EXPERT REACTION: Chemicals in some disinfectants and flame retardants damage supporting cells of the brain in the lab

We are exposed to thousands of chemicals each day, and the toxicity of many of these chemicals is poorly known. Testing the myriad of chemicals we are exposed to is a daunting technical challenge. One solution is to use tissue culture, where pure cultures of cells are grown and exposed to chemicals. However, the choice of tissue to be used can be limiting. This paper looks at the effect of a range of environmental chemicals on the cells that support nerves, oligodendrocytes, these cells are largely overlooked, although they play critical roles in helping nerves to function.

This paper not only looks at the support cells in isolation but uses a novel organoid method to mimic brain development with a mixture of oligodendrocytes and model nerve cells, as well as exposure of mice to compounds selected based on screening.

This approach allowed the authors to rapidly screen 1,823 chemicals, of which 292 killed oligodendrocytes. While this approach shows great promise the applicability of these results to humans is not clear. Although the organoid approach is a step forward, the chemicals are directly applied to the cells, and neither the blood-brain barrier, which limits access of chemicals to the brain, nor metabolism, which breaks down these chemicals, are present. Both these barriers will reduce the exposure of brain oligodendrocytes (and nerves) to chemicals.

Also, the concentrations and doses used are much larger than humans would be typically exposed to. The mouse pups were exposed to 200-2,000 times the proposed exposure limits to the flame retardant. The highest estimate of child exposure, 15.03 μg/kg-day, is enormously below the 10 mg/Kg-day given to the mouse pups. Similarly for cetylpyridinium chloride, the dose of 1 mg/Kg-day for mouse pups is well above the estimated maximum dietary exposure of children (0.014 mg/Kg-day).

This paper represents a significant advance in the ability to screen chemicals in important cell populations that were previously too difficult to examine for a large number of chemicals quickly. However, the results do not suggest an immediate risk to human health and the authors emphasise the need for further study.

It's hardly surprising that chemicals in these two classes, quaternary compounds (quats) and organophosphates (OPs) show toxicity in cell cultures because their toxicity is well known. The quats are water soluble and used in domestic and industrial disinfectants to kill bacteria and viruses. In recent years they featured a lot in cleaning of structures to ward off COVID. It's hard to see how they could find their way to brain cells and the authors don't comment on this.

The OP flame retardants owe their activity to the phosphate group and are not to be confused with the organophosphate insecticides which are much more toxic. The OP flame retardants are fat-soluble and can be absorbed through the skin and find their way around the body. They have come into greater use in recent years as replacements for the organobromine compounds that have been banned under the Stockholm Convention on persistent organic pollutants (POPS).

During the deliberations about the organobromine compounds, the organophosphate flame retardants were discussed but no action was taken about them, because Stockholm is an intergovernmental convention about environmental impacts, whereas the evidence for the toxicity of the organophosphate flame retardants has come largely from studies of human development. Watch out for them to come to the attention of the Stockholm Convention when it's done struggling with organofluorines (PFAS)!

I think the screening platform the authors have developed in this study is useful and it is interesting to see the possible effects of certain chemicals on nerve cells. However, it is important to be careful about directly translating results from the lab to the real world. 

When we're evaluating the risks of a chemical we need to consider things like the dose (how much of the compound we are exposed to) the route (how we are exposed) and the duration (how long we are exposed). It is not a question of if something is toxic or not but if it is toxic under the conditions to which we are likely to be exposed. 

In this case, the authors have exposed cells in a Petri dish to a relatively high amount of these compounds which is not the same dose route or duration of exposure that humans might encounter normally. Many of the experiments were carried out on mice rather than human cells and mice are not mini humans. 

So although the work reveals some potentially interesting data it should be treated as preliminary. As the authors themselves are good enough to admit more studies are required to determine the full impact (if any).