FDA Admissions/Conclusions in Responses to Petitions

Release of Mercury Vapor

  • 610, Page 2; 163, Pg. 2 – Dental amalgam contains elemental mercury and releases mercury vapor. At high enough levels, mercury vapor is a neurotoxicant and can have adverse health effects. A central question in assessing the risk of dental amalgam is whether the levels of mercury vapor released from dental amalgam are harmful or are associated with adverse health effects and, if so, to what extent.
  • 610, Page 6; 357, Pg. 7 – FDA agrees with your claim that some mercury vapor is released from dental amalgam but disagrees with your claim that this exposure presents a substantial and unreasonable risk of illness or injury that would support a ban of dental amalgam.
  • 610, Page 7; 357, Pg. 8 – FDA acknowledges that dental amalgam releases mercury vapor, notably during placement and removal of amalgam, but finds that these levels do not present a substantial and unreasonable risk of illness.
  • 357, Pg. 1 – dental amalgam contains elemental mercury and releases mercury vapor. At high enough levels, mercury vapor is a neurotoxicant and can have adverse health effects.
  • 357, Pg. 7 – You reference Kudsk to support your claim that eighty percent of the mercury inhaled into the lungs is absorbed into the bloodstream. This article does not provide any new scientific information for FDA to evaluate.  FDA acknowledged the absorption rate of elemental mercury through inhalation in its final rule.
  • 357, Pg. 8 – The issue of mixture risk assessment is complex. FDA does not discount the possibility of synergism or additivity when patients are simultaneously exposed to more than one chemical or drug, but the study discussed in the petition is of little value for estimates of risk to patients with amalgam.
  • 357, Pg. 8 – recommended professional labeling for dental amalgam vis-à-vis mercury vapors: “Mercury vapor concentrations are highest immediately after placement and removal of dental amalgam but decline thereafter.”
  • 357, Pg. 9 – the reliability of these studies is questionable as it is very difficult to make accurate quantitative estimates of mercury release from dental amalgam and the amount absorbed by the body.
  • FDA TREATMENT
  • Treated in the Guidance Documents section F. Information for Use

Effects on Pregnant Women/Fetuses and other sensitive persons

  • 610 and 357, Page 2; 163, Pg. 3 – The FDA acknowledges that there is limited to no clinical information available regarding long-term health outcomes in pregnant women and their developing fetuses, and children under the age of six, included infants who are breastfed. There is, however, information that indicates that certain that certain individuals with a pre-existing hypersensitivity or allergy to mercury may be at risk for adverse health effects from mercury vapor released from dental amalgam.
  • 610, Page 10 – Very few well-controlled animal studies or human epidemiological studies have evaluated the potential effect of low-level mercury vapor exposure on fetal development, especially at exposures experienced by dental amalgam bearers. Although the data are limited, FDA concluded when issuing the final rule that “the existing data do not suggest that fetuses are at risk for adverse health effects due to maternal exposure to mercury vapors from dental amalgam.” Even so, FDA did recommend professional labeling warning for dental amalgam addressing possible sensitivity to mercury by fetuses and young children.
  • 610, Page 13; 163, Pg. 6 – FDA in the final rule stated that very few available studies have evaluated the effects of elemental mercury exposure on pregnancy outcomes in humans. Although mercury has the ability to cross the placental barrier, the limited human data do not demonstrate an association between exposures to the mercury from dental amalgam and adverse reproductive outcomes such as low birth weight babies or increased rates of miscarriage.
  • 610, Page 16; 163, Pg. 7 – FDA acknowledged that mercury present in a nursing mother’s body is transmitted to her infant through breast milk.
  • 610, Page 17-18; 357, Pg. 28; 163, Pg. 6-7 – FDA concluded in the final rule that very few well-controlled animal studies or human epidemiological studies have evaluated the potential effect of low-level mercury vapor exposure on fetal development, especially at exposures experienced by dental amalgam bearers. There is limited to no clinical information concerning the effects of prenatal exposure from maternal sources of mercury vapor at relevant concentrations.  Even so, FDA did include the language in “Information for Use” section in the recommended professional labeling for dental amalgam. 
  • 610, Page 45 – FDA agrees that certain potentially sensitive subpopulations (i.e., fetuses, breastfed infants, and children under six) may be at higher risk for adverse health effects from mercury in dental amalgam, but FDA has already taken steps in its final rule and special controls guidance document to protect these subpopulations.
  • Referring to the statement found in the “Information for Use” section regarding the recommended professional labeling: “The developing neurological systems in fetuses and young children may be more sensitive to the neurotoxic effects of mercury vapor. Very limited to no clinical information is available regarding the long-term health outcomes in pregnant women and their developing fetuses, and children under the age of six, including infants who are breastfed.”
  • 163, Pg. 5 – FDA reviewed the available scientific evidence for potentially sensitive subpopulations and does not believe that the risk of the use of dental amalgam clearly outweighs the benefit in any patient population such that a contraindication is warranted, except “in persons with a known mercury allergy,” for which FDA has already recommended a contraindication.
  • 163, Pg. 5 – in terms of toxicodynamics, FDA acknowledges that infants and children under 6 might have an inherent higher sensitivity to the effects of mercury vapor compared to adults; however, FDA found no clinical studies that evaluate the effects of mercury vapor exposure from dental amalgam in children under 6.
  • FDA TREATMENT
  • Treated in the Guidance Documents section F. Information for Use

Mercury Bioaccumulation

  • 610, Page 9; 357 Pg. 9-10 – FDA agrees with your claim that mercury bioaccumulates in certain tissues of the body but disagrees that the accumulation from dental amalgam causes adverse health effects that would support a ban on these devices
  • 610, Page 9; 357, Pg. 10 – FDA acknowledged mercury bioaccumulation in the preamble to the final rule, stating that mercury bioaccumulates in the kidneys, brain, and fetus and that the kidneys accumulate the highest organ concentration of mercury following exposure to mercury vapor. The concentration of mercury in the kidneys has been associated with the number of dental amalgams placed.  Despite mercury accumulation in the kidneys, FDA’s review of the literature in the final rule did not find adverse health effects associated with bioaccumulation of mercury from dental amalgam.
  • 357, Pg. 11 – However, there is limited to no clinical information concerning the effects of prenatal exposure from maternal sources of mercury vapor at relevant concentrations. Although the data are limited, FDA concluded when issuing the final rule that “the existing data do not suggest that fetuses are at risk for adverse health effects due to maternal exposure to mercury vapors from dental amalgam. Even so, FDA did recommend professional labeling warning for dental amalgam addressing possible sensitivity to mercury by fetuses and young children.
  • 357, Pg. 11 – In issuing the final rule FDA concluded that it “is aware that, in autopsy studies, mercury has been found to accumulate in the brain. However, it is difficult to draw conclusions from autopsy studies regarding a potential association between exposure to dental amalgam and adverse health outcomes without information concerning the individual’s lifetime history of exposure to mercury in fish and other environmental sources.”
  • 163, Pg. 9 – FDA acknowledged that mercury has been found to accumulate in the brain and kidneys. FDA acknowledges that the total mercury body burden is derived from various sources, including occupational exposures, dental amalgam, fish consumption, and environmental exposure.
  • FDA TREATMENT
  • No discussion in either the Guidance Documents or Final Rule
  • The term “bioaccumulation” is not found anywhere in either document
  • The following is the only passage arguable relating to bioaccumulation: High levels of maternal mercury vapor exposure were associated with the accumulation of mercury in fetal tissues. (Final Rule, page 6, ¶ Animal Studies)

Risk to Dental Professionals

  • 610, Page 11 – FDA acknowledges that dental professionals may be exposed to mercury vapor in the workplace during the preparation, placement, and removal of dental amalgam, but FDA disagrees with your claim that dental professionals using proper occupational workplace controls, such as proper handling, vacuum, and ventilation, experience neurobehavioral deficits as a result of exposure to dental amalgam.
  • 357, Pg. 12 – As noted by the Dental Product Panel prior to rulemaking, improper use of dental amalgam exposes dental professionals to risks associated with mercury toxicity. Improper storage, trituration, and handling contribute to this risk.
  • 357, Pg. 13-14 – Regarding reproductive effects on dental professionals, FDA in the final rule stated that very few available studies have evaluated the effects of elemental mercury exposure on pregnancy outcomes in humans. Although mercury has the ability to cross the placental barrier, the limited human data do not demonstrate an association between exposures to the mercury from dental amalgam and adverse reproductive outcomes such as low birth weight babies or increased rates of miscarriage.
  • FDA TREATMENT
  • Arguably treated in Guidance Documents section E. Precautions
  • Discussed at length in Final Rule, beginning on page 7

General Toxicity inside body/Neurological Effects

  • 610, Page 15; 357, Pg. 15-16 – FDA acknowledged in final rule that mercury toxicity has been demonstrated in a variety of organ systems in laboratory studies and that the central nervous system and the kidneys are both target organs sensitive to mercury vapor. FDA further stated in the final rule, “FDA recognizes that dental amalgam releases low levels of mercury, and that there are scientific data showing mercury vapor, at high enough exposures, to be a neurotoxicant and nephrotoxicant.”  Based on the weight of the available evidence, FDA concluded and continues to hold the view that exposures to vapor from dental amalgam do not put individuals age six and older at risk for mercury-associate adverse health effects.
  • 357, Pg. 15 – While FDA acknowledges that mercury exposure at high levels can result in adverse health effects to the neurological system, the agency finds that the information you have provided does not support the conclusion that dental amalgam presents an unreasonable and substantial risk of illness or injury that would justify a ban.
  • 357, Pg. 18 – FDA concluded in the final rule that the existing data support a finding that exposures to mercury vapor at levels associated with dental amalgams do not result in neurological deficits, tremors, peripheral neuropathies, or Alzheimer’s disease in population six and older.
  • 357, Pg. 30 – FDA believes the scientific studies implicating mercury exposure from dental amalgam and systemic diseases/conditions such as inflammation, bone loss and IDCM are not sufficiently robust to draw definitive conclusions.
  • FDA TREATMENT
  • Arguably treated in Guidance Documents Section F. Information for Use – specifically the first bullet listed above in this category.
  • Gender Differences and Genetic Polymorphisms
  • 610, Page 18 – FDA has reviewed this exhibit and finds that the study was well conducted and provides evidence that individuals with certain genetic polymorphisms may be at a higher risk for adverse health effects due to mercury from dental amalgam. FDA does not believe, however, that the evidence you have provided and the evidence it has evaluated demonstrate an unreasonable and substantial risk of illness or injury that would justify a ban of dental amalgam.
  • FDA TREATMENT
  • No discussion regarding gender differences or genetic polymorphisms in final rule or guidance documents (other than effects on pregnant and nursing women)

Parkinson’s, MS, and ALS

  • 610, Page 22 – Few studies that evaluate a link between dental amalgam and Parkinson’s.
  • 357, Pg. 19 – In general, data on this disease are combined with other various neurological or neurodegenerative diseases, such as Alzheimer’s disease, MS, ALS and autism. In general, these studies are inconclusive because the findings are limited by a number of concerns.
  • 610, Page 24; 357, Pg. 20 – Few studies that evaluate a link between dental amalgam and MS.
  • 610, Page 26; 357, Pg. 22 – Few controlled studies that evaluate a link between dental amalgam and ALS. FDA concluded in final rule that existing data do not support a finding that exposures to mercury vapor at levels associated with dental amalgams result in neurological deficits, tremors, peripheral neuropathies, or Alzheimer’s in the population age six and older.
  • FDA TREATMENT
  • See page 5 of Final Rule – determined no enough evidence to link mercury to any of these conditions.

Kidney Dysfunction

  • 610, Page 29 – FDA believes that further independent study is necessary to confirm the Geier, et al., findings. FDA also believes that elevations in urinary biomarkers of kidney exposure do not necessarily indicate an adverse health outcome, especially at the small percent increase shown from the study’s re-analysis of the data, without more conclusive evidence of an adverse clinical outcome related to kidney injury.
  • 610, Page 29; 357, Pg. 24 – In general, while FDA acknowledges that mercury exposure from dental amalgam results in increased mercury levels in tissues, including in the kidneys, and that exposure to mercury from various other sources at high levels can result in adverse health effects to the renal system, FDA finds that the information provided does not support a conclusion that dental amalgam should be banned.
  • 610, Page 29; 357, Pg. 24 – FDA acknowledged in the final rule that mercury toxicity has been demonstrated in a variety of organ systems in laboratory studies and the central nervous system and the kidneys are both target organs sensitive to mercury vapor. FDA further states in the final rule, “FDA recognizes that dental amalgam releases low levels of mercury, and that there are scientific data showing mercury vapor, at high enough exposures, to be a neurotoxicant and a nephrotoxicant.”
  • FDA TREATMENT
  • Reference to kidney impairment from mercury exposure are found throughout the final rule
  • Page 2 – FDA specifically admits that kidneys and the central nervous system are both target organs sensitive to mercury vapor.

Hearing Loss

  • 610, Page 30; 357, Pg. 25 – The panel discussed that this finding may have significance but that other studies in a larger patient population are needed to corroborate the effects seen in this study. FDA agrees with this statement and finds that the information you have provided regarding your claim that dental amalgam fillings are associated with hearing loss does not support the conclusion that dental amalgam presents an unreasonable and substantial risk or illness or injury that would justify a ban.
  • FDA TREATMENT
  • No specific treatment in Guidance Documents and only cursory mention on page 13 of Final Rule.

Allergy, Hypersensitivity, or Autoimmune

  • 610, Page 31; 357, Pg. 25 – While FDA acknowledges that some individuals are hypersensitive or allergic to mercury and/or other metals, the agency’s view is that such reactions are rare and may be attributed to immediate type allergic reactions to one or more components or dental amalgam other than mercury.
  • 610, Page 32; 357. Pg. 26 – FDA concluded in the preamble to the final rule that the existing data indicate that certain individuals with a pre-existing hypersensitivity or allergy to mercury may be at risk for adverse health effects from mercury vapor released from dental amalgam. In order to mitigate this risk, FDA established a Class II special controls guidance on dental amalgam and recommended labeling stating that it should not be used in persons with a known mercury allergy.
  • 357, Pg. 26-27, FN 90: The classification regulation for dental amalgam, 21 C.F.R. 872.3070, provides that the special control for dental amalgam is FDA’s “Class II Special Controls Guidance Document: Dental Amalgam, Mercury, and Amalgam Alloy.” Although the special controls listed in that guidance document are described as recommendations, the guidance document makes clear that “any firm currently marketing, or intending to market, dental amalgam, mercury, or amalgam alloy will need to address the issues covered in this special controls guidance.  The firm must show that its device addresses the issues of safety and effectiveness identified in this guidance, either by meeting the recommendations of this guidance or by some other means that provides equivalent assurances of safety and effectiveness.
  • 357, Pg. 27 – In conclusion, inorganic mercury exposure may cause adverse effects on the immune system. However, there is no evidence that autoimmune disease is provoked in humans by mercury exposure from amalgam fillings.  In some patients with allergy to mercury, clinical improvement is seen after removal of amalgam fillings.  There is some evidence that exposure to mercury influences proinflammatory cytokine levels, but the clinical implications are not clear.
  • FDA TREATMENT
  • Final Rule, page 8 – “FDA concludes that existing data indicate that certain individuals with a pre-existing hypersensitivity or allergy to mercury may be at risk for adverse health effects from mercury vapor released from dental amalgam.”
  • Also discussed at middle, bottom of Final Rule page 17.

Request to Place Dental Amalgam into Class III

  • 610, Page 36; 357, Pg. 35 – In the final rule, FDA identified exposure to mercury, allergic response including adverse tissue reaction, contamination, mechanical failure, corrosion, and improper use as some of the potential risks to health associated with the use of dental amalgam devices. FDA established special controls to address and mitigate each of these risks described in the Class II (specific labeling and biocompatibility testing)
  • 610, Page 38 –357, Pg. 18 – FDA concluded in the final rule that the existing data support a finding that exposures to mercury vapor at levels associated with dental amalgams do not result in neurological deficits, tremors, peripheral neuropathies, or Alzheimer’s disease in population six and older.
  • 357, Pg. 18 – FDA concluded in the final rule that the existing data support a finding that exposures to mercury vapor at levels associated with dental amalgams do not result in neurological deficits, tremors, peripheral neuropathies, or Alzheimer’s disease in population six and older.
  • FDA TREATMENT
  • See Final Rule, page 15 for rationale for not-banning, but placing as Category II

Inadequacy of ATSDR MRL

  • 610, Page 42 – FDA has reviewed the exhibits and believes they highlight many of the uncertainties in a dental amalgam risk assessment, specifically with regard to both an exposure assessment and acceptable reference exposure levels.
  • 610, Page 44; 357, Pg. 41 – FDA also believes that even though amalgam patients with numerous amalgam-filled surfaces could be exposed to daily doses of mercury vapor above the available RELs, this alone does not necessarily indicate that adverse health effects from dental amalgam will occur.
  • 357, Pg. 40 – The responses also indicated that the point-of-departure approach with the application of UFs may be unsuitable for elemental mercury, given that a no observed adverse effect level (NOAEL) has not been defined, which presents uncertainties with regards to the toxicity thresholds for chronic, low level mercury vapor exposure from dental amalgam.
  • 357, Pg. 41 – Although daily exposures at or above an REL over a lifetime do not necessarily indicate that adverse health effects will occur, doses far above the REL suggest that probability of adverse health effects is more likely, especially in sensitive subpopulations.
  • 357, Pg. 42 – Since the weight of clinical evidence has not established an association between dental amalgam use and adverse health effects in adults and children age six and older, the agency believes that its current classification of dental amalgam provides a reasonable assurance of safety and effectiveness. FDA also agrees that certain potentially sensitive subpopulations may be at higher risk of adverse health effects from mercury in dental amalgam, but FDA has already taken steps in its final rule and special controls guidance document to protect these subpopulations.
  • FDA TREATMENT
  • Extensive discussion beginning on middle of page 3 of the Final Rule

Labeling

  • 357, Pg. 42 – The warning in the specific labeling about the presence of mercury in dental amalgam and the disclosure of mercury content by weight is intended to alert dental professionals of the potential for exposure to mercury vapor and remind them of the need for protective measures.
  • 357, Pg. 43 – As explained in the final rule, the purpose of the information for use statement is to help dental professionals plan appropriate treatment recommendations for their patients by providing them with FDA’s current assessment of the most current, best available evidence regarding potential risks to health from mercury vapor released from dental amalgams
  • 357, Pg. 43; 163, Pg. 11 – FDA believes that the recommended labeling statements in the special controls guidance document will provide dentists with important information that will improve their understanding of the devices and help them make appropriate treatment decisions with their patients.
  • 163, Pg. 11 – In addition, FDA notes that dental amalgam is a prescription device and, therefore, patients cannot receive the device without the involvement of a learned intermediary, the dental professional. Therefore, FDA has concluded that it is not necessary to require that dentists provide this information to patients in order to provide reasonable assurance of the safety and effectiveness of the device.
  • FDA TREATMENT
  • See “Specific Labeling Recommendation” – Final Rule, page 8
  • Section F. Information for Use found in Guidance Document is intended as a recommended label for products containing mercury.