Next Generation Risk Assessment of Acute Neurotoxicity from Organophosphate Exposures Using the In Vitro-In Silico Derived Dietary Comparator Ratio

Organophosphate (OP) pesticides are common environmental contaminants, of which the resulting acetylcholinesterase (AChE) inhibition and concomitant neurotoxic effects following exposure remain a global concern. To evaluate the safety upon acute exposure to OP pesticides, the Dietary Comparator Ratio (DCR) approach was used for the first time for this class of chemicals. Six OPs including chlorpyrifos, diazinon, fenitrothion, methyl parathion, profenofos, and chlorfenvinphos were selected as model compounds. Seventy-four reports of human exposures were collected, and a DCR value at each defined exposure level was calculated with in vitro determined AChE inhibition potency and in silico simulated internal exposures. Results indicate that the DCR outcomes are comparable to the actual knowledge on the presence or absence of in vivo AChE inhibition and adverse effects for the respective exposure scenarios. Of all collected scenarios, only four false positives but no false negatives were obtained. No safety concern on acute neurotoxicity appears to be raised for the evaluated environmental exposure scenarios to OPs. To conclude, the described DCR approach provides an adequate evaluation of the OP-induced adverse outcomes for humans, shedding light on its utility for 3Rs-compliant safety assessment of chemicals with different toxicity mechanisms especially for which in vitro bioassays are available.