A Combined Morphometric and Statistical Approach to Assess Nonmonotonicity in the Developing Mammary Gland of Rats in the CLARITY-BPA Study

Montévil, Maël; Acevedo, Nicole; Schaeberle, Cheryl M.; Bharadwaj, Manushree; Fenton, Suzanne E.; Soto, Ana M.

doi:10.1289/ehp6301

Cited by 32 publications

(60 citation statements)

References 74 publications

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“…For some organs such as the mammary gland, there was a break between 25 and 250 μg/kg/day doses in all datasets at all ages, which was analyzed by specific statistical methods appropriate for non-monotonicity. The fact that this break is present in all time points analyzed and in the vast majority of the specific measurements clearly indicate that the NMDRC is not spurious [ 17 ]: on the contrary, it shows that there is an underlying causal relationship.…”

Section: Integrated Discussionmentioning

confidence: 99%

“…Results of the Core guideline study were published in a single report [ 2 ], and results of several academic studies were published independently in peer-reviewed journals [ [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] ]. Assessments of the overall study design [ 18 , 19 ] and a summary of available datasets from multiple CLARITY-BPA studies [ 20 ] are also published in peer-reviewed journals.…”

Section: Introductionmentioning

confidence: 99%

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Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Heindel

Belcher

Flaws

et al. 2020

Reproductive Toxicology

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Consortium Linking Academic and Regulatory Insights on BPA Toxicity" (CLARITY-BPA) was a comprehensive "industry-standard" Good Laboratory Practice (GLP)-compliant 2-year chronic exposure study of bisphenol A (BPA) toxicity that was supplemented by hypothesis-driven independent investigator-initiated studies. The investigator-initiated studies were focused on integrating disease-associated, molecular, and physiological endpoints previously found by academic scientists into an industry standard guideline-compliant toxicity study. Thus, the goal of this collaboration was to provide a more comprehensive dataset upon which to base safety standards and to determine whether industry-standard tests are as sensitive and predictive as molecular and disease-associated endpoints. The goal of this report is to integrate the findings from the investigator-initiated studies into a comprehensive overview of the observed impacts of BPA across the multiple organs and systems analyzed. For each organ system, we provide the rationale for the study, an overview of methodology, and summarize major findings. We then compare the results of the CLARITY-BPA studies across organ systems with the results of previous peer-reviewed studies from independent labs. Finally, we discuss potential influences that contributed to differences between studies. Developmental exposure to BPA can lead to adverse effects in multiple organs systems, including the brain, prostate gland, urinary tract, ovary, mammary gland, and heart. As published previously, many effects were at the lowest dose tested, 2.5μg/kg /day, and many of the responses were non-monotonic. Because the low dose of BPA affected endpoints in the same animals across organs evaluated in different labs, we conclude that these are biologically-and toxicologically-relevant.

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Section: Integrated Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Heindel

Belcher

Flaws

et al. 2020

Reproductive Toxicology

Self Cite

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“…However, for each outcome there is a lack of consistency across existing studies." For the CLARIY-BPA study by Montevil (Montevil et al 2020) recently highlighted (Soto et al 2021) as a key effect observed in CLARITY and discussed here in Appendix A, EFSA concluded "In the absence of any clear biological explanation why the dose response curve may behave in such non-linear manner and taking into consideration lack of overall significance (from the NULL model) the pattern observed may be a result of overfitting of the data rather than a true biological relationship. In any case, the findings from this paper need to be replicated before any conclusions on relevance and adversity can be made.…”

Section: Nmdr Effects For Bpa?-the View Of Efsamentioning

confidence: 98%

“…Although the CLARITY-BPA study was conducted blinded, some of these assessments are post hoc analyses after un-blinding. See Appendix A for a detailed discussion on the study on the mammary gland development (Montevil et al 2020) highlighted as the study providing "the strongest evidence of non-monotonicity within the CLARITY study" by Soto et al (Soto et al 2021).…”

Section: Science's First Principle: Replicationare Low-dose Nmdr Effects Replicated In Independent Repetitions?mentioning

confidence: 99%

Scientific discrepancies in European regulatory proposals on endocrine disruptors—REACH regulation quo vadis?

Natsch

2021

Arch Toxicol

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The EU chemical strategy for sustainability places a high focus on endocrine-disrupting chemicals (ED), the importance of their identification with increased testing and a ban in consumer products by a generic approach. It is assumed that for ED no threshold and hence no safe dose exists, leading to this generic approach. This view appears to be linked to the claim that for ED ‘low-dose non-monotonic dose response’ (low-dose NMDR) effects are observed. Without this hypothesis, there are no scientific reasons why classical risk assessment cannot be applied to the ED mode-of-action. Thus, whether for ED low-dose NMDR effects are considered a reproducible scientific fact by European authorities is Gretchen’s question in this politicized field. Recent documents by the SCCS, EFSA and ECHA reviewed herein illustrate the diverging views within European scientific bodies on this issue. Furthermore, ED researchers never replicated findings on low-dose NMDR in blinded inter-laboratory experiments and the CLARITY-BPA core studies could not find evidence for reproducible NMDR for BPA. ECHA proposes a battery of in vitro tests to test all chemicals for ED properties. However, these tests were never validated for relevance and their high positivity rate could lead to increased follow-up animal testing. Based on (i) lack of reproducibility data for low-dose NMDR, (ii) diverging views within European authorities on NMDR and (iii) lack of fully validated in vitro test methods it might be premature to fast-track the wide-ranging changes in the regulatory landscape proposed by the authorities ultimately leading to drastically increased animal testing.

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“…Finally, a few other reports from the CLARITY project have suggested some indications of NMDR. The outcomes assessed, including different measures of fetal urogenital sinus (Uchtmann et al., 2020 ), mammary gland response (Montévil et al., 2020 ), modest changes in % basophil and serum bile acid concentrations (Badding et al., 2019 ). A detailed assessment of these studies is provided in Annex A .…”

Section: Assessmentmentioning

confidence: 99%

Opinion on the impact of non‐monotonic dose responses on EFSA′s human health risk assessments

More¹,

Benford²,

Bennekou³

et al. 2021

EFS2

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This Opinion assesses the biological relevance of the non‐monotonic dose responses ( NMDR ) identified in a previous EFSA External Report (Beausoleil et al., 2016) produced under GP / EFSA / SCER /2014/01 and the follow‐up probabilistic assessment (Chevillotte et al., 2017a,b), focusing on the in vivo data sets fulfilling most of the checkpoints of the visual/statistical‐based analysis identified in Beausoleil et al. (2016). The evaluation was completed with cases discussed in EFSA assessments and the update of the scientific literature. Observations of NMDR were confirmed in certain studies and are particularly relevant for receptor‐mediated effects. Based on the results of the evaluation, the Opinion proposes an approach to be applied during the risk assessment process when apparent non‐monotonicity is observed, also providing advice on specific elements to be considered to facilitate the assessment of NMDR in EFSA risk assessments. The proposed approach was applied to two case studies, Bisphenol A and bis(2‐ethylhexyl phthalate ( DEHP ) and these evaluations are reported in dedicated annexes. Considering the potential impact of NMDR s in regulatory risk assessment, the Scientific Committee recommends a concerted international effort on developing internationally agreed guidance and harmonised frameworks for identifying and addressing NMDR s in the risk assessment process.

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A Combined Morphometric and Statistical Approach to Assess Nonmonotonicity in the Developing Mammary Gland of Rats in the CLARITY-BPA Study

Cited by 32 publications

References 74 publications

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Scientific discrepancies in European regulatory proposals on endocrine disruptors—REACH regulation quo vadis?

Opinion on the impact of non‐monotonic dose responses on EFSA′s human health risk assessments

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