Evaluating the evidence for non-monotonic dose-response relationships: A systematic literature review and (re-)analysis of in vivo toxicity data in the area of food safety

Anti-Cancerous Potential of Polysaccharides Derived from Wheat Cell Culture

“…[ 53 ]. It is suggested in the literature that there is a need for further research and identification of substances with non-monotonic dose–response, because they are rarely published [ 54 ]. However, no previous evidence suggests this reverse dose-dependency for polysaccharides.…”

Avoiding Regrettable Substitutions: Green Toxicology for Sustainable Chemistry

“…This difficulty is illustrated by two recent systematic reviews of in vivo, in vitro, and epidemiological evidence for NMDRs which found that the overwhelming number of articles had relatively weak evidence for NMDRs (i.e., only one outlying dose, insufficient number of doses to establish an NMDR). 46,47 In fact, while 14% of the data sets concerned BPA, this was not one of the data sets that actually demonstrated an NMDR. 46 This is not to say that NMDRs do not exist, and perhaps are more common than traditional toxicology would indicateour own research indicates different mechanisms of BPA at a low point on the dose−response curve vs the higher dose 48 but it does point to a need to rethink how we approach such questions.…”

“…However, finding statistically robust evidence of a non-monotonic dose–response curve is difficult using in vitro studies, such as transcriptomics, owing to the intrinsic noise of such studies and the use of models that presume some linearity in gene response to interpret them, and equally challenging in in vivo studies owing to the expense of using enough dose–response points and the overall variability of animals. This difficulty is illustrated by two recent systematic reviews of in vivo, in vitro , and epidemiological evidence for NMDRs which found that the overwhelming number of articles had relatively weak evidence for NMDRs (i.e., only one outlying dose, insufficient number of doses to establish an NMDR). , In fact, while 14% of the data sets concerned BPA, this was not one of the data sets that actually demonstrated an NMDR . This is not to say that NMDRs do not exist, and perhaps are more common than traditional toxicology would indicateour own research indicates different mechanisms of BPA at a low point on the dose–response curve vs the higher dosebut it does point to a need to rethink how we approach such questions.…”

Susceptibility of male reproductive system to bisphenol A, an endocrine disruptor: Updates from epidemiological and experimental evidence

“…[121,124,126] Badding et al [127] also reported some evidence for NMDR in the Consortium Linking Academic and Regulatory Insights on Bisphenol-A Toxicity (CLARITY-BPA) Core study. These six checkpoints originally proposed by Varret et al [128] to describe the NMDR are: i) Whether at least one NMDR model fits better than null model?, ii) Whether it is better than monotonous dose response model?, iii) whether the NMDR is coming from an single dose (a plausible case of outlying), iv) whether the effect size is ± 5%, v) is the slope of the dose-response curve is within the biologically plausible range, and vi) whether the NMDR is consistent in both the directions. The EDCs produce effects on many physiological systems including endocrine tissues through numerous modes of action.…”