Analysis of the Effects of Cell Stress and Cytotoxicity onIn Vitro Assay Activity Across a Diverse Chemical and Assay Space

Judson, Richard S.; Houck, Keith A.; Martin, Matt; Richard, Ann M.; Knudsen, Thomas B.; Shah, Imran; Little, Stephen B.; Wambaugh, John F.; Setzer, R. Woodrow; Kothiya, Parth; Phuong, Jimmy; Filer, Dayne L.; Smith, Doris; Reif, David M.; Rotroff, Daniel M.; Kleinstreuer, Nicole; Sipes, Nisha S.; Xia, Menghang; Huang, Ruili; Crofton, Kevin M.; Thomas, Russell S.

doi:10.1093/toxsci/kfw148

Cited by 89 publications

(89 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At concentrations that are already cytotoxic superinduction compared to the maximum response of the 2,3,7,8-TCDD reference compound can be observed. This is clearly an artifact of the cytotoxicity burst (Judson et al 2016), which does not indicate a specific effect but is a consequence of nonspecific toxicity. Fitting a specific effect beyond cytotoxicity would not be mechanistically meaningful and could confuse mixture modeling.…”

Section: Examples Of Applicationsmentioning

confidence: 95%

The advantages of linear concentration–response curves for in vitro bioassays with environmental samples

Escher

Neale

Villeneuve

2018

Enviro Toxic and Chemistry

117

View full text Add to dashboard Cite

In vitro assays and high-throughput screening (HTS) tools are increasingly being employed as replacements for animal testing, but most concentration-response curves are still evaluated with models developed for animal testing. We argue that application of in vitro assays, particularly reporter gene assays, to environmental samples can benefit from a different approach to concentration-response modeling. First, cytotoxicity often occurs at higher concentrations, especially for weakly acting compounds and in complex environmental mixtures with many components. In these cases, specific effects can be masked by cytotoxicity. Second, for many HTS assays, low effect levels can be precisely quantified because of the low variability of controls in cell-based assays and the opportunity to run many concentrations and replicates when using high-density well-plate formats (e.g., 384 or more wells per plate). Hence, we recommend focusing concentration-response modeling on the lower portion of the concentration-response curve, which is approximately linear. Effect concentrations derived from low-effect level linear concentration-response models facilitate simple derivation of relative effect potencies and the correct application of mixture toxicity models in the calculation of bioanalytical equivalent concentrations. Environ Toxicol Chem 2018;37:2273-2280. © 2018 SETAC.

show abstract

Section: Examples Of Applicationsmentioning

confidence: 95%

The advantages of linear concentration–response curves for in vitro bioassays with environmental samples

Escher

Neale

Villeneuve

2018

Enviro Toxic and Chemistry

117

View full text Add to dashboard Cite

show abstract

“…4,[7][8][9][10][11][12][13][14][15] However, application of HTS approaches to toxicity screening continues to face significant research challenges, not least of which is developing the means to manage, process and extract insights from the large, complex datasets being produced. 4,[16][17][18][19] In addition, there is growing recognition that the challenge of reliably predicting downstream biological responses of toxicological relevance will require integration of many different types of data, knowledge, and informational resources. 4,14 From a biological perspective, a better understanding of the implications of chemical-target interactions and cellular effects in the context of biological processes and adverse outcome pathways is needed.…”

mentioning

confidence: 99%

“…20,21 Equally important is gaining a better understanding of the technological limitations and sources of noise in the various HTS assay platforms, while identifying or inferring missing elements such as metabolism, pharmacokinetic and species-specificity. 14,19,22 Each of these considerations plays an important role in validating the application of HTS results in toxicity prediction models. 23,24 Of central importance to the interpretation and application of HTS data is the nature of the increasingly diverse chemical library fueling these efforts (e.g., detailed composition, physicochemical properties, and analytical data quality) and how to best apply this foundation of chemical information to meeting the overall ToxCast program objectives.…”

mentioning

confidence: 99%

ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology

Richard

Judson

Houck

et al. 2016

Chem. Res. Toxicol.

Self Cite

504

392

View full text Add to dashboard Cite

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 to support the development of improved toxicity prediction models. Launched in 2007, Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay end points. In Phase II, the ToxCast library was expanded to 1878 chemicals, culminating in the public release of screening data at the end of 2013. Subsequent expansion in Phase III has resulted in more than 3800 chemicals actively undergoing ToxCast screening, 96% of which are also being screened in the multi-Agency Tox21 project. The chemical library unpinning these efforts plays a central role in defining the scope and potential application of ToxCast HTS results. The history of the phased construction of EPA's ToxCast library is reviewed, followed by a survey of the library contents from several different vantage points. CAS Registry Numbers are used to assess ToxCast library coverage of important toxicity, regulatory, and exposure inventories. Structure-based representations of ToxCast chemicals are then used to compute physicochemical properties, substructural features, and structural alerts for toxicity and biotransformation. Cheminformatics approaches using these varied representations are applied to defining the boundaries of HTS testability, evaluating chemical diversity, and comparing the ToxCast library to potential target application inventories, such as used in EPA's Endocrine Disruption Screening Program (EDSP). Through several examples, the ToxCast chemical library is demonstrated to provide comprehensive coverage of the knowledge domains and target inventories of potential interest to EPA. Furthermore, the varied representations and approaches presented here define local chemistry domains potentially worthy of further investigation (e.g., not currently covered in the testing library or defined by toxicity "alerts") to strategically support data mining and predictive toxicology modeling moving forward.

show abstract

“…First, we selected the records where AC50 of individual FRs were relatively low (lower AC50 values indicate higher toxicity). To reduce the risk of selecting non specific hits that may occur when AC50 is close to the concentrations at which general cytotoxicity is observed [28], we used only AC50 values that were below the cytotoxicity limits provided in the ToxCast dashboard (see Table 2). Almost half of the FRs (13 of 28) can be considered as non cytotoxic in the concentration range tested (cytotoxicity limit of 1000 µM).…”

Section: Using Toxcast Data For "In Vitro Prioritization" and Identifmentioning

confidence: 99%

Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

2019

View full text Add to dashboard Cite

Background: Flame retardants (FRs) are used in most consumer products and textiles to comply with current flammability standards. After the restriction of polybrominated diphenyl ethers, a large number of chemically diverse replacement FRs are increasingly used, but the risk they represent is not yet properly evaluated and their toxicity pathways are still poorly understood. Approach:We collected in vivo toxicological information on 62 (including 52 non-regulated) FRs and established five prioritization categories (Cat I to V) based on data availability and toxicological concern. We then considered available in vitro toxicological data from ToxCast, as a complement to in vivo information. By combining these information sources, we then explored relevant toxicity mechanisms for nine selected FRs (Cat I) using the AOP (Adverse Outcome Pathway) framework. Results:For 20 FRs (Cat V), toxicological data on mammals were absent. Data available were scarce for another 22 FRs, of which 14 FRs (Cat II) may be of toxicological concern. We found substantial information for only ten replacement FRs, of which nine (Cat I) present some toxicological concern: tris-2-chloroethyl phosphate (TCEP), tris(1,3dichloropropyl)phosphate (TDCIPP), triphenyl phosphate (TPhP), tricresyl phosphate (TMPP), tetrabromobisphenol A (TBBPA), tri-n-butyl phosphate (TNBP), tri(2-butoxyethyl) phosphate (TBOEP), tris(1-chloro-2-propyl) phosphate (TCIPP), 2-ethylhexyl diphenyl phosphate (EHDPP). ToxCast results confirmed in vivo based categorization for several FRs and identified potential molecular targets. For the nine Cat I FRs, we identified several molecular targets, health outcomes and some potential AOPs. However, the complete toxicity pathways leading from molecular targets to adverse health outcomes are still unknown, with the exception of TBBPA-induced neurotoxicity. Conclusions:The approach presented in this study was particularly useful for the categorization of a large group of replacement FRs with relatively low data availability. We highlight priority compounds that critically need more toxicological studies or FRs for which regulatory measures could be envisaged. Our research also suggests that high toxicity indicated by ToxCast is particularly relevant for predicting higher hazard in vivo. Finally, we indicate several gaps and directions for future research, such as molecular targets that could be tested in vitro and health outcomes for cohort studies. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

show abstract

Analysis of the Effects of Cell Stress and Cytotoxicity onIn Vitro Assay Activity Across a Diverse Chemical and Assay Space

Cited by 89 publications

References 42 publications

The advantages of linear concentration–response curves for in vitro bioassays with environmental samples

The advantages of linear concentration–response curves for in vitro bioassays with environmental samples

ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology

Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

Contact Info

Product

Resources

About