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Mixtures of chemicals present at so-called "safe" levels cause liver damage

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Published: 07 June 2018
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Laboratory worker holds a flask

Glyphosate part of chemical cocktail found toxic at regulatory permitted exposure levels

New research shows that chemicals at low levels deemed safe by regulators for each individual substance are toxic when present in mixtures.

The experiment was designed to reflect real-life scenarios, in which the general population is exposed to combinations of chemicals at low doses from dietary and environmental sources.

In an experiment on the combined toxicological effects of chemical mixtures, four groups of Sprague-Dawley rats were administered mixtures containing carbaryl, dimethoate, glyphosate (used on the majority of GM crops), methomyl, methyl parathion, triadimefon, aspartame, sodium benzoate, calcium disodium ethylene diamine tetra-acetate, ethylparaben, butylparaben, bisphenol A, and acacia gum in their drinking water for a period of 6 months.

The control group received water free from the chemical mixture.

Mixtures were administered containing each chemical in the following doses to each treatment group:
* Low dose: a quarter of the EU acceptable daily intake (ADI, the level that is supposedly safe to ingest over a long-term period)
* Medium dose: the same level as the ADI
* High dose: five times the ADI.

In relation to the animals' body weight gain, major increases (above 10%) were observed in all male groups relative to controls throughout the 6 months follow-up period. Modest increases were observed also for the females of the medium and high dose groups, although an increase above 10% was observed only in the high dose group at 6 months.

Adverse effects were observed in liver parameters, especially at the low dose and affecting mainly male rats.

Non-linear dose responses were observed for most of the endpoints studied, meaning that the toxic effect did not increase in line with the dose, but lower doses had a more toxic effect.

Overall, the results suggest that exposure to low doses of the chemical mixture might induce liver damage as a result of the combination of different toxic mechanisms.
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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.
Docea AO, Gofita E, Goumenou M, Calina D, Rogoveanu O, Varut M, Olaru C, Kerasioti E, Fountoucidou P, Taitzoglou I, Zlatian O, Rakitskii VN, Hernandez AF, Kouretas D, Tsatsakis A.
https://www.ncbi.nlm.nih.gov/pubmed/29621577

Abstract

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.

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