Review of non‐monotonic dose‐responses of substances for human risk assessment

Abstract

In this project, the evidence for the non-monotonic dose-response (NMDR) hypothesis was evaluated by critically reviewing the scientific peer-reviewed literature in the last decade (from 2002 onwards) for substances in the area of food safety. The project was performed according to the systematic review methodology. After a detailed analysis of previous reports published on the issue of NMDRs, a literature search was performed to identify in vivo, in vitro and epidemiological/human studies containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. Of studies with at least 5 dose groups, dose-response datasets were extracted and analysed by PROAST software package. The resulting dose-response results were evaluated for possible evidence of NMDR by applying six checkpoints. These checkpoints addressed both random and non-random errors. The plausibility of NMDRs was assessed based on the number of fulfilled checkpoints. In total, 202 in vivo datasets (from 49 studies), 311 in vitro datasets (from 91 studies) and 9 epidemiological/human datasets (from 2 studies) were identified. Among them, 179 in vivo and 13 in vitro dose-response datasets were analysed and evaluated using the checkpoints. For 23 in vivo datasets there were data limitations, which made the data unsuitable for dose-response analysis. For the in vitro studies, only continuous dose-response datasets presented in tables were analysed. None of the datasets from epidemiological/human studies could be analysed (one of the epidemiological studies was not analysed due to quantal data and the other due to data limitations). In most of the in vivo datasets, the apparent NMDR might have been caused by a single outlying dose group. In total, only 10 out of the 179 in vivo datasets fulfilled all six checkpoints. The latter datasets included studies on the substances quercetin, resveratrol, alpha-benzene hexachloride, and methyl-mercury.