The Fourth Industrial Revolution and TEH

Today’s society, which according to Schwab (2017) is post the first three industrial revolutions (the industrial age, the age of science and mass production, and the age of the digital revolution), has created an environment where humans are presented with numerous chemical, physical, and biological exposures on a regular basis. Not only workers but all people receive exposures. With the understanding that each person can have one or more exposures with excess risk and a high potential to end in disease, the need for exposure science services is highly likely to increase and the need for IH and EHS expertise will become more necessary. TEH as a framework aims to establish the IH profession with support from EHS as the providers of exposure services to any who need it. Many IHs will continue to serve employees primarily and account for the impacts of occupational and nonoccupational exposures, but many will also serve the non-working population and will account for any exposures which could be an increased risk individually.

Today the world is beginning the fourth revolution, and according to Vivek Wadhwa (2016), medicine is expected to advance in lOyears more than it has in the last 100years. These advances will include paying for genomic sequencing at a price comparable to a blood test, having a true understanding of genetic proclivity to disease, and discovering the impact of the microbiome to health. These, among many other advancements in medicine, will allow medical professionals to deliver prevention and medical intervention to the masses (Wadhwa and Salkever 2017). Taking the TEH framework, this last step requires a number of developments that are underway as society begins the fourth revolution with advances in genomics, computational toxicology, the interconnections of things, and much more.

Computational Toxicology

The Methods in Molecular Biology book series has volume 929, What Is Computational Toxicology? Its short definition is a perfect description to understand the core components of this subject:

Computational toxicology is a vibrant and rapidly developing discipline that integrates information and data from a variety of sources to develop mathematical and computer- based models to better understand and predict adverse health effects caused by chemicals, such as environmental pollutants and pharmaceuticals. Encompassing medicine, biology, biochemistry, chemistry, mathematics, computer science, engineering, and other fields, computational toxicology investigates the interactions of chemical agents and biological organisms across many scales (e.g., population, individual, cellular, and molecular). This multidisciplinary field has applications ranging from hazard and risk prioritization of chemicals to safety screening of drug metabolites and has active participation and growth from many organizations, including government agencies, not- for-profit organizations, private industry, and universities.

(Reisfeld and Mayeno 2012)

Computational toxicology (CompTox) has a number of distinct advantages over the classic toxicology described earlier because it can include human data, and it observes cellular function and connects it with genetic expression. Chapters 6 and 7 of this volume provide two example areas where exposures of concern are being identified through computational toxicology methods. This area of science promises to not only identify exposures of concern in society but also identify what genes are activated incident upon the exposure. Once the gene is activated, the molecular biological process that the gene controls is then identified. In simplified terms, the resulting cascade of additional activations and changes to cell function or output is able to be tracked and identified. In this way, we can fully understand the effects of an exposure. These effects at the cellular and gene expression level provide a more complete understanding of what generates what scientists describe as disease, namely where organ function or cellular function is negatively changed.

This understanding of the disease often uses human cells, so there is not a need to translate the results across species. There are challenges, and toxicologists have been developing new techniques to overcome the challenges as they arise, but significant new' understanding of risk-based exposure and response and the mechanism of disease is impacting the knowledge base the IH and EHS use every day. If an IH or EHS expects simply to meet the law or regulation on acceptable or non-acceptable exposure, then until the law changes, the practice does not need to change. If the IH community believes disease prevention is the purpose for the profession, then adopting and using the knowledge coming from the CompTox arena is vital.

Genetic Expression

CompTox and its ability to track gene expression has a valuable sister science in genetics. Geneticists are working across the globe to understand what the DNA in the human genes does specifically, not generally, and with the intent to decipher the functions of each gene identified in the Human Genome Project. The geneticists working on this identification of gene function identify the function and then move to the next gene because they estimate there are up to 25,000 human genes, and that is a lot of unfinished work (US National Institute of Health 2019). Other scientific communities use the knowledge gained by geneticists to determine if the information is beneficial in their own areas of science. The combination of geneticists identifying the gene function and CompTox determining the activation of the gene from an exposure alone assists in understanding disease and exposure levels that are more protective of the population on the whole.

An exciting part of the research which has not been discussed yet in this chapter are the genes that are not identical across the population. The genes which have differences in the sequence of DNA are called alleles. Geneticists also now understand that genes that appeared to have no active function get activated or inactivated based on external stimuli (exposure), internal stimuli (metabolomics), or by other sections of the genome once they are activated (the cascade of activated genes mentioned earlier). The alleles that each person has not only determine the physical characteristics of a person but also how the person responds to exposure. Simply put, there are some alleles that either alone or in combination with other genes cause cells to respond to an exposure differently, and this accounts for the outlier individuals in the dose-response curves. One of these alleles which is a single-nucleotide polymorphism (SNP) at rs7598759 demonstrated an NIHL risk with an odds (risk) ratio of 12.75 in a small population (Grondin et al 2015). A larger metanalysis of over 30 studies showed a risk ratio of 4.61 with a 95% confidence interval (Tserga et al. 2019). A risk ratio shows the increased risk that having the genetic variation increases the risk above the normal population; therefore, current understanding would place the risk to NIHL at an over four-and-a-half-fold increase (4.6 times) above the risk for a person without the genetic variation. This exciting type of science then provides the IH and EHS the ability to identify the individuals at increased risk of disease. As more of these alleles are identified, and their exposure-based risk factor increases or decreases, additional options to provide true primary prevention become available.

Novel Controls Additions to the Hierarchy

The hierarchy of controls available to IH is increasing, and the methods of employing the current controls are evolving as well under TEH. The exposure assessment strategies through various organizations have recommended SEGs for the last 25 years.

Using an SEG allows for treating a specific group with the same set of controls since it has exposures assumed to be similar. Having SEGs as practiced today does not account for exposures apart from the direct occupational exposures and does not account for individuals which may have the same exposure but are more susceptible to disease from that exposure due to their genetic differences. Collecting at-w'ork exposure data will still be possible using SEG, but the IH profession using TEH will add strategies of control which account for the unique individuality of each person essentially taking the set to an N = 1.

Individual Exposure Health Risk Profile (IEHRP)

The Individual Exposure Health Risk Profile (IEHRP) (Chapter 2) was developed simultaneously during the development of the TEH framework to be a component of the full framework. Dr. Hartman and Dr. Oxley were specifically employed by Kirk Phillips to deliver this component of the TEH framework to the Department of Defense. Drs. Hartley and Oxley were charged with developing a method to help bring the management of the expected plethora of information into a manageable process. IEHRP is being developed as a method to combine exposure data not only from the traditional IH practice but also from genetic proclivity and data in other sources discussed in this chapter. These total exposures and clinical data from medical and diagnostic exams are being combined in this process to describe an individual’s risk to the exposure. Using these multiple variables, the relative impact of the exposure to an individual can be visualized, and the IH will have a guide as to which exposures require additional controls. The protective impacts of providing a particular control compared to all the risk from exposures to the individual will be possible as well (Hartman and Oxley 2019).

Preexposure Prophylaxis

A new' tool in the hierarchy of controls that will be available to IHs is pharmaceutical. There is at least one area of EH specialized protection against exposure which is the uptake of iodine for thyroid protection from radiation. The need for universal protection resulted in iodine being added to table salt assuring a regular daily small dose for majority of people. Therefore, the IH and the EHS are not in the habit of considering this prevention strategy as a control. A second pharmaceutical is for the protection of the body from radioactive cesium and thallium exposure in a nuclear event by reducing the biological half-life. Prussian Blue given just before or after a nuclear event is one of the IH’s or health physicist’s control methods, but these rare treatments have not resulted in list space in the hierarchy of control. This will change with the advent of the CompTox community’s understanding of disease causation from exposures and the ensuing changes at the cellular level and the cascade of chemical process changes. The net result of these changes is the production or reduction of bioactive chemicals regulating cell and organ functions. By understanding these changes, medicine has the ability to target pharmaceutical treatments that prevent the effects from the chemical cascade. Therapies can interrupt the chemical cascade preventing the activation of the allele and breaking the chemical cascade so that the final resulting bioactive chemical is not produced or counteracts or blocks the damaging cellular process before acting in the body. Finally, pharmaceutical therapies will be able to act to increase the body’s active repair mechanism at the time and location of the potential damage and mitigate harmful effects. One example which is nearing the commercial market involves prevention of NIHL. For NIHL, the allele appears to be related to the SNP rsl872328 on gene variant ACYP2, which plays a role in calcium homeostasis and increases the risk of ototoxicity activation in the body (Tserga et al. 2019). Calcium is necessary in a primary chemical process for signal transduction in the inner ear, specifically in the cochlear hair cell stereocilia mechanotransduction channels (Mammano 2011). Any therapeutic which balances these calcium levels would be protective. Audiologist and molecular biologist O’Neill Guthrie from Northern Arizona University (2019) is collaborating with a pharmaceutical company on a dietary supplement that would be protective as a preexposure prophylaxis for NIHL. His expectation is that within 3 years he will have the proper dosing and evidence that taking the drug, which is similar to a vitamin, before exposure to noise will provide protection and repair mechanism to prevent NIHL. Le Prell et al. (2019) pointed out that one of the current limitations of the prophylaxis is to determine what population would benefit from pharmaceutical interventions and to identify the factors that drive individual variability in humans. Understanding the genetic proclivity mentioned earlier is a solution to this problem. Armed with the direction by a provider that an individual has an increased genetic proclivity to NIHL, the employer or the medical community could provide a vitamin treatment that results in the risk of the individual from noise exposure returning close to the normal population.

It is exciting to think of the other preexposure prophylaxis treatments which will be possible for other types of exposure in the future. This one example of how these developing technologies are opening up new areas of research highlights how important it is that the IH profession uses the TEH framework and is ready to include these controls in the hierarchy.

Self-Limiting Exposures

The discussion previously on the Apple watch and its ability to identify loud environments and notify the user of risk is an example where a person is provided the necessary information and then takes steps to reduce the exposure. Another example where recent scientific studies of NIHL can have an immediate application would be a publicly accessible kiosk where an individual could attach the headphones and the matching mobile device to a specialized monitoring system. The kiosk would then take the playlist, listening period, volume settings, and waveforms of the music (available from the internet) and set the delimiter on the volume to limit the mobile device from generating hazardous noise to the ear. Informative solutions like these are important as the youth today are experiencing NIHL prior to working age. The Centers for Disease Control and Prevention reported how recent scientific studies can have immediate applications. Its report showed, among other things, that 20% of youth have hearing loss by the age of 20. It also reported that 24% of NIHL in workers is from loud workplaces with the remaining exposures coming from non-work sources such as mowing, rock concerts, and sporting events (Harris 2017).

If genetic testing indicated increased risk to any particular exposure and this information was available at a young age to a person when selecting an occupation or making a lifestyle choice, he or she could then make informed choices to reduce exposure by avoiding the exposure entirely or choosing enhanced controls whenever the exposure is likely.

Nonoccupational PPE/Increased Occupational PPE

The goal of TEH is to consider work exposures and non-work exposures as equally important in providing overall protection. Using the TEH framework, the IH would understand that a worker likely has exposures away from work. Once all available data is collected, the IH should consider providing PPE which adequately addresses the total potential exposure and any genetic proclivity to disease. For instance, if the IH learns that a worker will be leaving his automobile painting job with exposure to VOCs to moonlight in a second self-owned business doing automotive repair with VOC-containing products, the IH should consider providing respiratory protection with a high enough protection factor to account for the additional post-workplace exposure. A possible preventive measure would be to provide a mask and filters for use at the moonlight position. Another possible option would be to inform the employee of the need to provide his own protection. To provide no intervention, or only intervention while in the workplace, poses more risk to the employer as disability resulting from exposure does not have to be proven to be entirely from the employer to be the responsibility of the employer for workers’ compensation. The prevention of the disease is the best course of action, and providing an easy way to ensure the worker is protected 24hours a day will, in many cases, be the lowest total cost option.

Durable Medical Equipment

Illness and injury from repetitive motion or acute injury occur in the joints and ligaments due to work and non-work causes. Dr. Kim and his research team from Stanford University have been researching elite athletes and have identified alleles through genome-wide association screens (GWAS) to identify DNA variants which increase the likelihood of ankle injuries (Kim et al. 2017). Jon Brazier and his team (2019) from Manchester Metropolitan University performed similar research to identify variants for increased risk to tendon and ligament injuries in rugby players. Braces and other durable medical equipment could be useful along with special training on proper movement to prevent injury for individuals with these gene variants. This research easily translates to workers or recreational sports and would provide an opportunity to prevent injury or disease. At present, a safety and health professional would need to wait for the occupational health department or family physician to identify a person with repeated injuries before recommending the regular use of a brace or wrap. With the TEH framework, the individuals with increased risk genetically could receive preexposure joint support and training from either the medical community or as a form of PPE prior to any injuries from the workplace, thereby providing true primary prevention. Giving every w'orker joint support would likely be too costly and would have low' compliance, but providing the medical equipment to the individuals w'ho w'ould benefit the most could be cost-effective based on increased time on the job and reduced medical costs.

Blood Chemistry Tracking

Blood chemistry values have normal ranges w'hich are generally well understood for monitoring changes in the body. There are some tests, though, which rely on changes from normal values to determine if there have been changes in the body. Some of these tests, while not regularly given to the population, are exposure specific. Cholinesterase testing on pesticide workers is used as a baseline test before exposure and then ongoing monitoring is used to verify if controls from exposure are working. Few individuals receive this testing unless they are expected to have work-related exposure to pesticides. Individuals with potential lifestyle exposures (e.g., gardening, vegetable-based dieting, beekeeping, living in rural areas) are those individuals who could benefit from having a baseline test especially if they are tested and learn that they have a known genetic risk to exposure to pesticides in the future.

TEH—Bringing It All Together

The primary customers for IHs at the present time are the workers, and as society moves forward in the fourth revolution, fewer and fewer workers will be in positions with large exposures over the regulatory limits or even in positions with classic industrial exposures at all. The new paradigm will be individuals w'ho will receive as much exposure from their lifestyles, the environment, and clinically as they do in the workplace. In order to maintain relevancy to society, the IH and the EHS need to become the exposure scientists collecting and providing relevant data on the exposures to be used in primary prevention methods such as IEHRP and enhanced PPE. The IH’s role w ill be to give individuals knowledge of the many options of controls they have so that they can reduce their exposures and the prevalence of disease. See Figure 1.4.

In its fully evolved state, TEH is a bold and innovative framework which associates exposures to the lowest common denominator—the individual’s exposure—and, when possible, to the DNA (N= 1), enriching occupational and environmental health decisions to provide true primary prevention. Under the TEH framew'ork, the IH and EH research communities pair w'ith the geneticists, computational toxicologists, molecular biologists, occupational and primary care physicians, data experts using Internet of Things (IoT), and researchers to bring the latest advancements in science, technology, and informatics to protect and advance the health and well-being of all.

New knowledge of the relationships between individuals’ genetic predispositions, epigenetic factors, and exposure to chemicals from lifestyle, occupation, and the environment can now support development of diagnostic approaches, treatment methods, and intervention strategies that consider all variables collectively. Hence, a

Current and future state of exposure science with TEH

FIGURE 1.4 Current and future state of exposure science with TEH.

comprehensive understanding of multiple exposures with genomic information will support a necessary paradigm shift from healthcare to health wellness by promoting more rapid identification of risks to health and well-being and enabling earlier and more tailored interventions.

Accurate calculation of disease risk factors will involve developing diagnostic systems that merge genomics to find relationships at the individual level to inform risk of disease, promote health and well-being through intervention, and mitigate these risks along with various big data from sensors, medical records, and various disparate unstructured data sets in order to understand the root causes of injury and disease and with the TEH framework truly establish the IH and EH as the means to deliver true primary prevention healthcare.


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