Health & Environment

Are EDCs too swamped by the body’s own hormones to pose a threat to health?

It is sometimes argued that endocrine disrupting chemicals (EDCs) pose negligible threat to human health because any effect they might have is swamped by the presence of endogenous hormones and the natural signalling processes happening in the body.

Exactly what it means to be “swamped”, however, is not always clear. It could mean that concentrations of EDCs are vastly outweighed by endogenous hormones, so that any effect EDCs might be having fades to nothing against the volume of hormonal signalling in the body.

To say EDCs are “swamped” could also mean they simply do not cross concentration thresholds sufficient to pose any sort of conceivable risk to health, regardless of other signalling which is taking place.

The reality, as always, is more complex than simple arguments one way or the other permit. Here, we examine two elements of the total picture.

Firstly, endocrine disruption as a concept is complex enough that the idea of “swamping” is, even if partially right, at best an incomplete argument against the concerns being voiced about EDCs.

Secondly, new understanding of non-classic hormone signalling pathways should undermine confidence in our ability to estimate how oestrogenic man-made substances might be. These recent scientific developments illustrate why the precautionary principle, in spite of criticism, has a key role to play in chemicals policy.

What is a hormone?

Before we look at definitions of EDCs, it may be worthwhile revisiting what hormones are and how they work.

Every living organism is, in essence, a molecular factory. In their simplest, single-celled form, they are enclosed units receiving raw material inputs, manufacturing outputs with a set of complex molecular machinery.

Single-celled organisms stay alive insofar as they are able to manufacture the molecules that sustain themselves in an ever-changing environment. If they cannot respond to those changes, be they alterations of temperature, nutrient supply or harmful substance, they will perish.

Multicellular organisms are the same in principle, except that each cell in the organism survives because it is a member of a team. Some cells make the whole organism move to keep it safe from physical harm; other cells are assimilate nutrients and energy to keep the whole organism fuelled; others still allow the whole organism to reproduce.

As with the inner workings of single-celled organisms, the survival of the whole organism process is still completely dependent on each cell producing the right molecules at the right time.

If cells make the wrong molecules at the wrong time, there will either be too much or too little of the materials the body as a whole needs for its overall survival, increasing the risk of it perishing.

Because each cell is not only making molecules for itself but also making molecules essential for the survival of other cells in the body, it has to be told what to do by these other cells.

The communication systems in the human body are the nervous system (for fast responses) and the endocrine system (for slow responses). Without them, complex organisms could not survive.

Hormones are the molecules which carry the endocrine signals around the body. They change the molecules a cell makes by binding to receptor proteins, causing them to change shape.

This change in physical shape in the receptor protein initiates a cascade of chemical reactions in the cell, reprogramming it so it starts manufacturing the molecules the body now needs, or stops manufacturing the ones the body does not.

Endocrine disruptors are molecules thought to interfere with these processes, causing the body to make molecules when it does not need them, or prevent their manufacture when it does.

What is it for a chemical to be an EDC?

The US Environmental Protection Agency defines an EDC as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction and developmental processes”.

Although not definitive, the EPA’s definition is helpful for indicating the mechanisms by which hormone signalling in the body may be disturbed and obviously goes beyond simple interference with how hormones bind to receptors, leaving little conceptual space for the idea of “swamping” in which to operate.

The thyroid system on its own presents several examples of how hormonal homeostasis may be disrupted by EDCs without any direct interference in how thyroid hormones bind to their receptors [see H&E #30 for more detail].

• The NIS protein which pumps iodine into the thyroid gland can be blocked by perchlorate and possibly phthalates, which may interfere with manufacture of thyroid hormone.
• The enzyme TPO plays a vital role in synthesis of T3 and T4 thyroid hormones, but can be inhibited by pesticides and fungicides.
• TTR is a protein which binds to thyroid hormone when in the blood so it can be stored and transported to cells before being activated and used. Metabolites of PBDE flame retardants and PCBs can attach themselves to TTR potentially reducing the amount of thyroid hormone stored in the blood. (Marchesini et al. 2008)

None of these potential disturbances to thyroid hormone homeostasis involve exogenous substances competing with thyroid hormone to bind to thyroid receptors.

It may be that large quantities of exogenous substances are required before significant effects on homeostasis are observed via the above mechanisms.

Nor will interfering with one of these processes in a minor way necessarily harm health, as the hormone system involves many homeostatic control loops which compensate for deficiencies and excess.

However, as a highly complex system, it is difficult to predict which variations are harmless – especially when there are so many potential EDCs, often acting on the same systems, in the human body at a given time.

To predict these results requires models which reflect the complexity of the biological systems in the body. Since we as yet have limited understanding of how hormones work in the body, anticipating how exogenous substances may interact with this system is some way beyond us yet.

New science about oestrogens

One class of EDC of particular interest to researchers and regulators are the xenooestrogens, molecules which function in the body as if they are an oestrogen.

Oestrogens are a broad class of molecules including estradiol, estriol and estrone, all produced by the body, and also phytoestrogens, found in soy, and a number of man-made chemicals, the most famous of which is BPA.

Oestrogens are steroid hormones and have been considered to act by one mode of action: diffusing naturally through the cell membrane before crossing into the cell nucleus, where they bind to a protein which attaches itself to the cellular DNA, then turning on and off the genes in the genetic code which tells the machinery of the cell what to manufacture.

In the 1970s, the researcher Clare Szego published papers (Pietras & Szego 1975; Pietras & Szego 1977) documenting surprisingly rapid responses by cells to oestrogen – response speeds more typical of the membrane receptor pathway seen with insulin and neurotransmitters than the genomic pathway traditionally associated with oestrogen.

Szego’s findings spent much of the next 25 years gathering dust, not forgotten but in need of new experimental techniques to develop her observations.

Now Cheryl Watson, Professor of Biochemistry and Molecular Biology at the University of Texas, is one of a small group of researchers who for the last decade have been exploring these rapid cellular responses to oestrogens, asking if they all act in the same way, or if there are multiple mechanisms by which cells respond to oestrogen signals.

Watson and her colleagues have not only found that there are indeed oestrogen receptors in the cell membrane, but these receptors have different affinities for oestrogens than those in the cell nucleus.

The reason is, receptor proteins embedded in the cell membrane are in a fat-based environment rather than a water-based one. The receptor is subjected to different molecular forces, twisting the molecule into a slightly different shape.

As a result, the pocket in the receptor protein which recognises and binds to oestrogens is also a slightly different shape, changing how easily it binds to the various oestrogens with which it might interact.

The consequences of these slight changes are dramatic. For example, where BPA has 1,000th of the affinity of estradiol for one of the nuclear oestrogen receptors, it has equal affinity to estradiol for one of the membrane oestrogen receptors. Watson has reported cellular responses to environmental oestrogens at levels as low as nanomolar and picomolar concentrations.

Consequences for health policy

Watson says what this means for human health is as yet unclear. It is difficult to extrapolate from the in vitro mechanistic studies of her research to what is happening in a complex whole organism, with its multiple hormonal signalling systems and also its multiple exposures to environmental oestrogens which, besides BPA, include UV filters, substances in red wine, phytoestrogens in soy, pharmaceuticals, and so on.

What we do know, however, is that receptors on the cell membrane do respond to very tiny quantities of environmental oestrogens, and much more readily than the nuclear receptors which have been the subject of almost all the research into how chemicals may interfere with hormone signalling.

So at the very least, the research of Watson and her colleagues shows that we do not know how potent an oestrogen BPA is. To find out, Watson and her colleagues are developing new analytical techniques to determine the affinity of steroid hormones for membrane receptors.

The question is, what does one do when new models and research which cast doubt on previously-held beliefs, but there is uncertainty about what these new models mean for health?

It is this not knowing which drives the sometimes-maligned “precautionary principle”. Rather than blocking research and innovation, as some accuse it of doing, it simply says that in the face of uncertainty about the consequences of an action, but in the knowledge the action may be harmful, then it is better to avoid the action until its consequences are better understood.

The fact is, Watson’s research undermines some assumptions about how strong an oestrogen BPA is. Scientists and policy-makers would do well to remember that, when new information comes along, the skeptical stance of the scientific method cuts both ways: one is required to doubt not only the new information, but also the old information which the new may refute.

Too often, old information is used simply to cast doubt on the new: this is a one-eyed skepticism which overvalues what we think we know, to the detriment of learning something new.