A German archive of pesticide studies in rats and mice shows that, for 27 of 154 substances, more animals survived to the end of the study in at least one treated group than in the untreated control
A German archive of pesticide studies in rats and mice shows that, for 27 of 154 substances, more animals survived to the end of the study in at least one treated group than in the untreated control
On November 1, Aging Cell published a paper by researchers at Newcastle University, Durham University and the German Federal Institute for Risk Assessment. The authors selected studies from the institute’s archive with 50 or more animals per dose and sex and examined them for survival outcomes.
Demonstrating hormesis in mammals is difficult. This protective response to a low dose of a toxic substance or stress can extend lifespan, but showing it requires long experiments with several doses and large groups. EU law requires such studies for pesticide approval: rats receive the substance in their feed for about two years, and mice for one and a half to two years, while researchers count the survivors.
A random sample of 545 archive records yielded long-term data for 154 substances, providing more than 2000 comparisons with untreated control groups. For 27 substances, at least one group defined by species, sex and dose had 10% or more additional survivors at the end of the study compared with its control, a statistically significant difference; 15 of these substances can be publicly identified. The authors describe the analysis as exploratory: with so many comparisons, some significant differences could have occurred by chance. A correction for multiple comparisons that allows, on average, one false finding in ten leaves two of the 168 comparisons for the 15 named substances statistically significant: the insecticide clothianidin in male rats and the herbicide bromoxynil in female rats.
Diet may explain part of the survival improvement: at doses that increased survival, clothianidin reduced food intake and body weight, and food restriction itself extends lifespan in rodents. Bromoxynil, the other substance whose result remained significant after correction, reduced body weight while food intake remained unchanged.
Mild disruption of mitochondrial function can trigger protective responses and extend lifespan in worms and mice. In 2008, low doses of 2,4-dinitrophenol, a mitochondrial uncoupler that allows cells to consume oxygen while storing less energy as ATP, reduced body weight and extended lifespan in mice.
According to the literature, six of the 15 substances disrupt energy production in plants and insects. In human lung cells, about half of the 15 altered oxygen consumption, a measure of mitochondrial function, and bromoxynil increased it. When ATP production was blocked in the cells, oxygen consumption still increased with bromoxynil, as it does with known uncouplers. This indicates that bromoxynil uncouples mitochondria, consistent with the loss of body weight despite unchanged food intake.
The authors tested bromoxynil in C. elegans worms, which live for about three weeks. With bromoxynil, more worms were active during the first week of adulthood, and older worms moved faster; movement reflects nerve and muscle function and metabolism. More worms receiving bromoxynil survived exposure to the poison paraquat, consistent with hormesis. However, the worms’ lifespan decreased by about two days. The authors suggest:
“The window for hormesis may shift or narrow with age, and the stress caused by mitochondrial uncoupling may change from beneficial to harmful as the animals age.”
In the same archive, bromoxynil caused liver tumours in male mice. In 2017, the European Food Safety Authority concluded that the mechanism responsible for these tumours was not relevant to humans, while in 2011 the US Environmental Protection Agency classified the substance as a possible human carcinogen.
The authors propose using such archives to supplement conventional compound screening and to train AI to select interventions for testing in mammals.