Investigating endocrine‐disrupting properties of chemicals in fish and amphibians: Opportunities to apply the 3Rs

Burden, Natalie; Embry, Michelle R.; Hutchinson, Thomas H.; Lynn, Scott G.; Maynard, Samuel K.; Mitchell, Constance A.; Pellizzato, Francesca; Sewell, Fiona; Thorpe, Karen L.; Weltje, Lennart; Wheeler, James R.

doi:10.1002/ieam.4497

Cited by 13 publications

(10 citation statements)

References 35 publications

(46 reference statements)

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“…This MTC is generally aimed at providing test exposures at the highest concentration at which no overt toxicity is observed. However, the process for determining the MTC is poorly described in the test guidelines and often focuses on acute mortality effects; consequently, it is not uncommon for the highest test concentration to produce confounding, sublethal toxic effects (Burden et al, 2022). Potentially, these could include thyroid histopathological findings in AMA studies that might be interpreted as chemically mediated changes in thyroid activity, if the test guidelines' decision logic and associate guidance (ECHA/EFSA/JRC, 2018) is uncritically applied.…”

Section: Discussionmentioning

confidence: 99%

“…The identification of endocrine‐disrupting properties of chemicals has recently become a requirement for different substance types across regions (Burden et al, 2022). Environmental test guidelines for the thyroid modality relies on amphibian in vivo tests in the form of the amphibian metamorphosis assay (AMA; Organisation for Economic Co‐operation and Development [OECD], 2009; US Environmental Protection Agency [USEPA], 2009) or the Larval Amphibian Growth and Development Assay (LAGDA; OECD, 2015; USEPA, 2015).…”

Section: Introductionmentioning

confidence: 99%

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An Amphibian Metamorphosis Assay Dietary Restriction Study: Lessons for Data Interpretation

Marini¹,

Wolf

Mingo³

et al. 2023

Enviro Toxic and Chemistry

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The amphibian metamorphosis assay (AMA) is a key in vivo endocrine screen to investigate chemicals with potential thyroid activity. The test guidelines and associated guidance consider that treatment‐related effects on thyroid gland histomorphology automatically result in the assay being considered positive for thyroid activity, independent of the direction of change or conflicting results in the other biological endpoints. An AMA study was conducted with five different feeding rations equivalent to 50%, 30%, 20%, 10%, and 5% of the recommended feeding rate. Biological endpoints relating to growth and development, including thyroid gland histopathology, were evaluated, and the specificity of these endpoints for the determination of thyroid activity was assessed. There was no effect on survival or clinical signs of toxicity. Effects related to feed reduction generally occurred in a feeding ration–response manner and included reduced development stage; reduced body weight and body length metrics; decreased prevalence of thyroid follicular cell hyperplasia and hypertrophy, and the occurrence of thyroid atrophy; reduced liver vacuolation; and the occurrence of liver atrophy. The results indicate that treatment‐related histopathological changes in the AMA can be induced by Non‐chemical factors; therefore histopathological results are not necessarily diagnostically specific for chemically induced thyroid endocrine activity. Consequently, the interpretation of data from AMA studies should be adjusted accordingly. We recommend that the decision logic presented in the test guidelines and associated guidance be changed to reflect a requirement for directional agreement between the thyroid histopathology findings and the growth and developmental endpoints before it is concluded that a test substance has thyroid endocrine activity. Environ Toxicol Chem 2023;42:1061–1074. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Amphibian Metamorphosis Assay Dietary Restriction Study: Lessons for Data Interpretation

Marini¹,

Wolf

Mingo³

et al. 2023

Enviro Toxic and Chemistry

Self Cite

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“…The challenges of identifying endocrine disruptors in a regulatory context have been an important topic in recent discussions (Burden et al, 2022). A key challenge is being able to translate endocrine laboratory data in select species to predictions of adverse effects on wild populations, which is the protection goal.…”

Section: Challenges Linking Endocrine Activity To Population‐relevant...mentioning

confidence: 99%

Current testing programs for pesticides adequately capture endocrine activity and adversity for protection of vertebrate wildlife

Staveley

Freeman

McArdle

et al. 2023

Integr Envir Assess & Manag

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The toxicity and ecotoxicity of pesticide active ingredients are evaluated by a number of standardized test methods using vertebrate animals. These standard test methods are required under various regulatory programs for the registration of pesticides. Over the past two decades, additional test methods have been developed with endpoints that are responsive to endocrine activity and subsequent adverse effects. This article examines the available test methods and their endpoints that are relevant to an assessment of endocrine-disrupting properties of pesticides. Furthermore, the article highlights how weight-of-evidence approaches should be applied to determine whether an adverse response in (eco)toxicity tests is caused by an endocrine mechanism of action. The large number of endpoints in the current testing paradigms for pesticides make it unlikely that endocrine activity and adversity is being overlooked.

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“…At these developmental stages, the embryos, although hatched, still rely on their maternally supplied reserves of vitellus and are not yet free‐feeding. Under European regulation, eleuthero‐embryonic life stages are not defined as a protected life stage and their use as an alternative to protected life stages is considered to be in line with the 3R's principles of replacement, reduction, and refinement (Burden et al, 2022; European Parliament and Council of the European Union, 2010).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the endocrine activity of surface water samples using aquatic eleuthero‐embryos—A comparison with in vitro assays

Tindall

Pasquier

Lemkine

2023

Water Environment Research

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Over the previous decade, numerous new approach methodologies (NAMs) have been developed and validated for the detection of endocrine activity of individual chemicals or environmental samples. These NAMs can be largely separated into three categories, in silico tools, in vitro assays, and in vivo assays using organisms or life stages not considered as laboratory animals, each with their own advantages and disadvantages. While in vitro assays provide more mechanistic information, the use of whole organisms such as fish or amphibian embryos provides a more holistic view of the net effects of an environmental sample on hormonal activity. A panel of bioassays was used to test the endocrine activity of several samples from the Danube River at Novi Sad, Serbia. The results of the in vitro assays have been published previously. Here, we present the results of the in vivo assays that were performed at the same time on the same samples. These whole organism assays are based on the use of transgenic fish and amphibian eleuthero‐embryos and included the Xenopus Eleuthero‐embryo Thyroid Assay (XETA), the Rapid Estrogen ACTivity In Vivo assay (REACTIV), and the Rapid Androgen Disruption Activity Reporter (RADAR) assay. Discrepancies between the different in vitro assays have previously been reported. The results of the in vivo studies also indicate discrepancies between the in vivo and in vitro data with an underestimation of the endocrine activity by the in vitro tests. Therefore, a battery of tests is advised with the initial diagnostic performed with in vivo tests to cover a wider range of modes of action and to allow the appropriate in vitro assay(s) to be selected to confirm the mode of action.Practitioner Points Endocrine activity was quantified in surface water using in vitro and in vivo models. The in vivo results fit with previously reported in vitro results. Higher activity was observed in water samples with in vivo models, which cover a wider range of modes of action. Endocrine activity of surface water samples may be underestimated when measured with in vitro models.

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Investigating endocrine‐disrupting properties of chemicals in fish and amphibians: Opportunities to apply the 3Rs

Cited by 13 publications

References 35 publications

An Amphibian Metamorphosis Assay Dietary Restriction Study: Lessons for Data Interpretation

An Amphibian Metamorphosis Assay Dietary Restriction Study: Lessons for Data Interpretation

Current testing programs for pesticides adequately capture endocrine activity and adversity for protection of vertebrate wildlife

Evaluation of the endocrine activity of surface water samples using aquatic eleuthero‐embryos—A comparison with in vitro assays

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