Bisphenol A: Lose Dose Effects

Laura N. Vandenberg, PhD Assistant Professor University of Massachusetts – Amherst School of Public Health, Division of Environmental Health Science Amherst, MA Interview with:
Laura N. Vandenberg, PhD
Assistant Professor
University of Massachusetts – Amherst School of Public Health,
Division of Environmental Health Science
Amherst, MA  01003 What are the main findings of the study?

Dr. Vandenberg: Back in 2007, a group of 38 researchers wrote the Chapel Hill consensus statement about BPA (vom Saal et al. Reproductive Toxicology 2007). We also wrote 5 separate review articles summarizing what was known at the time about

  • 1) BPA and cancer;
  • 2) BPA and its effects on wildlife animals and in environmental matrices (air, water, soil, etc.);
  • 3) BPA and molecular mechanisms in cultured cells;
  • 4) BPA levels in humans and their exposure sources;
  • 5) BPA’s effects on laboratory animals.

    Several of these groups analyzed what effects BPA has at “low doses”, i.e. at doses below those tested in traditional toxicology studies. (These are doses that are thought to be “safe” for animals and humans.)

    For the past few years, our group has been revisiting all of the Chapel Hill statements from 2007 and updating them. The Chapel Hill groups identified low dose effects for a number of study types (for example, they found strong evidence that developmental exposures to BPA affect development of the male reproductive tract; in 2007, multiple studies from independent laboratories had identified that low doses of BPA during early development could affect adult prostate weight, for example.) We set aside the endpoints that the Chapel Hill groups found there was significant evidence for low dose effects. We instead focused on areas that lacked sufficient studies to make a conclusion in 2007.

We were able to identify a number of study areas that did not have sufficient data in 2007 for any conclusion. Several of these areas of study revealed reproducible, consistent low dose effects that were found in multiple independent laboratories. These included the effects of developmental exposures on female reproduction, mammary gland development and neoplasias, and mammary gland response to carcinogenic challenges; and the effects of adult exposures on brain morphology and metabolic endpoints.

Similar to other recent reviews, we also discussed the results of recent epidemiology studies. In the past six or seven years, the number of epidemiology studies focusing on BPA has increased tremendously. Now, more than 60 human studies suggest relationships between BPA exposures and diseases or other dysfunctions.

Looking at all published studies on BPA, we concluded that:

(1) Consistent, reproducible low dose effects have been demonstrated for BPA in cell lines, primary cells and tissues, laboratory animals, and in some human populations.

(2) Many of these low dose effects should be considered adverse.

(3) Doses that reliably produce statistically significant effects in animals are 1–4 magnitudes of order lower than the current lowest observable adverse effect level (LOAEL) of 50 mg/kg/day.

(4) Endocrine disruptors, including BPA, often pose a greater threat when exposure occurs during early development, organogenesis, or during critical postnatal periods during which tissues are differentiating. Were any of the findings unexpected?

Dr. Vandenberg: What was done in 2007 with the Chapel Hill group was a one-of-a-kind (or perhaps first-of-a-kind) analysis. It was truly ground breaking, and brought light to the areas of study with convincing results and also helped researchers identify the areas of study that needed additional research. We found that many of these areas that had limited information in 2007 had significantly more information available in 2013, suggesting that those “data gaps” identified in 2007 were helpful in steering scientific studies – and were tackled  by numerous laboratories. Thus, what we did in writing this new paper is to “carry the scientific torch” and readdress and reassess the body of evidence, again asking “Do low doses of BPA affect these endpoints?”. The BPA literature continues to grow exponentially and we did our best to assess it all at once – we studied more than 400 new low dose studies published since the Chapel Hill reviews in 2007.

We also used a new approach to look at endpoints from an integrative assessment, asking “Do we see similar effects in cultured cells, in laboratory animals, and in humans?” We did this for five endpoints – endpoints that were selected because a relatively large amount of data was available. Not every single study showed an effect of BPA on these endpoints, but overwhelmingly the data suggest that BPA has effects at low doses on cells, animals and human populations. Using this approach, we could clearly see that there were patterns visible across multiple levels of biological organization… what we see in cells could predict what we would see in animals. Or what we see in animals could predict what was observed in human populations. For example, we saw that BPA affects oocytes (eggs) and ovarian cells in culture. It affects ovarian cells and eggs in animals. And it appears to have some relationship with IVF outcomes in women. From a scientific perspective, this is not terribly surprising because we expect that cultured cells are chosen because they accurately predict effects in animals, and that animal models predict the effects of chemicals on humans; this is consistent with evolutionary theory. But in practice, it is actually a lot harder to see these kinds of relationships. Animal studies are tightly controlled, and human exposures are not! Thus, it was somewhat surprising that there are a significant number of endpoints with consistent low dose effects at multiple levels of biological organization. What should clinicians and patients take away from your report?

Dr. Vandenberg: Our group found strong evidence for low dose effects of BPA. A relatively large number of animal studies found effects of BPA at doses that humans typically encounter. Furthermore, the large number of epidemiology studies showing relationships between BPA and human diseases suggest that exposures are not without harm. Thus, all patients should avoid sources of BPA whenever possible. Clinicians should educate themselves on endocrine disruptors in general, as well as BPA. The 2012 “State of Science” document from the World Health Organization and United Nations Environment Programme is a great place to start. What recommendations do you have for future research as a result of this study?

Dr. Vandenberg: We made a number of recommendations for the scientific community including:

(1)    The use of a consistent definition of “low dose” and “low dose effects” in the endocrine disruptor literature.

(2)    Improved data on the sources of BPA exposure.

(3)    Incorporation of low doses and additional sensitive endpoints in guideline studies.

(4)    Evaluation of additive and synergistic effects of BPA with other endocrine disruptors including phytoestrogens.

(5)    To better define critical windows of vulnerability for various endpoints shown to be sensitive to low doses of BPA.


Low dose e ects of bisphenol A: An integrated review of in vitro, laboratory animal, and epidemiology studies

Vandenberg LN, Ehrlich S, Belcher SM, Ben-Jonathan N, Dolinoy DC, Hugo ER, Hunt PA, Newbold RR, Rubin BS, Saili KS, et al. Low dose effects of bisphenol A: An integrated review of in vitro, laboratory animal, and epidemiology studies. Endocrine Disruptors 2013; 1:0 – -1;