Mapping Interindividual Variability of Toxicodynamics Using High-Throughput Transcriptomics and Primary Human Hepatocytes from Fifty Donors

Environmental Health Perspectives, vol. 132, pp. 37005

Abstract

BACKGROUND: Understanding the variability across the human population with respect to toxicodynamic responses after exposure to chemicals, such as environmental toxicants or drugs, is essential to define safety factors for risk assessment to protect the entire population. Activation of cellular stress response pathways are early adverse outcome pathway (AOP) key events of chemical-induced toxicity and would elucidate the estimation of population variability of toxicodynamic responses. OBJECTIVES: We aimed to map the variability in cellular stress response activation in a large panel of primary human hepatocyte (PHH) donors to aid in the quantification of toxicodynamic interindividual variability to derive safety uncertainty factors. METHODS: signaling. Using a population mixed-effect framework, the distribution of benchmark concentrations (BMCs) and maximum fold change were modeled to evaluate the influence of PHH donor panel size on the correct estimation of interindividual variability for the various stimuli. RESULTS: signaling-related genes, respectively. Population modeling revealed that small PHH panel sizes systematically underestimated the variance and gave low probabilities in estimating the correct human population variance. Estimated toxicodynamic variability factors of stress response activation in PHHs based on this dataset ranged between 1.6 and 6.3. DISCUSSION: -based prediction of adverse responses, in particular hepatotoxicity. https://doi.org/10.1289/EHP11891.

Authors 11

1. Marije Niemeijer Aachen Division of Drug Discovery and Safety

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, LACDR, Leiden University, Leiden, The Netherlands

2. Witold Więcek

   Simcyp (United Kingdom)

   Affiliation as printed

   Simcyp Division, CERTARA, Sheffield, UK

3. Shuai Fu

   Simcyp (United Kingdom)

   Affiliation as printed

   Simcyp Division, CERTARA, Sheffield, UK

4. Suzanna Huppelschoten Aachen Division of Drug Discovery and Safety

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, LACDR, Leiden University, Leiden, The Netherlands

5. Peter Bouwman Aachen Division of Drug Discovery and Safety

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, LACDR, Leiden University, Leiden, The Netherlands

6. Audrey Baze
   Affiliation as printed

   KaLy-Cell, Plobsheim, France

7. Celine Parmentier
   Affiliation as printed

   KaLy-Cell, Plobsheim, France

8. Lysiane Richert
   Affiliation as printed

   KaLy-Cell, Plobsheim, France

   Zylan, Obernai, France

9. Richard S. Paules

   National Institutes of Health · National Institute of Environmental Health Sciences

   Affiliation as printed

   Division of the National Toxicology Program, NIEHS, NIH, Research Triangle Park, North Carolina, USA

10. Frédéric Y. Bois

    Simcyp (United Kingdom)

    Affiliation as printed

    Simcyp Division, CERTARA, Sheffield, UK

11. Bob van de Water Aachen Division of Drug Discovery and Safety

    Leiden University

    Affiliation as printed

    Division of Drug Discovery and Safety, LACDR, Leiden University, Leiden, The Netherlands