Response to Kortenkamp et al. Rebuttal

We thank Kortenkamp et al. (in press) for their comments on our critique (Rhomberg et al., 2012) of their document on the State of the Art of Endocrine Disupters (referred to below by their abbreviation, SOTA ED; Kortenkamp et al., 2011). As we noted in our critique, it is a formidable task to survey and characterize the state of scientific understanding of endocrine disruption as an environmental and public health issue across all potential adverse health and environmental impacts and across numerous agents of possible concern; Kortenkamp et al. are to be commended for undertaking the challenge to construct an overview within a limited time and with practical limits to the length of the document. We fully understand and acknowledge that the aim of the SOTA ED was not to investigate particular agents or toxicities in detail, nor to draw conclusions on the potential impacts of particular agents, and it is not this lack that prompted our concern.

Rather, their purpose was (in the words of Kortenkamp et al., in press) to produce “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” and, further, “to evaluate the scientific basis” for any such concerns. We endorse these objectives, but we continue to contend that addressing them in a way that can most usefully meet the goal of informing future policy decisions necessarily entails a critical appraisal of whether alleged instances of such effects (i) represent isolated observations or confirmed patterns, (ii) are merely suggested or well characterized empirically, (iii) are only hypothetically linked to endocrine disruption or have been elucidated mechanistically, and (iv) have alternative explanations (aside from endocrine disruption as the cause) for any patterns. Firm answers to these questions need not be provided, but if one is setting out to characterize the “state of the art” of this (or any other) scientific endeavor, it is central to evaluate what is known versus merely suspected; whether, how fully, and how firmly potential causal processes have been elucidated; where holes in our understanding exist; and what the prospects may be for resolving these problems with further scientific investigation. In particular, when a field has marked and vigorously contended scientific debates on fundamental questions – as, in our view, endocrine disruption has on such questions as very low dose effects, nonmonotonic dose-response relationships, and appropriate testing protocols – it seems inescapable that a “state of the art” assessment should acknowledge the questions and the main arguments on each side.

Again, we are not asking for a full analysis of these questions, an adjudication of controversies, or a drawing of conclusions. Rather, a survey of where things have been scientifically settled, where they remain unsettled, and what all this might mean for assessing the ability of science as it now stands (and as it might be hoped to advance) to bear on the question of “whether endocrine disruption is a problem” is necessary. It is in this spirit that we called for a more explicit weight-of-evidence approach – as a tool for exploring the extent and limits of current knowledge. We agree that widely endorsed weight-of-evidence methods are not readily available; indeed, several of us have publicly addressed this very lack and have proposed approaches that might be appropriate for endocrine disruption evaluation (e.g. Borgert et al., 2011; Rhomberg et al., 2010). We cited the WHO/IPCS (2002) approach to this question because, first, it seemed a reasonable approach that would be appropriate to the present case and, second, the SOTA ED itself suggested it was following this approach.

Our critique also noted the WHO/IPCS (2002) state-of-the-science review in particular because of our concern that the SOTA ED might, inappropriately, be taken as a successor to and superceder of that report. This concern stems from the similarity in titles, the clear statements that the WHO/IPCS document served as a starting point, and the title of an earlier draft of the SOTA ED that was published on the internet as a “Second Interim Report.” Moreover, Kortenkamp et al. claimed to have used “WHO/IPCS 2002 criteria for attribution to an endocrine mode of action to summarise the state-of-the-science,” yet they did so without a comprehensive evaluation of all available data or definition of their scoring system. A principal motivation for our commentary was to ensure that the SOTA ED not be seen to supersede the WHO/IPCS report. We are glad that the Kortenkamp et al. (in press) rebuttal acknowledged the distinctness in purposes and methods of the SOTA ED from the WHO/IPCS effort and that the SOTA ED authors disclaim following the WHO/IPCS weight-of-evidence approach. We recognize that a governmental organization such as the European Commission has a different set of interests and different prospects for taking actions than does an international organization such as WHO/IPCS. Nonetheless, we would suggest that – from the point of view of surveying the “state of the art” and asking what science is able to tell us about “whether endocrine disruption is a problem” – the WHO/IPCS (2002) effort has much to offer as a model, and the SOTA ED could have benefited by emulating it more closely.

With regard to our discussion of biases in the information gathering and reporting approach as applied in the SOTA ED, we felt it was critical to point out that the method used by Kortenkamp et al. (2011) for identifying reviews and the narrative approach to evaluation of particular studies can fail to convey the legitimate scientific basis for doubts about the prima facie interpretation of cases of apparent endocrine disruption. In our citing examples of particular omitted studies, we ascribe no motivation nor do we assert some kind of intentional skewing of results. Our aim was to show that the approaches used by the authors of the SOTA ED inherently cause examples of possible effects to be emphasized and at the same time minimize the basis for doubts, and we wanted to document that our concerns were not merely hypothetical.

We understand that the European Commission faces the issue of deciding whether and how to consider potentially endocrine-disrupting chemicals as formally designated “substances of concern.” How this question is resolved will have notable consequences for chemical regulation in Europe, and, indeed, it will influence how these matters are approached in the rest of the world. An insightful characterization of the state of the art based on the totality of the scientific evidence – not an immediate adjudication of cases, but an overview of what science can tell us, what remains in question, and what the potential for environmental and public health impacts should be judged to be based on current understanding – is critical.

We continue to feel that there is still much to do to create a state-of-the-art characterization that can serve as the underpinning of a sound and effective regulatory approach to the potential for endocrine disruption. Deciding which concerns are substantive, what actions are warranted, and what impacts – intended and unintended – might arise from different regulatory actions all require a forthright, balanced, and prudent assessment of our state of understanding and evidence.

Declaration of interest

The employment affiliations of the authors are as shown on the cover page. Lorenz Rhomberg and Julie Goodman are employees of Gradient, a private consulting firm that provides services to both private and public organizations on toxicological and human health risk assessment issues. Christopher Borgert is an employee of Applied Pharmacology and Toxicology, Inc., a private firm that offers scientific consultation and research in human and environmental health. Warren Foster is on the faculty of McMaster University and, as an independent consultant, has provided technical advice to industry and government organizations on the health impacts associated with exposure to environmental contaminants on an occasional contractual basis. Glen Van Der Kraak has served as a consultant to Syngenta Crop Protection, LLC on the effects of triazines on wildlife. The American Chemistry Council (ACC) provided funding to support preparation of the original paper and this response. ACC was provided the opportunity to review a draft of the original paper and this response and to offer comments for consideration by the authors. The authors have sole responsibility for the content and the writing of the paper and this response. The interpretations and views expressed in the paper and this response are not necessarily those of the American Chemistry Council or the authors’ employers or clients.