A two-step gas chromatography-tandem mass spectrometry method for measurement of multiple environmental pollutants in human plasma.

Individuals are exposed to a wide variety of chemicals over their lifetime, yet current understanding of mixture toxicology is still limited. We present a two-step analytical method using a gas chromatograph-triple quadrupole mass spectrometer that requires less than 1 mL of sample. The method is applied to 183 plasma samples from a study population of children with autism spectrum disorder, their parents, and unrelated neurotypical children. We selected 156 environmental chemical compounds and ruled out chemicals with detection rates less than 20% of our study cohort (n = 61), as well as ones not amenable to the selected extraction and analytical methods (n = 34). The targeted method then focused on remaining chemicals (n = 61) plus 8 additional polychlorinated biphenyls (PCBs). Persistent pollutants, such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and PCB congeners 118 and 180, were detected at high frequencies and several previously unreported chemicals, including 2,4,6-trichlorophenol, isosafrole, and hexachlorobutadiene, were frequently detected in our study cohort. This work highlights the benefits of employing a multi-step analytical method in exposure studies and demonstrates the efficacy of such methods for reporting novel information on previously unstudied pollutant exposures.

Intervention to reduce gymnast exposure to flame retardants from pit foam: A case study.

Gymnasts can have high exposures to flame retardants (FRs), which are used in gymnastics safety equipment such as the loose foam pit. Therefore, we aimed to reduce gymnast exposure to FRs by replacing the foam in the pit using foam free of additive FR and measuring personal exposure during practice using hand-wipes. To assure maintenance of fire safety we first conducted a flammability study and facilitated a fire inspection for our partner gym. The FR-treated cubes had similar heat release rates to the non-FR treated cubes, required a 11 cm larger flame size applied for 6 s longer to ignite, and took 4 min longer to reach peak flame height. Based on these findings and the presence of other fire safety measures including smoke detectors and a sprinkler system, the local fire and building departments approved replacement of the foam pit with FR-free foam. We then replaced foam in the gym's pit, verified it was free of any additive FRs, and quantified common halogenated and organophosphate FRs on hand-wipes collected from ten collegiate gymnasts before and after practice, pre- and post-intervention. We observed a 5-fold decline in the median mass of FRs found in pit foam that accumulated on hand-wipes during practice among gymnasts who used the foam pit (p = 0.02), indicating that replacing the foam in a pit using materials free of FRs can reduce gymnast exposure to these chemicals during practice.

Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors.

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

Design and structure-activity relationship of heterocyclic analogs of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones as inhibitors of receptor tyrosine kinases.

Herein are described a series of novel heterocyclic analogs of the 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one scaffold. These compounds are potent inhibitors of receptor tyrosine kinases and exhibit favorable pharmacokinetic profiles. The synthesis and SAR of these compounds are described.