Gut microbiota-mediated pesticide toxicity in humans: Methodological issues and challenges in the risk assessment of pesticides.

Many in vivo and in vitro studies have shown that pesticides can disrupt the functioning of gut microbiota (GM), which can lead to many diseases in humans. While the tests developed by the Organization of Economic Cooperation and Development (OECD) are expected to capture most apical effects resulting from GM disruptions, exclusion of GM in the risk assessment might mischaracterize hazards or overestimate/underestimate risks, especially when extrapolating results from one species to another species or population with a substantially different GM. On the other hand, direct assessment of GM-mediated effects may face challenges in identifying hazards, since not all GM perturbations will lead to human adverse effects. In this regard, reliable and validated biomarkers for common GM-mediated adverse effects may be very useful in the identification of GM-mediated pesticide toxicity. Nevertheless, proving causality of GM-mediated effects will need modifications of Bradford Hill criteria as well as Koch's postulates, which are more suitable for the "one-pathogen" paradigm. Furthermore, risk assessment of GM-mediated effects may require pesticide toxicokinetics along the gut, possibly through modeling, and the establishment of the involvement of GM in the mechanism of action (MOA) of the pesticide. Risk assessment of GM mediated effects also requires the standardization of experimental approaches as well as the establishment of microbial reference communities, since variations exist among GM in human populations.