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Mercury-containing dental fillings may harm pregnant women and young children.

That's the general, and not particularly useful, lede provided by most media outlets last week, while reporting on a settlement in the case of Moms Against Mercury et al v. Leavitt et al. As part of the settlement, the FDA will reopen a comment period, beginning July 28, 2008, to potentially reclassify dental amalgam and will issue a final ruling 1 year later. And that's really all that's news, if you call that news.

Essential background on the issue can be found from the American Dental Association, which states in a press release that the "FDA has different classifications for encapsulated amalgam and its component parts, dental mercury and amalgam alloy. The FDA's proposed reclassification, which the ADA has supported since 2002, would place encapsulated amalgam and its components under one classification." The organization also writes, "As far as the ADA is aware, the FDA has in no way changed its approach to, or position on, dental amalgam."

However, last week the media latched onto the following statements made at the FDA web site, in response to the settlement:

Dental amalgams contain mercury, which may have neurotoxic effects on the nervous systems of developing children and fetuses. When amalgam fillings are placed in teeth or removed from teeth, they release mercury vapor. Mercury vapor is also released during chewing. FDA’s rulemaking...will examine evidence concerning whether release of mercury vapor can cause health problems, including neurological disorders, in children and fetuses.

Pregnant women and persons who may have a health condition that makes them more sensitive to mercury exposure, including individuals with existing high levels of mercury bioburden, should not avoid seeking dental care, but should discuss options with their health practitioner.

This information is best couched in the FDA's statements indicating that there is not enough information to know whether dental amalgam—which is approximately 50% mercury and has been widely used for more than a century—is harmful to pregnant women or young children. Other countries (Canada, France, Sweden), follow a "precautionary principle" in these populations, given the lack of data. During the comment period, the FDA requests "empirical data and scientific evidence concerning this classification and special controls for dental amalgam."

The original cause of the brouhaha, the "Petition to Order Mercury Amalgam Withdrawn From Interstate Commerce," is, itself, a curious document. For one, the diverse group of petitioners (listed) shows how the ultra-right and ultra-left often come together in their own Bizarro World. They are the following:

• Moms Against Mercury, a nonprofit organization located in North Carolina and founded by Amy Carson, who believes that the ethylmercury-containing vaccine preservative Thimerosal causes autism—despite a wealth of medical data to the contrary.
• The Connecticut Coalition for Environmental Justice, an organization dedicated to eliminating environmental toxins in the state and their effects, particularly on low-income or minority populations. The coalition is led by president Mark A. Mitchell, MD. 
• Oregonians for Life, a pro-life/anti-abortion organization.
• California Citizens for Health Freedom, one of the more "out-there" health-related nonprofits. The CCHF is dedicated to a "toxic-free environment" and the right to access alternative medical treatments for cancer. The organization also opposes the fluoridation of public drinking water.
• Kevin J. Biggers, a candidate for the California state senate and a public member of the Dental Board of California.
• Karen Johnson, an Arizona state senator whose "issues of concern" include the "precious right to life of the unborn," "eradicating pornography," and "standing resolutely against the homosexual agenda."
• Linda Brocato, an Illinoisan who believes that mercury-containing dental fillings caused her multiple sclerosis, and that her symptoms improved substantially after the removal of these fillings.
• R. Andrew Landerman, DDS, a California dentist whose advertised "services" include acupuncture, ayurveda, homeopathy, and the use of the Cavitat device.
• Anita Vasquez Tibau, the California organizer of the Consumers for Dental Choice. Tibau believes that mercury in dental fillings caused her asthma.

The hapless respondents demonstrate, once again, that a visible government job is a gift that keeps on giving: Mike Leavitt, DHHS Secretary; Andrew von Eschenbach, MD, FDA Commissioner; and Dan Schultz, MD, and Mary S. Runner, DDS, both of the FDA's CDRH.

Generally the petitioners allege that the FDA has been negligent in its duty to classify dental amalgam and specifically imply that the FDA has taken a deliberate, passive stance to maintain a profitable status quo for the subversive, pro-amalgam ADA and amalgam manufacturers.

Among the more intriguing allegations in the petition is the following:

It should come as no surprise that all government literature reviews on amalgam's toxicity have been managed by groups composed mainly of dentists. For example, a multimillion dollar grant to study amalgam was given to a dentist sitting on the ADA's Council of Scientific Affairs; that person chose a defenseless group—institutionalized Portuguese orphans—on which to experiment with mercury, without disclosures of health risks. The study is now under investigation by the Secretary's Office of Human Research Protections, the watchdog charged with stopping unethical medical experimentation.

The petitioners are presumably referring to a 2006 study in JAMA by DeRouen et al from the University of Washington and the University of Lisbon. The prospective study was funded by the Cooperative Agreement U01 DE11894 for the National Institute of Dental and Craniofacial Research (NIDCR) of the NIH. According to a 2005 Business Wire story, the University of Washington School of Dentistry did receive $22 million from the NIDCR; however, it is highly unlikely that this chunk of change was consumed by the JAMA study. The story indicated that DeRouen was the designated principal investigator and chair of a research network among his institution, the Washington Dental Service, and the School of Dentistry at Oregon Health Sciences University.

In the JAMA study, more than 500 Portuguese children (aged 8-10 years) received either randomly assigned posterior dental amalgam or resin-based composite as required dental work. The children enrolled were students within the Casa Pia system. According to Wikipedia, Casa Pia is Portugal's largest educational institution for children at risk of "social exclusion or without parental support." Casa Pia has been described as an orphanage in the mainstream press and, parenthetically, is at the center of an ongoing sex-abuse scandal and trial—which should be neither here nor there as far as the DeRouen study is concerned.

It is noted within the JAMA article that the study protocol was approved by the institutional review boards at the University of Washington and the University of Lisbon, and that written, informed consent was obtained from parents or guardians. DeRouen et al reported no significant differences in urinary mercury levels or neurologic function between the 2 treatment groups over the course of 7 years. However, after 5 years, "the need for additional restorative treatment was approximately 50% higher in the composite group."

Regarding implied ethical violations by the study investigators (and presumably the petitioners are referring to the DHHS Office for Human Research Protections), a 2006 AP news report indicated that the counsel for Consumers for Dental Choice, Charlie Brown (who, by george, is one of the petition drafters) found the Casa Pia study unethical because "guardians were never told of the potential risks of the mercury fillings."

DeRouen shot back in the AP story, "We weren't doing anything experimental. We were giving standard dental treatment." A University of Washington review board evidently found the allegations to be unfounded; however, a spokesperson for the OHRP said that the DeRouen study was "under investigation."

According to letters at the OHRP web site, the office did find that the University of Washington's informed consent document "failed to adequately describe the reasonably foreseeable risks of amalgams and composite materials used in dental procedures," as required by DHHS regulations. In response, UW developed a new policy and guidance for its institutional review board concerning the risks of standard-of-care procedures and revised its informed-consent templates to reference this policy. These changes, which appear to be general changes regarding the risks of standard of care and not mercury-related risks specifically, satisfied the OHRP as of April 2007.

Photo: iStockPhoto.

In a cautionary, online slide show, the Multnomah County* Sheriff's Department warns of the cosmetic toll of meth addiction. Before-and-after mug shots show the result of drug-induced formication and the damaged caused by the victim's scratching and digging at skin, in an attempt to alleviate the creepy-crawly sensation.

Meth users with skin lesions may be especially prone to MRSA infection. Last year, investigators at the CDC and Georgia health departments reported an association between meth use and skin and soft-tissue infections (SSTI) due to MRSA in rural populations. Patients presenting to emergency or urgent-care facilities with MRSA SSTI were significantly more likely to have used meth within the last 3 months than control individuals (adjusted odds ratio, 5.10; 95% CI: 1.55, 16.79), and frequent skin picking was independently associated with MRSA SSTI (adjusted OR, 2.53; 95% CI: 1.22, 5.23).

MRSA: methicillin-resistant Staphylococcus aureus.

*Oregon.

The idea that thimerosal-containing vaccines are associated with the development of autism has been broadly and compellingly refuted (see, for instance, authoritative conclusions rendered by the Institute of Medicine and the CDC). Moreover, autism rates have continued to climb, despite the removal of the ethylmercury preservative from routine childhood vaccines since 2001.* Nevertheless, the editorial board of the Journal of the Neurological Sciences, a self-described peer-review journal, finds it necessary to revive the debate in arguably unnecessary fashion by publishing a study that was funded by the Autism Petitioners' Steering Committee and written by plaintiffs' consultants in vaccine litigation.

Talk about your potential conflicts of interest. Given the well-known positions of the study's coauthors—in particular, those of Mark R. Geier, MD, PhD, and his son David Geier (see, for instance, a 2005 profile of the duo by the NYT and a considerable amount of research conducted by Kathleen Seidel at the neurodiversity blog)—it is not surprising that the authors concluded an "association between increased Hg exposure from Thimerosal-containing vaccine and neurodevelopmental disorders."

But the article and additional investigation raise several questions that go beyond the merits of the study itself (which will be discussed in another post). For instance:

1. Was the study protocol, which drew on Kaiser HMO data from the CDC's Vaccine Safety Datalink (VSD), in fact, approved by Kaiser's institutional review board (IRB) as described?
2. What was the decision process among the editorial members of the Journal of the Neurological Sciences that led to the publication of such a questionable study?
3. What exactly is the nature of the body of work conducted by Geier and Geier?

For now, I will address (in as much as I can) the first and second questions.

In the article's Materials and Methods section, the authors claim, "The study protocol employed was approved by the US Centers for Disease Control and Prevention (CDC), the Institutional Review Board (IRB) of Kaiser North-West, and the IRB of Kaiser Northern California." However, an online source suggests that this may not be so, or that there was at least a hitch in the approval of the study given the conduct of its researchers.

In a February 2004 letter to the IRB administrator of Kaiser of Northern California, the then Acting Associate Director for Science of the National Immunization Program at the CDC, Jeanne Santoli, MD, warned Kaiser of "potential breaches in confidentiality and execution of analyses that were not approved in advance," when Mark and David Geier visited the CDC Research Center in Hyattsville, MD, in October 2003 and in January 2004 to collect data from the VSD.

Kaiser's IRB administrator, Leigh Pruneau, RN, PhD, then wrote a letter the following week, informing Mark Geier that his research project was suspended pending his response to the CDC allegations. The letter advised Geier that "you and your co-investigator are prohibited, until notified otherwise, from accessing VSD data derived from Colorado Kaiser Permanente and Northern California Kaiser Permanente institutional officials," and continued:

Federal regulations and KPNC/IRB policy prohibit conduct of research that has been suspended by the IRB. The IRB is required to report, and will proceed to report, the suspension of this study to the CDC and Kaiser Permanente institutional officials.

The following actions are required:

• You must immediately cease all activities which involve Kaiser Permanente data, as it is required by federal regulations and KPNC IRB policy.
• You must inform the IRB of any research-related activity continued beyond this notification of study suspension, providing the reason(s) for continuation.
• You must provide written notification of study suspension and the required cessation of all research activities to the co- and sub- investigators, if any, participating in this research within five business days of receiving this notification.

The IRB requires that you provide your response to the CDC's letter to KFRI via e-mail to KPNC IRB on Lotus Notes, or KPNC.IRB@kp.org, or by U.S. Mail by noon on March 8, 2004, for review at the March 18, 2004 IRM meeting.

It is currently unknown to me if the CDC's allegations were resolved or even addressed by Geier and his coinvestigator or if Kaiser ever gave the go-ahead to continue the study. An inquiry to the CDC reveals that the current Acting Director of the CDC's Immunization Safety Office, John Iskander, is aware of the published study, and that the CDC is preparing a response. E-mails sent to Kaiser's public relations office and its IRB office regarding Kaiser's approval of the study are, so far, unanswered.

On the flip side, Ed Silverman at Pharmalot published yesterday a less-than-thoughtful piece on the study's publication, which frankly reads like a press release from the study's researchers and/or the Autism Petitioners' Steering Committee. Beginning with Silverman's graf 7, the steering committee chides the Federal government, the vaccine makers, and the HMOs for not conducting any studies in the VSD database, and claims that the study's investigators were hampered in their mining of the VSD data: 

First, the government refused to produce the automated data in a way that would have allowed the investigators to link vaccine-mercury exposure to outcome data in individuals...

Second, the government and the HMO’s refused to permit access to any data entered after the year 2000, which meant that the maximum follow up period of the neurodevelopmental disorders for some children was only to four years of age. Specifically, for children born in 1997 or later, this restriction to access prevented any examination of true prevalence rates for those later birth cohorts.

Third, only three of the eight HMO’s participating in the taxpayer funded database permitted even this limited access (Northern California, Colorado, and Oregon Kaiser plans). Other HMO’s blocked access to the data on hundreds of thousands of additional children.

The steering committee then alleges that plaintiffs' families have been denied access to the "taxpayer-funded" VSD by the government and the courts. Regardless of what the steering committee believes, their statements do not address the IRB approval of the study and, in fact, suggest unresolved issues with respect to the use of the VSD data by the study's authors.

Nevertheless, it is certainly possible that the CDC's alleged confidentiality breaches from 2004 were resolved by Geier and that the study protocol as published in the Journal of the Neurological Sciences was, in fact, ultimately approved by the CDC and the respective Kaiser IRBs; however, if this is not the case, the study's claim of IRB approval would be seriously undermined and suggest poor judgment on the part of the journal's editorial board to publish the work.

To that end, I e-mailed Robert Lisak, MD, the journal's editor (as well as chair of the Department of Neurology at Wayne State University and a highly regarded neurologist), asking for any comments on the study's publication. His response was disappointing and of ultimate brevity: "None."

05/21/08 update: An e-mail reply from the Kaiser IRB office provides the following information. "The objections stated in the referenced letter were resolved and the study was ultimately approved by the IRB—as is stated in the published article." How the objections were resolved is not described.

*Thimerosal has not been used as a preservative in routinely recommended childhood vaccines since 2001, with the exception of some influenza vaccines.

Chinese health officials continue to claim that the artificial contaminant, oversulfated chondroitin sulfate, in lots of Baxter's recalled heparin was not the cause of the 81 associated deaths and hundreds of allergic reactions that occurred in the United States, reports Reuters. The Chinese assertion comes in the wake of reports in the NEJM and Nature Biotechnology, which described the contaminant as structurally identical to a withdrawn intramuscular drug, Arteparon, and the contaminant's actions on the kinin-kallekrein pathway.

The Chinese food and drug agency points to the fact that only patients in the United States or Germany experienced adverse reactions to the tainted heparin, whereas the contaminant has been found in heparin products in other countries. The Chinese agency also claims that adverse reactions have occurred with some batches that did not contain the contaminant. Both of these assertions, however, have already been rebutted by the US FDA, which cited the relatively common practice of heparin bolusing in the United States and Germany and the initial use of an insufficiently sensitive test for the heparin contaminant.

In what appears to be a digressive move, Chinese officials accuse Baxter of obstructing their investigation of the company's tainted heparin, a charge that Baxter denies. A Chinese regulator is quoted by Reuters: "Baxter failed to provide necessary cooperation in the process of the investigation, which is not conducive to further identifying the reasons for the adverse reactions to heparin." Baxter is also accused of destroying some drug samples and relevant production records—an allegation also denied by the company. Chinese officials also point a finger at Baxter's Chinese heparin supplier Changzhou SPL, implying that the company avoided registration with China's food and drug administration because the company was considered a chemical manufacturer, not a drug maker.

Most important, however, Chinese health officials have yet to explain how the artificial contaminant made its way into heparin. Information to date suggests that the contaminant, which is considerably cheaper than crude heparin, was intentionally introduced into supplies at the workshop level, before processing at Changzhou SPL. 

A Chinese health official* said today that the oversulfated chondroitin sulfate found in batches of Baxter's recalled heparin could not have caused the reported allergic reactions and deaths, because only some of the implicated batches contained the contaminant. In a weird turnaround, Chinese health officials state that they will visit Baxter's plant in New Jersey, presumably for inspection purposes. Baxter has numerous manufacturing facilities worldwide, including one in Cherry Hill, NJ.

Source: Reuters

Update: The Philly Inquirer reports that, in February, the FDA inspected Baxter's 372,000-square-foot facility in Cherry Hill, NJ, and observed no infractions.

*Jin Shaohong, deputy director-general of the China National Institute for the Control of Pharmaceutical and Biological Products.

A prospective study of 5 large cohorts (N > 1 million), presented Wednesday at the annual meeting of the American Academy of Neurology, showed that the relative risk of amyotrophic lateral sclerosis (n = 633) increased significantly with the duration of smoking and the number of cigarettes smoked per day (AAN abstract P04.076). Investigators reported that the multivariate-adjusted RR increased from 1.2 for 1-19 pack-years to 1.4 for ≥20 pack-years (P = .03), and that the risk did not vary by sex.

Investigators also reported the risk of ALS mortality as a function of chemical exposure in more than 1 million participants in the Cancer Prevention Study II (AAN abstract S25.005). From 1989 to 2002, the risk of death due to ALS (n = 937) was not associated with regular exposure (self-reported) to pesticides or herbicides (RR = 1.1). However, regular exposure to formaldehyde did increase the risk of ALS-related mortality (RR = 1.5), and this risk increased with more years of exposure.

Formaldehyde Exposure, y	RR	95% CI
<4	1.7	0.6, 4.7
4-10	2.4	0.9, 6.2
>10	4.3	2.1, 8.7

The investigators advised that this finding is unlikely the result of bias, because of the longitudinal design of the study. (It is important to remember that increased relative risks do not indicate cause-and-effect relationships.)

According to OSHA, formaldehyde exposure occurs most often by means of gas inhalation, but absorption of formaldehyde liquid through the skin is also possible. High-risk exposure is observed most commonly in the health care professions (particularly pathology and histology), in mortuary work (duh), and among students or teachers who handle preserved specimens.

Forehead-slapping insights like these explain why Andrew von Eschenbach's head of the FDA and you're not.

Physicians in Leipzig, Germany, identified lead intoxication in 29 regular smokers of marijuana, according to correspondence in the latest issue of the NEJM. Elemental lead was discovered by means of atomic absorptiometry or plain-old eyeball (left) in partially used weed samples from 3 of the affected users. It is believed by authorities that the lead was deliberately cut into the marijuana to increase its weight and therefore the profits from a street product that is sold by the gram. The lead is thought to be easily absorbed through the respiratory tract, once the tainted marijuana is smoked.

Photo: Close-up of partially used dime (euro) bag of marijuana with visible, grayish lead particles from the NEJM.

The FDA has released new information on the number of reported heparin-related deaths and the subset of deaths associated with allergic or hypotensive symptoms since January 2007. According to the FDA, there have been 103 reported deaths since the beginning of 2007, 91 (88%) of which were reported during 2008. Among these deaths, 62 (60%) were associated with one or more allergic or hypotensive reactions—the kinds of reactions that led to the recent recall of Baxter's heparin; 56 of the 62 were reported during 2008. The FDA advises that the presence of allergic or hypotensive symptoms does not necessarily indicate a cause of death.

 

Also according to FDA records, there were 55 heparin-associated deaths during 2006 in individuals with "a variety of underlying medical conditions." Only 3 were reported to be associated with allergic or hypotensive events.

*Heparin from any manufacturer.

According to the FDA, the chemically modified chondroitin sulfate found in lots of Baxter's recalled heparin made up as much as 50% of the product's raw ingredient, reports today's Chicago Tribune. The source of the faux heparin, derived from animal cartilage, is currently unknown; however, an expert suspects that the contaminant was deliberately put into Baxter's product, given that it was found in most batches (20 of 28) of the Chinese supplier's samples.