Including genetic susceptibility towards Parkinson's disease in NAM-based hazard and risk assessment of pesticides: a semi-systematic review.

Parkinson's disease (PD) prevalence has been steeply increasing over the last years. Environmental pollution, including certain pesticides, is considered a significant contributor to this rise. Certain genetic factors may pose an individual or subpopulation at increased risk to develop pesticide-induced PD. To support New Approach Methodologies (NAMs)-based hazard and risk assessment while considering known sources of interindividual variability, the aim of the current work was to identify biological factors related to increased susceptibility towards pesticide-induced PD onset and progression. To this end, a semi-systematic literature search was performed using Sysrev. We identified 61 relevant records. Potential gene-environment interactions were identified for several genes related to toxicokinetics, mitochondrial functioning, neurotransmission and proteostasis. These genes, except those related to toxicokinetics, have been described in Adverse Outcome Pathways (AOPs) leading to parkinsonian motor symptoms. Untargeted (epi)genetic analyses identified potential new targets. NAMs offer the opportunity to include human-relevant genetic interindividual variability in toxicological hazard and risk assessment. For example, an additional test condition with mutations of interest for each Key Event (KE) could be included in a test strategy. Whole-organism models combined with CrispR-CAS techniques are suitable to study the effects of specific mutations on PD risk. Induced pluripotent stem cells (iPSCs) are promising to study interindividual variability in disease susceptibility based on material from genetically diverse donors. Since additional experiments are resource-intensive, further research is required to establish the need and way to include genetic susceptibilities in a regulatory context.