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Approaches to the assessment of toxicity data with endpoints related to endocrine disruption
1National Centre for Environmental Toxicology, WRc-NSF Ltd, Henley Road, Medmenham, Marlow, Bucks SL7 2HD, UK. harvey_p@wrcplc.co.uk
Abstract:
There has been a substantial proliferation in the number of studies reporting endocrine effects as an endpoint. The vast majority have focused on oestrogenicity in vitro but, with recent recommendations by the USEPA Endocrine Disrupter Screening and Testing Advisory Committee, tests are now being developed for (anti)-androgenicity and effects on the thyroid, largely because of the potential for altering reproduction or development via these mechanisms. Despite being a vital organ and involved in reproduction and development, there is currently no provision for assessing adrenocortical function. Similarly, the entire process of steroidogenesis poses multiple molecular targets for toxic disruption that are not included in current test strategies and at present there is no clear position on the significance of the data being generated. This review provides a framework for approaching endocrine data: that all the glands, tissues, receptors, transporter proteins and enzymes that comprise the endocrine system are targets for toxicity. They should be considered in much the same way as other target organs, with appropriate provision for the special cases of carcinogenesis and teratogenesis, and a pragmatic weight of evidence approach should be adopted considering all available data and recognizing its limitations. In this approach, structure-activity relationships and in vitro and targeted in vivo screens provide useful data but repeat-dose regulatory studies with defined endpoints provide the most powerful tools for hazard assessment. Pragmatic consideration should be given to exposure issues (which may highlight the practical irrelevance, for example, of very low potency oestrogens) and subsequently whether endocrine disruption is the critical or most sensitive endpoint for a compound. Finally, endocrine disruption may be considered a mechanism and, as with other toxic endpoints, knowledge of effect and no-observable-effect levels and reversibility is as important as identifying the target tissue or any inherent hormone-like property.
Insights
This review proposes a framework for assessing endocrine disruption, emphasizing a weight-of-evidence approach for all endocrine targets. It highlights the need for comprehensive testing beyond estrogenicity to evaluate reproductive and developmental risks.
Area of Science:
- Endocrinology
- Toxicology
- Environmental Health
Background:
- Growing number of studies on endocrine effects, primarily focusing on estrogenicity.
- Emerging tests for anti-androgenicity and thyroid effects due to reproductive/developmental concerns.
- Lack of assessment for adrenocortical function and steroidogenesis disruption in current strategies.
Purpose of the Study:
- To provide a framework for evaluating endocrine disruption data.
- To advocate for considering all endocrine system components as potential toxicity targets.
- To promote a pragmatic, weight-of-evidence approach for hazard assessment.
Main Methods:
- Reviewing current testing strategies and identifying gaps (e.g., adrenocortical function, steroidogenesis).
- Proposing a framework treating the endocrine system like other target organs for toxicity assessment.
- Emphasizing a weight-of-evidence approach incorporating various data types.
- Considering structure-activity relationships, in vitro/in vivo screens, and regulatory studies.
- Integrating exposure assessment and evaluating endocrine disruption as a critical endpoint.
Main Results:
- The endocrine system's glands, tissues, receptors, transporters, and enzymes are all potential targets for toxic disruption.
- Current strategies are insufficient, lacking provision for assessing adrenocortical function and steroidogenesis.
- A weight-of-evidence approach is crucial, integrating diverse data and acknowledging limitations.
- Regulatory repeat-dose studies with defined endpoints are powerful tools for hazard assessment.
- Understanding effect levels, no-observable-effect levels, and reversibility is key.
Conclusions:
- A comprehensive framework is needed to assess endocrine disruption, encompassing all endocrine system components.
- Current testing strategies require expansion to include underrepresented targets like the adrenal cortex and steroidogenesis.
- A pragmatic, evidence-based approach, considering exposure and critical endpoints, is essential for accurate hazard assessment.
- Knowledge of dose-response and reversibility is as vital as identifying the target and inherent properties.