PubMed · 14367041
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1955-05-07. LEAD POISONING.. https://doi.org/10.1001/jama.1955.02960010049015
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A series of column studies, using site-specific soil and groundwater, were conducted to determine the feasibility of biologically active zone enhancement (BAZE) process for reductive biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in groundwater. This treatability study examined the use of four amendments (acetate, ethanol, soluble starch, and acetate plus ammonium), which served as electron donors. Triplicate columns, with groundwater residence time of about 27.5 h, were used for each amendment treatment and the amendment control. In treatment columns amendment dosing was 500 mg/L C for carbon sources and 100 mg/L N for ammonium. Each of the amendment treatments reduced RDX inlet concentrations of 100 microg/L to less than 1 microg/L. The highest first-order RDX biodegradation rate ranged between 0.140 and 0.447 h(-1) for acetate amended columns as compared to 0.037 to 0.083 h(-1) in control columns (no amendment). The addition of soluble starch resulted in increased toxicity (based on Microtox analysis) that was partially removed by biological activity in the columns. Ethanol addition itself did not result in increased toxicity but biological activity in this system did induce Microtox toxicity. Acetate did not have any Microtox toxicity associated with it. The addition of ammonium as a nitrogen source did not significantly increase the removal rate of RDX. Based on these observations acetate was selected for the field demonstration.
Elevation of glycine levels and activation of the NMDA receptor by inhibition of the glycine transporter 1 (GlyT-1) is a potential strategy for the treatment of schizophrenia. A novel series of GlyT-1 inhibitors have been identified containing the 2-arylsulfanyl-phenylpiperazine motif. The most prominent member of this series, (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)-phenyl]-2-methyl-piperazin-1-yl-acetic acid (31) is a potent glycine transporter-1 inhibitor (IC(50)=150 nM), which elevated glycine levels in rat ventral hippocampus as measured by microdialysis in vivo at doses of 1.2-4.6 mg/kg s.c.
Phenoxyacetic acids including 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxyacetic acid (MCPA) are widely utilized organic acid herbicides that have undergone extensive toxicity and pharmacokinetic analyses. The dog is particularly susceptible to the toxicity of phenoxyacetic acids and related organic acids relative to other species. Active renal clearance mechanisms for organic acids are ubiquitous in mammalian species, and thus a likely mechanism responsible for the increased sensitivity of the dog to these agents is linked to a lower capacity to secrete organic acids from the kidney. Using published data describing the pharmacokinetics of phenoxyacetic and structurally related organic acids in a variety of species including humans, inter-species comparative pharmacokinetics were evaluated using allometic parameter scaling. For both 2,4-D and MCPA, the dog plasma half-life (t(1/2)) and renal clearance (Clr; mL/h) rates did not scale as a function of body weight across species; whereas for all other species evaluated, including humans, these pharmacokinetic parameters reasonably scaled. This exceptional response in the dog is clearly illustrated by comparing the plasma t(1/2) at comparable doses of 2,4-D and MCPA, across several species. At a dosage of 5mg/kg, in dogs, the plasma t(1/2) for 2,4-D and MCPA were approximately 92-106 and 63 h, respectively, which is substantially longer than in the rat (approximately 1 and 6 h, respectively) or in humans (12 and 11 h, respectively). This longer t(1/2), and slower elimination in the dog, results in substantially higher body burdens of these organic acids, at comparable doses, relative to other species. Although these results indicate the important role of renal transport clearance mechanisms as determinants of the clearance and potential toxicity outcomes of phenoxyacetic acid herbicides across several species, other contributing mechanisms such as reabsorption from the renal tubules is highly likely. These findings suggest that for new structurally similar organic acids, a limited comparative species (rat versus dog) pharmacokinetic analysis early in the toxicology evaluation process may provide important insight into the relevance of the dog. In summary, the substantial difference between the pharmacokinetics of phenoxyacetic acids and related organic acids in dogs relative to other species, including humans, questions the relevance of using dog toxicity data for the extrapolation of human health risk.