Sick building syndrome (SBS) and exposure to water-damaged buildings: Time series study, clinical trial and mechanisms
Introduction
The hypothesis that chronic exposure to the indoor environments of water-damaged buildings (WBD) causes a multi-system illness, often referred to as “sick building syndrome” (SBS), remains controversial [2], [3], [4], [17], [24], [27]. Reviews by the authors and the California Research Board of the scientific literature on studies investigating the association between WBD exposure and SBS identified many studies that supported the hypothesis [95], [110]. The WDB environment supported microbial amplification in the indoor environment, and indoor air contained a complex mixture of substances, including toxigenic fungi, bacteria, mycotoxins, endotoxins, antigens, lipopolysaccharides, and biologically produced volatile organic compounds. Many occupants of the WDBs reported multiple-system symptoms. Objective measurements indicated that irritant and allergic characteristics of airborne particles adversely impacted pulmonary function. However, methodological limitations in the past had prohibited the definitive attribution of multiple-system illness to the WDB environment. Our previous reports described studies that attempted to overcome some of those limitations [95], [97]. Critical study components included a prospective experimental design in which clinical data were collected at five time points; the use of objective indicators of effect; the interventions of successful therapy; removal from exposure; and re-exposure [95]. The study results indicated that SBS acquired in WDBs might be a form of “biotoxin-associated illness”, a term used to indicate that some forms of illness may be caused by exposure to toxins produced by single-cell organisms such as fungi, dinoflagellates, cyanobacteria, diatoms, and bacteria. The multiple-system illness identified in patients previously exposed to aquatic environments inhabited by the suspected toxigenic dinoflagellates, Pfiesteria sp., represented a form of biotoxin-associated illness [40], [96], [103], termed “Possible Estuary Associated Syndrome” (PEAS) by the Centers for Disease Control and Prevention [23]. The current study attempted to confirm the previous observations and further characterize the physiological and biochemical characteristics of SBS acquired in WDBs.
Our previous reports described the results from SBS studies that used a powerful ABB′AB study design that allow participants to serve as their own controls. This design provided the advantage that the participants' environmental and genetic characteristics remained constant as they were monitored over time and experimental interventions were enacted. The interventions were the initiation of successful therapy, exposure avoidance, re-exposure, and a second round of therapy. The results showed a spectrum of multiple-system symptoms that were acquired by patients following chronic exposure to WDBs. High symptom prevalence was accompanied by large deficits in visual contrast sensitivity [95], [97], an indicator of neurologic function in the visual system [13], [48], [49], [50], [51], [52], [91], [103]. Most patients also reported upper airway symptoms, but pulmonary function tests indicated that few patients had obstructive or restrictive lung function. Elevated levels of leptin and decreased levels of alpha melanocyte stimulating hormone (MSH) indicated that the illness likely involved pathology in the hypothalamus. Increased levels of leptin indicated probable damage to leptin receptors in the hypothalamus [44], [62], [117] that could result from a toxin-triggered increase in the release of pro-inflammatory cytokines by adipose cells [60]. Inability of the damaged leptin receptors to be stimulated by leptin would result in overproduction of leptin [70] and reduced secretion of MSH [43]. MSH deficiency causes abnormal function in the pituitary gland [8], gastrointestinal system [26], and immunologic system [66], [67], and are associated with chronic pain [57] and sleep disturbance [18]. Participants received 2 weeks of treatment with cholestyramine (CSM). Cholestyramine is a non-absorbable polymer that removes a variety of toxins from bile through anion-exchange binding, thereby causing toxin elimination rather than reabsorption during enterohepatic recirculation [5], [9], [15], [16], [22], [25], [28], [29], [54], [58], [59], [64], [74], [75], [86], [87], [100], [111]. CSM therapy resulted in a dramatic decrease in symptom prevalence concomitant with normalization of VCS [95], [97]. Group-mean leptin levels were decreased and MSH levels were increased following CSM therapy [95], [97]. Health status continued to show marked improvement following CSM therapy while the study participants avoided re-exposure to the WDBs. However, all participants relapsed within 7 days of re-exposure to the WDBs. Readministration of CSM again resulted in a highly significant improvement in the health status indicators. The positive response to toxin-elimination therapy, the maintenance of good health without re-exposure to the WDBs, and the relapse with re-exposure strongly supported the hypothesis that illness was causally associated with exposure to the WDBs.
The current study again used a prospective experimental design with clinical assessments occurring at five points in time to test the general study hypothesis that SBS is associated with exposure to WDBs. Evaluations occurred immediately after the screening of potential study participants; after 2 weeks of CSM therapy; after the avoidance of exposure to WDBs; following re-exposure to the WDBs; and after a second course of CSM therapy. Symptom prevalence, VCS, pulmonary function, and leptin and MSH concentrations were measured in an attempt to confirm the previously observed results. Levels of immunoglobulin E (IgE), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor (VEGF) were measured to help further characterize underlying pathology. A double-blind, placebo-controlled clinical trial was conducted in 13 of the 26 study participants at the onset of the time series-study to assess the efficacy of CSM therapy on health status relative to placebo treatment. Following baseline assessments, the clinical trial participants were randomly assigned to either receive 2 weeks of placebo therapy prior to receiving 2 weeks of CSM therapy or to immediately receive 2 weeks of CSM therapy.
Section snippets
General hypothesis
SBS is associated with exposure to WDBs.
Confirmatory hypotheses
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Time series study
- 1.a.
Group-mean scores for (i) number of symptoms; (ii) leptin; and (iii) MMP9 show statistically significant decreases between Time Points 1–2, 1–5, and 4–5.
- 1.b.
Group-mean scores for VCS show a statistically significant increase between Time Points 1–2; 1–5; and 4–5.
- 1.c.
The number of participants with abnormal VEGF scores shows a statistically significant decrease between Time Points 1–5.
- 1.d.
Group-mean scores for pulmonary function do not differ significantly between
Building descriptions
All 26 study buildings had visible evidence of water damage and microbial amplification (Table 1). Plumbing leaks, water intrusion in basements, in or around the roof and behind window and door casements, and flooding were the primary causes of water damage. Qualitative laboratory analyses of tape lift or bulk samples revealed one or more sites of fungal colonies in each of the 24 buildings sampled. Analysis of the samples indicated the fungal genera of Aspergillus sp. (16 samples), Penicillium
Discussion
The results from the time series study both confirmed and expanded upon results previously reported. All participants selected for study inclusion presented evidence of exposure potential, a multiple-system illness, and an absence of confounding factors.
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Symptoms: The medical assessments conducted at Time Point 1 indicated an average of 23 out of 37 symptoms in multiple organ systems. Below normal concentrations of MSH in 25 of the 26 participants at Time Point 1 (Hypothesis 1.e.) indicated
Acknowledgements
The authors gratefully acknowledge the contributions of H. Kenneth Hudnell, PhD, U.S. Environmental Protection Agency, Office of Research and Development, Neurotoxicology Division (MD:B105-05), Research Triangle Park, NC 27711, to this study and article.
A third party paid the cost of laboratory analyses for all patients regardless of whether they chose to participate in the study or to receive medical assistance outside of the study. There was no other funding source for the study. The authors
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