Biology of amalgam fillings

DENT 5301Introduction to Oral Biology© Dr. Joel Rudney

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The amalgam controversy

What is amalgam? Alloy of Hg (50%), silver (35%), tin (13%), copper, zinc Historically the most widely used dental material Desirable properties of malleability and durability Still a popular choice for restoring caries Gold; composite resins are other options

The question of mercury Hg (and other metals) are toxic in high doses Amalgam releases very low levels of Hg vapor Is this exposure to Hg sufficient to cause adverse effects?

The opposing sides The ADA/NIH position

Amalgam has been used for over a century Minimal evidence of harmful effects with proper use It is inappropriate to:

Encourage patients to have amalgams removed (costly)Promote amalgam removal as a cure for any diseaseRemove healthy tooth structure just to remove amalgam

The anti-amalgam position Prevalent among the alternative medicine community Claim any exposure to Hg is toxic in susceptible people Claim amalgams are responsible for many diseases Claim amalgam removal/Hg chelation can cure diseases e.g.

Chronic fatigue, MS, Alzheimer's, auto-immune diseases

The toxicology of mercury (26) Cases of overt Hg toxicity (CNS effects) Environmental releases (pesticides, pollution, seafood) Occupational exposures

"Mad hatters" Thermometer factories Chemical industries (chloralkali workers) Dental personnel (safety procedures, level of exposure)

Symptoms are dose-dependent; increase with exposure Tremor; impaired motor skills Mood disturbances (irritability, behavior changes) Memory problems Fatigue; weakness Gastrointestinal disturbances; kidney problems

Diagnostic criteria

Because symptoms are so vague, diagnosis based on: Documented source of exposure Outside population norms on standardized tests

Mood scales, motor skills, cognitive function, etc. Elevated Hg in urine, blood etc.

WHO threshold level above which subtle effects occur Urinary level of 35 µg Hg/g creatinine (26)

Persons with amalgams and no other Hg exposure Urinary Hg averages about 10-fold lower than threshold (26)

Claims of “amalgam illness” Popularized by media in Scandinavia and Germany Has led to proposals that amalgam be banned Swedish Assn. of Patients Damaged by Dental Treatment

Symptoms they consider to be signs of amalgam illness:

Muscle and joint pain, tiredness, vertigo, headache, G.I.

disorders, dry eyes, other eye problems, smarting/

ulceration in mouth, heart trouble, circ. disorders/cold

hands & feet, memory loss, difficulty breathing, ears

stopped up, depression, difficulty concentrating, rash,

eczema, itching, throat trouble, restlessness, anxiety,

nervousness, trembling, twitches, cramps, nausea,

vomiting, prickling/creeping sensation, tension,

tremor, heat sensation, sinusitis, hair loss (24)

Standards of evidence

Similar broad symptoms claimed for: Chronic fatigue syndrome Multiple chemical sensitivity syndrome (28)

Evidence is anecdotal, based on case reports Patients claimed to improve after:

Amalgam removalChelation therapy (used for overt Hg poisoning)

This standard of evidence fails to exclude: Placebo effect Spontaneous remission

Other claims Amalgam also has been claimed to cause:

Alzheimer's disease Multiple sclerosis Kidney damage Development of antibiotic resistant oral/fecal bacteria Cardiovascular disease Male infertility Smoking Immune system dysfunction

T-cell abnormalitiesAuto-immune diseasesAllergy

Some suggest treatment by amalgam removal/chelation

Standards of evidence

Some claims are anecdotal; others based on limited studies No controls or inappropriate controls

Anti-amalgam authors (25, 37-45, U2, U5, U9, U11-12, U16 ) M. J. Vimy, F. L. Lorscheider, R. L. Siblerud (25, 37-45) International Academy of Oral Medicine and Toxicology

Others have been unable to replicate their findings Some articles distort or misrepresent contrary findings

“The study cited by Gotwald et al. as proof of there being no connection between Hg and Alzheimer’s disease (Saxe et al., 1999) was published in a dental association trade journal, which is not a peer-reviewed scientific journal” (U12)

This statement refers to JADA All scientific articles published in JADA are peer-reviewed

Hg release from amalgam

Low levels of Hg vapor released from amalgam (26) Mostly excreted in urine, but some stays in tissues Hg higher in persons with amalgams Hg in body fluids correlated with # of amalgams

Are levels of exposure unacceptably high? Depends on calculation methods Amalgam opponents criticized for method errors (26)

Not adjusting Hg vapor meter for lung volumeTheir estimates too high vs. brain uptake data

• 16 µg/day vs. 2 µg/day for avg. 12.6 fillings

Hg levels and symptoms

Are Hg levels higher in "amalgam illness" patients? 10 self-diagnosed patients compared to 8 controls (4)

Amalgam levels the sameHg vapor every 30-40 min for 13.25 h; blood, urineNo difference in uptake (2 µg/day)Urine Hg lower in Pts., 10-fold lower than threshold

No Hg differences in 50 pts. and 50 controls (7) No Hg differences in 99 pts. and 272 controls (28)

Symptoms and special cases

Few case reports of high Hg linked to excessive gum, bruxers Levels much higher than self-diagnosed patients (3, 23)

Dentists working with amalgam (9, 22, U13) No Hg toxicity in Swedish dentists w/proper handling Very subtle "preclinical effects" in US, British dentists

Test results within norms, but correlated with Hg levelsNo control for amalgam handling procedures

Symptoms and Siblerud

Limited by cross-sectional design, self-referred patients

Siblerud - more symptoms in persons w/amalgams (43) 50 amalgam-free; 50 amalgam subjects Amalgam group smoked and drank more-confounding? Results not replicated by anyone else

The evidence from Europe

Big studies n = 4,787, n = 1,024, n =428 (1, 29, U8) Number/type of symptoms vs. number of amalgams No correlations or inverse correlations

587 twins, many raised apart (5) No correlations between amalgams and health No diff. between pairs w/ and w/o amalgam Genetic variation held constant

Retrospective study; n=78 (31) All same occupation Symptoms recorded pre-"amalgam illness" publicity No or inverse correlations w/amalgam (more smokers)

Studies of “amalgam illness”

"Amalgam illness" patients compared to controls Ten consistent studies (8, 16, 24, 28-30, U1, U6, U8, U17) Patients have different psych. profiles than controls Multiple symptoms including TMD Anxiety, depression, somatization, stressful life events No differences in amalgam number or Hg levels

No evidence for dose response between Hg and symptoms

Amalgam and neurotoxicity

550 non-dental university employees ages 30-49 (U4) Evaluated for neurological symptoms associated with Hg No correlation with amalgam # or urinary Hg

The Air Force Health Study (U18) 1663 Vietnam-era veterans

Higher levels of amalgam than general population Comprehensive neurological examination Controls for alcohol use, diabetes, wartime dioxin exposure Neuropathy due to diabetes, dioxin, could be detected No associations between neuropathy and amalgam #

Amalgam and Alzheimer's

Hg levels in patient, blood, urine, brain same as controls (11-13) Cognitive tests not correlated to amalgams in elderly nuns (36) Saxe et al. 1999 (U14)

Multidisciplinary study - U of Ky Alzheimer’s Research Center Longitudinal - subjects agreed to donate brains after death 68 AD patients, 33 controls

AD confirmed by brain histology Determined amalgam history from interviews/dental records

Traced back for up to 20 years No differences in amalgam history No differences in Hg levels - six regions of the brain

Amalgam and chronic disease Multiple sclerosis

Siblerud claim - patients studied without controls (41) Hg levels in patient brains lower than controls (11) Community studies with matched controls (2, U3)

No differences by amount or age of amalgams Kidney/cardiovascular damage (32, 35, 39, 45, U11)

Claims from sheep/ clinical chemistry studies Healthy clinical chemistry in "amalgam illness" No difference before and after amalgam removal

Hg levels temporarily rise after removal

Other claims

Antibiotic resistance in bacteria (10, 25, 33) Genes for antibiotic and mercury resistance linked Vimy claim-amalgam increased resistance in monkeys No difference in flora of persons w/ and w/o amalgam No difference before and after amalgam removal

Male infertility (15) No correlation between infertility and Hg, amalgam

Amalgams and smoking (42) Siblerud claim because amalgam group smoked more He also cited study w/amalgam unrelated to symptoms (31)

Amalgam and immunity

T-cell subpopulations (B-cells, TH, TS, NK, etc.)

Anecdotal claims - altered proportions of different types No diff. between patients w/ and w/o amalgam (27, U7) No change over time (46)

Within patients getting amalgams for first timeWithin patients having all amalgams removed

Amalgam and allergy

Allergic responses not specific to Hg (asthma, rhinitis, etc.) Adolescents with and without allergic diseases (18, 19)

No difference in amalgam or Hg levelsNo correlation between Hg levels and IgE

Adolescents with and without amalgams (17)No difference in eczema or rhinitisAsthma more common in kids without amalgamsAsthmatic children had lower numbers of amalgams

Contact hypersensitivity

Contact hypersensitivity to amalgam (6, 21, 33, 47) Oral lichenoid reactions (white reticular mucosal lesions)

Oral lichen planus - disseminated lesionsContact lesions - in direct contact with amalgam

Lichen planus does not heal after amalgam removal 90+% of contact lesions heal after amalgam removal

Specific contact hypersensitivity to amalgamNot a systemic immune responseNot associated with "amalgam illness" symptoms

Genetic Hg sensitivity - mice

There is a mouse model (20) Strains are genetically susceptible or resistant to Hg Linked to histocompatibility (tissue typing) genotypes Susceptible strains show distinct autoimmune response

High IgE, anti-laminin antibodies, immune complexes Amalgams in teeth - susceptible vs. resistant strains

Caused response in susceptible strains

Human genetic Hg sensitivity?

Can this explain low Hg levels in "amalgam illness"? Hard to exclude completely at this point

“You can’t prove a negative”Always possible to claim insufficient sample sizeNo biochemical markers knownStudies of patient MHC genotypes would be helpful

Arguments against (5, 18, 19, 22)Amalgams same in controls, immune complex kidsIgE uncorrelated with Hg levelsNo high IgE or anti-laminin with high Hg exposureSame symptoms in twin pairs w/ and w/o amalgam

Standards of evidence

If true, Hg reduction should be required for recovery Double-blind placebo-controlled studies needed

No placebo possible for amalgam removalChelation treatment can be placebo-controlled

20 amalgam illness patients - chelation vs. placebo (34)No difference in symptoms

50 amalgam illness patients - very well-controlled (14)Immediate and long-term relief seen in both groupsNo difference - symptoms negatively correlated w/Hg

39 amalgam illness volunteers - exposed to Hg vapor or airDouble blind - no difference in symptoms (U15)

Other metals in amalgam

Recent finding that amalgam was toxic to cultured neurons (U10) Toxicity was proved to be due to Zn in amalgam, not Hg Unlike Hg, body Zn levels are tightly regulated

Should limit any risk from Zn in amalgams in the mouth Zn-free amalgam currently being tested in same model

My conclusions - safety

Amalgam seems safe for the vast majority of people Dental personnel should use safe handling procedures Difficult to rule out genetic Hg susceptibility altogether

Genotyping studies should be done If susceptible genotypes exist, they are very rare Would need to exclude "symptom-prone" genotypes

"Amalgam illness" symptoms can't be linked to amalgam Symptoms may be real, but attributable to other factors Response should be compassionate, but evidence-based Encourage consideration of alternative explanations

My conclusions - removal

Removal of sound amalgams is not justified by data Unnecessary expense Potential source of false hope Exception: lichenoid lesions in direct contact

Large prospective studies do not support sensitivity issue (U19, U20) Published in JAMA Long term follow-up after amalgam or composite placement 500 Portuguese children for 7 years; results published in 2006 534 New England children for 7 years; results published in 2006 No differences, in IQ, nerve function, behavior, or kidney function Amalgam opponents are not convinced (“low sample size”)

The ADA code of ethics