RESUMEN

An accurate and precise analysis procedure is presented for the detection and quantification of cyclophosphamide (CP), 4-ketocyclophosphamide (4-keto-CP), a primary metabolite of CP, and ifosfamide (IF) in human urine. CP and IF are common antineoplastic drugs used for the treatment of many types of cancer. Workers in the healthcare field, including nurses and pharmacists who interact with or prepare prescriptions for patients, have potential low-level exposure to the parent drugs; therefore, an analysis procedure is needed. The main focus of this procedure is the quantitation of 4-keto-CP because it is a primary metabolite of CP exposure and stable under physiological conditions. Sample preparation consists of liquid-liquid extraction of urine with ethyl acetate, and the analysis consists of reversed-phase high-performance liquid chromatography coupled with tandem mass spectrometry for detection of the analytes. Accuracy and precision of this procedure is demonstrated by means of recovery experiments. Recoveries are between 97-105% of theory for the three target analytes at various concentrations (25, 50, 100, and 375 ng/mL for 4-keto-CP; 1, 2, 4, and 15 ng/mL for CP and IF) with relative standard deviations of 8.4% or less. The limit of detection for this procedure is 1 ng/mL for 4-keto-CP, 0.1 ng/mL for CP, and 0.05 ng/mL for IF in urine.

Asunto(s)

RESUMEN

An analytical procedure was developed for the detection and quantification of N-acetyl-S-(n-propyl)-l-cysteine (n-propylmercapturic acid, AcPrCys), a metabolite and biomarker for exposure to 1-bromopropane (1-BP). 1-BP is used as an industrial solvent and exposure is a health concern for industrial workers due to its toxicity. It has been associated with neurological disorders in both animals and humans. Urine sample preparation for the determination of AcPrCys consisted of solid phase extraction (SPE). Urine samples on preconditioned SPE (C18) columns were washed with 40% methanol/60% water solution prior to elution with acetone. Quantification was by means of a liquid chromatograph (LC) equipped with a mass spectrometer (MS) using an Aqua 3 microm C18 300A column and [d(7)]-AcPrCys was used as internal standard. Electrospray ionization (ESI) was used with the MS operated in the negative ion mode and selected ion monitoring (SIM) at m/z 204 for AcPrCys and m/z 211 for [d(7)]-AcPrCys. Demonstrated recovery of urine samples fortified at multiple levels (0.625-10 microg/ml) varied between 96 and 103% of theory with relative standard deviations (RSD) of 6.4% or less. The limit of detection (LOD) for the procedure was approximately 0.01 microg/ml AcPrCys in urine. These data will be discussed as well as other factors of the development of this test procedure.

Asunto(s)

RESUMEN

A test procedure was developed for the detection and quantification of 1- and 2-bromopropane in human urine. 1-Bromopropane (1-BP) is a commonly used industrial solvent, and 2-bromopropane (2-BP) is often found as an impurity component in industrial grade 1-BP. Both compounds are a health concern for exposed workers due to their chronic toxicity. Bromopropanes have been associated with neurological disorders in both animals and humans. Sample preparation consisted of diluting urine with water and fortification with 1-bromobutane (1-BB), which was used as an internal standard; then each sample was sealed in a headspace vial. A static-headspace sampler (Teledyne-Tekmar Model 7000) was used to heat each sample at 75 degrees C for a 35-min equilibrium time. Quantification was by means of a gas chromatograph (GC) equipped with an electron capture detector (ECD) and a dimethylpolysiloxane (DB-1) capillary column. A recovery study using fortified urine samples at multiple concentrations (0.5-8 microg/ml) demonstrated full recovery; 104-121% recovery was obtained. Precision ranged from 5 to 17% for the 15-20 spiked samples used at each concentration, which were analyzed over multiple experimental trial days. The limit of detection (LOD) for this test procedure was approximately 2 ng/ml 1-BP and 7 ng/ml 2-BP in urine. A recovery study of 1- and 2-BP from fortified urine stored in vials appropriate for field collection was also completed. These results and other factors of the development and validation of this test procedure will be discussed.

Asunto(s)

RESUMEN

An accurate and precise method was developed for the detection and quantification of 3-bromopropionic acid (3-BPA), a metabolite and biomarker for exposure to 1-bromopropane (1-BP). 1-BP is used as an industrial solvent and exposure is a health concern for industrial workers due to its toxicity. It has been associated with neurological disorders in both animals and humans. Urine sample preparation for the determination of 3-BPA consisted of liquid-liquid extraction (LLE) with ethyl acetate and silylation with N-methyl-N-[tert-butyldimethylsilyl]trifluoroacetamide (MTBSTFA). Quantification was by means of a gas chromatograph (GC) equipped with a mass selective detector (MSD) using a dimethylpolysiloxane (HP-1) capillary column and 3-chloropropionic acid was used as an internal standard in the procedure. Demonstrated accuracy and precision during this method's validation was good; recovery varied between 93 and 98% with relative standard deviations (R.D.S.) of 5.7% or less. The limit of detection (LOD) for the procedure was approximately 0.01microg/ml 3-BPA in urine. These data and other factors of the development and validation of this test method will be discussed.

Asunto(s)

RESUMEN

An accurate and precise procedure was developed for the detection and quantification of (2-methoxyethoxy)acetic acid (MEAA), a metabolite and biomarker for human exposure to 2-(2-methoxyethoxy)ethanol. The compound 2-(2-methoxyethoxy)ethanol has a wide array of industrial applications including its use as an additive in military jet fuel. Exposure to 2-(2-methoxyethoxy)ethanol is a health concern owing to its toxicity which includes developmental and teratogenic properties. Sample preparation consisted of liquid-liquid extraction (LLE) and esterification of MEAA to produce the ethyl ester. Measurement was by a gas chromatograph (GC) equipped with a mass selective detector (MSD) using a HP-1 capillary column. Recovery studies of spiked blank urine demonstrated good accuracy and precision; recovery varied between 95 and 103% with relative standard deviations of 8.6% and less. The limit of detection (LOD) for this procedure was found to range from 0.02 to 0.08 microg/ml equivalent levels of MEAA in urine. These data and other aspects of the validation of this procedure will be discussed.

Asunto(s)

RESUMEN

OBJECTIVE: To determine the potential for asphalt fume exposure to increase DNA damage, we conducted a cross-sectional study of roofers involved in the application of roofing asphalt. METHODS: DNA strand breaks and the ratio of 8-hydroxydeoxyguanosine (8-OHdG) to 2-deoxyguanosine (dG) were measured in peripheral blood leukocytes of roofers. In addition, urinary excretion of 8-OHdG and 8-epi-prostaglandin F2alpha (8-epi-PGF) was also measured. The study population consisted of 26 roofers exposed to roofing asphalt and 15 construction workers not exposed to asphalt during the past 5 years. A subset of asphalt roofers (n = 19) was exposed to coal-tar pitch dust (coal tar) during removal of existing roofs prior to applying hot asphalt. Personal air monitoring was performed for one work-week to measure exposure to total particulates, benzene-soluble fraction of total particulates, and polycyclic aromatic compounds (PACs). Urinary 1-OH-pyrene levels were measured as an internal biomarker of PAC exposure. RESULTS: Full-shift breathing zone measurements for total particulates, benzene-solubles and PACs were significantly higher for coal-tar exposed workers than for roofers not exposed to coal tar. Similarly, urinary 1-OH-pyrene levels were higher in coal-tar exposed roofers than roofers not exposed to coal tar. Total particulates or benzene-soluble fractions were not associated with urinary 1-OH-pyrene, but PAC exposure was highly correlated with urinary 1-OH-pyrene. When stratified by 1-OH-pyrene excretion, DNA strand breaks increased in a dose-dependent manner, and leukocyte 8-OHdG/dG decreased in a dose-dependent manner. Significant changes in DNA damage appeared to be linked to PACs from coal-tar exposure, although asphalt fume alone was associated with a small but significant increase in urinary 1-OH-pyrene and DNA strand breaks. CONCLUSIONS: Results are consistent with previous reports that asphalt or coal-tar exposure can cause DNA damage. Urinary 8-epi-PGF remained relatively constant during the week for virtually all subjects, regardless of exposure indicating that neither asphalt nor coal-tar exposure induces an overt oxidative stress. A small, but statistically significant increase in 8OHdG was evident in end-of-week urine samples compared with start-of-week urine samples in roofers exposed to coal-tar. The increase in urinary 8OHdG coupled with the decrease in leukocyte 8-OHdG/dG, suggests that coal-tar exposure induces protective or repair mechanisms that result in reduced levels of steady-state oxidative-DNA damage.

Asunto(s)

RESUMEN

Exposure of pregnant rats to the solvent 2-methoxyethanol (2ME) and radiofrequency (RF) radiation results in greater than additive fetal malformations (Nelson, B.K., Conover, D.L., Brightwell, W.S., Shaw, P.B., Werren, D.W., Edwards, R.M., Lary, J.M., 1991. Marked increase in the teratogenicity of the combined administration of the industrial solvent 2-methoxyethanol and radiofrequency radiation in rats. Teratology 43, 621-34; Nelson, B.K., Conover, D.L., Shaw, P.B., Werren, D.W., Edwards, R.M., Hoberman, A.M., 1994. Interactive developmental toxicity of radiofrequency radiation and 2-methoxyethanol in rats. Teratology 50, 275-93). The current study evaluated the metabolism of 14C-labeled 2ME and the distribution of methoxyacetic acid (MAA) in maternal and embryonic tissues of pregnant Sprague-Dawley rats either exposed to 10 MHz RF radiation or sham conditions. Additionally, adduct formation for both plasma and embryonic protein was tested as a possible biomarker for the observed 2ME/RF teratogenicity. Rats were administered [ethanol-1,2-(14)C]-2ME (150 mg/kg, 161 microCi/rat average) by gavage on gestation day 13 immediately before RF radiation sufficient to elevate body temperature to 42 degrees C for 30 min. Concurrent sham- and RF-exposed rats were sacrificed at 3, 6, 24 or 48 h for harvest of maternal blood, urine, embryos and extra-embryonic fluid. Tissues were either digested for determination of radioactivity or deproteinized with TCA and analyzed by HPLC for quantification of 2ME metabolites. Results show the presence of 2ME and seven metabolites, with the major metabolite, MAA, peaking at 6 h in the tissues tested. MAA, the proximal teratogen, was detectable in maternal serum, urine, embryo and extraembryonic fluid 48 h after dosing. Clearance of total body 14C was significantly reduced for the RF-exposed animals (P<0.05) for the 24-48 h period, but MAA values for serum, embryos and extraembryonic fluid were similar for both sham- and RF-exposed rats. Additionally, no difference was noted for 2ME metabolite profiles in urine or tissue for sham- or RF-exposed rats, thus eliminating an effect of RF radiation on MAA production as a possible explanation for the reported RF-2ME synergism. Subsequently, serum and embryo protein-bound adducts were evaluated by analysis of covalently bound radioactivity. Serum protein binding was significantly higher for sham than RF rats at 3- and 6-h - highest for sham rats at 6 h (519+/-95 microg as parent 2ME/g of protein) whereas RF serum values were highest at 24 h (266+/-79 microg/g protein). Embryonic protein binding was significantly higher for sham rats at 6 h, but binding was highest for both groups at 24 h (sham=229+/-71 microg/g, RF=185+/-48 microg/g). Formation of protein adducts after 2ME is thought to be related to levels of methoxyacetaldehyde, a reactive intermediate in the formation of MAA. These results suggest that no direct relationship exists for covalent binding in the embryo which would explain RF-2ME synergistic malformations. In comparison with urinary metabolites, the relatively slow elimination of adducted serum 2ME indicates that analysis of protein-bound concentrations could be a potential tool for long- term biomonitoring of worker exposure.

Asunto(s)

RESUMEN

Adolescence is a time of dramatic neuroendocrine changes that are required for sexual maturation. Hormonal mimicking or inhibiting chemicals can cause significant impairment during this critical period. Vinclozolin (Vin) has been shown to be an anti-androgen affecting male offspring in rats in utero, and its mechanism of action may be mediated by inhibition of androgenic receptor action. The majority of teenagers working on farms are male, and therefore a systemic fungicide, vinclozolin, was selected for study. The rabbit has proved to be an excellent species for modelling reproductive toxicant effects in the male and was selected as the test species. The peripubertal phase for the rabbit was determined to be between the 3rd and 4th months. A 2-month dosing period was therefore initiated at 3 months of age and carried through to the 4th month. Vin was administered by dermal application (100 mg kg(-1) in 100 microl of dimethylsulphoxide) daily. Body weights were determined weekly. The rabbits were then held until fully mature (6 months of age). Semen was collected and evaluated from sexually mature males on a weekly schedule for 5 weeks to maximize sperm output. An automated solid phase extraction procedure for monitoring exposures through isolation and quantification of Vin and its metabolic products was developed. Increased plasma levels of Vin and M2 were found throughout the experimental period. The exposed rabbits had a smaller weight gain during pubertal growth (approaching significance; P=0.059). At maturity, the accessory sex glands of the exposed animals weighed less than those of the controls (P=0.016). Surprisingly, the pooled sperm count of the exposed animals was significantly higher (P=0.017) than that of the unexposed animals. The anti-androgenic effects of Vin may have blocked the negative feedback mechanism of testosterone on the hypothalamus or pituitary gland, allowing for an increase in gonadotrophin release, and consequently increasing sperm production at puberty.

Asunto(s)

RESUMEN

Although a rare disease, PPH is deadly. Until recently, patients had little hope for remission of this disease. Originally viewed as a "bridge to transplantation," new research findings suggest that epoprostenol significantly improves PPH so that transplantation may not be necessary. Treatment with epoprostenol is difficult to manage, however, because it requires continuous central infusion. Nurses have a key role in ensuring that patients safely and effectively manage this therapy.

Asunto(s)

RESUMEN

Critically ill patients often can express their levels of pain--even when intubated. Follow these guidelines to measure their pain and provide pharmacologic and nonpharmacologic relief.

Asunto(s)

RESUMEN

The purpose of this study was to examine the relationship between adolescents' exposure to traumatic events and their self-health assessments, and to examine the protective effects of social support and self-efficacy on this relationship. Survey results (N = 1,427) indicated that experiencing violent and nonviolent negative life events and being exposed to a disaster were inversely associated with adolescents' positive health assessments. As social support and self-efficacy decreased, adolescents' health assessments worsened. Female and Black adolescents had less favorable health assessments than their male and White counterparts. Findings suggest that traumatic events are predictive of adolescents' health assessments and that social support and self-efficacy prevent adolescents' health assessments from declining following traumatic events.

Asunto(s)

RESUMEN

Pain has immunosuppressive effects among the critically and chronically ill, and opioids may immunomodulate pain's deleterious effects. However, little is known about the relations between acute pain, acute illness, and morbidity among previously healthy surgical patients. This study retrospectively examined these relations in appendectomy patients (N = 61). Eleven patients (18%) had morbidity, with atelectasis (11.5%) the most frequent complication. There were no differences between those patients with and without morbidity and pain intensity, method of opioid administration, and total opioid dose. Patients who received nonopioid analgesics received fewer opioids, less preemptive analgesia, and had less morbidity, whereas patients whose appendixes perforated received higher opioid doses and received more preemptive analgesia. Although the relations between acute pain, opioid use, and morbidity among previously healthy surgical patients are unclear, findings infer that clinical practice does not follow guidelines advocated by analgesic experts.

Asunto(s)

RESUMEN

The case study illustrates the recovery of a patient with multiple trauma who was fed a peptide-based formula via the enteral route soon after the trauma. Although the clinical course might have been worse if D.H. had not received this treatment, his generally excellent recovery might be partly attributable to this therapy. Although stress hypermetabolism occurs in most patients with multiple trauma within 48 hours after injury, no known treatment can arrest or reverse this problem. However, the lethal catabolic and septic effects of stress hypermetabolism can be at least partly thwarted through delivery of enteral nutrients within 72 hours after trauma.

Asunto(s)

RESUMEN

Unrelieved pain in critically ill patients can increase mortality, morbidity, length of stay, and use of resources. This article reviews the physiologic basis of acute pain and the pathophysiologic sequelae that may ensue when critically ill patients experience acute pain. The author recommends strategies critical care nurses and advanced practice nurses can use to provide effective analgesia and potentially improve patient outcomes.

Asunto(s)

RESUMEN

The genotoxic potential of two occupationally significant chemicals, 4,4'-methylene-bis-2-chloroaniline (MOCA) and 2-phenyl-1,4-benzoquinone (PBQ), was explored by monitoring the induction of mutations at the HPRT locus of AHH-1 human lymphoblastoid cells. Exposure of AHH-1 cells to the putative carcinogenic metabolite of MOCA, N-OH-MOCA, induced a 6-fold increase in mutant frequency and resulted in base pair substitutions primarily at A:T base pairs. In contrast, exposure to PBQ did not result in an increased mutant frequency although this compound was significantly more cytotoxic than N-OH-MOCA at equimolar doses. The induction of mutations at A:T sites by N-OH-MOCA is consistent with the type of DNA damage known to be produced by MOCA and provides a specific marker of genotoxic damage for exposed populations.

Asunto(s)

RESUMEN

Many bladder cancers are indolent, and since there are no biomarkers to predict progression, the prognosis is problematic. Utilizing an in vitro/in vivo human uroepithelial cell (SV-HUC.PC) transformation system, we investigated several molecular events occurring along the continuum of exposure to disease outcome as potential biomarkers for occupational carcinogenesis. The model also served to generate information on the occupational carcinogenicity of N-hydroxy-4,4'-methylene bis(2-chloroaniline) [N-OH-MOCA]. Two of 14 groups of SV-HUC.PC treated with various concentrations of N-OH-MOCA formed carcinomas in athymic nude mice. Each of the biomarkers investigated demonstrated potential for interventions/prevention applications of occupational bladder cancers but will require validation and further evaluation. Those investigated displaying potential occupational utility included the induction of ornithine decarboxylase (ODC), DNA adducts, and altered proteins, as detected on HUC two-dimensional polyacrylamide gel electrophoresis protein maps.

Asunto(s)

RESUMEN

The tumorigenic transformation of certain occupationally significant chemicals, such as N-hydroxy-4-4'-methylenebis[2-chloroaniline] (N-OH-MOCA), N-hydroxy-ortho-toluidine (N-OH-OT), 2-phenyl-1,4-benzoquinone (PBQ) and N-hydroxy-4-aminobiphenyl (N-OH-ABP) were tested in vitro using the well established SV40-immortalized human uroepithelial cell line SV-HUC.PC. SV-HUC cells were exposed in vitro to varying concentrations of N-OH-MOCA, N-OH-OT, N-OH-ABP and PBQ that caused approximately 25% and 75% cytotoxicity. The carcinogen treated cells were propagated in culture for about six weeks and subsequently injected subcutaneously into athymic nude mice. Two of the fourteen different groups of SV-HUC.PC treated with different concentrations of N-OH-MOCA, and one of the three groups exposed to N-OH-ABP, formed carcinomas in athymic nude mice. 32P-postlabeling analyses of DNA isolated from SV-HUC.PC after exposure to N-OH-MOCA revealed one major and one minor adduct. The major adduct has been identified as the N-(deoxyadenosin-3',5'-bisphospho-8-yl)-4-amino-3-chlorob enz yl alcohol (pdAp-ACBA) and the minor adduct as N-(deoxyadenosin-3',5'-bisphospho-8-yl)-4-amino-3-chlorot oluene (pdApACT). Furthermore, SV-HUC.PC cytosols catalyzed the binding of N-OH-MOCA to DNA, in the presence of acetyl-CoA, to yield similar adducts. The same adducts were also formed by chemical interaction of N-OH-MOCA with calf thymus DNA, suggesting that the aryl nitrenium ion may be the ultimate reactive species responsible for DNA binding. The tumorigenic activity of N-OH-MOCA in this highly relevant in vitro transformation model, coupled with the findings that SV-HUC.PC cells formed DNA-adducts in vitro and contained enzyme systems that activated N-OH-MOCA to reactive electrophilic species that bound to DNA, strongly suggest that MOCA could be a human bladder carcinogen. These findings are consistent with the International Agency for Research on Cancer's classification of MOCA as a probable human carcinogen.

Asunto(s)

RESUMEN

The probable human carcinogen 4,4'-methylene-bis(2-chloroaniline) (MOCA) was utilized to develop biomarkers of exposure to occupational carcinogens. The 32P postlabeling assay, utilizing the nuclease P1 enhancement procedure, was used to evaluate MOCA-DNA adduct formation in target tissues. Male Sprague-Dawley rats were treated with different dosing regimens of MOCA, and DNA was isolated from the liver. Additionally, a human uroepithelial cell (HUC) line was treated with N-hydroxy-MOCA for 24 hr, cells were harvested, and DNA was isolated. DNA was analyzed for MOCA-DNA adduct formation by the 32P postlabeling assay. Five MOCA adducts were detected in rat liver DNA. Adduct A, which corresponded to N-(deoxyadenosin-8-yl)-4-amino-3-chlorobenzyl alcohol, was the major adduct in rat liver DNA appearing in all treatment groups. Levels of adduct A were higher when MOCA was administered by ip injection versus oral gavage. Phenobarbital pretreatment increased the amount of adduct A approximately 12-fold. The pathway leading to the formation of adduct A in DNA from HUC appeared to be saturated at the concentrations used: 2.5, 5, and 10 microM. However, an additional adduct (E) was observed at the 10 microM treatment level only. A major DNA adduct was detected in the target tissue of rats and target human cells for MOCA-induced carcinogenesis, thus making it useful as a biomarker of exposure. Other DNA adducts were also observed with the different doses and routes of exposure investigated.

Asunto(s)

RESUMEN

Alterations of the phosphorylation pattern of histones by the carcinogen, 4,4'-methylene-bis(2-chloroaniline) (MOCA) were investigated using rodent spleen cells. Spleen cells were isolated from Sprague-Dawley rats and treated with either 5, 10, 25, or 50 microM MOCA or acetone vehicle controls for 1, 2, 4, or 8 hours. Cells were incubated with 32P-phosphoric acid, and histones from these cells were fractionated utilizing two-dimensional polyacrylamide gel electrophoresis. Marked stimulation of histone phosphorylation was observed with the 10 microM MOCA treatment. A transient decrease in histone phosphorylation was observed at the 1 and 2 hour time points followed by a marked stimulation at 4 hours.

Asunto(s)

Asunto(s)