Matrix-derived combination effect and risk assessment for estragole from basil-containing plant food supplements (PFS)

Abstract

Basil-containing plant food supplements (PFS) can contain estragole which can be metabolised into a genotoxic and carcinogenic 1'-sulfoxymetabolite. This study describes the inhibition of sulfotransferase (SULT)-mediated bioactivation of estragole by compounds present in basil-containing PFS. Results reveal that PFS consisting of powdered basil material contain other compounds with considerable in vitro SULT-inhibiting activity, whereas the presence of such compounds in PFS consisting of basil essential oil was limited. The inhibitor in powdered basil PFS was identified as nevadensin. Physiologically based kinetic (PBK) modeling was performed to elucidate if the observed inhibitory effects can occur in vivo. Subsequently, risk assessment was performed using the Margin of Exposure (MOE) approach. Results suggest that the consequences of the in vivo matrix-derived combination effect are significant when estragole would be tested in rodent bioassays with nevadensin at ratios detected in PFS, thereby increasing MOE values. However, matrix-derived combination effects may be limited at lower dose levels, indicating that the importance of matrix-derived combination effects for risk assessment of individual compounds should be done on a case-by-case basis considering dose-dependent effects. Furthermore, this study illustrates how PBK modeling can be used in risk assessment of PFS, contributing to further reduction in the use of experimental animals.

Keywords: 3′-phosphoadenosine-5′-phosphosulfate; 7-hydroxycoumarin; 7-hydroxycoumarin sulfate; 7HC; 7HCS; BMD; BMDL(10); Benchmark Dose; DMSO; E-3′-N(2)-dGuo; Estragole; HPLC; MOE; Margin of Exposure; Matrix-derived combination effect; N(2)-(trans-isoestragol-3′-y1)-2′-deoxyguanosine; Nevadensin; PAPS; PBK; PCP; PFS; Physiologically based kinetic (PBK) modeling; Plant food supplements (PFS); Risk assessment; SULT; TFA; UDS; ULC/MS; UPLC; dimethyl sulfoxide; high performance liquid chromatography; lower confidence limit of the benchmark dose resulting in a 10% extra cancer incidence; pentachlorophenol; physiologically based kinetic; plant food supplements; sulfotransferase; trifluoroacetic acid; ultra liquid chromatography/mass spectrometry; ultra performance liquid chromatography; unscheduled DNA synthesis.