document

Biochemical and behavioral effects of soman vapors in low concentrations

Bajgar, J. (author), Ševelová, L. (author), Krejčová, G. (author), Fusek, J. (author), Vachek, J. (author), Kassa, J. (author), Herink, J. (author), de Jong, L.P.A. (author), Benschop, H.P. (author)

Soman belongs to the most dangerous nerve agents because of the low effectiveness of the presently available antidotes. Soman acts by inhibiting acetylcholinesterase (AChE) both peripherally and centrally, with a subsequent accumulation of neuromediator acetylcholine and other metabolic changes. From the data published in literature it can be...

article 2004

document

Procedure for monitoring exposure to sulfur mustard based on modified Edman degradation of globin

Noort, D. (author), Fidder, A. (author), Benschop, H.P. (author), de Jong, L.P.A. (author), Smith, J.R. (author)

A procedure for the modified Edman degradation of globin for determination of sulfur mustard adducts to the N-terminal valine residue in human hemoglobin has been developed for use under field laboratory conditions. The minimum detectable exposure level of human blood (in vitro) to sulfur mustard using this procedure is 100nM. The...

article 2004

document

Standard operating procedure for immunuslotblot assay for analysis of DNA/sulfur mustard adducts in human blood and skin

van der Schans, G.P. (author), Mars-Groenendijk, R. (author), de Jong, L.P.A. (author), Benschop, H.P. (author), Noort, D. (author)

A standard operating procedure has been developed for an immunoslotblot assay of sulfur mustard adducts to DNA in human blood and skin for use in a field laboratory. A minimum detectable level of exposure of human blood in vitro (≥ 50nM) sulfur mustard is feasible with the assay. In the case of human skin, a 1 s exposure to saturated sulfur...

article 2004

document

Immunochemical detection of sulfur mustard adducts with keratins in the stratum corneum of human skin

van der Schans, G.P. (author), Noort, D. (author), Mars-Groenendijk, R.H. (author), Fidder, A. (author), Chau, L.F. (author), de Jong, L.P.A. (author), Benschop, H.P. (author), Prins Maurits Laboratorium TNO (author)

As part of a program to develop methods for diagnosis of exposure to chemical warfare agents, we developed immunochemical methods for detection of adducts of sulfur mustard to keratin in human skin. Three partial sequences of keratins containing glutamine or asparagine adducted with a 2-hydroxyethylthioethyl group at the ω-amide function were...

article 2002

document

In vitro adduct formation of phosgene with albumin and hemoglobin in human blood

Noort, D. (author), Hulst, A.G. (author), Fidder, A. (author), van Gurp, R.A. (author), de Jong, L.P.A. (author), Benschop, H.P. (author), Prins Maurits Laboratorium TNO (author)

The development of procedures for retrospective detection and quantitation of exposure to phosgene, based on adducts to hemoglobin and albumin, is described. Upon incubation of human blood with [14C]phosgene (0-750 μM), a significant part of radioactivity (0-13%) became associated with globin and albumin. Upon Pronase digestion of globin, one of...

article 2000

document

Lessons learned by use of stereomers of soman - An organophosphorus inhibitor with two chiral centers on the functional architecture of human acetylcholinesterase

Ordentlich, A. (author), Barak, D. (author), Kronman, C. (author), Benschop, H.P. (author), de Jong, L.P.A. (author), Ariel, N. (author), Barak, R. (author), Segall, Y. (author), Velan, B. (author), Shafferman, A. (author)

Structural architecture of the human acetylcholinesterase (HuAChE) active center and the effect of adduct configurations on the aging process were explored through phosphylation and aging reaction of the AchE wild type and selected mutants using the four stereoisomers of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman). Reactivity of wild...

conference paper 2000

document

Immunochemical detection of sulfur mustard-adducts with DNA and proteins: Exploratory research on adducts with proteins

van der Schans, G.P. (author), Noort, D. (author), Mars-Groenendijk, R.H. (author), van Dijk-Knijnenburg, H.C.M. (author), Fidder, A. (author), de Jong, L.P.A. (author), Benschop, H.P. (author)

We have developed two modes of a standard operating procedure (SOP) for immunochemical detection of sulfur mustard adducts to DNA in human blood and skin. In the shortened mode data could be generated within 9 h after in vitro exposure of human blood to > 1 μM sulfur mustard. The sensitive mode allows detection of exposure to 50 nM sulfur...

conference paper 2000

document

A physiologically based model for the toxicokinetics of C(±)P(±)-soman in the atropinized guinea pig and marmoset - Effect of scavengers and hydrolytic enzymes promoting elimination

de Jong, L.P.A. (author), Sweeney, R.E. (author), Maxwell, D.M. (author), Langenberg, J.P. (author), Benschop, H.P. (author)

Previously, we developed a physiologically based model describing the toxicokinetics of the summed C(±)P(-)-isomers and of the individual C(±)P(+)-isomers in anesthetized, atropinized and mechanically ventilated guinea pigs after intoxication with i.v. doses of 0.8 – 6 LD50 of C(±)P(±)-soman. Some improved parameters have been introduced into...

conference paper 2000

document

Diagnosis and dosimetry of exposure to sulfur mustard: Development of a standard operating procedure for mass spectrometric analysis of haemoglobin adducts - Exploratory research on albumin and keratin adducts

Noort, D. (author), Fidder, A. (author), Hulst, A.G. (author), de Jong, L.P.A. (author), Benschop, H.P. (author), Department of Chemical Toxicology, TNO Prins Maurits Laboratory, PO Box 45, 2280 AA Rijswijk, Netherlands Department of Analysis of Toxic and Explosive Substances, TNO Prins Maurits Laboratory, PO Box 45, 2280 AA Rijswijk, Netherlands (author)

Experiments were carried out to develop a standard operating procedure for analysis of sulfur mustard adducts to the N-terminal valine in haemoglobin and to explore adduct formation with albumin and keratin. In the first approach, gas chromatography-negative chemical ionization/mass spectrometry (GC-NCI/MS) of the thiohydantoin sample subsequent...

article 2000

document

Biomonitoring of exposure to lewisite based on adducts to haemoglobin

Fidder, A. (author), Noort, D. (author), Hulst, A.G. (author), de Jong, L.P.A. (author), Benschop, H.P. (author), Prins Maurits Laboratorium TNO (author)

The development of a procedure for retrospective detection and quantitation of exposure to the arsenical dichloro(2-chlorovinyl)arsine (lewisite; L1) has been initiated. Upon incubation of human blood with [14C]L1 (20 nM-0.2 mM) in vitro, more than 90% of the total radioactivity was found in the erythrocytes and 25-50% of the radioactivity...

article 2000

document

Diagnosis and dosimetry of exposure to sulfur mustard: Development of a standard operating procedure for hemoglobin adducts: Exploratory research on albumin and keratin adducts

Noort, D. (author), Fidder, A. (author), de Jong, L.P.A. (author), van der Schans, G.P. (author), Benschop, H.P. (author)

A standard operating procedure (SOP) for determination of the sulfur mustard adduct to the N-terminal valine in hemoglobin was developed. By using this SOP, it was found that the Nterminal valine adduct in globin of hairless guinea pigs and marmosets which had been exposed to sulfur mustard (0.5 LD50) is persistent for at least 56 and 94 days,...

conference paper 2000

document

Alkylation of human serum albumin by sulfur mustard in vitro and in vivo: Mass spectrometric analysis of a cysteine adduct as a sensitive biomarker of exposure

Noort, D. (author), Hulst, A.G. (author), de Jong, L.P.A. (author), Benschop, H.P. (author)

To develop a mass spectrometric assay for the detection of sulfur mustard adducts with human serum albumin, the following steps were performed: quantitation of the binding of the agent to the protein by using [14C] sulfur mustard and analysis of acidic and tryptic digests of albumin from blood after exposure to sulfur mustard for identification...

article 1999

document

Retrospective detection of exposure to organophosphates: Analysis in blood of human beings and rhesus monkeys

Polhuijs, M. (author), Langenberg, J.P. (author), Noort, D. (author), Hulst, A.G. (author), Benschop, H.P. (author), de Jong, L.P.A. (author), TNO Prins Maurits Laboratorium (author)

The terrorist attacks with nerve agents in Japan as well as the ongoing debate on a possible relationship between the so-called Gulf War Syndrome and accidental exposure to traces of nerve agents have made clear that improved methods for detection of exposure to organophosphates are needed. Low level exposures can not be detected by the methods...

bookPart 1999

document

Exploring the active center of human acetylcholinesterase with stereomers of an organophosphorus inhibitor with two chiral centers

Ordentlich, A. (author), Barak, D. (author), Kronman, C. (author), Benschop, H.P. (author), de Jong, L.P.A. (author), Ariel, N. (author), Barak, R. (author), Segall, Y. (author), Velan, B. (author), Shafferman, A. (author)

The stereoselectivity of the phosphonylation reaction and the effects of adduct configuration on the aging process were examined for human acetylcholinesterase (HuAChE) and its selected active center mutants, using the four stereomers of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman). The reactivity of wild type HuAChE toward the P(S)...

article 1999

document

Low level nose-only exposure to the nerve agent soman: Toxicokinetics of soman stereoisomers and cholinesterase inhibition in atropinized guinea pigs

Benschop, H.P. (author), Trap, H.C. (author), Spruit, H.E.T. (author), van der Wiel, H.J. (author), Langenberg, J.P. (author), de Jong, L.P.A. (author), Prins Maurits Laboratorium TNO (author)

In order to initiate a quantitative basis for the toxicology of low level exposure to nerve agents, the toxicokinetics of soman stereoisomers during nose-only exposure for 5 h to 20 ppb (160 μg/m3) of C(±)P(±)- soman in air were studied in restrained, anesthetized, and atropinized guinea pigs. The concentrations of the toxic C(±)P(-)-soman...

article 1998

document

Direct determination of the chemical composition of acetylcholinesterase phosphonylation products utilizing electrospray-ionization mass spectrometry

Barak, R. (author), Ordentlich, A. (author), Barak, D. (author), Fischer, M. (author), Benschop, H.P. (author), de Jong, L.P.A. (author), Segall, Y. (author), Velan, B. (author), Shafferman, A. (author)

While non-reactivability of cholinesterase from their phosphyl conjugates (aging) is attributed to an unimolecular process involving loss of alkyl group from the phosphyl moiety, no conclusive evidence is available that this is the only reaction path and involvement of other post-inhibitory processes cannot be ruled out, To address this issue,...

article 1997

document

Protection of guinea pigs against soman poisoning by pretreatment with p-nitrophenyl phosphoramidates

TNO Prins Maurits Laboratorium (author), Langenberg, J.P. (author), de Jong, L.P.A. (author), Benschop, H.P. (author)

Several p-nitrophenyl phosphoramidates with the general formula RO(NH2)P(O)OC6H4-p-NO2, in which R = CH2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2CH2CH2CH3, and CH2CH2Cl, as well as (NH2)2P(O)OC6H4-p-NO2 were administered intravenously to guinea pigs as pretreatment compounds for protection against the lethal effects of 1,2,2-trimethylpropyl...

article 1996

document

Characterization of sulfur mustard induced structural modifications in human hemoglobin by liquid chromatography-tandem mass spectrometry

Noort, D. (author), Verheij, E.R. (author), Hulst, A.G. (author), de Jong, L.P.A. (author), Benschop, H.P. (author), Prins Maurits Laboratorium TNO TNO Voeding (author)

In this paper we describe the use of tandem mass spectrometry to identify modified sites in human hemoglobin after in vitro exposure to bis(2- chloroethyl) sulfide (sulfur mustard). Globin isolated from human whole blood which had been exposed to sulfur mustard was degraded with trypsin, and the digests were analyzed by micro LC/MS. Alkylated...

article 1996

document

The bispyridinium-dioxime HLö-7. A potent reactivator for acetylcholinesterase inhibited by the stereoisomers of tabun and soman

de Jong, L.P.A. (author), Verhagen, M.A.A. (author), Langenberg, J.P. (author), Hagedorn, I. (author), Löffler, M. (author), Prins Maurits Laboratorium TNO (author)

Purification of (+)-tabun was accomplished by treatment with electric eel acetylcholinesterase (AChE) in order to bind contaminating (-)-tabun, the more potent enantiomer with respect of AChE inhibition. Electric eel AChE inhibited with (-)-tabun and with purified (+)-tabun show similar properties in reactivation reactions with oximes (pH 7.5,...

article 1989

document

Stabilisation, analysis and toxicokinetics of the four stereoisomers of the nerve agent pinacolyl methylphosphonofluoridate (soman) in rats

Prins Maurits Laboratorium TNO (author), Benschop, H.P. (author), van Helden, H.P.M. (author), de Jong, L.P.A. (author)

conference paper 1987