The report summarises advances in the state of the science since 2002 and maps out ways of dealing with endocrine disrupters in important pieces of EU chemicals regulation, such as e.g. the Plant Protection Product Regulation, PPPR (1107/2009), the new Biocide Regulation and the chemicals regulation, REACH (1907/2006).
1. The context of concerns about endocrine disruption and its relation to some chemicals
During the last two decades evidence of increasing trends of many endocrine-related disorders in humans has strengthened.
Although the correct description of disease time trends is often complicated by a lack of uniform diagnostic criteria, unfavourable disease trends have become apparent where these difficulties could be overcome. There are negative impacts on the ability to reproduce and develop properly. There is good evidence that wildlife populations have been affected, with sometimes widespread effects.
Multiple causes underlie these trends, and evidence is strengthening that chemical exposures are involved. Nevertheless, there are significant difficulties in identifying specific chemicals as contributing to risks. Especially where chemicals do not stay for long periods in tissues after exposures have occurred, it is impossible to detect associations when exposure measurements cannot cover periods of heightened sensitivity.
For the WHO/IPCS, “an endocrine disrupter is 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.” An adverse effect was further specified in the context of reproductive effects: “A change in morphology, physiology, growth, reproduction, development or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increased susceptibility to the harmful effects of other environmental influences”.
The notion that chemical exposures contribute to endocrine disorders in humans and wildlife is supported by extensive laboratory studies. Exposure during critical periods of development can cause irreversible and delayed effects that do not become evident until later in life. It is these toxicological properties thatjustify consideration of endocrine disrupting chemicals (EDCs) as substances of concern equivalent to “carcinogens, mutagens and reproductive” toxicants (“CMRs”), as well as persistent, bioaccumulative and toxic chemicals (“PTBs”).
In connection with efforts to characterise the risks associated with EDCs it has been argued that the current risk assessment paradigm needs modification or has become obsolete, because EDCs elicit effects at doses much lower than normally used in regulatory testing. The existence of dose thresholds cannot be proven or ruled out by experimental approaches, because all methods for measuring effects have their limits of detection which will obscure thresholds, if they exist.
1.1. The ‘weight-of-evidence’ (WoE) approach adopted to evaulate endocrine disrupting effects in this report refers very generally to the synthesis or pooling of different lines of evidence. In the context of this report, it refers more specifically to the evidence of harm following exposure to a specific chemical substance. The term has been used to refer to a summary narrative of the result of hazard assessment where the methodological approach remains unspecified, systematic narrative reviews, criteria-based methods of causal inference, quantitative statistical techniques such as meta-analysis or as a label to a conceptual framework. Historically, the WoE approach is distinct from an alternative approach referred to as ‘strength of evidence’ which analyses the degree of positive evid ence from a subset of key studies that demonstrate a statistically significant result. In the ECHA guidance document on how to report weight of evidence, WoE is defined as “the process of considering the strengths and weaknesses of various pieces of information in reaching and supporting a conclusion concerning a property of the substance”
1.2. Epidemiological criteria of causal inference are almost invariably based on the so-called Bradford-Hill criteria featuring a list of nine ‘considerations’ for causation, given a body of statistically significant epidemiological evidence and some experimental toxicological evidence (see p 32 of the report).
The controversy about associations between specific chemicals and their purported endocrine disrupting properties can be directly related, says the report, to divergent interpretations and quantitative or qualitative weights that were attached to different types of available evidence. The need to better integrate epidemiological evidence in the hazard characterisation of chemical substances has been recognised. The very existence of epidemiological evidence of effects linked to endocrine disruption in humans and wildlife is indicative of a failure of accurately predicting the toxicity of a given substance.
1.3. Information about the mode of action can inform decisions regarding the shape of the dose-response curve, particularly at low doses, the relevance of effects observed in experimental animals to humans, and the variability of the response within the human population including susceptible subgroups.
1.4. To assess the human relevance of the postulated mode of action, the evidence collated within the framework is queried in sequence for the sufficiency of evidence 1/ to establish a mode of action in the experimental animal, 2/ whether human relevance of this mode of action could be reasonably excluded on the basis of fundamental qualitative differences in key events between experimental animals and humans, and finally 3/ whether the relevance of the mode of action in experimental animals could be reasonably excluded on the basis of quantitative differences either in toxicokinetic or toxicodynamic factors between experimental animals and humans.
2. Testing chemicals for their endocrine disrupting potential
Internationally agreed and validated test methods (OECD) for the identification of endocrine disrupters are generally regarded as useful, but it is acknowledged that they capture only a limited range of the known spectrum of endocrine disrupting effects. Considerable gaps exist for the identification of chemicals that can affect wildlife taxa. It is thus far not possible to infer the possibility of adverse effects from positive results in relatively cost-effective screening level assays.
For a wide range of endocrine disrupting effects, agreed and validated test methods do not exist. In many cases, even scientific research models that could be developed into tests are missing. Because of pre-existing internal exposures to steroidal estrogens, it can be inferred that any quantum of externally added estrogenic agent adds to the internal load, thereby exhibiting activity in a threshold-independent fashion. This is an important consideration for the role of estrogens in breast cancer, during the programming of the neuroendocrine system and timing of puberty.
This introduces considerable uncertainties, with the likelihood of overlooking harmful effects in humans and wildlife. Until better tests become available, hazard and risk identification has to rely also on epidemiological approaches.
The information and testing requirements laid down in important pieces of EU chemicals regulation do not capture the range of endocrine disrupting effects that can be measured with internationally agreed and validated test methods. Testing with the most sensitive and appropriate methods currently available and with exposure regimens that cover periods of heightened susceptibility during critical life stages is not conducted.
It is highly unlikely however, state the report (p 18) that the information required by adverse outcomes pathway or key event analyses that would establish causality will be available for most suspected endocrine disrupters. In the case of endocrine disrupters this is compounded by the fact that disruption of endocrine processes may result in a complex pattern of effects.
1. Some highlights from the State of the Science report for various families of chemical substances
The last 10 years have seen increases in the number of chemicals considered of concern in the context of endocrine disruption, and in the number of endpoints they have been connected with. Their coverage, however, has been skewed strongly towards reproductive endpoints governed by the actions of the sex steroids, and a large portion of the literature is devoted to legacy compounds such as DDT and its metabolites and PCBs, which are no longer in widespread use.
In the summer of 2011, the European Commission published a summary of the State of the Science on Endocrine Disrupters which was updated in January 2012.
As a result, the member companies of CEFIC, the umbrella organisation of European chemical manufacturers, and those of the European Crop Protection Association (ECPA) took the opportunity to publish combined comments on that Summary. These comments were published in September 2011.
PCBs (polychloro biphenyls) According to the report, a convincing link has been made between PCB exposure and an increased risk of breast cancer in women and there is some evidence that the incidences of fibroids, thyroid cancer and prostate cancer are also increased . Neurodevelopmental endpoints are also known targets of PCB exposure, which has been linked to serious and irreversible effects on cognition, motor and sensory function
In a variety of exposed vertebrate wildlife species, estrogen-related developmental perturbations, thyroid irregularities and the suppression of thyroid hormone synthesis have also been found.
Dioxins (PCDDs and PCDFs) These chemicals share some of the same mechanisms of action as “co-planar” PCBs, binding to the same cellular receptor, perturbing thyroid function, but they do not activate the cellular estrogen receptor. Exposure to TCDD (the “Seveso” dioxin) during infancy has been shown to lead to irreversible reductions in sperm motility and sperm concentration. Strikingly, the opposite effect was observed among men who were exposed during puberty
Reduced age at menopause has been associated with exposure in adult women. There is an association with high PCDD/PCDF exposures and breast cancer, and a suggestive, almost significant association with thyroid cancer.
Polybrominated biphenylethers (used a.o. as flame retardants) Exposure in utero or during early development can have profound and irreversible effects on neurodevelopment. Various possible effects on the reproductive function are described in the report but the evidence in most cases remains still hypothetical (“some evidence”, “may cause”, “may be affected”) .
Perfluorinated compounds (PFCs). In a human study of associations between exposure to one PFC, perfluorooctanoic acid (PFOA) and thyroid hormones was found suggesting that these chemicals interfere with thyroid hormone conversion. Although a causal link has yet to be established, mechanistic and epidemiological studies show a consistent positive association between PFC body burdens and increased cholesterol levels, indicating that they could create metabolic disorders. The endocrine effects of PFCs on wildlife have yet to be ascertained.
Pesticides. For dicarboxamides, despite experimental evidence of endocrine disrupting mechanisms for some substances (vinclozolin) , no direct evidence of exposure-disease associations exists yet for either humans or wildlife.
For Azole fungicides (including triazoles and imidazoles), the activities of these chemicals in humans have received little epidemiological attention. Studies of agricultural workers have detected statistically significant increases in reproductive abnormalities in the children of mothers exposed to these pesticides during pregnancy. Unfortunately, these studies do not identify the individual compounds or compound classes that the women were exposed to.
For Triazines, atrazine and simazine are the two most widely used herbicidal triazines, and of these atrazine has received the greatest attention for its ED properties, principally because feminised secondary sexual characteristics, intersex and gonadal dysgenesis have been observed in wild frogs collected from contaminated sites. Effects in mammals remain largely undetermined and the report does not mention a speficic effect on humans.
Heavy metals. Exposure to methylmercury and lead are known to produce deficits in cognitive, motor, auditory and visual function/ Methylmercury has multiple modes of action relating to the endocrine system. Lead exerts an endocrine mediated action via the enhanced pituitary release of the thyroid hormoneTSH. For cadmium, a weak link is made by some epidemiological studies of occupational exposure and breast cancer. There is also some evidence that cadmium may contribute to menstrual abnormalities and increased time to pregnancy but no association has been found with endometriosis and conflicting results are found in studies examining potential links between cadmimum exposure and the incidence of fibroids. Associations made between cadmium exposure and prostate cancer are weak, although these associations tend to be stronger for more aggressive forms of the disease. Investigations showed also a dose-response relationship between cadmium exposure and uterine weight. Its ED effects in wildlife are understudied.
Bisphenol A has been researched very thoroughly over the last few years. Its effects are multifaceted, mediated by its ability to bind the ER and PR, and its properties as a thyroid hormone antagonist. Exposure during organogenesis has been demonstrated to have irreversible adverse effects on reproductive development.
Phtahlates. Two key studies conducted in theUSA among young boys provide good evidence of associations of irreversible effects in the form of altered hallmarks of sexual differentiation with elevated phthalate exposures during fetal life. The effects on male development are attributed to the ability of phthalates to directly interfere with testosterone synthesis. Some phthalates, including benzyl butyl phthalate (BBP) and DEHP are also agonists of the estrogen receptor. A mixture of phthalates tested for antiandrogenic properties in vivo acted together in line with the dose addition model. Effects on wildlife remain largely uninvestigated.
Parabens. Epidemiological evidence in humans is very limited. An association emerged recently between blood serum paraben levels and mammographic breast density in postmenopausal women, but there is no evidence that exposure may increase breast cancer risk.
Other chemicals Multiple new chemicals and groups of chemicals have come to the fore over the last decade as being of potential concern. In addition to parabens, UV filters and artificial musks are present in many cosmetic and personal care products. As of yet direct evidence of either group of compounds having ED effects on humans is lacking, but some evidence exists from studies conducted in animals and in vitro that some of them may have endocrine disrupting properties.
4. Regulating endocrine disrupters in the E.U.
An overview of proposals for regulating endocrine disrupters by EU Member States and other organisations revealed some commonalities and areas of agreement. Controversial are proposals to deal with endocrine disrupters on the basis of potency-based cut-off values derived from Regulation No 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP). Such values are largely arbitrary and not scientificallyjustifiable.
Defining endocrine disrupters for regulatory purposes will have to rely on criteria for adversity and endocrine-related modes of action. Based on earlier proposals by variousMemberStatesand other organisations, including ECETOC, a decision tree approach is developed that proceeds in a step-wise manner by excluding substances that neither produce adverse effects, nor show endocrine-related modes of action. Substances producing effects shown to be of no relevance for humans or wildlife can also leave the decision tree, but in the absence of appropriate evidence, relevance should be assumed by default.
The final regulatory decision rests on a consideration of the toxicological profile of the substances in a weight-of-evidence approach. This weight-of-evidence approach will have to consider potency together with other factors such as severity and specificity of effect and irreversibility. Rigid potency-based cut-off values as decisive decision criteria are not recommended. Procedures that incentivise the provision of data in the case of data gaps are suggested. Regulatory decisions about endocrine disrupters will have to rely on weight-of-evidence procedures which are yet to be developed.
There are thus still enormous knowledge gaps that need to be addressed through research and development projects. Urgently needed are further methods for the identification of endocrine disrupters. Concerted efforts should be undertaken to identify the full spectrum of endocrine disrupters present in the environment and in human tissues.
5. The recommendations of the report
The following recommendations are made in this report :
Implement recently updated or enhanced validated and internationally recognised test methods in the testing and information requirements for PPPR (Plant Protection Products Regulations) and REACH,
Develop further guidance documents for the interpretation of test data,
Consider the creation of a separate regulatory class “Endocrine Disrupter” (ED),
Develop weight-of-evidence procedures that deal with the available evidence by weighing the criteria “adversity” and “mode of action” in parallel, but not by applying these criteria sequentially to exclude substances from the assessment,
Consider potency, together with other criteria such as lead toxicity, specificity, severity and irreversibility in a weight-of-evidence approach. Abandon “potency” as a rigid and decisive cut-off criterion for endocrine disrupters of regulatory concern, for lack of prospect of reaching a consensus by purely scientific criteria,
Create regulatory categories that stimulate the generation of the necessary data, including test methods that are not validated, beyond the OECD Conceptual Framework.
Reference : STATE OF THE ART ASSESSMENT OF ENDOCRINE DISRUPTERS
Final Report Project Contract Number 070307/2009/550687/SER/D3 23.12.2011
Authors: Andreas Kortenkamp, Olwenn Martin, Michael Faust, Richard Evans, Rebecca McKinlay, Frances Orton and Erika Rosivatz
note : the content of the “Highlights” proposed by Greenfacts of reports are not submitted to the peer review of its Scientific Committee.
 World Health Organisation/International Programme on Chemicals Safety