Toward an Integrative Definition of Endocrine Disruptors (Eds)

Toward an integrative definition of endocrine disruptors (EDs) Complementing hazard identification with risk assessment

General considerations on endocrine disruptors

The endocrine system is the body’s hormonal system that regulates different metabolic processes and organ functions via the glands. It is responsible for controlling mood, growth, development, tissue function as well as sexual functioning and the reproduction process. It represents a highly complex system of billions of interconnections, with the health of each component depending on the overall health status of the organs. This health can be disrupted by several factors including stress, lifestyle, diet, and endocrine disruptive substances (EDs) that can be found in food or the environment.

The difference between endocrine active and disruptive substances

When it comes to endocrine disruptive substances, it is important to distinguish between endocrine active and endocrine disruptive substances. Any substance that interferes with the body’s endocrine system is endocrine active. Examples are oestrogen, the primary female sex hormone, or vitamin D3, responsible for bone formation and –maintenance. Some of these substances are produced by the body itself, i.e. they are naturally occurring (endogenous), and are re-produced synthetically for medical or other purposes. Though having endocrine effects, these substances are not automatically endocrine disruptors.

Only if substances interfere with the body’s hormonal system adversely are they disruptors. Even though there are substances known to be intrinsically disruptive, such as dichlorodiphenyltrichloroethane (DDT) or Bisphenol A (BPA), often it depends on a combination of factors to determine whether a substance is disruptive. Vitamin D3, for example, is an endogenous substance which is known to have endocrine disrupting effects if administered at levels of >300.000 IU/day. However, this is 60x higher than the recommended maximum intake level (5.000 IU/day). As consumers realistically can never reach these levels, it would not make much sense classifying vitamin D3 as ED.

Challenges for regulators

In the current debate on regulatory ED definition criteria, where options are being discussed to base the ED definition of a substance only on its hazard identity without assessing the risk(s), substances like vitamin D3 could soon end up being defined as ED and as such, face severe regulatory consequences under EU sectorial legislation up to their removal from the market. Therefore, examples like vitamin D3 underline the need that the ED definition methodology be differentiated and integrative, considering not only the hazard profile of a substance but examining it in a comprehensive risk assessment as only this will allow decision makers to derive well-informed regulatory conclusions.

The current EU debate on regulatory ED definition criteria

Since 2015, the European Commission has been carrying out an impact assessment (IA) on possible future definition criteria of endocrine disruptors (ED) for regulatory purposes. This IA has now been finalised and though not yet official, it seems that DG Health favours an approach that would complement the hazard-based scientific identification (WHO/IPSC) with elements of risk assessment which would broaden the scientific 1 definition from mere hazard identification to also include considerations on hazard characterisation such as potency and an assessment of potential risk(s).

Whereas this presents a reasonable approach that would alleviate the pressure on regulators to make inflexible yes/no decisions; would be in line with international evaluation practises where risk assessment has meanwhile become the norm; and would not unnecessarily hamper many innovative EU industries, it seems that there is disagreement in- and outside the Commission on whether such approach should be followed. It seems that some services are of the opinion that the future ED definition should only consider a substance’s hazard profile irrespective of its potency, doses, use, exposure to it, or possible socio-economic implications from restrictions or removal.

Such approach, however, would break down a complex exercise to an over-simplified and undifferentiated solution with unreasonable regulatory consequences. The future ED definition criteria will concern a variety of EU sectorial legislation including on pesticides (PPPR), biocides (BPR), industrial chemicals (REACH) and cosmetics (CPR). Using purely hazard based definition criteria to inform regulatory decision-making would be highly problematic because many substances could be spuriously removed from the market although they are used safely; have important applications in medicine or in food/feed supplementation; or are essential from an agronomic and/or socio-economic viewpoint.

Why hazard-based ED definition criteria alone cannot inform regulatory decision-making: the example of Vitamin D3 (cholecalciferol)

Vitamin D3 is an endogenous substance continuously produced in the skin through UV light synthesis. It is also naturally occurring in food such as fatty fish (e.g. salmon), egg yolk and milk. It is an essential vitamin for controlling calcium and phosphorus homeostasis supporting bone formation and –maintenance. This is particularly important for infants and elderly people, where vitamin D3 is often administered supplementary to support infantile development or prevent/overcome health conditions in advanced age. Vitamin D3 is also administered to pregnant women to support the bone development of the unborn child. Some countries therefore officially recommend its use as supplement1.

Besides, vitamin D3 is also used as a biocide to control rodents (rodenticide). This is a new use reason why cholecalciferol is reviewed under the EU Biocides Regulation (528/2012).

Being a hormone, vitamin D is an endocrine active substance. Theoretically, it could have reproductive and developmental effects at disrupted physiological doses, though such are only relevant under laboratory conditions and cannot be reached under normal circumstances (see above). The Swedish Environment Agency, which is responsible for the review of vitamin D3 as a biocide, has confirmed this in its assessment, stating that even a dual exposure (supplement & rodenticide) does not pose a risk to consumers because adverse effect levels would not be reached under normal circumstances2.

Nevertheless, vitamin D3 could become identified as endocrine disruptor which would trigger the exclusion criteria under the Biocides Regulation if definition criteria look

1 E.g. Ireland officially recommends that all infants aged up to 12 months receive 5µg per day of Vitman D3 in form of a specifically formulated supplement. Also the EU-funded Odin project on food-based solutions for optimal vitamin D nutrition has come to the conclusion that one person in eight in the EU suffers from vitamin D deficiency and 40% have circulating vitamin D levels which are not adequate for good bone health, underlining the importance of its supplementation; cf: https://ec.europa.eu/research/bioeconomy/pdf/odin_questionaire.pdf 2 Cf. KEMI Draft Assessment Report on Cholecalciferol, April 2016, p. 35 2 exclusively at the hazardous profile without assessing the risk. This would result in the paradoxical situation where a substance that is also produced by the body itself is banned under EU sectorial legislation while being recommended by regulators as supplement for a healthy diet and being administered to children and pregnant women.

How to define endocrine disruptors: proposal for a four-step risk assessment

As the example of vitamin D3 shows, hazard identification alone cannot be used for regulatory purposes to define whether a substance is endocrine disrupting or not. Rather, the hazard identification should be the first step in a comprehensive risk assessment that also characterises the hazard, identifies exposure scenarios and assesses their risk(s), ultimately also asking whether or not they can be managed:

1. Identify the hazard a. Identification of type and nature of adverse effect (activity vs. disruption)

b. Assessment of toxicity and mode of action (MoA): endocrine or not

c. Causal relationship between primary endocrine MoA and the adverse effect (consistency) 2. Characterize the hazard: establishing a level of concern a. Dose-response relationship (threshold): at which dose do adverse effects occur?

b. Potency: is the substance sufficiently potent to be of concern? (inherent property of a substance)

c. Critical effect or lead toxic effect is ED (first adverse effect observed as dose increases, avoids double-checking)

d. Severity and irreversibility of effects 3. Identify the exposure (provided the substance is if of low or no concern; if high- concern: non-approval) a. Evaluation of human and environmental exposure: in which scenarios can humans / the environment be exposed to the substance? 4. Characterise the risk linked to the exposure scenario(s) a. Qualitative and quantitative determination of probability of occurrence of all adverse effects under relevant conditions of exposure 5. Risk management: Assess whether the risk can be managed a. Based on the four-step risk assessment, the risk managers will then be able to decide on the approval of a substance under certain circumstances and conditions if the risk can be managed (risk mitigation measures, etc.)

It should also be noted that this risk-assessment approach is in line with the scientific opinion of the European Food Safety Authority (EFSA) on the hazard assessment of endocrine disruptors which concluded that “to inform on risk and level of concern for the

3 purpose of risk management decisions, risk assessment (taking into account hazard and exposure data/predictions) makes best use of available information”.3

Lastly, a comprehensive and integrative assessment of endocrine disruptors for regulatory purposes also needs to consider the possible socio-economic impacts of a hazard definition. Regulation 178/2002 establishing and defining the mission of EFSA for instance says that “it is recognised that scientific risk assessment alone cannot, in some cases, provide all the information on which a risk management decision should be based, and that other factors relevant to the matter under consideration should legitimately be taken into account including societal, economic, (…) and the feasibility of controls”4.

Some EDs may have essential uses for society and banning them could lead to very adverse socio-economic consequences. In such cases, and as proposed in the Commission’s ED Roadmap under option C, the introduction of provisions into sectorial legislation should be envisaged that would allow ED substances to be used if they are essential to society. This is already the case in the Biocides Regulation where art. 5(2)c states that an endocrine disruptor may be approved if non-approval would have a “disproportionate negative impact on society when compared with the risk to human health, animal health or the environment arising from the use of the substance”.

Summary & Conclusion

ED definition criteria that look solely on the hazard identification of a substance are insufficient to properly inform decision makers for regulatory action. As the case of vitamin D3 shows, determining whether or not a substance is an ED is a complex undertaking that requires looking at more than just the intrinsic properties (hazard identity) as otherwise absurd regulatory situations will occur. Furthermore, excluding risk assessment from the ED definition would contradict already existing evaluation procedures under EU sectorial legislation such as REACH where risk assessment is a routine practise in substance evaluation, and would go against the global trend.

The European Commission and legislators are therefore strongly encouraged to opt for ED definition criteria that capture as much scientific information as possible to allow them to make well-informed regulatory decisions. The lead objective must be to ensure the highest levels of human and environmental protection without unnecessarily alarming the public and hampering industry. ED definition criteria based on a scientific multi-step risk assessment approach present the best solution to this end.

3 EFSA Scientific Opinion on the hazard assessment of endocrine disruptors: Scientific criteria for identification of endocrine disruptors and appropriateness of existing test methods for assessing effects mediated by these substances on human health and the environment. EFSA Journal 2013; 11(3): 3132; p. 1 4 Cf. Recital, (19) 4 5