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Two cases of anaphylactic reactions set off by the ingestion of a small amount of mustard sauce are described. Mediation by specific IgE to mustard was determined by skin prick tests and radioimmunoassay, which suggested a type I hypersensitivity mechanism. Despite the antigenic potency of mustard, a spice that is consumed frequently, very few cases of hypersensitivity from ingestion have been described.
Bifunctional alkylating agents are used in tumor chemotherapy to induce the death of malignant cells through blockage of DNA replication. Nitrogen mustards are commonly used chemotherapeutic agents that can bind mono- or bifunctionally to guanines in DNA. Mustard HN1 is considered a monofunctional analog of bifunctional mustard HN2 (mechlorethamine). Escherichia coli K12 mutant strains deficient in nucleotide excision repair (NER) or base excision repair (BER) were submitted to increasing concentrations of HN2 or HN1, and the results revealed that damage induced by each chemical demands different DNA repair pathways. Damage induced by HN2 demands the activity of NER with a minor requirement of the BER pathway, while HN1 damage repair depends on BER action, without any requirement of NER function. Taken together, our data suggest that HN1 and HN2 seem to induce different types of damage, since their repair depends on distinct pathways in E. coli.
New barrier creams known as topical skin protectants (TSPs) recently have been formulated and demonstrated to be effective in delaying skin penetration of the blistering warfare agent sulfur mustard (HD). To further inactivate or neutralize HD, compounds that react with the toxic agent must be incorporated in the formulations, which then become reactive topical skin protectants (rTSPs). Specific and fast screening methods are necessary to assess the decontaminating activity of rTSPs. A headspace sampling technique in conjunction with thermal desorption and gas chromatography-mass spectrometry was evaluated as a potential screening method. A lower detection limit of 1 ng and a coefficient of variation of <20% were observed for the repetitive measurements of residual HD. Using this method, we evaluated a candidate rTSP. The percentage recovery of HD applied to the rTSP decreased by 35% over a 20-min time period compared with a non-rTSP. The candidate formulation showed an instant decontamination of the HD simulant dibutyl sulfide (decontamination was achieved in 2 s). The instrument set-up has the potential to accommodate multiple samples and can be automated. The method can be extended also to test reactive dermal formulations with toxic organophosphorus compounds.
Activated cyclophosphamide (CP) is known to achieve its cytotoxic and alkylating capacity upon spontaneous hydrolytic breakdown of the oxazaphosphorine ring structure. Treatment of yeast cells with the chemically activated form of CP (4-hydroperoxy-CP, 4-OOH-CP) and with several potentially toxic cleavage products revealed that cytotoxicity is closely linked to the formation of DNA interstrand cross-links and to DNA fragmentation. While this holds true for 4-OOH-CP and its bifunctional alkylating breakdown products, phosphoramide mustard (PM) and nor-nitrogen mustard (NNM), equimolar concentrations of acrolein and the monofunctional analogon of activated CP were inactive. NNM, the ultimate cleavage product within the successive degradation of the oxazaphosphorine structure was five times more toxic than 4-OOH-CP, whereas the cytotoxic action of PM was only slightly enhanced. The high cytotoxicity of NNM was matched by its ability to induce DNA interstrand cross-links: at concentrations and treatment times producing equal cell killing, 4-OOH-CP and NNM produced the same extent of cross-linking and DNA fragmentation. Biochemical potency of NNM is in contrast to data found with the NBP colorimetric assay which suggest that NNM loses its alkylating activity at neutral pH. 4-OOH-CP and PM are much more stable than predicted from half-life measurements performed via the NBP colorimetric assay: they retain a considerable fraction of their cytotoxic and cross-linking activity in spite of a 12-h preincubation at pH 7 and 36 degrees C.
Animal models are employed to investigate mechanisms of injury and to evaluate protective measures against sulfur mustard (HD) exposure. The ability to detect and quantify HD enables the researcher to follow safe procedures in handling skin samples. We designed an experimental procedure to measure HD offgassing from animal models. A Minicams--a portable gas chromatograph equipped with a flame photometric detector and on-line sorbent collection and desorption--was used to monitor the HD concentration. Confirming measurements were made using a two-step process that trapped HD on a Tenax sorbent off-line and then transferred the sample by means of an ACEM 900 to a gas chromatograph equipped with either a flame photometric detector or a mass spectrometer. Sulfur mustard offgassing data are presented from three experiments in which weanling pigs were exposed to saturated HD vapor via vapor caps containing 10 microl of HD. The HD concentration was measured in time-weighted-average (TWA) units at a specific HD application site. The current 8-h maximum exposure limit for HD is 3-ng l(-1), (1 TWA unit). The largest TWA value measured near a 3 h time point was a Minicams measurement of 0.48 TWA at 2 h and 53 min after removal of a vapor cap containing HD from a single exposure site on an animal that had 24 concurrent dorsal exposure sites. Gas chromatography/flame photometric detection and gas chromatography/mass spectrometry were used to confirm the Minicams data and to provide greater sensitivity and selectivity down to 0.1 TWA. The gas chromatography/mass spectrometry data confirmed that HD concentrations fell below 0.1 TWA in <5 h for a specific site. These measurements of HD concentrations provided information on the expeditious and safe handling of HD-exposed tissue.
A gas chromatographic (GC-ECD) method was developed for the determination of nornitrogen mustard (NOR) and its hydrolysis products. The method was based on derivatization by heptafluorobutyric anhydride. The structures of the derivatives of NOR were established by GC-MS. The method was used to characterize the rate of transformation of NOR and phosphoramide mustard (PAM), important metabolites of cyclophosphamide, into secondary products in vitro at 37 degrees C and pH 7.4. The rate of disappearance of NOR had a half-life of 20 min. The half-life of appearance of N-(2-chloroethyl)-N-(2-hydroxyethyl)amine (NOR-OH) was 19 min. While most NOR appeared to be converted to NOR-OH, the yield of N,N-bis(2-hydroxyethyl)amine (NOR-OH-OH) was a small fraction of the starting material. The disappearance of NOR, when PAM was used as a starting material, had a half-life of 19 min; in these experiments NOR-OH and NOR-OH-OH were relatively much more abundant compared to when NOR was used as the starting material.
The alkylating agent isophosphoramide mustard (IPM) spontaneously forms a relatively stable aziridine derivative which can be directly observed using NMR spectroscopy. The protonations of IMP and its aziridine were probed using 1H, 31P, 15N, and 17O NMR spectroscopy. The positions of the 31P, 15N, and 17O resonances of IPM between pH 2 and 10 each exhibit a single monobasic titration curve with the same pKa of 4.31 +/- 0.02. On the basis of a comparison with other compounds and our earlier work with phosphoramide mustard, the NMR results for IPM indicate that protonation occurs at nitrogen and not oxygen. Over this same pH range, each of the 1H, 31P, and 15N resonances of IPM-aziridine also show a single monobasic titration with a pKa of 5.30 +/- 0.09. The magnitude of the change in chemical shifts suggests that the protonation of the IPM-aziridine occurs at the ring nitrogen. Theoretical gas-phase calculations of PM, IPM, and IPM-aziridine suggest O-protonation to be more likely; however, aqueous phase calculations predict the N-protonated forms to be most stable. Furthermore, for PM and IPM-aziridine, which contain nonequivalent nitrogens, the theoretical calculations and experimental data both agree as to which nitrogen undergoes protonation. These results suggest that the IMP-aziridine remains unprotonated under physiological conditions and may, in part, explain the lower alkylating activity of IPM as compared to PM.
31P nuclear magnetic resonance spectroscopy was used to measure the pKa (4.28 +/- 0.2) of isophosphoramide mustard (IPM) at 20 degrees C and to study the kinetics and products of the decomposition of IPM at a solution pH value of ca. 7.4 and at temperatures between 20 and 47 degrees C in the presence of nucleophilic trapping agents. At 37 degrees C, the half-life for the first alkylation was ca. 77 min and ca. 171 min for the second alkylation; these data may be compared with those for phosphoramide mustard (Engle, T.W.; Zon, G.; Egan, W.J. Med. Chem. 1982, 25, 1347), wherein the half-lives for the first and second alkylations are approximately the same (18 min). The rate of fragmentation of aldoifosfamide to IPM and acrolein was also studied by NMR spectroscopy (pH 7.0; 37 degrees C; 0.07 M phosphate); under the noted conditions, the half-life of aldoifosfamide was found to be ca. 60 min.
1. Human blood was incubated in vitro with a 1:1 mixture of [35S,12C4]- and [13C4]-sulphur mustard. Alkylated globin, containing the 2-hydroxyethylthioethyl (HETE) moiety, was isolated from the blood incubate following lysis of the erythrocytes and acidification with HCl in isopropanol. 2. The alkylated globin was hydrolysed with Pronase E to give a digest containing alkylated amino acids and alkylated dipeptides. A number of these were partially purified by hplc and identified by gc-ms and lc-ms. 3. The alkylated globin was hydrolysed with trypsin to give a digest containing alkylated peptides. Ten of these were partially purified by hplc, tentatively identified by lc-electrospray mass spectrometry, and the sequences and sites of alkylation determined using lc-electrospray tandem mass spectrometry. 4. (2-Hydroxyethylthioethyl)glutathione was also shown to be present in the pronase and trypsin digests of alkylated globin. 5. N-terminal valine, on both the alpha and beta chains, and histidine residues were identified as the key sites of interaction for targeting as biological markers of sulphur mustard poisoning.
Natural occurrence of aflatoxins at concentrations of 750, 87 and 1420 micrograms/kg was recorded in 44, 33 and 80 samples out of 100 samples each of seeds, oil and cakes of mustard respectively. Out of 17 species of fungi isolated from mustard seeds, percentage incidence of the Aspergillus flavus group was maximum during monsoon and summer. Twenty-five per cent of isolates (out of 1143 isolates screened) of the A. flavus group were toxigenic, producing different components of aflatoxins in varying concentrations.
Nitrogen mustard (HN2) and quinacrine mustard (QM) both inhibited the binding of NF kappa B to the GC-rich consensus sequence in the HIV long terminal repeat (LTR), as assessed by gel-shift assays. QM also inhibited the binding of OTF-1 to the AT-rich octamer present in the H2B promoter whereas HN2 was inactive. Inhibition of the binding of transcription factors was due to the drug interaction with DNA, since it also occurred when transcription factors were added to DNA after removal of free drug. In Jurkat cells transfected with pI3CAT, where the chloramphenicol acetyltransferase (CAT) gene is under the control of the HIV LTR, both HN2 and QM inhibited CAT gene expression. However, in Jurkat cells transfected with plasmid -147, where the CAT gene is under the control of the H2B promoter, QM inhibited CAT expression but HN2 did not. These results were obtained at concentrations of HN2 or QM that inhibited total DNA and RNA synthesis to a similar extent. The present results suggest that the more selective pharmacological activity of HN2 (HN2 is an active antineoplastic agent whereas QM is inactive and very toxic) might be related to its preferential functional inhibition of GC-rich consensus sequence, possibly important in the regulation of genes involved in the malignant proliferation and behavior of some tumors.
1. A technique for the quantitative cutaneous application of sulphur mustard vapour is described. The maximum rate of uptake of the agent vapour by shaved rat skin in vivo was estimated as 7 micrograms/cm2 per min. 2. The major route of excretion was through the kidneys: greater than 70% of the radioactivity of all doses was excreted in 3 days after either i.v. or i.p. injections of 35S-labelled sulphur mustard, but less (50-70% depending on dose) was excreted in the same time following cutaneous application. 3. This urinary excretion of 35S had a half-life of 1.4 days, and the decreased proportion of the applied dose excreted following cutaneous application may be accounted for by retention of radioactivity in the skin. 4. The contribution of faecal excretion was greater following cutaneous application.
A randomized study of patients with advanced Hodgkin's disease was designed to determine whether the improved therapeutic effectiveness of combination chemotherapy was due to the use of a combination of drugs or might be achieved with a single agent if given as intensively and for as long a period. A combination of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) was compared with nitrogen mustard (HN2) alone. Treatment with both regimens was given to tolerance on cylic basis and was continued for six cycles of treatment. Sixty-one evaluable patients were treated with MOPP and 47 with HN2. The complete remission rate of 47.5% with MOPP was significantly better than the 12.8% with HN2 (p less than .05). Complete remission lasted a median of 15 months after MOPP and 12 months after HN2. The survival of patients initially treated with MOPP was significantly better than that of those initially treated with HN2.
PURPOSE: To compare the efficacy of total skin electron beam therapy (TSEBT) with or without adjuvant topical nitrogen mustard (+/- HN2) with topical nitrogen mustard (HN2) alone as initial management of T2 and T3 mycosis fungoides (MF). METHODS AND MATERIALS: A retrospective analysis of 148 patients presenting to Stanford from January, 1970 through January, 1995 within 4 months of pathologic diagnosis of MF. Fifty-five patients with T2 and 27 with T3 disease received TSEBT +/- HN2. Fifty-four patients with T2 and 12 with T3 disease received HN2 alone. Boosts with radiotherapy were usually administered to cutaneous tumors of patients with T3 disease. RESULTS: TSEBT +/- HN2 yielded significantly higher complete response (CR) rates than did HN2 alone in patients with T2 and T3 disease (76% vs 39%, p = 0.03 for T2, and 44% vs 8%, p < 0.05 for T3, respectively). In T2 disease, treatment with adjuvant HN2 was associated with a longer freedom from relapse following TSEBT when compared to observation following a CR to TSEBT (p = 0.068). However, no significant differences in survival were observed for different management programs for T2 or T3 disease. In T2 disease, both TSEBT and HN2 were as effective as salvage therapy as when utilized as initial therapy. However, salvage therapy in T3 disease was rarely effective. Limited tumor involvement in T3 disease did not correlate with improved survival compared to more generalized tumorous disease. MF contributed to 27% and 68% of deaths in patients with T2 and T3 disease, respectively. CONCLUSION: Because of high response rates, management of significantly symptomatic or extensive T2 MF should include TSEBT, and adjuvant HN2 should be administered after a CR to TSEBT. Patients with T2 disease who fail TSEBT or HN2 can be salvaged with the other modality. TSEBT is also an effective treatment for T3 disease. The small subset of patients with limited T3 disease may also be treated with HN2 and local radiotherapy to the tumors. Further investigations are necessary to improve the overall outcome for T3 mycosis fungoides.
The nitrogen mustards bis(2-chloroethyl)ethylamine (HN1), bis(2-chloroethyl)methylamine (HN2), and tris(2-chloroethyl)amine (HN3) have the potential to be used as chemical terrorism agents because of their extreme vesicant properties. We modified a previously reported method to incorporate automated solid-phase extraction, improve chromatography, and include the urinary metabolite for HN3. The improved method was used to measure levels of the urinary metabolites N-ethyldiethanolamine (EDEA), N-methyldiethanolamine (MDEA), and triethanolamine (TEA) in rats dosed with HN1, HN2, and HN3, respectively, and to establish background levels of EDEA, MDEA, and TEA in human urine samples from a population with no known exposure to nitrogen mustards. Rat dosing experiments confirmed that EDEA, MDEA, and TEA could be detected in urine for at least 48 h after exposure to HN1, HN2, and HN3, respectively. Substantial amounts of EDEA (89 ng/mL), MDEA (170 ng/mL), and TEA (1105 ng/mL) were measured in the urine of rats exposed to 10 mg HN1, HN2, and HN3, respectively, 48 h after exposure. The background concentrations for TEA in the human population ranged from below the limit of detection (LOD 3 ng/mL) to approximately 6500 ng/mL. Neither EDEA (LOD 0.4 ng/mL) nor MDEA (LOD 0.8 ng/mL) was detected above the LOD in the human samples.
The effect of galactose-6-mustard (G-6-M) on cell growth and cell cycle kinetics was studied in murine P388 leukemia and Chinese hamster ovary (CHO) cells in vitro and compared with the effect of L-phenylalanine mustard (L-PAM). The IC50 values of G-6-M for the P388 and CHO cells were 10 and 100 microM, respectively. No difference of the IC50 value of L-PAM (2 microM) between the two cell lines was found. The effect of G-6-M and L-PAM on cell kinetics was similar for the two cell lines at IC50 doses. The relative cell outflow from the G2 stage was inhibited to a higher extent than the relative cell outflow from the S phase. The relative cell outflow from the G1 stage was only partly inhibited. These results are discussed in relation to growth conditions, differences in DNA repair capacity, and cellular uptake of G-6-M between P388 and CHO cells.
The mouse ear edema model is recognized for its usefulness in studying skin responses and damage following exposure to chemical irritants, and for evaluating pharmacological agents against chemically induced skin injury. We recently modified the mouse ear edema model for use with sulfur mustard (HD) and used this model to study the protective effect of 33 topically applied compounds comprising five pharmaceutical strategies (anti-inflammatories, protease inhibitors, scavengers/chelators, poly(ADP-ribose) polymerase (PARP) inhibitors, calcium modulators/chelators) against HD-induced dermatotoxicity. Pharmacological modulation of HD injury in mouse ears was established by a reduction in edema or histopathology (epidermal necrosis and epidermal-dermal separation) at 24 h following topical liquid HD exposure. Ten of the 33 compounds administered as single topical pretreatments up to 2 h prior to HD challenge produced significant reductions in edema. Five of these ten also produced significant reductions in histological endpoints. Three candidates (olvanil, indomethacin, hydrocortisone) showing protection at 24 h were evaluated further for 'extended protection' at 48 and 72 h after HD challenge and showed significant modulation of edema at 48 h but not at 72 h. Olvanil also showed significant reductions in histology at 48 and 72 h. Olvanil and indomethacin were shown to reduce significantly the edema at 24 h post-exposure when administered topically 10 min after HD challenge, with olvanil additionally protecting against epidermal necrosis. These results demonstrate prophylactic and treatment effects of pharmacological agents against HD-induced skin injury in an in vivo model and support the continued use of the mouse ear vesicant model (MEVM) for evaluating medical countermeasures against HD.
Considering the undefinite nature of lung pathology in patients exposed to sulfur mustard (SM) many years after exposure, we conducted this study to document and quantify lung disease in this setting. In a cross sectional study, we selected 23 patients exposed to SM gas approximately 14 years ago during the Iran-Iraq war (1980-1988). We studied their clinical history, physical examination, pulmonary function test (PFT), high-resolution computed tomography scan (HRCT) of the chest, bronchoscopy, and bronchoalveolar lavage (BAL) sampling, and transbronchial lung biopsies. Other potential causes of lung disease, including smoking of cigarettes, were excluded. All 23 patients were symptomatic with cough, dyspnea, and/or felt tight in the chest. All of them had significant air trapping in HRCT and a marked increase of residual volume in PFT. The most common inflammatory cell in BAL fluid was neutrophil (88%). Of the 23 cases, there was sufficient tissue for detailed evaluation in 22. Histologically, 11 cases showed airway epithelial injury, and nine of the 14 lung biopsies with alveoli had histopathological changes diagnosable as organizing pneumonia (OP) or bronchiolitis obliterans OP (BOOP). Two out of 14 cases showed changes suggestive of OP. Inhalation of SM can lead to persistant and clinically significant lung disease, including bronchial mucosal injury and OP, many years after exposure.