The use of in vitro assays in toxicological screening of flame retardants: towards comprehensive risk assessment

Date: 21 November 2018

Venue: Campus Middelheim, A.143 - Middelheimlaan 1 - 2020 Antwerpen (route: UAntwerpen, Campus Middelheim)

Time: 4:00 PM

Organization / co-organization: Department of Biology

PhD candidate: Boris Krivoshiev

Principal investigator: Ronny Blust & Steven Husson

Short description: PhD defence Boris Krivoshiev - Faculty of Science, Department of Biology



Abstract

Flame retardants are compounds used to prevent the spread of fire and are ubiquitously used due to the need for safer consumer products. Given that these chemicals are found in both human and environmental samples, there is increasing need to identify their risk to human and environmental health. Toxicity testing of these chemicals was developed decades ago and most are conducted using in vivo models. Such an approach therefore gives little insight into the molecular modes of action leading to toxic phenotypes, while also being very time consuming, with often great cost to animal wellbeing and significant cost to finances, leading to not all chemicals that humans may encounter being tested. There is therefore room for improvement regarding current toxicological testing approaches.

The aim was to identify the applicability and utility of high-throughput in vitro assays in identifying potential toxicity, toxicological modes of action, and quantitative risk to humans posed by flame retardants. Limited endpoint screening assays able to screen numerous flame retardants simultaneously identified that a majority of them significantly affected multiple toxicological modes of action. The prokaryotic stress gene assay indicated that these compounds can affect stress responses in response to protein perturbation, DNA damage, and membrane damage, with some compounds also resulting in growth arrest and oxidative damage. Estrogen disruption was identified for a number of flame retardants, ultimately indicating that these compounds can affect a wide variety of toxicological modes of action, while also indicating that organophosphates may not necessarily be more inert than their toxic brominated predecessors.

Flame retardants of interest were then subjected to toxicogenomics which allowed for the identification of potential modes of action over the whole transcriptome in an unbiased manner. Transcriptomics revealed that despite some differences in biological functions observed to be affected by the different compounds, common themes emerged such as changes to genes involved in general cellular metabolism, steroid hormone biosynthesis, wound healing, and inflammation. Ultimately, this indicated that many of these flame retardants may act as endocrine disruptors by affecting sex-hormone homeostasis and may in addition act as liver fibrotic hepatotoxins by affecting genes involved in wound healing and inflammation. Concentrations at which these effects were observed could also hold relevance to worst-case human exposure levels. As such, there is a need to study certain flame retardants more closely in order to identify their true risk to human health.



Link: http://www.uantwerpen.be/science