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US and Japanese Regulatory Agencies View the Low-Dose Hypothesis as Unproven

May 2, 2002

What is the Low-Dose Hypothesis?

In recent years, a hypothesis has been advanced claiming that exposure to extremely low doses of certain substances could cause adverse health effects in humans, including disruption of normal hormonal functions. According to this “low-dose hypothesis”, health effects occur at doses far below levels previously determined to be safe using well-established toxicological procedures and principles. The hypothesis further asserts that the dose-response relationship for these substances is “non-monotonic”, which means that health effects may only be observed at low doses while much higher doses result in no effects. The claimed non-monotonic dose-response relationship of the low-dose hypothesis is contrary to a fundamental principle of toxicology – “the dose makes the poison”.

US and Japanese Regulatory Agencies View the Low-Dose Hypothesis as Unproven

Governments worldwide have closely monitored and assessed the scientific evidence on the low-dose hypothesis. In the United States, the Environmental Protection Agency (EPA) released a statement on March 26, 2002 with their view of the low-dose hypothesis.¹ This statement is based on EPA’s assessment of the conclusions of an independent peer review of the low-dose hypothesis that was conducted by the U.S. National Toxicology Program (NTP).² Significantly, EPA refers to the claimed low-dose phenomenon as still a “hypothesis”, which in science is a postulate that has not been proven to be valid. Because the low-dose hypothesis has not been proven, EPA appropriately concluded, “it would be premature to require routine testing of substances for low-dose effects.”

The Japanese Ministry of Health, Labor and Welfare (MHLW) has also recently released a report from an expert review committee that has been evaluating the potential risks of endocrine disrupting chemicals.³ After evaluating experimental reports on low-dose endocrine disruption, the expert committee concluded, “no reproducible experimental results have been obtained, and at this point of time, it is doubtful whether we can conclude that there are endocrine disrupting effects in the low dose range.”

The EPA and MHLW assessments that the low-dose hypothesis has not been proven to be valid are fully supported by the weight of scientific evidence. The low-dose hypothesis has been tested repeatedly with large, well-designed scientific studies that followed internationally accepted GLP (Good Laboratory Practice) standards and were specifically designed to look for health effects from low doses of substances that have been claimed to cause low-dose effects. The wealth of data from these studies clearly shows that the low-dose hypothesis has not been demonstrated to be valid.

Weight of the Scientific Evidence Shows No Low-Dose Effects from Bisphenol A

One of the substances claimed to cause low-dose effects is bisphenol A (BPA), which is used to make polycarbonate plastic and epoxy resins. The NTP peer review panel that provided scientific input to EPA specifically evaluated the scientific evidence for low-dose effects from BPA and 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." ⁴

The totality of evidence on which the overall conclusion of the NTP panel was based most notably included a series of six comprehensive studies conducted by five different independent research entities, including the Japanese government, that were specifically designed to look for health effects from low doses of BPA. In every study, no low-dose effects were found and the validity of the low-dose hypothesis was not confirmed. The weight of scientific evidence clearly demonstrates that there is no basis for health concerns from low doses of BPA, which is fully consistent with the EPA and MHLW conclusions.

References

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

2 National Toxicology Program's Report of the Endocrine Disruptors Low Dose Peer Review, August 2001, available on-line at http://ntp.niehs.nih.gov/ntp/htdocs/liason/LowDosePeerFinalRpt.pdf. The NTP peer review was intended to evaluate the scientific evidence on reported low-dose effects and provide scientific input to EPA on the need to modify standard reproductive and developmental testing guidelines to detect potential low-dose effects.

3 “The Interim Risk Assessment Report by Review Committee Meeting of MHLW Regarding Hazards to Human Health of Endocrine Disrupting Chemicals”, Office of Chemicals Safety, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labor and Welfare, December 26 2001 (translated from Japanese).

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