Endotoxins: Small But Very Significant

Fever?

Fatigue?

Itchy eyes?

Scratchy throat?

You may be suffering from Bible Printer’s Fever, Monday Fever, or perhaps Mattress Maker’s Fever. These are a few of the sick building syndrome effects caused by endotoxins.

One of the universal hallmarks of endotoxins is fatigue.

Endotoxins are everywhere. They are in our water, food and air. The postcard below from Hugo, a University of Illinois student in 1912, indicates the state of water sanitation at that time in our area. Although we have improved water and food quality in the US since then, air quality in today’s homes and buildings is no better than water quality was in 1912. Whatever is in the building air is what you’ll breathe and maybe you’ll get used to it. Unfortunately, if endotoxins are part of the problem, you will not.

Endotoxins are molecules that adhere to dust particles. They are a parting gift from dead bacteria. Small doses cause many health problems. These molecules are very, very tough, requiring temperatures above 160F to destroy. They are very, very tiny, with more than a million covering a single bacteria. And, they are toxic. Effective fresh air ventilation is essential for minimizing the harmful effects of endotoxins as well as reduction of endotoxin generation sources.

What are endotoxins?

What types of problems do they cause?

And, what can we do to minimize their harmful effects in our homes?

Figure 1 Hugo’s 1912 postcard to his brother after arriving at the University of Illinois indicates the state of water sanitation. Today’s home and building air quality is similar as water quality was then, largely uncontrolled and unmeasured. We never know if proper ventilation is occurring in almost any building we walk into….unless it has a CERV.

Endotoxins

Endotoxins are chemical remnants of the outer cell wall of dead “Gram-negative” bacteria [1]. A Gram-negative bacteria is one that has a double-walled cell membrane structure in contrast to Gram-positive bacteria with a single wall. Hans Christian Gram (1853-1938) developed a special staining process in 1884 that could distinguish single-walled, Gram-positive bacteria (the “Gram stain” dyes these bacteria, for a “positive” result) versus double-walled, Gram-negative bacteria that do not stain (a negative result).

Figure 2 A naturally fermented vinegar contains “Mother” of vinegar, a bacteria mass that ferments cider.

The microbial world is immense and fascinating with its variety of bacteria, viruses and fungi. As we discuss the health hazards of endotoxins, it is important to keep in mind that maintaining good health is dependent on microbes, too. Alaana Collins [2] recent book, “10 Percent Human: How Your Body’s Microbes Hold the Key to Health and Happiness” provides an excellent description of our multi-faceted codependence with our human biome. Figure 2 is a picture of a natural vinegar in which cider is fermented with Lactobacillus. The Lactobacillus bacteria is also important for yogurts, kimchi, sauerkraut, pickles, cheese, beer, and many other gourmet delights. The Clostridium botulinum bacteria, infamous for botulism poisoning, has developed into a multi-billion dollar industry for cosmetic aesthetics and treatment of migraine headaches.

Among Gram-negative bacteria that inflict debilitating pain and suffering in humans are: Lyme disease, Rocky Mountain Fever, cat scratch fever, syphilis, cholera, dysentery, Legionnaires’ disease, pneumonia, whooping cough, gonorrhea, meningitis and chlamydia. Note that Gram-positive bacteria, viruses, and fungi also have many bad actors that afflict humans [1].

When a Gram-negative bacteria dies, lipopolysaccharide (LPS) molecules from the outer cell wall structure are released. These LPS compounds are endotoxins, and the terms LPS and endotoxin can be used interchangeably. Within a given bacteria, there is heterogeneity among the cell’s LPS compounds. Coupled with the heterogeneity of bacteria, the heterogeneity of a home’s microbiome, and the heterogeneity of human response to endotoxins, a frustratingly complex situation arises when endotoxins are afflicting one’s health [3].

Approximately 30% of a bacteria surface may be covered with LPS molecules, with 1 to 2 million LPS molecules on the outer wall of one E Coli bacteria cell. Using a very rough approximation, the characteristic length of an endotoxin molecule is 10nm (10 times 10-9 meters), which is in the size range of small viruses such as the poliovirus. An “Endotoxin Unit” has been defined that measures an endotoxin’s reactivity relative to that of a reproducible endotoxin reference. 1EU is approximately 0.1ng of endotoxin, which consists of 1 to 2 million molecules. And, just a little bit can cause a lot of problems. Within the particulate world, we would like to limit airborne dust to no more than 20 µg/m³. In the endotoxin world, 0.2 ng/m³, just 1/100,000th of the 20 µg/m³ particulate level can cause health problems!

Professor Donald Milton’s review of airborne endotoxins provides a detailed description of endotoxins from both historical and scientific contexts [3]. Scientific measurement and analysis techniques have advanced significantly since Milton’s 1996 review, however, his review provides a broad perspective that is difficult to find in more recent work.

In the outdoor environment, endotoxin concentrations range from 0.05ng/m³ to 0.5ng/m³, with the low range typical of snow covered terrain and the higher value typical of the growing season [3]. Elevated outdoor levels can be found near agricultural processing plants, cattle and hog feedlots, or similar areas that produce concentrated levels of bacteria. High levels of endotoxins are found in vegetable fiber processing industries, machining industries (“cutting” fluids for lubricating machine tools are prone to bacteria growth), offices, swimming pools and homes. Extremely high levels of endotoxins (2 to 27µg/m³, or more than 1000 times normal outdoor concentrations) have been found in environments with moist and wet processes such as waste water treatment plants, recirculating washwater spray processes, and homes with “cool-mist” humidifiers.

A study of nearly 2500 homes found that kitchens have the highest level of endotoxins (80.5EU/m2 floor area), followed by living rooms (63.9EU/m² floor area) and bedrooms (35.3EU/m² floor area) [4]. We will return to this study later as we discuss health implications, but at this point it is interesting to note that intra-room correlations of endotoxin concentration are weak. That is, a kitchen with elevated endotoxins does not indicate that the bedroom or living room will also be high. The variation of endotoxin concentration in homes is broad, too, with 5th and 95th percentiles having 9.8 and 512EU/m² for kitchens, 11.5 and 331EU/m² for living rooms, and 2 and 142EU/m² for bedrooms [4].

Figure 3 A cooking dish with “soaking” water and the vegetable scraps destined for the chicken coop are both sources of bacterial growth and subsequent endotoxin production.

The weak correlation of endotoxin concentration among rooms within a given home is possibly due to variations of infiltration and ventilation characteristics in homes. With uncontrolled ventilation, as is typical in today’s homes, one region of a house may be flushed or ventilated much differently than another. Our research at Build Equinox has shown repeatedly that where you live and where a house has infiltration leakage are not the same, and that having a “leaky” home does not equate to having good indoor air quality. Ventilation systems must be carefully designed in order to ensure that all rooms have air flowing through them, with fresh air purging the entire home.

Figure 4 Comparison of bacterial growth of dishwater (left) and untreated rainwater from Equinox House’s 1700 gallon rainwater harvesting cistern (right). The dishwater was left overnight after washing dinner dishes. The 5ml rainwater sample (right) produced only 4CFU (colony forming units) of bacteria. Treated “city” water usually produces no CFUs. The 5ml dishwater sample was unreadable with countless bacteria, indicated by the red coloration of the nutrient. As bacteria die, endotoxins from the bacteria are readily transferred into the kitchen air as the water is agitated.

Regardless of the weak correlation among rooms within a house, field study results indicate that kitchens are a primary generator of endotoxins. The authors of the large home field study cited a Dutch field study of 100 homes that found significantly higher endotoxin concentrations in homes with kitchen compost pails [4].

Food, food preparation surfaces, and dishwashing/sink areas are all wet areas that promote bacteria growth. Dirty dishwater left in a sink or a pan, as shown in Figure 3 from Equinox House, is a prime bacteria breeding ground. In our home, wet pan versus dry pan is an area of continuous, loud debate. Should one soak food encrusted dishes for later washing, or drain unwashed dishes until they are washed? Figure 4 compares bacteria growth in dirty dishwater and untreated rainwater. Just a few hours is sufficient for nutrient-rich dishwater to produce a fetid biological soup. Our rainwater is kept sealed and stored in a 1700 gallon food-grade cistern with minimal nutrients for promoting bacteria growth.

The correlation between endotoxin concentration and dust levels is also weak. A dusty home may be low in endotoxins and a home with minimal particulates can have high endotoxin levels. Dust levels in a home are due to a variety of sources (particulate infiltration through building envelope, house cleanliness, cooking, occupants, occupant activities) that are not strongly linked to endotoxin sources (kitchen food preparation surfaces, humidifiers, and other bacteria breeding grounds). Particulates in the 2 to 10 micron size range have plenty of surface area for endotoxin attachment because one bacteria of similar size is covered with a million or more endotoxin molecules.

Endotoxin Impacts on Human Health

Let’s start with the bad news of how endotoxins negatively affect our health, followed by the good news that we can avoid these impacts.

A Gram-negative bacteria does not have to be harmful to humans in order to produce harmful endotoxins. Saprophytic bacteria are a common, harmless-to-human bacteria that feeds on “dead” materials, such as cellulose in cotton and other vegetative matter. Endotoxins from saprophytic bacteria are harmful to humans, producing “Monday fever” and similar agriculture processing maladies [5].

Endotoxins are pyrogens, that is, endotoxins often cause a pyrogenic reaction (fever). Dyspnea (shortness of breath), skin irritations (eczema, psoriasis), cough, nausea and aches also occur with inhalation of endotoxin levels. In the good, old days when scientists would use themselves as test subjects, Pernis, et.al. [5] describes the results of a research group who inhaled pure endotoxins, with all participants succumbing to most or all of the above effects. They discontinued the work as some fevers reached dangerously high levels.

One of the most common effects of endotoxins is fatigue, a common characteristic of sick building syndrome. Milton [3] cites a study in which endotoxin levels in a series of homes ranged from 0 to 18ng/m3. An amazing finding was that 10% of occupants in homes with less than 0.1ng/m3 of endotoxins reported fatigue, while 91% of home occupants reported fatigue as endotoxin levels increase above 0.2ng/m3! Glucan, an indicator of molds, was also measured in the study, and while it was also found to be associated with an increase in fatigue, endotoxins were more strongly correlated with fatigue. Elevated endotoxin levels were also associated with increased cough, breathing difficulty, itchy eyes, and nausea.

An interesting feature of endotoxic induced illness is the temporary buildup of resistance, as denoted by the name “Monday fever”. Workers in industries with significant endotoxin levels have been found to be most afflicted on Monday, with reduced effects through the week. Endotoxin resistance is lost over the weekend, with the illness beginning anew the following Monday [5]. That is, you never get better! Unlike Hugo getting “used” to the water, over and over and over again, people in a sick building will never get used to the air and will continually suffer.

Endotoxins are “adjuvant”, meaning that they can amplify the effects of other harmful substances. For asthmatics, small concentrations of endotoxins can increase their sensitivity to asthma triggers. Michel [6] describes how endotoxins enhance asthmatic response. Michel also makes the point that endotoxins were not found to induce asthma attacks. Endotoxins were also found to not impact the severity of hayfever (rhinitis). Liu [7] states that as little as 10 LPS molecules per human cell are capable of inducing an immune response. Phthalates (plasticizers used to make toys and plastics more pliable and rubbery) in homes have been linked to increased asthma prevalence [8]. Perhaps endotoxins enhance the impact of phthalates on asthma?

Endotoxins are associated with sepsis, an extreme immune response by the body that often ends in death. Host, et.al. [9] states that septic shock syndrome has a mortality rate between 20 and 50 percent with 100,000 deaths per year occurring in the US attributed to sepsis. Ironically, the mass killing of bacteria by antibiotic treatments can result in sepsis by releasing a shockwave of endotoxins that elicit a strong immune response. High fever, high heart rate and high breathing rates occur. Medical researchers are working to reduce the release rate of endotoxins [10] caused by antibiotic treatments. Reducing overprescribed and mis-prescribed antibiotics could reduce endotoxin related mortalities [2].

What Can We Do?

The good news is that we can take actions to mitigate endotoxin impacts. And, some additional good news that endotoxins do have a beneficial side.

The cost of reduced human productivity due to endotoxin effects is high. In fact, anyone who places the value of energy above that of human health and comfort is losing at least $100 for every $1 spent on energy savings. Fatigue, cough, nausea, dyspnea, skin irritation and ache lower human productivity. A drop of only 5% work productivity costs $2500 per year for an employee with a $50,000 per year salary.

Effective ventilation that maintains low levels of carbon dioxide and VOCs (Volatile Organic Compounds) should also be sufficient for controlling endotoxin levels with an energy cost less than $50 per person per year in the harshest North American climate [11]. Note that simply blowing (aka, “supply ventilation”) or sucking (aka, “exhaust ventilation”) air out of a home is not a proper way to ventilate a home. Stagnation regions will occur with localized areas with poor air quality. The same level of care used to design a kitchen, or better yet, more effort than currently used to design a kitchen should be used to design a home’s ventilation system. Balanced ventilation that purges all regions of a home is essential.

Endotoxins do not float freely, but instead are attracted to dust particles. Reduction of dust is essential for controlling endotoxin levels. Dust reduction requires both fresh air filtration and filtered air recirculation. Continuous, low flow fresh air ventilation systems without recirculation do not effectively manage indoor particulates. Endotoxin levels and dust levels are not strongly correlated indicating that they come from independent sources. A single dust particle in the 2 to 10 micron range has sufficient surface area to hold a million or more endotoxin molecules (approximately 0.1ng of endotoxin). Therefore, reduction of dust is important regardless of whether one lives in a dusty or relatively dust-free environment. Our January 2017 newsletter provides a detailed description of recirculation’s ability to reduce particulate levels.

Coupled with proper ventilation is reduction of source generation of endotoxins. In the home environment, it is clear that kitchens are one source of endotoxin generation. Removal of food wastes and standing dishwater will reduce bacterial growth with subsequent production of endotoxins. Even a bowl of standing water will grow bacteria in a home. Bacteria and nutrients are ubiquitous indoors and outdoors, and they will land in water or moist regions where bacterial growth will occur.

Cold temperature (misting) humidifiers are strongly linked to high endotoxin levels. Vaporizing humidifiers that heat water to boiling have not been found to produce high levels of endotoxins. Note that vaporizing 1 liter of water with electric resistance heating requires 0.7kWh, which would be $2-3 per month energy cost. Cold temperature vaporization of water into a home uses energy in the air to vaporize liquid water, producing an evaporative cooling effect. A home’s heating system supplies energy to the house air used for the vaporization. If a home is heated with electric resistance heaters, the net energy impact of cold water vaporization is the same as heated vaporizers with $2-3 per month of heating used for vaporizing 1 liter per day. A home with heat pump heating, however, will have a 2:1 to 3:1 energy benefit, resulting in $1 per month for vaporizing 1 liter of water per day. In order to achieve this energy benefit without impairing one’s health, periodic sanitation of the humidifier must occur. As previously discussed, your health is worth much more than debating $1 or $3 per month.

An alternative method for achieving sanitized, cold temperature humidification in a home is through plant transpiration. Plants can reduce toxins in homes [12]. The plant-root matrix releases sanitized water into the air (assuming proper plant care that does not form a wet mass promoting fungal and bacterial growth). You still have to pay for the water vaporization energy because the energy for vaporizing cold water from the plant still comes from the surrounding air, but with a home heated by a heat pump, water vaporization will have the same efficiency benefit as a cool mist vaporizer.

We have approximately 50 plants scattered around Equinox House. We water once a week with 6 liters of water throughout the year (maybe a bit more in the winter and a bit less in the summer, but no more than +/-1 liter from the average). With our efficient minisplit heat pump, our plants “cost” us $1 per month of our solar energy production. We are repaid much more than a $1 per month with a feeling of well-being. Equinox House maintains comfortable humidity throughout the winter without active humidification. You can check it out yourself by exploring live and archived CERV data from Equinox House at our website.

As with botulism, there may be a positive side to endotoxins. Milton [3] suggests that the adjuvant nature of endotoxins could be used to enhance a body’s protection to some harmful substances as well as beneficially increase the impact of a medicinal treatment. Liu [7] addresses the Jekyll-Hyde nature of endotoxins from the viewpoint that endotoxin exposure to young children may be essential for immune system maturation.

Summary

We hope this introduction to endotoxins has been informative and created an awareness of something that has always been with us, but perhaps not well known.

We recommend taking a positive approach to creating a healthy indoor space. Rather than getting bogged down and perplexed by the myriad of things that degrade our indoor environments, we can follow a simpler solution path. This simple path is as follows: maintain an indoor environment that approaches the fresh and healthy nature of the outdoor environment. With today’s technologies that can automatically maintain excellent indoor air quality, you will have more time to enjoy other activities.

A positive approach to indoor air quality produces peace-of-mind that beneficially impacts our health [13]. A negative or defensive approach alerts our bodies to produce cortisol, the stress producing chemical that heightens our alertness. Continuous worry and production of cortisol damages our health and impairs our ability to heal. With a positive approach, our bodies are more likely to produce oxytocin, a beneficial chemical that enhances healing and creates a feeling of bonding (mothers and newborns produce oxytocin in abundance). Let’s take a positive approach to creating a better future for ourselves and those around us!

[1] K.P. Talaro and A. Talaro, Foundations in Microbiology; Basic Principles, 3rd Edition, McGraw-Hill, 1999.

[2] A. Collins, 10 Percent Human: How Your Body’s Microbes Hold the Key to Health and Happiness, HarperCollins publisher, 2015.

[3] D.K. Milton, “Bacterial Endotoxins: A Review of Halth Effects and Potential Impact in the Indoor Environment”, Indoor Air and Human Health, 2nd Edition; editors, R.B.Grammage and B.A. Berven, Lewis Publishers, 1996.

[4] Peter S. Thorne, Katarina Kulhankova, Ming Yin, Richard Cohn, Samuel J. Arbes, Jr., and Darryl C. Zeldin, “Endotoxin Exposure is a Risk Factor for Asthma; The National Survey of Endotoxin in US Housing”, Vol 172, American J of Respiratory and Critical Care Medicine, p1371-1377, 2005.

[5] B. Pernis, E. C. Vigliani, C. Cavagna, and M. Finulli, “The Role of Bacterial Endotoxins in Occupational Diseases Caused by Inhaling Vegetable Dusts”, British J Industrial Med, Vol 18, p120-129, 1961.

[6] O. Michel, “Role of Lipopolysaccharide (LPS) in Asthma and Other Pulmonary Conditions”, J of Endotoxin Research, Vol 9, No 5, p293-300.

[7] A.H. Liu, “Endotoxin Exposure in Allergy and Asthma: Reconciling a Paradox”, J Allergy and Clin Immun, p379-392, 2002.

[8]P.O. Fanger, “What is IAQ?”, Indoor Air, Vol 16, p328-344, 2006.

[9] O. Holst, A. J. Ulmer, H. Brade, H. Flad, E. T. Rietschel,” Biochemistry and Cell Biology of Bacterial Endotoxins”, FEMS Immun and Medical Microbiology, ElSevier Press, 16, p83-104, 1996.

[10] T. Kirikae, F. Kirikae, S. Saito, K. Tominaga, H. Tamura, Y. Uemura, T. Yokochi, and M. Nakano, “Biological Characterization of Endotoxins Released from Antibiotic-Treated Pseudomonas aeruginosa and Escherichia coli”, Vol 42, No 5, Antimicrobial Agents and Chemotherapy, p1015-1021, 1998.

[11] B.C. Wolverton, “How to Grow Fresh Air”, Penguin Books, 1996.

[12] S. Sinek, “Leaders Eat Last”, Portfolio/Penguin Publishers, 2014.