Agreement Between a Colorimetric Assay and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry for Quantifying Paracetamol Plasma Concentrations.

Special populations, like geriatric patients, experience altered paracetamol pharmacokinetics (PK), complicating pain management. More PK research is essential to optimize paracetamol (acetaminophen) dosing. Yet, the reference method ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is not readily available. Therefore, we aimed to evaluate the agreement between UPLC-MS/MS and the more accessible colorimetric Roche acetaminophen (ACETA) assay in quantifying paracetamol plasma concentrations, to facilitate PK studies and therapeutic drug monitoring for pain management. Patient data and plasma samples were obtained from a prospective study including geriatric patients admitted to the geriatric wards. ACETA and UPLC-MS/MS assays were performed in two separate laboratories. Bland-Altman plot and Passing-Bablok regression were used to assess agreement. Accuracy was evaluated using the McNemar test for a threshold value of 10 mg/L. Population PK modeling was employed to bridge PK data obtained from both methods (NONMEM 7.5). A total of 242 plasma sample pairs were available from 40 geriatric patients (age range, 80-95 years). Paracetamol plasma concentrations from ACETA (median 9.8 [interquartile range 6.1-14.4] mg/L) and UPLC-MS/MS (9.5 [6.2-14.8] mg/L) did not differ significantly (P > 0.05). No significant proportional nor additive bias was observed between both assay methods. The classification accuracy (at threshold 10 mg/L) was 85% (P = 0.414). The conversion factor between ACETA and UPLC-MS/MS was estimated at 1.06 (relative standard error 5%), yet with a 13.4% (relative standard error 23%) interindividual variability. ACETA assay showed no systematic bias in comparison with the UPLC-MS/MS assay in determining paracetamol exposure in geriatric blood samples despite the imprecision.

A False-Positive Gamma-Hydroxy Butyric Acid Urine Screening in a Patient with High Anion Gap Metabolic Acidosis Due to Ethylene Glycol Poisoning.

A young woman with a history of several suicide attempts was admitted to the hospital after suspicion of a new intoxication without definite identification of the causing agent. The patient had a high anion gap metabolic acidosis (HAGMA) with respiratory compensation, a lactate gap and an osmolar gap at admission. Initial toxicological screening showed no abnormalities except for a weak positive gamma-hydroxy butyric acid (GHB) enzymatic screen in urine. This finding could not be confirmed using chromatographic analysis nor be explained by the presence of known cross-reacting substances like ethanol. In this case, falsely elevated urinary GHB screening was caused by the ingestion of ethylene glycol. To confirm that the interference was due to ethylene glycol or its metabolites, we performed a spiking experiment. Cross reactivity was linked to ethylene glycol and was low in our experiments (0.1-0.2%). Substantial amounts of ethylene glycol are required to slightly elevated GHB results, depending on the endogenous cutoff used. We can conclude that ethylene glycol can give rise to falsely elevated urinary GHB levels at ethylene glycol concentrations that are typically found in intoxications.

Pooled Urine Analysis at a Belgian Music Festival: Trends in Alcohol Consumption and Recreational Drug Use.

BACKGROUND: Recreational drug use has become more and more accepted in society. Availability and purity are rising and new psychoactive substances (NPS) are popping up.The aim of this study was to provide objective data on illicit drug use at a Belgian festival in order to report on arising trends. This may provide additional information to help develop preventive strategies. METHODS: A cross-sectional study took place during a music festival in the summer of 2019, where 43 samples of pooled urine were collected at four different locations and at different moments of the day. Analysis was performed using gas chromatography with a flame ionization detector (GC-FID) to determine ethanol concentrations. Drugs of abuse were quantified using liquid chromatography-tandem mass spectrometry. A qualitative analysis was performed using high-resolution mass spectrometry. RESULTS: Median ethanol concentration was 0.88g/L. Cocaine, 3,4-methylenedioxymethamphetamine (MDMA), amphetamines, ketamine, and cannabis were detected in almost every sample and often in high concentrations. Furthermore, two NPS were detected and a variety of over-the-counter medication and adulterants were also found. DISCUSSION: The findings were largely in-line with trends outlined in the European Drug Report. Striking were the relatively high concentrations of MDMA and ketamine and detection of two synthetic cathinones. Two possible adulterants of cocaine were detected, namely flecainide and amlodipine. CONCLUSION: Music festivals are considered a high-risk setting for alcohol consumption and illicit drug use. Analysis of pooled urine samples at a festival therefore provides a valuable method to evaluate trends and to screen for new substances. Wide-spread use of classical drugs and identification of two NPS were observed during a major international music festival in Belgium. Results need to be interpreted carefully, taking into account the possibilities and limitations of the used techniques and a standardized sampling is required.

Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis.

BACKGROUND: There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable. OBJECTIVE: The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV. METHODS: Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling. RESULTS: A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V1) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V1, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained. CONCLUSION: The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02365272.

Combined exposure to phthalate esters and phosphate flame retardants and plasticizers and their associations with wheeze and allergy symptoms among school children.

BACKGROUND: Phthalate esters and phosphate flame retardants and plasticizers (PFRs) are both used as plasticizers and are commonly detected in indoor environments. Although both phthalates and PFRs are known to be associated with children's wheeze and allergic symptoms, there have been no previous studies examining the effects of mixtures of these exposures. OBJECTIVES: To investigate the association between exposure to mixtures of phthalate esters and PFRs, and wheeze and allergic symptoms among school-aged children. METHODS: A total of 128 elementary school-aged children were enrolled. Metabolites of 3 phthalate esters and 7 PFRs were measured in urine samples. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. In the primary model, we created a phthalate ester and PFR mixture exposure index, and estimated odds ratios (ORs) using weighted quantile sum (WQS) regression and quantile g (qg)-computation. The two highest chemicals according to qg-computation weight %s were combined to create a combination high × high exposure estimate, with ORs calculated using the "low × low" exposure group as the reference category. Concentrations of each metabolite were corrected by multiplying this value by the sex- and body size-Standardised creatinine concentration and dividing by the observed creatinine value. All models were adjusted for sex, grade, dampness index and annual house income. RESULTS: The odds ratio of rhinoconjunctivitis for the association between exposure to chemical mixtures according to the WQS index positive models was; OR = 2.60 (95% confidence interval [CI]: 1.38-5.14). However, wheeze and eczema of the WQS index positive model, none of the WQS index negative models or qg-computation result yielded statistically significant results. Combined exposure to the two highest WQS weight %s of "high-high" ΣTCIPP and ΣTPHP was associated with an increased prevalence of rhino-conjunctivitis, OR = 5.78 (1.81-18.43) to the "low × low" group. CONCLUSIONS: Significant associations of mixed exposures to phthalates and PFRs and increased prevalence of rhinoconjunctivitis was found among elementary school-aged children in the WQS positive model. Mixed exposures were not associated with any of allergic symptoms in the WQS negative model or qg-computation approach. However, the combined effects of exposure to two PFRs suggested an additive and/or multiplicative interaction, potentially increasing the prevalence of rhinoconjunctivitis. A further study with a larger sample size is needed to confirm these results.

Towards establishing indicative values for metabolites of organophosphate ester contaminants in human urine.

In 2015, nine laboratories from Belgium, USA, Canada, China, and Australia participated in an interlaboratory exercise to quantify metabolites of organophosphate ester (OPE) contaminants in pooled human urine. Pooled human urine available as SRM 3673 (Organic contaminants in non-smokers' urine) was obtained from the U.S. National Institute of Standards and Technology and was analyzed for its content of OPE metabolites. Each participating laboratory received 10 mL sample and used its own validated method and standards to report the concentrations of the OPE metabolites of its choice. Four OPE metabolites were consistently measured by most laboratories and they were the following diesters: bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), bis(2-chloroethyl) phosphate (BCEP), and bis(1-chloro-2-propyl) phosphate (BCIPP). Concentrations of other OPE metabolites in SRM 3673 were also reported but are only considered as informative values since they were measured by three laboratories at most. All laboratories used liquid chromatography with tandem mass spectrometry (LC-MS/MS) with or without solid-phase extraction (SPE). This is the first study to report indicative values for OPE metabolites in a human urine Standard Reference Material. It is expected that these indicative values obtained for these four metabolites will be used as quality control to ensure compatibility of results in biomonitoring studies and by other researchers who validate their own methods for the quantification of OPE metabolites in human urine.

Biomonitoring of organophosphate flame retardants and plasticizers in children: Associations with house dust and housing characteristics in Japan.

Indoor environments contain a wide range of new chemicals such as phosphate flame retardants and plasticizers (PFRs). Despite recent epidemiological evidence suggesting that children might be affected by widespread exposure to PFRs, questions remain about the various exposure pathways to these chemicals. Therefore, the aim of this study was to investigate exposure to PFRs by measuring the concentrations a set of urinary metabolites for schoolchildren from Japan (n = 128) and associating them with house dust concentrations and housing characteristics. Detectable concentrations of both diaryl and dialkyl phosphates (DAPs) and hydroxylated metabolites (HO-PFRs) were found in urine samples of almost all children. 2-Hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP) was the most frequently detected metabolite (98%) followed by 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP, 95%) and tris(chloroethyl) phosphate (TCEP). Next to BBOEHEP, two other metabolites of tris(2-butoxyethyl) phosphate (TBOEP) were also frequently detected. Significant correlations of moderate strength were found between parent compounds detected in high concentrations in house dust (TBOEP, tris(2-chloroisopropyl) phosphate (TCIPP)) and their corresponding metabolites, suggesting that dust is a primary exposure source for these PFRs. Several personal and housing characteristics, such as gender, income, and the use of PVC and ventilation were associated with metabolite concentrations in multivariate linear regression. Overall, this study showed that Japanese schoolchildren are exposed to a wide range of PFRs.

Simultaneous determination of 14 urinary biomarkers of exposure to organophosphate flame retardants and plasticizers by LC-MS/MS.

Organophosphate flame retardants and plasticizers (PFRs) are a group of chemicals widely added to consumer products. PFRs are quickly metabolized in the human body into two types of metabolites, (1) dialkyl and diaryl phosphate esters (DAPs), such as diphenyl phosphate (DPHP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP); and (2) hydroxylated PFRs (HO-PFRs), such as 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP) and 2-hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP). Existing analytical methods usually focus on DAPs; therefore, human biomonitoring data on HO-PFRs remain scarce. In this study, an analytical procedure was developed for the simultaneous quantification of multiple PFR metabolites in human urine, covering eight DAPs and six HO-PFRs. Sample preparation was optimized to include all target compounds using Bond-Elut C18 solid-phase extraction cartridges, followed by instrumental analysis based on liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS). Method performance was validated according to established guidelines and satisfactory results were obtained for all metabolites in terms of recovery, linearity, limits of quantification, precision, and accuracy. Recoveries ranged from 87 to 112%. Method detection limits from 0.002 ng/mL for 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-HO-EHDPHP) to 0.66 ng/mL for 4-hydroxyphenyl phenyl phosphate (4-HO-DPHP). Seven PFR metabolites were frequently detected in a small biomonitoring study (n = 14), among them bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DNBP), 5-HO-EHDPHP, and BBOEHEP. Highest mean concentrations were found for DPHP, 2-ethylhexyl phenyl phosphate (EHPHP), and BCIPHIPP, while 4-HO-DPHP, 5-HO-EHDPHP, and EHPHP were detected in urine for the first time. Overall, the obtained results demonstrate that the developed method can be used for the simultaneous determination of 14 urinary biomarkers of exposure to PFRs. Graphical abstract ᅟ.

Associations between allergic symptoms and phosphate flame retardants in dust and their urinary metabolites among school children.

BACKGROUND: Phosphate flame retardants (PFRs) are ubiquitously detected in indoor environments. Despite increasing health concerns pertaining to PFR exposure, few epidemiological studies have examined PFR exposure and its effect on children's allergies. OBJECTIVES: To investigate the association between PFRs in house dust, their metabolites in urine, and symptoms of wheeze and allergies among school-aged children. METHODS: A total of 128 elementary school-aged children were enrolled. House dust samples were collected from upper-surface objects. Urine samples were collected from the first morning void. Levels of 11 PFRs in dust and 14 PFR metabolites in urine were measured. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood questionnaire. The odds ratios (ORs) of the Ln transformed PFR concentrations and categorical values were calculated using a logistic regression model adjusted for sex, grade, dampness index, annual house income, and creatinine level (for PFR metabolites only). RESULTS: The prevalence rates of wheeze, rhinoconjunctivitis, and eczema were 22.7%, 36.7%, and 28.1%, respectively. A significant association between tris(1,3-dichloroisopropyl) phosphate (TDCIPP) in dust and eczema was observed: OR (95% confidence interval), 1.44 (1.13-1.82) (>limit of detection (LOD) vs LOD vs

Urinary metabolites of organophosphate esters: Concentrations and age trends in Australian children.

There is growing concern around the use of organophosphate esters (OPEs) due to their suspected reproductive toxicity, carcinogenicity, and neurotoxicity. OPEs are used as flame retardants and plasticizers, and due to their extensive application in consumer products, are found globally in the indoor environment. Early life exposure to OPEs is an important risk factor for children's health, but poorly understood. To study age and sex trends of OPE exposures in infants and young children, we collected, pooled, and analysed urine samples from children aged 0-5years from Queensland, Australia for 9 parent OPEs and 11 metabolites. Individual urine samples (n=400) were stratified by age and sex, and combined into 20 pools. Three individual breast milk samples were also analysed to provide a preliminary estimate on the contribution of breast milk to the intake of OPEs. Bis(1-chloroisopropyl) phosphate (BCIPP), 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP), bis(1,3-dichloroisopropyl) phosphate (BDCIPP), dibutyl phosphate (DBP), diphenyl phosphate (DPHP), bis(2-butoxyethyl) phosphate (BBOEP), bis(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate (3OH-TBOEP), and bis(2-butoxyethyl) hydroxyethyl phosphate (BBOEHEP) were detected in all urine samples, followed by bis(methylphenyl) phosphate (80%), and bis(2-ethylhexyl) phosphate (BEHP, 20%), and bis(2-chloroethyl) phosphate (BCEP, 15%). Concentrations of tris(2-chloroethyl) phosphate (TCEP), BCEP, tris(2-ethylhexyl) phosphate (TEHP), and DBP decreased with age, while bis(methylphenyl) phosphate (BMPP) increased with age. Significantly higher concentrations of DPHP (p=0.039), and significantly lower concentrations of TEHP (p=0.006) were found in female samples compared to males. The estimated daily intakes (EDIs) via breastfeeding, were 4.6, 26 and 76ng/kg/day for TCEP, TBP and TEHP, respectively, and were higher than that via air and dust, suggesting higher exposure through consumption of breast milk.