November 26, 2009 by Melanie Gross
Although several pieces of legislation have set out stricter criteria for the approval or authorisation of chemicals with endocrine disrupting properties, the fundamental scientific criteria that are necessary to define such properties have not been described in detail. This has left those responsible for both registering and authorising chemicals, particularly plant protection products, with a significant information gap. In an attempt to fill this gap, we recently developed a practical weight of evidence evaluation for assessing the endocrine disrupting potential of plant protection active substances. The outcome of the evaluation objectively describes the evidence for or against a substance having endocrine disrupting properties, and also identifies relevant data gaps and priorities for further evaluation.
Several European regulations have set out stricter criteria for the approval or authorisation of chemicals with endocrine disrupting properties (i.e. chemicals which cause an adverse effect in organisms by affecting endocrine controlled processes). In the revision of the 91/414 plant protection products directive and the 98/8/EC biocides directive, active substances considered to have endocrine disrupting properties that may be of toxicological significance in humans or non-target organisms will not be granted market approval. In addition to this, endocrine disrupting (ED) substances approved because of negligible exposure will become candidates for substitution during the authorisation stage at Member State level. The REACH regulations also indicate that substances (including intermediates, raw materials and formulation inerts) which have endocrine disrupting properties will require further investigation. A number of factors will be taken into account (e.g. possible substitution by other substances, exposure control, and socioeconomic factors) before such compounds can be authorised for use. Therefore, continued use of such substances will be restricted.
The burden of proof is placed on the notifier. However, the fundamental scientific criteria necessary to define “endocrine disrupting properties” are not described in any legislation. One way of determining whether a substance has ED activity is to use a weight of evidence (WoE) approach to evaluate formally all available data. We have reviewed two published WoE frameworks for the assessment of ED properties of chemicals (CEFIC EMSG 19991 , Brown et al. 20012) and combined elements of each into a practical WoE evaluation for active plant protection substances. The combined framework consists of four evaluation steps:
- Study reliability & quality of work undertaken,
- Study relevance & endpoint relevance to endocrine disruption,
- Study significance & based on the earlier assessments made for reliability and relevance,
- Balance of the weight of evidence, coherence and gap assessment.
Endpoints from regulatory toxicology and ecotoxicology studies provide relevant whole organism data for the assessment of endocrine disruption (effects on endocrine and reproductive organs, development, or reproduction). Our experience with reviews of plant protection products has shown that the regulatory studies required for product registration will generally determine whether the weight of evidence for endocrine disruption is negative or positive, but it has on occasion been equivocal. The results of regulatory studies are mainly of “indicative” significance, irrespective of whether they report effects consistent with endocrine disruption or not. This is because the endpoints in standard regulatory tests (e.g. reproduction, growth, and development) may be influenced by disruption of the endocrine system, but are also known to be affected by other factors, such as environmental stress, systemic toxicity, etc. For a study to be of “high” relevance it would need to report hormone concentrations or effects on processes known to be controlled by the endocrine system (e.g. vitellogenesis, gonadal development or metamorphosis).
When the balance of evidence is “indicative” for potential endocrine disrupting effects, additional targeted supporting in vitro and “high” relevance in vivo studies (either obtained from the open literature or commissioned by registrants) are likely to be required to confirm an endocrine mode of action. In these instances the results of a WoE assessment can help direct the testing strategy required. If the balance of weight of evidence is strongly “indicative” of no endocrine disrupting effects, further targeted supporting studies are not likely to be required as no adverse health effects would have been found in long term whole-organism tests.
US-EPA Endocrine Disrupter Screening Programme
In the United States the US EPA has recently issued its first test orders under theEndocrine Disruption Screening Programme (EDSP). Test orders for Tier 1 screeningwill be issued for 67 chemicals on an initial list of pesticide active and inert ingredients. Testing will eventually be expanded to cover all pesticides. One of the potential responses to a test order is the option to submit or cite existing data with a rationale for why it may be sufficient to satisfy part or all of a Tier 1 test order. The US EPA has issued general guidance on their approach for considering other scientifically relevant information (OSRI) under the EDSP. OSRI is:
“information that informs the determination as to whether the substance may have an effect that is similar to an effect produced by a substance that interacts with the estrogen, androgen, or thyroid hormonal system. OSRI may either be functionally equivalent to information obtained from the Tier 1 assay, that is, data from assays that perform the same function as EDSP Tier 1 assays or may include data that provide information on a potential consequence or effect that could be due to effects on the estrogen, androgen or thyroid systems.”
From discussions with colleagues in the US EPA we understand that it is unlikely that data from standard regulatory tests (e.g. for pesticide registration) will be sufficient to satisfy any part of a Tier 1 test order. At the present time, only functionally equivalent tests to Tier 1 assays will be considered to satisfy the test orders. However, the Tier 1 assay results will subsequently be considered together with OSRI in a WoE framework such as the one that we have developed and used. Early appreciation of the extent and quality of OSRI for individual chemicals on the Tier 1 screening list, even before testing is complete, is likely to help those responsible for their registration to better understand the potential of existing data to supplement Tier 1 testing and help to direct Tier 2 testing.
1. CEFIC EMSG. 1999. Towards the establishment of a weight of evidence approach to prioritising action in relation to endocrine disruption. Endocrine Modulation Steering Group, LRI-CEFIC: Brussels.
2. Brown et al. 2001. A critical review of the scientific literature on potential endocrine-mediated effects in fish and wildlife. Ecotoxicology and Environmental Safety 49:17-25.