John A. Curtis

Nanotechnology and nanotoxicology : A primer for clinicians

Nanotechnology is the manipulation of matter in dimensions <100nm. At this size, matter can take on different chemical and physical properties, giving the products characteristics useful to industry, medicine and technology. Government funding and private investors provide billions of research dollars for the development of new materials and applications. The potential utility of these technologies is such that they are expected be a trillion-dollar industry within the next 10 years.However, the novel properties of nanoengineered materials lead to the potential for different toxicity compared with the bulk material. The field of nanotoxicology is still in its infancy, however, with very limited literature regarding potential health effects. Inhalational toxicity is to be expected, given the known effects of inhaled fine particulate matter. However, the degree to which most nanoparticles will aerosolise remains to be determined. It has been proposed that dermal exposure will be the most relevant route of exposure, but there is considerably less literature regarding dermal effects and absorption. Less defined still are the potential effects of nanoproducts on fetal development and the environment.

Technologically enhanced naturally occurring radioactive materials.

Introduction. Naturally occurring radioactive materials (NORM) are ubiquitous throughout the earths crust. Human manipulation of NORM for economic ends, such as mining, ore processing, fossil fuel extraction, and commercial aviation, may lead to what is known as “technologically enhanced naturally occurring radioactive materials,” often called TENORM. The existence of TENORM results in an increased risk for human exposure to radioactivity. Workers in TENORM-producing industries may be occupationally exposed to ionizing radiation. TENORM industries may release significant amounts of radioactive material into the environment resulting in the potential for widespread exposure to ionizing radiation. These industries include mining, phosphate processing, metal ore processing, heavy mineral sand processing, titanium pigment production, fossil fuel extraction and combustion, manufacture of building materials, thorium compounds, aviation, and scrap metal processing. Methods. A search of the PubMed database (www.pubmed.com) and Ovid Medline database (ovidsp.tx.ovid.com) was performed using a variety of search terms including NORM, TENORM, and occupational radiation exposure. A total of 133 articles were identified, retrieved, and reviewed. Seventy-three peer-reviewed articles were chosen to be cited in this review. Results. A number of studies have evaluated the extent of ionizing radiation exposure both among workers and the general public due to TENORM. Quantification of radiation exposure is limited because of modeling constraints. In some occupational settings, an increased risk of cancer has been reported and postulated to be secondary to exposure to TENORM, though these reports have not been validated using toxicological principles. Conclusions. NORM and TENORM have the potential to cause important human health effects. It is important that these adverse health effects are evaluated using the basic principles of toxicology, including the magnitude and type of exposure, as well as threshold and dose response.

Serotonin syndrome triggered by a single dose of suboxone

Suboxone (buprenorphine/naloxone) is an oral medication used for the treatment of opiate dependence. Because of its mixed properties at the opiate receptors, buprenorphine has a ceiling on its euphoric effects. We report the first case of serotonin syndrome caused by buprenorphine and review other medications implicated in serotonin syndrome. A 54-year-old man on tricyclic antidepressants took an unprescribed dose of buprenorphine/naloxone. He presented to the emergency department with signs and symptoms of severe serotonin syndrome including clonus, agitation, and altered mental status. His agitation was not controlled with benzodiazepines and was electively intubated. At the recommendation of the toxicology service, cyproheptadine, a serotonin receptor antagonist, was administered with improvement in the patients symptoms. Emergency physicians should be aware of the potential of buprenorphine/naloxone to trigger serotonin syndrome.

The perception of odor is not a surrogate marker for chemical exposure: a review of factors influencing human odor perception

Context. Clinical toxicologists perform risk assessments and clinical evaluations for patients with potential exposure to airborne toxicants in which the patients self-reported perception of odor may be the only indicator that an exposure may have taken place. Objective. To review the factors that may affect the human ability to perceive chemical odors and relate those odors to specific chemical exposures. Methods. The medical literature, from 1950 through 2012, was searched using the OVID database and the PUBMED database. The searches returned 238 articles, of which 113 involved human studies and were published in the English language. Of these 113 articles, 40 articles discussed odor issues and thus were chosen as specifically relevant to the topic. Bibliographies of all articles were also searched for other relevant references and this found six additional articles, making a total of 46. Factors that may affect olfaction and the ability to perceive odor. Genetic/population. Ethnic background is associated with widely differing odor detection abilities and thresholds. A significant genetic influence for the ability to smell and perceive odor has been reported. Gender. Women are superior to men in their ability to identify odors. Age. Increasing age is correlated with higher odor detection thresholds. Medical conditions. A variety of medical conditions have been associated with deficits in olfaction, including diseases of the nose and sinuses, multiple sclerosis, and schizophrenia. Alcoholism and smoking. Abuse of alcohol results in impaired olfactory sense, and smoking tobacco products alters odor detection threshold in a dose-related manner. Occupational and environmental factors. Repeated inhalation of any chemical results in olfactory fatigue over relatively short time frames that leads to a decreased ability to accurately detect and identify an odor. Recent exposure to relatively high concentrations of a chemical has been shown to affect sensitivity to that particular odorant, altering subsequent detection thresholds by up to three orders of magnitude. Applicability of proposed odor thresholds. Humans are only able to identify three to four components of complex olfactory mixtures and the odorants present in the mixture affect which individual components are detected. Odorants present in suprathreshold concentrations in a mixture may effectively mask the presence of odorants present in perithreshold concentrations. Self-rating of olfactory function may not correlate with actual olfactory ability. It is even more difficult to accurately determine intensity of an odor in a quantifiable way. For example, under conditions of constant stimulation with hydrogen sulfide, perceptual intensity was reported to decrease exponentially with time of stimulation. Concomitant visual stimulation also affects odor intensity. Some chemicals, such as hydrogen sulfide, may induce reactions in humans related solely to their odor, even when they are present in concentrations substantially lower than those levels usually associated with the development of adverse clinical effects. There is a wealth of literature suggesting that the intensity of perceived odor, the degree of irritation, and the reported health effects of exposure to an odorant chemical are affected by psychological state and bias. Multiple theories have been proposed to explain the cognitive basis for perceived illness in association with the perception of odor. The concept of odor has been reported to be intrinsically and cognitively associated with illness rather than with health. Assigning negative bias to an odor prior to an exposure results in the reporting of significantly more health-related symptoms following exposure. This suggests that those symptoms are not mediated by the odor directly, but rather by an individuals cognitive associations between odor and health. Conclusions. Attempts to verify exposure intensity based on the report of a perceived odor is unreliable and has no useful application in legitimate exposure assessment paradigms. Detection of an odor does not imply a medically significant exposure to a toxicant and, due to subject bias and the difficulty of detecting individual odorants in mixtures, may not constitute an exposure to the purported substance.

Biological testing for drugs of abuse

Testing for drugs of abuse has become commonplace and is used for a variety of indications. Commonly employed testing methods include immunoassay and chromatography. Testing methods vary in their sensitivity, specificity, time, and cost. While urine remains the most common body fluid used for testing of drugs of abuse, over the last several decades the use of alternative matrices such as blood, sweat, oral fluids, and hair has increased dramatically. Each biological matrix offers advantages and disadvantages for drug testing, and the most appropriate matrix frequently depends on the indications for the drug test. Drugs of abuse that are most commonly tested include alcohol, amphetamines, cannabinoids, cocaine, opiates, and phencyclidine. Testing may involve detection of the parent compound or metabolites and sensitivity, specificity, and reliability of drug testing may vary depending on the drug being tested. Toxicologists have a responsibility to understand the strengths and limitations of testing techniques and matrices to be able to critically evaluate the results of a drug test.

Screening for drugs of abuse: hair as an alternative matrix: a review for the medical toxicologist.

Biological testing for drugs of abuse has a long history. It has been performed using a variety of different body fluids and tissues and for many different purposes, including historical interest, criminal investigation, medical monitoring, and screening for employment. Today, the vast majority of testing for drugs of abuse is performed for employment purposes and in the criminal justice system. Widespread testing for pre-employment screening represents a trend towards greater involvement of employers in the lives of the workforce. Early efforts in this regard include an attempt of the Ford Motor Company in 1914 to link employee profit sharing to evaluations of the quality of employee’s home lives by members of their corporate sociological department (1). While sobriety was only one of the aims of this early program, it is indicative of a trend that has extended drug testing to a large segment of the U.S. population. This results in an enormous number of tests whose results must be interpreted, and occasionally disputed. This had led to the development and evolution of a medico-legal drug-testing industry that relies on physician Medical Review Officers (MROs) and medical toxicologists for their expertise in these areas. The U.S. government began mandatory testing for drugs of abuse in the U.S. Army in an attempt to control what was perceived as the widespread abuse of cheap, illicit narcotics available to troops serving in Vietnam. During the 1980’s this policy was broadened to include the other branches of the military (2). Mandatory drug testing was then extended to federal employees in 1986 when President Reagan established the “Drug Free Workplace” with Executive Order 12564, which required testing of federal employees under the settings of reasonable suspicion, positions dealing with sensitive information or those affecting public safety (3). Many employers in the private sector have been equally interested in screening their employees in hopes of improving worker health and productivity. Testing for drugs of abuse has been conducted using a variety of matrices including urine, blood, saliva, oral fluid, and hair. Each technique has advantages and disadvantages relating to ease of testing, potential windows of detection, social acceptability of the test, and reliability of results. Currently, the majority of routine screens for drugs of abuse uses urine, and the Federal Register reports over 45 laboratories certified to perform urine testing for federal agencies. The efficacy and propriety of suspicionless drug testing continue to inspire debate. While cost-benefit analyses are difficult to perform, there is some evidence that industries experienced a lowering of injury rates and medical costs as drug-screening programs were phased in. One large laboratory, annually conducting millions of tests of employees in the general U.S. workforce, reports a decline in the rates of positivity from 13.6% in 1988 to the slightly higher than 4% in 1998. The percentage of positive tests has since remained relatively constant (4). Thus, the frequency of positive tests declined significantly in the decade following the widespread inception of employee drug testing, although it is unclear whether this reflects changing societal behavior patterns, a deterrent effect of mandatory testing, or more widespread testing resulting in a lower pretest probability. The overall decline in the numbers of positive tests may also reflect the fact that the workforce has become more aware of the limitations of urine drug screens. Drug users may therefore have become more adept at deceiving urine drug screens through various strategies, including sample switching, adulteration, and, most importantly, planned abstinence prior to an anticipated test. Testing of hair samples for drugs of abuse has been proposed as a potentially effective means of circumventing some of the limitations inherent to the standard urine drug screen. The use of hair as a biological matrix for detection of xenobiotics is not a recent phenomenon, and actually dates back over 150 years (5). While early efforts focused on forensic testing for heavy metals in criminal cases, the last half Received 12 August 2006; accepted 5 February 2007. Address correspondence to Michael Greenberg, Drexel College of Medicine, 245 North Broad Street, MailStop 1011, Philadelphia, Pennsylvania, 19102 USA. E-mail: jac67@drexel.edu C lin ic al T ox ic ol og y D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y M cM as te r U ni ve rs ity o n 11 /0 6/ 14

Case Files of the Medical Toxicology Fellowship at Drexel University Rhabdomyolysis and Compartment Syndrome Following Acute Diphenhydramine Overdose

This case report was presented in poster form at the EAPCCT conference in 2009 in Stockholm, Sweden.

The Prevalence of Fentanyl in Drug-Related Deaths in Philadelphia 2004–2006

Fentanyl is an increasingly common drug of abuse. The Philadelphia Medical Examiners Office reported 252 drug-related deaths in Philadelphia that tested positive for fentanyl during the year 2006 in comparison to 22 and 19 in 2005 and 2004, respectively. We reviewed the data from 2004 to 2006 from the Philadelphia Medical Examiners office. Key words such as fentanyl, drug, cocaine, ethanol, medic (medication), tox (intoxication), or poison were used as search words. In comparison to 2004 and 2005 data, there was a statistically significant increase in number of drug-related deaths (DRDs) and the percentage of DRDs that tested positive for fentanyl in 2006. We postulate that the increase in DRDs in 2006 may be related to increase use or abuse of fentanyl, lack of general public awareness that fentanyl is a potent opioid, inadequate dose of nalaxone and/or the surge of clandestinely manufactured fentanyl.

Legal liability of medical toxicologists serving as poison control center consultants: A review of relevant legal statutes and survey of the experience of medical toxicologists

IntroductionLegal liability is an increasing concern in many areas of medicine, although the extent to which this alters the practice of medicine is unclear. To date the risk for litigation against medical toxicologists serving in the role of poison control center (PCC) consultants has not been assessed.MethodsA survey questionnaire was mailed to medical toxicologists in the United States to assess their litigation history with regard specifically to their role as PCC consultants. In addition, state laws were examined for statutes that provide protective language with regard to medical toxicologists working as PCC consults.ResultsThis survey revealed that most medical toxicologists have served or currently serve as PCC consultants. Most had some degree of concern over legal liability, and several had been sued as a result of PCC consultations. Several states have specific statutes that limit the legal liability of PCCs and their employees, including medical directors and consulting medical toxicologists.DiscussionBased on the survey results, legal action against toxicologists serving as PCC consultants appears to be an uncommon occurrence. Lawsuits are usually based upon nonfeasance and have typically been settled or dropped before trial.ConclusionsLegal liability is a concern for PCC consultants. However, legal action against consultants appears to be rare, and respondents to the survey indicated that it did not affect their advice or willingness to serve as PC consultants. A limited number of states have enacted laws that provide protection for medical toxicologists serving as PCC consultants.