Sarah Vogel, Ph.D., is Director of EDF's Health Program.
Add liver cancer—a childhood cancer on the rise in the US—to the growing list of potential health effects associated with bisphenol A (BPA) exposure that are under scrutiny by researchers. A recent study by scientists at the University of Michigan, published in Environmental Health Perspectives, is the first ever to report a dose-dependent, statistically significant relationship between perinatal (before and just after birth) exposures to environmentally relevant levels of BPA and development of cancerous liver tumors later in life.
There are three particularly notable features of this study: first, the dose levels used; second, the timing of when those doses were delivered; and third, the age at which effects were observed.
Groups of female mice were exposed throughout pregnancy and lactation to one of three doses of BPA given through their food. The pups of these exposed mice were then followed for 10 months—the equivalent of about 25 years of age in humans. The doses of BPA used span the range of human exposures to BPA: 0.1-5 micrograms/kilogram body weight/day). [The doses used were 50 nanograms per kilogram body weight (ng/kg bw), 50 micrograms (µg)/kg bw and 50 milligrams (mg)/kg bw of mice feed, corresponding to an estimated BPA daily exposure of 10ng, 10µg and 10mg/kg bw/day, respectively.]
This dose range also includes exposures above and below the current BPA safety standard of 50 µg/kg bw/day. The safety standard was first established by the EPA in 1988, and was based on a 2-year cancer study commissioned by the National Toxicology Program (NTP). The NTP study, conducted from 1977 to 1979 and released in 1982, reported somewhat ambiguous findings, but ultimately concluded that there was “no convincing evidence” of carcinogenesis. In setting the safety standard for BPA, EPA relied on this study to determine the “lowest observable adverse effect level” (LOAEL) and then divided by 1,000 to account for uncertainty inherent in extrapolating results from rodents to humans and accounting for variability of response in the human population.
As a colorful, historical footnote, it turns out that at the time of the study, the contract laboratory conducting the research was being investigated by the government and was later found to have extremely poor laboratory conditions, resulting in the cancellation of the government contract.
While the Food and Drug Administration (FDA) now relies on more recent studies to defend the still-used 50 µg/kg bw/day safety standard, the standardized protocol for investigating carcinogenicity is the same as it was in the 1970s: adult animals are exposed continuously for two years to relatively high doses of a chemical. By contrast, the Michigan cancer study used real-world levels of exposure, doses 20-200 times lower than those in the NTP study, and looked for long-term effects not in the adult animals but rather in their offspring.
In addition, the offspring were followed for 10 months, which is quite a long time for a perinatal exposure study. By following the animals for as long as they did, the Michigan researchers were able to look for longer-term health effects of perinatal exposures to low doses of BPA. Had they stopped the study earlier—at weaning (around 21 days) or even 90 days—they might have missed the carcinogenic effects.
Other perinatal exposure studies have reported precancerous lesions in the prostate (Prins et al., 2008) and mammary glands (Vandenberg et al., 2008), but this is the first study to report fully cancerous tumors in any organ in response to BPA exposure
The importance of timing of exposure to potential hormonal carcinogens has been well understood since the early studies of the synthetic estrogen, diethylstilbestrol (DES), dating from the 1970s and 1980s, which found that daughters born to women who took DES during pregnancy were at a greater risk of developing a rare vaginal cancer and other reproductive problems later in life.
So what are the implications of this new study?
For starters, given that the study found a statistically significant increase in liver tumor risk with increasing dose, long-held presumption of a threshold effect for BPA at low doses needs careful re-examination. If, indeed, BPA is carcinogenic at doses well below the current safety standard level, it certainly means the safety standard is not in fact safe and needs to be adjusted.
FDA has been waiting for the completion of a series of long-term studies, expected to be finished in the next several years, before revisiting its current standard. A new cancer study should cut the cue and reignite a fire under the agency.
It should be noted that a just-released study by the FDA on BPA found no adverse effects at low doses. Animals in this particular study were exposed during pregnancy to BPA (given orally via gavage or forced feeding) and the offspring were followed for 90 days. The study has been criticized, however, due to the presence of BPA in the supposed no-exposure control animals. But it also differs markedly from the Michigan study in that effects were looked for after only 90 days as opposed to 10 months.
The adequacy of the current BPA safety standard has been a topic of controversy and debate for over a decade. While the FDA stands by its assessment and the current standard, the European Food Safety Authority has recently recommended a temporary reduction in the safety standard from 50 to 5 µg/kg bw/day, based on new studies of low-dose effects on the liver, kidney and mammary gland.
What I find most interesting and alarming about the Michigan study, is that it addresses a critical question at the heart of the current debate: Can low-dose exposures to BPA during critical developmental periods result in adult disease? That the authors found a statistically significant increase in cancerous liver tumors at all doses tested should raise considerable concern.