Iron Packaging Regulations in the United States and Pediatric Morbidity: A Retrospective Cohort Study.

Iron poisoning was a leading cause of pediatric morbidity and mortality. We sought to assess whether the removal of strict iron packaging requirements in 2003 resulted in an increase in iron-related morbidity and mortality in pediatric exposures. We performed a retrospective cohort study utilizing the National Poison Data System from 2000 to 2017. A total of 4110 exposures met inclusion criteria: 847 from before (2000-2003) and 3263 after removal of unit-dose package regulations (2004-2017). The incidence of any marker of severity (7.2% vs 3.8%; odds ratio = 0.51, 95% confidence interval = 0.37-0.69) and frequency of deferoxamine use were both higher in the early time period (2.6% vs 1.0%; odds ratio = 0.38, 95% confidence interval = 0.22-0.66). There was no difference in the frequency of key serious effects (acidosis, elevated transaminases, hypotension). Despite removal of iron packaging regulations in the United States, there continues to be a decrease in the incidence of severe iron exposures in children.

Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment.

INTRODUCTION: Iron (Fe) and manganese (Mn) are essential nutrients for humans. They act as cofactors for a variety of enzymes. In the central nervous system (CNS), these two metals are involved in diverse neurological activities. Dyshomeostasis may interfere with the critical enzymatic activities, hence altering the neurophysiological status and resulting in neurological diseases. Areas covered: In this review, the authors cover the molecular mechanisms of Fe/Mn-induced toxicity and neurological diseases, as well as the diagnosis and potential treatment. Given that both Fe and Mn are abundant in the earth crust, nutritional deficiency is rare. In this review the authors focus on the neurological disorders associated with Mn and Fe overload. Expert commentary: Oxidative stress and mitochondrial dysfunction are the primary molecular mechanism that mediates Fe/Mn-induced neurotoxicity. Although increased Fe or Mn concentrations have been found in brain of patients, it remains controversial whether the elevated metal amounts are the primary cause or secondary consequence of neurological diseases. Currently, treatments are far from satisfactory, although chelation therapy can significantly decrease brain Fe and Mn levels. Studies to determine the primary cause and establish the molecular mechanism of toxicity may help to adapt more comprehensive and satisfactory treatments in the future.

Iron overdose epidemiology, clinical features and iron concentration-effect relationships: the UK experience 2008-2017.

Background: Iron poisoning is potentially serious, but mortality has fallen worldwide since implementation of pack size and packaging restrictions, and changes in iron use during pregnancy. The management of individual cases of overdose remains problematic due to uncertainty about indications for antidote. We examine the epidemiology of iron overdose in hospital cases referred to the UK National Poisons Information Service (NPIS) and evaluate the toxicokinetics of iron in patients ingesting only iron preparations. Methods: Anonymized hospital referral patient data from the NPIS database were collated for the period 1 January 2008 to 31 July 2017. Information was extracted, where recorded, on type of ingestion [iron alone (single), or combined with other agents (mixed)], reported dose, iron salt, timed iron concentrations and symptoms. In single-agent ingestions, the relationships between reported elemental iron dose, early concentrations (4-6 h), and symptoms were evaluated in teenagers and adults (≥13 years) and children (≤12 years) using standard statistical techniques (correlation and unpaired nonparametric comparisons). In those patients with sufficient sample points (three or more), a simple kinetic analysis was conducted. Results: Of 2708 patients with iron overdoses referred by UK hospitals for advice during the 9.7 years study period, 1839 were single-agent ingestions. There were two peaks in age incidence in single-agent exposures; 539/1839 (28.4%) were <6 years (54.1% males) while 675/1839 (36.7%) were between 13 and 20 years (91% females), the latter a substantial excess over the proportion in the totality of hospital referrals to the NPIS in the same period (13-20 years: 23,776/144,268 16.5%; 67.5% female) (p < .0001 overall and for female %). In 475 teenagers and adults and 86 children, with at least one-timed iron concentration available, there was no correlation between stated dose and iron concentration measured 4-6 h post-ingestion. Observed peak iron concentrations were not related to reported symptoms in adults. Initial iron concentrations were significantly higher in 30 patients (25 adults, 5 children) who received desferrioxamine (DFO) compared to those that did not [no DFO: mean 63.8 µmol/L (95% CI 62.1-65.6), median 64; DFO: mean 78.5 µmol/L (95% CI 69.2-87.7), median 78.1; Mann-Whitney p < .0018). No significant differences in symptoms were observed pre-treatment between DFO-treated and untreated groups. No patients died in this cohort. Conclusion: Single-agent iron exposures reported from UK hospitals were most common in children <5 years and young people aged 13-20 years. Poisoning with organ failure was not identified and there were no fatalities. No correlations were observed between reported iron doses and early concentrations, or between iron concentrations and symptoms in this cohort of mild-to-moderate poisoning.

In vitro and in vivo assessment of EDTA-modified silica nano-spheres with supreme capacity of iron capture as a novel antidote agent.

Mesoporous silica nanoparticles having structure of MCM-41 category with amine and EDTA functional groups in the pores were prepared using a co-condensation reaction. The synthetic steps eventuated in the mesoporous silica nanoparticles with spherical sizes lower than 50nm supposed to have high surface area. The nanoparticles' structure and functionality were characterized by FTIR spectroscopy and CHN analysis and the topography were examined by SEM and TEM and hydrodynamic sizes were demonstrated by DLS. The crystallinity and mesoporous pattern were figured out by XRD technique. Then the efficiency of these materials was tested in vitro and in vivo in adsorbing ferrous sulfate which is a supplement normally prescribed in treating iron deficiency and its overdose is potentially lethal, especially in young children. In vivo experiments illustrated that both nanoparticles could efficiently be administrated as an antidote agent against iron overdose, but EDTA-MSN nanoparticles were superior to NH2-MSN nanoparticles.

Interleukin-6 and lipopolysaccharide modulate hepcidin mRNA expression by HepG2 cells.

Iron homeostasis is controlled by hepcidin (Hpc) as well as other ways. Hpc expression is regulated by iron (Fe) storage and by inflammation, but the joint effect of both stimuli remains unclear. We studied the modulatory role of inflammatory agents (IL6 and LPS) over Hpc and DMT1 mRNA expression in HepG2 cells preloaded with Fe. HepG2 cells were preloaded with different Fe concentrations (holo-Tf or Fe-NTA) and then incubated with IL6 or LPS. We measured intracellular Fe levels by AAS with graphite furnace, transferrin receptor (TfR) by ELISA and mRNA relative abundance of Hpc and DMT1 by qRT-PCR. The maximum effect on Fe uptake was observed in cells incubated with 30 ng/ml IL6 (p < 0.01) and 500 ng/ml LPS (p < 0.05). In HepG2 cells preloaded with holo-Tf or Fe-NTA and challenged with IL6 and LPS, we observed a decreased: (a) Hpc mRNA relative abundance (two-way ANOVA: p < 0.05 and p < 0.001, respectively), (b) DMT1 mRNA relative abundance and TfR1 protein levels (two-way ANOVA: p < 0.001), and (c) intracellular Fe concentration (two-way ANOVA: p < 0.001 and p < 0.01, respectively) compared to control cells incubated only with Fe (holo-Tf or Fe-NTA). Our results support the idea that Fe storage and inflammation act together to regulate Fe homeostasis and suggest a negative regulation in this hepatic cellular model to prevent excessive increases in Hpc.

A comparison of the biological activities of human osteoblast hFOB1.19 between iron excess and iron deficiency.

Bone metabolism has a close relationship with iron homeostasis. To examine the effects of iron excess and iron deficiency on the biological activities of osteoblast in vitro, human osteoblast cells (hFOB1.19) were incubated in a medium supplemented with 0-200 µmol/L ferric ammonium citrate and 0-20 µmol/L deferoxamine. The intracellular iron was measured by a confocal laser scanning microscope. Proliferation of osteoblasts was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptotic cells were detected using annexin intervention V/PI staining with a flow cytometry. Alkaline phosphatase (ALP) activity was measured using an ALP assay kit. The number of calcified nodules and mineral area was evaluated by von Kossa staining assay. The expressions of type I collagen and osteocalcin of cultured osteoblasts were detected by reverse transcriptase polymerase chain reaction and Western blot. Intracellular reactive oxygen species (ROS) was measured using the oxidation-sensitive dye 2,7-dichlorofluorescin diacetate by flow cytometry. The results indicated that excessive iron inhibited osteoblast activity in a concentration-dependent manner. Low iron concentrations, in contrast, produced a biphasic manner on osteoblasts: mild low iron promoted osteoblast activity, but serious low iron inhibited osteoblast activity. Osteogenesis was optimal in certain iron concentrations. The mechanism underlying biological activity invoked by excessive iron may be attributed to increased intracellular ROS levels.

Iron intoxication in a dog consequent to the ingestion of oxygen absorber sachets in pet treat packaging.

Oxygen absorbers are commonly used in packages of dried or dehydrated foods (e.g., beef jerky, dried fruit) to prolong shelf life and protect food from discoloration and decomposition. They usually contain reduced iron as the active ingredient although this is rarely stated on the external packaging. Although reduced iron typically has minimal oral bioavailability, such products are potential sources of iron poisoning in companion animals and children. We present a case of canine ingestion of an oxygen absorber from a bag of dog treats that resulted in iron intoxication necessitating chelation therapy. A 7-month-old female Jack Russell terrier presented for evaluation of vomiting and melena 8-12 h after ingesting 1-2 oxygen absorber sachets from a package of dog treats. Serum iron concentration and ALT were elevated. The dog was treated with deferoxamine and supportive care. Clinical signs resolved 14 h following treatment, but the ALT remained elevated at the 3-month recheck. The ingestion of reduced iron in humans has been reported to cause mild elevation of serum iron concentration with minimal clinical effects. To our knowledge, no cases of iron intoxication following the ingestion of oxygen absorbers have been reported. The lack of ingredient information on the packaging prompted analysis of contents of oxygen absorber sachets. Results indicate the contents contained 50-70% total iron. This case demonstrates that iron intoxication can occur following the ingestion of such products. Human and veterinary medical personnel need to be aware of this effect and monitor serum iron concentrations as chelation may be necessary.

Hyperbaric oxygen treatment reduces mortality in acute iron intoxication in rats.

Acute iron intoxication is one of the leading causes of overdose morbidity and mortality in children. The toxicity of iron has been postulated to be related to free radical formation and subsequent lipid peroxidation. Hyperbaric oxygen treatment can result in a number of beneficial biochemical, cellular and physiological effects, and has recently been shown to induce cellular protection against ischaemia, and in some cases against free radical formation. In the current study, we aimed to investigate the effects of hyperbaric oxygen treatment on mortality in acute iron intoxication in rats. After iron administration, 57 animals were divided into two groups: a treatment group receiving hyperbaric oxygen treatment (n = 30) and a control group (n = 27), and followed for 48 hr for signs of severe intoxication. In the second part of the study, 21 animals were divided into a treatment group receiving hyperbaric oxygen treatment (n = 10) and a control group (n = 11), and markers of oxidative stress were evaluated. We showed a significant reduction in mortality in hyperbaric oxygen-treated animals from 17 of 27 (62.9%) among untreated rats to 6 of 30 (20%). Surprisingly, in the treatment group, levels of oxidative stress markers were higher. We postulate that hyperbaric oxygen has a potentially beneficial effect in acute iron intoxication.

Universal versus selective iron supplementation for infants and the risk of unintentional poisoning in young children: a comparative study of two populations.

BACKGROUND: Iron continues to be a common cause of poisoning in young children, in part due to its widespread use and easy accessibility. OBJECTIVE: To determine differences in the epidemiology and outcome of unintentional iron ingestion by young children in populations practicing selective (eg, US) versus universal (eg, Israel) iron supplementation to infants. METHODS: All cases of unintentional iron ingestion in children younger than 7 years in a one year period were identified through the poison control center databases of 2 sites (Illinois and Israel). Parameters compared include patient sex and age; type, form, and dose of iron preparation; circumstances and clinical manifestations; management; and outcome. RESULTS: A total of 602 children were identified: 459 in Illinois and 143 in Israel. The majority of Illinois children ingested multivitamin preparations (94%), whereas Israeli children ingested single-ingredient iron preparations (78%) (p < 0.001). Iron doses ingested were higher in Israel (median 14.5 vs 6.6 mg/kg; p < 0.001) but remained within the nontoxic range for most children. No deaths or severe poisonings were reported, and 93% of children in both groups were asymptomatic. The majority of ingestions in both locations were due to unintentional self-ingestion. However, parental miscalculation occurred more frequently in Israel (16%) than in Illinois (1%). CONCLUSIONS: Universal iron supplementation to infants was not associated with a negative impact on the outcome of pediatric unintentional ingestions. Low-dose exposures were safely managed by on-site observation.

Acute iron poisoning: what every pediatric intensive care unit nurse should know.

Iron is a substance commonly found in the homes of many children, leading to a high potential for accidental ingestion. Without proper recognition and treatment, iron poisoning can be fatal. This article reviews the case of a toddler who presents to the pediatric intensive care unit with iron poisoning.

Copper deficiency in yaks on pasture in western China.

The clinical signs of a disorder in yaks (Bos grunniens), known locally as "swayback ailment," in the Qing Hai-Tibetan Plateau are described. The purpose of this study is to investigate the possibility that swayback ailment is iron (Fe)-induced copper (Cu) deficiency. The mean concentrations of Cu in soil and forage from affected areas and unaffected areas are similar and within the normal ranges. The mean concentrations of Cu in blood and hair from the affected yaks was significantly lower (P < 0.01) than that in unaffected yaks. The mean concentrations of Fe in soil and forage were significantly higher (P < 0.01) in affected than in unaffected areas. Affected yaks showed a hypochromic microcytic anemia and a low level of ceruloplasmin. Oral administration of copper sulphate prevented and cured the disease. We conclude that "swayback disorder" of yaks is caused by secondary Cu deficiency, mainly due to the high Fe content in forage.

Iron: not a benign therapeutic drug.

PURPOSE OF REVIEW: This article reviews the pathophysiology and clinical presentation of iron poisoning. Recently proposed guidelines for triage of children with iron ingestion will be discussed as well as diagnostic and treatment modalities. Finally, the potential impact of unit-dose packaging as a primary preventative measure will be discussed. RECENT FINDINGS: Carbonyl iron has a greater safety margin than the iron salts. There have been no published reports of serious or fatal poisoning from the ingestion of carbonyl iron products. Evidence-based consensus guidelines have determined that the threshold for referral to a healthcare facility is 40 mg/kg of elemental iron in the form of adult iron formulations. Unit-dose packaging of iron preparations appeared to decrease the number of exposures to iron and deaths in the United States during the period they were instituted. SUMMARY: Iron poisoning remains primarily a clinical diagnosis, although certain laboratory and radiological testing may provide helpful evidence to guide evaluation and management. Primary prevention is the best modality for decreasing morbidity and mortality for all poisonings including iron.

Unit-dose packaging of iron supplements and reduction of iron poisoning in young children.

BACKGROUND: Iron poisoning is a major cause of unintentional poisoning death in young children. The US Food and Drug Administration proclaimed a regulation for unit-dose packaging of iron supplements in 1997. OBJECTIVE: To determine whether the requirement for unit-dose packaging of iron supplements decreases the incidence of iron ingestion and the incidence of deaths due to iron poisoning in children younger than 6 years. METHODS: This is a preintervention-postintervention study of the US federally mandated requirement for unit-dose packaging of iron supplements. The 10 years prior to the intervention were compared with the 5 years after its promulgation. The incidences of iron ingestion and of iron poisoning deaths for children younger than 6 years were obtained from the annual reports of the American Association of Poison Control Centers (Washington, DC). RESULTS: The average number of iron ingestion calls per 1000 of all calls to poison control centers regarding children younger than 6 years decreased from 2.99 per 1000 to 1.91 per 1000 (odds ratio, 1.29 [95% confidence interval, 1.27-1.32]; P<.001). The number of deaths decreased from 29 to 1 (odds ratio, 13.56 [95% confidence interval, 1.85-99.52]; P = .03). CONCLUSIONS: These are the first data that show a decrease in the incidence of nonintentional ingestion of a specific drug by young children and a decrease in mortality from poisoning by this drug after the introduction of unit-dose packaging. There was a decrease in the incidence of iron ingestion and a dramatic decrease in the number of deaths due to iron poisoning. This validates unit-dose packaging as an effective strategy for the prevention of iron poisoning and iron poisoning deaths in young children. This highly effective intervention should be considered for other medications with a high hazard for morbidity and mortality when taken as an overdose.

Acute iron poisoning: management guidelines.

Serum iron level may not be available and fully reliable in management decision and prognostication in our setting. An estimated ingestion of >60 mg/kg elemental iron, onset of symptoms, blood sugar >150 mg/dL, total leukocyte count >15,000 cumm and presence of iron tablets on abdominal radiograph indicates severe toxicity and need for chelation therapy. Appearance of "vin-rose" color urine following a dose of desferrioxamine may be helpful, but is not seen consistently after chelation therapy. Early decontamination of gut (gastric lavage/whole gut irrigation), desferrioxamine infusion (15 mg/kg/hour in saline), and aggressive management of shock, and organ failure preferably in a PICU are mainstay of management, and has improved the outcome. Shock, coagulopathy (prothrombin index <50%), severe acidosis and acute liver failure are poor prognostic indicators. Guardians should be counseled about safe storage of iron tablets made for adults, and general poisoning prevention measures.

HBED ligand: preclinical studies of a potential alternative to deferoxamine for treatment of chronic iron overload and acute iron poisoning.

We have continued the preclinical evaluation of the efficacy and safety of the hexadentate phenolic aminocarboxylate iron chelator N, N'-bis(2-hydroxybenzyl) ethylenediamine-N, N'-diacetic acid monosodium salt (NaHBED) for the treatment of both chronic transfusional iron overload and acute iron poisoning. We examined the effect of route of administration by giving equimolar amounts of NaHBED and deferoxamine (DFO) to Cebus apella monkeys as either a subcutaneous (SC) bolus or a 20-minute intravenous (IV) infusion. By both routes, NaHBED was consistently about twice as efficient as DFO in producing iron excretion. For both chelators at a dose of 150 micromol/kg, SC was more efficient than IV administration. The biochemical and histopathologic effects of NaHBED administration were assessed. No systemic toxicity was found after either IV administration once daily for 14 days to iron-loaded dogs or after SC administration every other day for 14 days to dogs without iron overload. Evidence of local irritation was found at some SC injection sites. When the NaHBED concentration was reduced to 15% or less in a volume comparable to a clinically useful one, no local irritation was found with SC administration in rats. Because treatment of acute iron poisoning may require rapid chelator infusion, we compared the effects of IV bolus administration of the compounds to normotensive rats. Administration of DFO produced a prompt, prolonged drop in blood pressure and acceleration of heart rate; NaHBED had little effect. NaHBED may provide an alternative to DFO for the treatment of both chronic transfusional iron overload and of acute iron poisoning.

Do poison center triage guidelines affect healthcare facility referrals?

BACKGROUND: The purpose of this study was to determine the extent to which poison center triage guidelines influence healthcare facility referral rates for acute, unintentional acetaminophen-only poisoning and acute, unintentional adult formulation iron poisoning. METHODS: Managers of US poison centers were interviewed by telephone to determine their center's triage threshold value (mg/kg) for acute iron and acute acetaminophen poisoning in 1997. Triage threshold values and healthcare facility referral rates were fit to a univariate logistic regression model for acetaminophen and iron using maximum likelihood estimation. RESULTS: Triage threshold values ranged from 120-201 mg/kg (acetaminophen) and 16-61 mg/kg (iron). Referral rates ranged from 3.1% to 24% (acetaminophen) and 3.7% to 46.7% (iron). There was a statistically significant inverse relationship between the triage value and the referral rate for acetaminophen (p < 0.001) and iron (p = 0.0013). The model explained 31.7% of the referral variation for acetaminophen but only 4.1% of the variation for iron. CONCLUSION: There is great variability in poison center triage values and referral rates for iron and acetaminophen poisoning. Guidelines can account for a meaningful proportion of referral variation. Their influence appears to be substance dependent. These data suggest that efforts to determine and utilize the highest, safe, triage threshold value could substantially decrease healthcare costs for poisonings as long as patient medical outcomes are not compromised.

Intoxicación aguda por hierro en un caso / Acute iron poisoning: report of case

The ingestion of iron-containing products is a potential toxicological emergency. It is a leading cause of pediatric unintentional ingestion fatalities because some iron-containing compounds are readily available (vitamin mixtures, iron pills). Among adults, it has been described as accidental overdoses (mainly in pregnancy) and as suicidal attempts. We report a 42 years old woman, admitted due to the intentional ingestion of iron pills with suicidal purposes. A plain abdominal X ray showed at least 20 pills in the gastric fundus and antrum. She was successfully treated with intravenous desferroxamine chelation. Plain abdominal X ray examination can be very useful in the diagnosis of acute iron poisoning