Is it time to end concerns over the estrogenic effects of bisphenol A?

For more than a decade, there has been a heated controversy over whether or not the environmental chemical, bisphenol A, exerts adverse estrogenic effects in animal studies, and by extrapolation, in humans. In the present issue of Toxicological Sciences, Ryan et al. (2009) publish a detailed study that throws cold water on this controversy by showing complete absence of effect of a range of bisphenol A exposures perinatally on reproductive development, function, and behavior in female rats. Will this help to resolve the controversy? Before considering details of the study, and their implications, it is appropriate to consider the backdrop to these studies and the fundamental scientific issues on which they impact. If, like me, you are uninvolved in bisphenol A research, you may be puzzled by the seemingly never-ending controversy, as the scientific process usually sorts out what is right, given time. So why has this not happened? Therefore, without wishing to detract in any way from the impact and importance of the study by Ryan et al. (2009), I have tried below to evaluate the wider (scientific) aspects of this topic and to emphasize how the present study contributes to resolving some of the controversial issues. Let me begin with a dose of scientific philosophy. Anyone involved in biomedical research knows that scientific ‘‘facts’’ that remain untouched by the ravages of further research are a rare commodity. Usually, most facts change their form with time (evolve), and their meaning, and probably their importance, also will change. Disappointing as this may be for our scientific egos, it represents something far more important—scientific progress. It is inevitable that scientific progress, in the form of new facts, will trample over our bright ideas, hypotheses, and even over our results. This apparently destructive process is in fact constructive, and as scientists, we have to embrace this evolution and to accept that the sacrifice of our initial beliefs (and our precious results and our interpretations) is part and parcel of advancing understanding. I spout this scientific philosophy as it seems to me that research on bisphenol A has been trying to go through this process but has become literally bogged down in the mire of controversy, much of which stems from the earliest findings and seems to have little to do with the current state of the science. The study by Ryan et al. (2009) can be considered as another attempt to release bisphenol A research from the grip of the mire back into the normal pathway of scientific evolution. The results from Ryan et al. (2009) are unequivocal and robust and are based on a valid and rational scientific foundation. They tell us that, in vivo in female rats, bisphenol A is an extremely weak estrogen—so weak that even at levels of exposure 4000-fold higher than the maximum exposure of humans in the general population there are no discernible adverse effects, whereas the potent estrogen ethinyl estradiol (EE; the positive control) caused major adverse effects at doses used in earlier contraceptive pills and that were associated with increased risk of thromboembolism in women. In this particular study, the end points of interest were female reproductive development and function and several aspects of adult sex hormone–dependent behavior, but the results join with others from the same and other groups that show a similar absence of reproductive effects in male rats and mice when exposed orally to bisphenol A (Ema et al., 2001; Howdeshell et al., 2008; Tinwell et al., 2002; Tyl et al., 2002). These findings come from studies involving large numbers of animals and were conducted by recognized world expert groups. Yet, to judge from correspondence in the wider (nonscientific) media (blogs and environmental websites) on the publication by Ryan et al. (2009), this research is flawed and incorrect, for example, ‘‘because it uses an estrogen-insensitive rat strain,’’ which is patently not the case (see below). The latter argument has been used previously to ‘‘explain away’’ the lack of repeatability of many of the studies on bisphenol A (Myers et al., 2009), although it seems unlikely that the rather minor differences in