Six months exposure to a real life mixture of 13 chemicals' below individual NOAELs induced non monotonic sex-dependent biochemical and redox status changes in rats

Food Chem Toxicol. 2018 May;115:470-481. doi: 10.1016/j.fct.2018.03.052. Epub 2018 Apr 3.


This study assessed the potential adverse health effects of long-term low-dose exposure to chemical mixtures simulating complex real-life human exposures. Four groups of Sprague Dawley rats were administered mixtures containing carbaryl, dimethoate, glyphosate, methomyl, methyl parathion, triadimefon, aspartame, sodium benzoate, calcium disodium ethylene diamine tetra-acetate, ethylparaben, butylparaben, bisphenol A, and acacia gum at doses of 0, 0.25, 1 or 5 times the respective Toxicological Reference Values (TRV): acceptable daily intake (ADI) or tolerable daily intake (TDI) in a 24 weeks toxicity study. Body weight gain, feed and water consumption were evaluated weekly. At 24 weeks blood was collected and biochemistry parameters and redox status markers were assessed. Adverse effects were observed on body weight gain and in hepatotoxic parameters such as the total bilirubin, alanine aminotransferase (ALT) and alkaline phosphatase (ALP), especially in low dose and affecting mainly male rats. The low dose group showed increased catalase activity both in females and males, whereas the high dose group exhibited decreased protein carbonyl and total antioxidant capacity (TAC) levels in both sex groups. Non-monotonic effects and adaptive responses on liver function tests and redox status, leading to non-linear dose-responses curves, are probably produced by modulation of different mechanisms.

Keywords: Food additives; Mixture; Pesticides; Real life exposure; Toxicological reference values.

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Complex Mixtures / toxicity*
  • Dose-Response Relationship, Drug
  • Drinking Behavior / drug effects
  • Feeding Behavior / drug effects
  • Female
  • Liver / drug effects
  • Liver / enzymology
  • Liver Function Tests
  • Male
  • No-Observed-Adverse-Effect Level*
  • Oxidation-Reduction
  • Rats, Sprague-Dawley
  • Sex Factors*
  • Time Factors
  • Weight Gain / drug effects


  • Complex Mixtures