Giovanna Di Sauro

This is the second part of a series of posts dedicated to Bisphenol A (BPA) and research about its toxicity and estrogenic activity. In the first part, I introduced the concept of xenoestrogen, talked a little bit about what bisphenol A is and what it is used for, and told the story of the discovery of its – initially unsuspected – effects on systems usually regulated by estrogen and similar hormones. In this second and last post, I will talk about the research regarding BPA toxicity, carcinogenicity, and hint at the medical and ecological implications of BPA presence in our environment.

BPA was tested for toxicity a very long time ago, and it was found to be mainly non-toxic, until toxicity effects started showing up in dental patients. A short review published in 1996 in the journal Environmental Health Perspectives (PMID: 8732943) suggests that, according to different studies on different brands on dental sealants, sometimes up to 30-40% of sealant is released, in the form of unpolymerized BPA-based compounds, and could then be potentially absorbed in the intestine. The amount of BPA released has estrogenic activity. Dental sealants are used during the treatment of cavities; after the tooth is cleaned and filled, a layer of sealant is swabbed onto the tooth, and drying of coating components is induced using a heat or light source. The sealant is used frequently, especially in children, as it has been shown to reduce subsequent cavities by up to 50%. While the American Dental Association (ADA) endorses the use of dental sealants and is skeptical about the significance of BPA release, research on this topic is still being pursued. As you can imagine, the controversy has not been resolved yet: while the ADA continues to attack the results of studies on BPA in sealants, studies continue to notice that, although the amounts of BPA being released might be of negligible importance in humans, they are still amounts with biological effects in smaller organisms (rats).

The situation for food can coating resins (also known to release biologically active amounts of BPA) is similar, with industry studies contrasting research on the amount of leaching from food cans.

Does this mean that one of the sides is lying? Well, a honest skeptical answer would be…no. There is no need for conspiracy theories to explain these disagreements. Mostly, the debate is fueled by the fact that nobody really knows how to assess the effects of xenoestrogen in humans and their significance. What amount of BPA do we need to ingest such that it will have an impact on our health? Should we consider amounts that are ingested all at once, in a short period of time, or over a lifetime? Is the concept of “lifetime xenoestrogen load” useful or not?

Answering these questions is what would unlock the current debates, as by now all sides are at least willing to accept that BPA has unquestionable biological activity as a xenoestrogen. Here is a short list of papers (there are many more) discussing the biological effects of BPA absorption in animals, effects directly related to estrogenic activity:

• Prepubertal exposure to compounds that increase prolactin secretion in the male rat: effects on the adult prostate. Biol Reprod. 1999 Dec;61(6):1636-43 (PMID: 10570013)
  
• The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract. Endocrinology. 1998 Jun;139(6):2741-7 (PMID: 9607780)
• The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology. 1997 May;138(5):1780-6 (PMID: 9112368)
• The developmental toxicity of bisphenol A in rats and mice. Fundam Appl Toxicol. 1987 May;8(4):571-82 (PMID: 3609543)
• Bisphenol A in the aquatic environment and its endocrine-disruptive effects on aquatic organisms. Crit Rev Toxicol. 2007;37(7):607-25 (PMID: 17674214)

You might have noticed that these papers are about ten years old. What is the current consensus on the biological activity of BPA, and its mode of action in animals? Here are a few more recent papers addressing these questions:

• In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007 Aug-Sep;24(2):199-224. (PMID: 17683900)
• An evaluation of evidence for the carcinogenic activity of bisphenol A. Reprod Toxicol. 2007 Aug-Sep;24(2):240-52. (PMID: 17706921)
• In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol. 2007 Aug-Sep;24(2):178-98. (PMID: 17628395)

The second paper is of special interest, as it summarizes the results of a panel discussion organized by the National Institutes of Health (NIEHS, NIDCR) and the United States Environmental Protection Agency, which “convened an expert panel of scientists with experience in the field of environmental endocrine disruptors, particularly with knowledge and research on bisphenol A (BPA)”. This review suggests that there is a wide scientific consensus regarding the possible role of BPA in carcinogenesis. The consensus arising from the panel discussions is succintly summarized in the Conclusions section of the paper:

Based on existing evidence, we are confident of the following:
1. Natural estradiol-17β is a carcinogen as classified by the International Agency for Research on Cancer [37], [106] and [107].
2. BPA acts as an endocrine disruptor with some estrogenic properties among other hormonal activities.

Based on existing evidence, we believe the following to be likely but requiring more evidence:
1. BPA may be associated with increased cancers of the hematopoietic system and significant increases in interstitial-cell tumors of the testes.
2. BPA alters microtubule function and can induce aneuploidy in some cells and tissues.
3. Early life exposure to BPA may induce or predispose to pre-neoplastic lesions of the mammary gland and prostate gland in adult life.
4. Pre-natal exposure to diverse and environmentally relevant doses of BPA alters mammary gland development in mice, increasing endpoints that are considered markers of breast cancer risk in humans.

Based on existing evidence, the following are possible:
1. BPA may induce in vitro cellular transformation.
2. In advanced prostate cancers with androgen receptor mutations, BPA may promote tumor progression and reduce time to recurrence.

The paper also highlights areas of BPA research that require further enquiry:

1. Does BPA exposure induce or promote cancers in mammary and prostate? What is its mode of action?
2. Does BPA increase cancer susceptibility in estrogen-target organs (prostate, mammary gland, uterus, vagina, testis, ovary, etc.)?
3. Does BPA reprogram target tissues during development through epigenetic mechanisms, including epigenetic marking of genes and morphogenetic processes involving tissue interactions?
4. What are the most appropriate life stages for examining BPA-induced cancer susceptibility?
5. Under what conditions might BPA promote DNA and/or microtubule aberrations?
6. Identify biological consequence of long term, low-dose exposure on genomic integrity, cooperation with oncogenic insult and tumor management.
7. Development of carcinogenesis paradigms with relevance to humans for assessing the ability of BPA to alter cancer risk.
8. What species/strains are the most appropriate for assessing BPA-induced cancer susceptibility?
9. Developing three-dimensional culture models to assess the mechanisms involved in altered morphogenesis of the target organs that may lead to neoplastic development.
10. Epidemiology studies and development of new methodologies to evaluate BPA-cancer risks in humans.
11. Development of markers for total xenoestrogen insult in humans.

Do you remember the recent studies published in the journal Cancer Research, which received strong media attention? One showed that BPA induces changes in gene expression in breast cancer cell lines coherent with those of high-grade lesions; the other suggested that BPA is also able to alter the epigenetic profile in the progeny of BPA-treated epithelial cells. These papers are already addressing points 1 and 3 in the “further research needed” list, even if partially.

Past and present data, as well as the current consensus, seem to suggest that it might be prudent to limit BPA intake in humans until further research determines whether BPA is relatively safe – as we already know that it is not absolutely safe. Until the time when more rigorous studies are conducted, and larger data sets on humans collected, we will not know for sure whether BPA poses a significant danger to human health – it is left to the individual, but also to public health agencies around the world to make a decision on whether to forbid BPA use especially in places where it can enter the food chain…or not. But it seems that there is reasonable evidence that BPA release in the environment should be limited as much as possible, as smaller organisms are sensitive to much smaller amounts of BPA than humans seem to be.

Making decision in relation to BPA is made even more complicated by the fact that there are many estrogen-like compounds in our environment which are already in the food chain, and which we can absorb by consuming both animal and vegetable products: BPA absorption might only be the tip of the iceberg when it comes to xenoestrogen intake. It would be useful to see what the “total xenoestrogen insult” is in an average adult who consumes meat, vegetables and dairy, and to see what role BPA is playing to increase this insult. Only then we will be able to assess whether cancer risk arising from BPA ingestion is significant, or whether we would do better to worry about different sources of xenoestrogen.

KERI, R., HO, S., HUNT, P., KNUDSEN, K., SOTO, A., PRINS, G. (2007). An evaluation of evidence for the carcinogenic activity of bisphenol A. Reproductive Toxicology, 24(2), 240-252. DOI: 10.1016/j.reprotox.2007.06.008

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