By Anthony Oliveri
As Laura Macaulay, Ph.D. Candidate, and the Research Translation Core have brought up in the past week,
flame retardants are proving to be a cause for concern for a number of health-related reasons. Laura covered the PBDEs, and how they may be toxic because of their tendency to mimic the thyroid hormones. I’d like to introduce another type of flame retardant into the story and discuss whether or not it can be toxic in its similarity to another class of toxic compounds.
Besides the PBDEs, another class of flame retardants are the organophosphates, or “OPs” for short. They are sometimes used in conjunction with other, halogenated flame retardants (meaning they contain a halogen like bromine, chlorine, or fluorine) similar to the PBDEs. For example, the flame retardant mixture Firemaster 550, a compound in current household use and studied by members of the Stapleton lab, is a mixture of OP and halogenated flame retardants. Obviously, this leads to the need to understand both the individual toxicities of the halogenated and OP flame retardants, and how those toxicities interact when the compounds are combined.
Organophosphates are used as both flame retardants and as pesticides and while the same organophosphates aren’t typically used for both purposes, there are some structural similarities between those used as pesticides and those used as flame retardants. Some of these pesticides, including one called chlorpyrifos, have been studied extensively by Ted Slotkin in Project 1 of our Superfund Research Center. These compounds act by blocking an enzyme called acetylcholinesterase (AChE). AChE breaks down the neurotransmitter acetylcholine at the neuromuscular synapse, or the point where your nerves tell your muscles to contract. When pesticides like chlorpyrifos prevent AChE from doing its job, there is an overabundance of acetylcholine at the synapse, which in turn leads to overstimulation and prolonged contraction of muscles, disabling or killing the insect (or any other animal that receives a large enough dose).
Research in our Superfund Center, including here in the Levin lab, has shown that young rats exposed to chlorpyrifos develop to have abnormal behavioral patterns, performing worse on a number of tests and tasks compared to unexposed rats. An interesting part of this research was that the dose of chlorpyrifos was too low to produce any normal signs of chlorpyrifos toxicity (significant decrease in AChE function), suggesting that chlorpyrifos may be interfering with brain development without affecting the acetylcholine system. In support of this, further studies we have done using zebrafish have shown that early life exposure to chlorpyrifos produces similar abnormal behavior, including decreased accuracy in a memory test and larger responses to a startling stimulus, that occurs along with a decrease in dopamine that lasted through to adulthood. These findings provided a hint that impaired development of the dopamine system may be behind the behavioral toxicity of chlorpyrifos.
Building upon this research, I am looking into whether or not exposure to the OP flame retardants during development also produces abnormal behaviors. Although they were not designed to be AChE inhibitors, the fact that the OP pesticides produce their neurotoxicity independent of AChE inhibition leads to the possibility that something about the OP compounds, whether pesticide or flame retardant, disrupts the development of the brain in some common way, possibly through dopamine.
While some OP insecticides, including chlorpyrifos, have been banned for home use, they are still used in agriculture, and nearly all Americans have detectable traces of OP pesticides and OP metabolites in their body. Additionally, the OP flame retardants are still being used in a number of household items, including in furniture, as discussed in our previous post. Clearly, if they can cause problems for the development of children and contribute to behavioral, cognitive, or mental disorders, it is important to investigate and identify the mechanisms of their toxicities.