Sci Total Environ. 2012 Jun 7;431C:188-196. [Epub ahead of print]
Effect of mercury (Hg) dental amalgam fillings on renal and oxidative stress biomarkers in children.
Al-Saleh I, Al-Sedairi AA, Elkhatib R.
We examined the effect of mercury (Hg) associated with dental amalgam fillings on biomarkers of renal and oxidative stress in children between the ages of 5-15.5years. Urine samples were analyzed for N-acetyl-β-d-glucosaminidase (NAG), α(1)-microglobulin (α(1)-MG), β(2)-microglobulin (β(2)-MG), retinol binding protein (RBP), albumin (ALB), 8-hydroxy-2-deoxyguanosine (8-OHdG) and malondialdehyde (MDA).
The level of urinary Hg (UHg-C) was calculated as μg/g creatinine. Multiple regression analyses revealed that the excretion of urinary NAG was significantly associated with the presence of dental amalgam fillings (β=0.149, P=0.03) and the levels of UHg-C (β=0.531, P=0), with an interaction between the two (P=0).
The increase in urinary NAG in relation to UHg-C levels had a dose-effect pattern. The lowest observed effect was seen at UHg-C levels above 1.452μg/g creatinine, which is lower than previously reported. In contrast, α(1)-MG was negatively associated with the presence of dental amalgam fillings (β=-0.270, P=0), but positively with UHg-C levels (β=0.393, P=0).
There were 7 children without, and one child with, dental amalgam fillings with urinary α(1)-MG levels above the reference limit of >7mg/g creatinine. Even though α(1)-MG seems to be a reliable biomarker for early changes in renal functions, it might exert its effect only at a higher level of exposure. An inverse relationship was also observed between urinary 8-OHdG levels and the presence of dental amalgam fillings. This might suggest that the dental amalgam does not increase DNA damage but reduces the capacity to repair DNA, leading to lower urinary excretion of 8-OHdG.
On the other hand, we found that Hg affected the excretion of urinary 8-OHdG in a dose-related pattern that was mostly associated with long-term exposure to low Hg levels.
Urinary NAG levels were positively associated with urinary MDA levels (β=0.516, P=0) but not with 8-OHdG (β=0.134, P=0.078) after adjustment for potential confounders. Both UHg-C and the presence of dental amalgam fillings remained predictors of the NAG model.
Our data provide evidence that low exposure to Hg from dental amalgam fillings exerts an effect on kidney tubular functions in children. Oxidative stress may have played a role in this mechanism. The results of this study would also suggest that urinary NAG is the most sensitive of all the investigated renal biomarkers. These results should be confirmed with further investigation.
Most previous studies showed that mercury (Hg) could be toxic when inhaled, ingested or absorbed through the skin (Goldman et al., 2001). Its absorption and relative toxicity depend on its chemical form (Clarkson, 1997). The sources of exposure are also markedly different for the various forms of Hg. Diet, especially fish and other seafood is the main source of exposure of the general public to organic Hg that has the greatest potential neurotoxicity (WHO, 1990).
Both elemental and inorganic mercury are nephrotoxic (WHO, 2003).
Clinical health when compared with children who received resin composite materials without amalgam. The authors still believe, though as a precaution, that future use of amalgam should be avoided since, it does involve some level of mercury exposure. According to Needleman (2006), both studies by Bellinger et al. and DeRouen et al. represent thoughtful and important contributions to understanding the question of dental amalgamrisks to children, but the question of themore subtle effects remains open.
Although Ye et al. (2009) found that urinary Hg levels were slightly elevated among children with amalgam fillings, no evidence of adverse effects on the outcomes evaluated was found. A recent study by Geier et al. (2011) retested samples collected fromchildren with and without dental amalgamfillings previously collected by DeRouen et al. (2006) for urinary porphyrins as a biomarker of mercury toxicity (Woods, 1996). The authors found that cumulative exposure to Hg from dental amalgam might distort porphyrin metabolism.
Metal toxicity usually involves the production of reactive oxygen species (ROS) that in return damage lipids in membranes, proteins or enzymes in tissues, and DNA (Valko et al., 2005). Normally, ROSs are balanced by natural anti-oxidant enzymes (Ercal et al., 2001; Gobe and Crane, 2010). The imbalance between these ROSs and natural anti-oxidants creates the condition of oxidative stress that can play a vital role in disease pathogenesis (Roberts et al., 2010). Recent studies (Sabolić, 2006; Jan et al., 2011) have described how inorganic Hg induces the production of ROSs that plays a role in its nephrotoxic effect. Stacchiotti et al. (2009) reported that exposing experimental animals to subcytotoxic doses of inorganic Hg increased ROS, reactive nitrogen species (RNS) and the expression of metallothioneins that can lead to nephrotoxicity.
Monitoring urinary Hg is useful for controlling the nephrotoxic risk of overexposure, particularly to its inorganic form. It should not exceed 50 μg/g creatinine in order to prevent cytotoxic and functional renal effects (Roels et al., 1999). Urinary N-acetyl-β-D-glucosaminidase activity (NAG), α1-microglobulin (α1-MG), and β2-microglobulin (β2-MG) were used as markers of renal tubular damage, especially for nephrotoxic assessment of non-occupational exposures to Hg (Ohno et al., 2007). A study by Jarosińska et al. (2008) found that exposure to Hg had no effects on the kidney markers (particularly NAG) in occupationally exposed workers. In recent years, 8-hydroxy-2′- deoxyguanosine (8-OHdG) has been used widely in many studies as a biomarker for the measurement of endogenous oxidative DNA damage as well as a risk factor for many diseases, including cancer (Valavanidis et al., 2009). Chen et al. (2005) recommended the use of urinary 8-OHdG as a marker of oxidative DNA damage in mercury-exposed populations. However, they also mentioned that one should take into account the anti-oxidative repair systems that might minimize DNA lesions caused by Hg. It has been shown that Hg can oxidize the unsaturated fatty acids in themembrane lipid bilayer leading to an increase in lipid peroxidation (Milaeva, 2006). Hg and/or other heavy metals might induce vascular effects due to increased oxidative stress and lipid peroxidation (Houston, 2007).
Malondialdehyde (MDA) is one of the major secondary oxidation products derived from polyunsaturated fatty acids in body fluids or tissues and has been widely used as a biomarker of lipid peroxidation (Del Rio et al., 2005; Lykkesfeldt, 2007).
In Saudi Arabia, high rates of dental caries (94%) among primaryschool children have been reported (Al Dosari et al., 2004; Al-Malik and Rehbini, 2006). This might lead to the increased use of dental amalgam fillings. Data on the use of amalgam in children, though, are still not available. Mahmood et al. (2004) conducted a crosssectional study of 10 polyclinics within the Riyadh metropolitan area and found that amalgam was the most commonly used restorative material (53%).
Our data provide evidence that low exposure to Hg from dental amalgam fillings exerts an effect on kidney tubular functions in children. Oxidative stress may have played a role in this mechanism. Although the oxidative properties of Hg have been studied, the actual mechanism of inducing oxidative stress to renal tubules is still unclear. The results of this studywould also suggest that urinary NAG is the most sensitive of all the investigated renal biomarkers. These results should be confirmed with further investigation.