Authors
Vom Saal FS and Hughes C.

Title:
An Extensive New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment.

Source:
Environmental Health Perspectives: 113(8):926-933, 2005.

Summary:
Bisphenol A (BPA) is a monomer of polycarbonate plastic and a known environmental estrogen that is used as a lining for most food and beverage cans, in hard plastic baby and water bottles, toys, dental sealants, and as an additive in other widely used consumer products. Heat and contact with acidic or basic compounds increases the rate of leaching of BPA into food and beverages which may result in adverse effects in laboratory animals (Raloff 1999) and humans (Takeuchi et al. 2004). In addition, another potential source of human exposure is water used for drinking and bathing (Kawagoshi et al.2003; Coors et al. 2003). Widespread human exposure to BPA recently has been shown by Calafat et al. (2005) who discovered that 95% of urine samples from people in the United States have measurable BPA levels (range, 0.4 ppb to 8 ppb) which are consistent with findings from other countries. According to the findings of Schonfelder et al. (2002) and Ikezuki et al.(2002), levels of BPA in human blood and tissues are also in the same range (0.1-10 ppb). Measurements of current human contamination indicate that exposure of human fetus of BPA already occurs at levels within the range demonstrated to cause adverse effects in fetal rodents (Schonfelder et al. 2002). A recently published case-control study (Takeuchi 2004) offered convincing evidence that the adverse effects at low doses of BPA should be of concern for human health. It was reported that ovarian disease and body fat in Japanese women were related to blood levels of BPA. BPA is one of the highest-volume chemicals produced worldwide (2,214,000 metric tons per year), it is recognized that the assessment and management of risk of adverse health effects from exposure to low doses of BPA is a high scientific and public health priority.

In the present paper, Vom Saal & Hughes discussed new experimental findings concerning the adverse effects of low doses of BPA reported in animals, the mechanisms mediating the effects, and recent epidemiological data showing the need for the re-evaluation of the potential health risks from exposure to low doses of BPA. According to Vom Saal & Hughes, by the end of December 2004 there were 115 published in vivo experimental studies concerning the adverse effects of low-doses of BPA, and 94 of these demonstrated significant effects at concentrations of BPA below levels of 50 mg/kg which is currently accepted as the lowest observed adverse effect level in laboratory animals (LOAEL) and was used to determine a safe daily dose for humans of 50 µg/kg/day (Reference Dose) (IRIS 1988).

Recently published experimental findings have shown that exposure of laboratory animals to low doses of BPA, with tissue levels of BPA within and even below the range of human exposure, significantly affects the rate of growth in both males and females and sexual maturation in females, alters plasma luteinizing hormone and testosterone levels, increases prostate size in male offspring, decreases daily sperm production and fertility in males, and affects fertility, immune function, enzyme activity in adult males, brain structure and brain chemistry, and behavior patterns. Many of these effects were reported due to exposure during early development (gestation and/or lactation) or post-weaning-through-adult exposure. The effects of BPA were often mediated by both genomic and non-genomic estrogen-response mechanisms, with disruption of cell function occurring at doses as low as 1 ppt (Wozniak et al.2005). The potential to disrupt thyroid hormone function has been reported by Moriyama et al. (2002) and Zoeller et al.(2005).

A key outcome of the present review was the verification of the presence of a non-monotonic (inverted-U shape) dose response function of target cells to very low BPA concentrations (parts per billion to parts per million). The controversial but observable fact is that low doses of BPA may actually cause a greater specific response of target cells, whereas much higher doses may inhibit the same response. The mechanisms mediating qualitative changes in response over a wide range of doses are now being elucidated at multiple levels, such as gene-response profile (Coser et al.2003), changes in tissue expression of receptors (Gupta 2000), and changes in neuroendocrine feedback systems (Rubin et al.2001; Telsness et al.2000). According to Vom Saal & Hughes, the new findings clearly demonstrate that extrapolation of "safe" doses from data on effects at high doses often is not valid for endocrine disrupting chemicals such as BPA and should lend a strong challenge to the traditional toxicological approach for chemical risk assessment based on linear-threshold dose responses model.

Vom Saal & Hughes also found that the positive findings of adverse effects to low doses of BPA reported in more than 90% of government-funded studies were significantly different from the 21 industry-funded studies that reported no adverse effect. Von Saal & Hughes suggested that some specific factors (other than source of funding), such as used of low-responsive animal models to endocrine active agents, lack of attention to the importance of appropriate positive controls, variability in components of commercial animal feed, and use of out-of-date experimental approaches may account for the differences in reported results.

In conclusion, Vom Sall & Hughes proposed that a new risk assessment is needed to establish a new LOAEL and a new reference dose of BPA and re-evaluate the potential human health hazard of exposure to low-doses of BPA based on 1) the extensive new literature reporting adverse effects in animals at doses below the current reference dose; 2) the high rate of leaching of BPA from food and beverage containers leading to widespread human exposure; 3) new findings that the median BPA level in human and human fetal blood is higher than the level that causes adverse effects in rodents; and 4) recent epidemiologic evidence that BPA is related to disease in women.

According to the new findings presented in this paper, it is clear that considerable work remains to be done at the laboratory and science policy level. Improvements in the use of existing data and predictive models are needed in order to strengthen the scientific foundation for evaluating low-dose response relationships for endocrine disruptors. This would allow for improvements in the establishment of a safe level of exposure to humans and reduce the risk of adverse health effects from endocrine disruptor chemicals to the population.

References:

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