In summary, a comprehensive up-to-date analysis by regulatory agencies is needed to evaluate the potential hazards to humans from exposure to BPA at doses below the prior LOAEL of 50 mg/kg/day; low doses of BPA have now been reported to alter brain chemistry and structure, behavior, the immune system, enzyme activity, the male reproductive system, and the female reproductive system in a variety of animals, including snails, fish, frogs, and mammals. There are also a number of in vitro
studies showing that the particular type of ER (α or β) and the specific coregulators present in cells can markedly influence the dose of BPA required to stimulate a response (e.g., Routledge et al. 2000
). This is consistent with estrogen-responsive tissues within the same animal showing marked differences in the dose of BPA required to elicit a response.
Not all effects of BPA are mediated by the classical nuclear ERs (α and β). Very low part-per-trillion doses of BPA can stimulate responses in cultured mouse pancreas cells, rat pituitary tumor cells, and human breast cancer cells via rapid induction of calcium uptake (Quesada et al. 2002
; Walsh et al. 2005
; Wozniak et al. 2005
); these same low doses of BPA stimulate proliferation in mouse (Gupta 2000
) and human (Wetherill et al. 2002
) prostate cells in culture. Nongenomic cell signaling systems involve serial activation of kinases via ligand binding to receptors associated with the cell membrane, and these pathways are known to have tremendous amplifying capacity.
In the now outdated perspective of the HCRA report (Gray et al. 2004
), it was stated that “In the case of BPA the only proposed mechanism for low-dose effects is through modulation of the [nuclear] estrogen receptor.” Instead, the recent findings concerning the multiple mechanisms of action of BPA show that at concentrations < 1 ppt, BPA activates receptors associated with the plasma membrane of selected target cells. As the BPA “dose at target” increases, various responses in the same or different cells are activated or inhibited (MacLusky et al. 2005
), with the specific dose required being dependent on the subtype of nuclear ER and specific coactivators or coinhibitors that are present. At even higher concentrations (parts per billion to parts per million), inhibition of androgen-stimulated and thyroid-hormone–stimulated responses can also occur. That the integrated output across a 1-million-fold dose range can be nonmonotonic (inverted-U shape) is thus not unexpected by scientists who study hormones and hormonally active drugs or chemicals (Welshons et al. 2003
). Regulatory agencies that conduct risk assessments have not addressed the implications of nonmonotonic dose–response curves for endocrine-disrupting chemicals with regard to the linear-threshold model currently used to predict “safe” doses for humans.
The in vitro
findings at low (and even sub) part-per-trillion doses of BPA have to be viewed in relation to potential effects of free (unconjugated and unbound) BPA levels in human blood. Data from numerous studies show that unconjugated BPA in human blood and tissues is in the low part-per-billion range (Endocrine Disruptors Group 2005
) and that BPA shows limited binding to human plasma binding proteins that regulate the uptake of estrogenic chemicals into tissues (Nagel et al. 1999
). Importantly, new analytical methods have been developed since the published literature was reviewed in 1998 for the last BPA risk assessment conducted by the European Union (ECB 2003
). These new methods have now made it possible to detect BPA in blood within the range that it shows biologic activity, which was not previously the case. There is thus convincing evidence that biologically active levels of BPA in human blood are above the range that has been demonstrated to cause changes in function in human tissues based on in vitro
The literature we reviewed shows that the rate of leaching from commonly used BPA-containing products (the lining of tin cans and polycarbonate food and beverage containers) is high enough to result in adverse effects in laboratory animals (Raloff 1999
). These recently published findings indicate that the accepted migration limit [recently set by the European Union (ECB 2003
)] of 30 ppb BPA from polycarbonate or resins into food and beverages is not sufficiently protective of human health. The case–control study reporting that ovarian disease in Japanese women is related to blood levels of BPA provides a first confirmation of this prediction in adult humans (Takeuchi et al. 2004
Almost one-half of the low-dose BPA studies have been published in just the last 2 years, and there were only five published low-dose BPA studies as of 1998 when the initial comprehensive literature search was conducted for the last risk assessment conducted by the European Union (ECB 2003
). A thorough analysis of the entire published low-dose BPA literature associated with a new risk assessment by regulatory agencies that takes into account the issues discussed here and elsewhere is now warranted (vom Saal 2005
; vom Saal and Sheehan 1998
; vom Saal et al. 2004
, in press; Welshons et al. 2003
). It is important that a reexamination of the BPA low-dose literature include a discussion of the requirement for appropriate positive controls, which was identified by the NTP panel as a significant problem in studies claiming to find no low-dose effects.
The initial NTP review concerning BPA as a carcinogen concluded that “there was no convincing evidence that [BPA] was carcinogenic,” because the background level of cancer was high in untreated males (NTP 1982
). This conclusion has been criticized by a scientist in the NTP: Huff (2002)
concluded that, if these findings (NTP 1982
) were officially reanalyzed based on the approach to interpreting cancer in animal studies used today, BPA would be interpreted as being associated with an increase in tumors of blood cells, the testes, and the mammary glands.
In summary, a new risk assessment is needed to establish a new LOAEL and a new reference dose for BPA based on the extensive new information from low-dose studies. In addition, the low-dose literature for BPA and other endocrine-disrupting chemicals shows that regulatory agencies need to begin the process of reevaluating the assumptions that provide the basis for the linear-threshold model used in risk assessments.