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Of Rats, People and Bisphenol A

The hormone-like activity of BPA has been known since the 1930s and, using rodents, acute toxicity was not difficult to determine and was found to be low. The question, however, is about exposure to trace amounts over the long term. Can such exposure have consequences on health?

Bisphenol A (BPA) first hit the headlines in 2008 when Canada banned polycarbonate baby bottles because of possible leaching of the chemical from the plastic into the contents. Concern had been raised because BPA was known to have hormone-like activity, placing it in the category of “endocrine disruptors.” Hormones are the body’s chemical messengers and are active in very small doses. Our pituitary gland, for example, produces only about 1 microgram of hormones a day, a very, very, small amount, yet it is critical to life. Estrogen levels in the blood are measured in units of picograms per mL. A picogram is one-trillionth of a gram!

Any substance that interferes with the activity of hormones, whether by blocking or mimicking their activity is of concern since it is well known that abnormal amounts, such as can occur naturally, are linked to disease. Elevated estrogen levels can trigger breast cancer and low pituitary output can stunt growth. Although the cornerstone of toxicology is that “the dose makes the poison,” clearly with potential endocrine disruptors, that dose can be very small since the hormones that can be interfered with are present in very low concentrations.

The hormone-like activity of BPA has been known since the 1930s and since then hundreds of research papers have been published on almost every aspect of this chemical. Using rodents, acute toxicity was not difficult to determine and was found to be low. However, that doesn’t mean much given that nobody worries about keeling over after drinking from a polycarbonate bottle. The question is about exposure to trace amounts over the long term. Since BPA can be measured in the urine, we now know that virtually everyone has had some exposure. The most likely source is food since many cans and transport containers are lined with an epoxy resin formulated with bisphenol-A. It has also been a component of thermal paper as used in cash register receipts and of liners in water pipes. Can such exposure have consequences on health?

The experiment that would give us a definitive answer cannot ever be carried out. One obviously cannot expose a group of human subjects to different amounts of BPA over decades to see what happens. Besides ethical considerations, such a trial would also be logistically and economically not feasible. However, there are alternatives. Blood and urine levels can be measured in populations and any link to behaviour, physiology or disease can be investigated. This has been done and associations detected with obesity, diabetes, heart disease and infertility. The problem here is that an association cannot prove a cause-and-effect relationship. For example, it may be that people with heart disease consume more sugary soft drinks and eat salty foods from cans lined with resins that can release BPA. This would explain a higher blood level of BPA in people with heart disease without BPA being a causative factor. Still, it being a causative factor cannot be ruled out, so we have a conundrum.

The effects of BPA on cells can be studied in the proverbial test tube, and effects noted, but the human body is not a giant test tube. Rodents cannot object to being exposed to different amounts of BPA over their lifetime, but their lifetime is not very long. And, of course, people are not exactly giant rats. Nevertheless, experiments with rodents can offer insight, which is why the National Toxicology Program in the U.S. organized the “CLARITY-BPA” trial, the most extensive rodent experiment ever performed with BPA.

University research groups around the country were asked to study different outcomes when rats were exposed to varying amounts of BPA. Effects on mammary glands, testes, ovaries, prostate, thyroid gland, uterus, the brain, the heart and the immune system were all investigated by different groups. The common feature was that they all used daily exposures of 2.5, 25, 250, 2500, or 25000 micrograms per kg body weight. These amounts nicely bracket the 50 micrograms per kg, the highest dose to which the general population may be exposed. There were also control animals treated with ethinyl estradiol, an estrogen.

So, what were the results? Given that there was such a diversity of doses, there were certainly some effects noted, although rarely with doses in the range of human exposure. The most noteworthy finding was that in a few cases the response was “nonmonotonic,” meaning that a larger effect was seen at a smaller dose than with a larger one. This flies in the face of the usual tenets of toxicology but that is what the researchers found. Perhaps the most interesting finding was that in spite of the excellent work by many groups, the scientists were unable to come to a consensus about the risks posed by BPA exposure.

This then is where we stand. After hundreds and hundreds of papers published in numerous journals by researchers around the globe, we have no definitive answer about what the trace amounts of BPA floating around our bloodstream can do. And keep in mind that this is just one chemical that has been labelled as an endocrine disruptor. There are hundreds of others, ranging from phthalates and perfluoroalkyl substances (PFAS) to naturally occurring isoflavones in soybeans. Unfortunately, when it comes to exposure to trace chemicals over the long term, science cannot always provide an answer. Remember also that there are thousands and thousands of all sorts of chemicals in our body at any given time. Just a sip of coffee will introduce over a thousand compounds, and a sniff of perfume can contribute hundreds. If any of these were isolated and tested extensively in rodents a la BPA, surely some effects would be found. Relevant to humans? Essentially undeterminable.

Nevertheless, since bisphenol A is certainly not essential for our bodily functions, there is no harm in trying to reduce exposure. Industry is searching for replacements and many cans and plastic products are now labelled as “BPA free.” But being “free” of one of the thousands and thousands of chemicals constantly circulating in our body may not mean very much.


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