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Body burden of mercury is associated with acute atopic eczema and total IgE in children from southern Germany

2004; Elsevier BV; Volume: 114; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2004.04.011

1097-6825

Stephan Weidinger, Ursula Krämer, Lothar Dunemann, Matthias Möhrenschlager, Johannes Ring, Heidrun Behrendt,

Contact Dermatitis and Allergies

To the Editor: Atopic eczema (AE; atopic dermatitis) is the most common inflammatory skin disease among children. Interactions among susceptibility genes, the host's environment, and immunologic factors are involved in its pathogenesis.1.Leung D.Y. Bieber T. Atopic dermatitis.Lancet. 2003; 361: 151-160Abstract Full Text Full Text PDF PubMed Scopus (1169) Google Scholar Most patients show sensitizations against environmental allergens with high serum levels of total and allergen-specific IgE.1.Leung D.Y. Bieber T. Atopic dermatitis.Lancet. 2003; 361: 151-160Abstract Full Text Full Text PDF PubMed Scopus (1169) Google Scholar Increasing prevalence rates of AE during the last decades have been attributed to changes in environmental factors.1.Leung D.Y. Bieber T. Atopic dermatitis.Lancet. 2003; 361: 151-160Abstract Full Text Full Text PDF PubMed Scopus (1169) Google Scholar With industrialization, heavy metals have been increasingly released into the environment, which may be incorporated through food, water, air, tobacco smoke, and medical prostheses.2.Han F.X. Banin A. Su Y. Monts D.L. Plodinec M.J. Kingery W.L. et al.Industrial age anthropogenic inputs of heavy metals into the pedisphere.Naturwissenschaften. 2002; 89: 494-507Crossref Scopus (227) Google Scholar A variety of these metals, such as arsenic, cadmium, and mercury, are of relevance to human health. They may interact with body stores of iron, vitamin C, and other essential nutrients, induce genomic instability, exert immunomodulatory effects, and cause contact dermatitis in sensitized persons.3.Schuppe H.C. Ronnau A.C. von Schmiedeberg S. Ruzicka T. Gleichmann E. Griem P. Immunomodulation by heavy metal compounds.Clin Dermatol. 1998; 16: 149-157Abstract Full Text PDF PubMed Scopus (37) Google Scholar Low doses of mercury salts have been shown to induce an immune response with polyclonal B cell activation, high levels of IgE, and autoantibody production.4.Pollard K.M. Hultman P. Effects of mercury on the immune system.in: Sigel A. Sigel H. Mercury and its effects on environment and biology. Marcel Dekker, Basel1997Google Scholar Recently, it could be demonstrated that mercury also enhances IgE-dependent mediator release from human basophils.5.Strenzke N. Grabbe J. Plath K.E.S. Rohwer J. Wolff H.H. Gibbs B.F. Mercuric chloride enhances immunoglobulin-E-dependent mediator release from human basophils.Toxicol Appl Pharmacol. 2001; 174: 257-263Crossref PubMed Scopus (20) Google Scholar In contrast, cadmium seems to inhibit IgE synthesis but enhance mast cell degranulation.6.Marth E. Jelovcan S. Kleinhappl B. Gutschi A. Barth S. The effect of heavy metals on the immune system at low concentrations.Int J Occup Med Environ Health. 2001; 14: 375-386PubMed Google Scholar On the basis of the assumption that body burdens of (heavy) metals may serve as triggering factors, we investigated their associations with AE and total and specific IgE in a nested case-control study. The study base consisted of a cross-sectional study with all school beginners in Augsburg, Bavaria, in 1996 (n = 1673). Of these individuals, we recruited 164 children with AE and 213 controls (196 boys, 181 girls). Parents completed a standardized questionnaire with basic allergy questions of the International Study of Childhood Asthma and Allergy in Childhood survey and were interviewed about parental history and the child's symptoms of atopic diseases and environmental risk factors, including exposure to metals. All children received a skin examination according to the criteria of Hanifin and Rajka. AE severity was assessed with the Scoring Index of Atopic Dermatitis (SCORAD) system. Total and specific serum IgE was measured by enzyme immunoassay (allergens: mite, cat, egg white, milk, ascaris, soya bean, birch pollen, mug wort pollen, timothy grass pollen, Alternaria, Blatella germanica; CAP-FEIA, Pharmacia, Sweden). Childrens' dental restorations, including the number of amalgam fillings, were evaluated. At the day of examination, arsenic, cadmium, and mercury were measured in morning urine by atomic absorption spectrometry.7.Ewers U. Krause C. Schulz C. Wilhelm M. Reference values and human biological monitoring values for environmental toxins.Int Arch Occup Environ Health. 1999; 71: 255-260Crossref Scopus (177) Google Scholar Urinary creatinine was determined by using a commercial test kit (Merck AG, Darmstadt, Germany) to adjust for differences in urine concentration. The concentrations of mercury, cadmium, and arsenic did not exceed actual reference values.7.Ewers U. Krause C. Schulz C. Wilhelm M. Reference values and human biological monitoring values for environmental toxins.Int Arch Occup Environ Health. 1999; 71: 255-260Crossref Scopus (177) Google Scholar Mean concentrations were 0.12 μg/L mercury, 0.18 μg/L cadmium, and 7.02 μg/L arsenic. Seventy-three of the children with AE were classified as having acute AE because of actual skin lesions, and 98 as having a history of AE because of a physician's diagnosis of AE in the past. Logistic regression analysis was performed to assess the independent influence of the exposure variables (heavy metal content of urine) on the risk of acute AE or AE in history while controlling for known or assumed risk factors (sex, social status, family size, parental history of AE, exposure to environmental tobacco smoke, urinary creatinine). The parameter estimates were transformed to odds ratios (ORs) with 95% CIs (profile-likelihood method), giving an estimate of the maximal effect in the population after exclusion of extremes. The range units of the exposure concentrations of arsenic, cadmium, and mercury were different. To ensure comparability, ORs were calculated to describe the change in AE prevalence when changing the exposure from the 5th to the 95th percentile (inner 90% range). Results were considered statistically significant if the CI did not include the 1. Logistic regression was also applied to assess the influence of urinary metal concentrations on specific IgE (any positive: >0.35 kU/L). To test the association with total IgE, log-linear regression models were performed. Children with amalgam fillings (n = 47) showed significantly higher urinary mercury concentrations than children with no fillings or other fillings (0.12 μg/L vs 0.27 μg/L; P = .01, t test). Urinary mercury excretion was significantly correlated with the number of amalgam fillings (r = 0.31; P < .001). Regression analysis revealed significantly higher urinary mercury concentrations in children with acute AE compared with children with history of AE or controls (OR, 1.68; 95% CI, 1.06-2.68; Table I). This association did not remain significant when restricting the analysis to children without amalgam fillings (OR, 1.10; 95% CI, 0.42-2.89). It was independent from total IgE. Children with acute AE showed no significant association between urinary mercury concentration and AE severity. There was no relationship between arsenic or cadmium levels and AE.Table IResults of logistic regression analyses evaluating associations between AE and urinary concentration of heavy metalsOR∗ORs when changing exposure from the 5th to the 95th percentile (0.45 μg/L mercury, 0.44 μg/L cadmium, and 11.8 μg/L arsenic). Adjusted for sex, social status, number of persons in home, parental history of AE, exposure to environmental tobacco smoke, and urinary creatinine. (95% CI)History of AEAcute AEUrinary cadmium concentration1.34 (0.79-2.30)1.06 (0.57-1.97)Urinary arsenic concentration1.21 (0.57-2.57)1.37 (0.58-3.23)Urinary mercury concentration0.66 (0.29-1.47)1.68 (1.06-2.68)∗ ORs when changing exposure from the 5th to the 95th percentile (0.45 μg/L mercury, 0.44 μg/L cadmium, and 11.8 μg/L arsenic). Adjusted for sex, social status, number of persons in home, parental history of AE, exposure to environmental tobacco smoke, and urinary creatinine. Open table in a new tab Linear regression revealed a significant relationship between mercury concentration but not with the other metal concentrations and total IgE (Table II).Table IILinear regression analyses for total serum IgE levels (log-transformed) as dependent variable and metal concentrations in urinenAdjusted change∗Change in geometric mean value (95% CI) when changing exposure from the 5th to the 95th percentile (0.45 μg/L mercury, 0.44 μg/L cadmium, and 11.8 μg/L arsenic). Adjusted for sex, social status, persons in home, parental history of AE, exposure to environmental tobacco smoke, urinary creatinine, and case/control status. in geometric means (95% CI)Urinary cadmium concentration2641.35 (0.93-1.95)Urinary arsenic concentration2621.18 (0.68-2.04)Urinary mercury concentration260−1.54 (1.12-2.11)∗ Change in geometric mean value (95% CI) when changing exposure from the 5th to the 95th percentile (0.45 μg/L mercury, 0.44 μg/L cadmium, and 11.8 μg/L arsenic). Adjusted for sex, social status, persons in home, parental history of AE, exposure to environmental tobacco smoke, urinary creatinine, and case/control status. Open table in a new tab There was no significant association between metal concentrations and presence of specific IgE. The results of this population-based case-control study in children with AE show a strong association between the body burden of mercury and disease state, indicating a possible role for mercury as triggering factor. Exposure to mercury in the general population mainly results from dental amalgams, with mercury concentrations in urine and blood associated with amalgam exposure.2.Han F.X. Banin A. Su Y. Monts D.L. Plodinec M.J. Kingery W.L. et al.Industrial age anthropogenic inputs of heavy metals into the pedisphere.Naturwissenschaften. 2002; 89: 494-507Crossref Scopus (227) Google Scholar, 3.Schuppe H.C. Ronnau A.C. von Schmiedeberg S. Ruzicka T. Gleichmann E. Griem P. Immunomodulation by heavy metal compounds.Clin Dermatol. 1998; 16: 149-157Abstract Full Text PDF PubMed Scopus (37) Google Scholar Health problems caused by mercury released from dental amalgam have been subjects of controversial debates. However, extensive scientific risk evaluations could not demonstrate a clear-cut relationship. In contrast, toxic and immunomodulatory effects of mercury compounds are well-known.3.Schuppe H.C. Ronnau A.C. von Schmiedeberg S. Ruzicka T. Gleichmann E. Griem P. Immunomodulation by heavy metal compounds.Clin Dermatol. 1998; 16: 149-157Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 4.Pollard K.M. Hultman P. Effects of mercury on the immune system.in: Sigel A. Sigel H. Mercury and its effects on environment and biology. Marcel Dekker, Basel1997Google Scholar HgCl2 directly activates murine mast cells and enhances mediator release, including IL-4, thereby facilitating TH2-lymphocyte development and polyclonal IgE production.4.Pollard K.M. Hultman P. Effects of mercury on the immune system.in: Sigel A. Sigel H. Mercury and its effects on environment and biology. Marcel Dekker, Basel1997Google Scholar, 8.Bagenstose L.M. Salgame P. Monestier M. Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans.Immunol Res. 1999; 20: 67-78Crossref PubMed Scopus (76) Google Scholar In addition, HgCl2 enhances anti-IgE–induced secretion of histamine, leukotriene C4, IL-4, and IL-13 from human basophils in a dose-dependent fashion. These effects were observed at mercury concentrations comparable with those measured in the children of this study.5.Strenzke N. Grabbe J. Plath K.E.S. Rohwer J. Wolff H.H. Gibbs B.F. Mercuric chloride enhances immunoglobulin-E-dependent mediator release from human basophils.Toxicol Appl Pharmacol. 2001; 174: 257-263Crossref PubMed Scopus (20) Google Scholar Nonlethal exposure to various forms of mercury is known to induce autoimmunity (HgIA) in susceptible rats, which is characterized by significant increases of IL-4 and IL-10 and hypergammaglobulinemia predominantly of the TH2-related IgG1 and IgE isotypes.8.Bagenstose L.M. Salgame P. Monestier M. Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans.Immunol Res. 1999; 20: 67-78Crossref PubMed Scopus (76) Google Scholar, 9.Fournie G.J. Mas M. Cautain B. Savignac M. Subra J.F. Pelletier L. et al.Induction of autoimmunity through bystander effects: lessons from immunological disorders induced by heavy metals.J Autoimmun. 2001; 16: 319-326Crossref PubMed Scopus (74) Google Scholar Recent findings provided evidence that HgIA is also dependent on IFN-γ, and that the immunomodulatory effects of mercury strongly depend on the host's genetic background.10.Kono D.H. Balomenos D. Pearson D.L. Park M.S. Hildebrandt B. Hultman P. et al.The prototypic Th2 autoimmunity induced by mercury is dependent on IFN-gamma and not Th1/Th2 imbalance.J Immunol. 1998; 161: 234-240PubMed Google Scholar In conclusion, we observed a clear-cut relation between body burdens of mercury and acute but not chronic AE. Children with amalgam fillings exhibited significantly higher urinary mercury concentrations than children without, and there was a significantly higher risk for acute eczematous lesions with higher urinary mercury concentrations. In addition, there was a positive and linear association between exposure to mercury and serum levels of total but not specific IgE. It might be speculated that mercury exacerbates allergic disorders by promoting a TH2-cytokine profile and facilitating production of IgE against yet unknown antigens, such as autoantigens. Further investigations are necessary to elucidate the interrelation among amalgam fillings, body burdens of mercury, and the formation of acute eczematous lesions in AE, its underlying mechanisms, and its clinical significance. CorrectionJournal of Allergy and Clinical ImmunologyVol. 114Issue 4PreviewWith regard to the August 2004 letter entitled "Body burden of mercury is associated with acute atopic eczema and total IgE in children from southern Germany" (2004;114:457-9): In Table II (page 458), the adjusted change in geometric mean for urinary mercury concentration was presented incorrectly. A correct version of the Table is presented here: Full-Text PDF