IN VIVO NEUROPHYSIOLOGICAL ASSESSMENT OF IN SILICO PREDICTIONS OF NEUROTOXICITY: CITRONELLAL, 3,4-DICHLORO-1-BUTENE, AND BENZYL BROMOACETATE
Neurotoxicants may be widespread in the environment and can produce serious health impacts in the human population. Screening programs have generated data for thousands of chemicals, but these in vitro methods alone have not been shown to accurately predict neurotoxicity requiring repeated exposure for accurate prioritization of every neurotoxicant. Previously we have used the Hard-Soft Acid-Base (HSAB) in silico model to evaluate a group of structurally diverse chemicals by focusing on electrophilic properties (Melnikov et al., 2020). However, the accuracy of these predictions for structurally diverse chemicals have not been evaluated using in vivo methods. We selected three predicted cumulative toxicants, citronellal (CIT), 3,4-dichloro-1-butene (DCB), and benzyl bromoacetate (BBA) for in vivo neurotoxicological testing. Adult male Long-Evans rats were treated orally with CIT, DCB, or BBA for 8 weeks. Behavioral observations were recorded weekly to assess motor function. Peripheral neurophysiological measurements included nerve excitability (NE) tests which included compound muscle action potentials (CMAPs) in the tail and foot, and mixed nerve action potentials (MNAPs) in the tail. Traditional compound nerve action potentials (CNAPs) and nerve conduction velocity (NCV) in the tail were also quantified. Central nervous system function was examined using somatosensory evoked potentials recorded from the cortex (SEPCTX) and cerebellum (SEPCEREB). CIT or BBA did not result in significant alterations to peripheral nerves or somatosensory function. DCB reduced grip-strength and altered peripheral nerve function. The MNAPs required less current to reach 50% amplitude and a lower calculated rheobase, suggesting increased excitability. Increased CNAP amplitudes and greater NCV were also observed. Novel changes were found in the SEPCTX with an abnormal peak forming in the early part of the waveform of treated rats, and decreased latencies and increased amplitudes were observed in SEPCEREB recordings. Overall, this data contributes to refining the HSAB in silico model for use in predicting cumulative neurotoxicity and assisting with prioritization of testing chemicals to protect human health.