A Health Intersection of Toxicology and Clinical Medicine

Introduction: The Nature of Medicine

The objective of practicing medicine is simple: keep people healthy and avoid pathologies by using standard-of-care clinical practices. However, many activities in life appear simple on the surface but are more complex once they are examined more closely. Practicing medicine is one of those activities. Consequently, clinicians are always searching for tools and strategies to reduce complexity and improve the delivery of care to their patients. One improvement in healthcare delivery is the use of biomarkers to assist clinicians with their tasks. An important part of the development and evolution of human medicine by using biomarkers has occurred outside of clinical practice and can be understood by looking at the more generic fields of biology with particular attention to toxicology. Knowledge of biomarkers and understanding the continuum in which they function in and for toxicology facilitates not only an understanding of medicine but also its clinical practice.

Indeed, biomarkers have their place in medicine and they are an important component of toxicological assessments of therapeutics as they are being developed. For example, biomarkers assist the toxicologist in assessing exposure to new drug entities. When toxicologists develop new biomarkers for drugs, it is not uncommon that the same biomarkers find their way into clinical uses.

Biomarkers are not limited for toxicologists who participate in drug developments; they are useful tools for assessing the extent and consequences of all types of xenobiotic exposures. The exposures can occur from all types of products of intentional uses and material known to wander through the environment which are likely to be materials of non-intentional use. Biomarkers, the sentinels of biology, are useful tools in assessing the progress of toxicity (toxicodynamics) or following the progression of a disease (pathodynamics). It is interesting to note that the nexus of toxicodynamics and pathodynamics became apparent in the COVID-19 pandemic when the toxicity of a potential treatment was necessarily viewed in the context of the progression or pathodynamics of the SARS-CoV-2 infection.

The noteworthy theme for biomarkers whether they are used in medicine or result from intentional use of products or unintentional exposure to materials that exist in the environment is that biomarkers identify and quantify homeostasis.

The Essence of Homeostasis

Health can be understood as a system in balance and not distorted outside its normal limits. The balance of a biologic system both within itself and with its surroundings is called homeostasis. Because medicine is a biologic enterprise, it necessarily follows that its directives are mandated by homeostasis. Consequently, health refers to a homeostatic state, and non-health or sickness is the absence of homeostasis or at least a disruption of it beyond some limit. Whether naturally or through overt actions, deviations from homeostasis occur, most of which should be addressed.

While health is a state conforming to a natural or normal homeostatic standard, determining the extent of deviation from homeostasis that constitutes the absence of health and how much therapy is necessary to re-establish homeostasis and restore a healthy state can be problematic. Many variables confound the issue of a deviation from homeostasis and restoring a homeostatic condition. For example, individuals’ responses to diseases vary, resulting in differing capacities to tolerate deviations from homeostasis. The extent of deviation from homeostasis may not be possible to physically measure. In addition, developing therapies without experimenting on the actual disease is difficult if not impossible in certain situations. Thus, problems abound.

The numerous ways in which a system can diverge from its homeostatic state generate an even larger list of questions about how to restore the system to a homeostatic condition. The tasks of practicing medicine, maintaining homeostasis in patients, and providing appropriate therapy without further compromising patients' health are challenging. The initial task is to identify a treatment and determine its safe use. To do this, surrogate indicator systems are used to identify and test therapies that will contribute to maintaining homeostasis in humans or restoring homeostasis (health) after it has been compromised.

Once a treatment has been identified and tested for its safety and efficacy, the next set of challenges has the patient as its focus. These challenges fall into three main categories: diagnostic, prognostic, and therapy monitoring. ¹ Sentinel indicators are needed to overcome these main challenges and to monitor the homeostatic condition of a patient before, during, and after a treatment for a disease. The conclusion is that the whole process of monitoring a patient’s health can be carried out by sentinel indicators or biomarkers that convey (1) when a patient is deviating from homeostasis; (2) the patient’s progress during treatment; and (3) when the patient returns to a homeostatic condition. Indeed, using the comprehensive function of biomarkers is an efficient strategy to maintain people’s health.

The description of homeostasis in the practice of medicine has analogous roles and functions in toxicology: the principles are the same. While in the case of medicine, diseases cause the distortion of homeostasis, and in the case of toxicology, toxicants and toxins are responsible for the changes and distortions of health.

Definitions of Biomarker for Clinical Practice

In the strictest sense, a descriptive definition for marker includes the notion that it is a label, indicator, representative, or proxy that has been identified for something else requiring attention or consideration. At times, the word marker is combined with another word for specificity or to limit its scope. When a marker is used in a biological setting to identify or measure a variable related to homeostasis, the resulting portmanteau, biomarker, is an indicator of a biological change. While biomarker may reasonably represent an identifier in the scope of biology, this term is vague and lacks precision. Fortunately, the Biomarkers Definitions Working Group ² developed a descriptive definition for the term biomarker:

A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

The Working Group ² also provided categories for additional clarity to the biomarker definition by describing discrete functions for biomarkers when they are used as tools in medicine. Following are the Working Group’s categories with an added synoptic description for additional clarity:

• Diagnosing a disease: Does a patient have a particular disease?

• Staging the extent of a disease: How far has the disease progressed?

• Prognosticating a disease’s outcome: What is the likely outcome for a patient the disease?

• Assessing a response to a therapeutic intervention: Is the disease responding to therapy?

The essence embodied in the descriptive and operational definitions of biomarkers can be described in many ways. The concept of a biomarker is like an exquisitely sculptured statue: it requires viewing from 360°. The term biomarker and all of the necessary components embodied in the descriptive and operational components are necessary and useful, but either individually or collectively they do not convey the important concept of homeostasis.

The whole purpose of biomarkers is to identify, define, and negotiate a path to achieve and maintain homeostasis, with the ultimate result being good health.

In a practical sense, clinicians use biomarkers to assist in maintaining homeostasis in patients.

For a biomarker to achieve its intended objective, certain criteria and standards must be met. As the first and most important criterion, a biomarker must function such that it provides accurate responses, yielding reliable information. Second, a biomarker must be responsive in a dose range that is physiologically relevant, and if the biomarker is a surrogate for a particular drug, it must respond reliably at the therapeutic dose levels of the target drug. The third requirement for a biomarker is that it must react in a dose–response manner to the signal for which it is a surrogate. Finally, the relationship between a biomarker and the change that it reflects must be an empirically demonstrated. ³

Biomarker Needs in Medical Practice

While the explosion of genomics research has influenced the practice of medicine,^4,5 the practice of medicine may have also caused the surge in genomics research. History may reveal the driver and the element being driven. In any event, the practice of medicine is heading in a positive direction, supported by the contributions that biomarkers make.

The future of the practice of medicine is not certain. However, optimizing people’s health and facilitating their health maintenance constitute one established objective of the practice of medicine. Achieving this objective is manageable when guided by an orderly approach rather than relying on serendipity. Biomarkers play an important role in clinical practice for achieving and maintaining homeostasis. Some spheres of activity related to the future practice of medicine are already forming or are inevitable based on how technology is advancing and society is evolving. A genetic understanding of patient populations is driving the practice of medicine toward a more individualized approach called personalized medicine.^5,6 The terms personalized medicine and precision medicine are used interchangeably. Precision medicine describes an intended outcome, while personalized medicine describes the process by which the intended outcome is achieved for a typical treatment. The National Research Council ⁷ cautions that personalized medicine does not mean creating therapeutics for individual patients; instead, personalized medicine serves as a means to emphasize the focus of therapies or susceptibility toward a particular ailment and a subpopulation with that ailment. Implementing personalized medicine requires greater efficiency and effectiveness in the practice of medicine, and biomarkers are an integral part of helping medicine meet those demands.

Based on the two powerful mandates of medicine of delivering healthcare to more people and reducing healthcare costs, a continued emphasis will be placed on translational medicine. The road to translational medicine, bench-to-bedside, starts with therapeutic developments and ends with patients receiving the necessary care. In addition to currently practiced healthcare delivery mechanisms, a new form of medical practice is emerging, the name of which may be mobile or remote medicine. This new form of clinical practice has three distinct dimensions: (1) mobile medicine, where a clinic comes to the patient, reflecting an expanded (complete clinic) version of the “house call” or a reverse form of urgent care centers; (2) telemedicine, including mobile phone apps; and (3) home test kits. It is easy to see how biomarkers will help to implement these new delivery mechanisms and facilitate communication between the patient and clinician.

In addition to quicker delivery from a better focused healthcare system, another driver of precision medicine is the requirement for more favorable economic results. The “sheep dip” practice where a standard protocol is used for patients who fit specific criteria is potentially more costly on two counts: (1) standard protocol-directed care may be excessive and wasteful and (2) for genetic reasons, including the severity of a disease for specific individuals, protocol-directed care may be inadequate. Tailored biomarkers can help precision medicine achieve its goal of being more focused.

The effectiveness of personalized medicine efforts increases with enrichment strategies for population segments. While the current mantra of society calls for diversity, the exact opposite is necessary to implement personalized medicine. The strategies for achieving homogeneity are in opposition to personalized medicine. For achieving the goals of personalized medicine, it is necessary to distinguish or minimize biological variability such that the pool of participants selected results in a population that is more likely to contain patients that would receive the greatest benefit. One type of enrichment is called predictive enrichment, which is based on the correspondence between a patient’s biological criteria and a disease mechanism. Essentially, the system is skewed toward a successful outcome, where knowing a patient’s biological traits and the mechanism of a disease allows the selection of an appropriate course of action. The success of this process can be substantially augmented by using biomarkers.

When implementing precision medicine, two opportunities for biomarker use emerge, the first of which is enrichment of the patient pool by identifying patient subset pools. The second opportunity occurs when matching the enriched patient pool with a treatment based on the biological mechanism of the disease in question. Both of these real-time processes involve an understood use of some sort of biomarker to characterize a disease both for and within a patient and for understanding the disease’s progress. This dual role for biomarkers reflects the importance of the disease mechanism, that is, pathodynamics, in understanding the time course or progress of a disease. Good examples demonstrating the simultaneous identification of a disease’s progress and concurrent monitoring of disruptions in homeostasis are diseases associated with aging.

An Example of Biomarker Use and Age-Related Disease

Biomarker use in clinical investigations and treatments is not new. For example, biomarkers are commonly used to identify and quantify exposures to xenobiotics from various sources, as previously mentioned. Indeed, biomarkers have a rich history and have been used in a wide range of investigations such as mechanism studies, organ damage, and no-effect levels. Their use, however, has not been exploited for understanding the ubiquitous biologic principle of homeostasis. The nexus of biomarkers to homeostasis is important because a mere change in biomarker metrics is not a clear indication that a permanent change like irreversible toxicity had occurred. Using biomarker requires wisdom and a backdrop of understanding the significance of homeostasis.

Using biomarkers for assessing the homeostasis status is not always straight-forward and simple, especially in senescence. The broad disruption of homeostasis associated with the aging process and senescence-related morbidities increases vulnerability to a multitude of diseases, one of which is Alzheimer’s disease (AD). Lessons from AD research and experience in managing AD can provide valuable insight into senescence-related disruption of homeostasis. ⁸ AD is an interesting example of multiple disease variables that result in distortion of homeostasis. Geriatric diseases such as arthritis, coronary artery disease, and cancer have their own portfolios of variables and complexities. However, maintaining a focus on causes of and treatments for diseases through homeostatic monitoring provides the best avenue to help patients with universal geriatric or senescence-related diseases.

As a practical matter, assumptions must be developed when exploring treatments for diseases, some of which are generic while others are disease-specific. These assumptions become a map for treatments that work together with suitable monitoring using biomarkers. In the case of AD, many assumptions create opportunities for various types of biomarkers to monitor homeostasis. One of these assumptions, which is a generic assumption, is that the clinical manifestations of the disease are preceded by pathological changes; these changes may be biochemical, structural, or both.

Clinical manifestations of a disease being preceded by either a biochemical or structural change represent a reasonable assumption, and two important questions emerge:

1. When do the pathological changes appear (when does the disruption in homeostasis begin)?

2. How much pathological damage is necessary before the disease is identified in clinical practice? In other words, how much disruption in homeostasis is necessary to see the clinical significance of the disease?

In the case of AD, these two questions are difficult to answer because in vivo structural changes are almost impossible to measure and correlate with a distortion in homeostasis as judged by clinical examination. However, some progress in imaging techniques has provided an opportunity for noninvasive assessments of structural changes and changes at the molecular level. Some success has been achieved using various imaging techniques with the imaging biomarker approach. The real value will likely lie in understanding the pathogenesis and course of a disease.^9,10 Easier, quicker, and less expensive biomarker monitoring in dementia and its influence on deviations from homeostasis have been established for AD based on molecular indicators in blood and cerebrospinal fluid.^11,12 Could the ultimate key for identifying the disruption of homeostasis inherent to AD lie in a biomarker that signals the onset of the disease in a population subset and at the same time serve to identify a therapeutic target such as the case with innate immunity protein IFITM3 ¹³ ? By focusing on maintaining homeostasis with biomarkers, clinicians are able to address all aspects of AD management.

Conclusion

The practice of medicine today and in the future will focus on maintaining or restoring homeostasis. Since health is defined according to the status of homeostasis, biomarkers serve as the homeostatic indicator. By using biomarkers as indicators of health, clinicians can actively bring into their practice the important relationship between disease and homeostasis. Toxicology supports the biomarker-homeostasis nexus seen in clinical practice when it uses biomarkers to identify and quantify distortions in homeostasis that drive toxicity and pathologies.^14,15 Biomarkers, regardless of their labels, ¹⁶ are the greatest tools available to preclinical developers and clinicians for guiding these practitioners in developing new therapies as well as maintaining homeostasis and health in patients who are treated in clinical practice.