Toxicity and risk assessment of bisphenol A

[[abstract]]Bisphenol A (BPA) has been receiving increasing attention because of evidence of its reproductive toxicity in laboratory animal studies, the growing literature correlating environmental BPA exposure to adverse effects in humans, its high production volume, its widespread human exposure, and the potential health effects from such exposures. A particular concern is the possibility of low-dose effect and that nonmonotonicity of BPA would occur at doses lower than those used in regulatory toxicity studies, thus having an implication in toxicity testing and risk assessment for regulatory decision making. Several international regulatory agencies/scientific bodies have evaluated the health effects data and some have derived a no observed adverse effect level (NOAEL) of 5 mg/kg/day for BPA based on systemic effect in a two-generation study in mice. After considering biomonitoring and estimated intake data, they concluded that existing scientific evidence does not suggest that the very low levels of BPA dietary exposure in humans pose a health risk. In addition, the European Food Safety Authority (EFSA) has established a temporary tolerable daily intake (t-TDI) of 4 µg/kg/day based on the same study and changes in the mean relative kidney weight in male mice of the F0 generation assuming the BPA to be unconjugated as a conservative approach, with an additional uncertainty factor for other potential effects. There were no estrogen-dependent effects at and below the systemic no observable effect level (NOEL), and a reproductive/developmental NOEL of 50 mg/kg/day was derived based on effect in the testes of F1/F2 offspring. Different views have been expressed on the effects on the mammary gland, and reproductive, neurobehavioral, immune, and metabolic systems at low doses, and nonmonotonicity. The nonmonotonic dose-response curve (NMDRC) is characterized by a change in the sign of the slope, and the function can take on the shape of a U, the shape of an inverted U, or another shape that has more than one inflection point. This is different from the conventional monotonic dose-response curve showing a consistent incremental increase in effects with increasing doses, thus challenging the traditional toxicological dose-response principle. Although it is difficult to make causal links with epidemiological studies, existing data suggest the potential concern for low levels of exposure