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Definitive Peer-Reviewed Study Reports No Low-Dose Effects

July 2, 2002

Summary

Toxicological Sciences, one of the most highly regarded peer-reviewed scientific journals in the field of toxicology, has just published the most comprehensive study ever conducted to test the validity of the low-dose hypothesis.¹ Specifically designed to look for reproductive and developmental effects from exposure to low doses of Bisphenol A (BPA), the three-generation study found no such effects. The results of this study are fully consistent with and confirm the results of other large-scale studies, all of which demonstrate that the low-dose hypothesis is not valid. This weight of scientific evidence clearly supports the safety of BPA and provides strong reassurance that there is no basis for human health concerns from exposure to low doses of BPA.

Non-Monotonic Low-Dose Claim is Contrary to Basic Toxicology Principle

Beginning in the mid-1990’s, a low-dose hypothesis has been advanced that claims exposure to extremely low doses of certain substances can cause adverse health effects in humans by disruption of normal hormonal functions. The hypothesis further claims that the dose-response relationship for these substances is “non-monotonic”, which means that health effects may be observed only at low doses while much higher doses may show no effects. This aspect of the low-dose hypothesis is contrary to a fundamental principle of toxicology – “the dose makes the poison.”

Low-Dose Hypothesis Put to the Test by Three-Generation Study Design

The low-dose hypothesis is based on limited small-scale studies that have not been confirmed or replicated in larger-scale studies. To definitively test the validity of the low-dose hypothesis, a three-generation reproductive toxicity study on BPA in CD® Sprague-Dawley rats was conducted at the Research Triangle Institute (now RTI International) in Research Triangle Park, North Carolina under the direction of Dr. Rochelle Tyl as the principal investigator. Key elements of the study were carefully designed to overcome deficiencies in earlier small-scale studies that claim low-dose effects, including:

• An extremely wide range of doses, spanning more than five orders of magnitude from 1 mg/kg/day to 500 mg/kg/day and including doses both above and below those claimed to cause low-dose effects, to ensure that dose-response relationships for any effects found in the study could be unambiguously characterized;
   
• Use of the oral route of exposure, which is the predominant mode of real-life potential exposure, to ensure relevance to human health;
   
• Dose groups of 30 males and 30 females to ensure adequate statistical power for detection of subtle effects at any dose; and
   
• Compliance with international Good Laboratory Practice (GLP) standards.

In contrast, earlier small-scale studies generally included only a small number of doses, sometimes as few as one or two; tested many fewer animals per dose group, as low as five to seven; did not comply with GLP standards; and frequently used a route of exposure that is not relevant to humans (e.g. subcutaneous or intraperitoneal injection). In addition to conventional toxicological endpoints, the Tyl study also explored a wide range of endocrine-sensitive endpoints, including the endpoints that small-scale studies have claimed are affected.

Tyl Study Does Not Confirm Reported Low-Dose Effects

The total absence of low-dose effects in the comprehensive three-generation study provides a definitive conclusion that BPA does not cause reproductive or offspring effects, including endocrine-mediated effects, at low doses. Key findings that support this conclusion include:

• Normal monotonic dose-response relationships for the few treatment-related effects observed at the two highest doses;
   
• No effects on reproduction or development at low doses;
   
• No significant changes in prostate or other reproductive organ weights in any of the three generations of laboratory rats at any dose;
   
• No effects on daily sperm production or efficiency of sperm production in any generation at any dose; and
   
• No significant changes in markers of sexual maturity below the highest dose tested.

Consequently, the results of this study, particularly when examined with other large-scale GLP studies that reach the same conclusion, provides definitive evidence that the low-dose hypothesis is not valid.

Multiple Independent Reviews Confirm the Validity and Significance of Tyl Results

The significance of the Tyl study results has led to an unprecedented level of scrutiny by government bodies and independent scientific panels as well as by the peer reviewers of the journal. In each case, the study has been recognized as robust, thorough, and both scientifically and statistically sound. Indeed, government bodies have relied on the Tyl study results for several key regulatory decisions. Significant examples of the reviews to which the Tyl study has been subject include:

• A comprehensive GLP inspection conducted jointly by the German Federal Institute for Health Protection of Consumers and Veterinary Medicine, and the US Environmental Protection Agency, which the study passed with flying colors;
   
• The EU Risk Assessment on BPA, which established No-Observed-Adverse-Effect-Levels (NOAELs) of 50 mg/kg/day for both reproductive and developmental toxicity based on the results of the study² ;
   
• Independent review of the EU Risk Assessment conclusions by the CSTEE (Scientific Committee for Toxicity, Ecotoxicity, and the Environment, an advisory committee to the European Commission), which agreed with the NOAELs, stated that: “a number of high quality studies on the reproductive and developmental effects of bisphenol A are already available and do not support low-dose effects”, and concluded that: “there is no convincing evidence that low doses of bisphenol A have effects on developmental parameters in offspring…”³
   
• Review of BPA by the SCF (Scientific Committee on Food, also an independent advisory committee to the European Commission on food safety matters), which derived a threshold for lifelong daily intake of BPA (Tolerable Daily Intake) based on the results of this study⁴ ;
   
• Detailed reviews by both the Statistics and Dose-Response Modeling, and Bisphenol A Subpanels of the Low-Dose Peer Review Workshop conducted by the US National Toxicology Program, which described the study as “arguably the most comprehensive of the studies we evaluated.” Based partially on this study, the Bisphenol A Subpanel concluded:

"There is credible evidence that low doses of BPA can cause effects on specific endpoints. However, due to the inability of other credible studies in several different laboratories to observe low dose effects of BPA, and the consistency of these negative studies, the Subpanel is not persuaded that a low dose effect of BPA has been conclusively established as a general or reproducible finding. In addition, for those studies in which low dose effects have been observed, the mechanism(s) is uncertain (i.e., hormone related or otherwise) and the biological relevance is unclear."⁵ ; and

• A significant policy statement from the US Environmental Protection Agency based extensively on the conclusions of the NTP Peer Review Panel, which stated that “it would be premature to require routine testing of substances for low-dose effects.”⁶

Safety of Bisphenol A Reaffirmed

This three-generation study is the latest in a series of studies conducted by five different independent research entities – including a similar reproductive health study sponsored by the Japanese government – all of which reaffirmed the safety of BPA. The weight of scientific evidence provided by these studies clearly supports the safety of BPA and provides strong reassurance that there is no basis for human health concerns from exposure to low doses of BPA.

Refernces

¹“Three-Generation Reproductive Toxicity Study of Dietary Bisphenol A in CD Sprague-Dawley Rats”, R. W. Tyl, C. B. Myers, M. C. Marr, B. F. Thomas, A. R. Keimowitz, D. R. Brine, M. M. Veselica, P. A. Fail, T. Y. Chang, J. C. Seely, R. L. Joiner, J. H. Butala, S. S. Dimond, S. Z. Cagen, R. N. Shiotsuka, G. D. Stropp, and J. M. Waechter, Toxicol. Sci. (2002) 68 (1): 121-146.

² The final Risk Assessment Report is available on the Internet at http://ecb.jrc.it/existing-chemicals/.

³ Available on the Internet at http://europa.eu.int/comm/food/fs/sc/sct/out156_en.pdf.

⁴ Available on the Internet at http://europa.eu.int/comm/food/fs/sc/scf/out128_en.pdf.

⁵ National Toxicology Program's Report of the Endocrine Disruptors Low Dose Peer Review, page 1-11, August 2001 (emphasis added). The report is available on-line at http://ntp.niehs.nih.gov/ntp/htdocs/liason/LowDosePeerFinalRpt.pdf.

⁶ EPA Statement Regarding Endocrine Disruptor Low-Dose Hypothesis,
March 26, 2002.