Project title: Integration of Biological Responses and PBTK Modeling in Chemical Toxicity Assessment: А Case Study of Perfluorooctanoic Acid (PFOA

Acronym: ToxIN

Funded by Science Fund of the Republic of Serbia – Program PRISMA

Project duration: 2023-2026

Principal investigator: dr Nebojša Andrić

OBJECTIVES:

Regulatory agencies worldwide put significant effort into evaluating harmful effects of environmental chemicals. This is an important step in setting safety limits to better protect the health of people, thus reducing the social and economic burden of chemicals’ exposure. One of the critical components of this evaluation is an application of a sensitive, precise, and efficient testing methodology. Currently, the assessment methodology is mostly based on human biomonitoring/epidemiological studies and monitoring of the adverse effects observed in animal studies; however, all these studies have some limitations, thus rendering evaluation of the chemicals’ adverse effects not efficient. To address these limitations, novel integrating approaches and emerging technologies are necessary to better protect different human populations from chemical exposure and exposure-related illnesses or disabilities. Evaluation of thousands of chemicals would be substantially more efficient with the use of an advanced testing system. In the ToxIN project, we will set up a novel tiered testing framework by coupling toxicological analysis with physiologically-based toxicokinetic (PBTK) modeling. This tiered testing approach will be exercised using perfluorooctanoic acid (PFOA) as a model compound.

The main objective of the ToxIN project is to integrate the toxicogenomic and apical endpoints data with PBTK modeling (tiered testing framework) to achieve the following project goals (PG):

PG1. Derive bioactivity exposure ratios (BERs) and novel bioactivity concentration ratios (BCRs) for PFOA

PG2. Use BERs and BCRs to determine sensitivity of biological assays, tissues, and specific populations to PFOA

The overall PGs will be achieved through three specific objectives:

Objective 1 (O1). Obtain the dose-response data and the benchmark doses-lower confidence limits (BMDLs) after in vitro exposure of human cell lines to PFOA

Objective 2 (O2). Obtain the dose-response data and the BMDLs after in vivo oral exposure of female mice to PFOA.

Objective 3 (O3). Assess PFOA disposition and toxicity potential in humans using computational modeling.