Bisphenol A: Research to Impact Human Health

Recovery Act Limited Competition for NIH Grants: Research and Research Infrastructure "Grand Opportunities" (RC2)

Bisphenol A (BPA) is a high production estrogenic endocrine-disrupting chemical used primarily in the production of polycarbonate plastics and epoxy resins. There is significant human exposure as detectable levels of BPA have been found in 93% of urine samples collected from people 6 years and older. The estimated amount of BPA ingested in humans is similar to the doses used in animal models that cause a variety of diseases/dysfunctions.

The National Toxicology Program’s Center for the Evaluation of Risks to Human Reproduction (CERHR) and an NIEHS sponsored Workshop recently independently reviewed the literature on BPA (over 700 publications) and both reports independently came to the conclusion that there is evidence from animal studies that BPA may be causing adverse effects at levels to which humans are exposed. It was also noted that there were significant data gaps that needed to be filled. Endpoints reported to be affected by exposure to environmentally relevant doses of BPA include fertility, weight gain, behavioral changes, early onset puberty, prostate and mammary gland cancer, aneuploidy, and diabetes. Based on the CERHR assessment of the literature and the CERHR report, the NTP concluded that the only endpoints where there were data of sufficiently high quality were those that showed effects on brain and behavior and the prostate gland. A significant portion of the literature was not able to be fully considered in the NTP evaluation due to a variety of experimental limitations including the use of a single dose, small numbers of animals per group, non-oral route of administration, lack of proper statistics and lack of data on specific phenotypic endpoints.

This initiative is therefore focused on developing new data in a limited number of strategic areas where there is paucity of data and to also stimulate the replication and expansion of published studies that have been deemed by CERHR to have specific deficiencies.

The goal of this initiative is to produce both the animal and human data to allow for a comprehensive assessment of the human health effects of BPA.

Under this initiative, two year animal or human studies that focus on either developmental exposure (in utero or neonatal ) or adult chronic exposures to low environmentally relevant doses of BPA will be supported. The endpoints of interest include but are not limited to:

• obesity/diabetes/metabolic syndrome,
• reproductive disorders including age at puberty,
• development of prostate, mammary gland and uterine cancer,
• disorders of the developing immune system that result in increased susceptibility to asthma or infections and autoimmune diseases,
• cardiovascular diseases including athererogenesis and altered blood pressure,
• studies that show phenotypes across three generations,
• physiologically-based pharmacokinetic models for animals and humans to facilitate cross species extrapolations.
  In order for the data produced to have the greatest impact on our ability to assess the human health effects of BPA, animal studies (developmental exposures or adult chronic exposures) must pay special attention to the following:
  • diet (must not interfere with the sensitivity of the model to BPA),
  • species and strain of animals ( must be sensitive to estrogenic chemicals at low doses),
  • sufficient sample size to ensure power to detect a statistical difference between experimental groups.,
  • internal dose of BPA (total and free BPA should be measured in blood and if possible also in urine throughout the study),
  • dose responses (single dose experiments are not acceptable),
  • phenotype (endpoint must be an actual phenotype, disease/dysfunction not just toxicity),
  • litter must be used as statistical unit for developmental exposures,
  • route of exposure should be oral or justified to provide similar blood levels as oral route,
  • males and females should be used when feasible,
  • molecular targets and mechanism should be assessed when possible including gene expression, receptor binding and epigenetic studies. These effects should be linked to the exposure and the disease/dysfunction endpoints.

While the main focus is on developmental exposures, studies of cumulative risk from multiple exposures to BPA across the life stages are also encouraged (e.g. combinations of developmental, neonatal, pubertal and or adult chronic exposure).

Data supporting the human health effects of BPA have been limited, and therefore we have particular interests in supporting studies in populations that have the ability to explore the link between developmental exposures to BPA (i.e. cord blood or maternal blood levels of total and free BPA or urinary BPA) with follow-up measures as listed above. Because of the limited time frame and resources, we strongly encourage proposed human studies to use extant datasets with banked specimens with relevant outcome data. We encourage existing longitudinal studies to complete new analyses on the human health effects of BPA exposure during pregnancy and/or the neonatal/prepubertal period and to link them to disease/dysfunctions later in life.

Multiple PI applications or applications with multiple investigators are encouraged, especially those that would measure multiple endpoints in animal studies or those that would measure the same endpoints in human and animal studies along with measurements of BPA in blood and/or urine of both species.

The NIEHS intends to commit $5 million for this initiative. While the "Grand Opportunities" initiative allows for applications greater than $500,000 per year, budgets must be justified. Applicants should also set aside funds to attend a grantee meeting in the second year of funding.

Contact Information

Animal Studies
Jerrold J. Heindel, Ph.D.
Scientific Program Administrator

Division of Extramural Research and Training
National Institute of Environmental Health Sciences
Tel (919) 541-0781
heindelj@niehs.nih.gov

Human Studies
Kimberly A. Gray, Ph.D
Scientific Program Administrator

Division of Extramural Research and Training
National Institute of Environmental Health Sciences
Tel (919) 541-0293
gray6@niehs.nih.gov

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