Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays

J Toxicol Environ Health B Crit Rev. 2023 Aug 18;26(6):307-341. doi: 10.1080/10937404.2023.2213903. Epub 2023 May 29.

Abstract

The purpose of this study was to determine the toxicological and pharmacokinetic properties of sucralose-6-acetate, a structural analog of the artificial sweetener sucralose. Sucralose-6-acetate is an intermediate and impurity in the manufacture of sucralose, and recent commercial sucralose samples were found to contain up to 0.67% sucralose-6-acetate. Studies in a rodent model found that sucralose-6-acetate is also present in fecal samples with levels up to 10% relative to sucralose which suggest that sucralose is also acetylated in the intestines. A MultiFlow® assay, a high-throughput genotoxicity screening tool, and a micronucleus (MN) test that detects cytogenetic damage both indicated that sucralose-6-acetate is genotoxic. The mechanism of action was classified as clastogenic (produces DNA strand breaks) using the MultiFlow® assay. The amount of sucralose-6-acetate in a single daily sucralose-sweetened drink might far exceed the threshold of toxicological concern for genotoxicity (TTCgenotox) of 0.15 µg/person/day. The RepliGut® System was employed to expose human intestinal epithelium to sucralose-6-acetate and sucralose, and an RNA-seq analysis was performed to determine gene expression induced by these exposures. Sucralose-6-acetate significantly increased the expression of genes associated with inflammation, oxidative stress, and cancer with greatest expression for the metallothionein 1 G gene (MT1G). Measurements of transepithelial electrical resistance (TEER) and permeability in human transverse colon epithelium indicated that sucralose-6-acetate and sucralose both impaired intestinal barrier integrity. Sucralose-6-acetate also inhibited two members of the cytochrome P450 family (CYP1A2 and CYP2C19). Overall, the toxicological and pharmacokinetic findings for sucralose-6-acetate raise significant health concerns regarding the safety and regulatory status of sucralose itself.

Keywords: Sucralose; gene expression; genotoxicity; intestinal barrier; sucralose-6-acetate.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Feces / chemistry
  • Humans
  • Research Design
  • Sucrose* / chemistry
  • Sucrose* / metabolism
  • Sucrose* / toxicity
  • Sweetening Agents* / metabolism
  • Sweetening Agents* / toxicity

Substances

  • trichlorosucrose
  • Sucrose
  • Sweetening Agents