studies have not shown a direct correlation between the amount of toughening and the amount of threshold shift experienced.[15] This suggests that even a toughened cochlea may not be completely protected.Substances[edit]Both furosemide and salicylic acid are considered ototoxic at certain doses. Research has been done to determine their ability to protect against auditory fatigue and permanent damage through toughening phenomena, a state described by reduced active cochlear displacements. Although limited research has been done with these two substances in terms of protective drug regimes because of their associated risks, both have shown positive results in reducing auditory fatigue by the decrease in ROS formation through individual mechanisms described below.[5][17]Furosemide[edit]Furosemide injections prior to noise exposure have been shown to decrease the endocochlear potential.[18] This decrease results in a reduction of active cochlear displacements and it is believed that the protection by furosemide stems from the limitation of excessive vibrations while the cochlear amplifier is depressed.[19]Salicylic Acid[edit]Salicylic acid competitively interferes with anion binding to OHC prestin which thereby reduces motility. This reduction in active displacement is again associated with depression of the cochlear amplifier which decreases the excessive vibrations experienced during noise-exposure.[6][7][8][10]Antioxidants[edit]Vitamins A, C and E have been shown to be 'free radical scavengers' by studies looking for protective tendencies of antioxidants.[20] In addition, NAC, or N-acetyl-L-cysteine (acetylcysteine), has been shown to reduce ROS formation associated with the excessive vibrations induced by the noise exposure.[9][21][22]Limitations[edit]Although auditory fatigue and NIHL protective measures would be helpful for those who are constantly exposed to long and loud noises, current research is limited due to the negative associations with the substances.[5] Furosemide is used in congestive heart failure treatments because of its diuretic properties. Salicylic acid is a compound most frequently used in anti-acne washes, but is also an anticoagulant. Further uses of these substances would need to be personalized to the individual and only under close monitoring. Antioxidants do not have these negative effects and therefore are the most commonly researched substance for the purpose of protecting against auditory fatigue.[5] However, at this time there has been no marketed application. In addition, no synergistic relationships between the drugs on the degree of reduction of auditory fatigue have been discovered at this time.[23]Risk increasing factors[edit]Physical exerciseHeat exposureWorkloadOtotoxic chemicalsThere are several factors that may not be harmful to the auditory system by themselves, but when paired with an extended noise exposure duration have been shown to increase the risk of auditory fatigue. This is important because humans will remove themselves from a noisy environment if it passes their pain threshold.[11] However, when paired with other factors that may not physically recognizable as damaging, TTS may be greater even with less noise exposure. One such factor isphysical exercise. Although this is generally good for the body, combined noise exposure during highly physical activities was shown to produce a greater TTS than just the noise exposure alone.[24][25] This could be related to the amount of ROS being produced by the excessive vibrations further increasing the metabolic activity required, which is already increased during physical exercise. However, a person can decrease their