Richard Judson

United States Environmental Protection Agency | US EPA · National Center for Computational Toxicology

High-throughput transcriptomics (HTTr) uses gene expression profiling to characterize the biological activity of chemicals in in vitro cell-based test systems. As an extension of a previous study testing 44 chemicals, HTTr was used to screen an additional 1,751 unique chemicals from the EPA’s ToxCast collection in MCF7 cells using 8 concentrations...

Chemicals assessment and management frameworks rely on regulatory toxicity values, which are based on points of departure (POD) identified following rigorous dose–response assessments. Yet, regulatory PODs and toxicity values for inhalation exposure (i.e., reference concentrations [RfCs]) are available for only ∼200 chemicals. To address this gap,...

The rapid increase of publicly available chemical structures and associated experimental data presents a valuable opportunity to build robust QSAR models for applications in different fields. However, the common concern is the quality of both the chemical structure information and associated experimental data. This is especially true when those dat...

Background: Per- and polyfluoroalkyl substances (PFAS) encompass a class of chemically and structurally diverse compounds that are extensively used in industry and detected in the environment. The US Environmental Protection Agency (US EPA) 2021 PFAS Strategic Roadmap describes national research plans to address the challenge of PFAS. Objectives:...

The growing number of chemicals in the current consumer and industrial markets presents a major challenge for regulatory programs faced with the need to assess the potential risks they pose to human and ecological health. The increasing demand for hazard and risk assessment of chemicals currently exceeds the capacity to produce the toxicity data ne...

Background: Regulatory toxicity values used to assess and manage chemical risks rely on the determination of the point of departure (POD) for a critical effect, which results from a comprehensive and systematic assessment of available toxicity studies. However, regulatory assessments are only available for a small fraction of chemicals. Objective...

Per- and polyfluoroalkyl substances (PFAS) are a diverse group of man-made chemicals that are commonly found in body tissues. The toxicokinetics of most PFAS are currently uncharacterized, but long half-lives (t½) have been observed in some cases. Knowledge of chemical-specific t½ is necessary for exposure reconstruction and extrapolation from toxi...

Chemical risk assessment considers potentially susceptible populations including pregnant women and developing fetuses. Humans encounter thousands of chemicals in their environments, few of which have been fully characterized. Toxicokinetic (TK) information is needed to relate chemical exposure to potentially bioactive tissue concentrations. Observ...

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...

The United States Environmental Protection Agency has proposed a tiered testing strategy for chemical hazard evaluation based on new approach methods (NAMs). The first tier includes in vitro profiling assays applicable to many (human) cell types, such as high-throughput transcriptomics (HTTr) and high-throughput phenotypic profiling (HTPP). The goa...

Background The advent of high-throughput transcriptomic screening technologies has resulted in a wealth of publicly available gene expression data associated with chemical treatments. From a regulatory perspective, data sets that cover a large chemical space and contain reference chemicals offer utility for the prediction of molecular initiating ev...

Many applications of chemical screening are performed in concentration or dose-response mode, and it is necessary to extract appropriate parameters, including whether the chemical/assay pair is active and if so, what are concentrations where activity is seen. Typically, multiple mathematical models or curve shapes are tested against the data to ass...

Purpose Reducing chemical pressure on human and environmental health is an integral part of the global sustainability agenda. Guidelines for deriving globally applicable, life cycle–based indicators are required to consistently quantify toxicity impacts from chemical emissions as well as from chemicals in consumer products. In response, we elaborat...

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...

Endocrine-disrupting chemicals have the ability to interfere with and alter functions of the hormone system, leading to adverse effects on reproduction, growth and development. Despite growing concerns over their now ubiquitous presence in the environment, endocrine-related human health effects remain largely outside of comparative human toxicity c...

Human health risk assessment for environmental chemical exposure is limited by a vast majority of chemicals with little or no experimental in vivo toxicity data. Data gap filling techniques, such as quantitative structure–activity relationship (QSAR) models based on chemical structure information, can predict hazard in the absence of experimental d...

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...

Phenotypic profiling assays are untargeted screening assays that measure a large number (hundreds to thousands) of cellular features in response to a stimulus and often yield diverse and unanticipated profiles of phenotypic effects, leading to challenges in distinguishing active from inactive treatments. Here, we compare a variety of different stra...

Screening certain environmental chemicals for their ability to interact with endocrine targets, including the androgen receptor (AR), is an important global concern. We previously developed a model using a battery of eleven in vitro AR assays to predict in vivo AR activity. Here we describe a revised mathematical modeling approach that also incorpo...

New approach methodologies (NAMs) for chemical hazard assessment are often evaluated via comparison to animal studies; however, variability in animal study data limits NAM accuracy. The US EPA Toxicity Reference Database (ToxRefDB) enables consideration of variability in effect levels, including the lowest effect level (LEL) for a treatment-related...

There is a growing recognition that application of mechanistic approaches to understand cross-species shared molecular targets and pathway conservation in the context of hazard characterization, provide significant opportunities in risk assessment (RA) for both human health and environmental safety. Specifically, it has been recognized that a more...

There is a growing recognition that application of mechanistic approaches to understand cross-species shared molecular targets and pathway conservation in the context of hazard characterization, provide significant opportunities in risk assessment (RA) for both human health and environmental safety. Specifically, it has been recognized that a more...

Synthesis of 11 steroid hormones in human adrenocortical carcinoma cells (H295R) was measured in a high-throughput steroidogenesis assay (HT-H295R) for 656 chemicals in concentration-response as part of the US Environmental Protection Agency's ToxCast program. This work extends previous analysis of the HT-H295R dataset and model by examining the ut...

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...

Recently, numerous organizations, including governmental regulatory agencies in the U.S. and abroad, have proposed using data from New Approach Methodologies (NAMs) for augmenting and increasing the pace of chemical assessments. NAMs are broadly defined as any technology, methodology, approach or combination thereof that can be used to provide info...

Acceptance of new approach methodologies (NAMs)for use in characterizing chemical hazard and risk requires informed expectations regarding the minimum precision and maximum accuracy of their results. Uncertainty in NAMs derived from variability in the traditional reference data used to train or validate performance of the NAM, and uncertainty in th...

BACKGROUND: The Life Cycle Initiative, hosted at the United Nations Environment Programme, selected human toxicity impacts from exposure to chemical substances as an impact category that requires global guidance to overcome current assessment challenges. The initiative leadership established the Human Toxicity Task Force to develop guidance on asse...

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-...

Endocrine disrupting chemicals (EDCs) are xenobiotics that mimic the interaction of natural hormones at the receptor level and alter synthesis, transport and metabolism pathways. The prospect of EDCs causing adverse health effects in humans and wildlife has led to the development of scientific and regulatory approaches for evaluating bioactivity. T...

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...

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...

In an effort to address a major challenge in chemical safety assessment, alternative approaches for characterizing systemic effect levels, a predictive model was developed. Systemic effect levels were curated from ToxRefDB, HESS-DB and COSMOS-DB from numerous study types totaling 4379 in vivo studies for 1247 chemicals. Observed systemic effects in...

The US EPA is charged with screening chemicals for their ability to be endocrine disruptors through interaction with the estrogen, androgen and thyroid axes. The agency is exploring the use of high-throughput in vitro assays to use in the Endocrine Disruptor Screening Program (EDSP), potentially as replacements for lower-throughput in vitro and in...

Current environmental monitoring approaches focus primarily on chemical occurrence. However, based on concentration alone, it can be difficult to identify which compounds may be of toxicological concern and should be prioritized for further monitoring, in-depth testing, or management. This can be problematic because toxicological characterization i...

Consensus computational modeling approaches to screen chemicals for their endocrine disrupting activity.

The androgen receptor (AR, NR3C4) is a nuclear receptor whose main function is acting as a transcription factor regulating gene expression for male sexual development and maintaining accessory sexual organ function. It is also a necessary component of female fertility by affecting the functionality of ovarian follicles and ovulation. Pathological p...

The increasing number and size of public databases is facilitating the collection of chemical structures and associated experimental data for QSAR modeling. However, the performance of QSAR models is highly dependent not only on the modeling methodology but also the quality of the data used. In this study we developed robust QSAR models for endpoin...

Background: In order to protect human health from chemicals that can mimic natural hormones, the U. S. Congress mandated the U.S. EPA to screen chemicals for their potential to be endocrine disruptors through the Endocrine Disruptor Screening Program (EDSP). However, the number of chemicals to which humans are exposed is too large (tens of thousand...

Alternatives analysis (AA) is a method used in regulation and product design to identify, assess, and evaluate the safety and viability of potential substitutes for hazardous chemicals. It requires toxicological data for the existing chemical and potential alternatives. Predictive toxicology uses in silico and in vitro approaches, computational mod...

The increasing number and size of public databases is facilitating the collection of chemical structures and associated experimental data for QSAR modeling. However, the performance of QSAR models is highly dependent not only on the modeling methodology, but also on the quality of the data used. In this study we developed robust QSAR models for end...

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...

Interpretation and use of data from high-throughput assays for chemical toxicity require links between effects at molecular targets and adverse outcomes in whole animals. The well-characterized genome of Drosophila melanogaster provides a potential model system by which phenotypic responses to chemicals can be mapped to genes associated with those...

There are little available toxicity data on the vast majority of chemicals in commerce. High-throughput screening (HTS) studies, such as being carried out by the U.S. Environmental Protection Agency (EPA) ToxCast program in partnership with the federal Tox21 research program, can generate biological data to inform models for predicting potential to...

The NRF2-ARE antioxidant pathway is an important biological sensing and regulating system that responds to xenochemicals. NRF2 senses chemically-caused production of reactive oxygen species (ROS) and electrophilic interactions with chemical species. Upon NRF2 activation, the expression of a wide array of genes will be upregulated to counteract oxid...

Testing thousands of chemicals to identify potential androgen receptor (AR) agonists or antagonists would cost millions of dollars and take decades to complete using current validated methods. High-throughput in vitro screening (HTS) and computational toxicology approaches can more rapidly and inexpensively identify potential androgen-active chemic...

The increasing availability of large collections of chemical structures and associated experimental data provides an opportunity to build robust QSAR models for applications in different fields. One common concern is the quality of both the chemical structure information and associated experimental data. Here we describe the development of an autom...

Motivation: Large high-throughput screening (HTS) efforts are widely used in drug development and chemical toxicity screening. Wide use and integration of these data can benefit from an efficient, transparent, and reproducible data pipeline. Summary: The tcpl R package and its associated MySQL database provide a generalized platform for efficien...

Recent international efforts have led to proposals for modified carcinogenicity testing paradigms based on data from shorter-term studies. The main goal of the current study was to evaluate the negative predictive value (NPV) of short-term toxicity indicators on carcinogenicity study outcomes and cancer classifications for chemicals previously revi...

Thyroid hormones (THs) are involved in multiple biological processes and are critical modulators of fetal development. Even moderate changes in maternal or fetal TH levels can produce irreversible neurological deficits in children, such as lower IQ. The enzyme thyroperoxidase (TPO) plays a key role in the synthesis of THs, and inhibition of TPO by...

The US Environmental Protection Agency's (EPA) Endocrine Disruptor Screening Program (EDSP) is using in vitro data generated from ToxCast/Tox21 high-throughput screening assays to assess the endocrine activity of environmental chemicals. Considering that in vitro assays may have limited metabolic capacity, inactive chemicals that are biotransformed...

Toxicity is a concern with many chemicals currently in commerce, and with new chemicals that are introduced each year. The standard approach to testing chemicals is to run studies in laboratory animals (e.g. rats, mice, dogs), but because of the expense of these studies and concerns for animal welfare, few chemicals besides pharmaceuticals and pest...

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...

The US EPA’s ToxCast program is screening thousands of chemicals of environmental interest in hundreds of in vitro high-throughput screening (HTS) assays. One goal is to prioritize chemicals for more detailed analyses based on activity in assays that target molecular initiating events (MIEs) of adverse outcome pathways (AOPs). However, the chemical...

Chemical toxicity can arise from disruption of specific biomolecular functions or through more generalized cell stress and cytotoxicity-mediated processes. Here, responses of 1060 chemicals including pharmaceuticals, natural products, pesticidals, consumer, and industrial chemicals across a battery of 815 in vitro assay endpoints from 7 high-throug...

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...

Background: The Next Generation (NexGen) of Risk Assessment effort is a multiyear collaboration among several organizations evaluating new, potentially more efficient molecular, computational and systems biology approaches to risk assessment. This paper summarizes our findings, suggests applications to risk assessment, and identifies strategic res...

There is a growing need in the field of exposure science for monitoring methods that rapidly screen environmental media for suspect contaminants. Measurement and analysis platforms, based on high resolution mass spectrometry (HRMS), now exist to meet this need. Here we describe results of a study that links HRMS data with exposure predictions from...