There is a critical need to understand and evaluate the risks of exposure to chemical mixtures, from an environmental, human health as well as regulatory perspective. Endocrine disruptors are of particular concern as low doses can cause severe effects, especially during critical stages of development. RiskMix will in particular address the Swedish environmental quality objective entitled “a non-toxic environment”.

Humans are exposed to a wide range of endocrine disrupting chemicals (EDCs), which can work together to produce combined effects, making accurate risk assessment difficult. From a regulatory point of view, it is of greatest importance to know the spectrum of EDCs present in relevant exposure scenarios. This information is currently fragmentary, and it is likely that the full extent of risks associated with EDCs might be underestimated. We will investigate the internal exposure profile to a selection of populations of special concern, including developing children. For that, we will combine existing data from various cohorts and state-of-the-art chemical analytical methods. Using existing data are time and budget efficient.

The prime aim of the project

The prime aim of the project with the full title “Risk modeling of Mixtures of endocrine disrupting chemicals relevant to human exposure, using zebrafish (Danio rerio) embryo as model organism” is development of a novel generic approach, the RiskMix strategy, to estimate the accumulated toxicity and risk of exposure to complex chemical mixtures. The approach will be based on internal exposure and dose-at-target levels, and assuming dose addition, a conservative approach that in practice avoids underestimating the risk. The RiskMix strategy will identify chemicals of concern for different population groups, as a basis for design of relevant chemical mixtures. The modeled risk estimation will be validated experimentally using adult zebrafish (ZF) and ZF embryos. Internal ZF exposure doses will be determined by chemical analysis and physiological based toxicokinetic (PBTK) modeling, allowing interspecies comparisons and extrapolations to humans. Effects on the thyroid hormone (TH) system will be in focus as a critical endocrine pathway and founded by extensive experience of the RiskMix partners from the FORMAS-funded project MiSSE. Critical are also metabolomics and gene expression studies that will be deployed in search for new biological markers of effects on the TH system.

The RiskMix strategy will address the following main objectives:

  • Deriving detailed exposure profiles for several population groups, based on existing data and complementary state-of-the-art chemical analysis
  • Creation of a database containing hazard information and internal exposure concentrations, derived using PBTK modeling
  • Compilation of complex chemical mixtures based on a ranking and prioritization procedure using exposure and hazard data
  • Experimental validation of predicted mixture effects using ZF and ZFET and establishment of ZFET as an alternative test system for TH related effects
  • Identification of new biomarkers of thyroid hormone disruption

Partners

Stockholm University

  • Assoc. Prof. Jana Weiss Project leader (PI)
  • Josefin Engelhardt PhD student
  • Assoc. Prof. Lillemor Asplund

Swedish University of Agricultural Sciences, Uppsala

  • Assoc. Prof. Stefan Örn
  • PhD. Oksana Golovko

Umeå University

  • Prof. Patrik Andersson
  • Elena Dracheva PhD student

VU University, Amsterdam

  • Prof. Pim Leonards
  • PhD. Jessica Legradi