present concerns for persistence, bioaccumulation and toxicity. Whilst a handful of PFAS have been characterised for their hazard profiles, the vast majority of PFAS have not been studied. The US Environmental Protection Agency (EPA) underto...
Article
The Threshold of Toxicological Concern (TTC) is a pragmatic approach used to establish safe thresholds below which there can be no appreciable risk to human health. Here, a large inventory of ∼45,000 substances (referred to as the LRI dataset) was profiled through the Kroes TTC decision module within Toxtree v3.1 to assign substances into their res...
Article
Full-text available
Structure-activity relationships (SARs) in toxicology have enabled the formation of structural rules which, when coded as structural alerts, are an essential tool in in silico toxicology. Whilst other in silico methods have approaches for their evaluation, there is no formal process to assess the confidence that may be associated with a structural...
Article
Acute toxicity in silico models are being used to support an increasing number of application areas including (1) product research and development, (2) product approval and registration as well as (3) the transport, storage and handling of chemicals. The adoption of such models is being hindered, in part, because of a lack of guidance describing ho...
Article
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Research in environmental health is becoming increasingly reliant upon data science and computational methods that can more efficiently extract information from complex datasets. Data science and computational methods can be leveraged to better identify relationships between exposures to stressors in the environment and human disease outcomes, repr...
Article
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Background: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram n...
Article
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Regulatory agencies rely upon rodent in vivo acute oral toxicity data to determine hazard categorization, require appropriate precautionary labeling, and perform quantitative risk assessments. As the field of toxicology moves toward animal-free new approach methodologies (NAMs), there is a pressing need to develop a reliable, robust reference data...
Article
Full-text available
Per- and polyfluoroalkyl substances (PFAS) are a class of man-made chemicals of global concern for many health and regulatory agencies due to their widespread use and persistence in the environment (in soil, air, and water), bioaccumulation, and toxicity. This concern has catalyzed a need to aggregate data to support research efforts that can, in t...
Article
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Perfluorooctanoic acid (PFOA) and related compounds are per- and polyfluorinated alkyl substances (PFASs) of concern from toxicological, environmental, and regulatory perspectives. In 2019, the Conference of the Parties to the Stockholm Convention on Persistent Organic Pollutants listed PFOA, its salts, and PFOA-related compounds in Annex A to the...
Article
Changes in the regulatory landscape of chemical safety assessment call for the use of New Approach Methodologies (NAMs) including read-across to fill data gaps. One critical aspect of analogue evaluation is the extent to which target and source analogues are metabolically similar. In this study, a set of 37 structurally diverse chemicals were compi...
Article
The Toxic Substances Control Act (TSCA) became law in the U.S. in 1976 and was amended in 2016. The amended law requires the U.S. EPA to perform risk-based evaluations of existing chemicals. Here, we developed a tiered approach to screen potential candidates based on their genotoxicity and carcinogenicity information to inform the selection of cand...
Article
Read-across is a data gap filling technique utilized to predict the toxicity of a target chemical using data from similar analogues. Recent efforts such as Generalized Read-Across (GenRA) facilitate automated read-across predictions for untested chemicals. GenRA makes predictions of toxicity outcomes based on “neighboring” chemicals characterized b...
Article
Per- and polyfluoroalkyl substances (PFAS) are a broad class of hundreds of fluorinated chemicals with environmental health concerns due to their widespread presence and persistence in the environment. Several of these chemicals have been comprehensively studied for experimental toxicity, environmental fate and exposure, and human epidemiology; how...
Article
Full-text available
Background: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditi...
Article
Motivation Generalised Read-Across (GenRA) is a data-driven approach to estimate physico-chemical, biological, or eco-toxicological properties of chemicals by inference from analogues. GenRA attempts to mimic a human expert’s manual read-across reasoning for filling data gaps about new chemicals from known chemicals with an interpretable and automa...
Article
Regulatory agencies world-wide face the challenge of performing risk-based prioritization of thousands of substances in commerce. In this study, a major effort was undertaken to compile a large genotoxicity dataset (54,805 records for 9299 substances) from several public sources (e.g., TOXNET, COSMOS, eChemPortal). The names and outcomes of the dif...
Article
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The requirements of amended Toxic Substances Control Act (TSCA) stipulates that the US Environmental Protection Agency (US EPA) evaluate existing chemicals and make risk based assessments. There are ~33,000 substances that are active in commerce on the TSCA public non-confidential inventory, many of which lack available toxicity and exposure inform...
Article
The toxicokinetic (TK) parameters fraction of the chemical unbound to plasma proteins and metabolic clearance are critical for relating exposure and internal dose when building in vitro-based risk assessment models. However, experimental toxicokinetic studies have only been carried out on limited chemicals of environmental interest (∼1000 chemicals...
Article
Environmental exposure to metals is known to cause a number of human toxicities including cancer. Metal-responsive transcription factor 1 (MTF-1) is an important component of metal regulation systems in mammalian cells. Here, we describe a novel method to identify chemicals that activate MTF-1 based on microarray profiling data. MTF-1 biomarker gen...
Article
The Toxic Substances Control Act (TSCA) mandates the US EPA perform risk-based prioritisation of chemicals in commerce and then, for high-priority substances, develop risk evaluations that integrate toxicity data with exposure information. One approach being considered for data poor chemicals is the Threshold of Toxicological Concern (TTC). Here, T...
Article
Full-text available
Read-across approaches continue to evolve as does their utility in the field of risk assessment. Previously we presented our generalised read-across (GenRA) approach (Shah et al., 2016), which utilises chemical descriptor and/or in vitro bioactivity data to make read-across predictions on the basis of the similarity weighted average of nearest neig...
Article
The molecular initiating event for many mechanisms of toxicological action comprise the reactive, covalent binding between an exogenous electrophile and an endogenous nucleophile. The target sites for electrophiles are typically peptides, proteins, enzymes or DNA. Of these, the formation of covalent adducts with proteins and DNA are perhaps the mos...
Article
Read-across is a well-established data gap-filling technique applied for regulatory purposes. In US Environmental Protection Agency's New Chemicals Program under TSCA, read-across has been used extensively for decades, however the extent of application and acceptance of read-across among U.S. federal agencies is less clear. In an effort to build re...
Article
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Traditional approaches for chemical risk assessment cannot keep pace with the number of substances requiring assessment. Thus, in a global effort to expedite and modernize chemical risk assessment, New Approach Methodologies (NAMs) are being explored and developed. Included in this effort is the OECD Integrated Approaches for Testing and Assessment...
Article
Full-text available
The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure charact...
Article
Full-text available
Per- and polyfluoroalkyl substances (PFASs) are a group of fluorinated substances of interest to researchers, regulators, and the public due to their widespread presence in the environment. A few PFASs have comparatively extensive amounts of human epidemiological, exposure, and experimental animal toxicity data (e.g., perfluorooctanoic acid), where...
Article
The application of toxic equivalency factors (TEFs) or toxic units to estimate toxic potencies for mixtures of chemicals which contribute to a biological effect through a common mechanism is one approach for filling data gaps. Toxic Equivalents (TEQ) have been used to express the toxicity of dioxin-like compounds (i.e., dioxins, furans, and dioxin-...
Article
Full-text available
Regulatory agencies across the world are facing the challenge of performing risk-based prioritization of thousands of chemicals in commerce. Here, we present an approach using the Threshold of Toxicological Concern (TTC) combined with heuristic high-throughput exposure (HTE) modelling to rank order chemicals for further evaluation. Accordingly, for...
Article
Adverse Outcome Pathways (AOPs) establish a connection between a molecular initiating event (MIE) and an adverse outcome. Detailed understanding of the MIE provides the ideal data for determining chemical properties required to elicit the MIE. This study utilized high-throughput screening data from the ToxCast program, coupled with chemical structu...
Article
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In early 2018, the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) published the "Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of Chemicals and Medical Products in the United States" (ICCVAM 2018). Cross-agency federal workgroups have been established to implement this roadmap for va...
Article
Full-text available
Read-across is a useful data gap filling technique used within category and analogue approaches in regulatory hazard and risk assessment. Recently we developed an algorithmic, approach called Generalised Read-Across (GenRA) (Shah et al., 2016) which makes read-across predictions of toxicity effects using a similarity weighted average of source anal...
Article
Predictive testing to characterise substances for their skin sensitisation potential has historically been based on animal models such as the Local Lymph Node Assay (LLNA) and the Guinea Pig Maximisation Test (GPMT). In recent years, EU regulations, have provided a strong incentive to develop non-animal alternatives, such as expert systems software...
Article
Read-across is a popular data gap filling technique used within analogue and category approaches for both regulatory and product stewardship purposes. In recent years, there have been many efforts focused on the challenges involved in read-across development, its scientific justification and documentation for both chemical hazard and risk assessmen...
Article
Full-text available
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 the information needed for protocols to support in silico pre...
Presentation
Full-text available
Chemical risk assessment is both time-consuming and difficult because it requires the assembly of data for chemicals generally distributed across multiple sources. The US EPA CompTox Chemistry Dashboard is a publicly accessible web-based application providing access to various data streams on ~760,000 chemical substances. These data include experim...
Presentation
Full-text available
Researchers at EPA’s National Center for Computational Toxicology integrate advances in biology, chemistry, and computer science to examine the toxicity of chemicals and help prioritize chemicals for further research based on potential human health risks. The goal of this research program is to quickly evaluate thousands of chemicals, but at a much...
Chapter
This chapter highlights some of the cheminformatics approaches and protocols that have demonstrated usefulness and high relevance for absorption, distribution, metabolism, excretion, and toxicology (ADMET) profiling in various published case studies and/or have attracted the attention of the research community. The ultimate success of the ADMET mod...
Article
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Despite an abundance of online databases providing access to chemical data, there is increasing demand for high-quality, structure-curated, open data to meet the various needs of the environmental sciences and computational toxicology communities. The U.S. Environmental Protection Agency’s (EPA) web-based CompTox Chemistry Dashboard is addressing t...
Article
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Animal testing alone cannot practically evaluate the health hazard posed by tens of thousands of environmental chemicals. Computational approaches making use of high-throughput experimental data may provide more efficient means to predict chemical toxicity. Here, we use a supervised machine learning strategy to systematically investigate the relati...
Article
There is an expectation that to meet regulatory requirements, and avoid or minimize animal testing, integrated approaches to testing and assessment will be needed that rely on assays representing key events (KEs) in the skin sensitization adverse outcome pathway. Three non-animal assays have been formally validated and regulatory adopted: the direc...
Article
Full-text available
Read-across is a popular data gap filling technique used within analogue and category approaches for regulatory purposes. In recent years there have been many efforts focused on the challenges involved in read-across development, its scientific justification and documentation. Tools have also been developed to facilitate read-across development and...
Article
The information characterizing key events in an Adverse Outcome Pathway (AOP) can be generated from in silico, in chemico, in vitro and in vivo approaches. Integration of this information and interpretation for decision making are known as integrated approaches to testing and assessment (IATA). One such IATA was published by Jaworska et al., which...
Poster
Full-text available
The U.S. Environmental Protection Agency (EPA) Computational Toxicology Program integrates advances in biology, chemistry, and computer science to help prioritize chemicals for further research based on potential human health risks. This work involves computational and data driven approaches that integrate chemistry, exposure and biological data. T...
Presentation
Full-text available
The U.S. Environmental Protection Agency (EPA) Computational Toxicology Program integrates advances in biology, chemistry, and computer science to help prioritize chemicals for further research based on potential human health risks. This work involves computational and data driven approaches that integrate chemistry, exposure and biological data. A...
Article
Predictive toxicity models rely on large amounts of accurate in vivo data. Here, we analyze the quality of in vivo data from the U.S. EPA Toxicity Reference Database (ToxRefDB), using chemical-induced anemia as an example. Considerations include variation in experimental conditions, changes in terminology over time, distinguishing negative from mis...
Chapter
In this chapter, we provide an overview of how (Quantitative) Structure Activity Relationships, (Q)SARs, are validated and applied for regulatory purposes. We outline how chemical categories are derived to facilitate endpoint specific read-across using tools such as the OECD QSAR Toolbox and discuss some of the current difficulties in addressing th...
Chapter
In this chapter, we explain how Integrated Approaches to Testing and Assessment (IATA) offer a means of integrating and translating the data generated by toxicity testing methods, thereby serving as flexible and suitable tools for toxicological decision making in the twenty-first century. In addition to traditional in vitro and in vivo testing meth...
Article
Predictive testing to characterize substances for their skin sensitization potential has historically been based on animal tests such as the Local Lymph Node Assay (LLNA). In recent years, regulations in the cosmetics and chemicals sectors have provided strong impetus to develop non-animal alternatives. Three test methods have undergone OECD valida...
Article
Full-text available
The U.S. Environmental Protection Agency’s (EPA) ToxCast program is testing a large library of Agency-relevant chemicals using in vitro high-throughput screening (HTS) approaches in order to support development of improved toxicity prediction models. Launched in 2007, Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds...
Article
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It is widely accepted that substances that cannot penetrate through the skin will not be sensitizers. LogKow and molecular weight (MW) have been used to set thresholds for sensitization potential. Highly hydrophilic substances e.g. LogKow ≤ 1 are expected not to penetrate effectively to induce sensitization. To investigate whether LogKow >1 is a tr...
Article
It is widely accepted that substances must have a molecular weight (MW) < 500 to penetrate effectively through the skin to induce sensitization. Roberts et al. (2012. Contact Dermatitis 68: 32-41) evaluated a data set of 699 substances taken from the TIMES-SS expert system and identified that of the 13 substances with a MW > 500, five were sensitiz...
Article
Read-across is a popular data gap filling technique within category and analogue approaches for regulatory purposes. Acceptance of read-across remains an ongoing challenge with several efforts underway for identifying and addressing uncertainties. Here we demonstrate an algorithmic, automated approach to evaluate the utility of using in vitro bioac...
Article
Full-text available
Assessments of methodological and reporting quality are critical to adequately judging the credibility of a study's conclusions and to gauging its potential reproducibility. To aid those seeking to assess the methodological or reporting quality of studies relevant to toxicology, we conducted a scoping review of the available guidance with respect t...
Article
Full-text available
Grouping of substances and utilizing read-across of data within those groups represents an important data gap filling technique for chemical safety assessments. Categories/analogue groups are typically developed based on structural similarity and, increasingly often, also on mechanistic (biological) similarity. While read-across can play a key role...
Article
Exploiting non-testing approaches to predict toxicity early in the drug discovery development cycle is a helpful component in minimizing expensive drug failures due to toxicity being identified in late development or even during clinical trials. Changes in regulations in the Industrial chemicals and Cosmetics sectors in recent years have prompted a...
Article
Full-text available
An Adverse Outcome Pathway (AOP) represents the existing knowledge of a biological pathway leading from initial molecular interactions of a toxicant and progressing through a series of key events (KEs), culminating with an apical adverse outcome (AO) that has to be of regulatory relevance. An AOP based on the mode of action (MOA) of rodent liver tu...
Article
Carcinogenicity is a complex endpoint of high concern yet the rodent bioassay still used is costly to run in terms of time, money and animals. Therefore carcinogenicity has been the subject of many different efforts to both develop short-term tests and non-testing approaches capable of predicting genotoxic carcinogenic potential. In our previous pu...