TDP-43 proteinopathy is a defining hallmark of ALS and FTD. 95% of reported ALS cases result from spontaneous mutations with over 97% being attributed to TDP-43 misfunction. TDP-43 is a nuclear RNA binding protein responsible for RNA metabolism with its most notable role being splicing of RNA. TDP-43 pathology is defined by nuclear clearance known as a loss-of-function and cytoplasmic aggregation, a gain-of-function. Loss of function results in cryptic splicing leading to the inclusion of cryptic exons that induce frameshifts causing RNA degradation or cryptic peptides. This disruption of cellular homeostasis leads to neuronal death in both cortical and motor neurons, a defining characteristic of ALS. Studies of the cause of ALS have implicated the exposure to environmental toxins as a risk factor for the progression of ALS. Here we use a fluorescent reporter of TDP-43 cryptic splicing in I3neurons in an assay of 22 environmental toxins to characterize the effects of persistent organic pollutants (POPs) and heavy metals on TDP-43 protein function. We show that increased concentrations of toxins reduce survivability of neurons and increase cryptic splicing events. We conclude that exposure to environmental toxins may contribute to ALS progression by disrupting TDP-43 protein function.