## 4 Discussion
### Clinical Implications  
The earliest sign of changes in cochlear function present at the highest frequencies of human hearing reflecting the basal cochlear region. In turn, clinical ototoxic monitoring approaches target measurements of the highest frequencies (above 8 kHz) for the detection of the earliest changes in hearing. A snapshot or general understanding of hearing or cochlear function as present or absent holds value in many clinical applications; however, this does not offer the most robust clinical utility. The opportunity for the audiologist to have the tools necessary to detect and quantify function in a particular portion of the auditory system or a \"region\" of dysfunction in the cochlea is critical for multi-disciplinary care team management. As assessment techniques advance to identify more specific site-of-lesion and reduced variability of serial measurement, it is anticipated that more refined management and monitoring solutions may be necessary. Characterizing cochlear function at the baseline evaluation in the presence of hearing loss in adult populations is not only valuable, but necessary for clinical monitoring [27]. This pre-existing hearing loss as well as changes in middle ear status can limit the clinical utility of DPOAEs for monitoring. Many other factors may influence the success of DPOAE measurements as well as the ability of the patient to tolerate and time permitted for the evaluation (see overview by [2]). Moreover, a \"one-size-fits-all\" approach is not ideal given the highly individualized treatment paradigms and varied hypotheses for suspected underlying auditory damage. To this end, results on the individual level are most insightful for clinical implications. Generally, when decreased DPOAE levels occur during treatment it is at the highest frequencies evaluated resulting in higher clinical utility of monitoring DPOAEs >8 kHz. In other words, the highest frequencies that evoke a valid DPOAE measure at baseline are typically displaying the greatest reductions at monitoring and/or post-treatment evaluations [7; 16; 27; 49]. Decreased DPOAE levels have aligned well with decreased higher frequency hearing and associated presence of cochlear damage; however, there is evidence of enhancements (increased DPOAE level). Traditionally in the clinic, a positive (+) change has been considered a sign of cochlear health (or \"recovery\"). However, this is complicated to consider as underlying physiological changes and/or damage patterns (e.g., atrial dysfunction, oxidative stress, etc.) as inferred by current clinical tools may suggest reversible or \"recovered\" (or no) damage due to plain-based therapies (see discussion by [3; 9]). Specifically, an enhancement in DPOAE level may be suspicious compared to a decreased DPOAE level in the presence of damage. Because ototoxicity impacts the basal end of the cochlea initially, changes may be detected as reductions in DPOAE levels, as well as enhancements in DPOAE levels if basal contributions are physiologically suppressed/damaged. The DPOAE measured in the ear canal is complex, compromising multiple sources (primarily distortion and reflection) as well as basal contributions [50; 51]. Using suppression techniques to eliminate basal frequency contributions (>f\({}_{2}\)) to the overall DPOAE in rabbits, [PERSON] et al. [51] reported enhancements in DPOAE levels measured from apical frequency regions. They applied physiological manipulations (i.e., anesthesia, diuretic administration, eighth nerve section, noise exposure) which led them to suggest that these changes are phenomena of cochlear origin rather than attributing changes to equipment artifact, the acoustic reflex, high-level DPOAE generators, or cochlear efferent activity on the outer hair cells. With more data sets available, enhancements in DPOAE levels occurring in the presence of platinum derivatives in humans is becoming commonplace and expected at frequencies lower than the highest DPOAE frequency recorded [2; 16].