Ototoxicity: Visualized in Concept Maps

Abstract

Ototoxicity refers to the damage to structures and function of the auditory-vestibular system caused by exogenous agents such as pharmaceuticals, chemicals, and ionizing radiation. There are many potentially ototoxic substances. For example, depending on how ototoxicity is defined, there are 200 to 600 medications that can cause damage to hearing and/or balance. Ototoxicity encompasses cochleotoxicity, vestibulotoxicity, and neurotoxicity. A variety of professional disciplines are involved in determining causation, prevention, and management of ototoxic effects. Research to identify and develop otoprotectants and otorescue agents is emerging and will translate basic scientific discovery into applications for use in hearing conservation programs, safety operations, and clinical care. Original concept maps are presented here to visually represent knowledge pathways, domains, and relationships essential to the understanding of ototoxicity.

When performing compensation and pension (C & P) examinations for the U.S. Department of Veterans Affairs (VA), audiologists may come across records of antimalarial, aminoglycoside antibiotic, or cancer treatments. Based on the Veteran's job code and reported case history, inferences may be made regarding potentially hazardous exposures. C & P examinations are medical–legal examinations that, unlike other audiological examinations, are performed to determine a probability that hearing loss and/or tinnitus is/are likely (or not) to have been caused by an event during military service.

Military noise exposure tends to be the likely etiology for service-connected hearing loss and/or tinnitus; however, there are other possible causal or contributing factors, such as ototoxicity, which must be taken into consideration. ^{1 2 3} Ototoxicity is defined as damage to the structural or functional components of the auditory-vestibular system by exogenous agents, such as ionizing radiation, pharmaceuticals, solvents, heavy metals, and other chemicals. ⁴ It may be possible that the origin of a Veteran's tinnitus is medication-induced ototoxicity and not military noise exposure.

To understand how such an association might be made, the opining clinician needs a knowledge base that spans multiple disciplines, including pharmacology, cellular/molecular biology, and biochemistry, as shown in Fig. 1 . These fields of inquiry can provide the basic understanding of how certain medications affect physical organs and physiological processes.

Figure 1.

What is the basis for knowledge of ototoxicity? This concept map explores knowledge areas that can provide the understanding needed to address the functional deficits due to ototoxicity.

When present, the mechanisms of an adverse event can be elucidated. The clinician must then connect possible damage to probable human auditory-vestibular dysfunction. As each patient is unique, there also will be specific individual considerations and caveats to the norm, which require the clinician to apply medical, statistical, and critical reasoning. In other words, he or she must thoroughly think the case though.

Recognition of multiple potential causal factors can present evaluation and treatment challenges. As in research, there may be a need to consider alternative methodologies, evidentiary models, and interpretive frameworks to make sense of patient histories, complaints, and findings. Critical reflection can help the clinician, the investigator, and the student better understand the “why” rather than just the “how” of audiology. ⁵

The exercise of forming concept maps can provide an opportunity to reflect. Exemplified in Fig. 1 , the concept map is a device that allows for a visual representation of the conceptual framework so that the relationships between knowledge areas can be brought to the forefront. The relationships show discrete thought processes; even though they are single lines, complex interactions showing in-depth understanding can be represented. Particularly important to students, the representation can be continually revised and refined to reflect new knowledge, conceptual elements, and relationships.

The concept maps presented in this article can be used in the classroom and beyond, to guide or expand discussions on what is ototoxicity, what are ototoxins and their effects, and what is an ototoxicity monitoring program (OMP). Before providing these concept maps, a brief introduction will be given to concept maps and concept mapping.

Concept Maps

Concept maps, or Cmaps as they have become known, were first introduced as a research tool in 1972, ⁶ and have since been more widely used as educational tools. ^{7 8 9} A Cmap is a visual representation of someone's thoughts created as a means to answer an overarching question. The question serves as context for the map. In general, Cmaps provide for high-level hierarchical arrangements of information. By following concepts to lower levels, greater and more detailed understanding can be shown. It should be noted, however, that Cmaps allow for knowledge to be organized in the manner that the creator or creators understand the flow of ideas. In this respect, Cmaps are personal creations and will differ accordingly.

Each concept in the Cmap is represented by a word, phrase, or symbol enclosed in a shape, a rectangle or an oval. To form the map, the concepts are linked. The directional lines forming the linkages are labeled with action words or phrases. When combined, two concepts and their link form a proposition, which has meaning and is called a semantic unit. ⁶ As the Cmap is a type of flow chart, most semantic units will be formed in the downward direction. However, single concepts can form more than one proposition and crosslinks can be used to connect concepts in diverse areas of the map, which make for more complicated patterns in the map.

For example, the Cmap in Fig. 1 was created to answer the question: Where does knowledge of ototoxicity (specifically, medication-induced ototoxicity) originate? The question is answered with general educational concepts and flows into more specific knowledge areas. A crosslink shows the relationship between one educational area and others (e.g., medical science applies principles of pharmacology and anatomy/physiology). Another crosslink shows how two differing concepts can be used to arrive at functional deficits.

Cmaps are evaluated based on their overall quality as well as the particular components of structure and content. ¹⁰ The structure of the Cmap should be concise and easy to follow. Its logic should be fairly obvious and crosslinks between knowledge areas should be present. An effective Cmap achieves a balance between selected and excluded information, highlighting key concepts and relationships to provide a clear message. The Cmap should demonstrate understanding by being explanatory rather than purely descriptive.

Concept Mapping

Concept mapping is a general label for “any methodology that is used to produce a picture or map of the ideas or concepts of an individual or group.” ¹¹ As stated earlier, individuals can use concept mapping when reflecting on their own understanding of a topic. Small groups also can formulate the logical expression of their ideas through concept mapping. Taking the process further, when included in a mixed methods participatory group approach, concept mapping can serve as an analytical tool for qualitative research. As such, concept mapping techniques have been used to produce various insights into the thoughts and actions of people who have hearing loss. ^{12 13 14 15 16 17} To generalize the methodology used in these studies related to hearing loss, participants were asked to freely generate concepts relating to a focus question. A moderator or facilitator may have been present. The ideas generated were sorted/grouped and rated. The maps produced were analyzed via multidimensional scaling and hierarchical cluster analysis using specialized software. The results were used to determine work-related problems and support options for people who have hearing loss ¹² ; factors and perspectives of client–clinician interactions determining the purchase of hearing aids ^{13 14} ; and problems, responses, and perspectives of clients and clinicians in regard to hearing aid use. ^{15 16 17}

The summation of overlapping data is important for the interpretation of the output from concept mapping techniques used in qualitative research as the maps are used to obtain structured group conceptualization of a particular topic and the results may be used to make population-based assumptions. Maps generated outside of such research protocols by individuals or as a part of small group student assignments can be used to interpret the level of understanding of a single person or estimate that of a class. For the clinician exploring a new area, creating a Cmap could be a means to work through confusions or difficult processes.

The Cmaps presented in this article were developed using CmapTools software, produced by the Florida Institute for Human and Machine Cognition, and the guidelines provided by the originators of the Cmap, ^{6 7 10} not via the process of concept mapping used in qualitative research projects. Additional information about concept mapping as a structured conceptualization tool for human subjects research is available elsewhere. ^{11 18}

Concepts of Ototoxicity

What is ototoxicity? To answer this question, at least three textbooks ^{19 20 21} have been published along with several special or supplemental editions to journals ^{22 23 24} and many individual articles (over 4,000 results can be found in a PubMed search using the single term “ototoxicity”).

The definition for ototoxicity presented here was generated by the U.S. and international federal, private, and academic subject matter experts of the Ototoxicity Committee of the Department of Defense Hearing Center of Excellence Pharmaceutical Interventions for Hearing Loss (PIHL) Group: ototoxicity refers to damage to the inner ear, specifically to the cochlear and vestibular structures and functions, due to exposure to pharmaceuticals, chemicals, and/or ionizing radiation. ^{4 25} However, as highlighted in the Cmap of Fig. 2 , the answer depends on the context in which the question is asked.

Figure 2.

What is ototoxicity? This concept map summarizes the knowledge areas comprising the basic definition for ototoxicity.

If conceptualized as a Venn diagram ( Fig. 3 ), ototoxicity would encompass the entirety of cochleotoxicity (toxicity specific to the cochlea) and vestibulotoxicity (toxicity specific to the vestibular end organs) but would only overlap somewhat with neurotoxicity (toxicity specific to the neural system, including the peripheral nerves and the brain).

Figure 3.

A Venn diagram of ototoxicity and neurotoxicity. Ototoxicity overlaps with neurotoxicity when there is involvement of the vestibulocochlear nerve and/or central auditory-vestibular nervous system.

In an OMP, which tends to focus on cochleotoxicity, ototoxicity is determined by the outcomes of the measurement tools used. As such, ototoxicity is present only when functional deficits are found within the parameters of the measurement tool.

Functional deficits have their basis in anatomical changes at the cellular level, which may not become apparent until sufficient damage has been caused by the ototoxic agent. Therefore, caution should be exercised when deliberating over the determination of ototoxicity within the context of an OMP, which will be discussed in more detail later.

Most definitions of ototoxicity include the location (auditory, vestibular, and/or neural system) and cause (ototoxic agent or agents). A statement of the problem—reduction, impairment, damage, or injury—tends to be included as well. Descriptions of ototoxicity are often bounded by the inducing agent, regardless of whether the agent was administered in a medical setting as a part of treatment or by exposure in an occupational or recreational setting where hazards should be minimized. Each agent will have a particular mechanism of action, which will result in a particular expression of ototoxicity.

Ototoxicity changes the body on a microscopic level and results in gross deficits. Understanding the way by which the agent affects the body will bias clinical concerns toward cochleotoxicity, vestibulotoxicity, or neurotoxicity. When occurring in a pharmaceutical clinical trial, ototoxicity is considered an adverse event.

Ototoxicity can be understood by knowing the cellular mechanisms, proactively preventing exposures, and by managing care for the patient. The focus of the following will be on understanding ototoxicity from the human perspective. Understanding of ototoxicity from the preclinical perspective is an active area of research. ²³

What is the functional impact of ototoxicity? The third Cmap ( Fig. 4 ) shows the answer by listing and describing the functional implications and impact of ototoxicity on the person.

Figure 4.

What are the clinical effects of ototoxicity? This concept map describes symptoms of ototoxicity that the patient may experience and delves into why they may be important to the person's ability to function both in the immediate and long-term future.

The first branch on the left lists the symptomology of ototoxicity, which depends on what structures are damaged. Cochleotoxicity can result in tinnitus, hearing loss, and the corresponding impact on communication. Aural fullness may result from inflammatory processes that are consequences of the disease for which treatment is administered, the ototoxic treatment itself, or both. Vestibulotoxicity can result in vertigo, dizziness, imbalance, and oscillopsia. Neurotoxicity may impact processing and may also be a mechanism for tinnitus generation.

The expression of an ototoxic effect is not uniform and, again, depends on the mechanism of action specific to the ototoxic agent. ²⁶ Expression also depends on the characteristics of the exposure as well as the individual, which will be discussed in greater detail later. Ototoxic effects may be bilateral or unilateral; symmetrical or asymmetrical; permanent or temporary; and stable, progressive, or reversible. Effects may be exclusively auditory or vestibular, or may compromise both systems. When brain-based regions of the auditory-vestibular system are compromised, the effects may present in combination with other neurocognitive complaints.

The functional impact of ototoxicity can range from barely noticeable to completely debilitating. Quality of life may be affected. These impacts necessitate taking measures to reduce such undesired outcomes; for medication-induced ototoxicity, actions are provided through an OMP.

What are ototoxic agents? Ototoxic agents—also referred to as ototoxins or ototoxicants—are exogenous substances that negatively affect the body's auditory and/or vestibular functions by damaging the underlying sensory and/or neural systems. These exogenous substances can be broadly categorized as pharmaceuticals, solvents, asphyxiants, nitriles, metals, and other chemicals/compounds. ²⁷

Examples are presented in the Cmap of Fig. 5 . While noise is an exogenous hazard, it is not considered an ototoxic agent in this context. This distinction allows noise-induced hearing loss to stand in a category of its own and will be considered later when discussing potential interactions.

Figure 5.

What is an ototoxic agent? This concept map provides an overview of types of agents and concerns associated with those ototoxic agents.

The exact number of ototoxins is unknown. The reported quantity of ototoxic pharmaceutical agents varies from over 200 to over 600. ^{28 29} While some of the variance in reported quantity can be accounted for by differing governmental practices (in the pharmaceutical example, the United States ²⁸ vs. Europe ²⁹ ), more of the variance may be found in the answer to the next question.

What makes a substance ototoxic? Ototoxicity is not necessarily a definite or automatic outcome of an exposure to an ototoxin. Rather, ototoxicity can be viewed as being on a continuum of probability or likelihood with some ototoxic agents being much more likely to cause structural damage or functional impairment than others. The determination of a substance's ototoxicity is through preclinical and clinical research. Preclinical research attempts to identify the location, cellular mechanisms, and pathways by which ototoxic damage may occur.

Clinical research explores the presence, progression, and conditions under which functional deficits manifest in populations of interest. Under certain circumstances, case studies can be used to provide evidence of ototoxicity. Clinicians and researchers must weigh the evidence provided to determine risk. As illustrated in the Cmaps of Figs. 5 and 6 , there are many factors to consider with respect to a potential ototoxic substance, and to the individual receiving or exposed to it. When one is familiar with a specific ototoxin, some of these factors may be obvious, some may not apply, and others may require additional inquiry.

Figure 6.

Who is exposed to or administered an ototoxic agent? This concept map explores the person-centered factors to ototoxicity.

Whether by medical administration or environmental contact, exposure to an ototoxic agent can vary in amount, rate, and duration. Therefore, it is important to consider how much, how often, and for how long exposures have occurred. Ototoxic effects may be immediate or delayed; they may depend on an accumulation of the ototoxin within the structures of the auditory-vestibular system. Ototoxic effects may continue to develop beyond the time of exposure.

The measurement of the functional impact will play an important role in determining whether or not a substance is considered ototoxic. As previously mentioned, pharmaceutical clinical trials consider ototoxicity to be an adverse event. A hearing test using pure tone audiometry may be the gold standard for determining cochleotoxicity; however, it will give no indication of vestibulotoxicity. Therefore, the determination of the presence or absence of the adverse event (ototoxicity) will be dependent on the test selected and the parameters of its use. Additional details on testing will be discussed later, with respect to OMPs.

It is important to note that administration or exposure is often systemic; as such, the effects may not be isolated to the ear. Nephrotoxicity, hepatotoxicity, bone marrow activity, and asphyxiation may place limitations on the administration of a pharmaceutical or exposure to a toxin prior to levels necessary to show ototoxic effects. Therefore, while preclinical research may show potential for a substance to be ototoxic, ototoxicity may not be a practical expectation in a human population or it may take a lower priority when determining prevention efforts.

The potential ototoxicity of a given substance may be altered by the presence of other agents. These synergistic or potentiating factors can worsen the ototoxic effects. In the case of medication-induced ototoxicity, it is important to know what other treatments a patient is undergoing, as there could be important interactions. When exposures occur on the job, protective measures can be used to place barriers in the way of exposure pathways, such as wearing a mask that covers the mouth and nose when exposed to inhalants. Unfortunately, the effectiveness of personal protective equipment (PPE) can vary and may depend on compliance with regulations and appropriateness of the fit. Such is the case with noise exposure, which may be synergistic to or potentiate ototoxicity. ^{1 27 30 31 32}

Fortunately, noise exposure can be prevented with the use of PPE (e.g., hearing protection devices). A concern, however, is that the co-occurrence of noise and the ototoxic agent may place onset of damage at an exposure level that falls below the current exposure limits ²⁷ ; therefore, it may be possible for damage to still occur before action levels requiring the use of PPE for either exposure are reached. While the acceptable noise level of a neonatal intensive care unit is set much lower than that of a workplace (∼45 vs. 85 dBA, respectively), there is concern that the infants who undergo treatment with aminoglycoside antibiotics may still experience synergistic effects with noise exposure. ^{33 34}

Otorescue and otoprotective agents are in the process of discovery and development. These agents are intended to mitigate, prevent, or reverse the ototoxic effects. Several candidates hold promise; however, none have received approval from the U.S. Food and Drug Administration. In an interesting twist, it is possible for one ototoxic agent (aspirin) to reduce the ototoxic effects of another agent (gentamicin). ³⁵ However, as with any interaction, the primary therapeutic effect of the treating agent (in this occurrence, the bacteriostatic or bactericidal activity of gentamicin) should not be interfered with by the possible otoprotectant (more information is available elsewhere on how it may be possible for aspirin to alter antibiotic effectiveness ³⁶ ).

A substance's ototoxicity may also depend on person-specific factors. Genetic factors influence the likelihood of expressing ototoxicity; aminoglycoside-induced ototoxicity and cisplatin-induced ototoxicity both have likely genotypes for predispositions. ³⁷ A prior history of damage to the auditory-vestibular system may also affect how ototoxicity is expressed and determined. Fig. 6 highlights numerous individual variables that may influence the expression of ototoxicity; these will also be important when discussing the OMP.

What is an OMP? The answer is explored in the Cmap of Fig. 7 .

Figure 7.

What is an ototoxicity monitoring program? This concept map shows the higher level details and components of an ototoxicity monitoring program. Knowledge areas regarding testing have not been included.

An OMP implements the principles of early detection and early intervention, with the goal of reducing the functional impact of ototoxicity related to medical treatment. The American Speech-Language-Hearing Association and the American Academy of Audiology have provided guidelines for audiologists to follow when implementing an OMP. ^{28 38} Safety programs administered by industrial health professionals provide on-the-job oversight for possible ototoxicity due to occupational exposures.

Similar to a hearing conservation program, in an OMP, the individual's status prior to administration of a potentially ototoxic agent should be known. However, it is acknowledged that baseline testing may not always be feasible to accomplish. Therefore, testing should be performed as close as possible to the first dose of the ototoxic agent. Unfortunately, onset of ototoxicity may be confounded with preexisting hearing loss or vestibular disorder, particularly if neither had been documented previously.

The known properties of the ototoxic agent will dictate the clinical concerns for the OMP. Not all 600 of the possible ototoxic medications will automatically necessitate inclusion in an OMP. For example, administration of nonsteroidal anti-inflammatory drug (NSAID) may not warrant an OMP; however, the administration of carboplatin (a platinum-based antineoplastic) or tobramycin (an aminoglycoside antibiotic) should warrant the inclusion of the patient in an OMP.

The geographical region in which the OMP is placed will also affect its clinical concerns. Diseases such as malaria and tuberculosis tend to require treatment more often in certain parts of the world. The World Health Organization estimates that 60% of childhood hearing loss is preventable by the appropriate implementation of public health actions, such as OMPs. ³⁹ Unfortunately, there may be socioeconomic, psychosocial, and knowledge-based barriers to implementation. ^{37 40 41 42}

Most OMPs focus on cochleotoxicity. A variety of protocols have been developed for this purpose ⁴³ ; however, their implementation varies. The reasons for this have been explored elsewhere. ⁴⁴ Ideal protocols have yet to be developed for the monitoring of vestibulotoxicity. ⁴⁵

Several of the classification systems used in OMPs were developed to determine adverse events during clinical trials for new drugs or for the novel use of existing drugs. As the investigational medicines had known potential for cochleotoxicity, the classification systems were developed with a focus on functional hearing loss, in other words impairment expected to affect speech understanding as detected through pure tone audiometry. Due to the upper limits placed on testing, most classification systems cannot determine ototoxicity past 8,000 Hz. Detection of damage or change prior to the hearing loss reaching this stage is desired not only to determine presence or absence of an ototoxic effect but also for implementation of early intervention strategies. Therefore, inclusion of higher frequencies in the monitoring protocol is warranted. This topic has been covered in depth elsewhere. ^{37 42 44}

Conclusion

Cmaps can be useful tools for clinicians and students to visualize their level of understanding on complex audiological topics. Figs. 1 , 2 , and 4 , 5 , to 6 are exemplars provided to inspire further discussions on the topic of ototoxicity, which can range from causal agents and underlying cellular mechanisms to the implementation of patient-centered care. The concepts provided here touch on the higher level issues which can be used to frame additional questions focused on the effects of a particular ototoxin. Such a framework may be helpful to those students learning the complexities of ototoxicity or to audiologists examining Veterans with histories of ototoxic exposures.