Glyphosate exposure in early pregnancy and reduced fetal growth: a prospective observational study of high-risk pregnancies.

BACKGROUND: Prenatal glyphosate (GLY) exposure is associated with adverse reproductive outcomes in animal studies. Little is known about the effects of GLY exposure during pregnancy in the human population. This study aims to establish baseline urine GLY levels in a high-risk and racially diverse pregnancy cohort and to assess the relationship between prenatal GLY exposure and fetal development and birth outcomes. METHODS: Random first trimester urine specimens were collected from high risk pregnant women between 2013 and 2016 as part of the Indiana Pregnancy Environmental Exposures Study (PEES). Demographic and clinical data were abstracted from mother and infant medical records. Urine glyphosate levels were measured as a proxy for GLY exposure and quantified using liquid chromatography-tandem mass spectrometry. Primary outcome variables included gestation-adjusted birth weight percentile (BWT%ile) and neonatal intensive care unit (NICU) admission. Relationships between primary outcome variables and GLY exposure were assessed using univariate and multivariate linear and logistic regression models. RESULTS: Urine GLY levels above the limit of detection (0.1 ng/mL) were found in 186 of 187 (99%) pregnant women. Further analyses were limited to 155 pregnant women with singleton live births. The mean age of participants was 29 years, and the majority were non-Hispanic white (70%) or non-Hispanic Black (21%). The mean (± SD) urine GLY level was 3.33 ± 1.67 ng/mL. Newborn BWT%iles were negatively related to GLY (adjusted slope ± SE = -0.032 + 0.014, p = 0.023). Infants born to women living outside of Indiana's large central metropolitan area were more likely to have a lower BWT%ile associated with mother's first trimester GLY levels (slope ± SE = -0.064 ± 0.024, p = 0.007). The adjusted odds ratio for NICU admission and maternal GLY levels was 1.16 (95% CI: 0.90, 1.67, p = 0.233). CONCLUSION: GLY was found in 99% of pregnant women in this Midwestern cohort. Higher maternal GLY levels in the first trimester were associated with lower BWT%iles and higher NICU admission risk. The results warrant further investigation on the effects of GLY exposure in human pregnancies in larger population studies.

Exposure to Perfluoroalkyl Substances in a Cohort of Women Firefighters and Office Workers in San Francisco.

Studies of firefighters have shown increased exposures to carcinogenic compounds and elevated rates of certain cancers compared to the general population, yet this research has focused almost exclusively on men. To address this gap, the Women Firefighters Biomonitoring Collaborative created a biological sample archive and analyzed levels of perfluoroalkyl substances (PFAS) among women firefighters (N = 86) and office workers (N = 84) in San Francisco. Serum samples were collected and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure and compare PFAS levels between firefighters and office workers. 7 of 12 PFAS congeners were detected in the least 70% of the study population, and 4 congeners were detected in 100% of participants. In regression models comparing PFAS levels by occupation and adjusting for potential confounders, firefighters had higher geometric mean concentrations of PFAS compared to office workers PFHxS (2.22 (95% CI = 1.55, 3.18)), PFUnDA (1.83 (95% CI = 0.97, 3.45)), and PFNA (1.26 (95% CI = 1.01, 1.58)). Among firefighters, occupational position predicted exposure-firefighters and officers had higher PFNA, PFOA, PFDA, and PFUnDA levels compared to drivers. Women firefighters are exposed to higher levels of some PFAS compared to office workers, suggesting that some of these exposures may be occupationally related.

Integrating Exposure Knowledge and Serum Suspect Screening as a New Approach to Biomonitoring: An Application in Firefighters and Office Workers.

Firefighters (FF) are exposed to recognized and probable carcinogens, yet there are few studies of chemical exposures and associated health concerns in women FFs, such as breast cancer. Biomonitoring often requires a priori selection of compounds to be measured, and so, it may not detect relevant, lesser known, exposures. The Women FFs Biomonitoring Collaborative (WFBC) created a biological sample archive and conducted a general suspect screen (GSS) to address this data gap. Using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry, we sought to identify candidate chemicals of interest in serum samples from 83 women FFs and 79 women office workers (OW) in San Francisco. We identified chemical peaks by matching accurate mass from serum samples against a custom chemical database of 722 slightly polar phenolic and acidic compounds, including many of relevance to firefighting or breast cancer etiology. We then selected tentatively identified chemicals for confirmation based on the following criteria: (1) detection frequency or peak area differences between OW and FF; (2) evidence of mammary carcinogenicity, estrogenicity, or genotoxicity; and (3) not currently measured in large biomonitoring studies. We detected 620 chemicals that matched 300 molecular formulas in the WFBC database, including phthalate metabolites, phosphate flame-retardant metabolites, phenols, pesticides, nitro and nitroso compounds, and per- and polyfluoroalkyl substances. Of the 20 suspect chemicals selected for validation, 8 were confirmed-including two alkylphenols, ethyl paraben, BPF, PFOSAA, benzophenone-3, benzyl p-hydroxybenzoate, and triphenyl phosphate-by running a matrix spike of the reference standards and using m/z, retention time, and the confirmation of at least two fragment ions as criteria for matching. GSS provides a powerful high-throughput approach to identify and prioritize novel chemicals for biomonitoring and health studies.

Stimulant drugs are associated with violent and penetrating trauma.

BACKGROUND: Substance abuse is associated with traumatic injuries. Prior studies of drug use and injury have relied on urine drug of abuse screens, which have false positives, false negatives and inability to detect novel drugs. Our study characterizes the relationship between injury mechanism and drugs of abuse detected in serum via confirmatory testing. METHODS: This prospective observational study was conducted from Jan-Sept 2012 at a level 1 trauma center on trauma patients > 13 years who had blood drawn for routine tests. Demographic, injury and standard laboratory data were abstracted from patient charts. Comprehensive serum drug testing was done using liquid chromatography-time-of-flight mass spectrometry (LC-TOF/MS, LC1200-TOF/MS 6230, Agilent, Santa Clara, CA). RESULTS: Of 272 patients, 71.0% were male, 30.5% had violent injury type and 32.4% had a penetrating injury mechanism. Violent injury type and penetrating injury mechanisms were more frequent in patients who were male, younger age, Black, or Hispanic (p < 0.05 for all). LC-TOF/MS showed that 46.0% were positive for at least one drug. Stimulant drugs were associated with violent injury type (OR 2.9; 95% CI 1.64-5.15) and penetrating injury mechanism (OR 3.3; 95% CI 1.86-5.82). Tobacco use was associated with violent injury type (OR 3.9; 95% CI 2.25-6.77) and penetrating injury mechanism (OR 4.14; 95%CI 2.4-7.14). CONCLUSIONS: Many drugs are present in trauma patients that are not routinely detected on urine drug of abuse tests. Both stimulant drugs and cigarette smoking are indicators of multidimensional hazardous behaviors, which were associated with more violent and penetrating trauma.

Seizures, Systemic Inflammatory Response, and Rhabdomyolysis Associated With Laboratory-Confirmed 2C-I and 25-I Exposure.

The 2C drugs are hallucinogenic phenethylamines. They and their n-benzyloxymethyl analogs have become popular as "legal highs," and significant toxicity has been attributed to their use. We report on a case of seizures, systemic inflammatory response, and rhabdomyolysis associated with laboratory-confirmed 4-iodo-2,5-dimethoxyphenethylamine and 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine exposure. A 17-year-old male teenager developed seizures after taking "2 strips of acid." The seizures resolved with midazolam, but he became apneic and was intubated. His head computed tomography was unremarkable. Initial creatinine level was 1.5 mg/dL, with a creatine kinase of 112 U/L. His urine immunoassay drug screen was negative. He was extubated within 12 hours but had elevated temperatures for 48 hours. He was treated with antibiotics, but no source of infection was identified. His creatinine level peaked at 2.46 mg/dL. His creatine kinase peaked 72 hours later at 14579 U/L. He was treated with intravenous fluids and did not require renal replacement therapy. He recovered fully and was discharged after 5 days. Serum and urine samples were tested using liquid chromatography time-of-flight mass spectrometry. We detected 4-iodo-2,5-dimethoxyphenethylamine and 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine in both serum and urine. No other substances were detected. The 2C drugs and their n-benzyloxymethyl analogs are potent serotonergic agents. Their use has been associated with multiple adverse effects including seizures, rhabdomyolysis, and death. They should be considered in differential diagnosis for drug-induced seizures and as a cause for systemic inflammatory response. This case highlights the significant toxicity seen with these compounds.

Fentanyl and a Novel Synthetic Opioid U-47700 Masquerading as Street "Norco" in Central California: A Case Report.

In 2013 and 2014, more than 700 deaths were attributed to fentanyl and fentanyl analogues in the United States. Of recent concern is the cluster of unintentional fentanyl overdoses because of tablets thought to be "Norco" purchased on the street in Northern California. U-47700 (trans-3,4-dichloro-N-[2-(dimethyl-amino)cyclohexyl]-N-methylbenz-amide) is a nonfentanyl-based synthetic opioid with 7.5 times the binding affinity of morphine to µ-opioid. We report a case of fentanyl and U-47700 intoxication from what was thought to be illicitly purchased Norco. A 41-year-old woman presented to the emergency department (ED) for altered mental status shortly after ingesting 3 beige Norco pills bearing a Watson imprint. She had pinpoint pupils and respiratory depression, which reversed after 0.4 mg naloxone administration intravenously. She had complete recovery and was discharged from the ED after a 4-hour observation period. Serum testing with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC 1260 QTOF/MS 6550; Agilent, Santa Clara, CA) confirmed the presence of the medications the patient reported receiving, and additionally fentanyl (15.2 ng/mL) and U-47700 (7.6 ng/mL). In this case report, street Norco purchased in Central California resulted in altered mental status requiring naloxone reversal because of fentanyl and the novel synthetic opioid U-47700. Because these compounds are not detected by routine urine drug testing and physical examination findings are similar to those of a traditional opioid toxidrome, emergency providers should use the patient's history and other circumstantial details to aid in diagnosis. In cases with suspicion of opioid or opioid analogue cause, we recommend that emergency providers contact their local poison control center, medical toxicologist, or public health department to aid in the investigation.

Hot and Cold Drugs: National Park Service Medication Stability at the Extremes of Temperature.

STUDY OBJECTIVE: National Park Service (NPS) Parkmedics provide medical care in austere environments. The objective of this study was to evaluate the stability of specific medications used by Parkmedics at extremes of temperatures likely to be faced in the field. METHODS: This is a bench research study conducted in the laboratory setting over a 4-week period. Parenteral medications were separated into 4 temperature exposure groups: A) 45°C (hot); B) -20°C (cold); C) hot then cold temperatures alternating weekly; and D) cold then hot temperatures alternating weekly. At study start and the end of each week, three aliquots from each group were sampled to determine the remaining drug concentration through liquid chromatography-quadrupole time-of-flight mass spectrometry (Agilent LC 1260- QTOF/MS 6550). Quantitative analysis was done using Agilent MassHunter Quantitative Analysis software. The mean drug concentration from triplicate aliquots was expressed as percentage of its baseline concentration to monitor the drug's stability during storage. RESULTS: Eight medications were analyzed (atropine, diphenhydramine, fentanyl, hydromorphone, midazolam, morphine, naloxone, ondansetron). Hydromorphone, morphine, and ondansetron showed the greatest stability, at above 90% of original concentration in all study arms. Diphenhydramine, fentanyl and midazolam showed heat independent degradation, degrading the same way regardless of heat exposure. By the end of the study period, 51-56% midazolam remained in all groups. Atropine and naloxone showed heat dependent degradation, degrading more when exposed to heat. Atropine had the most degradation, being undetectable after 4 weeks of heat exposure. CONCLUSIONS: We recommend that EMS providers replace atropine, naloxone, diphenhydramine, fentanyl, and midazolam frequently if they are practicing in low call volume or high-temperature environments. Further studies will be needed to determine if re-dosing midazolam, naloxone, and atropine is the appropriate clinical strategy in this setting if adequate clinical effect is not reached with a single dose.

Direct measurement of Bisphenol A (BPA), BPA glucuronide and BPA sulfate in a diverse and low-income population of pregnant women reveals high exposure, with potential implications for previous exposure estimates: a cross-sectional study.

BACKGROUND: Bisphenol A (BPA) is a ubiquitous, endocrine-disrupting environmental contaminant that increases risk of some adverse developmental effects. Thus, it is important to characterize BPA levels, metabolic fate and sources of exposure in pregnant women. METHODS: We used an improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytic method to directly and simultaneously measure unconjugated BPA (uBPA), BPA glucuronide and BPA sulfate in the urine of a population of ethnically and racially diverse, and predominately low-income pregnant women (n = 112) in their second trimester. We also administered a questionnaire on dietary and non-dietary sources of exposure to BPA. RESULTS: We found universal and high exposure to uBPA and its metabolites: median concentrations were 0.25, 4.67, and 0.31 µg/g creatinine for uBPA, BPA glucuronide, and BPA sulfate, respectively. The median Total BPA (uBPA + BPA in glucuronide and sulfate forms) level was more than twice that measured in U.S. pregnant women in NHANES 2005-2006, while 30 % of the women had Total BPA levels above the 95th percentile. On average, Total BPA consisted of 71 % BPA in glucuronide form, 15 % BPA in sulfate form and 14 % uBPA, however the proportion of BPA in sulfate form increased and the proportion of uBPA decreased with Total BPA levels. Occupational and non-occupational contact with paper receipts was positively associated with BPA in conjugated (glucuronidated + sulfated) form after adjustment for demographic characteristics. Recent consumption of foods and beverages likely to be contaminated with BPA was infrequent among participants and we did not observe any positive associations with BPA analyte levels. CONCLUSION: The high levels of BPA analytes found in our study population may be attributable to the low-income status of the majority of participants and/or our direct analytic method, which yields a more complete evaluation of BPA exposure. We observed near-universal exposure to BPA among pregnant women, as well as substantial variability in BPA metabolic clearance, raising additional concerns for effects on fetal development. Our results are consistent with studies showing thermal paper receipts to be an important source of exposure, point to the difficulty pregnant women have avoiding BPA exposure on an individual level, and therefore underscore the need for changes in BPA regulation and commerce.

Internet-purchased ibogaine toxicity confirmed with serum, urine, and product content levels.

UNLABELLED: Ibogaine, a psychotropic indole alkaloid, is gaining popularity among medical subcultures for its purported anti addictive properties. Its use has been associated with altered mental status, ataxia, gastrointestinal distress, ventricular arrhythmias, and sudden and unexplained deaths.Its pharmacokinetics in toxic states is not well understood. Case report:A 33-year-old man overdosed on ibogaine in an attempt to quit his use of heroin. He developed altered state of consciousness, tremor, ataxia,nausea, vomiting, and transient QT interval prolongation, which all remitted as he cleared the substance. Ibogaine was confirmed in his urine and serum with a peak serum concentration of 377 ng/mL. Nonlinear elimination kinetics and a formula match to its active metabolite noriobgaine were observed as well. CONCLUSION: This case presents the unique description of serial serum concentrations as well as urine and product-confirmed ibogaine toxicity with transient toxin-related QT interval prolongation.

A Common Source Outbreak of Severe Delirium Associated with Exposure to the Novel Synthetic Cannabinoid ADB-PINACA.

BACKGROUND: Since 2009, synthetic cannabinoid (SC) use has emerged as a growing public health threat in the United States (US). Several outbreaks of unexpected, severe toxicity linked to SC use have been reported since 2012. Reports of varied and significant morbidity after SC use are expected to increase because newer compounds enter the marketplace more frequently as manufacturers attempt to circumvent regulatory efforts. CASE REPORT: We report a cluster of 7 patients who experienced a spectrum of anxiety, delirium, psychosis, and aggressive behaviors after smoking the same SC-containing product at a party. An 8th patient with the same exposure source presented with delayed onset seizures. Biologic samples were analyzed for novel, newly identified SCs belonging to the FUBINACA family of compounds. A previously unknown SC, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (ADB-PINACA) was identified in biologic samples from 7 of the individuals. ADB-PINACA was identified in the SC-containing product ("Crazy Clown") seized by law enforcement and identified as the product smoked by the 8 patients in the reported cluster. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The information compiled using this cluster of cases, and a similar reported outbreak of altered mental status in Colorado, implicating the same SC (ADB-PINACA) and brands of SC-containing products, aided the US Drug Enforcement Administration in its temporary scheduling of ADB-PINACA and three other SCs. In this outbreak, close cooperation between public health and law enforcement allowed for a rapid intervention, which halted the outbreak by interrupting the common source and accelerated regulatory efforts to prevent further morbidity and mortality.

A round robin approach to the analysis of bisphenol A (BPA) in human blood samples.

BACKGROUND: Human exposure to bisphenol A (BPA) is ubiquitous, yet there are concerns about whether BPA can be measured in human blood. This Round Robin was designed to address this concern through three goals: 1) to identify collection materials, reagents and detection apparatuses that do not contribute BPA to serum; 2) to identify sensitive and precise methods to accurately measure unconjugated BPA (uBPA) and BPA-glucuronide (BPA-G), a metabolite, in serum; and 3) to evaluate whether inadvertent hydrolysis of BPA-G occurs during sample handling and processing. METHODS: Four laboratories participated in this Round Robin. Laboratories screened materials to identify BPA contamination in collection and analysis materials. Serum was spiked with concentrations of uBPA and/or BPA-G ranging from 0.09-19.5 (uBPA) and 0.5-32 (BPA-G) ng/mL. Additional samples were preserved unspiked as 'environmental' samples. Blinded samples were provided to laboratories that used LC/MSMS to simultaneously quantify uBPA and BPA-G. To determine whether inadvertent hydrolysis of BPA metabolites occurred, samples spiked with only BPA-G were analyzed for the presence of uBPA. Finally, three laboratories compared direct and indirect methods of quantifying BPA-G. RESULTS: We identified collection materials and reagents that did not introduce BPA contamination. In the blinded spiked sample analysis, all laboratories were able to distinguish low from high values of uBPA and BPA-G, for the whole spiked sample range and for those samples spiked with the three lowest concentrations (0.5-3.1 ng/ml). By completion of the Round Robin, three laboratories had verified methods for the analysis of uBPA and two verified for the analysis of BPA-G (verification determined by: 4 of 5 samples within 20% of spiked concentrations). In the analysis of BPA-G only spiked samples, all laboratories reported BPA-G was the majority of BPA detected (92.2 - 100%). Finally, laboratories were more likely to be verified using direct methods than indirect ones using enzymatic hydrolysis. CONCLUSIONS: Sensitive and accurate methods for the direct quantification of uBPA and BPA-G were developed in multiple laboratories and can be used for the analysis of human serum samples. BPA contamination can be controlled during sample collection and inadvertent hydrolysis of BPA conjugates can be avoided during sample handling.

The electric Kool-Aid NBOMe test: LC-TOF/MS confirmed 2C-C-NBOMe (25C) intoxication at Burning Man.

Designer drugs are constantly evolving, with the NBOMe derivatives of the 2C class of phenethylamines recently emerging in the US market. Cases of 2C-I-NBOMe toxicity have recently been reported in the literature. No reports to date describe the clinical effects 2C-C-NBOMe toxicity.

Prolonged ventilatory failure and flaccid quadriparesis after ingestion of poison hemlock.

INTRODUCTION: A 28-year-old man presented with acute flaccid paralysis and respiratory failure that persisted for 2 weeks after suicidal ingestion of unknown substances. METHODS: Extensive clinical, nerve, laboratory, and neuroimaging testing excluded alternative causes of this neuromuscular syndrome. Prompted by clues provided by family members, liquid chromatography time-of-flight mass spectrometry was used to investigate for the presence of poison hemlock. RESULTS: Testing of the residue in a jar used for the ingestion of a poisonous concoction confirmed the presence of the nicotinic alkaloid coniine. Analysis of patient serum suggested the presence of conhydrine. Concentrations of amitriptyline and diazepam were also found to be supratherapeutic, but only through the first few days of hospitalization. CONCLUSIONS: Herein we describe a case of reversible coma, flaccid quadriparesis, and neuromuscular respiratory failure caused by intentional ingestion of poison hemlock.

Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in midgestation umbilical cord serum in a northern and central California population.

Bisphenol-A (BPA) is an endocrine disrupting chemical used in numerous consumer products, resulting in universal exposure in the United States. Prenatal exposure to BPA is associated with numerous reproductive and developmental effects in animals. However, little is known about human fetal exposure or metabolism of BPA during midgestation. In the present study, we present a new liquid chromatography-tandem mass spectrometry method to directly measure concentrations of BPA and two predominant metabolic conjugates-BPA glucuronide and BPA sulfate-in umbilical cord serum collected from elective second trimester pregnancy terminations. We detected at least one form of BPA in all umbilical cord serum samples: BPA (GM 0.16, range

Multiple MDMA (Ecstasy) overdoses at a rave event: a case series.

Twelve patients with 3,4-methylenedioxymethamphetamine (MDMA) toxicity from a single rave event presented to multiple San Francisco Bay area hospitals with various life-threatening complications including seizures and hyperthermia. Eight required emergent endotracheal intubation and six had hypotension. Hyperkalemia, acute kidney injury, and rhabdomyolysis were present in most of the patients. In all, 2 patients died, 4 survived with permanent neurologic, musculoskeletal, and/or renal sequelae, and 6 survived without any apparent lasting deficits. Hyperthermia was present in 10 patients and was severe (40.9-43° C) in 7. Using multiple cooling methods, the average time to achieve cooling was 2.7 hours. Serum drug analysis was performed on 3 patients, demonstrating toxic MDMA concentrations without the presence of other xenobiotics. Two capsules confiscated by police at the event contained 82% and 98% MDMA, respectively, without other pharmacologically active compounds. Capsule #2 contained 270 mg MDMA, which is more than twice the amount of MDMA usually contained in 1 dose. The MDMA-induced hyperthermia significantly contributed to the morbidity and mortality in this case series. Factors contributing to the severity of the hyperthermia include ingestion of large doses of MDMA, a warm ambient environment, and physical exertion.

Cardiotoxicity in a citalopram and olanzapine overdose.

BACKGROUND: This is a case of a citalopram and olanzapine overdose causing seizures and severe cardiotoxicity. CASE REPORT: A 21-year-old man presented unresponsive, with seizures, to an Emergency Department. The patient's initial electrocardiogram demonstrated a widened QRS of 160 ms and a normal QT/QTc interval of 400/487 ms consistent with cardiac sodium channel blockade. Within 30 min of arrival, peak citalopram and olanzapine levels were measured to be 522 ng/mL and 505 ng/mL, respectively. Measured levels remained supratherapeutic until 13.6 h and 42.6 h after arrival for citalopram and olanzapine, respectively. The patient developed bradycardia and hypotension that required multimodal therapies including sodium bicarbonate boluses, vasopressors, and transvenous pacing. Seizures and cardiotoxicity continued while citalopram, but not olanzapine, was supratherapeutic. CONCLUSIONS: This case describes cardiotoxicity directly correlated with supratherapeutic citalopram levels in overdose.

Glyphosate exposure and preterm birth: A nested case-control pilot study.

Preterm birth (PTB) is associated with a high risk of infant mortality and long-term adverse health effects. Glyphosate is a broad-spectrum herbicide applied in agricultural and non-agricultural settings. Studies suggested an association between maternal exposure to glyphosate and PTB among mostly racially homogenous populations, though results were inconsistent. The objective of this pilot study was to inform the design of a larger and more definitive study of glyphosate exposure and adverse birth outcomes in a racially-diverse population. Urine was obtained from 26 women with a PTB as cases and 26 women with a term birth as controls, from participants enrolled in a birth cohort in Charleston, South Carolina. We used binomial logistic regression to estimate associations between urinary glyphosate and the odds of PTB, and multinomial regression to estimate associations between maternal racial identity and urinary glyphosate among controls. Glyphosate was unrelated to PTB (odds ratio (OR) = 1.06, 95% CI: 0.61, 1.86). Women who identified as Black had greater odds (OR = 3.83, 95% CI: 0.13, 111.33) of having categorical "high" glyphosate (> 0.28 ng/mL) and lesser odds (OR = 0.79, 95% CI: 0.05, 12.21) of "low" glyphosate (< 0.03 ng/mL) relative to women who identified as white, suggesting a potential racial disparity, although the effect estimates were imprecise and included the null. Given concerns of potential reproductive toxicity of glyphosate, the results merit confirmation in a larger investigation to determine specific sources of glyphosate exposure, incorporating longitudinal urinary glyphosate measures during pregnancy and a comprehensive measure of diet.

Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA.

Over 200 synthetic cannabinoid receptor agonists (SCRAs) have been identified as new psychoactive substances. Effective monitoring and characterization of SCRAs are hindered by the rapid pace of structural evolution. Ahead of possible appearance on the illicit drug market, new SCRAs were synthesized to complete a systematic library of cumyl-indole- (e.g., CUMYL-CPrMICA, CUMYL-CPMICA) and cumyl-indazole-carboxamides (e.g., CUMYL-CPrMINACA, CUMYL-CPMINACA), encompassing butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl tails. Comprehensive pharmacological characterization was performed with three assay formats, monitoring the recruitment of either wild-type or C-terminally truncated (ßarr2d366) ß-arrestin2 to the activated cannabinoid 1 receptor (CB1) or monitoring Gßγ-mediated membrane hyperpolarization. Altered compound characterization was observed when comparing derived potency (EC50) and efficacy (Emax) values from both assays monitoring the same or a different signaling event, whereas ranges and ranking orders were similar. Structure-activity relationships (SAR) were assessed in threefold, resulting in the identification of the pendant tail as a critical pharmacophore, with the optimal chain length for CB1 activation approximating an n-pentyl (e.g., cyclopentylmethyl or cyclohexylmethyl tail). The activity of the SCRAs encompassing cyclic tails decreased with decreasing number of carbons forming the cyclic moiety, with CUMYL-CPrMICA showing the least CB1 activity in all assay formats. The SARs were rationalized via molecular docking, demonstrating the importance of the optimal steric contribution of the hydrophobic tail. While SAR conclusions remained largely unchanged, the differential compound characterization by both similar and different assay designs emphasizes the importance of detailing specific assay characteristics to allow adequate interpretation of potencies and efficacies.