May 7, 2012

expert reaction to research into Bisphenol A and monkey mammary gland development

Pregnant rhesus monkeys exposed to the chemmical bisphenol A (BPA) developed altered mammary glands, a study in Proceedings of the National Academy of Sciences reports.

Professor Warren Foster, Department of Obstetrics & Gynecology, McMaster University, said:

“The paper by Tharp et al., 2012 examined the effect of developmental exposure to Bisphenol A (400 ug/kg BW) given from gestational day 100 to term in rhesus monkeys. At birth the mammary glands were removed and examined either by whole mount or histomorphometry and immunohistochemistry for estrogen receptors. The paper has a number of strengths which include the use of a non-human primate model that more closely reflects human development and physiology. In addition, the animals were exposed via an oral route to the test compound and the methods of analysis are appropriate for the stated objectives.

“There are several weaknesses with this paper which include but are not limited to the small sample size. It is appreciated that non-human primate studies are expensive and difficult to run, yet four and five animals/group is not robust and it is difficult to extrapolate the findings to the larger population. Furthermore, the authors state that their dosing paradigm resulted in blood concentrations of free BPA that are representative of the human population as summarized in the Vandenberg and colleagues review paper. However, the exposure to BPA is not representative of how humans are exposed. Specifically, the monkeys received a single high dose exposure which, at the time samples were collected, produced a circulating concentration that was representative of human serum concentrations. Note that the serum concentrations in human studies are in the range quoted in this study in small biomonitoring studies, whereas more recent larger studies show lower median concentrations. Moreover, humans are primarily exposed to BPA through the diet to low concentrations of BPA. Of note a recent pharmcokinetic study conducted by Teegaurden and colleagues shows that people consuming meals with relatively high concentrations of BPA did not result in detectable concentrations of BPA in their circulation, while conjugated BPA was measured in the urine. Hence, a large bolus of BPA administered once during the day can result in very high circulating concentrations of free BPA in the serum that fall through the concentration reported in biomonitoring studies but may not necessarily be reflective of how people and tissues are exposed. Other minor criticisms may arise from the use of a single dose and the absence of a positive control group for comparison. Finally, the results demonstrate premature development of the mammary gland but do not demonstrate any pre-cancerous lesions.

“Overall, this is a scientifically sound paper that extends the findings in rodents to the non-human primate. The results do not however suggest that BPA is a carcinogen or that it is implicated in breast cancer. Furthermore, the dosing paradigm is not representative of human exposure which make generalization of the study results to humans difficult.”

Professor Richard Sharpe, MRC Centre for Reproductive Health, Edinburgh University, said:

“This preliminary study shows that fetal exposure of rhesus monkeys to high levels of bisphenol A (a weakly oestrogenic chemical) may result in an increase in terminal end buds in mammary glands at birth (the only significant finding). It is unlikely the effects described have any health implications for humans, for two reasons.

“First, the exposure levels of BPA used in this study are 400- to 4000- times higher than exposure of the normal human population. Levels of unconjugated (biologically active) bisphenol A in blood in humans are so low they cannot be measured; this is probably because ingested bisphenol A is rapidly inactivated during absorption from the gut.

“Second, at birth in humans breast tissue is enlarged (boys as well as girls) because of exposure to the extremely high pregnancy levels of oestradiol. Additional exposure to minimal amounts of bisphenol A (more than 1000 times less potent than oestradiol) is unlikely to add significantly to this.

“Similar effects on mammary terminal end buds have been shown in laboratory rats exposed to bisphenol A, but again at exposure levels many times higher than in humans (as in the monkeys). However, even then no adverse long-term effects (eg mammary cancer) from exposure to bisphenol A alone have been shown to result.”

Statistical note:
“This is an extremely small study (N=4, 5) and terminal end bud number varied hugely in controls and overlapped with values for bisphenol A-exposed animals. This could mean the present findings are due entirely to chance.””

‘Bisphenol A alters the development of the rhesus monkey mammary gland’ by Tharp et al., published in PNAS on Monday 7 May.