A. The RfC and MRL are Outdated
The FDA incorrectly states that:
Castorina and Woodruff (2003) clearly demonstrate that: “Although noncancer outcomes may in some instances be reversible and considered less severe than cancer, our findings call into question the assumption that establishedRfD and RfC values represent negligibly small risk levels.”
The EPA recognizes that mercury vapor is a neurotoxin. As such, the toxicological assessment by EPA of mercury and derivation of a suitable reference air concentration (RfC) must comply with EPA’s (1998) guidance on the assessment of neutotoxins. The publication of that EPA guidance occurred three years after the publication of EPA’s RfC for mercury vapor, thus indicating that this RfC is out of compliance with EPA’s own policies and procedures for the assessment of neurotoxins. It is apparent, therefore, that this RfC is out of date and will eventually be (must be) updated to accurately reflect both the latest literature on mercury vapor toxicity andEPA’s own neurotoxin risk assessment guidance.
The FDA incorrectly cites the EPA documentation associated with the out-of-date EPA RfC. The FDA allege that a 2002 contractor’s report (screening assessment), prepared for the USEPA on toxicological studies of mercury vapor published between approximately 1995 and 2002, is evidence that the EPA found no new data or information warranting revision of the EPA RfCof 0.3 ug/m3. In fact, this is specifically contradicted by the EPA in the very citation referred to by the FDA:
Although it is apparent that the EPA has yet to consider these new studies with respectto revising or updating its RfC, this inaction by EPA cannot be properly cited by the FDA as‘evidence’ of a dearth of new and relevant studies. The EPA RfC was first published in 1995 (seehttp://www.epa.gov/ncea/iris/subst/0370.htm ) and has not been updated for new toxicologicalstudies since that time. In fact, contrary to the supposition of the FDA, the most recent study citedby the US EPA in support of its RfC is 1995.
FDA states that the EPA (1995) and ATSDR (1999) constitute ‘recent’ reviews of thetoxicological literature on mercury vapor. This is, in fact, incorrect. As previously mentioned,the EPA RfC cites no literature later than 1995, now some fourteen years out-of-date. The mostrecently dated citation within the ATSDR Toxicological Profile on Mercury (ATSDR, 1999) is1999, now some 10 years out-of-date.
The most recent review of the toxicological literature relating to mercury vapor by anational or international environmental health agency was prepared by Health Canada (2006),which was subsequently published in the scientific literature by Richardson, et al. (2009). IfFDA had undertaken a thorough and effective review of all literature up to July 2009, as reportedin their Final Rule, the Richardson, et al paper would have been identified. This is particularlytrue since the Richardson, et al paper is published in the journal Regulatory Toxicology andPharmacology, a significant journal with high respect paid by the national and internationalregulatory community dealing with chemical exposures, such as mercury from dental amalgam.
It is also standard practice among practitioners of risk assessment to contact relevantnational and international environmental health regulatory agencies to inquire of relevantunpublished reviews and documents. Had the FDA or their contractors followed that standardpractice and contacted Health Canada to inquire about any relevant information, they wouldhave been informed about both the document on mercury vapor and the subsequent journalpublication. In fact, had the FDA or their contractors simply done an internet search of HealthCanada’s various web pages, they would have discovered three key reports listed at:http://www.hc-sc.gc.ca/ewh-semt/contamsite/res/proj_pubs_journal-eng.php; three reportsemployed in Health Canada’s development of an up-to-date reference exposure level for mercuryvapor in the general population. It is also surprising that the FDA makes no mention of HealthCanada’s up-to-date REL (analogous to EPA’s RfC) for mercury vapor of 0.06 ug/m3, some five times lower than the out-of-date EPA RfC of 0.3 ug/m3, and more than three times lower than the ATDSR’s out-of-date MRL for mercury vapor of 0.2 ug/m3.
In a review by Ratcliffe, et al. (1996), a series of criteria were developed to criticallyevaluate available epidemiological, occupational and toxicological studies of Hg0, towardsdetermining if post-1980s studies provided evidence to warrant revision of the REL for Hg0. Thatreview found several studies that were positive for sub-clinical impairment of the CNS. The studyof Fawer et al. (1983), the primary basis of all existing REL values, did not meet the criteria onstudy quality established by Ratcliffe, et al.
Ratcliffe, et al. did not restrict their evaluation to studies of neurotoxicity. They alsoidentified a variety of studies that were positive or suggestive of sub-clinical nephrotoxic effects,occurring in the same general dose range associated with sub-clinical CNS effects. Additionalrecent studies have also identified nephrotoxic, neurotoxic and immunotoxic effects associatedwith Hg0 exposure, reported at doses or exposure levels at or lower than the exposure levelsassociated with the Fawer study. As a result of the development of these factors, confidence inthe current reference levels for Hg0 is low, at least outside of FDA, and an evaluation of recenttoxicological, epidemiological and occupational studies investigating neurologic, nephrologic andimmunologic effects, conducted since 1995, is necessary.
This was recognized by the EPA which, in 2002, appended to their IRIS summary on elementalmercury (mercury vapor) the following statement:
Screening-Level Literature Review Findings — A screening-level reviewconducted by an EPA contractor of the more recent toxicology literature pertinentto the RfC for Mercury, elemental conducted in September 2002 identified one or more significant new studies. [Emphasis added]
These more recent studies have most recently been reviewed and evaluated by Health Canada(2006; see also Richardson et al., 2009).