Supplemental Comments of the American Dental Association Before The Dental Products Panel of the Medical Devices Advisory

Committee [Docket No. FDA2010N0268]1 December 20101 It is the understanding of the ADA, that some seeking to ban dental amalgam are relying upon a certain report (Mercury Exposure and Risks from Dental Amalgam, November 8, 2010, prepared by SNC-Lavalin Environment, Ottawa, Canada (G. Mark Richardson, lead author)(the Richardson Paper). The report states that it was prepared in order to estimate current levels of mercury (Hg0) exposure from dental amalgam in the U.S. general population. Additionally, the report discusses the methodology and results of the Childrens Amalgam Trials, and compares Hg0 exposure from amalgam fillings to proposed Reference Exposure Levels (RELs). The Richardson Paper is seriously flawed and certainly cannot form the basis for any wellfounded recommendation to the FDA. Assumptions underlying portions of the paper are not explained and other data and extrapolations of data are not supported by the underlying source for that data. Finally, the critique of the Childrens Amalgam Trials found in the Richardson Paper ignores the universally accepted, gold standard of randomized clinical trials in favor of less scientifically reliable evidence in determining true cause and effect. It also relies upon a discredited study in doing so. Unfortunately, the Richardson Paper appears to be crafted to reach a particular result, rather than to properly focus on the best available scientific data. The ADA offers the following specific comments regarding this report. The data used to estimate the current levels of mercury exposure from dental amalgam is drawn from the CDC National Health and Nutrition Examination Survey (NHANES). Data presented in Table 1, Summary of NHANES data of 2001-02 and 2003-04, on page 23 of the Richardson paper is misleading. The age ranges (months) presented may not be appropriate for the defined age groups. The group defined as Toddlers, for example, range in age from 24 to 59 months. While there may not be a nationally defined range for toddlers, including 4 and 5 year old children in this group may increase the number of individuals with restored teeth in a group that is considered a sensitive population. One does not normally consider a toddler to be as old as 59 months. This may be why the Toddlers group as presented by Richardson et al. has more mean filled surfaces than children and adolescents. The sixth column Average number of restored surfaces (amalgam bearers only) is illogical. NHANES data does distinguish between the restorative material used (e.g. amalgam versus composite). And, it would be assumed that the values in this column would be lower than the previous one which represents the average number of restored tooth surfaces (all participants), assuming that this encompasses any type of restoration. The data in the sixth column also seem extraordinarily high, especially for toddlers. If this table is using Richardsons Scenario 1, then it will also drastically over estimate the number of amalgam surfaces.

Questions regarding these supplemental comments may be directed to Jerome Bowman, ADA Public Affairs Counsel at bowmanj@ada.org.

ADA in-house analysis of 2003-2004 NHANES data does not confirm the values presented in Richardsons Table 1. Average number of restored tooth surfaces for all participants and amalgam bearers only for both toddler and children age groups were significantly lower by ADA calculations. ADA analysis found all participants and amalgam bearers only to be 0.53 and 9.62 respectively for toddlers and 1.83 and 5.5 for children. Compared to the numbers reported by Richardson, (1.2 and 18.2) and (3.4 and 8.8), respectively. This may indicate an overestimate by Richardson of the mean numbers for restored tooth surfaces that were subsequently used to calculate Hg0 exposure from amalgam fillings. This discrepancy would be expected to affect the findings presented in Table ES-2 where estimates for the Proportion and numbers of US citizens with amalgam fillings that exceed doses associated with published reference exposure levels for Hg0 are presented.

Data presented in table ES-01, Summary of Hg doses estimated for the US population with amalgam fillings is also flawed. It appears that each of the following issues led to an over estimate of the dose of Hg associated with amalgam surfaces. These numbers were then used in Table ES-2 Proportion and numbers of US citizens with amalgam fillings that exceed doses associated with published reference exposure levels for Hg0. Number of filled surfaces column does not correspond to Average number of restored tooth surfaces column in table 1 (mentioned above). In Scenario 4, 30% of the population is excluded because it is assumed that their restorations are 100% amalgam free. It is not explained how this 30% was chosen. Improper methods would bias the US population estimates because they are based on specific weights that NHANES2 has provided for each individual. The mean numbers of filled surfaces are well above expected numbers. The authors state that these were derived as weighted US population mean, not the mean of NHANES participants. No other information on how the means were calculated is presented. A background urine Hg concentration of 0.50 g Hg/g creatinine was assigned for all age groups. This number is an estimate of the mean background urine Hg concentration for women of childbearing age with no restorations by Dye et al.3 It would be more appropriate to use the geometric mean of 0.31 g Hg/g. Also, background exposure in toddlers, children and adolescents should be lower. The last column, Hg concentration, which is estimated by the authors, does not correspond with actual laboratory measurements provided in the Fourth National Exposure Report. This report from the CDC summarizes urinary mercury (creatinine

Centers for Disease Control and Prevention: National Health and Nutrition Examination Survey (http://www.cdc.gov/nchs/nhanes.htm accessed 12-01-10). 3 Dye BA, Schober SE, Dillon CF, Jones RL, Fryar C, McDowell M, Sinks TH. Urinary mercury concentrations associated with dental restorations in adult women aged 16-49 years: United States, 1999-2000. Occup Environ Med. 2005;62(6):368-75.

corrected) concentrations in g/g of creatinine. Urine was collected and analyzed from 2537 of the same 2003-04 NHANES subjects >= 6 years of age. Never does the mean concentration for any of the group stratifications reach the minimum estimated value provided by Richardson in all scenarios and age groups (see CDC table below).

More transparent methods and results are necessary in order to accurately interpret the results of this study. Further analysis of NHANES data regarding surface restorations and urinary mercury concentrations would be useful for assessing the accuracy of the population estimates provided in the report. Richardsons arguments against the findings of the Casa Pia Childrens Amalgam Trial,4 because urinary Hg at baseline and year seven was not different between the amalgam and composite groups, is likewise without sound basis. This randomized controlled trial allowed examination of the effect of amalgam placement by comparing two statistically similar populations over seven years. The study clearly showed that the amalgam group had an increase in urine Hg after amalgam placement that peaked at two years with no effect on neurobehavioral function at year seven.

DeRouen TA, Martin MD, Leroux BG, Townes BD, Woods JS, Leitao J, Castro-Caldas A, Luis H, Bernardo M, Rosenbaum G, Martins IP. Neurobehavioral Effects of Dental Amalgam in Children: A Randomized Clinical Trial. JAMA. 2006; 295: 1784-1792.

Rather than assessing exposure in children using the gold standard randomized controlled studies, or RCTs, Richardson uses Lettmeiers5 derived REL, among others, to assess risk in the general population Lettmeiers calculations are based on a study conducted by Ngim et al.6 The Ngim study has a number of flaws quoted below. According to Mackert and Berglund,7 Two studies that reported subclinical neurobehavioral effects resulting from low-dose occupational exposure to mercury among dentists have attracted interest because of their potential for use in the establishment of exposure limits for mercury (Ngim et al., 1992; Echeverria et al., 1995). The Ngim et al. study was rejected for use in deriving an MRL [Minimal Risk Level] because of methodological and reporting deficiencies. by the ATSDR (1994). Among the deficiencies cited by the ATSDR were the following: The exposure status of the subjects was known to the investigator during testing, mercury levels were not reported for controls, and methods used to correct for confounders (especially the common use in this population of traditional medicine containing mercury) were not reported. Other deficiencies and inconsistencies in the Ngim et al. study involve the method in which exposure to mercury was estimated. The authors measured the dentists exposure on a single work day and used this measurement as an estimate of exposure, despite the fact that additional monitoring of four of the ten dentists showed large variations in the air mercury levels. Three of the four dentists offices exhibited high and low air mercury values that differed by a factor of two or more during the one-week monitoring period. It is not surprising, therefore, that the reported average (arithmetic mean) blood levels for the dentists in the Ngim et al. (1992) study (12.3 g/L) are much higher than would be expected from the known Hg-air:Hg-blood ratios (Roels et al., 1987). Using the regression equation of Roels et al. for relating Hg-blood to Hg-air, a blood level of 12.3 g/L would correspond to an air level of 28.5 g/m3, not 16.7 g/m3 (the arithmetic mean reported by Ngim et al., 1992). Other factors besides mercury can reasonably be cited as producing the measured performance differences on the neurobehavioral tests. For example, the dentists in the Ngim et al. study typically worked 10 hours per day, six days per week. It is unlikely that the staff members of the National University of Singapore who served as controls had comparably demanding work schedules. It must be borne in mind, when considering the relatively slight differences in the aggression scores (Figure 3 of Ngim et al., 1992) exhibited by dentists, that they are a self-selected group that likely would have garnered higher aggression scores even prior to entering dental school. Echeverria et al. (1995) criticized the Ngim et al. (1992) study for the lack of an appropriate referent group and other shortcomings. Based on these initial observations, the ADA believes that the findings of the report, Mercury Exposure and Risks from Dental Amalgam, November 8, 2010, prepared by SNC-Lavalin Environment are flawed and significantly over estimate Hg0 exposure from amalgam fillings.

Lettmeier B, Boese-OReilly S, Drasch G. 2010. Proposal for a revised reference concentration (RfC) for mercury vapour in adults. Sci Total Environ. 2010;408:3530-3535. 6 Ngim CH,Foo SC, Boey KW, Jeyaratnam J. Chronic neurobehavioural effects of elemental mercury in dentists. British Journal of Industrial Medicine 1992;49:782-790. 7 Mackert JR Jr, Berglund A. Mercury exposure from dental amalgam fillings: absorbed dose and the potential for adverse health effects. Crit Rev Oral Biol Med. 1997;8(4):410-36.