The compendium report of studies from the Consortium Linking Academic and Regulatory Insights on the Toxicity of Bisphenol A (CLARITY-BPA) was released Oct. 29. The project began in 2012 as a unique collaboration among NIEHS, the National Toxicology Program, and the U.S. Food and Drug Administration (FDA), and it included key contributions from institute-funded university researchers.

BPA is widespread in the environment. It is found in many plastics and epoxy resins, and in products ranging from infant bottles to water pipes. In the early 2000s, the National Health and Nutrition Examination Survey found that almost all Americans had BPA in their urine. The chemical often is called an endocrine disruptor because of its ability to alter hormone activity.

Most individuals are exposed to BPA through diet because the chemical is used widely in food packaging, bottle tops, and related products. Exposure also can occur via air, dust, and water. (Photo courtesy of Ekaterina_Minaeva / Shutterstock.com)

Understanding BPA

“CLARITY-BPA aimed to improve our understanding of how exposure to this substance affects human health with a special focus on the low-dose range,” noted lead author Kembra Howdeshell, Ph.D., a scientist in NIEHS Division of the National Toxicology Program (DNTP). “Goals included addressing knowledge gaps, informing regulatory decision-making, and identifying effective research approaches for endocrine-disrupting chemicals, such as BPA.”

Howdeshell works in the DNTP Integrative Health Assessments Branch, where she provides expertise in endocrinology, reproductive biology, and toxicology. (Photo courtesy of Steve McCaw / NIEHS)

The project featured a two-year study on the chronic toxicity of BPA in rats, called the core study, and complementary investigative research by NIEHS-funded university scientists. The FDA National Center for Toxicological Research conducted the core study in accordance with regulatory guidelines on toxicity testing, and it analyzed factors such as organ weight and tissue changes, which are assessed in standard toxicology studies.

Fourteen university scientists conducted the complementary investigative research, examining tissues from sibling animals in the core study. They measured different endpoints and assessed a wider range of potential effects, including those related to the brain and behavior; cardiovascular and immune systems; mammary and prostate glands; penile function; ovaries; urethra; testis and epididymis; metabolism and thyroid hormone; and uterus.

Grantees expand key research

“Traditional guideline studies often examine later stages of development, far into adulthood of laboratory rats, so it was hoped that the investigative research would shed light on whether there were earlier developmental changes leading to effects seen later in life,” said Howdeshell.

Changes in rat pituitary and reproductive tissues were reported in the core study but at exposures much higher than those typically experienced by humans. Other effects were shown at lower doses relevant to humans, but whether they were due to BPA exposure alone or biological variability was unclear to scientists who conducted the core study.

“We anticipated that NIEHS grantees could address those and other issues through broader study of the chemical, as they had greater flexibility to incorporate new technologies and research methods that are not typically used in regulatory guideline studies,” explained Howdeshell.

An illuminating report

For the final report, consortium members aimed to synthesize results from both the core study and complementary university research to provide a more complete picture of how BPA could affect human health. However, the authors did not reach a consensus.

Yet the collected findings are nonetheless illuminating, according to former DNTP Senior Scientist John Bucher, Ph.D. He played a key role in initiating CLARITY-BPA and worked closely on the project until his retirement in April (see sidebar).

“Although relatively low exposures to BPA led to essentially negative findings in the core study, many of the published university papers reported adverse health effects,” said Bucher. “This suggests that current guideline-compliant studies used in regulatory decision-making may not detect all potential hazards from real-world exposures to chemicals, especially hormone-disrupting substances such as BPA.”

Bucher, shown here at a 2014 meeting of the National Toxicology Program Board of Scientific Counselors, worked at NIEHS for nearly four decades. (Photo courtesy of Steve McCaw / NIEHS)

Effects on brain, mammary gland, prostate, and more

Examples of research highlighted in the final report include the following.

• Brain and behavior — The core study showed no changes in brain tissue in rats. University researchers found some structural changes, and they observed alterations in the expression of estrogen and androgen receptors. They also discovered changes in the expression of genes involved in sexual differentiation and neuroendocrine function in the hypothalamus, hippocampus, and amygdala, and limited sex-specific effects on learning and memory, among other results.
• Mammary glands — Cancer rates in female rats increased following administration of the lowest BPA dose in the core study, but authors of that study concluded that was not due to the chemical because effects were not seen at higher doses. University scientists found that low-level exposure in rodents caused changes in mammary gland development that may contribute to increased cancer risk, whereas higher doses did not cause those changes.
• Prostate – Neither the core study nor the investigative research reported cancerous lesions following BPA exposure. However, BPA did increase cancer following a later-life estrogen exposure simulating the aging human male, with the greatest effects observed at the per-day dose of 2.5 micrograms BPA per kilogram body weight. Also, evaluation of the developing male prostate and urethra showed a smaller urethra following exposure to low doses of BPA or ethinylestradiol, a synthetic estrogen.

Not the final word

“Although authors did not reach agreement on findings from the core study and university research, I believe CLARITY-BPA has been a valuable effort,” said Howdeshell. “All data have been made public, which will facilitate their further analysis,” she added, noting that some scientists already have published partial integrated assessments of CLARITY-BPA data.

“The compendium report is not the final word on BPA,” noted Howdeshell. “The report should help to inform whether there are new tools or additional metrics that could be applied to guideline studies to help scientists better understand the effects of endocrine disruptors.”