A tiered approach to population-based in vitro testing for cardiotoxicity: Balancing estimates of potency and variability

Blanchette, Alexander D; Burnett, Sarah D; Rusyn, Ivan; Chiu, Weihsueh A.

doi:10.1016/j.vascn.2022.107154

Cited by 10 publications

(11 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, propranolol was more potent (lower EC 50 ) in donor 1083 as compared to the standard donor and less potent (higher EC 50 ) in donor 1392. Interestingly, cisapride had the greatest efficacy ( E max ) in the standard donor as compared to the other 4 donors, suggesting that, for QT prolongation, the standard donor may be more sensitive than the “average.” As mentioned previously, the use of Bayesian population estimation with 5 unique donors allows us to average over these heterogeneous responses and provide accurate and precise central estimates of population-wide potency risk-based parameters such as margin of exposure …”

Section: Resultsmentioning

confidence: 99%

“…To increase the relevance of in vitro studies to human health protection, data on exposure, toxicokinetics, and interindividual variability are needed to estimate the margin of safety or margin of exposure. ,, Our previous studies have shown that using iPSC-derived cardiomyocytes from a population of individuals, rather than a single individual, improves risk characterization; ,, however, studies using cells from a large number of donors are far too complex to be used for safety testing on hundreds or thousands of environmental chemicals. Recent work on study size optimization for population-based in vitro testing, including iPSC-derived cardiomyocytes, provide information on the number of individuals and replicates sufficient for confident conclusions. For example, we recently showed that, for iPSC-derived cardiomyocyte studies, a population of 5 unique donors is acceptable to derive a central estimate of population-wide potency and is more accurate and precise than the standard practice of collecting replicates of the same cell line.…”

Section: Introductionmentioning

confidence: 99%

“…Recent work on study size optimization for population-based in vitro testing, including iPSC-derived cardiomyocytes, provide information on the number of individuals and replicates sufficient for confident conclusions. For example, we recently showed that, for iPSC-derived cardiomyocyte studies, a population of 5 unique donors is acceptable to derive a central estimate of population-wide potency and is more accurate and precise than the standard practice of collecting replicates of the same cell line. Moreover, this population size also allows for the estimation of risk-based parameters such as margin of exposure. , On the basis of these considerations, we hypothesized that a panel of iPSC-derived cardiomyocytes from healthy human donors can be used to screen for the potential cardiotoxicity hazard and risk of environmental chemicals.…”

Section: Introductionmentioning

confidence: 99%

“…For example, we recently showed that, for iPSC-derived cardiomyocyte studies, a population of 5 unique donors is acceptable to derive a central estimate of population-wide potency and is more accurate and precise than the standard practice of collecting replicates of the same cell line. Moreover, this population size also allows for the estimation of risk-based parameters such as margin of exposure. , On the basis of these considerations, we hypothesized that a panel of iPSC-derived cardiomyocytes from healthy human donors can be used to screen for the potential cardiotoxicity hazard and risk of environmental chemicals. Specifically, we characterized the potential cardiotoxicity hazard and risk of 1029 chemicals and drugs from a diverse range of chemical classes in a high-throughput population screening design.…”

Section: Introductionmentioning

confidence: 99%

“…12,13,23 Our previous studies have shown that using iPSC-derived cardiomyocytes from a population of individuals, rather than a single individual, improves risk characterization; 11,19,23 however, studies using cells from a large number of donors are far too complex to be used for safety testing on hundreds or thousands of environmental chemicals. Recent work on study size optimization for population-based in vitro testing, 24 including iPSC-derived cardiomyocytes, 25 provide information on the number of individuals and replicates sufficient for confident conclusions.…”

Section: ■ Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Cardiotoxicity Hazard and Risk Characterization of ToxCast Chemicals Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Multiple Donors

Burnett

Blanchette

Chiu

et al. 2021

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

Heart disease remains a significant human health burden worldwide with a significant fraction of morbidity attributable to environmental exposures. However, the extent to which the thousands of chemicals in commerce and the environment may contribute to heart disease morbidity is largely unknown, because in contrast to pharmaceuticals, environmental chemicals are seldom tested for potential cardiotoxicity. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes have become an informative in vitro model for cardiotoxicity testing of drugs with the availability of cells from multiple individuals allowing in vitro testing of population variability. In this study, we hypothesized that a panel of iPSC-derived cardiomyocytes from healthy human donors can be used to screen for the potential cardiotoxicity hazard and risk of environmental chemicals. We conducted concentration−response testing of 1029 chemicals (drugs, pesticides, flame retardants, polycyclic aromatic hydrocarbons (PAHs), plasticizers, industrial chemicals, food/flavor/fragrance agents, etc.) in iPSC-derived cardiomyocytes from 5 donors. We used kinetic calcium flux and high-content imaging to derive quantitative measures as inputs into Bayesian population concentration−response modeling of the effects of each chemical. We found that many environmental chemicals pose a hazard to human cardiomyocytes in vitro with more than half of all chemicals eliciting positive or negative chronotropic or arrhythmogenic effects. However, most of the tested environmental chemicals for which human exposure and highthroughput toxicokinetics data were available had wide margins of exposure and, thus, do not appear to pose a significant human health risk in a general population. Still, relatively narrow margins of exposure (<100) were estimated for some perfuoroalkyl substances and phthalates, raising concerns that cumulative exposures may pose a cardiotoxicity risk. Collectively, this study demonstrated the value of using a population-based human in vitro model for rapid, high-throughput hazard and risk characterization of chemicals for which little to no cardiotoxicity data are available from guideline studies in animals.

show abstract

Section: Resultsmentioning

confidence: 99%