Evaluation of endocrine-disrupting chemicals in 2011
In 2011, the focus for the SIN List was to identify specifically endocrine-disrupting chemicals (EDCs) as being Substances of Equivalent Level of Concern, identified on a case-by-case-basis.
The starting point was the European Commission’s database of potential endocrine disruptors developed under the “community strategy for endocrine disruptors”. This database consists of 553 substances that have been evaluated with regard to their endocrine-disrupting potential.
Only substances belonging to categories 1 or 2, for which there was evidence of EDC properties, were selected – leaving 319 substances. After removing non-REACH relevant substances and substances such as pesticides or chemicals with mainly intermediate use, 41 substances remained for scientific assessment.
For the scientific evaluation, ChemSec contracted The Endocrine Disrupting Exchange, TEDX, founded by Professor Theo Colborn and with Dr Carol Kwiatkowski as executive director. The process included a literature search, initial screening, abstract review, selection of studies, data entry and verification, and internal peer review, and was conducted during 2010–2011.
A comprehensive literature search was conducted in PubMed for each chemical. The general approach was to be inclusive, using terms such as endocrine, hormone and receptor, as well as terms for the many organs involved in endocrine activity. For a few chemicals, very little information was found on PubMed, and additional searches were performed in Web of Science and ToxLine.
Every effort was made to select the most scientifically robust studies. Studies that did not use appropriate control conditions or for which there were inconsistencies in the text or tables were not selected. No studies in which null findings directly contradicted significant findings from another study were found. High-dose studies measuring gross endpoints only (e.g. organ weights) in which the mortality rate was excessive were not selected. Exceptions were made for chemicals for which only high-dose studies were available and there was evidence of an endocrine effect (not a toxic effect).
Additionally, in some cases, effects were found only at the lowest doses studied. Such studies were evaluated carefully and were not rejected for this reason alone, as endocrine-related effects are known to exhibit non-monotonic dose responses.
The selection of substances for which there was sufficient evidence for identification as Substances of Very High Concern was led by ChemSec, with support from an external group of scientists and toxicologists.
The official REACH guidance document on how to identify equivalent level of concern SVHCs and prepare an Annex XV dossier as stated in the “Guidance for the preparation of an Annex XV dossier on the identification of substances of very high concern” dating from June 2007 was used as a basis for the SVHC assessment.
The guidance document and the definitions developed for the European Commission database, as well as advice from external EDC experts, were used as the basis for assessment. Only the studies carefully selected by TEDX, as described above, were considered. To establish a reliable and robust dataset, at least three studies were considered necessary with a minimum of two in-vivo studies, to qualify for in-depth evaluation.
Following this approach and the subsequent evaluation, 22 substances were identified as having strong enough evidence to be considered Substances of Very High Concern with regard to their endocrine-disrupting properties, and were subsequently added to the SIN List in 2011.
Evaluation of endocrine-disrupting chemicals in 2014
Initially ChemSec screened a number of sources for suspected EDCs, including scientific papers, reports, priority lists from authorities and from organisations. From this gross list substances already on the SIN List were removed, resulting in more than 1000 substances.
To narrow down the number of substances, ChemSec considered the use of the substances. Indicated consumer use was defined as substances being present on a selection of product-type related substances lists. About one hundred substances were prioritised and during discussions and first screenings with the scientists, 25 substances were selected for full evaluation.
For the scientific evaluation, ChemSec contracted The Endocrine Disrupting Exchange, TEDX, founded by Professor Theo Colborn and with Dr Carol Kwiatkowski as executive director.
Literature searches for each chemical were performed in PubMed. If the PubMed results yielded less than 500 records then an additional search using common name, common synonyms, and CAS# in Web of Science was performed. The records identified from the search process were then uploaded to an online systematic review software program (DistillerSR) for screening. Two independent reviewers screened all articles for relevance by reviewing the abstract and title.
Studies obtained for full review were read and data were extracted and entered into an Access database, then cross-checked for accuracy. All articles were reviewed independently by two reviewers. Discrepancies in the recording of data or the exclusion of studies were discussed between the two reviewers. A third reviewer was consulted when necessary.
All in vivo studies (e.g. experimental animal and epidemiological studies) were assessed for risk of bias (ROB) using a questionnaire developed by OHAT. Two independent reviewers answered applicable questions and noted justifications for each answer. Questions were designed to pick up biases in study design, analysis and reporting. For in vitro studies, questions about statistical methods, reporting, funding and laboratory conditions were answered.
The findings for each chemical were summarised and categorised by the model studied (i.e. human, animal, in vitro) and then by positive effect categories (e.g. estrogenicity, androgenicity). In vivo endpoints were summarised using the study quality for human and animal studies, then where appli- cable, in vitro findings with Evidence Assessments were used to support in vivo models.
For the final decision on inclusion on the SIN List, ChemSec based its evaluation on the summaries from TEDX as well as discussions with experts from authorities, NGOs and research institutes. Recent reports on identification and assessment of EDCs were also taken into account in the decision process.
As suggested by the expert advisory group and in the document “Key scientific issues relevant to the identification and characterisation of endocrine disrupting substances” from the European Commission Joint Research Centre, the following aspects were considered in the discussions on the available evidence:
- an endocrine mode of action
- probability for serious effects
- possible link between the two above