title: Complex mixtures: relevance of combined exposure to substances at low dose levels.
abstract: Upon analysis of chemically complex food matrices a forest of peaks is likely to be found. Identification of these peaks and concurrent determination of the toxicological relevance upon exposure is very time consuming, expensive and often requires animal studies. Recently, a safety assessment framework based on the Threshold of Toxicological Concern (TTC) was published to assess the safety of chemically complex matrices more efficiently. In this safety assessment framework, the toxicological relevance of exposure to unidentified substances in chemically complex food matrices can be related to the Cramer class III TTC threshold, currently set at 90 μg/day. However, possible additive or synergistic effects of combined exposure is not covered. The current evaluation describes the relevance of combined low dose exposure to unidentified substances in chemically complex food matrices. It is concluded that to some extent cumulative effects at exposure levels for each substance at or below the Cramer class III TTC threshold, being present in a complex mixture including food, might occur. However the health relevance of possible cumulative effects at this dose level is considered to be that low that a need for a correction factor to cover possible cumulative effects is very low to absent.
authors.affiliation: TNO, Utrechtseweg 48, PO Box 360, 3700 AJ Zeist, The Netherlands. winfried.leeman@tno.nl
authors.forename: Winfried R
authors.initials: WR
authors.lastname: Leeman
authors.forename: Lisette
authors.initials: L
authors.lastname: Krul
authors.forename: Geert F
authors.initials: GF
authors.lastname: Houben
mesh_terms: D000818:Animals; D045424:Complex Mixtures; D004305:Dose-Response Relationship, Drug; D005506:Food Contamination; D019055:No-Observed-Adverse-Effect Level
chemical_list: D045424:Complex Mixtures
keywords: AChE; ADI; ARfD; AT; BMDL; CAG; CCFM; Chemically complex food matrices; Complex mixtures; Cumulative effects; LOAEL; MOA; Mixture toxicity; NAEL; NOAEL; Risk assessment; TDI; TTC; Threshold of Toxicological Concern; Threshold of Toxicological Concern (TTC); acceptable daily intake; acetyl cholinesterase; acute reference dose; analytical threshold; benchmark dose level; chemically complex food matrices; cumulative assessment group; lowest observed adverse effect level; mode of action; no adverse effect level; no observed adverse effect level; tolerable daily intake