In 2002, the World Health Organization (WHO) defined an endocrine disruptor as, “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations.”1 It was not until 2009 that the WHO defined an adverse effect as, “Change in ‘the morphology, physiology, growth, development, reproduction or lifespan of an organism, system or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences.’”2 However, the WHO has not established scientific criteria for assessing the endocrine disrupting properties of chemicals.
In 2009, when Regulation (EC) No 1107/20093 was adopted to address plant protection products (PPPs) on the market, a need for scientific criteria to identify chemicals with endocrine disrupting properties was recognized. PPPs are active substances, safeners (a protective mechanism for non-target plants), or synergists intended to protect plants and plant products from harmful organisms. The regulation stated an active substance could not have an “inherent capacity to cause endocrine disrupting effects”. Therefore, the European Commission (hereinafter, “Commission”) was tasked with establishing scientific criteria to identify chemicals with endocrine disrupting properties by Dec. 14, 2013. The Commission failed to do so and was found to have breached EU law in 2015.4 It wasn’t until mid 2016, experts and member states began discussing scientific criteria. After multiple discussions, in July 2017 the Commission proposed scientific criteria to the Council and European Parliament (hereinafter, “Parliament”).5 Although the Council did not oppose the proposed scientific criteria for PPPs,6 the Parliament adopted a resolution to oppose the text stating the EC exceeded its regulatory power and that the proposal was not based on objective scientific data.7 Therefore, the Commission must withdraw the proposed scientific criteria and submit another proposal without delay.
The Commission proposed amending Annex II to Regulation (EC) No 1107/2009 to include criteria for active substances, safeners, or synergists considered to have endocrine disrupting properties that may cause adverse effects in humans or non-target organisms. If there is evidence demonstrating that the adverse effects identified are not relevant to humans or at the (sub)population level for non-target organisms, the substance would not be considered an endocrine disruptor. The substance would be considered an endocrine disruptor if:
“It shows an adverse effect in an intact organism or its progeny, which is a change in the morphology, physiology, growth, development, reproduction or life span of an organism, system or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences;
It has an endocrine mode of action, i.e. it alters the function(s) of the endocrine system; and
The adverse effect is a consequence of the endocrine mode of action.”5
Scientific criteria were also provided for the identification of a substance, safener, or synergist having endocrine disrupting properties that may cause adverse effects in humans:
All available relevant scientific data (in vivo studies or adequately validated alternative test systems predictive of adverse effects in humans or animals; as well as in vivo, in vitro, or, if applicable, in silico studies informing about endocrine modes of action): (a) scientific data generated in accordance with internationally agreed study protocols, in particular those listed in the Commission Communications4 in the framework of setting out the data requirements for active substances and plant protection products, in accordance with this Regulation; (b) other scientific data selected applying a systematic review methodology, in particular following guidance on literature data which is listed in the Commission Communications in the framework of setting out the data requirements for active substances and plant protection products, in accordance with this Regulation;
An assessment of the available relevant scientific data based on a weight of evidence approach in order to establish whether the criteria set out in the fifth paragraph are fulfilled; in applying the weight of evidence determination, the assessment of the scientific evidence shall, in particular, consider all of the following factors: (a) both positive and negative results; (b) the relevance of the study designs, for the assessment of adverse effects and of the endocrine mode of action; (c) the quality and consistency of the data, considering the pattern and coherence of the results within and between studies of a similar design and across different species; (d) the route of exposure, toxicokinetic and metabolism studies; (e) the concept of the limit dose, and international guidelines on maximum recommended doses and for assessing confounding effects of excessive toxicity;
Using a weight of evidence approach, the link between the adverse effect(s) and the endocrine mode of action shall be established based on biological plausibility, which shall be determined in the light of current scientific knowledge and under consideration of internationally agreed guidelines; and
Adverse effects that are non-specific secondary consequences of other toxic effects shall not be considered for the identification of the substances as endocrine disruptor.”5
The Commission also included the following exemption in the amendment: “If the intended plant protection mode of action of the active substance being assessed consists of controlling target organisms other than vertebrates via their endocrine systems, the effects on organisms of the same taxonomic phylum as the targeted one, shall not be considered for the identification of the substance as having endocrine disrupting properties with respect to non-target organisms.”5 Our interpretation of this exemption is: Organisms (other than vertebrates) in the same phylum as the target organism shall not be considered when identifying chemical’s endocrine disrupting properties in non-target organisms.
As previously stated, the Council supported the scientific criteria set forth in the amendment and expressed that the scientific criteria protect human and animal health and the environment and improve the internal market and agricultural production.6 However, Parliament did not come to the same conclusion. Instead, the Parliament opposed the amendment by issuing a resolution.7 The Parliament disagreed with organisms (other than vertebrates) in the same phylum as the target organism not being considered when identifying chemicals with endocrine disrupting properties in non-target organisms. The Parliament’s disagreement was based on the General Court (case T-521/14) judgment stating the scientific criteria must be objective and scientific, and independent of all other considerations, including economic considerations. The resolution stated the amendment was not based on “objective scientific data related to the endocrine system” and ordered the language to be deleted from the amendment.
The Commission may have attempted to satisfy the objectives of the agricultural industry while maintaining the protection of public health and the environment, according to the resolution.7 Evidently, the Parliament did not think the Commission succeeded and instead exceeded its power by attempting to regulate, despite the establishment of regulations under Regulation (EC) No 1107/20093 and the Commission’s lack of regulatory authority. The Commission was tasked with establishing criteria for identifying endocrine disruptors only, and not given the power to establish regulations.
The basic nature of this opposition is that the Parliament determined the proposal presented by the Commission was not strict enough, and allowed for the exemption of chemicals that may have endocrine disrupting properties. Moving forward, it seems inevitable that the next amendment presented to the Council and Parliament will result in even more chemicals being identified as potential endocrine disruptors. In order to fulfill the Parliament’s request for, and interpretation of “objective” scientific criteria, the exemption of chemicals will have to be removed. Without such an exemption in the amendment, surely more chemicals will be classified as endocrine disruptors or as having endocrine disrupting properties.
Additionally, given the progression from risk-based to hazard-based criteria during the discussions between experts and member states leading up to the proposed amendment being presented to the Council and Parliament, it seems likely that the amendment will employ a hazard-based assessment for identifying endocrine disruptors. Previous versions of the scientific criteria stated a substance shall be considered an endocrine disruptor if there is a “causal link” between an adverse effect and the chemical’s mode of action. However, the amendment presented to the Council and Parliament states the link between the adverse effect and the endocrine mode of action shall be established based on “biological plausibility”.5 There is a substantial difference between “causal link” and “biological plausibility”, when assessing the endocrine disrupting properties of a chemical. It is the difference between a risk-based assessment and a hazard-based assessment. With a hazard-based approach, again, there will be a higher likelihood of chemicals being identified and regulated as potential endocrine disruptors, despite the fact that there may be a low (or even insignificant) risk for the chemical to cause adverse effects in humans.
This movement in the EU poses many questions related to future EU regulations, future regulations in other countries, and the potential impact of the EU regulation on industries world-wide. Is this a slippery slope? Will the EU look to regulate chemicals with endocrine disrupting properties in other product types, not just PPPs? Once the EU has adopted scientific criteria for assessing chemicals’ endocrine disrupting properties in PPPs, will other regulatory bodies follow their lead? Will industry stakeholders from other countries be forced to comply with the scientific criteria, if currently importing to the EU, in order to maintain viability in the global marketplace? These are important questions to consider. Because the Commission is required, by law to put forth an amendment with scientific criteria for potential endocrine disruptors in PPPs, it is likely only a matter of time until it proposes an amendment that will be adopted by the Council and Parliament, with the potential for global disruption of the use/safety evaluation of PPPs.
In our opinion, the search for endocrine disruptors in PPPs will only be the start of an industry dedicated to the detection of endocrine disruptors in food ingredients, natural or added. There are easily seen parallels here with California’s Proposition 65, where special signs are required for restaurants or grocery stores: “Caution – Chemicals known to the State of California to cause cancer, birth defects or other reproductive harm may be present in foods or beverages sold or served here.” For foods: “This product contains chemicals known to the state of California to cause cancer or birth defects or other reproductive harm.” There is already a requirement in California for warnings on the presence of the endocrine disruptor BPA (bisphenol A) — are hops, cabbage and tofu next? Will FDA have a requirement for endocrine disruptor testing for all new food ingredients?
References:
World Health Organization International Program on Chemical Safety, Global assessment of the state-of-the-science of endocrine disruptors, 2002, WHO/PCS/EDC/02.2.
World Health Organization/International Program on Chemical Safety, 2009. Principles and Methods for the Risk Assessment of Chemicals in Food. Environmental Health Criteria 240.
REGULATION (EC) No 1107/2009 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC.
Judgment of the Court of Justice of 16 December 2015, Sweden v Commission, T-521/14, ECLI:EU:T:2015:976.
DRAFT COMMISSION REGULATION (EU) of XXX amending Annex II to Regulation (EC) 1107/2009 by setting out scientific criteria for the determination of endocrine disrupting properties.
12484/17 PRESSES 46: OUTCOME OF THE COUNCIL MEETING 3560th Meeting- General Affairs. Brussels, 25 September 2017.
Objection to an implementing act: Scientific criteria for the determination of endocrine disruption properties P8_TA-PROV(2017)0376. Site last visited October 24, 2017.
European Commission. Register of Commission Documents. Site last visited November 1, 2017.