Our Stolen Futurea book by Theo Colborn, Dianne Dumanoski, and John Peterson Myers
 
 

 

  Murray, TJ, MV. Maffini, AA Ucci, C Sonnenschein
and AM. Soto. 2006. Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reproductive Toxicology 23: 383-390.

Context
What did they do?
What did they find?
What does it mean?

News coverage of bisphenol A

More news about
 

Murray et al. report that prenatal exposure to bisphenol A causes breast cancer in adult rats. Prior work had shown that bisphenol A (BPA) altered the growth of mammary tissues in ways that increase the risk of breast cancer and increase the sensitivity of breast tissue to cancer causing agents.

This new result confirms and extends that earlier research. At all levels tested, from 2.5 µg/kg/day to 1000 µg/kg/day, exposure leads to the formation of aberrant cell growth patterns called ductal hyperplasias, which both in people and in rodents are considered to be the precursors of breast cancer. At the two highest levels, fetal exposure to bisphenol A was sufficient to cause breast cancer in the adults at just 95 days of age.

Other research suggests that the lower doses used in this experiment are within the range of daily human exposure to bisphenol A. The lowest level to cause cancer directly was only 5 times above the current EPA and FDA standard for safe exposure, 50 µg/kg/day. Critics of research on bisphenol A's regularly are quoted in newspapers asserting that the levels required to cause adverse effects are hundreds to thousands of times above human exposures. This clearly is not the case in this experiment.

What did they do? Murray et al. exposed pregnant female rats to a range of exposures of bisphenol A, from 2.5 µg/kg/day to 1000 µg/kg/day. Delivery was via a tiny pump implanted in the female. The bisphenol A was dissolved in dimethyl sulfoxide. Pumps implanted in the control animals delivered only dimethyl sulfoxide.

The research team tracked weights of the litters, measured anogenital distance in pups, and monitored time to puberty. Then at 50 days after birth, some of the females were sacrificed for histological examinations of mammary tissue. Another group was sacrificed at 95 days.

What did they find? When Murray et al. examined the mammary tissue of 50-day old females microscopically, they found a 3-4 fold increase in ductal hyperplasias in all animals exposed to BPA (figure to right). While all dosed animals had significantly more hyperplasias than controls, the treated animals did not differ from one another.

Graph to right: Percent hyperplastic ducts in mammary glands of 50-day old female rats, at different levels of exposure. Vertical bars are standard errors of the mean.

Hyperplastic ducts

Adapted from Murray et al.

 

Hyperplastic ducts at age 95 days  

By day 95, the percentage of hyperplastic ducts had decreased, with only the lowest dose of BPA showing a statistically significant increase compared to controls. Non-monotonic dose response curves like this have been found regularly in work with BPA.

Graph to left: Percent hyperplastic ducts at age 95 days.

In animals treated with the two highest levels, 250 and 1000 µg/kg/day, Murray et al. found cancerous lesions called carcinomas in situ, or CIS in the mammary glands. At 50 days of age, 25% of animals treated at those levels had CIS. This increased to 33% of animals by day 95.

When Murray et al. examined the density of estrogen receptors in the animal's mammary ducts, they found the hyperplasic ducts had an increased number of cells that tested positively for estrogen receptor α. This means that the cells were more sensitive to estrogen than those in the untreated animals. Histochemical analysis revealed higher rates of cell proliferation in the lesions. Both these tests are consistent with increased risk of breast cancer.

They found no effect of exposure on weight or on time to puberty. Males exposed in the womb had smaller anogenital distances.

Critics of research finding low level effects of BPA often assert, based on now out-of-date science, that BPA is merely a weak estrogen. That is contradicted not only by the 100+ studies that demonstrate adverse effects following exposure to low doses of BPA, but also by mechanistic studies that via an estrogen receptor on the cell's outer membrane, BPA is just as powerful as estradiol (the common human form of estrogen) and capable of altering cell signaling down to 0.23 parts per trillion.

  What does it mean? These experiments show that exposure to bisphenol A causes adult mammary cancers in rats exposed in the womb. All doses caused 'neoplastic' changes that set the stage for later cancers. The highest doses actually caused cancer. These results present a serious challenge to the safety threshold currently accepted by both the EPA and the FDA.

The current safety threshold, called the 'reference dose,' was set based on animal experiments showing that 50 milligrams per kg body weight caused weight loss in rodents. This was declared the 'lowest observed adverse effect level,' or LOAEL. Lower doses were not tested, so it wasn't possible to say, on the basis of those experiments, what exposure level caused no effect (what toxicologists call the 'no observed adverse effect level,' or NOAEL). A NOAEL is usually the basis of calculating a reference dose, with safety factors applied to take into account species differences and other sources of uncertainty. To arrive at the current official reference dose, it was assumed without further study that a dose 1000 times lower than 50 mg/kg/day, i.e., 50, µg/kg/day would be an acceptable reference dose. Applying this simplistic logic to the data from this experiment, would lead to a reference dose of 1/1000th of 250 µg/kg/day, or 250 nanograms/kg/day. That would lower the acceptable safety threshold by a factor of 200.

Murray et al.'s experiments, however, complicate this calculation. They found adverse effects (increases in ductal hyperplasias) down to 2.5 µg/kg/day. In other words, every level they tested, including the lowest, caused adverse effects. This means their research did not identify a NOAEL.

Earlier studies by the same research group have shown adverse effects down to 25 ng/kg/day, the lowest level they tested. Their exploration of the lower limits of exposure to date have failed to identify any level of BPA that does not cause an adverse effect (if one accepts the increase in risk of mammary gland tumors as an adverse effect). If EPA were to use 2.5 µg/kg/day from the current experiment as a LOAEL and apply the same logic used to establish the current standard, the reference (safe) dose would be 2.5 ng/kg/day.

If EPA were to use 25 ng/kg/day as the LOAEL, using the same logic the reference dose would become 25 picograms/kg/day. This would likely eliminate almost all commercial uses of BPA, especially in applications that put BPA-based materials in contact with food or water, or that are likely to come near babies's mouths.

Cell studies of BPA show major changes in cell signaling down to 0.23 parts per trillion. This is the lowest dose that has ever been tested, and it caused biologically important effects. With six billion pounds of BPA produced each year, no wonder there is such resistance to these low level results.

 

 
   
   

 

 

 

OSF Home
 About this website
Newest
Book Basics
  Synopsis & excerpts
  The bottom line
  Key points
  The big challenge
  Chemicals implicated
  The controversy
  Recommendations
New Science
  Broad trends
  Basic mechanisms
  Brain & behavior
  Disease resistance
  Human impacts
  Low dose effects
  Mixtures and synergy
  Ubiquity of exposure
  Natural vs. synthetic
  New exposures
  Reproduction
  Wildlife impacts
Recent Important    Results
Consensus
News/Opinion
Myths vs. Reality
Useful Links
Important Events
Important Books
Other Sources
Other Languages
About the Authors
 
Talk to us: email