BPA, brain and behaviour – experts respond

A study published this week in the journal PNAS finds that mice exposed to prenatal BPA exhibit changes in brain gene expression and increase in anxiety related behaviours.

Plastic not-so-fantastic?The study claims that the mice were given a dose of BPA that is comparable to human exposure. BPA is found in many plastics including bottles and food cans, and it can get into food through these containers.

Our colleagues at the Canadian, Australian and UK SMCs collected the following expert commentary. Feel free to use these quotes in your reporting. If you would like to contact a New Zealand expert, please contact the SMC (04 499 5476; smc@sciencemediacentre.co.nz).

Warren Foster, Department of Obstetrics and Gynecology, McMaster University:

“The paper itself is very good with state of the art methods and published in PNAS, a highly respected journal. Moreover, BPA, as you know, is highly controversial and thus this article is likely to attract quite a bit of attention.

“There are a number of limitations with the paper, the first of which is with the use of the term “low-dose”. Many investigators use this term freely today without giving it much thought. In the present paper the authors use it because they’re looking at doses of 20 and 200 micrograms per kilogram per day, and the FDA’s safe limit is 50 micrograms/kg/day. In effect they’re saying its environmentally relevant because their doses bracket the FDA rfd.

“The concern is when we humans are exposed to anything in our diet, we’re exposed to it at small amounts over the course of the day. What they’ve done here is give the dose as a bolus, i,e. the entire dose at once. The dosing solution is simply flushed down the animal’s throat. It’s convenient for research but people are not exposed like that. You’re getting your whole safe level or more all at once. When a risk assessment is done, the FDA estimates exposure over the course of a person’s daytime exposure. Regardless, the method of dosing the animals is a limitation of the study and of the interpretations.

“Another comment I have is, in the statistical methods – it’s hard to tell but it doesn’t look they took litter effects into consideration. A dam is giving birth to 12 to 17 pups per litter. Classically, what you’re supposed to do is take one pup from each litter and compare results across pups from different litters. The reason to do this is that it’s possible you have a dam that’s unusually sensitive or resistant to the effects of your test chemical that could unjustly skew results and mislead investigators.

“Finally, the other thing I take some exception with is – coming back to the issue of dose and human exposure. In a previous report, Justin Teeguarden and others have carried out pharmacological studies in humans with large BPA diets – canned peas and corn and stuff, diets graded 95th percentile for exposure to BPA. Of all the exposure they looked into, it was very hard to measure free BPA in the serum at all. So when studies in mice make the comment that its relevant for humans – I have some problems with those studies, if others have been unable to quantify the free (bioactive) form of BPA in the serum. It’s a question of whether free BPA is even present in most people and able to bind to receptors in target tissues.

“One final thing; there’s a line in the paper where they talk about BPA being associated in human children with behaviour and aggression. It is important to recognize that the investigators of those studies also look at many chemicals at once beside BPA, such as phthalates. Results of these studies are published as separate papers each reporting association between the chemical of concern and behavioural abnormalities. So at this point it’s hard to know if the association between BPA and behavioural problems is anything more than a simple statistical association. Drawing causal inferences then is very difficult.”

From the AusSMC:

Dr Ian Musgrave, Senior Lecturer in the Faculty of Health Sciences at the University of Adelaide, comments:

“This is a well-designed study that uses concentrations of BPA that cover the upper levels of permitted exposure for BPA in humans, as well as very high doses. The doses are given in a way which mimics human exposure.

“The most interesting results are those relating to behaviour. While there is huge variation in the responses of the mice, this study re-enforces our understanding that low doses of BPA, which are still higher than humans would be expected to be exposed to, have no significant effect on behaviour. ”

From the UK SMC:

Prof Andrew Smith, MRC Toxicology Unit, University of Leicester, and Royal Society of Chemistry’s Toxicology Group, said:

“This publication is in line with other reports suggesting that in pregnant experimental animals bisphenol A may influence the methylation of genes so controlling their action and leading to subtle differences in physiology of offspring.  The work is well organised but its findings emphasize the need for more fundamental research in this area.  Although administered by the authors at relatively low doses possibly compatible with human experience, there are important issues of the degree of exposure to bisphenol A versus the direction of methylation and behavioural/brain changes. These must be confirmed, clarified and mechanisms resolved before any extrapolation can be made to the human context especially in relation to mental and cognitive disorders.  Indeed, it is unclear how understanding consequences of low bisphenol A exposure fit in the landscape of human exposure to other chemicals.”

Prof Richard Sharpe, Research Group Leader/Professor, MRC Centre for Reproductive Health, University of Edinburgh, said:

“This study shows that exposure of pregnant mice to bisphenol A can cause changes in gene expression/function in the brains of offspring after birth and also lead to changes in certain aspects of behaviour. In general the study is well conducted and uses a route of exposure that is human relevant (>95% of our bisphenol A exposure is via our diet), although the method of results analysis is not the most reliable.

“Whilst these findings raise the possibility that comparable effects of bisphenol A could occur in humans, several factors suggest this is unlikely. First, the lowest dose use is still 10-20 times higher than normal human bisphenol A exposure. Second, the endpoints measured showed huge between-animal variation and considering that there were low numbers per group for some endpoints, the likelihood of false positive results is high, and no information on reproducibility of the results is provided (i.e. if the experiment was repeated would the same changes be detected).  Third, if the effects described work through an oestrogen mechanism, they are unlikely to be human relevant because pregnancy levels of oestrogens in humans are far higher than in mice and would swamp any weak oestrogenic effects of bisphenol A.”

Prof Tamara Galloway, Professor of Ecotoxicology, University of Exeter, said:

“The doses of BPA in the study are in an appropriate concentration range, spanning the suggested recommended tolerable limit for BSA in humans of 50 micrograms/kg body weight/day. As the authors quite rightly point out, there are differences in metabolism of BPA between humans and rodents, and they have taken account of this as far as they can in their planning. The doses have been administered orally, which is in line with current thinking on appropriate route of exposure. Earlier experiments by other groups have been criticised for administering BPA intravenously, which would bypass normal routes of metabolism in the gut.

“The non-monotonic dose response curves that the authors have obtained for many of the measured endpoints have also been reported by many other researchers, including ourselves, in both in vivo human population studies and in vitro laboratory experiments. I agree with their conclusion that environmentally relevant doses of BPA may induce very different effects dependent on the level of exposure and support the view that appropriate risk assessment of BPA toxicity should consider multiple low dose exposures.”