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	Articles Abstracts Conferences NEL Supplement MELISA® and LTT Links	If you have any suggestion for other important articles you would like to high-light here, please let us know. Send an email to london@melisa.org. Metals and Cardiovascular Diseases Metals and Psychiatric Disease Metals and Cancer and treatment with Vitamin C Metals, Fertililty and Fetal Exposure Metals and Skin Diseases Metals and Gastrointestinal Diseases Metals and Dentistry Metals and Oral Diseases Metals and Paediatric Exposure, Vaccines Metals and Detoxification and Chelation Metals and Genetic Susceptibility Metals and the Brain Metals and Occupational Exposure Diagnostic Procedures in the Determination of Metal Toxicity and Allergy Metals and Autoimmunity Metals As Possible Pathogenesis in Patients with Unclear Diagnosis (CFS, MCS) Metal Effects on Clinical Chemistry Findings Metals and Disturbance of HPA-axis Metals and Allergy Ortopedic Metal Implants Metals and Cardiovascular Diseases Title The impact of metallic allergy on stent implantation: metal allergy and recurrence of in-stent restenosis. Author Iijima R, Ikari Y, Amiya E, Tanimoto S, Nakazawa G, Kyono H, Hatori M, Miyazawa A, Nakayama T, Aoki J, Nakajima H, Hara K., The Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan. Raisuke329@aol.com Source Int J Cardiol. 2005 Oct 10;104(3):319-25. Abstract BACKGROUND: Relation between metallic allergy and in-stent restenosis (ISR) has been inconclusive. We hypothesized that mechanism of restenosis is different between initial stent implantation and dilatation for ISR. Thus, we studied metallic allergy and restenosis in these two different situations separately. METHODS AND RESULTS: We performed follow-up angiography and patch test for metallic allergy in a total of 174 stented consecutive patients, 109 patients (63%) for restudy of initial stent implantation and 65 patients (37%) for restudy of treatment following ISR. The positive rate of patch test in initial stent implantation was not significantly different between with or without restenosis (10% vs. 9%; p=ns). Whereas, following dilatation of ISR, the incidence of positive patch test was significantly higher in patients with recurrence of restenosis than those without the recurrence (39% vs. 12%; p=0.02). Multivariate analysis revealed that the positive patch test (Odd Ratio 4.39, p=0.02) and diffuse typed ISR (Odd Ratio 3.68, p=0.03) were significant predictors of recurrent restenosis. CONCLUSIONS: Metal allergy does not have any correlation with the restenosis after initial stent implantation. However, metal allergy is frequently observed in patients with recurrence of ISR. Metal allergy may contribute to a mechanism in the repeat recurrence of ISR, but not to restenosis after initial stent implantation. Title The role of mercury and cadmium heavy metals in vascular disease, hypertension, coronary heart disease, and myocardial infarction. Author Houston MC.,Vanderbilt University School of Medicine, USA. Source Altern Ther Health Med. 2007 Mar-Apr;13(2):S128-33. Abstract Mercury, cadmium, and other heavy metals have a high affinity for sulfhydryl (-SH) groups, inactivating numerous enzymatic reactions, amino acids, and sulfur-containing antioxidants (NAC, ALA, GSH), with subsequent decreased oxidant defense and increased oxidative stress. Both bind to metallothionein and substitute for zinc, copper, and other trace metals reducing the effectiveness of metalloenzymes. Mercury induces mitochondrial dysfunction with reduction in ATP, depletion of glutathione, and increased lipid peroxidation; increased oxidative stress is common. Selenium antagonizes mercury toxicity. The overall vascular effects of mercury include oxidative stress, inflammation, thrombosis, vascular smooth muscle dysfunction, endothelial dysfunction, dyslipidemia, immune dysfunction, and mitochondrial dysfunction. The clinical consequences of mercury toxicity include hypertension, CHD, MI, increased carotid IMT and obstruction, CVA, generalized atherosclerosis, and renal dysfunction with proteinuria. Pathological, biochemical, and functional medicine correlations are significant and logical. Mercury diminishes the protective effect of fish and omega-3 fatty acids. Mercury, cadmium, and other heavy metals inactivate COMT, which increases serum and urinary epinephrine, norepinephrine, and dopamine. This effect will increase blood pressure and may be a clinical clue to heavy metal toxicity. Cadmium concentrates in the kidney, particularly inducing proteinuria and renal dysfunction; it is associated with hypertension, but less so with CHD. Renal cadmium reduces CYP4A11 and PPARs, which may be related to hypertension, sodium retention, glucose intolerance, dyslipidemia, and zinc deficiency. Dietary calcium may mitigate some of the toxicity of cadmium. Heavy metal toxicity, especially mercury and cadmium, should be evaluated in any patient with hypertension, CHD, or other vascular disease. Specific testing for acute and chronic toxicity and total body burden using hair, toenail, urine, serum, etc. with baseline and provoked evaluation should be done. Title Contact allergy to gold in patients with gold-plated intracoronary stents. Author Svedman C, Tillman C, Gustavsson CG, Moller H, Frennby B, Bruze M., Department of Occupational and Environmental Dermatology, Malmo University Hospital, Sweden. Source Contact Dermatitis. 2005 Apr;52(4):192-6. Abstract An increasingly common and effective method for the treatment of atherosclerotic disease in the coronary arteries is percutaneous transluminal coronary angioplasty (PTCA) and stenting. The stents are made of different metals. An increased rate of restenosis when using gold-plated stents has been shown. Contact allergy to gold is common in many countries. Recently, a study has shown an increased rate of contact allergy to nickel among patients with restenosis and a nickel-containing stent. The aims of our study were to investigate whether there was an increased rate of contact allergy to gold among patients with gold-plated stents and if this increased the risk of restenosis. 22 patients who had received a gold-plated stent were patch tested. An age- and sex-matched population of 88 patients, previously patch tested because of a suspected contact dermatitis, served as controls. In the stent group, 10/22 (45.5%) had a contact allergy to gold, in the control group 18/88 (20.5%); the difference is statistically significant (P = 0.04). There was no significant difference regarding frequency of restenosis. Our study indicates that there is a risk of sensitizing the patient when implanting a gold-plated stent. Further studies are needed to confirm these results and to evaluate whether there is an increased risk of restenosis. Title Restenosis in gold-coated renal artery stents. Author Nolan BW, Schermerhorn ML, Powell RJ, Rowell E, Fillinger MF, Rzucidlo EM, Wyers MC, Whittaker D, Zwolak RM, Walsh DB, Cronenwett JL., Division of Vascular Surgery, Dartmouth-Hitchcock Medical Center, NH 03756, USA. Brian.Nolan@Hitchcock.org Source J Vasc Surg. 2005 Jul;42(1):40-6. Abstract BACKGROUND: Gold coating improves stent visibility under fluoroscopy. This is particularly valuable for precise stent placement during renal artery stenting (RAS). There is conflicting evidence regarding restenosis with gold-coated stents. To evaluate the effect of gold coating on restenosis after renal stenting, we reviewed the results of all patients undergoing RAS in our practice. METHODS: A retrospective cohort study of all patients undergoing RAS between June 2000 and September 2003 was performed. During this time, both gold-coated and stainless steel stents were used. Restenosis (>60% diameter) was determined by serial follow-up duplex exams (peak systolic velocity >180 cm/s and renal-aortic ratio >3.5). Restenosis rates were determined by using the Kaplan-Meier life-table method. Variables potentially affecting restenosis were evaluated with the log-rank test and Cox proportional hazards modeling. RESULTS: RAS was performed in 97 arteries (78 patients). Gold-coated (NIRoyal) stents were placed in 59 arteries (48 patients). Stainless steel stents (Corinthian, Genesis, and Herculink) were placed in 38 arteries (34 patients). Patient demographics, indication for treatment, technical success, and complications did not differ between gold and stainless steel stent groups. Mean follow-up was 15 months for gold-coated stents and 18 months for stainless steel stents (NS). By life-table method, 1-year and 2-year freedom from restenosis rates were 84% and 78% in arteries treated with stainless steel stents versus 69% and 39% in thosetreated with gold-coated stents (P = .012, log-rank test). By multivariate analysis, only the use of gold-coated stents (P = .018; hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.2 to 8.7) and bilateral disease (P = .046; HR, 2.3; 95% CI, 1.02 to 5.2) predicted restenosis. Stent diameter, patient demographics, and indication for RAS had no effect on restenosis by univariate analysis. According to American Heart Association criteria, 87% of patients in the stainless steel group had improved blood pressure at 1 year, compared with 77% in the gold-coated stent group (Kaplan-Meier; P = .042, log-rank test). There were no significant differences in the effect of RAS on serum creatinine levels between the two groups. CONCLUSION: Gold-coated renal stents had a substantially higher rate of restenosis than stainless steel stents in our series. These findings have led us to abandon the use of gold-coated stents for RAS. Patients who have received gold-coated stents for the treatment of atherosclerotic renal artery stenosis should be followed closely for evidence of restenosis. Title Granulation tissue with eosinophil infiltration in the restenotic lesion after coronary stent implantation. Author Kawano H, Koide Y, Baba T, Nakamizo R, Toda G, Takenaka M, Yano K.. Department of Cardiovascular Medicine, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan, hkawano@net.nagasaki-u.ac.jp Source Circ J. 2004 Jul;68(7):722-3. Abstract Although stents reduce the rate of vessel restenosis, in-stent restenosis is a recognized clinical problem and it appears that patients positive for allergic patch-test reactions to the stent components nickel and molybdenum have increased rates of it. A patient with angina pectoris had repeated episodes of restenosis after stent implantation and histological examination demonstrated granulation tissue with eosinophil infiltration in the restenotic lesion of the coronary artery. The patient was positive for an allergic reaction to the stent components. Email us for full artice Title Use of methyl prednisolone and antioxidants in mercuric cloride-induced experimental vasculitis. Author FJ Quasim, PW Mathieson, S Thiru, DBG Oliveira Source Clin Exp Immunol; 98:66-70 Summary The systematic vasculitides are characterized by necrotizing inflammation of blod vessels. Neutrophils are implicated in tissue damage by their presence at the site of injury. They can mediate injury by release of cellular contentincluding proteinases, citokines and reactive oxygen species. Antioxidants such as vitamin E and N-acetyl cysteine (NAC) may therefore be predicted to ameliorate oxidative damages in vivo and could be a cheap and non-toxic form of therapy. We examined the hypothesis in an experimental model of vasculitis which has some similarities to human disease, and in which depletion of neutrophils ameliorates tissue injury. Mercuric chloride (HgCl2) treatment includes an autoimmune syndrome and necrotizing leucocytoclastic vasculitis in the Brown Norway (BN) rat; anti-myeloperoxidase (MPO) anti-glomerular basement (GBM) antibodies are present, and vasculitis is reduced by antimicrobials. Methyl prednisolone given tintravenously was effective in reducing tissue injury, demonstrating that the model was responsive to a treatment used in man.m Vitamin E and NAC were given as daily injections intraperitoneally to BN rats either before, during or after HgCl2 administration. Serial blod samples were taken for anti-MPO and IgE antibodies, which were assayed by ELISA. Necropsies were performed on animals killed at peak disease. At doses of 50-200mg/kg per day vitamin E had no beneficial effect on tissue injury, regardless of timing of treatment. NAC at 100 or 200mg/kg also had no significant positive effect on vasculitis. Autoantibody and IgE levels were not affected by either methyl prednisolone or the antioxidants. The lack of benefits of vitamin E and NAC suggests that oxidative damage, whether generated by neutrophils or other cells, does not play a major role in the pathogenesis of vasculitis, and that antioxidant therapy is unlikely to be of benefit in systematic vasculitis in man. Title Mercury activates vascular endothelial cell phospholipase D through thiols and oxidative stress. Author Hagele TJ, Mazerik JN, Gregory A, Kaufman B, Magalang U, Kuppusamy ML, Marsh CB, Kuppusamy P, Parinandi NL. Source Int J Toxicol. 2007 Jan-Feb;26(1):57-69. Summary Currently, mercury has been identified as a risk factor of cardiovascular diseases among humans. Here, the authors tested the hypothesis that mercury modulates the activity of the endothelial lipid signaling enzyme, phospholipase D (PLD), which is an important player in the endothelial cell (EC) barrier functions. Monolayers of bovine pulmonary artery ECs (BPAECs) in culture, following labeling of membrane phospholipids with [32P]orthophosphate, were exposed to mercuric chloride (inorganic form), methylmercury chloride (environmental form), and thimerosal (pharmaceutical form), and the formation of phosphatidylbutanol as an index of PLD activity was determined by thin-layer chromatography and liquid scintillation counting. All three forms of mercury significantly activated PLD in BPAECs in a dose-dependent (0 to 50 microM) and time-dependent (0 to 60 min) fashion. Metal chelators significantly attenuated mercury-induced PLD activation, suggesting that cellular mercury-ligand interaction(s) is required for the enzyme activation and that chelators are suitable blockers for mercury-induced PLD activation. Sulfhydryl (thiol-protective) agents and antioxidants also significantly attenuated the mercury-induced PLD activation in BPAECs. Enhanced reactive oxygen species generation, as an index of oxidative stress, was observed in BPAECs treated with methylmercury that was attenuated by antioxidants. All the three different forms of mercury significantly induced the decrease of levels of total cellular thiols. For the first time, this study revealed that mercury induced the activation of PLD in the vascular ECs wherein cellular thiols and oxidative stress acted as signal mediators for the enzyme activation. The results underscore the importance of PLD signaling in mercury-induced endothelial dysfunctions ultimately leading to cardiovascular diseases. Top Metals and Psychiatric Disease Title Psychometric evidence that mercury from silver dental fillings may be an etiological factor in depression, excessive anger, and anxiety. Author Siblerud RL, Motl J, Kienholz E, Rocky Mountain Research Institute, Inc., Fort Collins, CO 80524 Source Psychol Rep 1994 Feb;74(1):67-80 Summary Scores on the Beck Depression Inventory were compared for 25 women who had silver dental fillings (amalgams) and for 23 women without amalgams. Women with amalgams had significantly higher scores and reported more symptoms of fatigue and insomnia. Anger scores from the State-Trait Anger Expression Inventory showed that the women with amalgams had statistically significantly higher mean scores on expressing anger without provocation and experiencing more intense angry feelings. The women without amalgams scored significantly higher on controlling anger, which suggested they invested more energy in monitoring and preventing the experience and expression of anger. Anxiety scores from the State-Trait Anxiety Inventory showed the women with amalgams scored significantly less pleasant, satisfied, happy, secure, and steady, and had a more difficult time making decisions. They had significantly higher Trait Anxiety scores. The women with amalgams also had significantly higher levels of mercury in the oral cavity before and after chewing gum. The study suggests that amalgam mercury may be an etiological factor in depression, excessive anger, and anxiety because mercury can produce such symptoms perhaps by affecting the neurotransmitters in the brain. Top Metals and Cancer and treatment with Vitamin C Title Metal ions and carcinogenesis. Author Durham TR, Snow ET., Centre for Cellular and Molecular Biology, School of Biological and Chemical Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria, Australia 3125. trd@deakin.edu.au Source EXS. 2006;(96):97-130. Abstract Metals are essential for the normal functioning of living organisms. Their uses in biological systems are varied, but are frequently associated with sites of critical protein function, such as zinc finger motifs and electron or oxygen carriers. These functions only require essential metals in minute amounts, hence they are termed trace metals. Other metals are, however, less beneficial, owing to their ability to promote a wide variety of deleterious health effects, including cancer. Metals such as arsenic, for example, can produce a variety of diseases ranging from keratosis of the palms and feet to cancers in multiple target organs. The nature and type of metal-induced pathologies appear to be dependent on the concentration, speciation, and length of exposure. Unfortunately, human contact with metals is an inescapable consequence of human life, with exposures occurring from both occupational and environmental sources. A uniform mechanism of action for all harmful metals is unlikely, if not implausible, given the diverse chemical properties of each metal. In this chapter we will review the mechanisms of carcinogenesis of arsenic, cadmium, chromium, and nickel, the four known carcinogenic metals that are best understood. The key areas of speciation, bioavailability, and mechanisms of action are discussed with particular reference to the role of metals in alteration of gene expression and maintenance of genomic integrity. Title Cadmium and prostate cancer: a critical epidemiologic analysis. Author Sahmoun AE, Case LD, Jackson SA, Schwartz GG., Department of Internal Medicine, University of North Dakota School of Medicine, Fargo, North Dakota, USA. Source Cancer Invest. 2005;23(3):256-63. Abstract Laboratory data implicate cadmium as a prostate carcinogen. However, epidemiological studies concerning the association between cadmium and prostate cancer are inconclusive. This article reviews the epidemiological literature on cadmium and prostate cancer with a special focus on highly exposed occupational cohorts. We searched the MEDLINE database from 1966 to 2002 for articles on cadmium and prostate cancer. All published analytical and descriptive studies that included relevant data were reviewed. In addition, we reviewed the experience of cohorts highly exposed to cadmium in nickel-cadmium battery plants. Of 4 descriptive studies, 3 reported a positive association between cadmium and prostate cancer. Of 10 case-control studies, 5 (50%) reported a positive association. Of 11 cohorts studies, 3 (33%) found a positive association. Finally, 4 studies on cohorts exposed in occupational nickel-cadmium batteries were identified and analyzed. The summary score of the standardized mortality ratios (SMRs) was weakly but not significantly positive 126 (95% confidence interval C.I.: 83-184). In contrast to laboratory studies, epidemiological studies do not convincingly implicate cadmium as a cause of prostate cancer. Future epidemiological studies that attempt to resolve the discrepancy between laboratory and epidemiological studies of cadmium carcinogenesis may benefit from incorporating biological measures of cadmium exposure. Title Estrogen-like activity of metals in MCF-7 breast cancer cells. Author Martin MB, Reiter R, Pham T, Avellanet YR, Camara J, Lahm M, Pentecost E, Pratap K, Gilmore BA, Divekar S, Dagata RS, Bull JL, Stoica A. Source Endocrinology. 2003 Jun;144(6):2425-36. Abstract The ability of metals to activate estrogen receptor-alpha (ERalpha) was measured in the human breast cancer cell line, MCF-7. Similar to estradiol, treatment of cells with the divalent metals copper, cobalt, nickel, lead, mercury, tin, and chromium or with the metal anion vanadate stimulated cell proliferation; by d 6, there was a 2- to 5-fold increase in cell number. The metals also decreased the concentration of ERalpha protein and mRNA by 40-60% and induced expression of the estrogen-regulated genes progesterone receptor and pS2 by1.6- to 4-fold. Furthermore, there was a 2- to 4-fold increase in chloramphenicol acetyltransferase activity after treatment with the metals in COS-1 cells transiently cotransfected with the wild-type receptor and an estrogen-responsive chloramphenicol acetyltransferase reporter gene. The ability of the metals to alter gene expression was blocked by an antiestrogen, suggesting that the activity of these compounds is mediated by ERalpha. In binding assays the metals blocked the binding of estradiol to the receptor without altering the apparent binding affinity of the hormone (K(d) = 10(-10) M). Scatchard analysis employing either recombinant ERalpha or extracts from MCF-7 cells demonstrated that (57)Co and (63)Ni bind to ERalpha with equilibrium dissociation constants of 3 and 9.5 x 10(-9) and 2 and 7 x 10(-9) M, respectively. The ability of the metals to activate a chimeric receptor containing the hormone-binding domain of ERalpha suggests that their effects are mediated through the hormone-binding domain. Mutational analysis identified amino acids C381, C447, E523, H524, N532, and D538 as potential interaction sites, suggesting that divalent metals and metal anions activate ERalpha through the formation of a complex within the hormone-binding domain of the receptor. Title Selenium/cadmium ratios in human prostates: indicators of prostate cancer risk of smokers and nonsmokers, and relevance to the cancer protective effects of selenium. Author Drasch G, Schopfer J, Schrauzer GN., Institut fur Rechtsmedizin, Ludwig-Maximillians Universitat, Munich, Germany. Source Biol Trace Elem Res. 2005 Feb;103(2):103-7. Abstract Selenium (Se) in a large-scale human supplementation trial has been shown to significantly reduce the incidence of prostate cancer in elderly men. Because Se is known to interact with cadmium (Cd), it has been suggested that its cancer protective action could be attributable in part to its interaction with Cd, a toxic and suspected carcinogenic element, which is found in many foods, in drinking water, and in the environment. Cadmium is considered a significant prostate cancer risk factor as it stimulates the growth of prostate epithelial cells and promotes their malignant transformation. Accordingly, prostate cancer risk is determined not only by Se status, but also the degree of Cd exposure. Determinations of Se and Cd in 129 prostates of deceased men aged 15-99 yr revealed Cd to accumulate in the prostate. Whereas the atomic Se/Cd ratios of the prostates of young men were invariably >1, indicating a stoichiometric excess of Se over Cd, they were found to decline with age, approaching the 1:1 ratio in elderly nonsmokers, a fact suggestive of the formation of a 1:1 Cd-Se complex. The associated physiological inactivation of Se could account for the increase of the prostate cancer risk with advancing age. The Se/Cd ratios dropped more steeply and consistently with age in smokers than in nonsmokers. In the prostates of some smokers, Se/Cd ratios even reached values , indicating a stoichiometric excess of Cd over Se. The excessive accumulation of Cd in the prostates of smokers along with sub-optimal Se intakes could explain why smokers develop more aggressive and lethal forms of prostate cancer than nonsmokers. Title Aluminium, antiperspirants and breast cancer. Author Darbre PD., Division of Cell and Molecular Biology, School of Animal and Microbial Sciences, The University of Reading, P.O. Box 228, Whiteknights, Reading, RG6 6AJ, UK. p.d.darbre@reading.ac.uk Source J Inorg Biochem. 2005 Se p;99(9):1912-9. Abstract Aluminium salts are used as the active antiperspirant agent in underarm cosmetics, but the effects of widespread, long term and increasing use remain unknown, especially in relation to the breast, which is a local area of application. Clinical studies showing a disproportionately high incidence of breast cancer in the upper outer quadrant of the breast together with reports of genomic instability in outer quadrants of the breast provide supporting evidence for a role for locally applied cosmetic chemicals in the development of breast cancer. Aluminium is known to have a genotoxic profile, capable of causing both DNA alterations and epigenetic effects, and this would be consistent with a potential role in breast cancer if such effects occurred in breast cells. Oestrogen is a well established influence in breast cancer and its action, dependent on intracellular receptors which function as ligand-activated zinc finger transcription factors, suggests one possible point of interference from aluminium. Results reported here demonstrate that aluminium in the form of aluminium chloride or aluminium chlorhydrate can interfere with the function of oestrogen receptors of MCF7 human breast cancer cells both in terms of ligand binding and in terms of oestrogen-regulated reporter gene expression. This adds aluminium to the increasing list of metals capable of interfering with oestrogen action and termed metalloestrogens. Further studies are now needed to identify the molecular basis of this action, the longer term effects of aluminium exposure and whether aluminium can cause aberrations to other signaling pathways in breast cells. Given the wide exposure of the human population to antiperspirants, it will be important to establish dermal absorption in the local area of the breast and whether long term low level absorption could play a role in the increasing incidence of breast cancer. Title Ascorbate depletion: a critical step in nickel carcinogenesis? Author Salnikow K, Kasprzak KS., Laboratory of Comparative Carcinogenesis, Building 538, Room 205 E., National Cancer Institute at Frederick/NIH, Frederick, MD 21702, USA., salnikow@ncifcrf.gov Source Environ Health Perspect. 2005 May;113(5):577-84. Abstract Nickel compounds are known to cause respiratory cancer in humans and induce tumors in experimental animals. The underlying molecular mechanisms may involve genotoxic effects; however, the data from different research groups are not easy to reconcile. Here, we challenge the common premise that direct genotoxic effects are central to nickel carcinogenesis and probably to that of other metals. Instead, we propose that it is formation of metal complexes with proteins and other molecules that changes cellular homeostasis and provides conditions for selection of cells with transformed phenotype. This is concordant with the major requirement for nickel carcinogenicity, which is prolonged action on the target tissue. If DNA is not the main nickel target, is there another unique molecule that can be attacked with carcinogenic consequences? Our recent observations indicate that ascorbate may be such a molecule. Nickel depletes intracellular ascorbate, which leads to the inhibition of cellular hydroxylases, manifested by the loss of hypoxia-inducible factor (HIF)-1alpha and -2alpha hydroxylation and hypoxia-like stress. Proline hydroxylation is crucial for collagen and extracellular matrix assembly as well as for assembly of other protein molecules that have collagen-like domains, including surfactants and complement. Thus, the depletion of ascorbate by chronic exposure to nickel could be deleterious for lung cells and may lead to lung cancer. Key words: ascorbate, carcinogenesis, collagens, extracellular matrix, hypoxia-inducible transcription factor, metals, nickel, protein hydroxylation. Title Cutaneous melanoma in Swedish women: Occupational risks by anatomic site. Author Perez-Gomez B, Aragones N, Gustavsson P, Plato N, Lopez-Abente G, Pollan M, Cancer and Environmental Epidemiology Section, National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain. Source Am J Ind Med. 2005 Oct;48(4):270-81. Abstract BACKGROUND: Few occupational studies have addressed melanoma in women. Accordingly, our aim was to identify occupations with higher risk of cutaneous melanoma, overall and by site, in Swedish female workers. METHODS: All gainfully employed Swedish women were followed-up from 1971 to 1989, using Death/Cancer Registers. Occupational risk ratios adjusted for age, period, town size, and geographic zone were computed for each site. Risk patterns for different sites were then compared. RESULTS: High risks were observed among educators, bank tellers, dental nurses, librarians/archivists/curators, horticultural workers, and hatmakers/milliners. Telephone operators and textile workers had increased risk, mainly in the leg. Other occupation-specific site excesses were also found. Upper-limb risks were correlated with head/neck and thorax, though these two sites were not associated. Legs registered a special pattern, with a moderate correlation with upper limbs or thorax, and no correlation with head/neck. CONCLUSIONS: Some occupations with possible exposure to arsenic/mercury displayed increased risk. The generalized excess risk among hatmakers/milliners warrants further attention. The weak correlation between legs and other sites suggests site specificity in melanoma risk factors. Title Intravenously administered vitamin C as cancer therapy: three cases. Author Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M., Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md 20892-1372, USA. Source CMAJ. 2006 Mar 28;174(7):937-42 Abstract Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 micromol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50-100 g) given intravenously may result in plasma concentrations of about 14,000 micromol/L. At concentrations above 1000 micromol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed. Dowload pdf article free: http://www.cmaj.ca/cgi/reprint/174/7/937 Title Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use Author Padayatty, et al. Source Ann Intern Med. 2004 Apr 6;140(7):533-7. Abstract Background: Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration. Conclusions: Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated. Dowload pdf article free: http://www.annals.org/cgi/reprint/140/7/533.pdf Title Orthomolecular oncology review: ascorbic acid and cancer 25 years later. Author Gonzalez MJ, Miranda-Massari JR, Mora EM, Guzman A, Riordan NH, Riordan HD, Casciari JJ, Jackson JA, Roman-Franco A. University of Puerto Rico, Medical Sciences Campus, Graduate School of Public Health, Department Human Development, Nutrition Program, PO Box 365067, San Juan, PR. mgonzalez@rcm.upr.edu Source Integr Cancer Ther. 2005 Mar;4(1):32-44. Abstract The effect of ascorbic acid on cancer has been a subject of great controversy. This is a follow-up review of the 1979 article by Cameron, Pauling, and Leibovitz published in Cancer Research. In this updated version, the authors address general aspects of ascorbic acid and cancer that have been presented before, while reviewing, analyzing, and updating new existing literature on the subject. In addition, they present and discuss their own mechanistic hypothesis on the effect of ascorbic acid on the cancer cell. The objective of this review is to provide an updated scientific basis for the use of ascorbic acid, especially intravenously as adjuvant treatment in pharmacological nutritional oncology. Dowload pdf article free: http://ict.sagepub.com/cgi/reprint/4/1/32 Title Increased levels of transition metals in breast cancer tissue. Author Ionescu JG, Novotny J, Stejskal VD, Latsch A, Blaurock-Busch E, Eisenmann-Klein M., Research Department of Spezialklinik Neukirchen, Neukirchen, Germany. info@spezialklinik-neukirchen.de. Source Neuro Endocrinol Lett. 2006 Aug 5;27(Suppl1) [Epub ahead of print] Abstract OBJECTIVES: High levels of transition metals such as iron, nickel, chromium, copper, and lead are closely related to free radical generation, lipid peroxidation, formation of DNA-strand breaks, and tumor growth in cellular systems. In order to determine the correlation to malignant growth in humans, we investigated the accumulation of heavy metals in 20 breast cancer biopsies and compared the findings to the levels found in 8 healthy biopsies. METHODS: The concentration of transition metals in breast cancer and control biopsies was assessed by a standardized Atomic Absorption Spectrofotometry (AAS) technique with acidic hydrolysis for sample preparation. Additionally, heavy metal analysis in control biopsies was also performed with an Inductive Coupled Plasma - Mass Spectroscopy (ICP-MS) technique. For statistical analysis of the results, the Mann-Whitney U Test was applied. RESULTS: A highly significant accumulation of iron (p<0.0001), nickel (p<0.00005), chromium (p<0.00005), zinc (p<0.00001), cadmium (p<0.005), mercury (p<0.005), and lead (p< 0.05) was found in the cancer samples when compared to the control group. Copper and silver showed no significant differences to the control group, whereas tin, gold, and palladium were not detectable in any biopsies. CONCLUSIONS: The data suggest that pathological accumulation of transition metals in breast tissue may be closely related to the malignant growth process. Title Biliary heavy metal concentrations in carcinoma of the gall bladder: case-control study Author Shukla VK et al, Departments of Surgery and Community Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, India, vkshukla@banaras.ernet.in Source British Medical Journal 1998;317:1288-1289 Abstract Carcinoma of the gall bladder is the third most common malignancy of the gastrointestinal tract in the eastern Uttar Pradesh and western Bihar regions of India.1 The two regions lie down stream of the river Ganges, which is the main source of drinking, bathing, and irrigation water in this part of India and receives untreated domestic sewage and industrial and agricultural effluent. High concentrations of cadmium have been reported in sewage, irrigation water, and vegetables grown in the area, and higher concentrations of heavy metals than recommended by the World Health Organisation have been reported in water from this region. Heavy metals as environmental pollutants have been implicated in human carcinogenesis. These metals, especially cadmium, are excreted and concentrated in the hepatobiliary system.3 Full text on: http://www.bmj.com/cgi/content/full/317/7168/1288?maxtoshow=&HITS= 10&hits=10&RESULTFORMAT=&fulltext=metal&andorexactfulltext=and&searchid= 1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT&eaf Top Metals, Fertililty and Fetal Exposure Title Maternal-fetal transfer of metallic mercury via the placenta and milk. Author Yang J, Jiang Z, Wang Y, Qureshi IA, Wu XD., Department of occupational Health, Shanghai Medical University, P.R. China. Source Ann Clin Lab Sci. 1997 Mar-Apr;27(2):135-41. Abstract To clarify the situation of trans-placental movement and milk screening of metallic mercury in human, the content of mercury was detected in the maternal blood, umbilical cord blood, milk, and placental tissues. In 18 parturient women, 9 had been occupationally exposed to metallic mercury whereas the other 9 had not. Mercury was detected by means of cold vapor atomic absorption spectrophotometry. Results showed that the concentrations of mercury of the umbilical cord blood and placental tissues were higher than that of maternal blood. The ratio of organic and total mercury of milk was markedly lower than that of maternal blood in the exposed group (P < 0.01). The ratio of inorganic to total mercury of milk was significantly higher than that of maternal blood (P < 0.01). Therefore, this study concluded that the metallic mercury can be transferred to the fetus via the placenta and secreted to a newborn via milk. Title Mercury burden of human fetal and infant tissues. Author Drasch G, Schupp I, Hofl H, Reinke R, Roider G., Institut fur Rechtsmedizin, Munchen, Germany. Source Eur J Pediatr. 1994 Aug;153(8):607-10. Abstract The total mercury concentrations in the liver (Hg-L), the kidney cortex (Hg-K) and the cerebral cortex (Hg-C) of 108 children aged 1 day-5 years, and the Hg-K and Hg-L of 46 fetuses were determined. As far as possible, the mothers were interviewed and their dental status was recorded. The results were compared to mercury concentrations in the tissues of adults from the same geographical area. The Hg-K (n = 38) and Hg-L (n = 40) of fetuses and Hg-K (n = 35) and Hg-C (n = 35) of older infants (11-50 weeks of life) correlated significantly with the number of dental amalgam fillings of the mother. The toxicological relevance of the unexpected high Hg-K of older infants from mothers with higher numbers of dental amalgam fillings is discussed. CONCLUSION: Future discussion on the pros and cons of dental amalgam should not be limited to adults or children with their own amalgam fillings, but also include fetal exposure. The unrestricted application of amalgam for dental restorations in women before and during the child-bearing age should be reconsidered. Title Mental retardation and prenatal methylmercury toxicity. Author Trasande L, Schechter CB, Haynes KA, Landrigan PJ., Department of Community and Preventive Medicine, Center for Children's Health and the Environment, New York, New York. Source Am J Ind Med. 2006 Mar;49(3):153-8 Abstract BACKGROUND: Methylmercury (MeHg) is a developmental neurotoxicant; exposure results principally from consumption of seafood contaminated by mercury (Hg). In this analysis, the burden of mental retardation (MR) associated with methylmercury exposure in the 2000 U.S. birth cohort is estimated, and the portion of this burden attributable to mercury (Hg) emissions from coal-fired power plants is identified. METHODS: The aggregate loss in cognition associated with MeHg exposure in the 2000 U.S. birth cohort was estimated using two previously published dose-response models that relate increases in cord blood Hg concentrations with decrements in IQ. MeHg exposure was assumed not to be correlated with native cognitive ability. Previously published estimates were used to estimate economic costs of MR caused by MeHg. RESULTS: Downward shifts in IQ resulting from prenatal exposure to MeHg of anthropogenic origin are associated with 1,566 excess cases of MR annually (range: 376-14,293). This represents 3.2% of MR cases in the US (range: 0.8%-29.2%). The MR costs associated with decreases in IQ in these children amount to $2.0 billion/year (range: $0.5-17.9 billion). Hg from American power plants accounts for 231 of the excess MR cases/year (range: 28-2,109), or 0.5% (range: 0.06%-4.3%) of all MR. These cases cost $289 million (range: $35 million-2.6 billion). CONCLUSIONS: Toxic injury to the fetal brain caused by Hg emitted from coal-fired power plants exacts a significant human and economic toll on American children. Am. J. Ind. Med. 49:153-158, 2006. (c) 2006 Wiley-Liss, Inc. Title Sensitization to inorganic mercury could be a risk factor for infertility. Author Podzimek S, Prochazkova J, Bultasova L, Bartova J, Ulcova-Gallova Z, Mrklas L, Stejskal VD., The Institute of Dental Research, 1st MF and GUH, Charles University, Prague, Czech Republic. stepanpodzimek@seznam.cz Source Neuro Endocrinol Lett. 2005 Aug;26(4):277-82. Abstract NTRODUCTION: Heavy metals can negatively influence the reproduction due to the fact that they are able to impair the immune reactions including autoantibody production in susceptible individuals. In such a way the infertility could be also caused by altered pathologic immune reaction. AIM OF THE STUDY: To investigate the in vitro lymphocyte reaction after stimulation with metals and production of gamma interferon and antisperm antibodies in supernatants after lymphocyte stimulation in patients with infertility and with proven antisperm antibodies in their serum. The cause of antisperm antibodies presence was not determined. METHODS: The diagnosis of metal allergy was performed by the lymphocyte proliferation method modified for metals (MELISA) in supernatants of tissue cultures of lymphocytes without the antigen stimulation and after stimulation with mercury chloride, the in vitro production of gamma interferon and antisperm antibodies was studied by ELISA. RESULTS: More than 50% of patients were reacting to mercury, iron, aluminium and silver as mean by lymphocyte reactivity. When compared the lymphocyte reaction in patients with and without mercury allergy we found that the lymphocytes of patients with mercury intolerance produced less gamma interferon and more antisperm antibodies in supernatants after mercury stimulation of their lymphocytes. CONCLUSION: In patients with metal intolerance diagnosed by the MELISA test the release of metal ions from dental materials can be one of the stimulating factors which may adversely affect fertility. Top Metals and Skin Diseases Title Ear piercing, and nickel and cobalt sensitization, in 520 young Swedish men doing compulsory military service. Author Meijer C; Bredberg M; Fischer T; Widström L Source Contact Dermatitis, 1995 Mar, 32:3, 147-9 Abstract Piercing the earlobes has increased in popularity among males in recent years. This habit would be expected to increase the incidence of nickel and cobalt sensitization. Patch testing with nickel sulfate and cobalt chloride was performed in 520 young Swedish men doing compulsory military service. The overall frequency of nickel/cobalt positive tests was 4.2%. The prevalence of nickel/cobalt positive tests was significantly higher (p < 0.05) in 152 men with pierced earlobes (7.9%) than in those 368 with unpierced earlobes (2.7%). A history of hand eczema (7/152 = 4.6%) or other types of eczema (22/152 = 14.5%) in individuals with pierced earlobes was no more common than in those with unpierced earlobes: 24/368 = 6.5% and 51/386 = 13.9%, respectively (n.s.). Hand eczema was no more common in sensitized (1/22 = 4.5%) than in nonsensitized individuals (32/498 = 6.4%) (n.s.). Title [Sarcoidal allergic contact dermatitis due to palladium following ear piercing] [Article in German] Author Blum R, Baum HP, Ponnighaus M, Kowalzick L., Klinik fur Hautkrankheiten und Allergologie der Vogtlandklinikum Plauen GmbH, Plauen. Source Hautarzt. 2003 Feb;54(2):160-2. Abstract Granulomatous tissue reactions due to jewelry made of gold, silver, nickel and palladium are rare but nevertheless have been known for a long time. A female patient developed nodular infiltrates after having been pierced with ear stickers containing palladium. A contact allergic reaction could be demonstrated as the underlying cause by inducing similar histological changes following patch testing with palladium. Title Potential efficacy of low metal diets and dental metal elimination in the management of atopic dermatitis: an open clinical study. Author Adachi A; Horikawa T; Takashima T; Komura T; Komura A; Tani M; Ichihashi M Source J Dermatol, 1997 Jan, 24:1, 12-9 Abstract We performed an open clinical study on the effects of low metal diets and/or dental metal elimination on 27 patients with moderate to severe atopic dermatitis (AD), who showed positive patch tests for metal allergens and/or clinical exacerbation by oral provocation tests with metal salts. All the patients were recommended to ingest low metal diets for 3 months and/or undergo dental metal elimination. Marked or moderate improvement was noted in 18 patients (67%); 7 patients (26%) showed marked improvement and 11 patients (41%), moderate improvement. Nine patients (33%) showed minimal improvement or no change. In the patients who showed marked or moderate improvement, we observed statistically significant decreases (p < 0.05) in both peripheral blood eosinophil counts and serum LDH levels after 3 months of treatment. The present study suggests that restriction of ingested metal allergens to which patients have positive patch tests and/or oral challenge tests may be useful in the management of some patients with AD who have metal sensitivity. Title Nickel allergy in adolescents in relation to orthodontic treatment and piercing of ears. Author Kerosuo H; Kullaa A; Kerosuo E; Kanerva L; Hensten Pettersen A Source Am J Orthod Dentofacial Orthop, 1996 Feb, 109:2, 148-54 Abstract The aim of this study was to investigate the frequency of nickel hypersensitivity in adolescents in relation to sex, onset, duration and type of orthodontic treatment, and the age at which ears were pierced. The subjects were 700 Finnish adolescents, from 14 to 18 years of age, of which 476 (68%) had a history of orthodontic treatment with metallic appliances. The study consisted of patch-testing for a nickel allergy and a patient history obtained by a questionnaire and from patient record. The frequency of nickel sensitization in the whole group was 19%. Nickel allergy was significantly more often found in girls (30%) than in boys (3%) and in subjects with pierced ears (31%) than in those with no piercing of ears (2%). Orthodontic treatment did not seem to affect the prevalence of nickel sensitization. None of the girls who were treated with fixed orthodontic appliances before ear piercing showed hypersensitivity to nickel, whereas 35% of the girls who had experienced ear piercing before the onset of orthodontic treatment were sensitized to nickel. The results suggest that orthodontic treatment does not seem to increase the risk for nickel hypersensitivity. Rather, the data suggests that treatment with nickel-containing metallic orthodontic appliances before sensitization to nickel (ear piercing) may have reduced the frequency of nickel hypersensitivity. Title Environmental contact factors in eczema and the results of patch testing Chinese patients with a modified European standard series of allergens Author Li LF, Guo J, Wang J. Department of Dermatology, Peking University Third Hospital, Beijing 100083, China. zoonli@sina.com Source Contact Dermatitis. 2004 Jul;51(1):22-5 Abstract Environmental contact factors in eczema were investigated in China by clinical questionnaire and patch testing patients with a modified European standard series of allergens. 217 consecutive eczema patients were studied. Contact dermatitis (CD) was clinically diagnosed in 30% of the patients. Among the patients patch tested, 46 patients had clinically diagnosed allergic CD (ACD), 20 patients clinically had non-ACD (NACD) (including 16 cases of irritant contact dermatitis, 1 case of phototoxic contact reaction and 3 cases of asteatotic eczema) and 115 patients had clinically suspected ACD. 45 patients (98%) in the ACD group went on to have relevant patch test results. The most common ACD was from metals, fragrance materials, cosmetics and rubber materials. The most common contact allergens identified were nickel, fragrance mix, para-phenylenediamine (PPD), carba mix and thimerosal. No adverse reactions were observed to patch testing, except for pruritus in patch-test-positive patients. The positive rate of patch testing in ACD was much higher than that in NACD (98% versus 15%, P < 0.05, chi(2)-test). 60 (28%) patients had facial dermatitis (FD). Among these, 20 (33%) were confirmed as having ACD. 48 (22%) patients had hand dermatitis (HD). Among these, 7 (15%) were confirmed as having ACD. Fewer patients were confirmed as having ACD in the HD group than in the FD (15% versus 33%, P < 0.05, chi(2)-test). Although the difference was not significant, the total positivity rate in the HD group (55%) was lower than in the other groups. 65 (30%) patients had unclassified endogenous eczema (UEE). The total positive rate of patch testing in the UEE group (56%) was no different from that in the FD or HD groups. However, the relevance of positive patch tests was hard to determine in UEE. These results indicate that CD is common in eczema; relatively more patients with FD have ACD, while other factors, such as irritation, may play more of a role in HD. The total positive rate of patch testing in the UEE group was no different from that in the FD or HD groups, suggesting that patch testing should be stressed in UEE and the relevance of positive patch test results in UEE should be studied further. It is effective and safe to patch eczema patients with a modified European standard series of allergens in China. Title Chronic allergic-like dermatopathies in nickel-sensitive patients. Results of dietary restrictions and challenge with nickel salts. Author Antico A, Soana R. Allergology Department, Asola Hospital, Mantova, Italy Source Allergy Asthma Proc. 1999 Jul-Aug;20(4):235-42 Abstract Nickel frequently contaminates foods. In sensitized patients, dietary nickel can cause a relapse of contact eczema and also widespread chronic dermatopathies quite similar to those triggered by authentic food allergy (IgE-mediated), from atopic dermatitis to chronic urticaria with angioedema. The present study was intended to evaluate the the results of an elimination diet and of the oral challenge test with nickel salts in a population of adults suffering from chronic urticaria or angioedema, pruritus or atopic dermatitis, and concomitant contract sensitization to nickel salts. The study involved a population of adult patients (112 subjects, 106 women and 6 men, aged from 16 to 58, mean age 29 +/- 10) with widespread allergic-like dermatopathies and contact sensitization to nickel salts (positive patch test). All of these subjects were prescribed a low nickel diet for four weeks. The patients who recovered or whose clinical manifestations greatly improved underwent an oral double-blind, placebo-controlled challenge: they were administered two successive, noncumulative doses of 10 and 20 mg nickel sulphate hexahydrate, respectively equal to 2.23 and 4.47 mg of elemental nickel. A search for specific IgE and the check on skin reactivity by skin-prick test against nickel were carried out in the patients who had shown particularly severe reactions after the oral challenge. A low nickel diet was effective in controlling the symptoms in 44 patients (39.28%, among whom there was one man). The oral double-blind, placebo-controlled challenge test was positive in all the patients who had favourably responded to the elimination diet, except one. In the patients with anaphylactoid reactions on the oral challenge, skin-prick tests were negative and no serum-specific IgE antibodies against nickel were found. Such findings appear to demonstrate that, in some patients with concomitant contact allergy, intolerance to ingested nickel salts might be the real cause of the onset and perpetuation of widespread, chronic, allergic-type dermatopathies.   Title Chronic urticaria due to nickel intake Author Abeck D, Traenckner I, Steinkraus V, Vieluf D, Ring J. Department of Dermatology, Universitats-Krankenhaus Eppendorf, Hamburg, Germany Source Acta Derm Venereol. 1993 Dec;73(6):438-9 Abstract A case of chronic urticaria is presented. The case of the disease was traced back to nickel intake by food as judged from type I and IV sensitization to nickel, a positive oral challenge test and long-standing, complete healing under a nickel-restrictive diet. Title Itchy plaques on the abdomen. Allergic contact dermatitis. Author Barankin B., Division of Dermatology, University of Alberta, Edmonton, Alberta. Source Am Fam Physician. 2005 Sep 1;72(5):871-3. Top Metals and Gastrointestinal Diseases Title Bowel dysfunction and irritable bowel syndrome in fibromyalgia patients [see comments] Author Sivri A; Cindas A; Dinçer F; Sivri B Source Clin Rheumatol, 1996 May, 15:3, 283-6 Abstract Fibromyalgia and irritable bowel syndrome are both common conditions which account for most of the referrals to physical medicine and rehabilitation-rheumatology and gastroenterology clinics, and they frequently coexist. In this study, we utilized a previously validated questionnaire to assess the prevalence of symptoms of bowel dysfunction and irritable bowel syndrome, and to survey the range of bowel pattern in 75 patients with fibromyalgia as compared to 50 normal controls. Symptoms associated with irritable bowel syndrome (p < 0.05) were reported in 41.8% of the fibromyalgia patients and 16% of the normal controls. In conclusion, we found that patients with fibromyalgia have a high prevalence of gastrointestinal complaints confirming the results indicating that fibromyalgia and irritable bowel syndrome frequently coexist. This may suggest a common pathogenic mechanism for both conditions. Title [Sensitization to nickel sulfate in patients with ileitis terminalis (Crohn disease)] [Article in German] Author Schofer H, Rosenberger G, Hottenrott C, Strohm WD, Burmester HJ, Gonnermann B, Hensel O. Zentren der Dermatologie und Venerologie, Johann Wolfgang Goethe-Universitat, Frankfurt/Main Source Derm Beruf Umwelt. 1988 Sep-Oct;36(5):157-62 Abstract The history of inpatients with Crohn's disease revealed several occurrences of contact dermatitis due to metal ions. Therefore, we considered the question as to whether allergic reactions to amalgam fillings or mercury, delivered in small amounts, could be a factor in the activity of regional enteritis. 23 patients with Crohn's disease (15 females, 8 males), aged from 20 to 44 years were screened by an extended standard patch test (following the rules of the ICDRG). Surprisingly, no case of hypersensitivity to amalgam and/or mercury was found. However, nickelsulfate yielded positive reactions in 39.1% of all tested patients (9/23). In comparison to the normal population this prevalence of nickelsulfate hypersensitivity is distinctly increased. It may be an epiphenomenon of Crohn's disease (sensitization via an enhanced permeability of the irritated mucous membranes for nutritive nickelsulfate) or an etiopathogenetic co-factor. In the latter case regional enteritis might be regarded as an allergic-irritative disease of the bowel. Title Tin: an overlooked contact sensitizer? Author Menne T, Andersen KE, Kaaber K, Osmundsen PE, Andersen JR, Yding F, Valeur G. Source Contact Dermatitis. 1987 Jan;16(1):9-10. Abstract Patch tests with metallic tin in 73 nickel-sensitive patients revealed 6 positive allergic reactions. Only 4 doubtful reactions were seen, which makes irritancy unlikely. The relevance and clinical significance of the unexpected finding deserves further evaluation. Top Metals and Dentistry Title Mercury amalgam dental fillings: An epidemiologic assessment. Author Bates MN., Division of Environmental Health Sciences, School of Public Health, 140 Warren Hall, University of California, Berkeley, CA 94720-7360, USA. Source Int J Hyg Environ Health. 2006 Jan 27; [Epub ahead of print] Abstract Dental amalgam fillings containing approximately 50% mercury have been used for almost 200 years and have been controversial for almost the same time. Allegations of effects caused by amalgams have involved many diseases. Recent evidence that small amounts of mercury are continuously released from amalgam fillings has fuelled the controversy. This is a comprehensive review of the epidemiologic evidence for the safety of dental amalgam fillings, with an emphasis on methodological issues and identifying gaps in the literature. Studies show little evidence of effects on general chronic disease incidence or mortality. Limited evidence exists for an association with multiple sclerosis, but few studies on either Alzheimer's or Parkinson's diseases. The preponderance of evidence suggests no renal effects and that ill-defined symptom complexes, including chronic fatigue syndrome, are not caused by amalgams. There is little direct evidence that can be used to assess reproductive hazards. Overall, few relevant epidemiologic studies are available. Most prior assessments of possible amalgam health effects have been based on comparisons of dental mercury exposures with occupational exposures causing harm. However, the amalgam-exposed population contains a broader, possibly more susceptible, spectrum of people. Common limitations of population-based studies of dental amalgam effects include inadequate longitudinal exposure assessment and negative confounding by better access to dental care in higher socioeconomic groups. Better designed studies are needed, particularly for investigation of neurodegenerative diseases and effects on infants and children. Title Mercury exposure from "silver" tooth fillings: emerging evidence questions a traditional dental paradigm. Author Lorscheider FL, Vimy MJ, Summers AO., Department of Medical Physiology, Faculty of Medicine, University of Calgary, Alberta, Canada. Source FASEB J. 1995 Apr;9(7):504-8. Abstract For more than 160 years dentistry has used silver amalgam, which contains approximately 50% Hg metal, as the preferred tooth filling material. During the past decade medical research has demonstrated that this Hg is continuously released as vapor into mouth air; then it is inhaled, absorbed into body tissues, oxidized to ionic Hg, and finally covalently bound to cell proteins. Animal and human experiments demonstrate that the uptake, tissue distribution, and excretion of amalgam Hg is significant, and that dental amalgam is the major contributing source to Hg body burden in humans. Current research on the pathophysiological effects of amalgam Hg has focused upon the immune system, renal system, oral and intestinal bacteria, reproductive system, and the central nervous system. Research evidence does not support the notion of amalgam safety. Title Investigation of reactions to dental materials. Author Gawkrodger DJ., Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK. david.gawkrodger@sth.nhs.uk Source Br J Dermatol. 2005 Sep;153(3):479-85. Abstract Patients undergoing dental treatment can be exposed to a wide range of potential allergens, but adverse events seem infrequent. Patients with symptoms or signs of stomatitis, burning, tingling, cheilitis, oral lichenoid lesions, lip and facial swelling may relate their problems to dental treatment or to the use of dental products. Investigation for immediate type or delayed type hypersensitivity is indicated using patch testing, prick testing and blood tests for allergen-specific IgE. The main allergic reactions found in patients include contact allergy to metals, cosmetics, food additives, flavours and acrylates, and immediate type allergy to latex. Adverse reactions following the administration of local anaesthetics are seen in about 0.5% of cases, but immediate type allergy to these agents is rare. In dental staff, occupationally related problems are common and usually take the form of hand or facial dermatitis or respiratory disease. The most common allergic reactions in dental staff are immediate type allergy to latex, and contact allergy to rubber additives, fragrances, acrylates and formaldehyde. Occupational irritant problems causing hand dermatitis are probably more common in dental personnel than is dermatitis caused by contact allergy. Patch testing and tests for immediate type allergy are useful investigative methods in the investigation of patients who present with oral or facial symptoms possibly related to dental treatments and are also beneficial in dental personnel who present with hand or facial dermatitis or respiratory symptoms. Title Cytotoxicity of dental composite (co)monomers and the amalgam component Hg(2+) in human gingival fibroblasts. Author Reichl FX, Simon S, Esters M, Seiss M, Kehe K, Kleinsasser N, Hickel R., Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University of Munich, Goethestr. 33, 80336, Munich, Germany, reichl@lmu.de. Source Arch Toxicol. 2006 Feb 11;:1-8 [Epub ahead of print] Abstract Unpolymerized resin (co)monomers or mercury (Hg) can be released from restorative dental materials (e.g. composites and amalgam). They can diffuse into the tooth pulp or the gingiva. They can also reach the gingiva and organs by the circulating blood after the uptake from swallowed saliva. The cytotoxicity of dental composite components hydroxyethylmethacrylate (HEMA), triethyleneglycoldimethacrylate (TEGDMA), urethanedimethacrylate (UDMA), and bisglycidylmethacrylate (Bis-GMA) as well as the amalgam component Hg(2+) (as HgCl(2)) and methyl mercury chloride (MeHgCl) was investigated on human gingival fibroblasts (HGFs) at two time intervals. To test the cytotoxicity of substances, the bromodeoxyuridine (BrdU) assay and the lactate dehydrogenase (LDH) assay were used. The test substances were added in various concentrations and cells were incubated for 24 or 48 h. The EC(50) values were obtained as half-maximum-effect concentrations from fitted curves. Following EC(50) values were found [BrdU: mean (mmol/l); SEM in parentheses; n=12]: (24 h/48 h) HEMA 8.860 (0.440)/6.600(0.630), TEGDMA 1.810(0.130)/1.220(0.130), UDMA 0.120(0.010)/0.140(0.010), BisGMA 0.060(0.004)/0.040(0.002), HgCl(2) 0.015(0.001)/0.050(0.006), and MeHgCl 0.004(0.001)/0.005(0.001). Following EC(50) values were found [LDH: mean (mmol/l); SEM in parentheses; n=12]: (24 h/48 h) HEMA 9.490(0.300)/7.890(1.230), TEGDMA 2.300(0.470)/1.950(0.310), UDMA 0.200(0.007)/0.100(0.007), BisGMA 0.070(0.005)/0.100(0.002), and MeHgCl 0.014(0.006)/0.010(0.003). In both assays, the following range of increased toxicity was found for composite components (24 and 48 h): HEMA < TEGDMA < UDMA < BisGMA. In both assays, MeHgCl was the most toxic substance. In the BrdU assay, Hg(2+) was about fourfold less toxic than MeHgCl but Hg(2+) was about fourfold more toxic than BisGMA. In the BrdU test, a significantly (P<0.05) decreased toxicity was observed for Hg(2+) at 48 h, compared to the 24 h Hg(2+)-exposure. A time depending decreased toxicity was observed only for Hg(2+) which can then reach the toxic level of BisGMA. Title Soft and hard tissue response to zirconium dioxide dental implants - a clinical study in man. Author Blaschke C, Volz U., Z-Systems Australasia, Auckland, New Zealand. cblaschke@z-systems.co.nz. Source Neuro Endocrinol Lett. 2006 Aug 5;27(Suppl1) [Epub ahead of print] Abstract Titanium dental implants have been used successfully in implantology for more than 40 years. Recent research, however, suggests that titanium might have more side effects than previously believed. Zirconia ceramics have been employed in orthopaedic surgery for approximately 30 years and were recently introduced into dentistry as a metal replacement for crown and bridge work as well as implant abutments. Zirconium dioxide has been shown in both in vitro and in vivo studies to have desirable osseointegrative properties. This clinical study shows that dental implants made from zirconia are a feasible alternative to titanium dental implants. In addition to excellent cosmetic results, zirconia implants allow a degree of osseointegration and soft tissue response that is superior to titanium dental implants. Top Metals and Oral Diseases Title Value of epicutaneous patch testing in patients with oral, mucosal lesions of lichenoid character. Author Skoglund A., Department of Oral and Maxillofacial Surgery, University Hospital of Umea, Sweden. Source Scand J Dent Res. 1994 Aug;102(4):216-22 Abstract The purpose of the present investigation was to determine, in patients with oral mucosal lesions of lichenoid character, whether it is possible with epicutaneous patch tests, to detect those who will react favorably to removal of amalgam. Of 48 patients, 19 (39.6%) showed positive patch test reactions to 1% mercury ammonium chloride, and 29 (60.4%) showed negative test results. The observation period varied from 3 months to 3 yr (mean value 1.5 yr). After treatment, 94.7% of the positive group and 86.2% of the negative group showed regression of lesions. Reactions exceeding the contact zone between amalgam restorations and lesions showed positive patch test results in 21% of the cases, as compared with 47% among those with lesions restricted to the contact areas; 85.7 and 93.9%, respectively, showed regression after removal of amalgam restorations. The results of the present study indicate that removal of amalgam usually affects the lesions favorably and that epicutaneous patch tests are of little prognostic value in patients with oral mucosal lesions of lichenoid character. Title An amalgam tattoo causing local and systemic disease? Author Thomas Weaver, Lieutenant Commander DC) USN, Paul L. Auclair. Commander (DC) USN and George M. Taybos, Captain (DC) USN Source Oral Surg. Oral Med. Oral Pathol. 1987;63:137-40 Summary Amalgam tattoos are common oral lesions. The case presented here involved a 33-year-old woman who had had an amalgam tattoo for 2 years and complained of localized soreness and occasional swelling as well as systemic symptoms of weight loss, fatigue, sinusitis, and headaches. After excisional biopsy of the lesion, the patient's complaints ceased dramatically. It is suggested that alterations in healing due to the presence of amalgam particles led to systemic as well as local disease. Title Mercury Released from Dental "Silver" Fillings Provokes an Increase in Mercury- and Antibiotic-Resistant Bacteria in Oral and Intestinal Floras of Primates Author Anne O. Summers, Joy Wireman, Murray J. Vimy, Fritz L. Lorescheider, Bonnie Marshall, Stuart B. Levy, Sam Bennett and Lynne Billard Source Anti-microbal Agents and Chemotherarp, April 1993, Vol. 37, No. 4, p. 825-834 Summary In a survey of 640 human subjects, a subgroup of 356 persons without recent exposure to antibiotics demonstrated that those with a high prevalence of Hg resistance in their intestinal tiaras were significantly more likely to also have resistance to two or more antibiotics. This observation led us to consider the possibility that mercury released from amalgam ("silver") dental restorations might be a selective agent for both mercury-and antibiotic-resistant bacteria in the oral and intestinal floras of primates. Resistances to mercury and to several antibiotics were examined in the oral and intestinal floras of six adult monkeys prior to the installation of amalgam fillings, during the time they were in place, and after replacement of the amalgam fillings with glass lonomer fillings (in four of the monkeys). The monkeys were fed an antibiotic-free diet, and fecal mercury concentrations were monitored. There was a statistically significant increase in the incidence of mercury-resistant bacteria during the 5 weeks following installation of the amalgam fillings and during the 5 weeks immediately following their replacement with glass lonomer fillings. These peaks in incidence of mercury-resistant bacteria correlated with peaks of Hg elimination (as high as 1 mM in the feces) immediately following amalgam placement and immediately after replacement of the amalgam fillings. Representative mercury-resistant isolates of three selected bacterial families (oral streptococci, members of the family Entcrobacteri-aceae, and enterococci) were also resistant to one or more antibiotics, including ampicilhin, tetracycline, streptomycin, kanamycin, and chloramphenicol. While such mercury- and antibiotic-resistant isolates among the staphylococci, the enterococci, and members of the family Enlerobacteriaceac have been described, this is the first report of mercury resistance in the oral streptococci. Many of the enterobacterial strains were able to transfer mercury and antibiotic resistances together to laboratory bacterial recipients, suggesting that the loci for these resistances are genetically linked. Our findings indicate that mercury released from amalgam fillings can cause an enrichment of mercury resistance plasmids in the normal floras of primates. Many of these phasmidis also carry antibiotic resistance, implicating the exposure to mercury from dental amalgams in an increased incidence of multiple antibiotic resistance plasmids in the normal floras of nonmedicated subjects. Title The Relationship Between Mercury from Dental Amalgam and Oral Cavity Health Author Robert L. Siblerud, M.S. Source Annals of Dentistry, Number 2, Winter 1990 p. 6-10 Summary The findings presented here suggest that mercury from dental amalgam may play a role in the etiology of oral cavity health. Comparisons between subjects with arid without amalgam showed significant differences of diseases of the mouth. Subjects who had amalgams removed re-ported that symptoms of diminished oral health were improved or eliminated after removal. The data suggest that inorganic mercury from dental amalgam does affect the oral cavity. Title Contact stomatitis to mercury associated with spontaneous mononuclear cell infiltrates in brown Norway (BN) rats with HgC12-induced autoimmunity. Author Warfvinge G; Larsson, Department of Oral Pathology, Lund University, Malmö, Sweden Source Oral Pathol Med, 23(l0):441-5 1994 Nov Summary Light microscopy and immnunocytochemistry have been used to study the tissue reaction to non-irritant concentrations of mercury painted onto the oral mucosa of genetically mercury-sensitive BN rats. Low-dose skin injections of HgCl2 in BN rats result in an autoimmune syndrome, including also a spontaneous migration of T lymphocytes into the oral mucosa. Our results show that such infiltrates confer an increased degree of reactivity (contact stomatitis) to HgCJ2 painted onto the BN (Hg) rat oral mucosa. In contrast, results were negative in the LEW rat strain, which is also resistant to development of autoimmunity to skin-injected mercury. The possible involvement of mucosal mercury-loaded macrophages is discussed. The results are also discussed with respect to possible etiologic and pathogenetic mechanisms involved in the development of dental material (amalgam)-associated lichenoid lesions of human oral mucosa. Title Contact allergy to dental restorative materials in patients with oral lichenoid lesions. Author Laine J; Kalimo K; Happonen RP Source Contact Dermatitis, 1997 Mar, 36:3, 141-6 Abstract 118 patients with oral lichenoid lesions (OLL) topographically related to dental fillings were patch tested (PT) to reveal contact allergy to restorative materials. 80 (67.8%) patients displayed positive PT reactions to metals of dental filling materials: 76 reactions were found to various mercury compounds, 4 to sodium aurothiosulphate, 3 to stannic chloride and 2 to silver nitrate. The positive patch test reactions appeared more commonly in patients with restricted contact lesions (85.1%, type-1 lesions) as compared to patients with lesions exceeding to the adjacent areas (38.6%, type-2 lesions). The replacement of dental fillings was carried out in 62/80 PT-positive and 15/38 PT-negative patients. 28 out of 62 (45.2%) PT-positive and 3/15 (20%) PT-negative patients showed complete healing of OLL after a mean follow-up time of 16 months. Complete healing occurred in 29/54 (54.0%) type-1 and 2/23 (8.7%) type-2 lesions. Topographical relation between the lesion and the filling material (restricted versus exceeding the contact area) indicated association of OLL lesion and the filling material, which could be further confirmed by patch testing in the majority of patients. The patch test series should include mercuric chloride (0.1%), mercury (0.5%) and mercury ammonium chloride (1.0%), each in pet. Title Release of elements from some gold alloys and amalgams in corrosion. Author Rolf Lappalainen and Antti Yli-Urpo, Institute of Dentistry, University of Kuopio, Kuopio, Finland Source Scand J Dent Res 1987: 95: 364-8 Summary Abstract - The release of Au, Ag, Cu and Zn elements from six commercially available gold alloys and three amalgam alloys was studied. The polarizing electropotential system with modified Fusayama solution was used. The cycle process was repeated 500 times between ± 1000 mV during a period of 5 h 22 mm. During the process samples of solution were analyzed in order to follow the release of elements. Results revealed rapid release of Zn from most alloys, release of Ag from most alloys and release of Au from two alloys. Also, rapid release of Cu was found from amalgams but not from gold alloys. Release of Ag from gold alloys showed very good passivation up to 3 h, after which it was released in varying amounts. Title Methylation of mercury from dental amalgam and mercuric chloride by oral streptococci in vitro. Author Heintze U; Edwardsson S; Dérand T; Birkhed D Source Scand J Dent Res, 1983 Apr, 91:2, 150-2 Abstract The capacity of the oral bacteria Streptococcus mitior, S. mutans and S. sanguis to methylate mercury was investigated in vitro. Mercuric chloride and pulverized dental amalgam in distilled water, respectively, were used as sources of mercury. Methylmercury was found in the bacterial cells of all three tested strains. The results indicate that organic mercury compounds may be formed in the oral cavity. Title Cell-mediated immune response to dog pulp tissue altered by N2 paste within the root canal. Author Block RM; Sheats JB; Lewis RD; Fawley J Source Oral Surg Oral Med Oral Pathol, 1978 Jan, 45:1, 131-42 Abstract After pulpal extirpation of twenty teeth in each of four dogs, these animals were primarily immunized intramuscularly with the dogs' own pulp (three dogs) altered by N2 paste and saline solution with pulp (one dog). A fifth dog was used as a control for skin tests. Secondary immunizations were accomplished via the root canal every 7 days over a 28-day period. Cell-mediated skin tests reactions demonstrated less of a response to the N2 paste alone than when the dogs' pulp was altered with this material. In vitro analysis of cell-mediated immune response (lymphocyte proliferation) showed a marked response to the pulp altered by N2 paste as compared to the saline-treated pulp (P less than 0.002). Therefore, dogs' pulp tissue became antigenically altered by the N2 material, recognized by the host, and a specific cell-mediated lymphocyte proliferation resulted. Title Oral lesions and symptoms related to metals used in dental restorations: a clinical, allergological, and histologic study Author Koch P, Bahmer FA. Department of Dermatology, University of the Saarland, Homburg/Saar, Germany Source J Am Acad Dermatol. 1999 Sep;41(3 Pt 1):422-30 Abstract BACKGROUND: Allergy to mercury as a cause of oral lichenoid lesions (OLL) remains controversial. Some authors reported high frequency of sensitization to mercury and beneficial effect from removal of amalgam fillings in such patients, whereas others state that this procedure affects favorably all OLL, whether patients are sensitized to inorganic mercury or not. OBJECTIVE: Our purpose was to determine the frequency of sensitization to metal salts in 194 patients (patients with OLL partly adjacent to amalgam fillings: 19, oral lichen planus (OLP) without close contact to amalgam: 42, other oral diseases: 28, oral complaints: 46, control group: 59). We further studied the histologic changes of biopsy specimens from positive patch tests to metal salts, and investigated the effect of removal of amalgam in OLL, to clarify whether it is possible to identify patients who will benefit from this procedure. METHODS: Patch testing was performed with the German standard series, a dental prosthesis series, and a metal salt series including gold, mercury, and palladium salts as well as other salts of metals used in dental restorations. Late readings (10 and 17 days after application of the patch tests) were performed in all patients. RESULTS: Of 19 patients with OLL adjacent to amalgam fillings, 15 (78.9%) were sensitized to inorganic mercury (INM), significantly more than those with OLL not adjacent to amalgam, other oral diseases or complaints, and the control group. In 5 of 15 (33.3%) of the patients with OLL, a positive patch test to INM was observed only at D10 or D17. Amalgam was removed in 18 patients with OLL (sensitization to INM: 15), and in 11 patients with OLP (sensitization to INM: 2). After removal, the lesions of 13 of 15 of the INM-sensitized patients with OLL (86. 7%) and 2 with OLP healed or improved significantly, but this was not observed with the INM negative patients. Frequency of sensitization to gold sodium thiosulfate (GST) and palladium chloride 1% pet (PDC) was high in all groups. This was partly because readings were performed late. Lesions of 2 patients with allergic contact stomatitis caused by gold and 1 caused by palladium healed completely after removal of these restorations. Histologically, lichenoid changes were observed in 14 of 36 biopsy specimens of positive patch tests from INM (9/21), GST (2/10), and PDC (3/5) in all patient groups, mainly in persistent patch tests at D10 or D17. This was not observed in 12 biopsy specimens taken from persistent patch tests from other substances, including nickel sulfate. CONCLUSION: Our results suggest that sensitization to mercury is an important cause of OLL, whether all lesions or only a part of them are adjacent to amalgam fillings. Sensitization to GST may reflect true gold allergy and should be considered as a cause of oral diseases in some patients. Sensitization to PDC is frequent but has yet only little clinical relevance. Patch tests may be positive only at D10 or D17. This suggests the importance of additional readings of GST, PDC, and mercury salts at this time. Title Cutaneous and oral eruption from oral exposure to nickel in dental braces Author Schultz JC, Connelly E, Glesne L, Warshaw EM. University of Minnesota, Minneapolis, MN, USA Source Dermatitis. 2004 Sep;15(3):154-7 Abstract Oral eruptions due to nickel allergy are rare. A common presentation of intraoral contact dermatitis is the presence of lichenoid plaques on the buccal mucosa adjacent to the offending antigen. We report an unusual case of cutaneous and mucosal nickel allergy arising after placement of dental braces. An 11-year-old boy was referred by his orthodontist to the University of Minnesota Occupational and Contact Dermatitis Clinic to be evaluated for a possible metal allergy. The patient developed an itchy rash on his abdomen and under his wristwatch 1 week after dental braces were placed. He was diagnosed with allergic contact dermatitis from nickel. The patient avoided cutaneous nickel exposure and had a minimal resolution of his symptoms. One year later, the patient developed swelling and burning of the lips. Secondary to extreme discomfort, the braces, which contained nickel, titanium, and zinc, were removed. The patient underwent standard patch testing; the final reading at 96 hours showed a +++ reaction to nickel, palladium, cobalt chloride, and neomycin. The patient experienced relief of his oral symptoms after removal of the braces. No current relevance to palladium, cobalt, or neomycin has been found.  Title Characterization of nickel-induced allergic contact stomatitis associated with fixed orthodontic appliances Author Genelhu MC, Marigo M, Alves-Oliveira LF, Malaquias LC, Gomez RS., Immunology Research Laboratory, School of Health Science, Vale do Rio Doce University, Governador Valadares, Minas Gerais, Brazil. genelhumc@uol.com.br Source Am J Orthod Dentofacial Orthop. 2005 Sep;128(3):378-81. Abstract INTRODUCTION: In some orthodontic patients, an oral inflammatory response is induced by corrosion of orthodontic appliances and subsequent nickel release. This inflammatory response is manifested as stomatitis (nickel-induced allergic contact stomatitis [NiACS]). The etiology and diagnosis of NiACS are difficult to determine. The purpose of this retrospective analysis was to investigate the roles of age, sex, previous allergic history, and time of exposure to fixed orthodontic appliances in the etiopathogeny of NiACS. METHODS: Forty-four orthodontic patients (range, 10-44 years) were divided into 2 groups, depending on their NiACS clinical manifestations. RESULTS: Young patients, especially females with a history of allergic reactions, had a greater predisposition to NiACS clinical manifestations; time of exposure to orthodontic appliances was not a significant factor. CONCLUSIONS: A previous allergic reaction should be considered a predictive factor of NiACS clinical manifestations and should be noted in the patient's medical history. Top Metals and Paediatric Exposure including Vaccines More abstracts on Vaccines and Thimerosal can be seen on our Thimerosal page. Title Mercury and autism: accelerating evidence? Author Mutter J, Naumann J, Schneider R, Walach H, Haley B., Institute for Environmental Medicine and Hospital Epidemiology, University Hospital Freiburg, Germany. joachim.mutter@uniklinik-freiburg.de Source Neuro Endocrinol Lett. 2005 Oct;26(5):439-46. Abstract The causes of autism and neurodevelopmental disorders are unknown. Genetic and environmental risk factors seem to be involved. Because of an observed increase in autism in the last decades, which parallels cumulative mercury exposure, it was proposed that autism may be in part caused by mercury. We review the evidence for this proposal. Several epidemiological studies failed to find a correlation between mercury exposure through thimerosal, a preservative used in vaccines, and the risk of autism. Recently, it was found that autistic children had a higher mercury exposure during pregnancy due to maternal dental amalgam and thimerosal-containing immunoglobulin shots. It was hypothesized that children with autism have a decreased detoxification capacity due to genetic polymorphism. In vitro, mercury and thimerosal in levels found several days after vaccination inhibit methionine synthetase (MS) by 50%. Normal function of MS is crucial in biochemical steps necessary for brain development, attention and production of glutathione, an important antioxidative and detoxifying agent. Repetitive doses of thimerosal leads to neurobehavioral deteriorations in autoimmune susceptible mice, increased oxidative stress and decreased intracellular levels of glutathione in vitro. Subsequently, autistic children have significantly decreased level of reduced glutathione. Promising treatments of autism involve detoxification of mercury, and supplementation of deficient metabolites. Title Neurotoxic effects of postnatal thimerosal are mouse strain dependent. Author Hornig M, Chian D, Lipkin WI., Jerome L and Dawn Greene Infectious Disease Laboratory, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. mady.hornig@columbia.edu Source Mol Psychiatry. 2004 Sep;9(9):833-45. Abstract The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity. Title [Effects of lead exposure on children's health] [Article in Spanish] Author Matte TD., CUES, NYAM, 1216 Fifth Avenue, Nueva York, NY 10029, USA. tmatte.@nyam.org Source Salud Publica Mex. 2003;45 Suppl 2:S220-4. Abstract Lead is an element that has no known physiologic function in humans but adversely affects a variety of fundamental biochemical processes. A large body of evidence shows adverse health effects of lead in children at levels common in populations around the world. Acute lead poisoning with encephalopathy, though infrequent, is life-threatening, requiring timely and aggressive treatment. It should be considered in the differential diagnosis of any unexplained illness that includes anemia, seizures, lethargy, abdominal pain, or recurrent vomiting. Many more children are harmed by chronic, subclinical effects of low-level lead exposure that include impaired cognitive development, adverse effects on behavior, subtle impairment of hearing acuity, and reduced height. Available evidence indicates that the only effective interventions to prevent low level lead toxicity are those that control lead exposure. The English version of this paper is available at: http://www.insp.mx/salud/index.html. Top Metals and Detoxification and Chelation Title Can nutrition affect chemical toxicity? Author Furst A., University of San Francisco, San Francisco, California, USA; and GNLD, International, Fremont, California, USA. artfurst@aol.com Source Int J Toxicol. 2002 Sep-Oct;21(5):419-24 Abstract Universally, the general population is exposed to a variety of "toxic" substances. Some of these are from manufactured goods and some from air and water pollution. Toxins are also normally found in many foods; however, unless the exposure is overwhelming, we are many times (even unknowingly) protected by the foods we eat. A judicious choice of food will counteract noxious agents. Therefore, the diet can be a major factor in determining who does and who does not show toxic symptoms following exposure. This review will cover three aspects. The first will be on protectors against metal toxicity. For example, whereas humans can consume fish that have absorbed mercury from contaminated bay water, selenium can act as a natural antagonist for mercury poisoning. (Naturally, too much selenium itself can be detrimental!) Some vegetables can accumulate cadmium from contaminated soil, and zinc from a variety of nuts is an antagonist of cadmium toxicity. Nitrites in preserved meats can be converted into nitroamines by saliva or mild stomach acid. Vitamin C found in oranges and bell peppers can inhibit that conversion. In addition, calcium antagonizes both lead and aluminum toxicity. The second aspect is on oxidants and antioxidants. Oxidative stress can lead to some cancers, atherosclerosis, and adverse effects of aging. Antioxidants are the best protectors of the damage caused by reactive oxygen species (ROS). The most effective antioxidants are found in highly colored fruits and vegetables such as carrots, tomatoes, and berries, called carotenoids. Flavonoids (polyphenols), another class of effective antioxidants that negate ROS, may or may not be colored. The third aspect is on gaps in current knowledge. Many foods naturally contain chemicals that are, in larger concentrations, quite toxic or carcinogenic. Biotransformations (detoxification mechanisms) involving type I and type II enzymes are known. Some foods do modify these enzymes either positively or negatively. Grapefruit contains a substance that inhibits an isoform of P450, making some cardiac drugs, as substrates, more toxic. There is inadequate information on what specific components are in a variety of foods that are associated with cancer prevention. The experimental carcinogenic compound (and suspected as a human carcinogen) found in overcooked, burnt, and fried meats and fish, namely IQ (2-amino-3-methyl-3H-imidazo[4,5f]quinoline, will be used as a prototype for what needs to be known about foods that will affect toxins. Title Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. Author Lin JL, Lin-Tan DT, Hsu KH, Yu CC., Division of Nephrology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Medical College of Chang Gung University, Taipei, Taiwan., jllin99@hotmail.com Source N Engl J Med. 2003 Jan 23;348(4):277-86. Abstract BACKGROUND: Previous research suggests that environmental lead exposure correlates with age-related decreases in renal function. METHODS: Two hundred two patients with chronic renal insufficiency (indicated by a serum creatinine level between 1.5 mg per deciliter and 3.9 mg per deciliter) who had a normal total-body lead burden and no history of exposure to lead were observed for 24 months. After the observation period, 64 subjects with an elevated body lead burden were randomly assigned to the chelation control groups. For three months, the patients in the chelation group received lead-chelation therapy with calcium disodium EDTA, and the control group received placebo. During the ensuing 24 months, repeated chelation therapy was administered weekly to 32 patients with high-normal body lead burdens (at least 80 microg but less than 600 microg) unless on repeated testing the body lead burden fell below 60 microg; the other 32 patients served as controls and received weekly placebo infusions for 5 weeks every 6 months. The primary end point was an increase in the serum creatinine level to 1.5 times the base-line value during the observation period. A secondary end point was the change in renal function during the intervention period. RESULTS: The primary end point occurred in 24 patients during the observation period; the serum creatinine levels and body lead burden at base line were the most important risk factors. The glomerular filtration rate improved significantly by the end of the 27-month intervention period in patients receiving chelation therapy: the mean (+/-SD) change in the glomerular filtration rate in the patients in the chelation group was 2.1+/-5.7 ml per minute per 1.73 m2 of body-surface area, as compared with -6.0+/-5.8 ml per minute per 1.73 m2 of body-surface area in the controls (P<0.001). The rate of decline in the glomerular filtration rate in the chelation group was also lower than that in the controls during the 24-month period of repeated chelation therapy or placebo. CONCLUSIONS: Low-level environmental lead exposure may accelerate progressive renal insufficiency in patients without diabetes who have chronic renal disease. Repeated chelation therapy may improve renal function and slow the progression of renal insufficiency. Top Metals and Genetic Susceptibility Title Immunocompetent cells in amalgam-associated oral lichenoid contact lesions Author Lame J, Konttinen YT, Beliaev N, Happonen RP Source J Oral Pathol Med 1999 Mar;28(3):117-21 Summary Inflammatory cells in amalgam-associated, oral lichenoid contact lesions (OLL) were studied in 19 patients by immunocytochemistiy using monoclonal antibodies. Ten of the patients displayed allergic patch test (PT) reactions to several mercury compounds and nine were negative. The immunocytochemical quantification showed a uniform composition of the inflammatory mononuclear cells in the two study groups. The number of HLA-D/DR-positive dendritic cells (P<0.001) and CD1a-positive Langerhans cells (P=0.035) was significantly lower in the PT-negative than PT-positive patients. HLA-D/DR expression on keratinocytes varied from negative to full thickness staining of the epithelium. HLA-D/DR expression in the full thickness of epithelium (3) or through the basal and spinous cell layers (2) was seen in 5 of 8 PT-positive patients, whereas none of the PT-negative patients had this staining pattern (P=0.045). These patients also showed a good clinical response after amalgam removal. Consequently, OLL may represent a true delayed hypersensitivity reaction with a trans-epithelial route of entrance of the metal haptens released from dental restorative materials. Top Metals and the Brain Title Dementia associated with toxic causes and autoimmune disease. Author Schofield P., Neuropsychiatry Service, Hunter Area Health and University of Newcastle, NSW, Australia. Peter.Schofield@hnehealth.nsw.gov.au Source Int Psychogeriatr. 2005;17 Suppl 1:S129-47. Abstract Toxic causes of dementia include exposure to heavy metals such as lead, mercury and aluminum as well as to carbon monoxide and solvents. Autoimmune conditions include such entities as multiple sclerosis, systemic lupus erythematosus, Behcet's disease and Sjogren's syndrome. These conditions share broadly similar cognitive effects giving rise to impairments with subcortical features. Individuals are often affected at a relatively young age. Optimal preventative strategies include avoidance of toxic substances. Comprehensive neuropsychological assessment is valuable not only diagnostically and for monitoring but also to identify the patients' strengths and weaknesses, so that compensatory strategies can be recommended. Title Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity. Author Godfrey ME, Wojcik DP, Krone CA., Bay of Plenty Environmental Health Clinic, Tauranga, New Zealand. Source J Alzheimers Dis. 2003 Jun;5(3):189-95. Abstract Apolipoprotein-E (apo-E) genotyping has been investigated as an indicator of susceptibility to heavy metal (i.e., lead) neurotoxicity. Moreover, the apo-E epsilon (epsilon)4 allele is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A theoretical biochemical basis for this risk factor is discussed herein, supported by data from 400 patients with presumptive mercury-related neuro-psychiatric symptoms and in whom apo-E determinations were made. A statistically relevant shift toward the at-risk apo-E epsilon4 groups was found in the patients p<0.001). The patients possessed a mean of 13.7 dental amalgam fillings and 31.5 amalgam surfaces. This far exceeds the number capable of producing the maximum identified tolerable daily intake of mercury from amalgam. The clinical diagnosis and proof of chronic low-level mercury toxicity has been difficult due to the non-specific nature of the symptoms and signs. Dental amalgam is the greatest source of mercury in the general population and brain, blood and urine mercury levels increase correspondingly with the number of amalgams and amalgam surfaces in the mouth. Confirmation of an elevated body burden of mercury can be made by measuring urinary mercury, after provocation with 2,3,-dimercapto-propane sulfonate (DMPS) and this was measured in 150 patients. Apo-E genotyping warrants investigation as a clinically useful biomarker for those at increased risk of neuropathology, including AD, when subjected to long-term mercury exposures. Additionally, when clinical findings suggest adverse effects of chronic mercury exposure, a DMPS urine mercury challenge appears to be a simple, inexpensive procedure that provides objective confirmatory evidence. An opportunity could now exist for primary health practitioners to help identify those at greater risk and possibly forestall subsequent neurological deterioration. Title Sodium-mediated axonal degeneration in inflammatory demyelinating disease. Author Bechtold DA, Smith KJ., Department of Neuroimmunology, Guy's Campus, King's College, London SE1 1UL, UK. Source J Neurol Sci. 2005 Jun 15;233(1-2):27-35. Abstract Axonal degeneration is a major cause of permanent neurological deficit in multiple sclerosis (MS). The mechanisms responsible for the degeneration remain unclear, but evidence suggests that a failure to maintain axonal sodium ion homeostasis may be a key step that underlies at least some of the degeneration. Sodium ions can accumulate within axons due to a series of events, including impulse activity and exposure to inflammatory factors such as nitric oxide. Recent findings have demonstrated that partial blockade of sodium channels can protect axons from nitric oxide-mediated degeneration in vitro, and from the effects of neuroinflammatory disease in vivo. This review describes some of the reasons why sodium ions might be expected to accumulate within axons in MS, and recent observations suggesting that it is possible to protect axons from degeneration in neuroinflammatory disease by partial sodium channel blockade. Title Immunological and Brain MRI Changes in Patients with Suspected Metal Intoxication Author Tibbling L; Thuomas KA; Lenkei R; Stejskal VD; Source International Journal of Occupational Medicine and Toxicology, Vol. 4, No. 2, 1995 Abstract Thirty-four patients with central nervous system (CNS) and systemic symptoms suggestive of intoxication from dental amalgam were examined with magnetic resonance imaging (MRI) of the brain (n=32) and with a Memory Lymphocyte Immuno Stimulation Assay (MELISA®) (n=17). Lymphocyte phenotype was analyzed with flow cytometry (FC) in 22 of the patients. One hundred twenty age-matched patients without CNS symptoms served as controls for the MRI study, seventy-seven healthy subjects with dental amalgam fillings served as controls for the MELISA® test, and seventy-five clinically healthy subjects were controls for the lymphocyte phenotype determination. Pathological MRI findings were present in 81% of the patients, most of them with signs of degeneration in the basal ganglia, but none in the controls. The lymphocyte phenotype determination was pathological in 58%. The MELISA® showed pathological findings in 88%, of which 60% showed an immune reaction to mercuric chloride, 62% of the patients had some kind of atopic disease, and 35% suffered from levothyroxine-treated hypothyreosis. A high rate of immunopathologies and objective signs of immunological reactions in the majority of the patients with MRI changes in the brain suggests that immunological mechanisms may play an important role in the development of the lesions. Title Current status of metals as therapeutic targets in Alzheimer's disease. Author Finefrock AE, Bush AI, Doraiswamy PM., Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710, USA. Source J Am Geriatr Soc. 2003 Aug;51(8):1143-8 Abstract There is accumulating evidence that interactions between beta-amyloid and copper, iron, and zinc are associated with the pathophysiology of Alzheimer's disease (AD). A significant dyshomeostasis of copper, iron, and zinc has been detected, and the mismanagement of these metals induces beta-amyloid precipitation and neurotoxicity. Chelating agents offer a potential therapeutic solution to the neurotoxicity induced by copper and iron dyshomeostasis. Currently, the copper and zinc chelating agent clioquinol represents a potential therapeutic route that may not only inhibit beta-amyloid neurotoxicity, but may also reverse the accumulation of neocortical beta-amyloid. A Phase II double-blind clinical trial of clioquinol with B12 supplementation will be published soon, and the results are promising. This article summarizes the role of transition metals in amyloidgenesis and reviews the potential promise of chelation therapy as a treatment for AD. Title Metals in our minds: therapeutic implications for neurodegenerative disorders. Author Doraiswamy PM, Finefrock AE., Department of Psychiatry, Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710, USA. dorai001@mc.duke.edu Source Lancet Neurol. 2004 Jul;3(7):431-4. Abstract BACKGROUND: Abnormal interactions of copper or iron in the brain with metal-binding proteins (such as amyloid-beta peptide [Abeta] or neuromelanin) that lead to oxidative stress have emerged as important potential mechanisms in brain ageing and neurodegenerative disorders. Although a controlled study of desferrioxamine in Alzheimer's disease (AD) had some promising results, concerns about toxicity and brain delivery have limited trials of traditional chelators. The therapeutic significance of metal dysregulation in neurodegenerative disorders has remained difficult to test. RECENT DEVELOPMENTS: Clioquinol was identified as a prototype metal-protein-attenuating compound (MPAC). In a blinded and controlled 9 week study of a mouse model of AD, oral clioquinol decreased brain Abeta by 49% without systemic toxicity. The concentrations of copper and zinc in the brain rose by about 15% in mice treated with clioquinol. Two other studies in mice showed that the raising of brain copper concentrations through diet or genetics could lower amyloid load and increase survival. A recent placebo-controlled trial in 36 patients with AD showed that clioquinol (250-750 mg daily) reduced plasma concentrations of Abeta(1-42), raised plasma concentrations of zinc, and-in a subset with moderate dementia-slowed cognitive decline over 24 weeks. Two recent experiments also showed the neuroprotective effects of iron chelation in a mouse model of Parkinson's disease. WHERE NEXT?: The experimental and transgenic-animal studies of metal-protein interactions are convincing but do not provide conclusive answers either about causality or whether this strategy will protect against neurodegeneration in human beings. The finding that clioquinol could modulate plasma concentrations of amyloid and cognition in patients with AD needs to be interpreted cautiously, but is an important first step. Clioquinol was withdrawn because of concerns of its association with subacute myelo-optic neuropathy in Japan; therefore, any additional studies with this drug will likely be small and closely monitored proof-of-concept studies. The development of optimal second-generation MPACs is a desirable goal and may permit greater insights into the significance of metal-protein interactions across several neurodegenerative disorders. Title [Relationship between exposure to environmental toxins and motor neuron disease: a case report] [Article in Italian] Author Vanacore N, Corsi L, Fabrizio E, Bonifati V, Meco G. Dipartimento di Scienze Neurologiche, Universita La Sapienza, Roma Source Med Lav. 1995 Nov-Dec;86(6):522-33 Abstract A case is reported of amyotrophic lateral sclerosis with occupational exposure to solvents and metals. The environmental toxin theory of motorneuron disease, including aspects of epidemiological, clinical, experimental and individual susceptibility is discussed. An overall evaluation of animal and human data was made using a methodological approach developed by the International Agency for Research on Cancer and a Scandinavian group of experts. It is concluded that there is a probable linkage between metals/solvents exposure and motorneuron disease. Title Inorganic mercury is transported from muscular nerve terminals to spinal and brainstem motoneurons Author Arvidson B. Department of Neurology, University Hospital, Uppsala, Sweden Source Muscle Nerve. 1992 Oct;15(10):1089-94 Abstract The distribution of mercury within the brainstem and spinal cord of mice was investigated with the autometallographic technique after intramuscular administration of a single dose of mercuric mercury (HgCl2). Deposits of mercury were localized to motor neurons of the spinal cord and to brainstem motor nuclei; i.e., neurons with their peripheral projections outside the blood-brain barrier. Unilateral ligation of the hypoglossal nerve prior to the injection of HgCl2 prevented the accumulation of mercury deposits in the ipsilateral hypoglossal nucleus. The selective accumulation of mercury in spinal and brainstem motoneurons is most probably due to a leakage of metal-protein complexes from capillaries in muscle into myoneural junctions, followed by uptake into nerve terminals and retrograde axonal transport. The possible link between this process and the development of motor neuron degeneration in ALS is discussed. Title The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: an adsorptive voltammetric study. Author Limson J, Nyokong T, Daya S., Department of Chemistry, Rhodes University, Grahamstown, South Africa. Source J Pineal Res. 1998 Jan;24(1):15-21. Abstract Melatonin, a pineal secretory product, and its precursors, tryptophan and serotonin, were examined for their metal binding affinities for both essential and toxic metals: aluminium, cadmium, copper, iron, lead, and zinc. An electrochemical technique, adsorptive stripping voltammetry, showed the varying abilities of melatonin and its precursors to bind the metals in situ. The results show that the following metal complexes were formed: aluminium with melatonin, tryptophan, and serotonin; cadmium with melatonin and tryptophan; copper with melatonin and serotonin; iron(III) with melatonin and serotonin; lead with melatonin, tryptophan, and serotonin; and zinc with melatonin and tryptophan. Iron(II) showed the formation of an in situ complex with tryptophan only. These studies suggest a further role for melatonin in the reduction of free radical generation and metal detoxification, and they may explain the accumulation of aluminium in Alzheimer's disease. Top Metals and Occupational Exposure Title A 30-year follow-up of residual effects on New Zealand School Dental Nurses, from occupational mercury exposure. Author Jones L, Bunnell J, Stillman J. School of Psychology, Massey University, Wellington, New Zealand. Source Hum Exp Toxicol. 2007 Apr;26(4):367-74. Abstract This paper reports possible residual adverse effects from occupational mercury exposure in dentistry. Thirty years ago, the all-women exposed group worked with both silver and copper amalgam filling material without protective gloves or a ventilation system, resulting in chronic mercury exposure. The aim of the study was to test the null hypothesis in a survey of general and reproductive health, and a battery of nine neurobehavioral tests. The population was the 115 graduates of one school for dental nurses from 1968 to 1971. The sample was 43 mercury-exposed women and 32 matched controls. Statistical comparisons revealed that the two groups were equivalent on cognitive tasks and four of the six mood subscales. Significant between-group differences were found in current health symptom experience and reproductive health, especially early hysterectomy experience. Reporting of Occupational Overuse Syndrome was strongly positively correlated with years of work. In general, the study suggests that acute symptoms from mercury exposure may be reversible, while some residual health effects may be becoming more of a concern with the women's increasing age. Title A study on the beryllium lymphocyte transformation test and the beryllium levels in working environment. Author Yoshida T; Shima S; Nagaoka K; Taniwaki H; Wada A; Kurita H; Morita K Source Ind Health, 35(3):374-9 1997 Jul Abstract The relationship between airborne concentration of beryllium in the working environment and workers' beryllium lymphocyte transformation test (Be-LTT) values was examined based on data obtained from a four-year survey (1992-1995) conducted at beryllium-copper alloy manufacturing factories. This study showed that the T cells of workers continuously exposed to beryllium of more than 0.01 microgram/m3 could be activated and that the cell-mediated immune response of workers could be promoted. On the other hand, the Be-LTT of workers exposed to beryllium levels of less than 0.01 microgram/m3 was shown to be unaffected by beryllium. These findings suggest that beryllium sensitization is not manifested when level of beryllium in working environment are less than 0.01 microgram/m3. Therefore, in such cases workers do not develop Chronic beryllium disease (CBD). We concluded that the Be-LTT can be applied as a medical indicator to detect the development of CBD. Title Occupational risk factors for the development of systemic lupus erythematosus. Author Cooper GS, Parks CG, Treadwell EL, St Clair EW, Gilkeson GS, Dooley MA., Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina 27709, USA. copper1@niehs.nih.gov Source J Rheumatol. 2004 Oct;31(10):1928-33. Abstract OBJECTIVE: There have been few studies of occupational exposures and systemic lupus erythematosus (SLE). We examined the association between the ri