Abstract
Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that report NMDR relationships with endocrine disruptors. Fifty-one experimental studies that investigated various effects associated with endocrine disruption elicited by many substances were selected. Scoring criteria were applied by adaptation of an approach previously used for identification of hormesis-type dose-response relationships. Out of the 148 NMDR relationships analyzed, 82 were categorized with this method as having a “moderate” to “high” level of plausibility for various effects. Numerous modes of action described in the literature can explain such phenomena. NMDR can arise from numerous molecular mechanisms such as opposing effects induced by multiple receptors differing by their affinity, receptor desensitization, negative feedback with increasing dose, or dose-dependent metabolism modulation. A stepwise decision tree was developed as a tool to standardize the analysis of NMDR relationships observed in the literature with the final aim to use these results in a Risk Assessment purpose. This decision tree was finally applied to studies focused on the effects of bisphenol A.
Highlights
Non-monotonic dose-response (NMDR) relationships are more frequently reported today in experimental studies than they were 10 years ago [1,2,3]
The procedure developed by Calabrese and Baldwin is a numeric scoring assignment value including the number of tested dose levels, the magnitude of the response associated with each dose compared to the basal level, the significance of the response at each dose, and the presence of other studies confirming these data (Table 1). These criteria were used because we considered these parameters important and sufficient to define the non-monotonic nature of a dose-response relationship and estimate the plausibility of a presumed NMDR relationship (Table 2)
The purposes of this work were to review the literature to identify NMDR relationships observed for some Endocrine disrupting chemical (EDC), to develop a methodology to assess whether those dose-response relationships were sufficiently reliable for use in risk assessments
Summary
Non-monotonic dose-response (NMDR) relationships are more frequently reported today in experimental studies than they were 10 years ago [1,2,3]. NMDR relationships were not considered plausible, and they were not published, reported, or interpreted as relevant biological phenomena. An increasing number of scientists think that NMDR relationships represent a toxicological reality, but supplementary effort is required to revisit the Paracelsus principle of “the dose makes the poison”. The term “NMDR” describes a dose-response relationship characterized by a curve whose slope changes direction within the range of tested doses. Non-monotonicity represents a challenge to fundamental concepts in toxicology and risk assessment. To assess the dose-response relationship of a chemical, several doses are typically tested to define the no observed adverse effect level (NOAEL) and/or the lowest observed adverse effect level (LOAEL). The NOAEL is considered a conservative default threshold below which a chemical is not expected to induce adverse effects, irrespective of the dose [5]
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