Charles A. McKay

Introduction to Special Issue: Use and Misuse of Metal Chelation Therapy

A 1-day symposium organized by the American College of Medical Toxicology (ACMT) was held at the CDC Conference Center in Chamblee, GA, on February 29, 2012, entitled “Use and misuse of metal chelation therapy” [1]. As physicians who specialize in the evaluation and treatment of patients with concerns about poisoning exposures, medical toxicologists frequently encounter patients who have had esoteric lab testing for environmental exposures or as a component of a workup of poorly defined neuropathies or other symptom complexes. The impetus for this conference was the widespread experience of these physicians with patients who had been treated for chronic symptoms incorrectly attributed to chronic metal toxicity. n nDuring the symposium, experts from a variety of backgrounds spoke to the importance of proper patient evaluation, historic and current use of diagnostic testing, and treatment for metal toxicity, including toxicity considerations for the commonly applied metal chelators. Paul Wax, MD, former president of the ACMT and its current executive director, provided a historical perspective on chelation, including the modern internet promotion of inappropriate chelation treatments. n nCarl Herbrandson, PhD, a toxicologist in the Minnesota Department of Public Health, described the questions presented to public health officials by both the public and medical providers regarding concern about environmental exposures and testing and interpretation of tests for metal exposure. He discussed the difficulties that public health officials have in responding to the lay publics’ requests for evaluation and concerns about some of the practitioner behavior cited by Dr. Wax. n nCharles Lee, MD, senior medical officer within the Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration (FDA), discussed the role of the Division of New Drugs and Labeling Compliance in attempting to track and counter illegitimate claims for chelating agents and unapproved indications [2]. n nRichard Wang, DO, a medical toxicologist in the Division of Laboratory Sciences in the National Center for Environmental Health (NCEH) of the Centers for Disease Control and Prevention (CDC), gave an important talk on the definition and derivation of “normal” laboratory test reference ranges. He emphasized factors that are critical to proper laboratory test interpretation, including the important distinction between a result that is “outside a reference range” and a “clinically relevant abnormal” result. In particular, Dr. Wang described the problem with using creatinine adjustment of urine results for children and women, using reference ranges for urinary creatinine excretion developed from adult men. n nTo further enhance our understanding of some of the important laboratory issues involved in testing for the very low concentrations of metals detectable in biologic matrices, Robert Jones, PhD, and Kathleen Caldwell, PhD, both of the Division of Laboratory Sciences of the NCEH, provided descriptions of the instrumentation, quality control procedures, and choice of biologic matrix that are critical for a given question of exposure in order to obtain a relevant, reliable, and reproducible test result. The absence of these careful analytical considerations in many commercial laboratories providing esoteric testing has been demonstrated in the past with hair testing [3] and is likely true of heavy metal testing today. n nMichelle Ruha, MD, a member of the board of directors of the ACMT, demonstrated the fallacy of using post-chelation challenge measurements of increased excretion of the compounds accessible to chelation as a marker of toxicity, particularly when compared to a non-chelated reference population. In particular, she discussed a simple study she and colleagues conducted, demonstrating the uselessness of one recently popular fad, transdermal DMPS [4, 5]. She expanded on Dr. Wang’s comments regarding creatinine-adjusted results by highlighting the implicit fraud of this method applied to post-challenge urine testing for metals. n nDonald Smith, PhD, Professor of Microbiology and Environmental Toxicology at the University of California at Santa Cruz, gave a presentation detailing the physiologic interaction of chelate and chelator (focusing on dimercaptosuccinic acid (DMSA)) and provided data for the efficacy of DMSA treatment of lead poisoning in primates. While early aggressive chelation removed lead from the brain of these animals, ongoing treatment had little effect. In both primate and rodent models, animals that were not lead exposed but given DMSA demonstrated impaired learning and memory similar to the lead-exposed animals. These results suggest that there is actual harm from chelation therapy when lead is only present at low concentrations. n nWalter Rogan, MD, a pediatrician who was the principal investigator in the National Institutes of Environmental Health Sciences Treatment of Lead-Exposed Children Trial (TLC), reviewed the conduct and findings of that pivotal study [6], which evaluated the impact of prolonged course(s) of DMSA chelation on IQ in more than 700 children with blood lead measurements between 20 and 44xa0μg/dL. Chelation treatment of moderate chronic lead poisoning did not improve intellectual ability or any subtest of neuropsychiatric performance, although blood lead can be decreased by treatment. He discussed the importance of the lead abatement component of the TLC study to decrease ongoing lead exposure. n nMary Jean Brown, ScD, from the Division of Emergency and Environmental Health Services of the NCEH/CDC discussed the impact of lead on our most vulnerable population, the human in utero. She reviewed CDC’s 2010 guidance document regarding the identification and management of lead exposure in pregnant and lactating women [7]. How do recommendations based on occupational or environmental exposure of adults apply to the rapidly developing fetus? Most would agree that some form of a precautionary approach in the face of uncertainty is warranted, but does that approach include consideration of chelation therapy? n nMichael Kosnett, MD, MPH, an occupational and environmental medicine physician specializing in medical toxicology at the University of Colorado and a previous president of the ACMT, discussed the historic and current role of chelation therapy in arsenic and mercury poisoning, highlighting the importance of dose and the actual biologic form of the toxin in terms of inducing toxicity as well as the critical element of time to treatment. n nSilas Smith, MD, a medical toxicologist at New York University, provided a review of the many other metals and metalloids that, from occupational or unique exposure settings, often need to be addressed by medical practitioners. He provided comments regarding evidence for and against the role of various chelating agents. n nIn addition, Jeffrey Brent, MD, PhD, a medical toxicologist at the University of Colorado and previous board member of ACMT, reviewed the complex psychosocial and medical issues evident in the controversy about vaccine safety, focusing on the mercury-containing preservative, thimerosal. Despite the fact that early reports linking thimerosal to pervasive developmental disorder or autism spectrum disorders have not been validated, and the seminal paper by Wakefield has been retracted by the Lancet [8], the controversy continues, reflecting more the polarity of worldviews than it does scientific uncertainty. Perhaps the most telling comment from Dr. Brent’s presentation was the red flag that should be raised when proponents conflate dire consequences related to massive exposures to a given element and attribution of serious disease to background levels of exposure in an individual. Combined with Dr. Ruha’s warnings about misapplying lab results and using non-appropriate comparison values, these comments form a reasonable basis for assessing the appropriate or inappropriate attribution of disease to these elements. n nDr. McKay, a medical toxicologist at the Hartford Hospital and the University of Connecticut and a member of the executive board of the ACMT, led a panel discussion to bring the key points generated in the day’s discussions to the practical question raised by Dr. Herbrandson: How do we as ethical practitioners respond to patients’ concerns about their environment, poisoning, and the legitimacy of varying claims for diagnosis, testing, treatment, and cure? n nWe have asked these experts and others to distill their presentations into short papers with sufficient references to provide guidance to the public and clinicians considering heavy metal poisoning. As you read through these presentations, we ask you to consider how the various aspects of exposure, completion of an exposure pathway, patient clinical presentation, careful laboratory testing, and interpretation all impact decisions regarding the use and misuse of metal chelation therapy. An article providing more detail on the analytical issues covered in the symposium by Dr. Wang, Dr. Jones, and Dr. Caldwell should appear in a future issue of the Journal of Medical Toxicology.

Toxin-induced Respiratory Distress

This article describes the impact of various toxic substances on the airway and pulmonary system. Pulmonary anatomy and physiology provide the basis for understanding the response to toxin-induced injury. Simple asphyxiants displace oxygen from the inspired air. Respiratory irritants include water-soluble and water-insoluble compounds. Several inhaled agents produce direct airway injury, which may be mediated by caustic, thermal, and hydrocarbon exposures. Unique pulmonary toxins and toxicants are discussed, as well as inhaled toxin mixtures. Several inhaled toxins may also impair oxygen transport. The pulmonary system may also provide a mechanism for systemic toxin delivery on respiratory exposure.

Intentional and Inadvertent Chemical Contamination of Food, Water, and Medication

Numerous examples of chemical contamination of food, water, or medication have led to steps by regulatory agencies to maintain the safety of this critical social infrastructure and supply chain. Identification of contaminant site is important. Environmental testing and biomonitoring can define the nature and extent of the event and are useful for providing objective information, but may be unavailable in time for clinical care. Clinical diagnosis should be based on toxidrome recognition and assessment of public health implications. There are several resources available to assist and these can be accessed through regional poison control centers or local/state public health departments.

Role of Chelation in the Treatment of Lead Poisoning: Discussion of the Treatment of Lead-Exposed Children Trial (TLC)

Lead exposure in children is one component leading to cognitive impairment. The Treatment of Lead-Exposed Children Trial (1994–2004) studied the effect of succimer in treating low levels of lead exposure (20–44xa0mcg/dL) in children 12 to 33xa0months old. While succimer was effective in reducing blood lead concentrations in the short term, treatment of blood lead levels did not result in any detectable improvement in a wide variety of measurements of cognitive or behavioral function. Furthermore, blood lead concentrations were not distinguishable between chelated and non-chelated individuals at 1xa0year. The most important treatment strategy is identification and termination of major sources of lead exposure.

Public Health Department Response to Mercury Poisoning: The Importance of Biomarkers and Risks and Benefits Analysis for Chelation Therapy

Chelation therapy is often used to treat mercury poisoning. Public health personnel are often asked about mercury toxicity and its treatment. This paper provides a public health department response to use of a mercury-containing cosmetic in Minnesota, a perspective on two unpublished cases of chelation treatment for postulated mercury toxicity, and comments on the use of a nonsystemic treatment for removal of mercury following the Iraqi seed coat poisoning incident. Physicians should evaluate sources of exposure, biomarkers, and risks and benefits before recommending chelation therapy for their patients. Potential risks to chelation therapy and its little understood subtle or latent effects are areas of public health concern.

ACMT and AACT Position Statement: Preventing Occupational Fentanyl and Fentanyl Analog Exposure to Emergency Responders

To cite this article: Michael J. Moss , Brandon J. Warrick, Lewis S. Nelson, Charles A. McKay, Pierre-André Dubé , Sophie Gosselin , Robert B. Palmer & Andrew I. Stolbach (2017): ACMT and AACT position statement: preventing occupational fentanyl and fentanyl analog exposure to emergency responders, Clinical Toxicology, DOI: 10.1080/15563650.2017.1373782 To link to this article: http://dx.doi.org/10.1080/15563650.2017.1373782

ACMT Position Statement: Alternative or Contingency Countermeasures for Acetylcholinesterase Inhibiting Agents

First responders and health care providers must prepare to provide care for patients poisoned by acetylcholinesterase (AchE) inhibitor chemical warfare agents or pesticides. However, pre-deployed medical countermeasures (MCMs) may not be sufficient due to production and delivery interruption, rapid depletion of contents during a response, expiration of MCM components, or lack of local availability of approved MCMs. To augment supplies of community-based and forward-deployed nerve agent countermeasures, the American College of Medical Toxicology (ACMT) supports several strategies: (1) The use of expired atropine, diazepam, and pralidoxime auto-injectors and vials if non-expired drugs are unavailable; and (2) Investigation, development, and identification of alternative countermeasures—commonly stocked drugs that are not approved for nerve agent poisoning but are in the same therapeutic class as approved drugs.

Commentary on “Transdermal DMPS”

Thus, did Jonathan Swift, an eighteenth century political activist, author, and satirist, characterize the art of political lying [1] several years before his writing of the allegorical Gulliver’s Travels, in which he lampooned the pseudoscientific fads and scams of his day. In this issue of the Journal of Medical Toxicology, Jennifer Cohen and colleagues provide a simple, elegant evaluation of a modern-day scam, so-called “TD-DMPS” [2]. The dermal application of a preparation of the chelating agent, sodium 2,3-dimercapto1-propanesulfonate (DMPS), has been promoted and reportedly patented [3] as a treatment for autism. Data exist on both the oral and parenteral absorption and kinetics of DMPS; and increased urinary excretion of a number of heavy metals occurs, irrespective of metal excess, when this compound (now renamed (RS)-2,3-bis(sulfanyl)propane-1sulfonic acid, 1 H2O sodium salt) is administered orally or parenterally [4]. However, there were no data available as to the dermal absorption of this compound. Cohen et al. obtained this non-FDA approved product via a compounding pharmacy and applied it to the skin of eight adult volunteers according to a protocol promoted by a practitioner still licensed in North Carolina [3]. Twelvehour complete urine collections (and a 24-h collection for one individual) were then assayed for both DMPS and changes in urine mercury excretion as an end point of chelator effectiveness. A positive control was also tracked after oral ingestion of the DMPS. There were no notable changes in urinary mercury excretion following dermal application of the DMPS. No subject had detectable plasma or urine DMPS when measured by the FDA Division of Pharmaceutical Analysis (other than one plasma sample from one patient which was thought to have been contaminated by DMPS on the skin at the time of blood draw). The manufacturer of DMPS (HEYL Chemischpharmazeutishce Fabrik) concludes in their product monograph (dated 2008) that

Editorial: Use and Misuse of Metal Chelation Therapy

The adjunctive role of metal chelation therapy for patients with acute exposure to large amounts of a variety of metals has long been accepted as playing a role in their care, although the value of chelating small quantities of metal has been appropriately questioned and prioritized below removal from ongoing exposure. The role for chelation in other conditions, such as subacute or chronic lead (Pb) exposure in children (or adults) and its role, or even the validity of a diagnosis of chronic metal toxicity, or a number of other entities attributed to chronic low-level exposure to a variety of other elements, is much more controversial. This is not just an esoteric question, as it has been estimated that nearly 200,000 people are chelated on multiple occasions annually throughout the USA [1]. As you read the articles in this issue regarding the use and misuse of metal chelation, notice that the range of estimated use is very broad among different groups, at least partially attributable to marketing and difficulty with regulation of non-prescription pharmaceuticals. Many of these treatments are performed by practitioners with a world view best described as “if it exists and has been described as harmful in some large amount, then getting rid of any amount will make you better.” While some doubtless sincerely believe this tautology, the prevalence of fraudulent testing and misdiagnosis is of great concern to American College of Medical Toxicology (ACMT) and public health entities. The basic premise that toxicity is a dose-related phenomenon involving the interaction of the toxin, host, and environment is still a foundational principle in toxicology. n nIt is illogical to argue at the same time that the consequences of exposure to heavy metals are so great as to “threaten a generation” while at the same time arguing that the changes are too subtle to be identified. Combined with warnings in the articles of this issue about misapplying lab results and using non-appropriate control values, a number of “red flags” can be identified, raising concern about misuse of testing and treatment for metal exposure or toxicity. n n nSome practitioners who provide post-provocation testing and chelation therapy for the erroneous diagnosis of chronic metal poisoning may just be ignorant of the problems with testing and treatment as outlined in the proceedings of the ACMT symposium and summarized in the papers of this issue. Others derive significant profit from the practice. For ethical providers attempting to address patient concerns and provide appropriate diagnoses and treatment, decisions about heavy metal exposures require attention to the following: n n npatient clinical presentation and differential diagnosis; n n npatient preparation for laboratory testing, including attention to diet and supplement intake; n n nappropriate selection of biologic matrix for testing; n n nassessment of the role of implanted devices (amalgam, prostheses) in altering test results; and n n nappropriateness of reference/comparison groups. n n n n nAll of these factors impact the interpretation of clinical and laboratory results. To assist in this process, the ACMT has provided a practice guideline and previously published an editorial addressing some of these issues [2, 3]. Another toxicology organization, the American Academy of Clinical Toxicology (AACT), has also published guidance for the public in conjunction with the Pediatric Environmental Health Specialty Units (PEHSU) [4]. A guideline in development by the ACMT and the American College of Occupational and Environmental Medicine (ACOEM) should also assist in this challenging area.

ACMT position statement: Dietary supplements

ConclusionsHerbal medication use as a dietary supplement is common. Many Americans use these products, federal legislation has implemented the USDSHEA, and there is now a National Center for Complementary and Alternative Medicine at NIH. Ethical herbal medication use of those single substances shown to be effective is growing. When patients are taking dietary supplements or herbal medications, the ingredients, origin, and potential toxicity or herb-drug interactions need to be determined. Education concerning these products and their potential toxicity, adverse effects, and interactions should become an essential component of medical toxicology. Clinicians caring for patients who may self-administer these products should attempt to obtain this history and familiarize themselves with the potential problems. The American College of Medical Toxicology strongly recommends consultation with or care by a medical toxicologist in cases of suspected or confirmed toxicity, adverse effects, or interactions from dietary supplements. We further encourage patients to report their use of these supplements to their physicians. FDA supervised labeling now requires a “Supplement Facts” label on each dietary supplement bottle marketed in the U.S. that describes and quantitates ingredients; supplements that do not have such a label should be used cautiously, if at all. The ACMT strongly supports the FDA’s plan to further review and regulate dietary supplements where clinical experience or scientific information suggests the possibility of harm.