Cellular and physiological mechanisms of halogenated and organophosphorus flame retardant toxicity

Flame retardants (FRs) are chemical substances used to inhibit the spread of fire in numerous industrial applications, and their abundance in modern manufactured products in the indoor and outdoor environment leads to extensive direct and food chain exposure of humans. Although once considered relatively non-toxic, FRs are demonstrated by recent literature to have disruptive effects on many biological processes, including signaling pathways, genome stability, reproduction, and immune system function. This review provides a summary of research investigating the impact of major groups of FRs, including halogenated and organophosphorus FRs, on animals and humans in vitro and/or in vivo. We put in focus those studies that explained or referenced the modes of FR action at the level of cells, tissues and organs. Since FRs are highly hydrophobic chemicals, their biophysical and biochemical modes of action usually involve lipophilic interactions, e.g. with biological membranes or elements of signaling pathways. We present selected toxicological information about these molecular actions to show how they can lead to damaging membrane integrity, damaging DNA and compromising its repair, changing gene expression, and cell cycle as well as accelerating cell death. Moreover, we indicate how this translates to deleterious bioactivity of FRs at the physiological level, with disruption of hormonal action, dysregulation of metabolism, adverse effects on male and female reproduction as well as alteration of normal pattern of immunity. Concentrating on these subjects, we make clear both the advances in knowledge in recent years and the remaining gaps in our understanding, especially at the mechanistic level.