Michele M. Burns

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment

Abstract The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is “probably carcinogenic to humans” (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC’s assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies. Two of the Panels (animal bioassay and genetic toxicology) also provided a critique of the IARC position with respect to conclusions made in these areas. The incidences of neoplasms in the animal bioassays were found not to be associated with glyphosate exposure on the basis that they lacked statistical strength, were inconsistent across studies, lacked dose-response relationships, were not associated with preneoplasia, and/or were not plausible from a mechanistic perspective. The overall weight of evidence from the genetic toxicology data supports a conclusion that glyphosate (including GBFs and AMPA) does not pose a genotoxic hazard and therefore, should not be considered support for the classification of glyphosate as a genotoxic carcinogen. The assessment of the epidemiological data found that the data do not support a causal relationship between glyphosate exposure and non-Hodgkin’s lymphoma while the data were judged to be too sparse to assess a potential relationship between glyphosate exposure and multiple myeloma. As a result, following the review of the totality of the evidence, the Panels concluded that the data do not support IARC’s conclusion that glyphosate is a “probable human carcinogen” and, consistent with previous regulatory assessments, further concluded that glyphosate is unlikely to pose a carcinogenic risk to humans.

Activated charcoal as the sole intervention for treatment after childhood poisoning.

Childhood poisonings account for approximately two thirds of all human toxic exposures reported annually to the American Association of Poison Control Centers. Activated charcoal (AC) is the mainstay of decontamination in the emergency department setting. This review focuses on six concepts: 1) description of AC and its method of action, 2) evolution of AC in the gastrointestinal decontamination process, 3) prehospital use of AC, 4) superactivated charcoal, 5) multiple-dose AC, and 6) complications of AC administration. The most recent evolving trends in decontamination of the pediatric patient include trends toward earlier decontamination, either in the home or by paramedics in the field. The newer, “super” activated charcoals, with their greater surface area, may improve compliance of oral administration of AC. Finally, guidelines have been set to limit use of multiple-dose activated charcoal regimens to certain pharmaceuticals only, as well as discouraging cathartic use with charcoal dosing.

Alternative medicine: herbal preparations

Abstract An extraordinary escalation has occurred in the number of individuals who use herbal preparations or essential oils, either alone or in combination with other alternative medicine practices, over the last decade in the United States. Currently, there is no regulation of the safety or efficacy of these products, but the National Institutes of Health is supporting research in this area. This report reviews 20 popular herbs and essential oils, with emphasis on their potential toxicity and interactions.

A Literature Review of the Use of Sodium Bicarbonate for the Treatment of QRS Widening

Sodium bicarbonate is a well-known antidote for tricyclic antidepressant (TCA) poisoning. It has been used for over half a century to treat toxin-induced sodium channel blockade as evidenced by QRS widening on the electrocardiogram (ECG). The purpose of this review is to describe the literature regarding electrophysiological mechanisms and clinical use of this antidote after poisoning by tricyclic antidepressants and other agents. This article will also address the literature supporting an increased serum sodium concentration, alkalemia, or the combination of both as the responsible mechanism(s) for sodium bicarbonate’s antidotal properties. While sodium bicarbonate has been used as a treatment for cardiac sodium channel blockade for multiple other agents including citalopram, cocaine, flecainide, diphenhydramine, propoxyphene, and lamotrigine, it has uncertain efficacy with bupropion, propranolol, and taxine-containing plants.

Glyphosate rodent carcinogenicity bioassay expert panel review

Abstract Glyphosate has been rigorously and extensively tested for carcinogenicity by administration to mice (five studies) and to rats (nine studies). Most authorities have concluded that the evidence does not indicate a cancer risk to humans. The International Agency for Research on Cancer (IARC), however, evaluated some of the available data and concluded that glyphosate probably is carcinogenic to humans. The expert panel convened by Intertek assessed the findings used by IARC, as well as the full body of evidence and found the following: (1) the renal neoplastic effects in males of one mouse study are not associated with glyphosate exposure, because they lack statistical significance, strength, consistency, specificity, lack a dose-response pattern, plausibility, and coherence; (2) the strength of association of liver hemangiosarcomas in a different mouse study is absent, lacking consistency, and a dose-response effect and having in high dose males only a significant incidence increase which is within the historical control range; (3) pancreatic islet-cell adenomas (non-significant incidence increase), in two studies of male SD rats did not progress to carcinomas and lacked a dose-response pattern (the highest incidence is in the low dose followed by the high dose); (4) in one of two studies, a non-significant positive trend in the incidence of hepatocellular adenomas in male rats did not lead to progression to carcinomas; (5) in one of two studies, the non-significant positive trend in the incidence of thyroid C-cell adenomas in female rats was not present and there was no progression of adenomas to carcinomas at the end of the study. Application of criteria for causality considerations to the above mentioned tumor types and given the overall weight-of-evidence (WoE), the expert panel concluded that glyphosate is not a carcinogen in laboratory animals.

Clinical effects of unintentional pediatric buprenorphine exposures: experience at a single tertiary care center

Abstract Context: Exploratory buprenorphine ingestions in young children have been associated with clinically significant toxicity. However, detailed data on the clinical presentation and management of these patients are lacking. In an attempt to obtain more comprehensive data, we sought to examine a single center cohort of patients with report of buprenorphine exposure and provide descriptive analysis of rates of respiratory depression, time to respiratory depression, interventions, disposition, and outcomes. Study design: We performed a retrospective cohort study at a single pediatric tertiary care center of children between the age of 6 months and 7 years of age hospitalized between 1 January 2006 and 1 September 2014 with report of buprenorphine or buprenorphine/naloxone exposure. Patients with possible exposure to more than one agent were excluded. We extracted clinical findings, including time to respiratory depression, interventions, and disposition from the medical record. Results: Eighty-eight patients met the inclusion criteria. Seven patients were excluded. The median age was 24 months [IQR 18–30]. 20 patients (23%) received activated charcoal while 48 (55%) were treated with naloxone. 36 (41%) patients were admitted to the ICU. Observed clinical effects included respiratory depression (83%), oxygen saturation by pulse oximetry (SpO2) < 93% (28%), depressed mental status (80%), miosis (77%), and emesis (45%). Median time from exposure to respiratory depression was 263 min [IQR 105–486]. The median hospital length of stay was 22 h [IQR 20–26] and was positively associated with estimated exposure dose (p = 0.002). Conclusion: Pediatric patients exposed to buprenorphine are likely to exhibit signs and symptoms of opioid toxicity, including respiratory depression, altered mental status and miosis. Although the majority of patients developed signs of clinical toxicity within 8 h of reported exposure, the optimum duration of monitoring remains unclear.

Ocular irrigant alternatives in pediatric emergency medicine

Abstract: Minimizing pain and discomfort is an important consideration in pediatric ocular decontamination. The pH of an irrigant solution plays a significant role in its tolerability, because a solution with a pH that is too low or too high may cause edema and discomfort to the conjunctiva. We reviewed several available ocular irrigation solutions with respect to their chemical composition, pH, and cost efficiency. Currently, the irrigation solution of first choice for most ocular decontaminations in the pediatric emergency department (ED) is 0.9 % saline solution or normal saline (NS), which has a pH range between 4.5 and 6.0. Alternative ocular irrigant solutions available include Lactated Ringers solution (LR), which has a pH range between 6.2 and 7.5, buffered NS with pH adjusted to 7.4 with sodium bicarbonate, and Balanced Salt Solution Plus (BSS Plus), which has a pH of 7.4. Of these alternative solutions, all except BSS Plus are comparable in cost efficiency to NS. The use of more pH neutral solutions such as LR, NS with bicarbonate buffer, or BSS Plus may decrease ocular pain and irritation associated with copious irrigation, and may improve tolerance of ocular decontamination by a child.

Drug-Drug Interactions Among Hospitalized Children Receiving Chronic Antiepileptic Drug Therapy.

OBJECTIVES Children treated with chronic medications are at risk of drug-drug interactions (DDIs) when hospitalized with an acute illness and prescribed new medications. We aimed to measure the prevalence of potential DDIs (pDDIs) among hospitalized children treated with antiepileptic drugs (AEDs) and to evaluate the impact of computerized physician order entry (CPOE) on pDDIs. METHODS We analyzed a national sample of pediatric hospitalizations from 2005 to 2012 associated with administration of an AED and identified those prescribed a second medication with risk of a DDI. The prevalence of hospitalizations associated with a pDDI was calculated for each AED. We identified the drugs most commonly implicated in pDDIs and factors associated with pDDIs. Rates of pDDIs were measured in pre- and post-CPOE implementation periods. RESULTS A pDDI was identified in 181 380 (41.7%) hospitalizations associated with the use of an AED, with 117 880 (27.1%) classified as severe pDDIs. AEDs most often implicated with a pDDI were phenobarbital, valproic acid, and phenytoin. Hospitalizations with pDDIs were associated with increased length of stay and a greater number of medications, ICU admissions, and operating room procedures. The implementation of CPOE did not result in a change in the rate of pDDIs (42.7% before versus 40.8% after; P = .48). CONCLUSIONS Children treated with AEDs are at risk of pDDIs while hospitalized. The use of CPOE has not been associated with a significant decrease in the rate of pDDIs. Additional investigation to better define the impact of pDDIs and to advance development of clinical decision support within CPOE systems is warranted.

The Poisoned Pediatric Patient

1. Michael S. Toce, MD, MS* 2. Michele M. Burns, MD, MPH*,† 1. *Harvard Medical Toxicology Program and 2. †Division of Emergency Medicine, Department of Medicine, Boston Children’s Hospital, Boston, MA * Abbreviations: AGMA: : anion gap metabolic acidosis ALT: : alanine aminotransferase APAP: : acetaminophen ASA: : acetylsalicylic acid AST: : aspartate aminotransferase Cl-: : chloride ECG: : electrocardiogram GI: : gastrointestinal GSH: : glutathione HCO3−: : bicarbonate IV: : intravenous K+: : potassium NAC: : N-acetylcysteine NAPQI: : N-acetyl-p-benzoquinoneimine NPDS: : National Poison Data System PO: : oral Poisonings remain a frequent source of morbidity and mortality in the pediatric age group. All pediatricians, whether in training or in practice, encounter these patients, yet toxicologic training is lacking in most pediatric residencies. After completing this article, readers should be able to: 1. Understand the epidemiology of pediatric poisonings and explain how developmental milestones influence behavior that may lead to a poisoning exposure. 2. Perform a focused toxicologic physical examination and describe the various toxidromes. 3. Explain the primary acid-base disturbance in salicylate toxicity. 4. Determine which patient requires treatment after acute acetaminophen ingestion. 5. Provide the differential diagnosis of an anion gap metabolic acidosis. 6. Identify which drugs can lead to QRS and QTc prolongation and the treatment for each abnormality. 7. Describe the toxicologic differential diagnosis for hypoglycemia and explain the physiologic reasons why pediatric patients are at increased risk for complications. This review focuses on the epidemiology and initial evaluation and treatment of the poisoned pediatric patient. We emphasize the diagnosis and treatment of acetaminophen and aspirin toxicity, identifying and treating prolonged QRS/QTc, and developing a differential diagnosis for an anion gap metabolic acidosis (AGMA) and hypoglycemia (Table 1). View this table: Table 1. Introduction to the Poisoned Patient Pediatric exposures and poisonings continue to be a significant cause of morbidity and mortality. According to the 2014 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), 1,326,789 toxic exposures occurred in children younger than age 20 years in 2014, representing 1,595 exposures per 100,000 …

An Altered, Unresponsive Teenager in the Emergency Department

*Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, †Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, ‡Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, §Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, kDepartment of Neurology, Harvard Medical School, Boston, Massachusetts, {Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, #Department of Emergency Medicine, Boston Children’s Hospital, Boston, Massachusetts, and **Regional Center for Poison Control and Prevention, Boston, Massachusetts Reprint Address: Emily S. Miller, MD, Department of Emergency Medicine, Massachusetts General Hospital, Zero Emerson Place, Suite 3B, Boston, MA 02118