The observed increased occurrences of harmful algal blooms (HABs) are largely a consequence of ocean warming due to climate change, eutrophication, and nutrient pollution, which raise concerns that HABs are negatively impacting aquatic ecosystems, coastal resources and the health of coastal communities. Among these HABs, Karenia (K.) brevis affects many Gulf Coast communities, particularly southwest Florida. Over the last decade, K. brevis blooms have caused massive destruction to marine life and morbidity and mortality of marine mammals. These harmful effects of K. brevis are attributed to the release of potent neurotoxins, brevetoxins (PbTx). Currently, the impact of aerosolized PbTx exposure on the human central nervous system (CNS) is not yet known. Human consumption of PbTx causes Neurotoxic Shellfish Poisoning (NSP), including a wide range of neurological symptoms. We recently showed that SW Florida residents exposed to aerosolized PbTx are experiencing NSP-like (NSPL) symptoms, and those with past medical histories (PMHx) of migraine and chronic fatigue syndrome (CFS) were particularly vulnerable to the neurological effects of aerosolized PbTx. Carriers of the apolipoprotein E (APOE) e4 allele who are genetically at a higher risk of cognitive impairment more frequently experience memory problems and fatigue during red tide blooms. We have detected PbTx in blood, and antibodies against PbTx correspond with the reporting of NSPL symptoms following exposure to aerosolized PbTx. However, a dose-response relationship between aerosolized PbTx exposure and the emergence of NSPL and neurological symptoms is currently unknown. Therefore, we will determine a dose-response relationship between aerosolized PbTx exposure and NSPL and neurological symptoms. We will determine whether individuals with preexisting neurological conditions or e4 carriers more frequently experience NSPL compared to general residents and non-carriers. We will also determine whether PbTx in biospecimens and blood PbTx antibodies can serve as biomarkers of NSPL and neurological symptoms. Currently, there is no information available on PbTx pharmacokinetics (PK) in humans. Therefore, we will determine the PK parameters using PbTx in biospecimens and determine their relationship to NSPL and neurological symptoms. Using physiology-based PK modeling, we will estimate the amounts of PbTx that can reach the human brain, which will be critical for understanding the adverse brain health effects from aerosolized PbTx exposure. This work will inform future decision-making for developing strategies to minimize the risks of neurological symptoms in humans following aerosolized PbTx exposure. Given the ongoing threat of climate change on the formation of powerful hurricanes in the Pacific and Atlantic Oceans and the Gulf of Mexico and subsequent occurrences of intense HABs in coastal waters, this poposed work will provide a roadmap for future investigations into studying the adverse human he...