Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system.

Of the three-quarters of a million service personnel involved in the Persian Gulf War, approximately 30,000 have complained of neurological symptoms of unknown etiology. One contributing factor to the emergence of such symptoms may be the simultaneous exposure to multiple agents used to protect the health of service personnel, in particular, the anti-nerve agent pyridostigmine bromide (PB; 3-dimethylaminocarbonyloxy-N-methylpyridinium bromide), the insect repellent DEET (N,N-diethyl-m-toluamide), and the insecticide permethrin (3-(2,2-dichloro-ethenyl)-2,2-dimethylcyclopropanecarboxylic acid (3-phenoxyphenyl)methyl ester). This study investigated neurotoxicity produced in hens by individual or simultaneous exposure to these agents (5 d/wk for 2 months to 5 mg/kg/d PB in water, po; 500 mg/kg/d DEET, neat, sc; and 500 mg/kg/d permethrin in corn oil, sc). At these dosages, exposure to single compounds resulted in minimal toxicity. Combinations of two agents produced greater neurotoxicity than that caused by individual agents. Neurotoxicity was further enhanced following concurrent administration of all three agents. We hypothesize that competition for liver and plasma esterases by these compounds leads to their decreased breakdown and increased transport of the parent compound to nervous tissues. Thus, carbamylation of peripheral esterases by PB reduces the hydrolysis of DEET and permethrin and increases their availability to the nervous system. In effect, PB "pumps" more DEET and permethrin into the central nervous system. Consistent with this hypothesis, hens exposed to the combination of the three agents exhibited neuropathological lesions with several characteristics similar to those previously reported in studies of near-lethal doses of DEET and permethrin. If this hypothesis is correct, then blood and liver esterases play an important "buffering" role in protecting against neurotoxicity in the population at large. It also suggests that individuals with low plasma esterase activity may be predisposed to neurologic deficits produced by exposure to certain chemical mixtures.

Neurotoxicity resulting from coexposure to pyridostigmine bromide, deet, and permethrin: implications of Gulf War chemical exposures.

Many books cover the emergency response to chemical terrorism. But what happens after the initial crisis? Chlorine, phosgene, and mustard were used in World War I. Only years after the war were the long-term effects of these gases realized. In the 60s, 70s, and 80s, these and other agents were used in localized wars. Chemical Warfare Agents: Tox

Chemical Warfare Agents : Toxicity at Low Levels

Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination.

The biodegradation of organic pollutants in aquifers is often restricted to the fringes of contaminant plumes where steep countergradients of electron donors and acceptors are separated by limited dispersive mixing. However, long-distance electron transfer (LDET) by filamentous 'cable bacteria' has recently been discovered in marine sediments to couple spatially separated redox half reactions over centimeter scales. Here we provide primary evidence that such sulfur-oxidizing cable bacteria can also be found at oxic-anoxic interfaces in aquifer sediments, where they provide a means for the direct recycling of sulfate by electron transfer over 1-2-cm distance. Sediments were taken from a hydrocarbon-contaminated aquifer, amended with iron sulfide and saturated with water, leaving the sediment surface exposed to air. Steep geochemical gradients developed in the upper 3 cm, showing a spatial separation of oxygen and sulfide by 9 mm together with a pH profile characteristic for sulfur oxidation by LDET. Bacterial filaments, which were highly abundant in the suboxic zone, were identified by sequencing of 16S rRNA genes and fluorescence in situ hybridization (FISH) as cable bacteria belonging to the Desulfobulbaceae. The detection of similar Desulfobulbaceae at the oxic-anoxic interface of fresh sediment cores taken at a contaminated aquifer suggests that LDET may indeed be active at the capillary fringe in situ.

Long-distance electron transfer by cable bacteria in aquifer sediments.

Comparative pyridostigmine kinetics in plasma were measured in 10 healthy subjects given 4 mg iv and 60 mg oral pyridostigmine bromide. As determined from the AUC ratio, oral availability was 11.5% to 18.9% (means = 14.3%). Mean t 1/2 of the plasma level decline after oral dosing was 200 minutes, twice as long as the terminal elimination t1/2 after intravenous infusion (97 minutes). Thus absorption may proceed at a slower rate than elimination. Comparison of intraindividual data revealed strict dependence of the AUC on the infused dose (2, 4, and 8 mg) in one subject and variability in AUC up to a factor of two when two subjects took oral pyridostigmine three times. Patients with myasthenia who were receiving continuous therapy with oral pyridostigmine had AUC values per unit dose corresponding to those in healthy subjects. Storage stability of pyridostigmine in plasma required acidification of samples and storage at -75 degrees C. When native plasma was kept at -20 degrees C, there was appreciable loss of pyridostigmine within 1 to 2 months, the extent of which depended on the initial concentration.

Pyridostigmine kinetics in healthy subjects and patients with myasthenia gravis

The unsaturated zone including the capillary fringe is a very dynamic and active environment for biogeochemical processes. Modeling of fate and transport of organic pollutants has to account for vapor phase and sewage water transport coupled to the biogeochemical processes occurring. This study presents results from numerical simulations validated with data of a well-controlled field experiment on volatilization of a multi-component organic mixture in the unsaturated zone. Sensitivity analyses show that the overall biodegradation rates depend mainly on properties of the organic pollutants such as Henry’s Law constant, the soil water content, and on the individual degradation rate constants or temperature. Low Henry’s law constants result in relatively high biodegradation rates whereas compounds with high vapor pressure und low water solubility are lost to the atmosphere. The contaminant transfer rates into groundwater are relatively small, but lead locally to concentrations above the legal limit in the capillary fringe region. Contaminant transport by seepage water is just minor compared to diffusive vapor phase fluxes of volatile compounds.

Natural Attenuation in the unsaturated zone and shallow groundwater: coupled modeling of vapor phase diffusion, biogeochemical processes and transport across the capillary fringe

Understanding the complex, interacting processes that determine the fate and transport of contaminants in groundwater is a major challenge for evaluating and predicting risks to clean water, human and ecological receptors and for designing effective remediation plans. Different physical and biogeochemical processes including advection, hydrodynamic dispersion, dissolution, sorption and biodegradation affect the migration of contaminants in saturated porous media like a groundwater system. In this chapter an overview of these processes is presented together with the basic theory on contaminant transport modeling, which represents an essential tool for a quantitative description of contaminant migration in the subsurface. Numerical simulations of typical contamination scenarios are presented, with the main goal of identifying the influence of different parameters on contaminant fate and transport such as transverse dispersivity, thickness and strength of the contamination source, recharge, biodegradation rates and mixing enhancement through flow focusing in high permeability zones. These numerical simulations are complemented by two examples, i.e. the reactive transport of toluene from a LNAPL source and a field study, where ammonium is continuously released from a leaking landfill to the underlying aquifer. The principal processes at the landfill site have been quantitatively integrated into the framework of a two-dimensional reactive transport model.

Contaminant Fate and Reactive Transport in Groundwater

Dispersive processes that diminish contaminant concentrations originating from an unsaturated source zone on the way to groundwater, were investigated. Simulations using the numerical model MIN3P were performed for a non-volatile, non-degrading contaminant from a persistent source after reaching a steady state. A 2-D vertical cross-section was used as geometry. Two different types of sandy sediment were simulated: a rather coarse sand with a capillary rise of 90% water saturation to 4 cm above the water table, and a silty sand showing a capillary fringe of 30 cm height (90% water saturation). Major dispersive fluxes were found to take place below the water table, thus dilution and concentration reduction at and above the water table is not very significant.

Ulrich Maier

Papers

Pyridostigmine kinetics in healthy subjects and patients with myasthenia gravis

Natural Attenuation in the unsaturated zone and shallow groundwater: coupled modeling of vapor phase diffusion, biogeochemical processes and transport across the capillary fringe

Contaminant Fate and Reactive Transport in Groundwater

Modelling the dilution of solutes due to mass transfer across the capillary fringe.