The Oxidative Stress Index Predicts the Likelihood of Non-Communicative Disease (NCD) Onset, Disease Prevention Strategy and Potential Impact on Human Survival

1. Introduction

1.1. Oxidative Stress

The body naturally produces free radicals, reactive oxygen species (ROS) and reactive nitrogen species (RON), as bye products cellular metabolic activities. ROS and RON protect against invading pathogens, promote wound healing and tissue repair and serve as essential signaling molecules. Overproduction of ROS/RON is naturally neutralized in the body by antioxidants. It is well established that excessive overproduction of ROS/RON and/or interference with antioxidant activity damages DNA, proteins and lipids and interferes with cell signaling and results in an imbalance known as oxidative stress (OS), a condition which leads to accelerated aging and the onset of numerous non-communicable diseases (NCDs) [1,2].

Though chronic toxic environmental chemical exposure is the primary cause of elevated OS, the presence of pre-existing diseases and other exogenous and endogenous causes have been identified as producers of OS [3]. These are listed in Table 1. Chronic environmental exposure to toxic chemicals, obesity and the presence of pre-existing non-communicative diseases (NCDs) are the primary OS causative agents. OS is additive from all contributing causes, and it is total OS that determines the likelihood of disease onset. Thus, though NCD onset can occur from a single high OS dose, it can also result from combinations of sub-disease-causing OS doses from multiple sources [4,5,6].

1.2. Toxic Environmental Chemicals

Environmental chemical exposure is the primary cause of NCD development, far eclipsing genetic factors [7]. Of all the causes of elevated OS listed in Table 1, absorption of environmental chemicals is by far the most responsible.

NCD prevalence has increased dramatically in the past eighty years. A plot of disease prevalence versus time from 1945 to the presence follows a hyperbolic curve that is identical to that of synthetic chem-ical production, pesticide use, energy production and air and water pollution [6].

Absorption of any toxic chemical species immediately sets off a cascade of events in the body as the immune system immediately acts to eliminate these, thereby interfering with homeostasis and raising OS. When absorption and/or retention is chronic, OS elevation is long term and leads to the onset of Non-Communicative Disease [3]. Lipophilic chemicals are readily absorbed and easily penetrate cell mem-branes. Whereas low molecular weight (LMW) lipophiles are rapidly metabolized and eliminated from the body, higher molecular weight species, known as persistent organic pollutants (POPs) are more slowly re-moved and can exert OS raising effects for years or even decades. Accordingly, long-term OS elevation may be caused by chronic elevation of LMW lipophiles, or short-term absorption of POPs [3]. Examples of POPs, also referred to as forever chemicals, include; polynuclear aromatic hydrocarbons (PAHs), organo-chlorine pesticides, polychlorinated biphenyls (PCBs) and per- and polyfluoroalkyl substances (PSAF). These are stored in body fat, are released into the blood stream during fasting, dieting, illness, strenuous exertion and lactation and are reabsorbed at numerous body locations and eventually reabsorbed for storage in fat. Thus, the OS raising effects of POPs can be produced over and over again over time, as they persist in the body for as long as decades [8].

Hydrophilic chemicals do not readily penetrate cell membranes and are rapidly eliminated by the body. When mixed with lipophiles, however, these are carried through cell membranes with resultant toxic effects that differ from those associated with those of the individual mixture components. These effects in-clude attack at organs not known to be targeted by the single species, enhanced and lower-level toxicity [9].

Toxic heavy metals, alone, cannot penetrate lipophilic membranes, but may be carried through cell lipid bilayers via pi-bonding with planar aromatic ring structures such as PAHs [10]. As heavy metals and PAHs are found in the air everywhere in the world, human exposure to such mixtures are impossible to avoid [3].

1.3. Oxidative Stress Index

Measuring of oxidative stress, traditionally has been carried out via analysis of serum biomarkers, includ-ing nucleic acid oxidation, protein oxidation and lipid peroxidation species [11]. Of these, malondialde-hyde (MDA), which is indicative of lipid peroxidation is most commonly used. Serum analysis, however, is invasive, requires a testing laboratory capable of such an analysis and may yield results that can vary wide-ly depending upon the effects of lifestyle factors including food eaten, toxic environmental exposures and the time of the day blood is drawn [12].

The Oxidative Stress Index (OSI) has been shown to be indicative of elevated OS and to predict the likelihood of non-communicative disease (NCD) onset [13]. The OSI is a non-invasive eight item patient questionnaire based upon the items listed in Table 1 and is similar to those used in annual medical wellness checkups and other medical gathering data, including the Charlson Comorbidity Index, the Alzheimer’s Questionnaire, the Asthma Control Questionnaire, The Danish Comorbidity Index and the COVID-19 Clin-ical Risk Score [14,15,16,17,18]. In its original form, the OSI, which contained more than 400 items, was found to be too cumbersome to be used in clinical settings. Subsequently, the condensed form of the OSI question-naire, which has been shown to generate meaningful OSI data from answers to only eight questions, was developed [19]. Here, each of the eight questions in the condensed OSI and how their answers can be ap-plied to measuring OSI scores are examined in detail.

Recently published research further confirms the validity of the OSI as a predictor of disease onset likelihood, suggests steps that can be taken to reduce OS, reinforces the roles of toxic environmental chem-icals in disease onset and suggests minor adjustments in some of the point values of this index [8]. These changes and the justifications for them are reported here.

2. Methods

The OSI condensed form is based upon health impacts of the eight parameters listed in Table 1, as reported in the literature, with each of the parameters assigned point values based upon their contributions to total OS and the OSI score equaling the point total [11].

3. Results and Disussion

The OSI not only predicts the likelihood of disease onset, but also can also be used to demonstrate how each of its parameters provides insight into steps that can be taken to reduce oxidative stress (OS) and thereby lower the likelihood of disease onset.

3.1. Oxidative Stress Index Parameters

The OSI incorporates the OS causing items into eight parameters. These are listed in Table 2.

An introduction to these items with the rationale for the OSI scoring for each follows.

3.1.1. Age

Aging, which generally begins around one’s fortieth year, is associated with genetic, environmental and biochemical factors, and progresses throughout life. Aging is accompanied by increasing multimorbidi-ty, is a factor in the onset of telomere shortening and numerous NCDs attributed to continual increasing in OS due to ROS/RON-induced damage [20,21,22,23,24,25,26].

The prevalence of NCD onset generally increases with age, starting at age 40 and increasing throughout life [25]. Accordingly, one OSI point is scored for each decade of age. For one aged 40–49, one OSI point is scored, 2 points are added for those aged 50–59, etc. [11].

3.1.2. Body Weight

Increasing body weight is a worldwide phenomenon. World Health Organization and United States Centers for Disease Control and Prevention data show that overweight and obesity in the world are contin-ually rising. Worldwide, in 2016, 39% of adults were overweight and 13% were obese. In the United States, obesity prevalence increased from 30.5% in 1999 to 42.3% in 2018 [3].

Oxidative stress levels rise with increasing weight with the resultant onset of numerous diseases in multiple body organs and systems that include, but are not limited to, those listed in Table 3 [3].

Body mass index (BMI), which is based on the relationships between height and weight, are used to categorize the four different levels of body weight; Normal, Overweight, Obese and Extreme Obesity [27]. These are shown in Appendix A.1 and reproduced with permission. In the OSI, the following point values for weight are assigned.

Table 4. The BMI table. United States National Institute of Health. National Heart, Lung and Blood Institute. NIH publication No. 22-HL-8190. September 2022.

	Weight	Overweight	Obese	Extremely Obese
BMI	19–24	25–29	30–39	40-and over
OSI Points	0	5	10	15

Table 4. The BMI table. United States National Institute of Health. National Heart, Lung and Blood Institute. NIH publication No. 22-HL-8190. September 2022.

	Weight	Overweight	Obese	Extremely Obese
BMI	19–24	25–29	30–39	40-and over
OSI Points	0	5	10	15

These point values reflect the increasing likelihood of disease onset with increasing body weight.

In addition to being unhealthy in its own right, excessive body fat also induces secondary effects by serving as a reservoir for PCBs, toxins via bioaccumulation of POPs, including; polynuclear aromatic hydrocarbons (PAHs), organochlorine pesticides, polychlorinated biphenyls (PCBs) and per- and polyfluoroalkyl substances (PSAF). These are released into the blood stream when fat is metabolized during fasting, dieting, illness, physically exertion and lactation and are reabsorbed at numerous body locations where toxic, oxidative stress inducing effects are induced [3].

3.1.3. Genetics

Genetics, where gene sequence determines heritable traits, is a factor in most NCDs with many, including Alzheimer’s disease, Parkinson’s disease and many cancers, known to “run in families” [28,29,30]. Recently, epigenetics (where heritable traits ensue from DNA modifications caused by the action of toxins such as those found in tobacco smoke, for example) as well, has been shown to lead to heritable diseases [32,33].

Though all NCDs are more prevalent in those whose ancestors have suffered from those diseases, parental disease is most closely associated with the likelihood of disease onset in an individual [31]. Accordingly, in the condensed OSI, one point is assigned for each NCD an individual has that was also present in that person’s mother and/or father. For each NCD present, one point is assigned if that NCD was present in one parent and two points if present in both parents. Effects associated with epigenetics are incorporated into the socioeconomic status value, as these are inversely proportional to socioeconomic status.

3.1.4. Socioeconomic Status

Socioeconomic status (SES) is well established as an indicator of detrimental lifestyle choices that raise OS [34]. These lifestyle choices include unhealthy diets high in fats, sugar, salt or processed foods, obesity, smoking tobacco, alcohol or recreational drug abuse, radiation exposure, the need to reside or work in a toxic environment and physical inactivity [5]. SES is also associated with an increased likelihood of having undiagnosed diseases [35,36,37,38,39,40,41].

SES can be obtained from annual income information, but requesting such information discourages people from completing questionnaires. Educational achievement is a recognized valid indicator of SES, with lower SES individuals more likely more likely to lead unhealthy, OS raising life styles and have undiagnosed diseases [42,43].

In the condensed OSI form, 5 education levels are identified: These, and their assigned OSI point values are listed in Table 5.

3.1.5. Exposure to Air Pollution

In the 21st century, virtually all of the world’s people, regardless of SES, are exposed to polluted outdoor air [41]. All air pollutants are toxic, raise OS in a dose response relationship, impact the OSI, and are responsible for the onset of numerous adverse health conditions, including, but not limited to, respiratory diseases, cardiovascular diseases, numerous cancers and neurodegenerative diseases [41,42,43,44].

In the United States, the Environmental Protection Agency (EPA) measures air quality in multiple locations on a daily basis and reports the data on-line regularly as the Air Quality Index (AQI) [45]. Worldwide, the World Air Quality Project similarly reports air quality data for hundreds of cities [46]. On an annual basis, these indices identify the number of days in which the air quality in a given locale is classified as either good, moderate, unhealthy for sensitive groups, unhealthy, very unhealthy or hazardous. Hazard numbers ranging from 1–6 have been assigned by EPA to six air quality classifications, as follows [47]. These are shown in Table 5 Also shown in this table are the OSI values assigned for those residing in the each of the average annual hazard classification category.

Air pollution is not restricted to outdoor air. Indoor air is polluted by tobacco smoke, cooking on wood or coal burning construction materials, furniture, carpeting, pet fur and dander, paints, adhesives, cleaning products, pesticides, fire places, candles and mold and mildew growth. If at least one resident in a household is a smoker, an OSI value of 5 is assigned. All of the other pollutants induce allergic responses. As it is often difficult to determine which of the other indoor pollutants is causative, allergic response is used in the OSI. An additional assignment of 5 is assigned for other indoor pollutants, if one of the residences experiences consistent allergic reactions while at home. The OSI values are summarized in Table 6.

Total air pollution OSI assignment equals the sum of the outdoor and indoor air pollution vales.

3.1.6. Pre-Existing NCDs

Disease is both a cause and an effect of OS. Thus, each prevalent NCD permanently elevates OS and the number of prevalent diseases is a critical contributor to total OS and the OSI [5,13]. All diseases have symptoms associated with them. These are individually addressed in the detailed OSI. The OSI con-densed form does not probe individual symptoms. Rather, it has been found that assigning five points for each prevalent disease adequately incorporates elevations in OS associated with the prevalent diseases. Re-spondents are asked to list all diseases they currently have been diagnosed with. Multiplying the number of prevalent diseases by five yields the disease number in the condensed OSI.

3.1.7. Medications Regularly Taken

In the United States, 69% of adults aged 40–79 take at least one prescription drug daily and 22% take five or more prescription drugs every day [CDC]. The numbers of drugs regularly taken increase stead-ily with age, as do NCD numbers, and all pharmaceutical medications regularly taken chronically raise OS [13,48]. In the condensed form, one OSI point is assigned for each medication regularly taken.

3.1.8. Chronic Psychological Stress

Psychological stress, anxiety and depression are associated with most diseases and become more pronounced as illnesses progress [49]. When chronically present, each of these conditions raise activate the stress response system and result in OS that triggers diseases in numerous systems and organs [50].

Respondents are asked to check if they often feel stressed, anxious and/or depressed. Five points are assigned on the OSI for each positive response for these three items.

3.1.9. Combined Effects

By individually increasing OS, each of the eight parameters that make up the OSI influence the oth-er factors, thus contributing to OS elevation that is greater than the individual factor alone [3]. The com-bined effects.

3.1.10. Summary

The relevance of the OSI to predicting disease onset probability as well as for other applications uses has been previously established [13,19]. When the OSI condensed form values are used as presented here an excellent correlation between standard form and condensed form OSI values obtains, with con-densed form values showing less than a 10% variation from standard form values.

To sum up, the point values assigned to each of the parameters contained in the OSI condensed questionnaire are as follows:

Age	1 for Each Decade of Age Starting at Age 40.
BMI	Weight	Overweight	Obese	Extremely Obese
	19–24	25–29	30–39	40-and over
OSI Points	0	5	10	15
Personal	0, 5, 10 or 15, depending upon BMI
Diseases	5 per prevalent chronic disease
Medications	1 per medication regularly taken
Genetics	1 per each prevalent disease also present in a parent
Education	1, 2, 3, 4, or 5 depending upon highest education level achieved
Residence	0, 1, 2, 3, 4, or 5, depending upon ambient air pollution level at Residence, 5 for households with a smoker and 5 if one experiences consistent allergic reactions while at home
Stress	0, 5, 10, 15, depending upon chronic psychological status

The OSI score has been shown to be related to the likelihood of further disease onset as follows [Zeliger, 2017]:

OSI LEVEL	DISEASE LIKELIHOOD
0–15	Indicative of good health
16–30	Disease onset predicted
31–45	Disease onset probable
46 or higher	Disease imminent

The OSI form and instructions for use are shown in Appendix A.2.

This can lead to clinically relevant follow up and preventive measures. The modified, currently used, detailed OSI form is shown in Table 2.

4. Lowering OS and Disease Prevention

Elevated OS is the key to NCD onset. In addition to suggesting the likelihood of disease onset, the OSI can suggest steps to be taken to reduce the effects of OS caused by each of it’s eight parameters, thus lowering the likelihood of disease onset.

Though the only way to stop aging is to perish, the effects of aging can be slowed down via healthy diet, not smoking or vaping, limiting amount of alcohol consumed, limiting contact with toxic chemicals and regularly exercising.

Being overweight or obese, in almost every instance, is caused by poor diet and/or lack of proper exercise. Proper steps can be taken to reduce body fat and mitigate its detrimental effect on OS.

Though genetics, per se, cannot be controlled, epigenetic effects can be reduced by limiting exposures to toxic chemicals.

Socioeconomic status is not easily changed for many. That said, educational programs can alert people to the effects of poor modifiable lifestyle choices that can reduce OS.

Though outdoor air pollution cannot be controlled by individual action, indoor pollution can be, by not smoking, limiting indoor cooking with fossil fuels and the use of toxic chemical products inside the home.

Pre-existing chronic illnesses cannot be cured, but proper treatment, monitored by a medical professional, can reduce OS.

Though regularly taken medications are essential for overall health, the entire spectrum of pharmaceuticals regularly taken should be periodically addressed by medical professionals to examine changes and alternatives that could lower the number of drugs used. In some instances, lifestyle changes can reduce dependency on pharmaceuticals. Such changes should be monitored by medical professionals.

Psychological stress is inevitable at times. Chronic stress, and thereby OS, can be lowered via professionally administered therapy.

Though the OSI can predict the likelihood of NCD onset, it cannot predict which disease(s) are likely to strike. The OSI, however, has been shown, in the case of COVID-19, to accurately predict the severity of infectious disease in COVID-19 infected individuals [51,52].

As this paper is being published, the use of AI in OSI applications in being investigated. These are presented in Appendix A.3.

5. Threat to Human Survival

Exposure to sources of oxidative stress began with the first appearance of the human species. Early humans inhaled toxic dust, fecal aerosols and spores. The use of fire began exposures to smoke. Pathogens associated with animals and limited sanitation spread as humans began living in densely populated communities. Industrialization started exposures to toxic fossil fuels, industrial chemicals and tobacco use [53].

The human genome, which is impacted by both genetic and epigenetic factors is very sensitive to oxidative stress and continues to evolve. The gamut of impact by OS increasing factors, such as those upon which the OSI is dependent, remains unknown [54].

6. Conclusions

Elevated OS is associated with the onset of all NCDs. Though the OSI can predict the likelihood of disease onset, it cannot predict which disease(s) are likely to strike.

A questionnaire, consisting of eight parameters that are representative of the factors that elevate total OS in a dose response relationship from multiple sources, can be used to generate the OSI. The OSI predicts the likelihood of NCD onset and also suggest steps that can be taken to lower total OS.

The long-term impact of continuously increasing oxidative stress on the human species remains speculative.

Appendix A.1. BMI Table

United States National Institute of Health. National Heart, Lung and Blood Institute. NIH Publication No. 22-HL-8190. September 2022.

Appendix A.2. Oxidative Stress Index Questionnaire

1. Age
2. BMI	High		weight
3. Diseases:	All diseases and diagnosed conditions you now have
4. Medications	Number of medications regularly taken
5. Genetics	Number of the above diseases parents had/have
	Mother		Father
6. Education	Check highest level achieved
	Some high school		high school graduate
	some college		college graduate
	graduate school
7. Residence	City		State
8. Stress	Check any that apply
	Do you often feel: Stressed
	Anxious
	Depressed
			OSI Total

INSTRUCTIONS

Age	1 for each decade of age starting age 40
BMI	19–24	25–29	30–39	40-and over
OSI Points	0	5	10	15
Diseases	5 per prevalent chronic disease
Medications	1 per medication regularly taken
Genetics	1 per each prevalent disease also present in a parent
Education	1, 2, 3, 4, or 5 depending upon highest education level achieved
Residence	0, 1, 2, 3, 4, or 5, depending upon ambient air pollution level at Residence, 5 for households with a smoker and 5 if one experiences consistent allergic reactions while at home.
Stress	5 per each item checked.

Appendix A.3. AI Applications for the Oxidative Stress Index (OSI)

Artificial Intelligence (AI) can be applied to predicting the likelihood of NCD onset in numerous ways. Following are some examples.

1. The OSI can be digitalized, facilitating data compilation and statistical evaluations of results.

2. OSI data points can be entered by respondents electronically, or can be directly entered by medical pro-fessionals during the course of examinations.

3. AI can instantly supply medical professionals with OSI scores as well as suggestions for reducing oxida-tive stress.

4. Making the OSI part of regular medical checkups, AI can plot an individual’s oxidative stress longitudi-nally thus monitoring an individual’s likelihood of noncommunicative disease onset over time.

5. The OSI’s can be used to predict infectious disease severity, thus supplying warnings to potentially vul-nerable individuals.

6. Statistical analyses of OSI data can potentially lead to better understanding disease onset patterns and to the identification of geographic area disease clusters.