CHE’s Top 10 Environmental Health Stories, October through December 2012

For our second quarterly Top 10 list, we again selected news articles, journal articles, policy decisions and events that we consider “game-changers” in one way or another: they all have had a significant impact, or are likely to have a significant impact on thinking and action in the field; they’ve changed the conversation on a topic or expanded the scope of the conversation to a new audience or awareness; and/or they are likely to be pivotal in defining a new trend.

These were selected from several dozen candidates for this list:

  1. Workshop ‘Low Dose Effects and Non-Monotonic Dose Responses for Endocrine Active Chemicals’
    This groundbreaking international meeting in September moved the conversation about low-dose effects from endocrine disrupting chemicals significantly forward in re-examining the ways in which chemicals are tested for endocrine disrupting properties and how risk to human health is managed.
    See also a report from the World Health Organization: Endocrine disrupters and child health; movement from the EPA: EPA responds to scientists’ concerns, initiates new effort for low-dose, hormone-like chemicals and an article in Nature magazine: Toxicology: the learning curve.
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Review of the Berlin Workshop Concerning Low Dose Effects and Non-monotonic Dose response for EACs (Endocrine Active Chemicals)

Sharyle Patton
Director of CHE Special Projects

Read more about this workshop held September 11 – 13, 2012.

The official workshop report will be published in a few weeks by workshop organizers, but I want to give you a sense right away of the nature and content of discussions.

First, the workshop successfully brought together experts and researchers in toxicology, endocrinology and epidemiology with European risk assessment regulators to discuss the implications of low dose effects and non-monotonic dose response curves for risk/safety assessment—or, endocrinology meets toxicology. If exposures to toxic chemicals at the low levels currently measured in the environment can cause harm through endocrine disruption, then risk assessment may need to change its approaches to toxicity testing.

Members from the chemical industry and the public interest community also participated in the workshop discussions, but the focus of discussion for all was the possibility of integration of the principles of endocrinology into current risk assessment practices and whether such integration requires a major overhaul of standard risk assessment or whether a few tweaks here and there might be sufficient.

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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.