A new study suggests fluoride exposure in utero might affect neurobehavior later on. But, honestly, it’s complicated.

I recently looked back at my folder full of these medical study commentaries – this thing we call Impact Factor and realized I’ve been doing this for a long time. More than 400 articles, believe it or not.

And I’ve learned a lot in that time – about Medicine of course – but also about how people react to certain topics. If you’ve been with me this whole time, or even for just a chunk of it, you’ll know I tend to take a measured approach to most topics – no one study is ever truly definitive after all. But regardless of how even-keeled I may be, there are some topics that I just know in advance are going to be a bit… divisive. There are studies about gun control. There are studies about Vitamin D.

And of course, there are studies about fluoride.

Shall we shake this hornet’s nest?

The fluoridation of the US water system began in 1945 with the goal of reducing cavities in the population. The CDC named water fluoridation one of the ten great public health achievements of the 20th century, alongside such inarguable achievements like the recognition of tobacco as a health hazard.

But fluoridation has never been without its detractors. One problem, though, is that the spectrum of beliefs about the potential harm of fluoridation is huge. On one end, you have science-based concerns – like the recognition that excessive fluoride intake can cause fluorosis. (I’ll note that the EPA regulates fluoride levels – there is a fair amount of naturally occurring fluoride in water tables around the world) to prevent this.  And of course on the other end of the spectrum you have beliefs that are essentially conspiracy theories – “they” add fluoride to the water supply to control us.

The challenge for me is that when one “side” of a scientific debate includes the crazy theories, it can be hard to discuss that whole spectrum  – since there are those who will see evidence of any adverse fluoride effect as confirmation that the conspiracy theory is true. That said, I can’t help this. So I’ll just say this up front – I am about to tell you about a study that shows some potential risk from fluoride exposure. I will tell you up front that there are some significant caveats to the study that call the results into question. And I will tell you up front that no one is controlling your mind, or my mind, with fluoride.

They do it with social media.

Alright let’s dive into to these shark-infested, fluoridated waters.

We’re talking about this study, which appears in JAMA Network Open.

It’s a study of 229 mother-child pairs from the Los Angeles area. The moms had their urinary fluoride level measured once at some time before 30 weeks of gestation. The children had a neurobehavioral battery called the Preschool Child Behavior Checklist administered at 36 months.

And the main thing you’ll hear about this study – in headlines, Facebook posts, and manifestos locked in drawers somewhere, is the primary result: a 0.68 mg/L increase in urinary fluoride in moms – about 25 percentile points – was associated with a doubling of the risk of neurobehavioral problems in their kids when they were three.

Yikes.

But this study is not a randomized trial. Researchers didn’t randomly assign some women to have high fluoride intake and some women to have low fluoride intake. They knew that other factors – factors that might lead to neurobehavioral problems – might also lead to higher fluoride intake. They represent these factors in what’s known as a directed acyclic graph as seen here and account for them statistically using a regression equation.

Not represented here?  Neighborhood characteristics. LA does not have uniformly fluoridated water, as you can see here – and neurobehavioral problems in kids are strongly linked to stressors in their environments. Fluoride level could be an innocent bystander.

I’m describing really just the classic issue of correlation versus causation here – the bane of all observational research – and, let’s be honest, a bit of a crutch that allows us to disregard the results of studies we don’t like provided the study wasn’t a randomized trial.

But I have a deeper issue with this study than the old “failure to adjust for relevant confounders” thing, as important as that is.

The exposure of interest in this study is maternal urinary fluoride, as measured in a spot sample. It’s not often I get to go deep on nephrology in this space, but let’s think about that for a second.

Let’s assume for a moment that fluoride is toxic to the developing fetus’ brain – the main concern raised by the results of the study. How would that work?  Well, presumably, mom would be ingesting fluoride from various sources (like the water supply), and that fluoride would get into her blood, and from her blood across the placenta to the babies blood, and into the babies brain.

Is urinary fluoride a good measure of blood fluoride?

It’s not great. Empirically, we have data that tells us that urine fluoride is not all that similar to serum fluoride. In 2014, a study investigated the correlation between urine and serum fluoride in a cohort of 60 schoolchildren and found a correlation coefficient of around 0.5.  The study doesn’t give a graph, but here’s what 0.5 looks like in a scatter plot.

OK – why is urine fluoride not a great proxy for serum fluoride? Well, the most obvious reason is urine concentration. Human urine concentration can range from about 50 mmols/L to 1200 mmols/L depending on hydration status – a 24-fold difference. Over the course of, say, 24 hours, the amount of fluoride you put out in your urine may be fairly stable with regard to intake, but for a spot urine sample?  Wildly variable. The authors know this, of course, and so they divide the measured urine fluoride by the specific gravity of the urine to give a sort of “dilution adjusted” value. That’s what is actually used in this study. But specific gravity is, itself, an imperfect measure of how dilute the urine is.

This is something that comes up a lot in urinary biomarker research and it’s not that hard to get around. The best thing would be to just measure blood levels of fluoride. The second best, 24-hour fluoride excretion. After that, the next best thing would be to adjust the spot concentration by other markers of urinary dilution – creatinine or osmolality – as sensitivity analyses. Any of these approaches would lend credence to the results of the study.

A bit more physiology of urine fluoride. Urinary fluoride excretion is pH dependent. The more acidic the urine, the less fluoride is excreted. Many things – including, importantly, diet – affect urine pH.  And it is not a stretch to think that diet may also affect the developing fetus. Neither urine pH nor dietary habits were accounted for in this study.

So… here we are. We have an observational study which suggests a harm that may be associated with fluoride. There may be a causal link here, in which case we need further studies to weigh the harm against the more well-established public health benefit. Or, this is all correlation – an illusion created by the limitations of observational data, and the unique challenges of estimating intake from a single urine sample. In other words, this study has something for everyone – fluoride boosters and skeptics alike. Let the arguments begin. But if possible, leave me out of it.