BPA Exposures in the Human Fetus

Ted Schettler, MD, MPH
Science Director

Nahar MS, Liao C, Kannan K, Dolinoy DC. (2012), Fetal liver bisphenol A concentrations and biotransformation gene expression reveal variable exposure and altered capacity for metabolism in humans. Journal of Biochemical and Molecular Toxicology. doi: 10.1002/jbt.21459

This recently published study shows that the developing fetus is generally exposed to much higher levels of free (unconjugated) BPA than to conjugated BPA. In 78% of the samples, the ratio of free to conjugated BPA was greater than one with a mean of 6.91. (the authors undertook a number of efforts to avoid sample contamination, as described in their paper).

Previous studies have shown free BPA in amniotic fluid.

This adds to the growing evidence that the fetus is regularly exposed to free (active) BPA; that the chemical is not rapidly inactivated and excreted as in adults. Efforts to control BPA exposure in infants and children do nothing to protect the fetus…The fetus can only be protected by reducing/eliminating exposures in adults.

Animal studies show that fetal and perinatal exposures to BPA alter the development of the mammary gland and prostate, making them more likely to develop cancer later in life. Over 93% of Americans have measureable levels of BPA/BPA metabolites in their urine….i.e. exposures are ubiquitous. Based on the animal data, we continue to expose virtually the entire human population to a chemical that increases the risk of breast and prostate cancer. When will this stop?

The Effect of Environmental Chemicals on Insulin Production: Implications for All Types of Diabetes

Sarah Howard
Coordinator of CHE’s Diabetes-Obesity Spectrum Working Group

In a recent review, published in the leading diabetes journal Diabetologia, Hectors et al. (2011) describe how numerous environmental chemicals affect the insulin-producing beta cells of the pancreas. These effects, the authors argue, may be significant in the development of type 2 diabetes. Chemicals like bisphenol A, PCBs, dioxin, organophosphorous pesticides, arsenic, heavy metals, and others, can all affect how the beta cells function, and can interfere with their capacity to secrete insulin.

In type 2 diabetes, both insulin resistance—the body’s inability to respond correctly to insulin—and beta cell malfunction contribute to the disease. The inability of the beta cells to produce enough insulin leads to high blood glucose levels, and eventually diabetes (in many people with type 2, insulin production is higher than normal, to compensate for the insulin resistance—but it is still inadequate to bring blood glucose under control).   

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Early Puberty: Another Sign of Our (Chemical) Times?

Elise Miller, MEd

A major study released earlier this week in Pediatrics concluded that girls are starting puberty earlier than ever. (See the New York Times article or the full text of the study). Though early puberty is influenced by multiple and interacting factors, including heredity, socioeconomic status, obesity, premature birth, formula feeding and more, synthetic chemicals, particularly those that can disrupt our bodies’ normal hormonal messaging systems from conception onward, are increasingly considered contributors to this growing concern.

Controversy about whether earlier puberty was in fact happening was significantly heightened after a study suggesting similar findings was published in Pediatrics in 1997. However, questions about the association between chemical exposures and health problems from breast cancer to reproductive abnormalities can easily be dated back to the time of Rachel Carson’s research. Dr. Sandra Steingraber’s 2007 report, “The Falling Age of Puberty: What We Know, What We Need to Know,” commissioned by the Breast Cancer Fund, was based on a comprehensive review of the literature on the timing of puberty. Given the scientific evidence, the report recommended a set of actions—from improving the built environment to encourage physical activity to making healthy food more accessible to reducing the use of endocrine disrupting chemicals, such as phthalates and bisphenol A, in consumer products. What is notable about these recommendations is that they could curb not only the worrisome implications of earlier and earlier puberty, but a plethora of other chronic diseases and disabilities that currently plague our country.

Given it is far harder to turn an ocean liner around than a row boat, many leading thinkers underscore the need for creative solutions to be generated on the community level in order to develop effective, sustainable models. One such person is Wilma Subra, a leading resource scientist for low-income communities in the Gulf Coast. Michael Lerner will interview Dr. Subra on our CHE Partnership call tomorrow (visit the call page to RSVP). Other leaders emphasize that reforming our chemical regulatory system on a national level must be a priority. Action is also being taken along those lines with the introduction of “Toxic Chemicals Safety Act” in the House just late last month (see CHE’s Chemical Policy Reform webpage).

At whatever level you choose to approach this work, the study on early puberty published in Pediatrics this week only affirms that we, in fact, already know what we need to do. The harder part is how to do it—how to implement effective and strategic interventions at all these levels of society. As a CHE partner, we hope you will continue to participate in our calls and working groups to help us collectively figure out what we can do now to ensure that health is a birthright, not an afterthought.

Can Environmental Contaminants Contribute to the Development of Diabetes?

Sarah Howard
CHE Partner

There is a well-documented and unexplained increase in the incidence of type 1 diabetes in children around the world, and alarmingly, this increase is most rapid in children under age 5. Type 2 diabetes shows a parallel increase, and is also now appearing even in children. About 6.4% of the world’s adults have diabetes – that’s 285 million people. Health expenditures due to diabetes are estimated to be $376-672 billion US dollars in 2010 worldwide, about 12% of total health expenditures, and this figure does not include expenditures on children with diabetes.

Type 2 is the most common type of diabetes, and the type normally associated with obesity and insulin resistance. Type 1, formerly called juvenile diabetes, is an autoimmune disease where the insulin-producing beta cells of the pancreas are destroyed. There are a number of similarities between type 1 and 2 diabetes, and intermediate types exist as well (such as Latent Autoimmune Diabetes in Adults (LADA), also known as “type 1.5”). For example, dysfunctional beta cells are present in both type 1 and type 2 diabetes, and about 10% of people with type 2 test positive for the autoantibodies characteristic of type 1. Excess weight gain and increased insulin resistance have been associated not only with the development of type 2 diabetes but also with type 1. Women who develop gestational diabetes, meanwhile, are at risk to develop either type 1 or type 2 after pregnancy. Many authors propose that type 1 and type 2 can be thought of as two ends of a “diabetes spectrum,” an idea consistent with findings of genetic susceptibility to these diseases.

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Does “the Dose Make the Poison?”

John Peterson Myers, PhD
CEO of Environmental Health Sciences

A core assumption of traditional toxicology is “the dose makes the poison.” Generations of toxicologists have begun their studies by learning this, countless experiments have provided support, and the laws protecting people from undue exposure all assume that it is true.

“The dose makes the poison” is taken to mean that the higher the dose, the greater the effect. And this implies that low exposures are less important. Indeed, based on “the dose makes the poison”, it is commonly argued that “background” levels of contamination aren’t worth worrying about.

Yet new evidence emerging from modern scientific research that combines toxicology, developmental biology, endocrinology and biochemistry is demonstrating that this assumption is wrong, at least in its simplest and most-widely used form. And the implications for this new realization are profound, because it means that the safety standards used to protect public health are built upon false assumptions and likely to be inadequate.

Two core patterns in this emerging research violate simplistic uses of “the dose makes the poison.”

  • One arises because sensitivity to contamination is not the same at all stages of the life of an individual. The same low dose that may pose no risk to an adult can cause drastic effects in a developing fetus.
  • The second involve dose-response curves in which low levels of a contaminant actually cause greater effects than higher levels, at the same stage of development. These dose-response curves, shaped like inverted-U’s, are called “nonmonotonic dose-response curves.”

Both of these patterns require a more sophisticated view of what it means for “the dose makes the poison.”

In the case of sensitivity varying from one stage of development to the next, “the dose makes the poison” is valid as long as one doesn’t wrongly assume that measurements at one stage can be extrapolated to another. The assumption holds true (as long as there is no nonmonotonic dose response curve, see below) within a stage of development, but not among them.

A recent dramatic example of this differential sensitivity was found in work comparing the impact of an herbicide on tadpoles vs. frogs. In frogs, the change from tadpole to frogs is exquisitely sensitive to chemical disruption of development. A dose of atrazine (a commonly used herbicide) 30,000 times lower than the lowest level known to affect adult frogs caused 20% of tadpoles to become hermaphroditic (containing both male and female sexual organs) in adulthood.

This pattern seen in frogs is not an exception. The scientific literature is full of examples demonstrating that in its early stages of development and organism can be more vulnerable than during adulthood. Thus it is important to realize that “the adult dose does not make the fetal poison.”

Inverted-U or nonmonotonic dose-response curves (NMDRCs) provide a more difficult challenge to the traditional interpretation of “the dose makes the poison,” i.e., that higher doses have greater impacts to lower doses. In NMDRCs, lower doses can have larger impacts than higher doses. One recent example arose in work on proliferation of prostate tumors:

A very low dose (1 nanomolar) of bisphenol A induces a stronger response than a much higher dose (100 nanomolar). The response to 1 nM is significantly greater than the control. 

Many examples of NMDRCs are now being published in the scientific literature (more). This raises three questions:

Why were they not found commonly before? Several factors may have contributed to the infrequency with which NMDRCs were reported previously in the scientific literature.

  • One may be simply that few scientists looked. Driven by “the dose makes the poison,” toxicologists would perform experiments at higher doses and work down the dose-response curve until they found a level at which no response was detectable. Experiments at doses 1/10th to 1/100th of that no-response level made no sense. But without experiments at much lower doses, the low-dose effects of NMDRCs could not be detected.
  • A second impediment arose from the statistical design used to analyze results in toxicology. Designs built on the assumption that “the dose makes the poison” are unlikely to find NMDRCs.

Why do they occur? This is an active area of research. Several ideas have been offered.

  • One is that within the range of very low doses showing NMDRC patterns, enzymatic defenses against chemical contaminants are not activated. The supposition here is that at these very low levels, the contaminants are at levels that are within the range where their biological activity resembles the normal hormonal mechanisms controlling development. As contaminant levels rise, defense mechanisms are activated, shutting down the original response.
  • Another is that as the low dose rises into a higher range, the contaminant stimulates new responses, perhaps activating different hormonal pathways that then operate in a negative feedback loop to shut down the system involved in the original response.

What do they mean for public health? NMDRCs are extremely troubling for regulatory toxicology because their presence undermines the validity of generations of toxicity testing that have been based on the assumption that “the dose makes the poison.” Prevailing federal safety standards are built upon research methods that are unlikely to find low-dose effects, and very few chemicals have been tested in ways that would reveal them.

For that reason NMDRCs were the subject of intense debate among scientists as it became clear they were not uncommon. The US National Toxicology Program went so far as to convene a special “low-dose panel” of scientists to conduct a full scale review. The panel’s findings, published in 2001, confirmed the reality of NMDRCs.

So what do NMDRCs mean for “the dose makes the poison”? In a literal sense, the dose still does, as for example, in the graph of prostate tumor proliferation above: A dose of 1 nanomolar bisphenol A produces a different response than does 100 nanomolar. Dose does matter. But with BPA and prostate proliferation, “a very low dose makes a higher poison.” It is no longer safe to assume that lower doses have lower impacts than higher doses. The science used to establish public exposure standards needs to incorporate this new concept.