Chapter Seven: Neurochemical effects of Halogenated Organic Compounds: Possible adverse outcome pathways and structure-activity relationships
Halogenated organic compounds (HOCs) are long-lived toxic compounds and are of major concern for ecosystem and health. The use and manufacture of several HOCs is banned or phased out in most countries, but some HOCs are still being used in several countries. The levels of certain HOCs, such as polychlorinated biphenyls (PCBs), declined in the environment, but new HOCs, such as polybrominated diphenyl ethers (PBDEs), have been increasing or stable. HOCs exposure is known to cause a wide spectrum of effects including reproductive, developmental, immunologic, carcinogenic, and neurotoxic effects. It is of particular concern that neurotoxic effects have been observed in humans at low parts per billion (ppb) environmental concentrations. Epidemiological and experimental evidence shows that PCB exposure is associated with motor, sensory, and cognitive deficits in humans and animal models. Although several adverse outcome pathways (AOPs) were postulated for PCB and other HOC-induced neurotoxic effects, changes in altered intracellular signaling processes including calcium and protein kinase C (PKC) signaling, altered neurotransmitters, oxidative stress, and thyroid hormone imbalance are predominant. The current chapter focuses on (1) discussing the potential AOPs in detail with data from both in vitro and in vivo studies (2) extend structure–activity relationship (SAR) among PCBs with other structurally related chemicals such as PBDEs and polychlorinated diphenyl ethers. For more details about role of thyroid hormone imbalance, please see Chapters 3 and 6. For the role of Ryanodine receptor in intracellular signaling processes, please see Chapter 4. This book chapter is a comprehensive review discussing molecular effects of HOCs at cellular level to the adverse effects seen in whole animals including structural, physiological, sensory, and functional changes.