Chiara De Lucaa, Maria G. Scordob, Eleonora Cesareoa, Saveria Pastorea, Serena Mariania, Gianluca Maiania, Andrea Stancatoa, Beatrice Loretic, Giuseppe Valacchid, e, Carla Lubranoc, Desanka Raskovicf, Luigia De Padovac, Giuseppe Genovesic and Liudmila G. Korkinaa. Toxicology and Applied Pharmacology. April 2010.

Abstract

Background

Multiple chemical sensitivity (MCS) is a poorly clinically and biologically defined environment-associated syndrome. Although dysfunctions of phase I/phase II metabolizing enzymes and redox imbalance have been hypothesized, corresponding genetic and metabolic parameters in MCS have not been systematically examined.

Objectives

We sought for genetic, immunological, and metabolic markers in MCS.
Methods

We genotyped patients with diagnosis of MCS, suspected MCS and Italian healthy controls for allelic variants of cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP2D6, and CYP3A5), UDP-glucuronosyl transferase (UGT1A1), and glutathione S-transferases (GSTP1, GSTM1, and GSTT1). Erythrocyte membrane fatty acids, antioxidant (catalase, superoxide dismutase (SOD)) and glutathione metabolizing (GST, glutathione peroxidase (Gpx)) enzymes, whole blood chemiluminescence, total antioxidant capacity, levels of nitrites/nitrates, glutathione, HNE-protein adducts, and a wide spectrum of cytokines in the plasma were determined.
Results

Allele and genotype frequencies of CYPs, UGT, GSTM, GSTT, and GSTP were similar in the Italian MCS patients and in the control populations. The activities of erythrocyte catalase and GST were lower, whereas Gpx was higher than normal. Both reduced and oxidised glutathione were decreased, whereas nitrites/nitrates were increased in the MCS groups. The MCS fatty acid profile was shifted to saturated compartment and IFNgamma, IL-8, IL-10, MCP-1, PDGFbb, and VEGF were increased.

Conclusions

Altered redox and cytokine patterns suggest inhibition of expression/activity of metabolizing and antioxidant enzymes in MCS. Metabolic parameters indicating accelerated lipid oxidation, increased nitric oxide production and glutathione depletion in combination with increased plasma inflammatory cytokines should be considered in biological definition and diagnosis of MCS.

Keywords: Catalase; CYP; Cytokine; Fatty acid; Gene polymorphism; GST

Abbreviations: CL, chemiluminescence; CYP, cytochrome P450; DHA, docosahexaenoic acid; Gpx, glutathione peroxidase; GSH and GSSG, reduced and oxidized forms of glutathione respectively; GST, glutathione S-transferase; HNE, 4-hydroxy-2-nonenal; IFNgamma, interferon gamma; IL, interleukin; MCP, macrophage chemotactic protein; MCS, multiple chemical sensitivity; PDGF, platelet-derived growth factor; PMA, phorbol 12-myristate-13-acetate; PUFA, polyunsaturated fatty acids; RT PCR, reverse transcription polymerase chain reaction; CuZnSOD, copper and zinc-containing superoxide dismutase; UGT, UDP-glucuronosyl transferase; VEGF, vascular endothelial growth factor.

Associated information:

Predictions of Multiple Chemical Sensitivity Mechanism Confirmed by Roman Study.  Press Release. Martin Pall. July 2000.

More Evidence of the Organic Nature of Multiple Chemical Sensitivity. Margaret Williams. 6th July 2010.

Schnakenberg et al. 2007. Journal of Environmental Health. Full study is available at the site.

Abstract
Background: N-acetyltransferases (NAT) and glutathione S-transferases (GST) are involved in the metabolism of several ubiquitous chemical substances leading to the activation and detoxification of carcinogenic heterocyclic and aromatic amines. Since polymorphisms within these genes are described to influence the metabolism of ubiquitous chemicals, we conducted the present study to determine if individuals with self-reported chemical-related sensitivity differed from controls without self-reported chemical-related sensitivity with regard to the distribution of genotype frequencies of NAT2, GSTM1, GSTT1, and GSTP1 polymorphisms.
Methods: Out of 800 subjects who answered a questionnaire of ten items with regard to their severity of chemical sensitivity 521 unrelated individuals agreed to participate in the study. Subsequently, genetic variants of the NAT2, GSTM1, GSTT1, and GSTP1 genes were analyzed.
Results: The results show significant differences between individuals with and without selfreported chemical-related sensitivity with regard to the distribution of NAT2, GSTM1, and GSTT1 gene variants. Cases with self-reported chemical-related sensitivity were significantly more frequently NAT2 slow acetylators (controlled OR = 1.81, 95% CI = 1.27-2.59, P = 0.001). GSTM1 and GSTT1 genes were significantly more often homozygously deleted in those individuals reporting sensitivity to chemicals compared to controls (GSTM1: controlled OR 2.08, 95% CI = 1.46-2.96, P = 0.0001; GSTT1: controlled OR = 2.80, 95% CI = 1.65-4.75, P = 0.0001). Effects for GSTP1 gene variants were observed in conjunction with GSTM1, GSTT1 and NAT2 gene.
Conclusion: The results from our study population show that individuals being slow acetylators and/or harbouring a homozygous GSTM1 and/or GSTT1 deletion reported chemical-related hypersensitivity more frequently.

Trends Neurosci. 2009 Sep;32(9):506-16. Epub 2009 Aug 26. Block ML, Calderón-Garcidueñas L.

Abstract

Air pollution has been implicated as a chronic source of neuroinflammation and reactive oxygen species (ROS) that produce neuropathology and central nervous system (CNS) disease. Stroke incidence and Alzheimer's and Parkinson's disease pathology are linked to air pollution. Recent reports reveal that air pollution components reach the brain; systemic effects that impact lung and cardiovascular disease also impinge upon CNS health. While mechanisms driving air pollution-induced CNS pathology are poorly understood, new evidence suggests that microglial activation and changes in the blood-brain barrier are key components. Here we summarize recent findings detailing the mechanisms through which air pollution reaches the brain and activates the resident innate immune response to become a chronic source of pro-inflammatory factors and ROS, culminating in CNS disease.

Full Text is available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743793/pdf/nihms132349.pdf

Genetic variability is one of the major contributors to drug and chemical sensitivity. Genetic variability exists between all individuals to one degree or another. This variation is the basis for all evolutionary change and our biological existence. (Includes examples of sensitive subpopulations due to genetic variation.)

Joffres, Sampalli, and Fox. 2005. Environmental Health Perspectives. Full study available.

Abstract: We conducted a pilot study using a randomized, single-blind, placebo-controlled exposure among 10 individuals with and 7 without reported chemical sensitivities in a dedicated testing chamber. Objectives of the study were to explore the length of the adaptation period to obtain stable readings, evaluate responses to different substances, and measure the level and type of symptomatic and physiologic reactions to low-level exposures. Reported and observed symptoms, electrodermal response, heart rate, skin temperature, surface electromyogram, respiratory rate, contrast sensitivity, and the Brown-Peterson cognitive test were used and compared between cases and controls and between test substances (glue, body wash solution, dryer sheet) and control substances (unscented shampoo and clean air). Subjects with chemical sensitivities (cases) took longer to adapt to baseline protocols than did controls. After adaptation, despite small study numbers, cases displayed statistically significant responses (all measures, p < 0.02) in tonic electrodermal response to test substances compared with controls and compared with the control substance. Symptoms were also higher in cases than in controls for the body wash solution (p = 0.05) and dryer sheets (p = 0.02). Test-retest showed good agreement for both symptoms and tonic electrodermal responses (McNemar's test, p = 0.32 and p = 0.33, respectively). Outside of skin conductance, other measures had no consistent patterns between test and control substances and between cases and controls. This study shows the importance of using an adaptation period in testing individuals with reported chemical sensitivities and, despite small numbers, raises questions about underlying mechanisms and level of reactivity to low-level chemical exposures in sensitive individuals. Key words: complex mixtures, electrodermal response, multiple chemical sensitivity, pilot project, randomized controlled trial, skin conductance. Environ Health Perspect 113:1178-1183 (2005). doi:10.1289/ehp.7198 available via http://dx.doi.org/ [Online 19 May 2005]

Caress and Steinemann. Environmental Health Perspectives. 2003.

The Full Text of this article is available as a PDF.

Abstract:

In this review we summarize the findings of a two-phase study of the prevalence, symptomatology, and etiology of multiple chemical sensitivities (MCS). We also explore possible triggers, the potential linkage between MCS and other disorders, and the lifestyle alterations produced by MCS. The first phase of the study consisted of a random sampling of 1,582 individuals from the Atlanta, Georgia, metropolitan area to determine the reported prevalence of a hypersensitivity to common chemicals. In this phase, 12.6% of the sample reported a hypersensitivity. Further questioning of individuals with a hypersensitivity indicated that 13.5% (1.8% of the entire sample) reported losing their jobs because of their hypersensitivity. The second phase was a follow-up questioning of the respondents who initially reported hypersensitivity. In this phase, we found that individuals with hypersensitivity experience a variety of symptoms and triggers. A significant percentage (27.5%) reported that their hypersensitivity was initiated by an exposure to pesticides, whereas an equal percentage (27.5%) attributed it to solvents. Only 1.4% had a history of prior emotional problems, but 37.7% developed these problems after the physical symptoms emerged. This suggests that MCS has a physiologic and not a psychologic etiology.

Saito et al. 2005. Psychosomatic Medicine 67:318-325 (2005). The full report of this study is also available online in pdf format.

Objective: This study was conducted to confirm the definition of multiple chemical sensitivity (MCS) in actual life: that multiple symptoms are provoked in multiple organs by exposure to, and ameliorated by avoidance of, multiple chemicals at low levels. We used the Ecological Momentary Assessment to monitor everyday symptoms and the active sampling and passive sampling methods to measure environmental chemical exposure ... Conclusions: MCS patients do not have either somatic or psychologic symptoms under chemical-free conditions, and symptoms may be provoked only when exposed to chemicals.