# Quantitative dose-response characterization for liver carcinogenicity with non-mutagenic modes of action

> **NIH NIH K25** · TRUSTEES OF INDIANA UNIVERSITY · 2024 · $152,688

## Abstract

PROJECT SUMMARY
The goal of this K25 Mentored Quantitative Research Development Award project is to allow the PI to obtain
systematic training in toxicology and prepare the PI to become an independent investigator. A research project
complement the proposal’s comprehensive career development plan that promotes the PI’s research career.
Human health risk assessment of chemical exposures is an important form of preventive medicine. Health risk
assessment has been widely applied in both industry and government to evaluate the potential human toxicity
of chemicals to properly protect human and environmental health. Modern toxicological science has provided
scientists new tools to dissect and understand the biological adverse pathways underlying toxicity. This
provides a great opportunity for risk assessment to characterize the dose-response relationship across the
entire dose continuum (especially in the low-dose region) and may significantly improve the plausibility and
accuracy of dose-response assessment. The long-term goal of this research is to develop a methodological
framework that integrates mechanistic plausibility, experimental data, and uncertainty and variability into dose-
response analysis in support of probabilistic carcinogen risk assessment. The objective of this project is to
combine evidence from a sequence of events following a plausible mode of action to quantitatively
characterize dose-response relationship across the entire dose continuum for liver carcinogenicity with non-
mutagenic modes of action (MOAs). The central hypothesis is that liver carcinogens sharing the same MOA
may have a similar shape of dose-response relationship which can be characterized by synthesizing evidence
of a series of key and associative events. To achieve the objective, three specific aims will be pursued: (1)
employ and improve existing framework to identify key and associative events with available data to
understand mode of action of liver carcinogenesis; (2) develop a modeling framework to quantitatively integrate
MOA information to characterize the dose-response relationship across the dose continuum; and (3) apply the
framework to different non-mutagenic MOA for liver carcinogenicity and evaluate its feasibility and plausibility.
The proposed methodological framework is highly innovative because it aims at quantitatively characterizing
dose-response relationship across the whole dose continuum without dichotomizing the extrapolation method
into linear vs. nonlinear (i.e., threshold). The success of the proposed methodological framework may
revolutionarily change the current practice in dose-response assessment and significantly advance the science
of chemical risk assessment by providing more scientifically plausible probabilistic risk estimation to support
risk management.

## Key facts

- **NIH application ID:** 10757362
- **Project number:** 5K25ES030402-05
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Kan Shao
- **Activity code:** K25 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $152,688
- **Award type:** 5
- **Project period:** 2020-01-13 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757362

## Citation

> US National Institutes of Health, RePORTER application 10757362, Quantitative dose-response characterization for liver carcinogenicity with non-mutagenic modes of action (5K25ES030402-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757362. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*