Rapid hazard characterization of environmental chemicals using a compendium of human cell lines from different organs

Abstract

that encourage the use of alternative test methods for hazard and risk assessment applications, such as read-across, prioritization, and screening (ECHA, 2016; US EPA, 2018;Taylor et al., 2014). Novel analytical and in vitro data, now commonly referred to as new approach methodologies (NAMs), are being used in support of regulatory decisions (Kavlock et al., 2018;Paul Friedman et al., 2020); however, concerns about the limitations of NAMs in decision-making also have been voiced (Gocht et al., 2015;Berggren et al., 2015). The US Environmental Protection Agency (EPA) is developing a strategic plan to reduce the use of vertebrate animals in testing chemical substances and promote the development of alternative test methods; the goal is to eliminate animal testing from regulatory requirements for pesticides and industrial chemicals by 2035 (US EPA, 2019).The efforts to expand the portfolio of NAMs and test their utility in decision-making are most prominent in the European

HeLa TI cell-based assay as a new approach to screen for chemicals able to reactivate the expression of epigenetically silenced genes

“…More than 90,000 chemicals are currently used in commerce, and the potential for chemical exposure to affect human health via epigenetic mechanisms has been evaluated for only a small fraction (<2%) of these chemicals [ 14 ]. The field of epigenetic toxicology is complicated by a steady stream of new compounds and growth in the annual turnover of manufactured chemicals, which has doubled during the past ten years [ 10 , 15 , 16 ]. Moreover, toxicity studies are usually performed for individual chemicals, and it is impossible to predict the hazardous effects for complex mixtures of chemicals exhibiting nonlinear dose responses [ 8 , 14 ].…”

Risk Characterization and Probabilistic Concentration–Response Modeling of Complex Environmental Mixtures Using New Approach Methodologies (NAMs) Data from Organotypic in Vitro Human Stem Cell Assays

“…This study adds to the body of the recent advances on using NAMs to characterize the toxicity of mixtures, having applied novel highthroughput in vitro models based on a diverse array of human cells. We took advantage of recently developed reproducible and physiologically relevant human in vitro models derived from iPSCs (Li and Xia 2019), models that have been successfully applied for screening of diverse chemicals (Chen et al 2020). To our knowledge, human iPSC-derived cell models have not been used to characterize the hazards of complex mixtures comprising a large number of diverse environmental chemicals.…”

“…First, we collected new data from in vitro testing in human induced pluripotent stem cell (iPSC)-derived models for a dilution-series of 8 "designed" mixtures (Tables S2-S5) of 42 Superfund Priority chemicals (Table S1). Next, we applied Bayesian concentration-response modeling to fit the experimental data for the designed mixtures, as well as for their individual chemical constituents [data previously reported in (Chen et al 2020)]. The fitted concentration-response relationships for the designed mixtures were compared to the concentration-response predicted from the individual chemical data assuming either CA or IA.…”

“…For each cell line, a number of phenotypes (Table S6) were evaluated using high-content imaging as detailed in (Chen et al 2020;Grimm et al 2015;Iwata et al 2017;Sirenko et al 2014). Table S6 lists the phenotypes for each cell type and chemical treatment duration time for each phenotype.…”

Potential Human Health Hazard of Post-Hurricane Harvey Sediments in Galveston Bay and Houston Ship Channel: A Case Study of Using In Vitro Bioactivity Data to Inform Risk Management Decisions

“…Samples were tested in a compendium of human primary or iPSC-derived cell lines from different tissues (hepatocytes, neuronal, cardiomyocytes, and endothelial) to test for concentration-dependent effects on various functional and cytotoxicity phenotypes (n = 34). We selected these cell types because many of the environmental chemicals expected to be present in tested sediments are known to be associated with hepatotoxicity, neurotoxicity, cardiotoxicity, and vascular toxicity (see literature review of the effects of Superfund priority list chemicals on different organs in [ 20 ]). We have published methods for using iPSC-derived cells [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ] to assess the toxicity of the individual chemicals [ 20 , 28 , 29 , 30 , 31 , 32 ], whole mixtures [ 11 , 16 ], and complex substances [ 33 , 34 ].…”