In the News
CFSAN's Review of Low-Dose BPA Studies Supports Earlier NOAEL
Jun 15, 2010
Based on a review of low-dose studies, the Food and Drug Administration's (FDA) Center for Food Safety and Applied Nutrition (CFSAN) concluded that a no observed adverse effect level (NOAEL) of 5 mg/kg bw/da for Bisphenol A (BPA) is the most appropriate for use in risk assessments. This conclusion was reported in an August 31, 2009 memorandum from Toxicology Group 1, Division of Food Contact Notifications, Office of Food Additive Safety, CFSAN, titled, "Bisphenol A (CAS RN. 80-05-7): Review of Low-Dose Studies." The memorandum was made public by FDA on April 5, 2010, along with four other documents related to the Agency's continuing assessment of BPA.
This is the same NOAEL that FDA recommended for BPA in its "Draft Assessment of Bisphenol A for use in Food Contact Applications," published August 14, 2008. However, the Agency was criticized for using only two multi-generational rodent studies in determining the 5 mg/kg bw/da NOAEL. In particular, a Subcommittee of FDA's Science Board Advisory Committee that reviewed the BPA draft assessment recommended that FDA provide a clearer explanation of the criteria it used to determine which studies were included, and suggested that the Agency consider the studies that were determined to be "adequate" and of "high utility" by the National Toxicology Program's (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) in its report on BPA, released in September 2008. (For more information, see the PackagingLaw.com article, "Additional BPA Studies Planned, FDA Tells Science Board.") CFSAN's review was conducted in response to the Science Board's recommendation.
In the memorandum, CFSAN stated that while there may be more sensitive endpoints, "these endpoints or the information relating these endpoints to toxicity are not adequate to allow the determination of a NOAEL." CFSAN concluded, "Until validated studies specifically designed to characterized these endpoints for dose response and implications on human health are conducted, the NOAEL of 5 mg/kg bw/day is the most appropriate for use in the risk assessment." Despite concluding that the NOAEL in 2008 BPA draft assessment is the most appropriate, FDA announced in January 2010 that based on the results of recent studies, it now had "some concern" about potential health effects from BPA (see the PackagingLaw.com article, "FDA to Increase Oversight of BPA, Cites "Some Concern" Over Possible Health Effects").
FDA also reported on the margin of safety (MOS) that CFSAN calculated for BPA, which ranged from approximately 2,000 for infants to 27,000 for adults. The agency said that since BPA is an impurity and not a food additive, it was more appropriate to use the MOS approach rather than determining an acceptable daily intake (ADI).
In a second memorandum from CFSAN's Toxicology Group 1, dated November 24, 2009 (also released by FDA on April 5), the group summarized several BPA studies that were made available after its initial assessment of the low-dose studies. One of these was an unpublished study commissioned by the American Chemistry Council that focused on the potential developmental neurotoxicity of dietary BPA in rats. The new studies "contained low dose evaluations and filled data gaps that were described in our previous evaluation of BPA, suggesting a lack of effects below the systemic NOAEL of 5 mg/kg bw/day on these neurodevelopmental endpoints," according to the memorandum. Based on the new studies, CFSAN's Toxicology Group recommended that the NOAEL for BPA should remain 5 mg/kg bw/day.
In addition to the two memorandums from CFSAN's Toxicology Group, FDA also released a review of CFSAN's assessment of the low-dose studies by five non-FDA government scientists, CFSAN's updated dietary exposure estimate from food contact uses of BPA, and CSFAN's review of available biomonitoring data on BPA. FDA announced the availability of the five documents the Federal Register (75 Fed. Reg. 17145 (April 5, 2010)), and requested public comments on the four documents that were prepared by CFSAN.
Scientists Disagree on NOAEL
The five experts who conducted scientific reviews of CFSAN's assessment of the low-dose BPA studies come to different conclusions. Dr. Leon Earl Gray Jr., a research biologist with the Environmental Protection Agency, and Dr. Marilyn Wind, U.S. Consumer Product Safety Commission, agreed with the NOAEL determined by CFSAN's Toxicology Group. Specifically, Dr. Gray stated, "I found that the criteria used by the FDA scientists to evaluate the utility of new studies for assessment of the potential low dose effects of BPA were clearly presented, they were extremely reasonable and well thought out, they were valid and, in addition, they were quite similar to the well-vetted criteria used by the NTP, CERHR [Center for the Evaluation of Risks to Human Reproduction] Expert Panel on BPA to evaluate studies in their assessment." However, CERHR's Dr. Kristina Thayler; Dr. John R. Bucher, Associate Director, NTP, National Institute of Environmental Health Sciences, National Institute of Health; and Dr. Jerrold Heindel, National Institute of Environmental Health Sciences, did not agree with the NOAEL determined by CFSAN.
While Dr. Thayer suggested that a lower dose level than 5 mg/kg bw/day could be supported, she recommended that if FDA retains this NOAEL, "then the Agency should also acknowledge the evidence for possible effect at doses well below this NOAEL." She added that this could be reflect in a guidance to consumers that FDA presents when a regulatory decision on BPA is announced.
The final two documents in the docket are memorandums from chemistry review groups in FDA's Division of Food Contact Notifications. An October 22, 2009 memorandum on exposure to BPA for infants, toddlers, and adults from the consumption canned food concluded that the mean estimate of exposure for children and adults two years of age and older is 0.1 µg/kg bw/da, or one half of the Agency's previous estimate. The mean estimate for infants 0 to two years ranged from 0.5 to 0.3 µg/kg bw/da.
A November 16, 2009 memorandum that summarized BPA biomonitoring studies, noted that results from a recent study found "substantial" BPA levels in subject's urine from non-food exposure. This contrasts with the literature statement that food is the predominate source of BPA, according to the memorandum. The memorandum concluded, "experimental pharmacokinetic studies of chronic BPA exposure, further examination of BPA levels and effects in fat may be required, as well as continued search for important non-food sources for BPA, such as water and dust that have been implicated in previous studies."
A copy of the documents release by FDA on April 5, can be found here.