Annex I
FA is a low-molecular-weight chemical, which is too small to stimulate the formation of specific antibodies. However it is presumed to combine rapidly with a variety of proteins, such as albumin to form an antigenic conjugate. There is possibility that inhaled FA induces FA-specific Ig E and causes bronchoconstruction. Although some studies investigated Ig G and/or Ig E antibodies to FA-human serum albumin conjugates, their results were not consistent (Vandenplas et al. 2004). On the other hand, no consistent evidence for FA-specific Ig E-dependent bronchospasm has been shown and it has also not yet been established whether FA causes any immunologically mediated disease (Bardana and Montanaro 1991; Grammer et al. 1993; Wantke et al. 2000). Ig E-mediated reactions to FA have been reported to occur from dental compounds (Haikel et al. 2000; Kunisada et al. 2000; Tas and Pletscher 2002) and in haemodialysis patients where FA was used as a sterilizing agent for the equipment (Maurice et al. 1986). There are also some case studies suggesting that the prevalence of Ig E sensitization to FA appears very low in children (Doi et al. 2003; Maurice et al. 1986). A significant increase in bacterial-specific Ig G, and blood monocytes were related to indoor FA concentrations, but no association between markers of sensitization and respiratory symptoms was also demonstrated (Erdei et al. 2003).
In animals, several studies have been carried out to examine the probable effects of FA on immune parameters. There is in vivo evidence for both enhancement and depression of immune responses after exposure to FA. In some animal experiments, changes in cytokines indicative of Th2 mediated immune responses including increases in IL-1, IL-4, and IL-5 and decreases in INF- have been reported (Im et al. 2006; Jung et al. 2007) but it was also found that in mice topical application of FA did not induce significant cytokine production (De Jong et al. 2009). Increased frequency of CD4+, CD8+, and INF- cells were also recorded in mice after FA exposure (Dearman et al. 1999). FA seemed to influence regulatory T cells in mice and the intensity of allergic contact hypersensitivity was suggested to be altered by FA (Fujiki at al. 2005).
In the present study, the percentages of lymphocytes, the absolute numbers and the percentages of T-lymphocytes (CD3+) and of NK (CD56+) cells and the levels of TNF- were significantly higher in FA-exposed workers compared to their controls (p0.05). No other alterations in peripheral blood lymphocytes and lymphocyte subsets were observed in our study population.
Zhang et al. (2009) reported that no differences in the white blood cells, lymphocytes or T cells were found in subjects environmentally exposed to acute FA, while in another study exposure to FA in humans was found to reduce white blood cell (WBC) counts (Kuo et al. 1997). Contrary to our findings related to increase in total T cells, analysis of 23 non-smoking students with a mean inhalation of 0.508 mg/m3(0.413 ppm) FA for 8 weeks during anatomy classes revealed a significant increase of B cells (CD19+) and a decrease of total T (CD3+) cells, T-helper (CD4+), and T-suppressor (CD8+) cells (Ye et al. 2005; Ying et al. 1999). Consistent with our data, no significant differences in WBCand haemoglobins (Hb) in potential exposure groups such as wood workers was reported (Feng et al. 1996). On the other hand, it was demonstrated in some studies that long-term exposure of FA can decrease the number of WBCwhite blood cells and possibly lower platelet and haemoglobin counts (Tang and Zhang 2003; Tong et al. 2007; Yang 2007).
Madison et al. (1991) examined immunological biomarkers associated with an acute exposure to exothermic byproducts of urea FA spill in 42 individuals and they found elevated percentage and absolute numbers of B cells, auto-antibodies and greater titers of Ig G and Ig M to FA-human serum albumin. In their study, the percentage of T and T-helper cells in the peripheral blood was found to be significantly lower. The mean exposure period of our workers was 7.3 0.8 years compared to subjects with short-term FA exposure and there are very limited studies on the immune biomarkers of the workers chronically exposed to FA in their occupational setting. NK cell population and the proportion of T (CD3+) lymphocytes did not change in a study with women workers exposed to toxic chemical mixtures including FA (De Celis et al. 2008).
In the present study, the blood levels of Ig G and Ig M were found significantly lower in the workers compared to their controls (p0.05) but the blood levels of Ig A and complement C3 and C4 were not different between the groups.
Long term exposure to FA significantly increased the numbers of NK (CD26+), IL-2 positive cells, B-cells, and autoantibodies in some patients with multiple organ symptoms involving upper and lower respiratory and central nervous system symptoms indicating an activated immune system in these patients (Thraser et al. 1990). At present no autoimmune disorders have been clinically observed in FA exposed workers. Also in our study, the workers have not reported about about any diseases including respiratory abnormalities and asthma.
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