Criterios Ergonómicos para el Diseño de Quirófanos / Ergonomic Criteria for Operating Room Design

Resumen El personal involucrado en el área quirúrgica se ve afectado con lesiones musculoesqueléticas por esfuerzos y movimientos repetitivos acumulados. La gravedad de sus lesiones está dada en función de las posturas de trabajo, la especialidad quirúrgica y la disposición de los elementos con los que interactúa. La ergonomía ha tomado relevancia ya que ha hecho aportes muy importantes para las condiciones de trabajo en diferentes áreas. Aun cuando en la literatura se pueden encontrar diversas investigaciones de la frecuencia y los efectos de las lesiones ocupacionales en el personal del área quirúrgica, escasos estudios han propuesto pautas para el diseño ergonómico de quirófanos. El presente estudio engloba cuatro criterios ergonómicos que deben considerarse para el diseño de quirófanos.

Abstract Personnel involved in the surgical area are affected with musculoskeletal injuries due to accumulated repetitive stress and movements. The severity of the injuries is given according to the work postures, the surgical specialty and the arrangement of the elements in the operating room. Ergonomics has become relevant since it has made very important contributions to working conditions in different areas. Although in the literature investigations of the frequency and effects of occupational injuries on surgical staff can be found, few studies have proposed guidelines for the ergonomic design of operating rooms. The present study encompasses four ergonomic criteria that should be considered for the design of operating rooms.

Characterization of a novel 3D printed patient specific phantom for quality assurance in cranial stereotactic radiosurgery applications.

In single-isocenter stereotactic radiosurgery/radiotherapy (SRS/SRT) intracranial applications, multiple targets are being treated concurrently, often involving non-coplanar arcs, small photon beams and steep dose gradients. In search for more rigorous quality assurance protocols, this work presents and evaluates a novel methodology for patient-specific pre-treatment plan verification, utilizing 3D printing technology. In a patient's planning CT scan, the external contour and bone structures were segmented and 3D-printed using high-density bone-mimicking material. The resulting head phantom was filled with water while a film dosimetry insert was incorporated. Patient and phantom CT image series were fused and inspected for anatomical coherence. HUs and corresponding densities were compared in several anatomical regions within the head. Furthermore, the level of patient-to-phantom dosimetric equivalence was evaluated both computationally and experimentally. A single-isocenter multi-focal SRS treatment plan was prepared, while dose distributions were calculated on both CT image series, using identical calculation parameters. Phantom- and patient-derived dose distributions were compared in terms of isolines, DVHs, dose-volume metrics and 3D gamma index (GI) analysis. The phantom was treated as if the real patient and film measurements were compared against the patient-derived calculated dose distribution. Visual inspection of the fused CT images suggests excellent geometric similarity between phantom and patient, also confirmed using similarity indices. HUs and densities agreed within one standard deviation except for the skin (modeled as 'bone') and sinuses (water-filled). GI comparison between the calculated distributions resulted in passing rates better than 97% (1%/1 mm). DVHs and dose-volume metrics were also in satisfying agreement. In addition to serving as a feasibility proof-of-concept, experimental absolute film dosimetry verified the computational study results. GI passing rates were above 90%. Results of this work suggest that employing the presented methodology, patient-equivalent phantoms (except for the skin and sinuses areas) can be produced, enabling literally patient-specific pre-treatment plan verification in intracranial applications.

BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells.

Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-κB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior preclinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or -resistant MCL.

Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.

The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

Aminolevulinic acid dendrimers in photodynamic treatment of cancer and atheromatous disease.

The use of endogenous protoporphyrin IX after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). We have previously reported that the conjugation of ALA dendrimers enhances porphyrin synthesis. The first aim of this work was to evaluate the ability of ALA dendrimers carrying 6 and 9 ALA residues (6m-ALA and 9m-ALA) to photosensitise cancer cells. For this aim, we employed LM3 mammary carcinoma cells. In these tumour cells, at low concentrations porphyrin synthesis from dendrimers was higher compared to ALA, whereas at high concentrations, porphyrin synthesis was similar from both compounds. Topical application of ALA dendrimers on the skin overlying a subcutaneous LM3 implanted tumour showed no diffusion of the molecules either to distant skin sites or to the adjacent tumour, suggesting a promising use of the ALA macromolecules in superficial cancer models. As a second objective, we proposed the use of ALA-dendrimers in vascular PDT for the treatment of atherosclerosis. Thus, we focused our studies on ALA-dendrimer's selectivity towards macrophages in comparison with endothelial cells. For this aim we employed Raw 264.7 macrophages and HMEC-1 microvasculature cells. Porphyrin synthesis induced in macrophages by 6m-ALA and 9m-ALA (3 h, 0.025 mM) was 6 and 4.6 times higher respectively compared to the endothelial cell line, demonstrating the high affinity of ALA dendrimers for macrophages. On the other hand, ALA employed at low concentrations was slightly selective (1.7-fold) for macrophages. Inhibition studies suggested that ALA dendrimer uptake in macrophages is mainly mediated by caveloae-mediated endocytosis. Our main conclusion is that in addition to being promising molecules in PDT of superficial cancer, ALA dendrimers may also find applications in vascular PDT, since in vitro they showed selectivity to the macrophage component of the atheromatous plaque, as compared to the vascular endothelium.

Treatment with melatonin after onset of experimental uveitis attenuates ocular inflammation.

BACKGROUND AND PURPOSE: Uveitis is a prevalent intraocular inflammatory disease and one of the most damaging ocular conditions. Pretreatment with melatonin prevented ocular inflammation induced by an intravitreal injection of bacterial LPS in the Syrian hamster. Here, we have assessed the anti-inflammatory effects of melatonin administered after the onset of ocular inflammation. EXPERIMENTAL APPROACH: The eyes of male Syrian hamsters were intravitreally injected with vehicle or LPS. Melatonin was injected i.p. every 24 h, starting 12 or 24 h after the LPS injection. A clinical evaluation (with a score index based on clinical symptoms), the number of infiltrating cells, protein concentration and PGE2 and PGF2α levels in the aqueous humour, as well as retinal NOS activity, lipid peroxidation and TNF-α levels were assessed. Retinal function was assessed by scotopic electroretinography, and light microscopy and immunohistochemistry were used to evaluate the state of the retinal structure. KEY RESULTS: Both treatment regimens with melatonin decreased clinical symptoms, reduced the leakage of cells and proteins, and decreased PG levels in aqueous humour from eyes injected with LPS. In addition, melatonin treatment blocked the decrease in scotopic electroretinogram a- and b-wave amplitude, protected the retinal structure and reduced the increase in NOS activity, lipid peroxidation and TNF-α levels, induced by LPS. CONCLUSIONS AND IMPLICATIONS: These results indicate that treatment with melatonin, starting after the onset of uveitis, attenuated ocular inflammation induced by LPS in the Syrian hamster and support the use of melatonin as a therapeutic resource for uveitis treatment.

New insights into clinical trial for Colostrinin in Alzheimer's disease.

BACKGROUND: The pathomechanism of Alzheimer's disease (AD) is multifactorial although the most popular hypotheses are centered on the effects of the misfolded, aggregated protein, amyloid beta (Abeta) and on Tau hyperphosphorylation. OBJECTIVES: Double blinded clinical trials were planned to demonstrate the effect of Colostrinin (CLN) on instrumental daily activities of AD patients. The potential molecular mechanisms by which CLN mediates its effects were investigated by gene expression profiling. METHODS: RNAs isolated from CLN-treated cells were analyzed by high-density oligonucleotide arrays. Network and pathway analyses were performed using the Ingenuity Pathway Analysis software. RESULTS: The Full Sample Analysis at week 15 showed a stabilizing effect of CLN on cognitive function in ADAS-cog (p = 0.02) and on daily function in IADL (p = 0.02). The overall patient response was also in favor of CLN (p = 0.03). Patients graded as mild on entry also showed a superior response of ADAS-cog compared to more advanced cases (p = 0.01). Data derived from microarray network analysis show that CLN elicits highly complex and multiphasic changes in the cells' transcriptome. Importantly, transcriptomal analysis showed that CLN alters gene expression of molecular networks implicated in Abeta precursor protein synthesis, Tau phosphorylation and increased levels of enzymes that proteolitically eliminate Abeta. In addition, CLN enhanced the defense against oxidative stress and decreased expression of inflammatory chemokines and cytokines, thereby attenuating inflammatory processes that precede Alzheimer's and other neurological diseases. CONCLUSION: Together these data suggest that CLN has promising potential for clinical use in prevention and therapy of Alzheimer's and other age-associated central nervous system diseases.

Tumorigenicity of nitropolycyclic aromatic hydrocarbons in the neonatal B6C3F1 mouse bioassay and characterization of ras mutations in liver tumors from treated mice.

The nitropolycyclic aromatic hydrocarbons (nitro-PAHs) 1-, 2-, and 3-nitrobenzo[a]pyrene, 1- and 3-nitrobenzo[e]pyrene, 2- and 3-nitrofluoranthene, 9-nitrodibenz[a,c]anthracene, and two of the parent PAHs fluoranthene and dibenz[a,c]anthracene were tested for tumorigenicity in the neonatal male B6C3F1 mouse. 6-Nitrochrysene was used as a positive control. Mice were administered three intraperitoneal injections of test agent (400 nmol total) on 1, 8, and 15 days after birth and evaluated for liver and lung tumors at 12 months of age. 2-Nitrobenzo[a]pyrene and 6-nitrochrysene induced a high incidence of liver tumors (91-100%), while the remaining test compounds did not induce tumors at a rate significantly higher than the solvent control. 6-Nitrochrysene was the only test agent to produce a significant increase in the frequency of lung tumors. K- and H-ras mutations were analyzed in liver tumors of treated mice and mainly occurred at the first base of K-ras codon 13, resulting in GGC --> CGC transversion. Since most of the tested nitro-PAHs are mutagens in vitro, the results of this study indicate that the in vitro mutagenicity of these compounds does not correlate with their tumorigenicity in the neonatal B6C3F1 mouse bioassay. Also, the results indicate that liver tumors from mice treated with nitro-PAHs possess ras mutations typical of PAHs and their derivatives.

A chemotherapy and infusion therapy flow sheet for outpatient oncology settings.

PURPOSE/OBJECTIVES: To describe the development and evaluation of a documentation tool for chemotherapy and infusion therapy for an outpatient oncology setting. DATA SOURCES: Journal articles, documentation tools, and cancer chemotherapy guidelines. DATA SYNTHESIS: Greater demands and expansion of treatments and procedures in the outpatient setting have necessitated documentation methods that conserve time, accommodate documentation of a variety of therapies, and communicate ongoing monitoring and evaluation of care. Flow sheet documentation is an acceptable documentation method that has been used extensively to meet these objectives. CONCLUSIONS: Use of this flow sheet has improved the quality and accommodated the scope of infusion therapy in the authors' setting. Documentation time has decreased, and standardization of documentation has occurred. IMPLICATIONS FOR NURSING PRACTICE: Nurses can use the flow sheet to document concisely chemotherapy and infusion therapy administration over a period of time. It also provides for continuity in patient assessment and education through easy accessibility of this information within the patient's chart.

GAP1 activity is dependent on cAMP in Saccharomyces cerevisiae.

General amino acid permease (GAP1) activity was evaluated in adenylate cyclase-deficient Saccharomyces cerevisiae to determine the effect of cAMP levels on GAP1 activity. Lowering cAMP concentrations in the culture media led to a decrease in the initial rates of L-citrulline uptake. Kinetics of the amino acid transport system showed a partial loss of transport capacity, with no apparent modifications in permease affinity.

RAS2/PKA pathway activity is involved in the nitrogen regulation of L-leucine uptake in Saccharomyces cerevisiae.

The aim of the present work is to study the participation of RAS2/PKA signal pathway in the nitrogen regulation of L-leucine transport in yeast cells. The study was performed on Saccharomyces cerevisiae isogenic strains with the normal RAS2 gene, the RAS2val19 mutant and the disrupted ras2::LEU2. These strains bring about different activities of the RAS2/PKA signal pathway, L-(14C)-Amino acid uptake measurements were determined in cells grown in a rich YPD medium with a mixed nitrogen source or in minimal media containing NH4+ or L-proline as the sole nitrogen source. We report herein that in all strains used, even in those grown in a minimal proline medium, the activity of the general amino acid permease (GAP1) was not detected. L-Leucine uptake in these strains is mediated by two kinetically characterized transport systems. Their KT values are of the same order as those of S1 and S2 L-leucine permeases. Mutation in the RAS2 gene alters initial velocities and Jmax values in both high and low affinity L-leucine transport systems. Activation of the RAS2/PKA signalling pathway by the RAS2val19 mutation, blocks the response to a poor nitrogen source whereas inactivation of RAS2 by gene disruption, results in an increase of the same response.

Isolation of a trifluoroleucine-resistant mutant of Saccharomyces cerevisiae deficient in both high- and low-affinity L-leucine transport.

A yeast mutant defective in permeases S1 and S2 which transport L-leucine was isolated from a parental strain already deficient in the general amino acid permease, GAP1. The mutant was selected as a spontaneous, trifluoroleucine-resistant (TFLR) strain. Full resistance depended upon the presence of two unlinked mutant genes designated let1 and let2. The let1 mutation completely inactivates the high-affinity leucine transport system defined kinetically as S1. Although the let2 mutation caused a marked decrease in the Jmax of the low-affinity transport system, S2, residual leucine transport in the let1 let2 gap1 mutant had the same KT as in the LET1 LET2 gap1 parent. The mutant exhibited a marked decrease in growth on minimal medium containing leucine, isoleucine or valine as a sole nitrogen source. Moreover, assimilation of methionine, phenylalanine, serine and threonine was decreased, whereas basic and acidic amino acids supported normal growth. This indicates that at least one of the leucine permeases has a fairly broad, but still limited, specificity. Reversion of the gap1 gene restored leucine transport. The revertant was sensitive to TFL when grown on proline but resistant when NH4+ was the nitrogen source. The previously published mutations (shr3, aat1, lup1 or raa) would not be related to either LET1 or LET2.

Identification of two N2-deoxyguanosinyl DNA adducts upon nitroreduction of the environmental mutagen 1-nitropyrene.

1-Nitropyrene, the most abundant nitro-polycyclic aromatic hydrocarbon in the environment, is a known mammalian and bacterial mutagen and a tumorigen in animals. Early studies on DNA adduct characterization for 1-nitropyrene identified N-(deoxyguanosin-8-yl)-1-aminopyrene as the major product from the modification of calf thymus DNA with N-hydroxy-1-aminopyrene, the activated metabolite from nitroreduction of 1-nitropyrene. In this paper, we report the identification of two N2-deoxyguanosinyl adducts, in addition to N-(deoxyguanosin-8-yl)-1-aminopyrene, formed from the reaction of N-hydroxy-1-aminopyrene, prepared in situ, with calf thymus DNA. These DNA adducts were identified as 6-(deoxyguanosin-N2-yl)-1-aminopyrene and 8-(deoxyguanosin-N2-yl)-1-aminopyrene. The two N2-deoxyguanosinyl adducts were also identified in an ascorbic acid-catalyzed activation of 1-nitrosopyrene and in the mammary gland of female Sprague-Dawley rats administered 1-nitropyrene. The DNA adducts were also formed when 1-nitropyrene was metabolized by xanthine oxidase in the presence of calf thymus DNA, and when 1-nitropyrene was activated by rat liver microsomes and cytosols, as well as from DNA isolated from Salmonella typhimurium suspension cultures incubated with 1-nitropyrene.

DNA adducts and carcinogenicity of nitro-polycyclic aromatic hydrocarbons.

We have been interested in the structure-activity relationships of nitro-polycyclic aromatic hydrocarbons (nitro-PAHs), and have focused on the correlation of structural and electronic features with biological activities, including mutagenicity and tumorigenicity. In our studies, we have emphasized 1-, 2-, 3-, and 6-nitrobenzo[a]pyrenes (nitro-B[a]Ps) and related compounds, all of which are derived from the potent carcinogen benzo[a]pyrene. While 1-, 2-, and 3-nitro-B[a]P are potent mutagens in Salmonella, 6-nitro-B[a]P is a weak mutagen. In vitro metabolism of 1- and 3-nitro-B[a]P has been found to generate multiple pathways for mutagenic activation. The formation of the corresponding trans-7,8-dihydrodiols and 7,8,9,10-tetrahydrotetrols suggests that 1- and 3-nitro-B[a]P trans-7,8-diol-9,10-epoxides are ultimate metabolites of the parent nitro-B[a]Ps. We have isolated a DNA adduct from the reaction between 3-nitro-B[a]P trans-7,8-diol-anti9,10-epoxide and calf thymus DNA, and identified it as 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-3-ni tro-B[a]P . The same adduct was identified from in vitro metabolism of [3H]3-nitro-B[a]P by rat liver microsomes in the presence of calf thymus DNA. A DNA adduct of 3-nitro-B[a]P formed from reaction of N-hydroxy-3-amino-B[a]P, prepared in situ with calf thymus DNA was also isolated. This adduct was identified as 6-(deoxyguanosin-N2-yl)-3-amino-B[a]P. The same adduct was obtained from incubating DNA with 3-nitro-B[a]P in the presence of the mammalian nitroeductase, xanthine oxidase, and hypoxanthine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of 3-nitrobenzothiazolo[3,2-a]quinolinium chloride (NBQ) and doxorubicin on lens regeneration in the adult newt: a morphological study.

The antitumor drug 3-nitrobenzothiazolo [3,2-a] quinolinium chloride (NBQ) stimulates the in vivo lens regeneration in the adult newt Notophthalmus viridescens and induces a differentiated state in HL-60 leukemia cells. Because the cytotoxic drug doxorubicin (Adriamycin) induces differentiation of HL-60 cells in vitro we decided to compare the effect(s) of doxorubicin with NBQ on lens regeneration in vivo. Both drugs were injected intraperitoneally at six different schedules. Morphological criteria of the different regeneration stages were used in the analysis of the regenerates. NBQ stimulated lens regeneration independently of the time intervals and the stage of regeneration at which the drug was administered. There was an increase in the mean number of mitoses suggesting that NBQ stimulated cell proliferation. Doxorubicin administered for five days did not modify the regenerative process. On the other hand, doxorubicin given for periods of nine or more days after lentectomy, strongly inhibited the formation of a new lens. Thus, the inhibitory effect of doxorubicin is dependent on the continuous long term contact with the tissue. Although NBQ and doxorubicin are both DNA intercalators, they induced the effects on lens regeneration through different mechanisms.

Formation of the adduct 6-(deoxyguanosin-N2-yl)-3-amino-benzo[a]pyrene from the mutagenic environmental contaminant 3-nitrobenzo[a]pyrene.

3-Nitrobenzo[a]pyrene (3-nitro-B[a]P) is a potent bacterial mutagen as a result of nitroreduction. Reaction of N-hydroxy-3-amino-B[a]P, prepared in situ from reduction of 3-nitro-B[a]P with calf thymus DNA, was studied. After enzymatic digestion of the DNA, the resulting modified nucleosides were analyzed by thermospray HPLC-MS and high-resolution proton NMR spectroscopy. The major adduct was identified as 6-(deoxyguanosin-N2-yl)-3-amino-B[a]P. The same adduct was obtained from incubation of DNA with 3-nitro-B[a]P in the presence of the mammalian nitroreductase xanthine oxidase, and hypoxanthine. These data indicate that a mammalian nitroreductase can metabolize 3-nitro-B[a]P to an activated derivative that reacts with DNA to give a novel adduct distant from the site of N-hydroxylation.

Products formed from the in vitro reaction of metabolites of 3-aminochrysene with calf thymus DNA.

3-Aminochrysene, a mutagenic geometric isomer of the mutagenic and carcinogenic aromatic amine 6-aminochrysene, has been synthesized and its metabolic activation studied by characterization of the products formed from the reaction of metabolites with calf thymus DNA. DNA adducts produced by 3-aminochrysene via N-oxidation were examined by preparing 3-nitrosochrysene and incubating the nitroso derivative with calf thymus DNA in the presence of ascorbic acid (to generate the N-hydroxy derivative) at pH 5. The major adduct, as determined by 1H-NMR and thermospray-mass spectrometry of the modified nucleoside obtained after enzymatic hydrolysis of the modified DNA, was N-(deoxyguanosin-8-yl)-3-aminochrysene. Thus, the reaction of N-hydroxy-3-aminochrysene with DNA differs from that of N-hydroxy-6-aminochrysene, which had previously been shown to generate N-(deoxyguanosin-8-yl)-6-aminochrysene, 5-(deoxyguanosin-N2-yl)-6-aminochrysene and N-(deoxyinosin-8-yl)-6- aminochrysene as major adducts. 32P-Postlabeling analysis of DNA treated with 3-aminochrysene in the presence of liver microsomes from rats pretreated with phenobarbital indicated an adduct pattern identical to that seen with DNA that had been treated with 3-nitrosochrysene and ascorbic acid. However, DNA treated with 3-aminochrysene (3-AC) in the presence of liver microsomes from rats pretreated with 3-methylcholanthrene contained a major adduct that was chromatographically distinct from N-(deoxyguanosin-8-yl)-3-aminochrysene.

In vitro metabolism and DNA adduct formation from the mutagenic environmental contaminant 2-nitrofluoranthene.

The metabolism and DNA adduct formation by the mutagenic environmental contaminant 2-nitrofluoranthene (2-NFA) were studied. Incubation under aerobic conditions with liver microsomes of rats pretreated with 3-methylcholanthrene yielded trans-7,8-dihydroxy-7,8-dihydro-2-nitrofluoranthene, trans-9,10-dihydroxy-9,10-dihydro-2-nitrofluoranthene, and 7-, 8-, and 9-phenolic metabolites. When the epoxide hydrolase inhibitor 3,3,3-trichloropropylene was present in the incubation, only phenolic metabolites were detected. Under hypoxic conditions, 2-aminofluoranthene was obtained, together with a trace of the ring-oxidized metabolites. The activated metabolite, N-hydroxy-2-aminofluoranthene, was prepared in situ and reacted with calf thymus DNA. Upon enzymatic hydrolysis of the DNA and purification by HPLC, a C8-substituted deoxyguanosine adduct, N-(deoxyguanosin-8-yl)-2-aminofluoranthene, was identified by mass and proton NMR spectral analysis. This adduct was also formed at a level of 10 pmol/mg of DNA when 2-NFA was metabolized by xanthine oxidase, 6 pmol/mg of DNA from incubation with liver microsomes of rats pretreated with 3-methylcholanthrene, and 3-pmol/mg of DNA from metabolism by liver microsomes of rats pretreated with phenobarbital.