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Low Risk to Human Reproductive and Developmental Health from Low Doses of Bisphenol A Confirmed by New Weight-of-Evidence Evaluation

June 19, 2006

Summary

A new weight-of-evidence evaluation supports the conclusion that low doses of bisphenol A (BPA) are not a risk to human reproductive and developmental health. The evaluation, in which studies published through February 2006 were critically reviewed by an expert scientific panel, has been published in the peer-reviewed journal Critical Reviews in Toxicology. The conclusion is consistent with and supports numerous assessments conducted by government and scientific bodies worldwide, all of which support the safety of bisphenol A. Overall, the panel concluded: “Taken together, the weight of evidence does not support the hypothesis that low oral doses of BPA adversely affect human reproductive and developmental health.”

Why was the Evaluation Done?

Claims have been made since the mid-1990’s that low doses of bisphenol A can cause adverse health effects by disruption of normal hormonal functions. The most commonly claimed effects involve reproduction and development. A so-called “low-dose hypothesis” further claims that a non-monotonic dose-response results in effects at low doses but not at higher doses. This concept is at odds with a fundamental principle of toxicology that “the dose makes the poison.”

Since the origin of this controversial hypothesis, a large number of studies on bisphenol A have been conducted to assess various aspects of the hypothesis. The research has been inconsistent and even contradictory. In several cases, effects reported in one study have not been replicated in other larger-scale studies.

Several years ago an expert scientific panel was convened by the Harvard Center for Risk Analysis to evaluate the weight of evidence supporting claims of low-dose effects from bisphenol A. The Harvard panel found “no consistent affirmative evidence of low-dose BPA effects for any endpoint.” (1) Since the Harvard panel’s evaluation, many new studies have been published. The current evaluation updates the Harvard panel’s evaluation and conclusions on reproductive and developmental effects of low doses of bisphenol A.

How was the Evaluation Done?

The new weight-of-evidence evaluation was conducted by a panel of scientific experts that included three members of the Harvard panel along with other experts. The same comprehensive, analytical methodology used by the Harvard panel was used to review more than 50 new studies that examined reproductive and developmental endpoints in laboratory animals at low doses of bisphenol A. Many other papers that provided additional relevant information from animal and human studies were also evaluated. Studies published through February 2006 were included in the evaluation.

Each individual study was critically reviewed to assess the significance of responses, the adequacy of study design and statistical analysis, the presence of dose-response relationships, and evidence for and against modes of action relevant to low-dose reproductive and developmental toxicity. An overall weight-of-evidence conclusion was then reached through a systematic, analytical framework that assessed reported low-dose effects against a series of criteria related to consistency, ability to generalize across species to humans, and biological plausibility. The evaluation has been published in the peer-reviewed journal Critical Reviews in Toxicology. (2)

What Were the Findings of the Evaluation?

After reviewing more than 70 animal studies, the evaluation concluded that there were no consistent effects on reproductive or developmental endpoints across multiple studies. Stated more directly, the most consistent findings are those showing no effects. Considering all endpoints, there is also no consistent and repeatable pattern of effects that would be expected if bisphenol A were acting as an estrogen at low doses, as asserted in the low-dose hypothesis.

Few studies have attempted to examine human health outcomes from bisphenol A exposure. All are small studies with significant methodological shortcomings. No credible findings of human reproductive toxicity at any bisphenol A exposure level were reported in the human health studies.

A number of biomonitoring studies that measure bisphenol A in urine provide estimates of human bisphenol A intake. These studies consistently indicate that typical human exposure to bisphenol A is in the range of approximately 20-60 nanograms/kg-body weight/day, levels that are well below the levels tested in nearly all of the “low-dose” animal studies. Human biomonitoring studies also confirm that bisphenol A is efficiently converted by humans to a non-estrogenic metabolite that is rapidly and entirely excreted in urine.

Considering the results from human and animal studies, and the low exposure levels in humans, it is unlikely that exposure to bisphenol A causes adverse effects on human health. Overall, the expert scientific panel concluded: “Taken together, the weight of evidence does not support the hypothesis that low oral doses of BPA adversely affect human reproductive and developmental health.”

How Does the Evaluation Compare With Other Reviews?

Government and scientific bodies worldwide have examined the scientific evidence supporting the safety of bisphenol A in recent years. The findings of this new weight-of-evidence evaluation are consistent with and support the findings of these earlier assessments, all of which support the conclusion that bisphenol A is not a risk to human health at the low levels to which people might be exposed. Key examples of recent assessments include:

  • A comprehensive risk assessment conducted by the Japanese National Institute of Advanced Industrial Science and Technology (2005) (3)
  • The Japanese Ministry of Environment, which conducted their own low-dose research on bisphenol A (2005) (4)
  • A weight-of-evidence evaluation of low-dose reproductive and developmental effects of bisphenol A conducted by a panel of scientific experts organized by the Harvard Center for Risk Analysis (2004) (5)
  • A comprehensive European Union (EU) risk assessment (2003) (6)
  • An independent assessment of the EU risk assessment by the Scientific Committee on Toxicity, Ecotoxicity and the Environment (2002) (7)
  • A detailed assessment of bisphenol A focused on food contact applications by the EU Scientific Committee on Food (2002) (8)
  • A scientific panel evaluation of low-dose effects from bisphenol A organized by the US National Toxicology Program (2001) (9)


 


1. Gray, G. M., Cohen, J. T., Cunha, G., Hughes, C., McConnell, E. E., Rhomberg, L., Sipes, I. G., and Mattison, D. 2004. Weight of the evidence evaluation of low-dose reproductive and developmental effects of bisphenol A. Human and Ecological Risk Assessment. 10:875-921. For a description of this study and a link to the full paper, see http://www.bisphenol-a.org/whatsNew/20040903Harvard.html.

2. Goodman, J. E., McConnell, E. E., Sipes, I. G., Witorsch, R. J., Slayton, T. M., Yu, C. J., Lewis, A. S., and Rhomberg, L. R. 2006. An updated weight of the evidence evaluation of reproductive and developmental effects of low doses of bisphenol A. Critical Reviews in Toxicology. 36:387-457. For a summary of this study, see http://www.gradientcorp.com/coinfo/RiskBull.html.

3. An abstract and detailed summary of the bisphenol A risk assessment are available at http://unit.aist.go.jp/crm/mainmenu/e_1-10.html. For further discussion on the assessment, see http://www.bisphenol-a.org/whatsNew/20060320.html.

4. Japanese Ministry of Environment. 2005. MOE’s perspectives on endocrine disrupting effects of substances. March 2005. Available on the internet at http://www.env.go.jp/en/chemi/ed/extend2005_full.pdf.

5. See footnote 1.

6. Available on the internet at http://ecb.jrc.it/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/SUMMARY/bisphenolasum325.pdf (summary) and http://ecb.jrc.it/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/bisphenolareport325.pdf (full report).

7. Available on the internet at http://ec.europa.eu/health/ph_risk/committees/sct/documents/out156_en.pdf.

8. See http://www.bisphenol-a.org/whatsNew/20020715EuropeanCommission.html for a discussion on the European Commission’s Scientific Committee on Food assessment of bisphenol A, and http://europa.eu.int/comm/food/fs/sc/scf/out128_en.pdf for the complete assessment.

9. National Toxicology Program's Report of the Endocrine Disruptors Low Dose Peer Review, August 2001, available on the internet at http://ntp.niehs.nih.gov/go/14446.




   
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