Response to A critique of the European Commission Document, “State of the Art Assessment of Endocrine Disrupters” by Rhomberg and colleagues – letter to the editor

The European Commission is in the process of preparing regulatory activities for endocrine disrupting chemicals. In support of this process, the European Commission has asked for a summary of the state of endocrine disrupter science which was to be completed within 12 months. A draft version of our science summary was published by the European Commission in the summer of 2011, with the aim of generating feedback from stakeholders. We have received comments from EU member state authorities and from the European Chemical Industry (CEFIC, ECPA) and these were all taken into account in the final version of the science summary. The final version of the science summary was submitted as an annex to our final SOTA ED (Kortenkamp et al., 2011) which was completed on 23 December 2011.

In their American Chemistry Council commissioned critique, Rhomberg et al. (2012) focus entirely on the draft version of the science summary, but largely ignore the main body of our report. Rhomberg et al. argue that because we did not use methodological approaches needed for comprehensive substance assessments, our report must be biased. This line of argumentation is deeply flawed. It might be the result of a lack of understanding of the distribution of competences in the European Union which the authors (all of them US or Canadian nationals) may not be familiar with.

Rhomberg et al. seem to have assumed that the European Commission would base their policy initiatives on detailed risk assessments of a large number of chemicals, in terms of their endocrine disrupting properties. But the European Commission (the executive arm of the European Union) itself is not responsible for risk assessments of chemicals. Rather, it shapes the general principles of European Union chemicals policy of which risk assessment is but one element. Accordingly, the European Commission did not ask for detailed and in-depth risk assessments for a large number of chemicals to support their policy initiatives, nor is such an analysis needed as a foundation for policy. In the European Union, the task of detailed chemical evaluations and risk assessments falls in the first instance to industry and under well defined circumstances to European agencies such as the European Food Safety Authority or the European Chemicals Agency and to competent authorities of European Union member states. What the European Commission needed, and what it requested us to prepare, was a summary of endocrine disrupter science, primarily with the aim of assessing whether policy initiatives in this area are scientifically justified and called for. Accordingly, they commissioned an assessment of whether endocrine disruption is a problem, and whether there are indications that chemical exposures play a role in endocrine-related health outcomes or wildlife effects. A specific objective in relation to a clause of the European chemicals regulation REACH was to evaluate the scientific basis for the notion that endocrine disrupting substances might cause effects of a concern equivalent to the hazards posed by carcinogens, mutagens and reproductive and developmental toxicants.

In line with these requirements, we prepared a science summary to assess the plausibility that xenobiotics might play a role in the aetiology of various health endpoints potentially related to endocrine disrupters. To achieve this aim, our assessment of the scientific evidence was based on the principles proposed by WHO/IPCS (2002) as a basis for attribution of effects to endocrine disruption (report chapter 3.16, p32). In dealing with this problem, it would have been inappropriate to utilize the causal criteria for assessing endocrine disrupters described in chapter 7 of the same report. This seems to have been entirely misunderstood by Rhomberg and colleagues.

Rhomberg et al. have also overlooked the fact that we have dealt extensively with the issue of weight of evidence, both in the science summary and in the main part of our report (Kortenkamp et al., 2011).They ignore the complexity of developing weight of evidence approaches and seem to assume that such approaches are already available and agreed upon. However, this is not the case. As we have stressed in our report (Kortenkamp et al., 2011), weight of evidence approaches for endocrine disrupters are yet to be developed. Indeed, this was one of our main recommendations. Developing such approaches will be a complicated task, because, uniquely, the issues of adversity and mode of action will have to be dealt with at the same time, which is currently without precedent.

In preparing the science summary, we consequently found ourselves in a situation of having to synthesise the literature without being able to rely on established weight of evidence approaches for endocrine disrupters. In much the same way as the WHO/IPCS (2002) report, to which two of the authors of this critique contributed (Foster, van der Kraak), and which Rhomberg et al. hold up as a positive example, we chose a narrative review to address the task we were set. But this does not render our report biased.

The accusation of bias would have been justified, if we had wilfully and consistently ignored evidence pointing in a specific direction. A fair assessment of that question is only possible by engaging scientifically with the content of our report. But this is precisely what Rhomberg et al. fail to do. Instead, they infer bias from the odd missed reference and from the literature search strategy that we have used. They write that “by using ‘endocrine disrupt*’ (a term suggesting a conclusion of adverse impacts) as the primary inclusion criterion [in our literature searches], the literature search appears to have biased the review toward studies purporting to show adverse effects of chemicals”. According to Rhomberg et al., we should instead have included the search terms “endocrine-active” or “endocrine modulator” so as to capture papers with a more measured view.

In attempting to substantiate this point, the authors conducted their own literature search using “endocrine disrupt*” as the search term (as we have done) and found 5918 papers in PubMed. Their search “hypospadias OR cryptorchidism OR testicular dysgenesis” yielded 15,639 articles. Combination of the two sets, they found, produced 188 papers, but, they pointed out, the “notable papers” by Thorup et al. (2010) and Cortes et al. (2008) were not among them. However, we cited the paper by Cortes et al. (2008). Astonishingly, the authors accuse us of bias because we did not mention Thorup et al. (2010).

To further support their allegation of bias, Rhomberg et al. claim that we have discussed only positive results and attempt to prove this by analysing how we dealt with PCBs and cryptorchidisms. On this point, our report reads: “The evidence for associations between cryptorchidisms and maternal PCB exposure during pregnancy is weak. Three case–control studies did not find any relationships, while another one offered qualified support for an association”. Rhomberg et al. write: “It seems inappropriate that one small study ( …) should form the basis for concluding that even a weak association exists when three other studies failed to find a significant association at all, especially since one of the negative studies had more statistical power”. They claim we are biased because we elected to call the association between PCBs and cryptorchidisms “weak”, instead of “non-existent”. These are indeed weak grounds for the serious allegation of bias.

We hope that we have clarified the misunderstandings which led Rhomberg et al. to make the allegation of bias against us.

In our report (executive summary, Kortenkamp et al., 2011), we come to the following general conclusions:

“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.

Extensive laboratory studies support the notion that chemical exposures contribute to endocrine disorders in humans and wildlife. 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 that justify consideration of endocrine disrupting chemicals as substances of concern equivalent to carcinogens, mutagens and reproductive toxicants, as well as persistent, bioaccumulative and toxic chemicals”.

We believe that this is a fair and balanced assessment of the current state of endocrine disrupter science. We hope that the path is now open for a fruitful and constructive debate with the American Chemistry Council about the substance and content of our report.

Declaration of interest

We have no financial, consulting, or personal relationships with other people or organizations to declare that could have influenced this work. The authors have won, by competitive tender, a contract from the European Commission, Directorate General for the Environment, to prepare a State of the Art Assessment for Endocrine Disrupters which is the topic of the critique by Rhomberg et al. This contract has been completed in December 2011. None of the authors are currently in contractual relationships with the European Commission, Directorate General for the Environment. The employment affiliations of the authors are as stated on the cover page. Michael Faust runs Faust and Backhaus Environmental Consulting, Bremen, Germany, a private firm that provides expert knowledge for the acquisition and execution of research and development projects in the area of chemical hazard and risk assessment as well as chemical regulation. These services are offered to universities, research institutes and private companies.