A systematic literature review of fenugreek seed toxicity by using ToxRTool: evidence from preclinical and clinical studies

Abstract

Fenugreek (Trigonella foenum graecum) seed extract is a bioactive ingredient of many food supplements. Hence, there is a need for systematic assessment of the quality of published toxicological studies for its use in human health, hazard consideration, and risk assessment. The aim of the present investigation was to determine the reliability of published toxicological studies of fenugreek seed by using ToxRTool (Toxicological data reliability assessment tool). A comprehensive systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, CPCI-S, ICTRP, Ovid, and Google Scholar till October 2018. Each identified study was evaluated for its quality using the ToxRTool with outcomes such as combined score, weighted score, and reliability category by three independent raters. Correlations of various criteria groups with the combined score were evaluated by Pearson correlation and Kendall rank correlation coefficient. Inter-rater consistency was measured by Cronbach's alpha coefficient. The database searches initially yielded 436 results, of which 391 (89.67%) studies were “not assignable”. The remaining 45 studies were included for quantitative analysis by ToxRTool. Based on the weighted score, 17 in-vivo, and 3 in-vitro studies were determined to be “Reliable Without Restriction” which were conducted according to international guidelines such as GLP. These studies have a significant difference (p < 0.05) for the combined and weighted score as compared to non-GLP studies. Remaining 28 in-vivo and 2 in-vitro studies were determined to be “Not Reliable.” The GLP studies conducted with “identified study material” have a significant difference (p < 0.0001) between combined and weighted score as compared to studies which used “non-identified study material”. For criteria group of ToxRTool I, III and V, the Pearson correlation with the combined score was found to be 0.875, 0.734 and 0.905, respectively and Kendall rank correlation coefficient was found to be 0.764, 0.551 and 0.752, respectively. Cronbach's alpha coefficient for combined score and weighted score were 0.920 and 0.887, respectively. In conclusion, the ToxRTool was found useful to identify seventeen toxicity studies of fenugreek seeds as “Reliable without Restrictions”. These studies showed a broad margin of safety for the standardized extract of fenugreek seeds and can form a basis for toxicological risk assessment with reasonable certainty.