Related Experiment Video
Updated: Jul 17, 2026
08:25
Advanced 3D Liver Models for In vitro Genotoxicity Testing Following Long-Term Nanomaterial Exposure
Published on: June 5, 2020
Integrating Adverse Outcome Pathways with In Vitro-to-In Vivo Extrapolation for Risk Assessment: A Case Study of
Fei-Fei Xu1, Meng Zhou1, Xin-Yi Li1
1Food Safety and Health Research Center, Guangdong-Hongkong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou510515, P. R. China.
Environmental Science & Technology
|July 15, 2026
Summary
This study integrates adverse outcome pathways (AOPs) with in vitro-to-in vivo extrapolation (IVIVE) for chemical safety assessment. The approach quantifies cadmium
Area of Science:
- Regulatory Science
- Toxicology
- Risk Assessment
Background:
- Next-generation risk assessment emphasizes new approach methodologies for chemical safety.
- Integrating mechanistic evidence with quantitative extrapolation is crucial for human health risk metrics.
Purpose of the Study:
- To establish an integrated framework combining Adverse Outcome Pathways (AOPs) with in vitro-to-in vivo extrapolation (IVIVE).
- To elucidate AOPs for cadmium-induced bone toxicity using toxicogenomic data and in vitro assays.
- To derive human-equivalent doses (HEDs) for risk characterization.
Main Methods:
- Utilized toxicogenomic data, bioinformatics, and human-relevant in vitro assays.
- Developed two AOP frameworks detailing key events in signaling pathways (RANKL/OPG, Wnt, BMP, MAPK) and cellular processes (osteogenic differentiation, apoptosis).
- Applied benchmark dose and physiologically based toxicokinetic modeling within IVIVE.
Main Results:
- Proposed AOP frameworks for cadmium-induced bone toxicity.
- Derived HEDs for key events, with Wnt and MAPK pathways yielding 0.03 μg/kg bw/day.
- Epidemiological evidence supported the scientific validity of the derived HEDs.
Conclusions:
- The AOP-IVIVE integration strategy advances mechanism-informed, human-relevant risk assessment.
- Provides a robust framework for chemical safety evaluation and regulatory decision-making.
- Highlights the importance of signaling pathways in cadmium-induced bone toxicity.
Related Concept Videos
01:23Types of Biopharmaceutical Studies: Controlled and Non-Controlled Approaches
Biopharmaceutical studies constitute a vital field aiming to enhance drug delivery methods and refine therapeutic approaches, drawing upon diverse interdisciplinary knowledge. In research methodologies, the choice between controlled and non-controlled studies significantly influences the study's reliability and accuracy.
Non-controlled studies, commonly employed for initial exploration, lack a control group, rendering them susceptible to biases and external influences. In contrast, controlled...
Non-controlled studies, commonly employed for initial exploration, lack a control group, rendering them susceptible to biases and external influences. In contrast, controlled...
01:25Mutagenicity and Carcinogenicity
Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
01:23Toxicity Testing in Animals
Toxicity tests in animals are grounded on two main assumptions: first, the effects observed in laboratory animals can be extrapolated to humans, especially when adjusted for body surface area; second, high-dose exposure in animals is essential to identify potential human hazards from lower doses. This is based on the quantal dose-response concept, which faces the challenge of extrapolating results from relatively few test animals to much larger human populations. For example, a 0.01% incidence...
01:20Drug Product Performance: In Vitro–In Vivo Correlation
In pharmaceutical development, it's crucial to establish a predictive in vitro–in vivo correlation (IVIVC) for two or more formulations to gain a comprehensive understanding of release properties. IVIVC reduces the need for costly in vivo studies and facilitates the establishment of meaningful dissolution specifications with significant cost savings and decreased regulatory burden. Furthermore, a meaningful IVIVC should predict Cmax and AUC within 20%, aligning with FDA guidance while adhering...
01:21Toxicokinetics: Overview
Studies that assess how a drug is absorbed, distributed, metabolized, and excreted (ADME) at toxic doses are termed toxicokinetics. Understanding toxicokinetics helps predict adverse drug reactions (ADRs) and manage toxicity in humans.Toxicokinetics differs from pharmacokinetics mainly in the dose levels studied, with toxicokinetics focusing on higher toxic doses. The kinetics at these levels can be non-linear due to altered physiological processes. Toxicodynamics examines the relationship...
01:20Study Designs in Epidemiology
Epidemiological study designs are fundamental tools for investigating the distribution, determinants, and control of health conditions in populations. They help researchers understand the relationships between exposures and outcomes, and they broadly fall into two categories: "observational" and "experimental" studies.
Observational studies are those where the researcher does not intervene but rather observes natural variations. They include cross-sectional, cohort, and case-control studies.
Observational studies are those where the researcher does not intervene but rather observes natural variations. They include cross-sectional, cohort, and case-control studies.