HOT TOPICS | Low dose effects and endocrine disrupters

Toxicology and the evaluation of the safety of chemicals rest on the principle of Paracelsus. This Swiss alchemist, astrologer and doctor enunciated in the XVIth century that « everything is a poison, nothing is without poison, what makes the poison is the dose». From the point of view of regulatory toxicology, this is interpreted as meaning that it is theoretically possible to determine a threshold dose below which there would be no harmful effects.

This principle is now controversed, and this for several reasons. The first is related to the statistical impossibility to determine a threshold experimentally that could be applied for all of the general population. Individuals are all different, and there is no such thing as zero risk. This has brought some experts to question the manner in which acceptable daily intakes (safe doses) are derived for chemical substances that are not genotoxic carcinogens. For the latter, authorised or safe doses are associated with a risk deemed acceptable (one additional cancer case per million person), and some consider this would be a better approach to the evaluation of all substances.

The second is related to the fact that a substance can elicit different effects at different dose intervals. The effect does not necessarily increase with the dose. The dose-effect curve can be shaped like a U or an inverted U. The problem then becomes, from a regulatory point of view, whether the dose interval that is tested in animals is relevant to the doses to which humans are or will likely be exposed. Traditionally, very high doses were tested in animals in an effort to avoid ‘false negatives’ (missing an effect), to ensure that any possible sign of toxicity would be detected in a relatively small number of animals. We are now demanding increasingly more information from toxicological tests, including some information on the possible mechanism of toxicity. At very high doses, some modes of toxicity may mask others.

Thirdly, the life stage during which an organism is exposed to a given substances further complicates matters. Some chemical compounds, of which endocrine disrupters, can disrupt the processes involved in growth and development if an individual is exposed to these substances during particularly sensitive periods, e.g. in utero. Given the role hormones play in development, if a substance interferes with their action during these critical stages, effects can be serious and irreversible. Conversely, if an adult is exposed to the same substance, his or her hormonal system is equipped to re-establish the normal state (homeostasis), and observed effects are not necessarily irreversible. Establishing a safe dose for a fetus is complex because if we know the dose administered to the mother, it is much harder to ascertain the dose that may have actually reached the fetus. Finally, some scientists have proposed that we cannot determine a threshold dose (without any effect) because the effects of endocrine disrupters add up to those of hormones already naturally present in an organism. This is however hotly debated, and others argue that a certain amount of chemicals (therefore a threshold) will be needed before natural development processes are disrupted.

It is because of these serious and irreversible effects that the European Commission wants to ban pesticides and other industrial chemicals considered to be endocrine disrupters, in line with carcinogens or compounds that have toxic effects on reproduction. There is, to date, no consensus over which substances should be designated endocrine disrupters.

The European Commission was meant to publish before the end of 2013 a list of criteria to help regulators decide whether a substance is considered to be an endocrine disrupter on the basis of results of toxicological tests. A major difficulty is that one test is generally not sufficient to make that decision. According to the definition of the WHO in 2002, to demonstrate that a substance is an endocrine disrupter, we need evidence that a substance has adverse (toxic) effects in an animal and also that this effect is linked to an effect on the hormonal system. This requires that a group of experts assess all these different elements and make a decision on the ‘weight-of-evidence’ that this substance is an endocrine disrupter, therefore the need for criteria to ensure that decision process is transparent.

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