BADGE (whose chemical names are bisphenol A diglycidylether and 2,2-bis(4-(2,3-epoxypropyl)phenyl)propane) is the lowest molecular weight oligomer in commercial epoxy resins and the major component in commercial liquid epoxy resins. The major application areas for epoxy resins are protective coatings and civil engineering. Additional applications include printed circuit boards, composites, adhesives and tooling, while a relatively small amount of epoxy resins (< 10%) finds use in protective coatings inside food and drink cans. The use of BADGE in food-contact applications was first regulated through EC Directive 2002/16/EC and amended in EC Directive 2004/13/EC with migration levels in food-contact applications being generally well below the regulatory thresholds. The paper discusses the commercial use of BADGE focusing on the current knowledge of human exposure from canned food applications. To assess the safety of this application, the exposure data are compared with no adverse effect levels (NOAEL) from various toxicological investigations with BADGE including reproductive and developmental assays, endocrine toxicity investigations, and sub-chronic and chronic assays. Consumer exposure to BADGE is almost exclusively from migration of BADGE from can coatings into food. Using a worst-case scenario that assumes BADGE migrates at the same level into all types of food, the estimated per capita daily intake for a 60-kg individual is approximately 0.16 microg kg(-1) body weight day(-1). A review of one- and two-generation reproduction studies and developmental investigations found no evidence of reproductive or endocrine toxicity, the upper ranges of dosing being determined by maternal toxicity. The lack of endocrine toxicity in the reproductive and developmental toxicological tests is supported by negative results from both in vivo and in vitro assays designed specifically to detect oestrogenic and androgenic properties of BADGE. An examination of data from sub-chronic and chronic toxicological studies support a NOAEL of 50 mg kg(-1) body weight day(-1) from the 90-day study, and a NOAEL of 15 mg kg(-1) body weight day(-1) (male rats) from the 2-year carcinogenicity study. Both NOAELS are considered appropriate for risk assessment. Comparing the estimated daily human intake of 0.16 microg kg(-1) body weight day(-1) with the NOAELS of 50 and 15 mg kg(-1) body weight day(-1) shows human exposure to BADGE from can coatings is between 250,000 and 100,000-fold lower than the NOAELs from the most sensitive toxicology tests. These large margins of safety together with lack of reproductive, developmental, endocrine and carcinogenic effects supports the continued use of BADGE for use in articles intended to come into contact with foodstuffs.

Vasocclusive pain crises are common among pediatric patients with sickle cell disease (SCD). Some patients with repeated pain crises develop chronic pain. We performed a retrospective cohort study of pediatric patients with SCD with chronic pain treated with methadone. We identified a significant reduction in pain hospitalizations following methadone treatment (0.35 ± 0.19 vs. 0.19 ± 0.17 hospitalizations/month, P = 0.016). In addition, we did not observe overt organ toxicity nor symptoms of opioid withdrawal during methadone wean. We suggest that methadone is safe and has some clinical benefit, which should be proven in prospective randomized trials for pediatric patients with SCD and chronic pain.

Since being introduced into clinical practice 20 years ago, fluoxetine, a serotonin-reuptake inhibitor, has remained one of the most popular antidepressants prescribed in the United States. Upon reviewing the literature, the highest reported postmortem central blood fluoxetine and norfluoxetine concentrations are 22 and 6.8 mg/L, respectively, and reported liver fluoxetine and norfluoxetine concentrations are 29-128 and 17 mg/kg, respectively. A 31-year-old female with convulsive activity was found at home by her husband. Emergency services was contacted, and responders found the patient unresponsive with agonal respirations, a pulse of 20 bpm, and no measurable blood pressure. Despite all resuscitative efforts, the patient expired. Postmortem analyses revealed concentrations of 33 mg/L fluoxetine and 12 mg/L norfluoxetine in central blood and 400 mg/kg fluoxetine and 460 mg/kg norfluoxetine in liver. Vitreous fluoxetine and norfluoxetine concentrations were 5.2 and 2.2 mg/L, respectively. Utilizing a sensitive and specific analytical procedure, we report the highest recorded central blood and liver fluoxetine and norfluoxetine concentrations.

Intentional abuse of 1,1-difluoroethane has been reported to cause transient symptoms such as confusion, tremors, pulmonary irritation, loss of consciousness and, rarely, coma. In the last five years, 17 cases from the San Diego County Medical Examiner's Office showed the presence of 1,1-difluoroethane in postmortem tissues, and the gas was cited in the cause of death in 13 of those cases. Detected during routine ethanol screening, 1,1-difluoroethane was evaluated for concentrations in peripheral blood, central blood and vitreous humor by a slightly modified method published by Avella et al. In many cases, death from abuse of 1,1-difluoroethane seemed to occur within minutes of intentional abuse; large concentrations (>100 mg/L) of the gas were still in the blood. It is important that forensic toxicology laboratories have routine screening procedures to detect 1,1-difluoroethane because cases exist in which evidence of use from cans may not be present in proximity to the decedent, or may be undiscovered in the debris of a motor vehicle accident. It is also important to quantify concentrations of 1,1-difluoroethane in both peripheral blood and central blood, whose ratio may be useful in interpreting how recently the use of the 1,1-difluoroethane occurred.

Introduction Patients with sickle cell disease (SCD) experience acute painful events; some patients develop chronic pain requiring daily short acting opioids, and frequent emergency department (ED) visits, and inpatient hospitalization. From the Cooperative Study of Sickle Disease (Platt, NEJM 1991), only 1% of patients with SCD experience more than 6 pain events per year. Methadone is a synthetic opioid used in chronic pain, but there is a paucity of data on its use and effectiveness in the pediatric SCD population. We hypothesized that methadone can be used safely in pediatric patients with SCD with severe chronic pain and would reduce ED visits and hospitalizations. Methods We conducted a retrospective cohort study (IRB approved) of 16 pediatric patients with SCD who received methadone for chronic pain management, indicating having more than 5 pain events per year. These patients were among 1100 total patients with SCD at our center. Primary SCD providers escalated doses to maximal effect and when clinically stable, doses were weaned. Follow-up started at time of methadone initiation and ended when a patient was weaned or transitioned to adult care; the 1 year period before treatment initiation was defined as the baseline period. We calculated descriptive statistics to characterize the study population. We compared clinical outcomes (ED visits or hospitalization for pain) for the baseline period and 1 year post methadone initiation using paired T test. To evaluate methadone dosing and dependency, we identified the mean dose, percentage of time at highest dose, and wean of methadone. We assessed withdrawal and safety by reviewing outpatient encounters, EKG screening for QTc > 450, eGFR by cystatin C to determine either a decrease in eGFR by 20% or an eGFR <80, and microalbumin/creatinine urinary excretion. Results Among the 16 participants, 10 (62.5%) were male and the genotypes of each patient were: 14 SS, 1 S/β0-thalassemia, 1 SC. The mean age was 15.5 (±2.8) years at time of methadone initiation and there was a medium follow-up of 2.1 years. Clinically, 13 (81.3%) had previous cholecystectomy, 6 (37.5%) had previous splenectomy, 7 (43.8%) had radiographic evidence of infarction of a long bone within the year prior to initiation of methadone, 10 (62.5%) were receiving chronic transfusion during methadone, and 10 (62.5%) received psychosocial counseling for depression and/or anxiety. The average number of ED visits per month was 0.31 (±0.27) in the baseline period and were 0.28 (±0.28, p=0.658) and 0.31 (±0.25, p=0.921) in the 1 year post and entire follow-up periods. The rate of hospitalizations per month decreased from 0.35 (±0.19) in the baseline period to 0.19 (±0.17, p=0.016) and 0.22 (±0.21, p=0.05) in the 1 year post and entire follow-up periods. The average initial starting dose was 12.5 mg and the mean highest dose was 26.6 mg. In 14 (87.5%) patients the final dose was less than the highest dose and 4 (25.0%) patients were weaned completely off of methadone. For the entire cohort, each patient spent a median of 183 days at their highest dose, a mean of 34% of the total time treated with methadone. No patients experienced signs consistent with opioid withdrawal during the follow-up period. The most common subjective complaints were sedation (12%), nausea and/or vomiting (24%) and constipation (6%). We found no documented new abnormal QTc intervals, changes in eGFR, or new onset proteinuria during the follow up period. Conclusion Methadone use in pediatric patients with SCD is well-tolerated and may lead to improved pain control as evidence by significant reduction in hospitalizations. Additionally, when followed closely, methadone can be used safely without concern for physiologic dependency; this is supported by our ability to wean patients off methadone entirely or weaning to a lower dose than their highest dose in the majority of the cohort. Hematologists should consider methadone as a part of chronic pain management in patients with SCD and severe chronic pain. Disclosures Lebensburger: ASH: Research Funding; NHLBI K23: Research Funding.