Abstracts

Abstracts

  1. Metals and Cardiovascular Diseases
  2. Metals and Psychiatric Disease
  3. Metals and Cancer and treatment with Vitamin C
  4. Metals, Fertililty and Fetal Exposure
  5. Metals and Skin Diseases
  6. Metals and Gastrointestinal Diseases
  7. Metals and Dentistry
  8. Metals and Oral Diseases
  9. Metals and Paediatric Exposure, Vaccines
  10. Metals and Detoxification and Chelation
  11. Metals and Genetic Susceptibility
  12. Metals and the Brain
  13. Metals and Occupational Exposure
  14. Diagnostic Procedures in the Determination of Metal Toxicity and Allergy
  15. Metals and Autoimmunity
  16. Metals As Possible Pathogenesis in Patients with Unclear Diagnosis (CFS, MCS)
  17. Metal Effects on Clinical Chemistry Findings
  18. Metals and Disturbance of HPA-axis
  19. Metals and Allergy
  20. Ortopedic Metal Implants
  21. Exposure to titanium

 

Metals and Cardiovascular Diseases

Title
Role of mercury toxicity in hypertension, cardiovascular disease, and stroke.
Author
Houston MC. Department of Medicine, Vanderbilt University School of Medicine, Division of Human Nutrition, Saint Thomas Medical Group, Saint Thomas Hospital, Nashville, TN, USA. boohouston@comcast.net
Source
J Clin Hypertens (Greenwich). 2011 Aug;13(8):621-7.
Abstract

Mercury has a high affinity for sulfhydryl groups, inactivating numerous enzymatic reactions, amino acids, and sulfur-containing antioxidants (N-acetyl-L-cysteine, alpha-lipoic acid, L-glutathione), with subsequent decreased oxidant defense and increased oxidative stress. Mercury binds to metallothionein and substitute for zinc, copper, and other trace metals, reducing the effectiveness of metalloenzymes. Mercury induces mitochondrial dysfunction with reduction in adenosine triphosphate, depletion of glutathione, and increased lipid peroxidation. Increased oxidative stress and reduced oxidative defense are common. Selenium and fish containing omega-3 fatty acids antagonize mercury toxicity. The overall vascular effects of mercury include increased oxidative stress and inflammation, reduced oxidative defense, thrombosis, vascular smooth muscle dysfunction, endothelial dysfunction, dyslipidemia, and immune and mitochondrial dysfunction. The clinical consequences of mercury toxicity include hypertension, coronary heart disease, myocardial infarction, cardiac arrhythmias, reduced heart rate variability, increased carotid intima-media thickness and carotid artery obstruction, cerebrovascular accident, generalized atherosclerosis, and renal dysfunction, insufficiency, and proteinuria. Pathological, biochemical, and functional medicine correlations are significant and logical. Mercury diminishes the protective effect of fish and omega-3 fatty acids. Mercury inactivates catecholaminei-0-methyl transferase, which increases serum and urinary epinephrine, norepinephrine, and dopamine. This effect will increase blood pressure and may be a clinical clue to mercury-induced heavy metal toxicity. Mercury toxicity should be evaluated in any patient with hypertension, coronary heart disease, cerebral vascular disease, cerebrovascular accident, or other vascular disease. Specific testing for acute and chronic toxicity and total body burden using hair, toenail, urine, and serum should be performed.

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.

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.

 

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.

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
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
INTRODUCTION: 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.

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.

Metals and Gastrointestinal Diseases

Title
Gastritis and dental metals

Author
C. Pföhler, T. Vogt, C. S. L. Müller

Source
Hautarzt DOI 10.1007/s00105-016-3773-7
Springer-Verlag Berlin Heidelberg 2016

Abstract
Only a few cases of contact allergic gastritis in patients with nickel allergy have been reported in the literature. We report a case of probable contact-allergic gastritis in a 46-year-old woman. Clinical examination revealed lichenoid mucosal lesions of the gums adjacent to a bridge and crowns that had been implanted several weeks previously. Since implantation, the patient suffered from gastrointestinal complaints including stomach pain. Gastroscopy and histological investigation of stomach biopsies showed eosinophilic gastritis. Patch testing done under the diagnosis of contact allergic stomatitis showed positive reactions to gold sodium thiosulphate, manganese (II) chloride, nickel (II) sulphate, palladium chloride, vanadium (III) chloride, zirconium (IV) chloride, and fragrances. The crowns and the bridge contained gold, palladium, and zirconium, hence they were replaced by titan-based dentition. Shortly after replacing the artificial dentition, all gastrointestinal symptoms resolved spontaneously without further treatment. Delayed-type allergy to components in the artificial dentition seem to have caused the gastritis. [Article in German]

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.

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.

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.

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.
Metals and Detoxification and Chelation

Title
EDTA Chelation Therapy, without Added Vitamin C, Decreases Oxidative DNA Damage and Lipid Peroxidation

Author
Anne Marie Roussel, PhD; Isabelle Hininger-Favier, PhD; Robert S. Waters, MD; Mireille Osman, MS; Karen Fernholz, RN; and Richard A. Anderson, PhD

Source
Alternative Medicine Review Volume 14, Number 1 2009

Abstract
Chelation therapy is thought to not only remove contaminating metals but also to decrease free radical production. However, in standard ethylene diamine tetraacetic acid (EDTA) chelation therapy, high doses of vitamin C with potential pro-oxidant effects are often added to the chelation solution. The authors demonstrated previously that the intravenous administration of the standard chelation cocktail, containing high amounts of vitamin C, resulted in an acute transitory pro-oxidant burst that should be avoided in the treatment of pathologies at risk of increased oxidative stress such as diabetes and cardiovascular disease. The current study was designed to determine the acute and chronic biochemical effects of chelation therapy on accepted clinical, antioxidant variables. An EDTA chelation cocktail not containing ascorbic acid was administered to six adult patients for five weeks (10 sessions of chelation therapy); antioxidant indicators were monitored. Immediately after the initial chelation session, in contrast with the data previously reported with the standard cocktail containing high doses of vitamin C, none of the oxidative stress markers were adversely modified. After five weeks, plasma peroxide levels, monitored by malondialdehyde, decreased by 20 percent, and DNA damage, monitored by formamidopyrimidine-DNA glycosylase (Fpg) sensitive sites, decreased by 22 percent. Remaining antioxidant-related variables did not change. In summary, this study demonstrates that multiple sessions of EDTA chelation therapy in combination with vitamins and minerals, but without added ascorbic acid, decreases oxidative stress. These results should be beneficial in the treatment of diseases associated with increased oxidative stress such as diabetes and cardiovascular diseases.
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.

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.
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.
Metals and the Brain

Title
Does inorganic mercury play a role in Alzheimer’s disease? A systematic review and an integrated molecular mechanism

Author
Joachim Mutter, Annika Curth, Johannes Naumann, Richard Deth and Harald Walach

Source
Journal of Alzheimer’s Disease;22(2010):357–374

Abstract
Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer’s disease (AD) might be in part caused or exacerbated by inorganic mercury, we conducted a systematic review using a comprehensive search strategy. Studies were screened according to a predefined protocol. Two reviewers extracted relevant data independent of each other. One thousand and forty one references were scrutinized, and 106 studies fulfilled the inclusion criteria. Most studies were case control or comparative cohort studies. Thirtytwo studies, out of 40 testing memory in individuals exposed to inorganic mercury, found significant memory deficits. Some autopsy studies found increased mercury levels in brain tissues of AD patients. Measurements of mercury levels in blood, urine, hair, nails, and cerebrospinal fluid were inconsistent. In vitro models showed that inorganic mercury reproduces all pathological changes seen in AD, and in animal models inorganic mercury produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that inorganic mercury may promote neurodegenerative disorders via disruption of redox regulation. Inorganic mercury may play a role as a cofactor in the development of AD. It may also increase the pathological influence of other metals. Our mechanistic model describes potential causal pathways. As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as soon as possible.

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.
Title
Toxic causes of mental illness are overlooked

Author
Genuis SJ.

Source
Neurotoxicology. 2008 Nov;29(6):1147-9. Epub 2008 Jun 24.

Abstract
While proper brain function requires the complex interaction of chemicals perpetually occupied in purposeful biochemistry, it is well established that certain toxic substances have the potential to disrupt normal brain physiology and to impair neurological homeostasis. As well as headache, cognitive dysfunction, memory disturbance, and other neurological signs and symptoms, disruption of brain function may also manifest as subtle or overt alteration in thoughts, moods, or behaviors. Over the last four decades, there has been the unprecedented development and release of a swelling repertoire of potentially toxic chemicals which have the capability to inflict brain compromise. Although the ability of xenobiotics to induce clinical illness is well established, the expanding public health problem of widespread toxicant exposure in the general population is a relatively new phenomenon that has spawned escalating concern. The emerging area of clinical care involving the assessment and management of accrued toxic substances such as heavy metals, pesticides, plasticizers and other endocrine disrupting or neurotoxic compounds has not been fully appreciated by the medical community and has yet to be incorporated into the clinical practice of many consultants or primary care practitioners.
Title
Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer’s disease.

Author
Gerhardsson L, Lundh T, Minthon L, Londos E.

Source
Dement Geriatr Cogn Disord. 2008;25(6):508-15. Epub 2008 May 5.

Abstract
BACKGROUND/AIMS: The homeostasis of essential metals such as copper, iron, selenium and zinc may be altered in the brain of subjects with Alzheimer’s disease (AD). METHODS: Concentrations of metals (magnesium, calcium, vanadium, manganese, iron, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, tin, antimony, cesium, mercury and lead) were determined in plasma and cerebrospinal fluid (CSF) by inductively coupled plasma mass spectrometry in 173 patients with AD and in 87 patients with the combination of AD and minor vascular components (AD + vasc). Comparison was made with 54 healthy controls. RESULTS: The plasma concentrations of manganese and total mercury were significantly higher in subjects with AD (p < 0.001) and AD + vasc (p <or= 0.013) than in controls. In CSF, however, the concentrations of vanadium, manganese, rubidium, antimony, cesium and lead were significantly lower among subjects with AD (p <or= 0.010) and AD + vasc (p <or= 0.047) than in controls. Strong positive correlations were noted between plasma Cs versus CSF Cs in subjects with AD (r(s) = 0.50; p < 0.001), and AD + vasc (r(s) = 0.68; p < 0.001). CONCLUSION: Besides the raised plasma mercury concentrations, no consistent metal pattern in plasma or CSF was observed in patients with AD.
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 risk of SLE and occupational exposures (mercury, solvents, and pesticides), specific jobs (ever worked in teaching, healthcare, and cosmetology), and working night or rotating shifts. METHODS: Patients with recently diagnosed SLE (n = 265) were recruited through 4 university based and 30 community based rheumatology practices in North Carolina and South Carolina, USA. Controls (n = 355) were identified through driver’s license records and were frequency matched to patients by age, sex, and state. Data collection included an in-person interview with detailed farming and work histories. RESULTS: Associations were seen with self-reported occupational exposure to mercury (OR 3.6, 95% CI 1.3, 10.0), mixing pesticides for agricultural work (OR 7.4, 95% CI 1.4, 40.0), and among dental workers (OR 7.1, 95% CI 2.2, 23.4). Although these associations were fairly strong and statistically significant, the prevalence of these exposures was very low and thus these estimates are based on a small number of exposed cases and controls. Weaker associations were seen between SLE and shift work (OR 1.6, 95% CI 0.99, 2.7) and among healthcare workers with patient contact (OR 1.7, 95% CI 0.99, 2.9). There was no association of SLE with use of solvents or among teachers or cosmetologists. CONCLUSION: This study reveals the potential contribution of occupational exposures to the development of SLE, and highlights some exposures and experiences that should be examined in other studies using more extensive exposure assessment techniques and in experimental studies of autoimmunity.
Diagnostic Procedures in the Determination of Metal Toxicity and Allergy

Title
Allergens responsible for allergic contact dermatitis among children: a systematic review and meta-analysis

Author
Bonitsis NG, Tatsioni A, Bassioukas K, Ioannidis JP

Source
Contact Dermatitis;64(5):245-257
Multiple studies have evaluated diverse allergens in paediatric populations. Consensus is still lacking on which allergens are most commonly implicated in allergic contact dermatitis. Objectives. To evaluate the proportion of positive reactions for allergens tested in children and to identify allergens with positive reactions in at least 1% of them. Methods. This was a systematic review of studies in PubMed (1966-2010) investigating allergens in at least 100 enrolled children. Proportions of positive reactions for each allergen were combined with random effects models across studies. Results. We included 49 studies with available data on 170 allergens. Each study tested a median of two allergens. Among the 94 allergens evaluated by at least two studies, 58 had estimates of positive reactions of at least 1% by random effects calculations, and for 21 of them the 95% confidence interval ensured that the proportion of positive reactions was at least 1%. The top five allergens tested by at least two studies included nickel sulfate, ammonium persulfate, gold sodium thiosulfate, thimerosal, and toluene-2,5-diamine (p-toluenediamine). For most allergens, the proportion of positive reactions was higher in studies published after 1995 than in earlier studies (p = 0.0065). Conclusions. This meta-analysis offers guidance on which allergens are most prevalent in the paediatric population and should have priority for inclusion in standardized allergen series.
Title
Metal Allergens of Growing Significance: Epidemiology, Immunotoxicology, Strategies for Testing and Prevention

Authors
G. Forte, F. Petrucci and B. Bocca Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy

Source
Inflammation & Allergy – Drug Targets, 2008, 7

Abstract
Metal-induced allergic contact dermatitis (ACD) is expressed in a wide range of cutaneous reactions following dermal and systemic exposure to products such as cosmetics and tattoos, detergents, jewellery and piercing, leather tanning, articular prostheses and dental implants. Apart from the well known significance of nickel in developing ACD, other metals such as aluminium, beryllium, chromium, cobalt, copper, gold, iridium, mercury, palladium, platinum, rhodium and titanium represented emerging causes of skin hypersensitivity. Despite the European Union directives that limit the total nickel content in jewellery alloys, the water soluble chromium (VI) in cement, and metals banned in cosmetics, the diffusion of metal-induced ACD remained quite high. On this basis, a review on the epidemiology of metal allergens, the types of exposure, the skin penetration, the immune response, and the protein interaction is motivated. Moreover, in vivo and in vitro tests for the identification and potency of skin-sensitizing metals are here reviewed in a risk assessment framework for the protection of consumer’s health. Avenues for ACD prevention and therapy such as observance of maximum allowable metal levels, optimization of metallurgic characteristics, efficacy of chelating agents and personal protection are also discussed. Contact london@melisa.org for a copy of this article.
Title
Human Hapten-Specific Lymphocytes: Biomarkers of Allergy in Man

Authors
Vera D. M. Stejskal, Ph.D.

Source
Drug Information Journal, Vol. 31, pp. 1379-1382, 1997

Abstract
Environmental pollutants and other chemicals may have increasing impact on the immune systems of human beings. Disregulation of the immune system by chemicals may be one of the reasons why the frequency of allergies and autoimmune diseases increases. Human hapten-specific memory lymphocytes can be detected in the blood from patients with drug-induced immunologic side-effects but not in similarly exposed healthy individuals. The immune reactivity of human lymphocytes in vitro to white coloring agent–titanium dioxide (TiO2), and to mercurial conservatives thimerosal and phenylmercury–has been studied. It was found that out of 650 patients tested, 3% reacted to titanium dioxide. The percentages for phenylmercury and thimerosal were 14% and 7%, respectively. Human memory cells can be used as markers of susceptibility in future choices of appropriate additives in pharmaceutic products.
Title
Mercury-specific lymphocytes: an indication of mercury allergy in man.

Author
Stejskal VD; Forsbeck M; Cederbrant KE; Asteman O

Source
Journal of Clinical Immunology, 16(1):31-40 1996 Jan

Abstract
In this study, 18 patients with oral lichen planus (OLP), adjacent to amalgam fillings, were tested in vitro with an optimized lymphocyte proliferation test, MELISA® (memory lymphocyte immunostimulation assay) and with a patch test. Twenty subjects with amalgam fillings but without oral discomfort and 12 amalgam-free subjects served as controls. The results show that patients with OLP have significantly higher lymphocyte reactivity to inorganic mercury, a corrosion product of amalgam, compared to control groups. Removal of amalgam fillings resulted in the disappearance of oral mucosal changes, thus indicating a causal relationship. Positive responses to phenylmercury (phenyl-Hg), a bactericidal agent in root fillings and in pharmaceutical preparations, were also noted in the oral lichen group but not in the control groups. Thus, low-grade chronic exposure to mercury may induce a state of systemic sensitization as verified by Hg-specific lymphocyte reactivity in vitro.
Title
Contact allergy to gold in dental patients.

Author
Räsänen L; Kalimo K; Laine J; Vainio O; Kotiranta J; Pesola I

Source
Br J Dermatol, 1996 Apr, 134:4, 673-7

Abstract
Gold sodium thiosulphate (GSTS) in patch test series commonly yields positive reactions. In this study of dental patients, the clinical relevance of these positive reactions, the suitability of gold compounds as patch test materials, and value of the lymphocyte proliferation test in gold contact allergy, were evaluated. The frequency of positive patch test reactions to GSTS was 12.4% in the dental series. Fifty-two patients, only two of whom were male, were studied. Thirteen (25%) had had symptoms from jewellery or dental restorations. However, in most cases gold allergy was subclinical. A 10% aqueous solution of gold sodium thiomalate (GSTM) was almost as good as 0.5% GSTS in petrolatum as a marker of gold contact allergy, but 0.001% potassium dicyanoaurate (PDCA) yielded a high percentage of false-negative results. Seventy-three per cent of the subjects with positive patch tests to GSTS responded to gold compounds in vitro in the lymphocyte proliferation test, whereas 13 controls without gold contact sensitivity were negative. Consistent results in skin and lymphocyte proliferation tests provide support for the concept that gold salt-induced ‘allergic-like’ reactions are truly allergic in nature.
Title
The relationship between IgE-mediated and cell-mediated hypersensitivities in an unselected Danish population: the Glostrup Allergy Study, Denmark.

Author
Nielsen NH; Menné T

Source
Br J Dermatol, 1996 Apr, 134:4, 669-72

Abstract
In this study, we have assessed the relationship between IgE-mediated and cell-mediated hypersensitivities in an unselected population living in western Copenhagen, Denmark. A total of 793 subjects, aged 15-69 years, were studied. Measurements of total serum IgE, prick tests with aero-allergens and patch tests with environmental haptens were performed in 561 (70.7% of 793) subjects. One or more positive prick tests were present in 28.4%, and contact sensitization occurred in 15.2%. When adjusted for the effects of sex and age, the probability of contact sensitization to one or more hapten was independent of serum IgE level (the odds ratio value (OR) = 1.0; 95% confidence interval (CI) = 0.7-1.4), and the probability of contact sensitization was independent of the number of positive prick tests (OR = 1.0; CI = 0.8-1.2). Contact sensitization appeared to be independent of enhanced IgE responsiveness in an unselected adult population.
Title
Contact allergies to nickel sulfate, gold sodium thiosulfate and palladium chloride in patients claiming side-effects from dental alloy components.

Author
Marcusson JA

Source
Contact Dermatitis, 1996 May, 34:5, 320-3

Abstract
397 patients claiming various subjective symptoms related to dental restoration materials have been tested for the presence of metal allergy. The resultant data have been compared with the corresponding allergies of eczematous patients. The frequency difference of metal allergy in the dental group is statistically significant or close to significance for nickel sulfate, potassium dichromate, cobalt chloride, palladium chloride and gold sodium thiosulfate. The findings suggest that the dental patient group represents a subgroup with a high frequency of metal allergy.
Title
Significance of the blood beryllium lymphocyte proliferation test.

Author
Newman LS

Source
Environ Health Perspect, 1996 Oct, 104 Suppl 5:, 953-6

Abstract
The blood beryllium lymphocyte proliferation test (BeLPT) is an in vitro measure of the beryllium antigen-specific cell-mediated immune response. This response to beryllium is now understood to play a central role in the immunopathogenesis of chronic beryllium disease (CBD). Although there remain some unresolved methodologic issues with testing, the blood BeLPT has already undergone sufficient development and field assessment to lead to a number of important conclusions: a) The BeLPT identifies beryllium sensitization and CBD earlier and better than any other clinical test presently available. b) The CBD cases identified with the blood test are clinically significant. c) A subset of the people identified by the BeLPT who do not yet have clinical disease will progress and require treatment with corticosteroids for impairing illness. d) The BeLPT can be used to improve clinical diagnostic accuracy and to correct mistaken diagnoses. e) The blood test can be used in screening large numbers of exposed workers because it is sensitive and specific and has high positive and negative predictive value for CBD. f) In every workforce studied to date, the BeLPT has identified beryllium sensitization and CBD that had been missed by conventional screening efforts. g) Worker populations that have been characterized using the BeLPT can help to elucidate the role of exposure genetics and dysregulated inflammation in the genesis of occupational lung disease.
Title
High frequency of contact allergy to gold sodium thiosulfate. An indication of gold allergy?

Author
Björkner B; Bruze M; Möller H

Source
Contact Dermatitis, 1994 Mar, 30:3, 144-51

Abstract
When gold sodium thiosulfate was added to the patch test standard series, positive reactions were obtained in 8.6% of 823 consecutive patients with suspect contact allergy. The test reactions were clinically of an allergic type and, in several cases, long-lasting. There was no correlation with other allergens in the standard series. In a special study on 38 patients with contact allergy to gold sodium thiosulfate, the following principal findings were obtained: positive patch tests to the compound itself in dilute concentration; positive patch tests to potassium dicyanoaurate; negative patch tests to gold sodium thiomalate, sodium thiosulfate, and metallic gold; positive intradermal tests to gold sodium thiosulfate. Our findings make gold sodium thiosulfate the 2nd most common contact allergen after nickel sulfate. It is suggested that a positive skin test to gold sodium thiosulfate represents gold allergy.
Title
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MELISAR–AN IN VITRO TOOL FOR THE STUDY OF METAL ALLERGY

Author
V. D. M. Stejskal, K. Cederbrandt, A. Lindvall, M. Forsbeck

Source
Toxicology in Vitro, Vol. 8; Number 5; pp. 991-1000, 1994

Abstract
The sensitizing properties of metals widely used in medical and dental care have been studied with the help of an optimized lymphocyte proliferative assay, MELISA®. MELISA® (memory lymphocyte immuno-stimulation assay) was originally developed for the screening of allergenic epitopes of drugs and other chemicals of low molecular weight, but has recently been adapted for the study of metal-induced sensitization. The patients studied suffered from various mucosal problems which were suspected to be caused by the release of metal ions from dental restorations. They were also troubled by chronic fatigue persisting over many years. One patient was also occupationally exposed to metals while working in a dental practice. Healthy subjects without any discomfort due to metal devices served as controls. In addition to metals used in dentistry, lymphocyte responses to organic mercurials used widely as preservatives in vaccines, eye/nose drops and contact lens fluids were studied. The results indicated that mercurials, as well as other metals such as gold or palladium, induce strong lymphocyte proliferative responses in patients with oral or systemic symptoms, but not in similarly exposed unaffected subjects. The results of MELISA® performed with a pair of identical twins with chronic fatigue syndrome (CFS) indicated that metal-specific responses may be dependent on the genetics of the patient. Thus, many metals that are today accepted for use in medicine and dentistry carry a definite sensitizing risk for certain genetically predisposed individuals. Therefore, the use of these metals should be limited in the future.
Title
Human exposure to mercury and silver released from dental amalgam restorations.

Author
Skare I; Engqvist A

Source
Arch Environ Health, 1994 Sep, 49:5, 384-94

Abstract
In 35 healthy individuals, the number of amalgam surfaces was related to the emission rate of mercury into the oral cavity and to the excretion rate of mercury by urine. Oral emission ranged up to 125 micrograms Hg/24 h, and urinary excretions ranged from 0.4 to 19 micrograms Hg/24 h. In 10 cases, urinary and fecal excretions of mercury and silver were also measured. Fecal excretions ranged from 1 to 190 micrograms Hg/24 h and from 4 to 97 micrograms Ag/24 h. Except for urinary silver excretion, a high interplay between the variables was exhibited. The worst-case individual showed a fecal mercury excretion amounting to 100 times the mean intake of total Hg from a normal Swedish diet. With regard to a Swedish middle-age individual, the systemic uptake of mercury from amalgam was, on average, predicted to be 12 micrograms Hg/24 h.
Title
Diagnostic value of the lymphocyte proliferation test in nickel contact allergy and provocation in occupational coin dermatitis.

Author
Räsänen L; Tuomi ML

Source
Contact Dermatitis, 1992 Oct, 27:4, 250-4

Abstract
The lymphocyte proliferation test (LPT) was compared with the patch test in the diagnosis of nickel contact sensitivity. Of the 21 subjects with nickel contact allergy, the patch test detected 20 (95%). The subject remaining negative in the patch test was positive in the intradermal test. 18/21 subjects with nickel contact sensitivity were positive in the LPT, whereas in the control group 2/23 subjects were false positive. These results were obtained at nickel sulfate concentrations of less than 10 micrograms/ml, higher concentrations led to nonspecific lymphocyte stimulation. 3 nickel-sensitive cashiers with suspected coin contact-induced deterioration of their hand eczema were challenged by having them count nickel-containing coins daily for 15 min. 2 of them developed vesicular eczema on their palms and fingers in 2 to 3 days. The present results show that the LPT is a reliable additional test in the diagnosis of nickel contact sensitivity. Furthermore, provocation is a valuable procedure when assessing the relevance of nickel contact in occupational hand eczema in certain occupations.
Title
Lymphocyte Transformation test for Diagnosis of Isothiazoline Allergy in Man

Author
V. D. M. Stejskal, M. Forsbeck, R. Nilsson

Source
The Journal of Investigative Dermatology 94:798-802, 1990

Abstract
The lymphocyte transformation test (LTT) has been used for evaluation of in vitro lymphocyte responses in 18 patients with dermatitis and positive patch tests to 200 ppm of a combination of 5-chloro-2-methylisothiazolinone and 2-methtylisothiazolinone (MCI) in nine patients with dermatitis unrelated to MCI and in seven subjects without skin diseases. Two workers sensitized by occupational exposure to formulation containing 1,2-benzisothiazolin-3-one (BIT)were also studied. Lymphocytes from nine patch-test-positive patients proliferated vigorously to MCI in vitro. Lymphocytes from the remaining nine patients were not stimulated. Lymphocytes from two BIT-sensitized workers responded to BIT in vitro. The lymphocyte proliferation to isothiazolines indicates the presence of memory cells in the patients blood and confirms immunologic reaction to the inducing agent. To establish clinical relevance of LTT results, 12 MCI patch-test-positive patients underwent “use test” with lotion containing 15 ppm MCI. Four of five LTT-positive patients were use-test-positive, whereas seven of seven LTT-negative patients were use-test-negative. LTT-positive and lotion-positive patients responded to 100 ppm or lower concentrations of MCI on patch testing, whereas seven of eight LTT-negative and lotion-negative patients responded to 200 ppm only. In the case of MCI, proliferation was due to the chlorinated component, indicating that this part contains an allergenic epitome. Finally, MCI-specific lymphocyte proliferation was observed only in patients with MCI-positive skin test, but not in nine patients with dermatitis induced by other agents, or in seven subjects without skin diseases. Thus, the lymphocyte transformation test is able to distinguish between irritant and allergic responses. It may also be valuable in establishing the clinically relevant patch-test concentration of allergens with irritative properties.
Title
In vitro studies in nickel allergy: diagnostic value of a dual parameter analysis.

Author
von Blomberg-van der Flier M; van der Burg CK; Pos O; van de Plassche-Boers EM; Bruynzeel DP; Garotta G; Scheper RJ

Source
J Invest Dermatol, 1987 Apr, 88:4, 362-8

Abstract
A comparison was made between the diagnostic value of assaying nickel-induced lymphocyte proliferation (lymphocyte transformation test, LTT) and migration inhibition factor (MIF) production in nickel contact sensitivity. Although lymphocyte proliferation was significantly increased in the group of patients with skin test reactivity to nickel, positive LTT were also frequently found in skin test-negative subjects: in 63% of subjects with and in 30% of subjects without a history of metal allergy. This would limit the value of the LTT as an in vitro correlate of skin test reactivity. However, in certain patients positive lymphocyte transformation may reveal nickel sensitization at a time of undetectable skin reactivity. Data obtained with the macrophage migration inhibition test (MMIT) showed a good correlation with nickel patch test reactions. Accurate determination of MIF became feasible by using cells from the human monocytoid cell line U937 as target cells in a microdroplet agarose assay. Using this MMIT, positive reactions occurred in 13% of the healthy controls and false-negative reactions were found in 26% of patients with positive skin test reactivity to nickel. As LTT and MMIT data appeared to be only weakly correlated in the individuals tested, a dual parameter analysis was performed. An excellent correlation [p = 1.8 (10(-8]] was found between skin test and in vitro reactivity for individuals with matching in vitro results (60% of all individuals tested). In those individuals with discordant in vitro data, skin testing will remain indispensable for diagnosing nickel allergy.
Title
The lymphocyte transformation test for diagnosis of drug-induced occupational allergy.

Author
Stejskal VD; Olin RG; Forsbeck M

Source
J Allergy Clin Immunol, 1986 Mar, 77:3, 411-26

Abstract
Twenty-five workers with clinically diagnosed or suspected occupational hypersensitivity caused by contact with bacampicillin, alprenolol, and/or quinidine were studied by the lymphocyte transformation test and by skin tests. Ten healthy exposed workers, 16 job applicants, and seven healthy nonexposed laboratory workers served as control subjects. Lymphocyte transformation was measured by 3H-thymidine uptake into DNA and by counting of lymphoblasts on cell smears. Lymphocytes from workers with contact eczema or with eczema in combination with conjunctivitis and rhinitis responded to offending drugs in vitro as demonstrated by an increased 3H-thymidine incorporation and by the presence of lymphoblasts in the cultures. In vitro proliferative responses were reproduced during a 4-year period. Drug-specific allergy was confirmed by positive patch test in most workers with eczema. In addition, bacampicillin-specific lymphocyte proliferation was also observed in workers with suspected bacampicillin hypersensitivity but with negative skin tests. They suffered mostly from eczema in combination with conjunctivitis and rhinitis or from conjunctivitis/rhinitis only. Lymphocytes from most control subjects did not respond in vitro to bacampicillin, alprenolol, or quinidine. Weak proliferative responses to bacampicillin were observed in two of the 16 job applicants. The exquisite specificity of drug-induced lymphocyte responses is demonstrated. Thus, lymphocytes from a quinidine-sensitive worker did not respond in vitro to the quinidine stereoisomer, quinine. Furthermore, lymphocytes from a bacampicillin-sensitive worker responded to some penicillins, such as pivampicillin and ampicillin, but not to others, such as benzylpenicillin or pivmecillinam. These data suggest the role of N-acylamido side chain in the sensitization of lymphocytes from this particular donor. In conclusion, lymphocyte transformation test can be used for the detection of offending agents in occupationally sensitized workers. Furthermore, lymphocytes from such individuals may serve as a model for study of specificity of cellular reactions underlying drug-induced hypersensitivity.
Title
Lymphocyte stimulation by trivalent and hexavalent chromium compounds in patients with chromium sensitivity. An aid to diagnosis.

Author
Al-Tawil NG; Marcusson JA; Möller E

Source
Acta Derm Venereol, 1983, 63:4, 296-303

Abstract
Peripheral blood lymphocytes from 31 patients with a positive patch test to potassium dichromate (K2Cr2O7) and from 24 healthy controls were stimulated with various concentrations of chromium chloride (CrCl3) and/or chromium basic sulphate (Cr4(SO4)5(OH)2), sodium chromate (Na2CrO4) or K2Cr2O7 on various days of culture. Both trivalent and hexavalent chromium compounds could induce lymphocyte transformation, as measured by increased DNA synthesis. The response occurred in the T-enriched population and was monocyte dependent. Lymphocytes from 11 of these patients could not be stimulated with the chromium compounds in vitro, whereas the in vivo serial dilution test (SDT) was positive in 4 and negative in 7 of them. Lymphocytes from 2 patients with a negative in vivo SDT showed a positive response in vitro. The strength of the in vivo SDT results did not correlate well with the height of in vitro responses. The DNA synthesis test seems to be a reliable in vitro method to aid in the diagnosis of chromium sensitivity.
Title
Development of beryllium lymphocyte transformation tests in chronic beryllium disease.

Author
Williams WR; Williams WJ

Source
Int Arch Allergy Appl Immunol, 1982, 67:2, 175-80

Abstract
We found that optimal conditions for the beryllium transformation test required the use of purified lymphocyte suspensions in 20% human serum, with beryllium sulphate at concentrations of 10(-6) to 10(-7) M. Using these conditions, all 15 chronic beryllium patients tested gave a stimulation index of more than 2. Despite the above, 10(-5) and 10(-6)M, BeSO4 inhibited spontaneous thymidine incorporation and lymphocyte transformation to PHA and PPD in normal subjects. Alternative methods, using whole blood, venous and thumb-prick samples, gave fewer and less reproducible positive results.
Title
The specificity of a nickel sulphate reaction in vitro: a family study and a study of chromium-allergic subjects.

Author
Silvennoinen-Kassinen S

Source
Scand J Immunol, 1981, 13:3, 231-5

Abstract
In vitro PPD and nickel sulphate lymphocyte blast transformation reactions were performed in ten families with one or more allergic nickel contact dermatitis patients. The healthy family members did not have an inherited ability to react to nickel in vitro. Their nickel stimulation response was significantly lower (P less than 0.005) than that among the allergic subjects. In the families studied, atopic members did not have higher nickel reactions than nonatopic subjects. Thus, the in vitro nickel reaction is not connected to atopy. This is further confirmed by the fact that the percentage of atopic subjects (19%) in these families is not higher than the percentage in the general population. In addition, six unrelated chromium-allergic patients were tested, and their lymphocytes did not cross-react with nickel sulphate in vitro. These results indicate that the in vitro nickel blast transformation reaction is specific to clinical nickel allergy in about 90% of nickel dermatitis patients.
Title
Lymphocyte transformation test in patients with nickel sensitivity: an aid to diagnosis.

Author
Al-Tawil NG; Marcusson JA; Möller E

Source
Acta Derm Venereol, 1981, 61:6, 511-5

Abstract
Peripheral blood lymphocytes from 16 patients with a positive patch test to 2.5% nickel sulphate (NiSO4) and 18 healthy controls were tested by the lymphocyte transformation technique where NiSO4 in six different concentrations was used and tested after various days of culture. Lymphocytes from all except one of the patients showed a significantly greater response than that of the controls. Lymphocyte transformation as measured by increased DNA synthesis seems to be a valuable tool for investigating the problems arising from false-positive or false-negative patch tests. With these data we have defined certain criteria for in vitro reactivity that should be fulfilled. Lymphocytes from controls responded non-specifically to high concentrations of NiSO4. Cord blood lymphocytes from 4 newborn infants could also be activated by NiSO4, thus confirming the assumption that NiSO4 is a weak mitogen.
Title
[Immunological studies on the peripheral blood mononuclear cells in metal allergy patients] [Article in Japanese]

Author
Nokiba K., Fixed Prosthodontics, Department of Restorative Sciences, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University.

Source
Kokubyo Gakkai Zasshi. 2005 Jun;72(2):159-71.

Abstract
Recently, the number of patients with dental metal allergy has risen significantly. The aim of this study was to evaluate the clinical availability of the lymphocyte stimulation test (LST) using metal reagents as a method for diagnosing metal allergy. In vitro, peripheral blood mononuclear cells (PBMC) from 18 patients with metal allergy and five healthy volunteers were examined by LST using 12 metal reagents (HAuCl4, PdCl2, NiSO4, CoCl2, CuSO4, SnCl4, K2Cr2O7, MoCl5, H2PtCl6, IrCl4, AgBr, FeCl3). To define metal allergy, a patch test (PT) was performed with metal reagents, and then the components of dental alloys in their mouth were analyzed. The expressions of CD 4, CD 8, CD 25, and CLA of metal-specific T cells were determined by flow cytometric analysis (FACS). PBMC from patients with positive PT showed LST positive for nickel sulfate (Ni), gold chloride (Au), palladium chloride (Pd) and cobalt chloride (Co). The results of LST in other metals indicated negative in spite of the positive result by PT. FACS results indicated the increase of CD 4 + T/CD 8 + alpha 4 + T cells, CD 4 + T/CD 8 + CLA+ T cells by stimulation with metal reagent. Thus, metal-specific T cells were stimulated in PT positive patients, so LST could be a more specific test for diagnosing dental metal allergy.
Title
Metal-specific lymphocyte reactivity is downregulated after dental metal replacement.

Author
Yaqob A, Danersund A, Stejskal VD, Lindvall A, Hudecek R, Lindh U., Foundation for Metal Biology, Uppsala, Sweden. yaqobamer@hotmail.com.

Source
Neuro Endocrinol Lett. 2006 Feb-Apr;27(1-2):189-97.

Abstract
OBJECTIVES: This study was done to evaluate the results and clinical relevance of an optimized lymphocyte proliferation test, MELISA®, for metal-induced inflammation in patients with CFS-like symptoms. The treatment of patients consisted of the replacement of incompatible dental materials (RID) together with supportive anti-oxidant therapy. DESIGN OF THE STUDY: 513 patients were tested by MELISA® at the beginning of the study. Out of this group, 248 patients were available for follow-up MELISA® after RID. METHODS: In MELISA®, lymphocytes are isolated from the blood and cultivated with different metal salts in tissue culture medium containing 10% inactivated human AB+ serum or autologous serum. After 5 days, the presence of metal-reactive lymphocytes are measured by isotope labelling of newly formed DNA in growing lymphoblasts and evaluated by calculating the Stimulation Index. RESULTS: Nickel was the most common sensitizer, followed by inorganic mercury, thimerosal, lead, cadmium, palladium and gold. After RID treatment, a decrease of metal-specific lymphocyte responses in patients who reacted to metals at the beginning of the study could be observed. The cultivation of lymphocytes in autologous and homologous serum did not significantly affect the results. Simultaneous, the health status of patients improved as well. CONCLUSIONS: Replacement of incompatible dental materials resulted in down-regulation of metal-induced lymphocyte sensitivity in vitro, as well as in the improvement of health status of majority of patients with unspecific CFS-like symptoms.
Metals and Autoimmunity

Title
Mechanisms of heavy metal-induced autoimmunity

Author
Rowley B, Monestier M. Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA

Source
Mol Immunol. 2005 May;42(7):833-8

Summary
Chemical exposure can trigger or accelerate the development of autoimmune manifestations. Although heavy metals are elementary chemical structures, they can have profound and complex effects on the immune system. In genetically susceptible mice or rats, administration of subtoxic doses of mercury induces both the production of highly specific autoantibodies and a polyclonal activation of the immune system. We review in this article some of the mechanisms by which heavy metal exposure can lead to autoimmunity.
Title
The beneficial effect of amalgam replacement on health in patients with autoimmunity

Author
Jarmila Prochazkova, Ivan Sterzl, Hana Kucerova, Jirina Bartova, Vera DM Stejskal

Source
Neuroendocrinology Letters 2004;25(3):211-218

Abstract
This study examines the health impact of amalgam replacement in mercury-allergic patients with autoimmunity. The suitability of MELISA® for the selection of susceptible patients and monitoring of sensitization was also examined. Amalgam fillings, which was the single restorative material in the patients’ teeth, were replaced with composites and ceramic materials. Follow-up health status and lymphocyte reactivity were assessed and evaluated half a year or later following amalgam removal. MELISA® indicated that in vitro reactivity after the replacement of dental amalgam decreased significantly to inorganic mercury, silver, organic mercury and lead. Out of 35 patients, 71% showed improvement of health. The remaining patients exhibited either unchanged health or worsening of symptoms. The highest rate of improvement was observed in patients with multiple sclerosis, the lowest rate was noted in patients with eczema.
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Title
Mercury and autoimmunity: implications for occupational and environmental health

Author
Silbergeld EK, Silva IA, Nyland JF. Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA

Source
Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):282-92

Abstract
Mercury (Hg) has long been recognized as a neurotoxicant; however, recent work in animal models has implicated Hg as an immunotoxicant. In particular, Hg has been shown to induce autoimmune disease in susceptible animals with effects including overproduction of specific autoantibodies and pathophysiologic signs of lupus-like disease. However, these effects are only observed at high doses of Hg that are above the levels to which humans would be exposed through contaminated fish consumption. While there is presently no evidence to suggest that Hg induces frank autoimmune disease in humans, a recent epidemiological study has demonstrated a link between occupational Hg exposure and lupus. In our studies, we have tested the hypothesis that Hg does not cause autoimmune disease directly, but rather that it may interact with triggering events, such as genetic predisposition, exposure to antigens, or infection, to exacerbate disease. Treatment of mice that are not susceptible to Hg-induced autoimmune disease with very low doses and short term exposures of inorganic Hg (20-200 mug/kg) exacerbates disease and accelerates mortality in the graft versus host disease model of chronic lupus in C57Bl/6 x DBA/2 mice. Furthermore, low dose Hg exposure increases the severity and prevalence of experimental autoimmune myocarditis (induced by immunization with cardiac myosin peptide in adjuvant) in A/J mice. To test our hypothesis further, we examined sera from Amazonian populations exposed to Hg through small-scale gold mining, with and without current or past malaria infection. We found significantly increased prevalence of antinuclear and antinucleolar antibodies and a positive interaction between Hg and malaria. These results suggest a new model for Hg immunotoxicity, as a co-factor in autoimmune disease, increasing the risks and severity of clinical disease in the presence of other triggering events, either genetic or acquired. PMID: 16023690
Title
Environmental chemicals and autoimmune disease: cause and effect

Author
Hess EV. Division of Immunology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0563, Cincinnati, OH 45267-0563, USA. hessev@email.uc.edu

Source
Toxicology. 2002 Dec 27;181-182:65-70

Abstract
Many important clues have been provided by the relationship of certain medications to lupus and other autoimmune syndromes. These are temporary conditions that resolve when the medication is removed. There are now over 70 such medications which have been reported related to these autoimmune conditions. Interest continues to grow in the potential for environmental substances to cause these syndromes. Among those under suspicion are hydrazines, tartrazines, hair dyes, trichloroethylene, industrial emissions and hazardous wastes. Other possible associations include silica, mercury, cadmium, gold and L canavanine. Two recognised outbreaks include ‘toxic oil syndrome’ related to contaminated rape seed oil in Spain in 1981 and exposure to a contaminated environmental substance associated with an autoimmune attack on muscle tissue in 1989. Recently, there have been proposals made for the definition and identification of environmentally associated immune disorders. The World Health Organisation (WHO) has also provided recent publications for other environmentally related problems. All these aspects will be presented and reviewed in detail.
Title
Mercury exposure in protein A immunoadsorption.

Author
Kramer L, Bauer E, Jansen M, Reiter D, Derfler K, Schaffer A., Department of Medicine IV, University of Vienna Medical School, Vienna, Austria. ludwig.kramer@akh-wien.ac.at

Source
Nephrol Dial Transplant. 2004 Feb;19(2):451-6.

Abstract
BACKGROUND: Immunoadsorption is increasingly used to treat antibody-mediated autoimmune diseases. To prevent microbial growth during storage, reusable protein A-Sepharose gel columns are primed with ethyl mercury thiosalicylate (thiomersal, 0.1% solution) and rinsed with phosphate buffer before use. In this study, we tested the hypothesis of systemic mercury exposure in protein A immunoadsorption.
METHODS: Whole blood mercury levels were measured by atomic absorption spectroscopy before and after protein A immunoadsorption (11 patients, 26 treatments), anti-IgG immunoadsorption (eight patients, 13 treatments) and LDL apheresis (DALI and Therasorb systems; nine patients, 14 treatments).
RESULTS: Patients treated with protein A immunoadsorption had significantly elevated baseline mercury levels compared with the other groups, which were not different from healthy controls. Following protein A immunoadsorption, mercury levels increased from 5.9+/-1.4 microg/l (mean+/-SEM, normal, CONCLUSION: This preliminary report suggests that protein A immunoadsorption columns primed with thiomersal during storage may cause a sustained increase of systemic mercury concentrations, which exceed current safety recommendations in a proportion of patients. Considering the potential for mercury-induced toxicity, every effort should be undertaken to reduce systemic mercury exposure, either by adding chelators to the rinsing solution or ideally by replacement of thiomersal
Metals As Possible Pathogenesis in Patients with Unclear Diagnosis (CFS, MCS)
Title
Metal exposure and common chronic diseases: a guide for the clinician.

Author
Krantz A, Dorevitch S., Section of Clinical Toxicology, John H. Stroger, Jr. Hospital of Cook County, University of Illinois at Chicago School of Public Health, USA.

Source
Dis Mon. 2004 May;50(5):220-62
Title
Mercury toxicity presenting as chronic fatigue, memory impairment and depression: diagnosis, treatment, susceptibility, and outcomes in a New Zealand general practice setting (1994-2006).

Author
Wojcik DP, Godfrey ME, Christie D, Haley BE. Northland Environmental Health Clinic, 2 Dip Rd, Kamo, Whangarei, Northland, New Zealand.

Source
Neuro Endocrinol Lett. 2006 Aug;27(4):415-23

Abstract
In a group of 465 patients diagnosed as having chronic mercury toxicity (CMT), 32.3% had severe fatigue, 88.8% had memory loss, and 27.5% had depression. A significant correlation was found between CMT and the Apo-lipoprotein E4 genotype (p=0.001). An investigation into an additional 864 consecutively seen general practice patients, resulted in 30.3% having evidence consistent with CMT, and once again a significant correlation was found with the APO-E4 genotype (p=0.001). Removal of amalgam mercury fillings when combined with appropriate treatment resulted in a significant symptom reduction (p<0.001) to levels reported by healthy subjects.
Title
The pathogenesis of chronic pain and fatigue syndromes, with special reference to fibromyalgia.

Author
Clauw DJ

Source
Med Hypotheses, 1995 May, 44:5, 369-78

Abstract
Syndromes characterized by chronic pain and fatigue have been described in the medical literature for centuries. Fibromyalgia is the term currently used to describe this symptom complex, and considerable research has been performed in the last decade to delineate the epidemiology, pathophysiology, and genesis of this entity. Although fibromyalgia is defined by its musculoskeletal features, it is clear that there are a large number of non-musculoskeletal symptoms, such that we now understand that there is considerable overlap with allied conditions such as the chronic fatigue syndrome, migraine and tension headaches, irritable bowel syndrome, and affective disorders. This article will review our current state of knowledge regarding fibromyalgia and these allied conditions, and present a unifying hypothesis that describes both the pathophysiology of symptoms and the genesis of these disorders.
Title
Chemical toxicity and reactive oxygen species.

Author
Parke DV, Sapota A. School of Biological Sciences, University of Surrey, Guilford, UK.

Source
Int J Occup Med Environ Health. 1996;9(4):331-40.

Abstract
Reactive oxygen species (ROS) are cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. ROS are produced in the metabolism of drugs and industrial chemicals by (i) one-electron peroxidase oxidations to form cation radicals, (ii) cytochrome P450 metabolism to free radical products, (iii) stabilisation of the ROS-generator, CYP2E1, and (iv) futile cycling of other cytochromes P450. ROS production initiates inflammation which unless quenched may result in chronic inflammatory disease states, e.g. hepatitis, nephritis, myositis, scleroderma, lupus erythematosus, multiple system organ failure. Quenching of ROS is affected by the redox buffer, glutathione (GSH), and the antioxidants, ascorbic acid, tocopherols, retinoids, in conjunction with the redox enzymes, GSH reductase, GSH peroxidase, catalase and superoxide dismutase. Many industrial workers with symptoms of systemic inflammation, resulting from exposure to toxic chemicals, are diagnosed as having rheumatoid arthritis, virus infections, or other microbial lesions, largely because many physicians are unaware that exposure to certain chemicals can initiate inflammatory disease states.
Title
Sleep, neuroimmune and neuroendocrine functions in fibromyalgia and chronic fatigue syndrome.

Author
Moldofsky H

Source
Adv Neuroimmunol, 1995, 5:1, 39-56

Abstract
The justification for disordered chronobiology for fibromyalgia and chronic fatigue syndrome (CFS) is based on the following evidence: The studies on disordered sleep physiology and the symptoms of fibromyalgia and CFS; the experimental studies that draw a link between interleukin-1 (IL-1), immune-neuroendocrine-thermal systems and the sleep-wake cycle; studies and preliminary data of the inter-relationships of sleep-wakefulness, IL-1, and aspects of peripheral immune and neuroendocrine functions in healthy men and in women during differing phases of the menstrual cycle; and the observations of alterations in the immune-neuroendocrine functions of patients with fibromyalgia and CFS (Moldofsky, 1993b, d). Time series analyses of measures of the circadian pattern of the sleep-wake behavioural system, immune, neuroendocrine and temperature functions in patients with fibromyalgia and CFS should determine whether alterations of aspects of the neuro-immune-endocrine systems that accompany disordered sleep physiology result in nonrestorative sleep, pain, fatigue, cognitive and mood symptoms in patients with fibromyalgia and CFS.
Title
Missed diagnoses and misdiagnoses of environmental toxicant exposure. The psychiatry of toxic exposure and multiple chemical sensitivity

Author
Hartman DE. Rush Presbyterian St. Luke’s Hospital, Chicago, Illinois, USA

Source
Psychiatr Clin North Am. 1998 Sep;21(3):659-70, vii

Abstract
Toxins such as carbon monoxide, lead, and mercury that present occasionally with primarily psychiatric symptoms can pose some of the most difficult diagnoses. This article reviews the clues that can allow the diagnostician to identify the role of one of these substances. Equally important, the article discusses the contentious issues that surround the phenomen known as multiple chemical sensitivity. Viewed primarily as a functional illness, often with legal overtones, this putative disorder is critically reviewed to see if it meets the same demanding standard of validity that is found in the psychiatric symptoms associated with other toxic disorders. Although questioning the strict medical origin of medical chemical sensitivity, the article outlines some treatment hints that may helpful in the management of this difficult group of patients.
Title
Metal-specific lymphocytes: biomarkers of sensitivity in man

Author
Vera Stejskal, PhD., et al.

Source
Neuroendocrinology Letters 1999; 20:289–298

Abstract
The biggest-ever MELISA® experiment was performed in more than 3,000 patients suffering from various symptoms resembling chronic fatigue, often in combination with intolerance to metal. Nickel was found to be the most common sensitizer followed by inorganic mercury, gold, cadmium and palladium. Replacement of amalgam and other dental metals resulted in health improvement for a majority of patients. Follow-up MELISA® tests show that, for these patients, the severity of their allergy had also subsidided.

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Title
Nickel Allergy Is Found in a Majority of Women with Chronic Fatigue Syndrome and Muscle Pain– And May Be Triggered by Cigarette Smoke and Dietary Nickel Intake

Author
Björn Regland, MD Olof Zachrisson, MD Vera Stejskal, PhD Carl-Gerhard Gottfries, MD.

Source
Journal of Chronic Fatigue Syndrome, Vol. 8(1) 2001

Abstract
Two hundred and four women with chronic fatigue and muscle pain, with no signs of autoimmune disorder, received immune stimulation injections with a Staphylococcus vaccine at monthly intervals over 6 months. Good response was defined as a decrease by at least 50% of the total score on an observer’s rating scale. Nickel allergy was evaluated as probable if the patient had a positive history of skin hypersensitivity from cutaneous exposure to metal objects. The patient;s smoking habits were recorded. Fifty-two percent of the patients had a positive history of nickel contact dermatitis. There were significantly more good responders among the non-allergic non-smokers (39%) than among the allergic smokers (6%). We also present case reports on nickel-allergic patients who apparently improved after cessation of cigarette smoking and reducing their dietary nickel intake. Our observations indicate that exposure to nickel, by dietary intake or inhalation of cigarette smoke, may trigger systemic nickel allergy and contribute to syndromes of chronic fatigue and muscle pain.

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Metal Effects on Clinical Chemistry Findings
Title
Metal Exposure from Amalgam Alters the Distribution of Trace Elements in Blood Cells and Plasma

Author
Ulf Lindh, Björn Carlmark, Sten-Olof Grönquist and Anders Lindvall

Source
Clin Chem Lab Med 2001;39 (21:134-142)

Summary
Twenty-seven consecutive patients with health prob-lems associated with dental amalgam were recruited. In spite of thorough medical examinations, there were no diagnoses available. The patient group was dominated by women. A healthy age- and sex-matched control group with dental amalgams with-out symptoms was also recruited. Metal level moni-toring in plasma and nuclear microscopy of isolated individual blood cells were carried out. Significant in-creases of copper, iron, zinc and strontium were found in patient plasma. There was no significant difference in plasma selenium between the groups. Mercury was significantly increased in patient plasma, although there was overlap between the groups. In erythro-cytes a significant increase in calcium and a signifi-cant decrease in magnesium, copper, manganese and zinc were found. Calcium, magnesium, manganese and copper increased in patient neutrophil granulo-cytes. A significant decrease was found for zinc. A conspicuous finding was the presence of measurable mercury in a few of the cells from the patient but not in the control group. Thus, nuclear microscopy of iso-lated individual blood cells might provide a better di-agnostic tool for metal exposure than blood plasma measurements.
Title
Mitochondrial calcium release as induced by Hg2+.

Author
Chávez E; Holguín JA

Source
J Biol Chem, 1988 Mar 15, 263:8, 3582-7

Abstract
Addition of Hg2+ to mitochondria of rat kidney induces efflux of intramitochondrial Ca2+. This reaction is accompanied by a diminution of the NAD(P)H/NAD(P) ratio and a decrease of the internal negative membrane potential. These effects were enhanced by dithiothreitol. The binding of mercuric ions to mitochondria saturates with a maximal binding of 9 nmol min-1 mg-1. The stoichiometry between Ca2+ released and Hg2+ bound showed that in the presence of dithiothreitol, the binding of approximately 1 nmol of Hg2+/mg of protein suffices to induce the release of the accumulated Ca2+. In the electrophoretic analysis of Hg-labeled mitochondrial proteins it was found that 203Hg2+ bound mainly to proteins that have molecular masses of 20 and 30 kDa. It is proposed that Hg2+-induced Ca2+ release is due to modification of–SH groups of these latter proteins.
Metals and Disturbance of HPA-axis

Title
Regulation of the HPA axis by cytokines.

yAuthor
Turnbull AV; Rivier C

Source
Brain Behav Immun, 1995 Dec, 9:4, 253-75

Abstract
Cytokines are a group of polypeptide mediators, classically associated with the regulation of immunity and inflammation. However, these peptides regulate not only local immune/inflammatory responses, but also elicit many CNS-mediated responses which accompany such immune/inflammatory reactions. This article reviews the evidence that interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNFalpha) produce hypothalamo-pituitary-adrenal (HPA) axis activation in response to various threats to homeostasis. To aid such an examination, and to gain insights into the potential mechanisms by which these cytokines influence the HPA axis, experimental findings are discussed within a framework of criteria. If a particular cytokine plays a significant role in the regulation of the HPA axis in response to a particular pathophysiology, then necessarily: (1) receptors for that cytokine should be present within tissues associated with the HPA axis; (2) administration of that cytokine should elicit HPA activation; (3) the HPA axis should be exposed to that cytokine; and (4) inhibition of the action of that cytokine should prevent HPA activation. The evidence discussed indicates that some, if not all, of these criteria are met for each of IL-1, IL-6, and TNFalpha. However, the extensive interactions between different cytokines, the broad spectrum of pathophysiologies associated with increased cytokine production (including inflammatory and non-inflammatory stresses), and the number of tissues/cells capable of either synthesizing or responding to cytokines, suggest that multiple mechanisms mediate the influence of cytokines on the HPA axis.
Metals and Allergy

Title
Widespread dissemination of metal debris from implants

Author
Case CP; Langkamer VG; James C; Palmer MR; Kemp AJ; Heap PF; Solomon L

Source
J Bone Joint Surg Br, 76(5):701-12 1994 Sep

Summary
In a post-mortem study, we compared subjects with metal implants with and without visible wear with an age-matched control group to determine the extent and effects of dissemination of wear debris. In subjects with stainless-steel and cobalt-chrome prostheses metal was found in local and distant lymph nodes, bone marrow, liver and spleen. The levels were highest in subjects with loose, worn joint prostheses and the main source of the debris was the matt coating. Metal levels were also raised in subjects with implants without visible wear and, to a less extent, in those with dynamic hip screws. Necrosis of lymph nodes was seen in those cases with the most wear, and potential damage to more distant organs such as the bone marrow, liver and spleen in the long term cannot be discounted. The consequences for the immune system and the role of metal dissemination in the possible induction of neoplasia are discussed.
Title
Exercise-induced anaphylaxis: improvement after removal of amalgam in dental caries.

Author
T Katasunuma MD, Y Iikura MD, T Negekura MD, H Saitoh MD, K Akimoto MD, A Akasawa MD and S Kindaichi MD

Source
Annals of Allergy, 1990, 64:472-475

Abstract
We present a case of exercise-induced anaphylaxis with improvement following the removal of dental amalgam. Although her symptoms were unresponsive to various kinds of therapy until removal of the amalgam, her symptoms related to exercise improved remarkably after the removal. The increase in plasma histamine levels for exercise provocation test also improved. This suggests that sensitivity to metals might cause exercise-induced asthma in some patients. Exercise-induced anaphylaxis (EIA) is a unique syndrome consisting of premonitory symptoms of generalized body warmth, pruritis and erythema that progresses on continued exertion to confluent urticaria, angioedema, gastrointestinal symptoms, headache, and sometimes unconsciousness. In many cases, an exercise-related elevation in serum or plasma histamine is recognized. This syndrome is known to be a distinct form of physical allergy. The severity and frequency of attacks in severe EIA patients is very difficult to control. In this paper, we describe an EIA patient in whom drug and food elimination therapies were not effective. After the removal of dental amalgam, the symptoms improved remarkably and the elevation in plasma histamine following exercise was remarkably reduced.
Ortopedic Metal Implants

Title
Implant-related inflammatory arthritis

Author
Thomas Dörner, Judith Haas, Christoph Loddenkemper, Volker von Baehr and Abdulgabar Salama

Source
Nature Clinical Practice Rheumatology (2006) 2, 53-56

Abstract
Background A 54-year-old woman presented with myalgia and arthralgia predominantly in the knees and small joints of the hands and feet with morning stiffness lasting for at least 2 h. The patient had received a wrought titanium 6-aluminium 4-vanadium alloy C cage implant 1.5 years previously, following a severe disc prolapse. No signs of rheumatic disease were evident before the C cage was implanted.
Investigations Physical examination, radiography, skin and muscle biopsies, serology tests, white blood cell count, HLA genotyping, tumor necrosis factor release assay, skin patch test, lymphocyte transformation test.
Diagnosis Implant-related inflammatory arthritis.
Management Combination therapy with corticosteroids, disease-modifying antirheumatic drugs and nonsteroidal anti-inflammatory drugs, and replacement of the titanium cage with a polyetherketone cage.
Title
Allergy to metals as a cause of orthopedic implant failure.

Author
Krecisz B, Kiec-Swierczynska M, Bakowicz-Mitura K.

Source
Int J Occup Med Environ Health. 2006;19(3):178-80

Abstract
BACKGROUND: A constantly growing social demand for orthopedic implants has been observed in Poland. It is estimated that about 5% of patients experience post-operation complications. It is suspected that in this group of patients an allergic reaction contributes to rejection of metal implants.
MATERIALS AND METHODS: The aim of our study was to assess contact allergy to metals in 14 people (9 women and 5 men) suffering from poor implant tolerance. In some of them, recurrent skin eruptions, generalized or nearby implants, have occurred and in 3 patients skin fistula was observed. These complaints appeared one year after operation. The patients underwent patch tests with allergens from the Chemotechnique Diagnostics (Malmo, Sweden), including nickel, chromium, cobalt, palladium, copper, aluminum. In addition, allergens, such as titanium, vanadium and molybdenum prepared by chemical laboratory in the Nofer Institute of Occupational Medicine, Lodiz, Poland, were introduced.
RESULTS AND CONCLUSIONS: Of the 14 patients, 8 persons (5 women and 3 men) were sensitized to at least one metal, mostly to nickel (7/14) and chromium (6/14). Of the 8 sensitized patients, 3 were reoperated. Owing to the exchange of prosthesis the complaints subsided, including healing up skin fibulas. These facts weight in favor of the primeval sensitizing effect of metal prosthesis and the relation between allergy and clinical symptoms of poor tolerance to orthopedic implants.
Title
Lymphocyte responses in patients with total hip arthroplasty

Author
Hallab NJ, Anderson S, Stafford T, Glant T, Jacobs JJ. Department of Orthopedic Surgery, Rush University Medical Center, 1653 W. Congress Parkway, Chicago IL 60612, USA. nhallab@rush.edu

Source
J Orthop Res. 2005 Mar;23(2):384-91

Abstract
How lymphocyte-mediated metal sensitivity affects orthopaedic implant performance remains poorly understood. Do patients with implants exhibit elevated lymphocyte reactivity to metals and is this reactivity more generalized or more implant-alloy specific? We investigated these questions by measuring lymphocyte responses to implant metals (Cr(+3), Co(+2), Ni(+2) at 0.1mM, and Ti(+4) at 0.001 mM) in six subject groups: Group 1a=young controls, Group 1b=age matched controls, Group 2a=subjects with osteoarthritis (OA) and no history of metal sensitivity, Group 2b=OA subjects with history of metal sensitivity, Group 3a=total hip arthroplasty (THA) subjects with no to mild radiographic osteolysis, and Group 3b=THA subjects with moderate osteolysis. Lymphocyte proliferation, using Lymphocyte Transformation Testing (LTT), and cytokine release provided quantitative reactivity measurement, where a stimulation index of >2 indicated metal sensitivity. OA subjects with a history of metal sensitivity (Group 2b) were more metal reactive to Ni than any other group, as expected (66% incidence and Stimulation Index >20). However, THA subjects (Groups 3a and b) were >3 fold more reactive to Cr (p<0.04), than were controls (Groups 1a & b) or OA subjects (Groups 2a & b). THA subjects with moderate vs mild osteolysis (Group 3b vs 3a) were more reactive to Co (43% vs 0% incidence). Only osteolytic THA subjects demonstrated increased cytokine responses with >two-fold (p<0.05) increases in soluble interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) levels in response to Cr challenge. This elevated incidence and averaged level of lymphocyte reactivity supports a metal-specific adaptive immune response and suggests involvement in the pathogenesis of poor implant performance, e.g. aseptic osteolysis.
Title
Screening for symptomatic metal sensitivity: a prospective study of 92 patients undergoing total knee arthroplasty

Author
Niki Y, Matsumoto H, Otani T, Yatabe T, Kondo M, Yoshimine F, Toyama Y. Department of Orthopaedic Surgery, Keio University, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. y.niki@lib.bekkoame.ne.jp

Source
Biomaterials. 2005 Mar;26(9):1019-26

Abstract
Metal sensitivity (MS) reactions to implant metals represent a rare but well-documented complication following total joint arthroplasty (TJA). Although 20-25% of post-TJA patients develop MS, only a few highly susceptible patients (< 1%) exhibit symptoms. Whether surgeons should perform screening for MS is currently a matter of debate. The present study investigated the clinical importance of screening for patients predisposed to symptomatic MS, and the specific metals causing symptomatic MS following total knee arthroplasty (TKA). Between 2000 and 2002, a total of 108 primary TKAs were performed on 92 patients. Preoperatively, all patients underwent modified lymphocyte stimulation test (mLST) to Ni, Co, Cr, and Fe. Of the 92 patients, 24 (26%) displayed positive preoperative responses to at least one metal. Five patients displayed implant metal-related eczema and were all mLST-positive preoperatively, suggesting that screening for symptomatic MS is clinically useful. Two of these underwent revision TKA and thereafter, eczema healed and mLST results changed from positive to negative. All mLST-positive patients were divided into three groups: Group I, patients with eczema; Group II, patients with clear history of MS; and Group III, patients neither eczema nor history of MS. When the type of sensitive metals were compared among the three groups, a significant association between presence of Cr-sensitivity and development of eczema (P < 0.05) was identified. No significant association was observed between other metals and development of eczema or history of MS. This indicates that Cr is a potential candidate metal for causing eczema in our TKA series, and Cr-sensitivity may offer a potential predictor for symptomatic MS. The present study indicates that the surgeons should undertake routine preoperative screening for MS, particularly to Cr.
Title
Lymphocyte transformation testing for quantifying metal-implant-related hypersensitivity responses.

Author
Hallab NJ., Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA. nhallab@rush.edu

Source
Dermatitis. 2004 Jun;15(2):82-90.

Abstract
Hypersensitivity to metallic implants has been documented in case reports and cohort studies. However, this phenomenon remains unpredictable and poorly understood. There is continuing concern about the extrapolation of dermal patch testing to the periimplant environment. The utility of lymphocyte transformation testing (LTT) for predicting implant-related sensitivity in orthopedic patients was evaluated by contrasting LTT and patch-testing protocols and examining original cohort LTT data of subjects with and without implants. LTT of peripheral blood lymphocytes was performed, using four groups: (1) age-matched controls; (2) patients with osteoarthritis (preimplant), with and without dermal metal sensitivity; and (3) patients with total hip arthroplasty. A stimulation index of greater than 2 ( p < .05) indicated metal sensitivity. Patients with osteoarthritis and a history of metal sensitivity were more reactive to nickel than were those of any other group, as expected (ie, 66% incidence and average stimulation index of > 20). However, subjects with implants (group 3) were threefold more reactive to chromium (p < .04) than were controls (group 1) or subjects with osteoarthritis (group 2). Quantifiable lymphocyte reactivity as exemplified by increased incidence and average reactivity levels was metal implant specific (characteristic of adaptive immune responses) and suggests that LTT may be useful in the determination of implant-specific sensitivity. Advantages of LTT include quantitative results and the facilitation of multichallenge agent and dose testing. Thus, LTT (provided by laboratories fully disclosing testing methods) may be an additional tool in the armamentarium of physicians.
Title
Cell-mediated Allergy to a Cerebral Aneurysm Clip: Case Report

Author
Ross, IB. MD; Warrington, R J. MD, PhD; Halliday WC. MD

Source
Sections of Neurosurgery (IBR), Clinical Immunology and Allergy (RJW), and Neuropathology (WCH), University of Manitoba and Health Sciences Center, Winnipeg, Manitoba, Canada

Abstract
BACKGROUND AND IMPORTANCE: Titanium aneurysm clips have superior imaging characteristics and have been supplanting their stainless steel counterparts. We report the case of a 36-year-old woman with a histologically demonstrated cell-mediated reaction to a cobalt alloy aneurysm clip.

CLINICAL PRESENTATION: The patient underwent a craniotomy and clip placement for a ruptured cerebral aneurysm. Both the aneurysm clip and the wires used to fix the craniotomy were made of stainless steel (cobalt and nickel) alloys. Postoperatively, the patient was plagued by intense pruritus.

INTERVENTION: Skin patch testing revealed a severe reaction to nickel and cobalt. Surgical removal of the aneurysm clip and wires resulted in the disappearance of the patient’s symptoms. A histological analysis of the tissue adjacent to the clip and wires was consistent with Type IV delayed type hypersensitivity.

CONCLUSION: Stainless steel surgical implants in the head can cause diffuse, severe pruritus in susceptible individuals. Although the role of the aneurysm clip, as opposed to the more superficial wires, in the genesis of the patient’s symptoms is not certain, this case demonstrates that a cobalt alloy aneurysm clip can activate T cells and cause an immunological reaction in the central nervous system.
Title
Granulomatous reaction to titanium alloy: an unusual reaction to ear piercing.

Author
High WA, Ayers RA, Adams JR, Chang A, Fitzpatrick JE. Department of Dermatology, University of Colorado Health Sciences Center, Denver 80045-0510, USA. wahigh50@hotmail.com

Source
J Am Acad Dermatol. 2006 Oct;55(4):716-20.

Abstract
A 68-year-old man presented with 4 firm, flesh-colored, and slightly erythematous nodules located on the superior pole and lobule of each ear. Although reluctant to provide details, it was discovered he had pierced his ears approximately 10 years earlier, and the nodules developed at the sites of the piercings. Keloids were suggested clinically and the lesions were excised. Microscopic examination demonstrated epithelialized tracts surrounded by a granulomatous infiltrate of macrophages, lymphocytes, and plasma cells. Closer examination revealed minute brown-black particles within macrophages. Dark-field microscopy confirmed the metallic nature of the particles. Environmental scanning electron microscopy with energy dispersive spectroscopy revealed the particles to be composed of titanium, aluminum, and vanadium. It would appear that in rare circumstances titanium alloy used in body piercing may engender a granulomatous dermatitis. The rarity of such a response to titanium alloy is discussed and the literature appraised.
Title
Hypersensitivity to titanium osteosynthesis with impaired fracture healing, eczema, and T-cell hyperresponsiveness in vitro: case report and review of the literature.

Author
Thomas P, Bandl WD, Maier S, Summer B, Przybilla B. Klinik und Poliklinik fur Dermatologie und Allergologie der Ludwig-Maximilians-Universitat, Munchen, Germany. peter.thomas@med.uni-muenchen.de

Source
Contact Dermatitis. 2006 Oct;55(4):199-202.

Abstract
There are very few reports on hypersensitivity reactions in association with titanium-based materials so that the existence of allergy to titanium is still put in question. We report on a patient in whom impaired fracture healing and eczema localized to the perioperative area developed upon titanium-based osteosynthesis. Patch testing gave no reactions to titanium nor to nickel, chromium, or cobalt. However, in the lymphocyte transformation test, the patient’s lymphocytes showed markedly enhanced proliferation in vitro to titanium. After removal of the titanium material, fracture healing was achieved and the eczema cleared. Parallel to this, in vitro hyperreactivity to titanium disappeared. Although contact allergic reactions to titanium have been very rarely reported, these findings support a diagnosis of titanium allergy in our patient.
Title
Metallosis after contemporary metal-on-metal total hip arthroplasty. Five to nine-year follow-up.

Author
Korovessis P, Petsinis G, Repanti M, Repantis T., Orthopaedic Department, General Hospital Agios Andreas, 65-67 Haralabi Street, 26224 Patras, Greece. korovess@otenet.gr

Source
J Bone Joint Surg Am. 2006 Jun;88(6):1183-91.

Abstract
BACKGROUND: Authors of recent studies have reported early periprosthetic osteolysis in patients who have been treated with a contemporary metal-on-metal total hip arthroplasty and have suggested that metal hypersensitivity associated with an immunologic response to metal may be of etiologic importance. We evaluated the results and histologic findings in patients who had undergone revision of a failed contemporary metal-on-metal total hip arthroplasty. METHODS: Two hundred and seventeen total hip arthroplasties (SL-Plus stem and Bicon-Plus cup) with a Sikomet metal-on-metal articulation were implanted in 194 consecutive patients, and the results were retrospectively reviewed at a mean of seventy-seven months postoperatively. Clinical follow-up with the Harris hip score and plain radiographic evaluation were performed. Periprosthetic tissues from fourteen hips that had undergone revision arthroplasty were subjected to histologic analysis. RESULTS: The mean Harris hip score improved from 45 points preoperatively to 88 points at the final evaluation. Fourteen hips (6.5%) were revised: nine because of aseptic loosening, two because of technical failure, and three because of septic failure. Histologic examination of the retrieved periprosthetic tissues from the eleven patients who had undergone revision because of aseptic loosening or technical failure showed metallosis and extensive lymphocytic and plasma-cell infiltration around the metal debris. With removal of the component because of aseptic loosening as the end point, survivorship was 93% for the stem and 98% for the cup. CONCLUSIONS: Our findings are in agreement with those in recent publications and support the possibility that periprosthetic osteolysis and aseptic loosening in hips with a metal-on-metal articulation are possibly associated with hypersensitivity to metal debris. Prospective, comparative, randomized long-term studies are necessary to determine the cause(s) of loosening of prostheses with this particular articulation.
Title
[Allergic potential of titanium implants]

Author
Schuh A, Thomas P, Kachler W, Goske J, Wagner L, Holzwarth U, Forst R., Orthopadische Klinik Rummelsberg, Schwarzenbruck. Schuh-Alexander@t-online.de

Source
Orthopade. 2005 Apr;34(4):327-8, 330-3.

Abstract
AIM: The aim of this investigation is to evaluate the allergic potential of titanium and titanium alloys for surgical implant applications. MATERIALS AND METHODS: Discs cut from rods supplied by five different titanium suppliers in several diameters were investigated. The samples were cp-Titanium as well as Ti6Al4 V and Ti6Al7Nb, 6 mm thick with a diameter of between 6 and 60 mm. The material was checked by optical spectral analysis. RESULTS: In all samples except iodidtitanium, a Nickel content of 0.012-0,034 wt% could be detected. CONCLUSION: The low nickel content in the implant material results from the production process. The nickel atoms are in solid solution in the titanium lattice. Nickel allergic patients may develop hypersensitivity reactions even due to this low nickel content. Hence, this reaction may be falsely attributed to the titanium material itself. Measurements of ion concentration in the body are helpful for quantifying the maximum content of nickel in titanium materials for surgical implant applications. In addition, technical questions related to the production of nickel free titanium materials for allergic patients have to be solved.
Title
Loosening and Osteolysis Associated with Metal-on-Metal Bearings: A Local Effect of Metal Hypersensitivity?
A case of severe metal hypersensitivity post tibial plating.

Author
Lachlan Host B.

Source
The Internet Journal of Orthopedic Surgery. 2009 Volume 11 Number 2

Abstract
Introduction: Metal hypersensitivity is a well-recognised phenomenon post implantation of orthopaedic devices, though rarely tested for or considered prior to implantation ofsaid devices. Our report outlines a case of severe metal hypersensitivity to stainless steel, and raises the issue of a need for pre-operative screening of patients for metal sensitivity prior to implantation. Studies would suggest a baseline incidence of nickel sensitivity in the general population to be in the order of 10-15%1,2, with the rates doubling in those with chronic nickel exposure. The role such hypersensitivity plays in hardware failure, pain, and cutaneous reactions remains unproven in clinical studies, though many cases, such as this one, suggest a direct causal relationship.
Immune Response to Implants

Title
Possible Health Effects of Amalgam and Other Dental Materials

Author
Steven I Rabin

Source
eMedicine Orthopedics 2009

Abstract
Metal hypersensitivity is commonly reported in the literature and can include hypersensitivity related to pacemakers, dental implants, and orthopedic hardware. The development of metal sensitivity after implantation of orthopedic hardware is common. The clinical significance of metal sensitization remains a question. Nonetheless, the orthopedic surgeon must be aware of the potential problem, and when other more common causes of implant failure have been excluded, the possibility of allergic reaction to the metal must be considered, evaluated, and treated.
Exposure to titanium

Title
Implant failure due to Titanium hypersensitivity/allergy? – Report of a case

Author
du Preez LA., Bütow KW, Swart TJP

Source
SADJ February 2007;62(1):22-25

Abstract
Six titanium implants were placed in the mandible between the left and right mental foramen of a 49-year old female patient. The implants were all constructed of the same grade IV titanium. Three types of implants were used, namely LIBB compression implant, cylindrical implant and Brånemarklike implant. These three types of implants were placed as part of a research project, which received approval from the ethics committee. The patient developed a severe reaction to all the implant units, with both clinical and radiological features of complication. The localised tissue reaction was severe enough to warrant removal of all the implants. The surrounding soft tissue was submitted for histological analysis, which revealed a chronic inflammatory response with concomitant fibrosis around all the implants as well as foreign body giant cell reaction around two implants. Following implant removal the patient recuperated well and the soft and hard tissue healed satisfactorily. Following is a case report of a possible true titanium allergy in a clinical setting.
Title
Suspected association of an allergic reaction with titanium dental implants: a clinical report

Author
Egusa H, Ko N, Shimazu T, Yatani H.

Source
J Prosthet Dent. 2008 Nov;100(5):344-7

Abstract
Recent reports have questioned whether metal sensitivity may occur after exposure to titanium. This clinical report demonstrates the emergence of facial eczema in association with a titanium dental implant placed for a mandibular overdenture supported by 2 implants. Complete remission was achieved by the removal of the titanium material. This clinical report raises the possibility that in rare circumstances, for some patients, the use of titanium dental implants may induce an allergic reaction.
Title
Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse.

Author
Shimizu M, Tainaka H, Oba T, Mizuo K, Umezawa M, Takeda K..

Source
Part Fibre Toxicol. 2009 Jul 29;6(1):20

Abstract
BACKGROUND: Nanotechnology is developing rapidly throughout the world and the production of novel man-made nanoparticles is increasing, it is therefore of concern that nanomaterials have the potential to affect human health. The purpose of this study was to investigate the effects of maternal exposure to nano-sized anatase titanium dioxide (TiO2) on gene expression in the brain during the developmental period using cDNA microarray analysis combined with Gene Ontology (GO) and Medical Subject Headings (MeSH) terms information. RESULTS: Analysis of gene expression using GO terms indicated that expression levels of genes associated with apoptosis were altered in the brain of newborn pups, and those associated with brain development were altered in early age. The genes associated with response to oxidative stress were changed in the brains of 2 and 3 weeks old mice. Changes of the expression of genes associated with neurotransmitters and psychiatric diseases were found using MeSH terms. CONCLUSIONS: Maternal exposure of mice to TiO2 nanoparticles may affect the expression of genes related to the development and function of the central nervous system.
Title
Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells.

Author
Gurr JR, Wang AS, Chen CH, Jan KY.

Source
Toxicology. 2005 Sep 15;213(1-2):66-73.

Abstract
Ultrafine titanium dioxide (TiO(2)) particles have been shown to exhibit strong cytotoxicity when exposed to UVA radiation, but are regarded as a biocompatible material in the absence of photoactivation. In contrast to this concept, the present results indicate that anatase-sized (10 and 20 nm) TiO(2) particles in the absence of photoactivation induced oxidative DNA damage, lipid peroxidation, and micronuclei formation, and increased hydrogen peroxide and nitric oxide production in BEAS-2B cells, a human bronchial epithelial cell line. However, the treatment with anatase-sized (200 and >200 nm) particles did not induce oxidative stress in the absence of light irradiation; it seems that the smaller the particle, the easier it is for the particle to induce oxidative damage. The photocatalytic activity of the anatase form of TiO(2) was reported to be higher than that of the rutile form. In contrast to this notion, the present results indicate that rutile-sized 200 nm particles induced hydrogen peroxide and oxidative DNA damage in the absence of light but the anatase-sized 200nm particles did not. In total darkness, a slightly higher level of oxidative DNA damage was also detected with treatment using an anatase-rutile mixture than with treatment using either the anatase or rutile forms alone. These results suggest that intratracheal instillation of ultrafine TiO(2) particles may cause an inflammatory response.
Title
Titanium allergy in dental implant patients: a clinical study on 1500 consecutive patients

Author
Sicilia A, Cuesta S, Coma G, Arregui I, Guisasola C, Ruiz E, Maestro A.

Source
Clin Oral Implants Res. 2008 Aug;19(8):823-35.

Abstract
BACKGROUND: In dentistry, allergic reactions to Ti implants have not been studied, nor considered by professionals. Placing permanent metal dental implants in allergic patients can provoke type IV or I reactions. Several symptoms have been described, from skin rashes and implant failure, to non-specific immune suppression. OBJECTIVE: Our objective was to evaluate the presence of titanium allergy by the anamnesis and examination of patients, together with the selective use of cutaneous and epicutaneous testing, in patients treated with or intending to receive dental implants of such material. MATERIAL AND METHODS: Thirty-five subjects out of 1500 implant patients treated and/or examined (2002-2004) were selected for Ti allergy analysis. Sixteen presented allergic symptoms after implant placement or unexplained implant failures [allergy compatible response group (ACRG)], while 19 had a history of other allergies, or were heavily Ti exposed during implant surgeries or had explained implant failures [predisposing factors group (PFG)]. Thirty-five controls were randomly selected (CG) in the Allergy Centre. Cutaneous and epicutaneous tests were carried out. RESULTS: Nine out of the 1500 patients displayed positive (+) reactions to Ti allergy tests (0.6%): eight in the ACRG (50%), one in the PFG (5.3%)(P=0.009) and zero in the control group. Five positives were unexplained implant failures (five out of eight). CONCLUSIONS: Ti allergy can be detected in dental implant patients, even though its estimated prevalence is low (0.6%). A significantly higher risk of positive allergic reaction was found in patients showing post-op allergy compatible response (ACRG), in which cases allergy tests could be recommended
Title
Titanium particles stimulate bone resorption by inducing differentiation of murine osteoclasts.

Author
Bi Y, Van De Motter RR, Ragab AA, Goldberg VM, Anderson JM, Greenfield EM.

Source
J Bone Joint Surg Am. 2001 Apr;83-A(4):501-8.

Abstract
BACKGROUND: Loosening of orthopaedic implants is mediated by cytokines that elicit bone resorption and are produced in response to phagocytosis of implant-derived wear particles. This accelerated bone resorption could be due to increased osteoclastic activity, survival, or differentiation. Although a number of in vitro studies have shown that wear particles increase osteoclastic activity, the increase was less than twofold in all cases. The objective of the current study was to test the hypothesis that wear particles stimulate bone resorption by inducing osteoclast differentiation. METHODS: Conditioned media were prepared from murine marrow cells or human peripheral blood monocytes incubated in the presence or absence of titanium particles. The effects of conditioned media on osteoclast differentiation were examined with use of a recently developed assay in which osteoclast precursors are co-cultured with mesenchymal support cells. RESULTS: The present study showed that titanium particles induced both murine marrow cells and human peripheral blood monocytes to produce factors that stimulated osteoclast differentiation. The mean increase in osteoclast differentiation was 29.3+/-9.4-fold. The stimulation of osteoclast differentiation led to a parallel increase in bone resorption. The amount of stimulation was regulated in a dose-dependent manner by the concentration of both titanium particles and conditioned media. The stimulation of osteoclast differentiation required interactions between the cells and the particles themselves and, therefore, was not due to metal ions, soluble contaminants released from the particles, or submicrometer particles. In contrast, conditioned media from control cells incubated in the absence of titanium particles had no detectable effect on any of the examined parameters. CONCLUSIONS: The present study showed that titanium particles stimulate in vitro bone resorption primarily by inducing osteoclast differentiation. In contrast, the titanium particles had only small effects on osteoclast activity or survival.
Title
In vitro corrosion of titanium.

Author
Strietzel R, Hösch A, Kalbfleisch H, Buch D.

Source
Biomaterials. 1998 Aug;19(16):1495-9.

Abstract
Titanium is used in dentistry for implants and frame work because of its sufficient chemical, physical and biological properties. The corrosion behaviour is from high interest to value biocompatibility. A static immersion test was undertaken with a titanium test specimen (30 mm x 10 mm x 1 mm, immersion time = 4 x 1 w, n = 3 for each series). The following parameters were investigated: specimen preparation, grinding, pH-value, different casting systems, comparison with CAD/CAM, influence of: chloride, thiocyanate, fluoride, lactate, citrate, oxalate, acetate. Atomic absorption spectroscopy was used to analyse the solutions weekly. The course of corrosion was investigated photometrically. Titanium reveals ion releases [(0.01-0.1) microg/(cm2 x d)] in the magnitude of gold alloys. There is little influence of grinding and casting systems in comparison with organic acids or pH value. The ion release increases extreme (up to 500 microg/(cm2 x d)) in the presence of fluoride. Low pH values accelerate this effect even more. Clinically, no corrosion effects were observed. Nevertheless it is recommended that it is best to avoid the presence of fluoride or to reduce contact time. In prophylactic fluoridation of teeth, a varnish should be used.