Regulatory challenges presented by endocrine disruptors

September 6, 2012 at 8:26 pm | Posted in Feature Articles | Leave a comment

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Chemical risk assessment is typically a four-stage process: the hazard which a chemical poses (understood here as the negative effect on health or the environment which the chemical might have); a dose-response assessment which determines the exposure level at which a chemical starts having a biological effect; an exposure assessment, which determines the level to which people are likely to be exposed in various scenarios; and a risk characterisation, which is the final calculation of likelihood of harm and informs the controls which risk managers will impose on use and release of the compound into the environment.

Without putting too fine a point on it, in complex biological systems this sort of risk assessment process involves a lot of educated guesswork. The process is therefore not without its critics (as readers of H&E will know). The problem is, if things did not already look unreliable enough, the possibility that some chemicals may interfere with hormone signaling systems is set to make things look a whole lot worse.

Endocrine disrupting chemicals are of increasing importance in chemicals regulation. Interpreted in Europe within REACH as posing a hazard of equivalent concern to classically toxic substances (such as mutagens or chemicals which are persistent, biocumulative and toxic), there are a number of issues which need to be sorted out before they can be adequately regulated.

Not least among these is how one defines “endocrine disruptor”: you need to be able to classify them before you can regulate them. And of course one needs to decide on how one is going to go about testing substances to see if they are endocrine disruptors or not.

The Endocrine Society argues that one feature shared by a number of proposed definitions of EDC is they conflate the potency of a substance as an EDC with whether or not the substance is classifiable as an EDC. For example, the definition offered by the joint UK-Germany paper on defining endocrine disruption, following the World Health Organisation: “It should be an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or (sub)populations.”

The problem here is that, in order to have an adverse effect on a complete biological system, an EDC must exceed a certain level of potency. Potency, however, is a matter determined in a later phase of risk assessment, which factors into the likelihood that a substance will cause harm. Conflating the two means that, by definition, a substance only presents a certain hazard if it is potent enough.

Classic toxicants such as carcinogens are not treated in this way: substances are either carcinogenic or they are not. If they are carcinogenic, some are more potently carcinogenic than others. Compounds are tested to find out how carcinogenic they are and risk management decisions are made in part on the basis of how carcinogenic a compound is.

For example, asbestos and diesel exhaust have both been classified as carcinogenic. They are not, however, treated equally, with use of asbestos certain to remain much more tightly restricted than exposure to diesel exhaust, which only faces tighter controls in certain occupational settings (indeed, different types of asbestos have differing degrees of carcinogenic potency). This is because asbestos is a much more potent carcinogen. That something is less potent may make its carcinogenicity more difficult to discover, but lower potency only figures in risk management, not in determining whether or not something is a carcinogen.

Besides defying precedent in risk assessment, another issue with incorporating potency into the definition of EDC is it sets the regulatory definition relative to what we already understand about EDC potency. And the problem here is, we don’t in fact know very much about this at all – EDCs are a relatively new issue, the science is only now beginning to emerge, there is little in the way of regulatory agreement on its significance, so it seems premature to define something as an EDC on the basis of adverse effects we can observe right now. It would arguably be better to keep the door open to their identification and assessment of potency on the basis of what we might learn in future about the effects of EDCs on health.

In contrast to the UK-German proposed definition of EDC, the Endocrine Society,  the world’s oldest, largest, and most active organization devoted to research on hormones and the clinical practice of endocrinology, instead proposes the following: “An ED is an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action.” (Zoeller et al. 2012)

Under the Endocrine Society definition, potency still determines risk. The problem, however, is that determining the potency of an EDC and the adverse effects an EDC has, is as complex as studying the role of the endocrine system in developmental and adult physiology.

But if we only have a limited understanding of what hormones do in the body, what chance do we have of understanding what exposure to hormone-like chemicals does in the body?

And if you cannot determine potency, how can you characterise the risk posed by an endocrine disruptor? The dose-response measurement critical to risk assessment becomes impossible, making risk impossible to characterise, meaning ultimately that EDCs present an uncontrolled environmental health risk.

The only way to manage the risk posed by EDCs, in this circumstance, is to make sure they do not come into contact with people or the environment.

And this is one reason why the sort of broad definition of EDC being offered by the Endocrine Society is being resisted: if perturbing endocrine function is sufficient to be an EDC, then a great many chemicals could end up being classified as EDCs, be restricted in use until proven safe, and have to be put through a rigorous testing process in order to prove they are safe.

The UK government is reported as believing this approach to defining what counts as an EDC as too expensive to countenance, according to EDC researcher Andreas Kortenkamp. Requiring a chemical to be a potent EDC in order to be regulated as an EDC would certainly be one way to prevent too many chemicals facing the REACH approval process.

Allowing economic considerations to determine whether or not something is an EDC does not exactly put chemical regulation on the soundest scientific footing: an EDC is an EDC regardless of how much it costs to regulate it or restrict its use.

The issue which concerns the Endocrine Society is if we want to have any hope of sensibly regulating EDCs in a scientifically-credible way, then we have to look to endocrinology for guidance when it comes to developing testing strategies which will identify EDCs and evaluate the risk they pose to health.

Here, the Society offers specific guidance (read the full set of recommendations here). One key consideration is understanding that one hormone can affect several different end-points, some of which may be more sensitive to the hormone than others. Then, dose-response curves can become very complex, and without knowing the full range of sensitivity and biological role of each of the end-points which the hormone affects, making inferences from high to low doses becomes very uncertain indeed, necessitating testing of a range of end-points over a range of doses to eliminate possible harmful effects.

Another is that the specific actions of hormones change throughout life, may be different in males and females, and in particular are different during fetal development, when the cells targeted are different and hormones instruct developmental processes. Some hormones are not present at all during certain stages of fetal development; if the environment supplies a hormone-like substance, this can trigger a developmental effect at the wrong time, with permanent consequences for health. Therefore, testing needs to occur not only at a wide spectrum of doses, but also a wide spectrum of life-stages.

These considerations have direct implications for current testing regimes for EDCs. The US Environmental Protection Agency has proposed a 2-tier system which, firstly, screens chemicals for endocrine activity, and then puts potential endocrine disruptors through a definitive series of tests to firmly establish whether or not the potential EDs need warrant being formally classified as such.

The criteria the tests have to meet are promising, demanding maximum sensitivity to eliminate false negatives (i.e. to prevent a substance with ED properties erroneously being classified as one without), tests on an appropriately wide range of organisms, across a wide range of modes of action, incorporating sufficient diversity among end-points to permit weight-of-evidence conclusions about the ED properties of a chemical.

The problem is that the EPA test methods fall some way short of achieving these goals, testing for only thyroid, androgen and oestrogen disruption, at a limited range of doses for a limited range of health end-points – in other words, the opposite of what is needed to identify EDCs.

For example, the EPA thyroid disruption test offers only three animal assays: amphibian metamorphosis, and a male pubertal and female pubertal rat assay. The rats are exposed to a purported thyroid disruptor for 20 days around the time of puberty, before serum T4 and TSH is measured and the thyroid is examined for physiological changes.

The problem is, T4 levels are so variable that the chances of finding anything outside what the test mandates as within normal range, is very unlikely. Nor are gross histopathological changes to the thyroid a good indicator that nothing is happening elsewhere in terms of thyroid disruption. Ultimately, says the Endocrine Society, the EPA tests would be unlikely even to determine that PCBs, a typical example of a thyroid-disrupting chemical, be identified as such.

Because we do not know how many EDCs there are, nor are we yet very far down the road of developing testing regimes for identifying them, EDCs present a major regulatory and testing challenge. This is, however, a challenge which has to be met, not ducked using definitions of EDC which protect commercial interests before providing a coherent, science-based foundation to regulation.

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