Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment

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.

Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis

“…A c c e p t e d m a n u s c r i p t BPA and BPA-A can generate non-monotonic dose-response relationships (NMDR), a feature frequently associated with BPA action (for reviews : Vandenberg, 2014;Lagarde et al, 2015).…”

Checking unimodality using isotonic regression: an application to breast cancer mortality rates

“…The basic principle of toxicology stating that the larger the dose of a chemical substance, the greater the response in the human body, is changing. In fact, some researchers have published studies where different non-linear relationships between dose and response, such as non-monotonicity, can possibly occur, implying that a more significant reaction could occur at a low dose as compared to the reaction observed at higher doses (see Vandenberg et al, 2012;Lim et al, 2013;Lagarde et al, 2015). This hypothesis needs to be scientifically verified with the appropriate statistical tools as it could highly impact the regulatory approaches for evaluating toxicity.…”

Effect of Petiveria alliacea Leaves Extract in Decreasing Serum Level of Blood Glucose Level Through Activation of AMPK-α1 in Diabetes Mellitus Rat Models

“…Kurva yang terbentuk antara peningkatan dosis dan respon farmakologis bisa berbentuk huruf U terbalik (bila respons pada dosis intermediet), huruf U (bila respons pada dosis terendah dan tertinggi), bifasik. 24 Penelitian ini membuktikan bahwa hubungan antara dosis dan respons berbentuk huruf U. 25,26 Petiveria alliacea mengandung berbagai bahan aktif meliputi benzaldehyde, benzyl 2-hydroxyethyl trisulphide, coumarin isoarborinol, isoarborinol acetate, isoarborinol cinnamate, isothiocyanates, polifenol, senfol, tanin,dan trithiolaniacine.…”

“…27 Berbagai senyawa tersebut diduga akan berikatan dengan reseptornya secara spesifik dan mempunyai mekanisme kerja obat yang berbeda antara senyawa yang satu dengan lainnya. 28 Senyawa tersebut kemungkinan dapat dimasukkan ke dalam Endocrine Disrupting chemicals (EDcs), 24 akan tetapi untuk membuktikannya, diperlukan penelitian lebih lanjut. Mekanisme kerja senyawa sehingga menghasilkan nonmonotomic dose response disebabkan karena berbagai macam teori yaitu, sitotoksisitas, spesifik reseptor dan kofaktor pada sel dan jaringan, selektivitas reseptor, receptor down regulation and desentsitization dan kompetitif reseptor serta umpan balik negatif.…”

“…28 Peneliti lain menyebutkan bahwa mekanisme kerja NMDR kemungkinan melalui keberadaan beberapa molekular target yang memiliki berbagai macam afinitas dan efek yang berseberangan, fenomena efek balik negatif, desensitisasi reseptor karena dosis tinggi, modulasi metabolisme yang tergantung dosis, toksisitas pada dosis tinggi, dan protein ionisasi tergantung dosis. 24 Pada penelitian ini, belum bisa dijelaskan mekanisme mana yang membuat hubungan antara dosis dan respons tidak linier.…”