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Peculiarities of N-nitramines carcinogenic action
Abstract
Carcinogenic action of dimethylnitramine (DMNO), diethylnitramine (DENO), and dibuthylnitramine (DBNO) on various animal species was studied. 200 ppm of DMNO in tap water induced no tumours in outbred rats, while DBNO induced hyperplastic lesions on the urinary bladder and DENO produced liver tumours in 2 of 5 rats. DMNO dissolve in aquarium water at a dose of 5 ppm induced tumours (kidney and liver adenocarcinomas and hemocytoblastosis) in 18 out of 40 and 6 out of 18 frogs respectively. Another amphibian species, Xenopus, showed similar sensitivity to DMNO action: hepatocellular cancers, cholangiocarcinomas and kidney tumours were found in 6 out of 14 animals and in another group, in 6 out of 17 animals treated with 400 ppm of DMNO dissolved in aquarium water. Few neoplasms were observed in experiments on fish (guppies zebrafish) and freshwater mollusks treated with DMNO and DENO. The carcinogenic effect of nitramines, appears to be much lower than that of related nitrosamines.
... Several studies show that some of the nitramines are indeed carcinogenic to rats (Druckrey et al., 1967;Goodall and Kennedy, 1976;Mirvish et al., 1980, Pliss 1982et al., Hassel et al,, 1987, Scherf et al., 1989. Both the nitrosamine metabolite and formaldehyde are among the metabolites proposed as possible mediators of the carcinogenic effect of N-nitrodimethylamine, but the mechanism of N-nitramine carcinogenicity is still unclear. ...
... Two studies compared the carcinogenicity of several N-nitroalkylamines. Pliss et al. (1982) reported on the carcinogenicity of N-nitrodimethylamine, N-nitrodiethylamine, and N-nitrodibuthylamine in various species including outbred rats. Rats (50 animals per substance) were given 200 ppm (15-20 mg/kg bw) daily of the test substance in the drinking water for 130 weeks. ...
... The high fecundity and relatively simple husbandry enable large experimental series in vivo . Early cancer models in zebrafish were largely developed using mutagens such as MNNG or DMBA, which were later supplanted by transgenic technologies (Beckwith et al., 2000;Pliss et al., 1982;Spitsbergen et al., 2000) . The initial transgenic cancer models were developed by injecting 1-cell zebrafish embryos with DNA constructs containing a promoter and oncogene. ...
Transgenic animals are invaluable for modeling cancer genomics, but often require complex crosses of multiple germline alleles to obtain the desired combinations. Zebrafish models have advantages in that transgenes can be rapidly tested by mosaic expression, but these typically lack spatial and temporal control of tumor onset, which limits their utility for the study of tumor progression and metastasis. To overcome these limitations, we have developed a method called Transgene Electroporation in Adult Zebrafish (TEAZ). TEAZ can deliver DNA constructs with promoter elements of interest to drive fluorophores, oncogenes, or CRISPR-Cas9-based mutagenic cassettes in specific cell types. Using TEAZ, we created a highly aggressive melanoma model by expression of BRAF V600E in spatially constrained melanocytes in the context of p53 deficiency and Cas9-mediated inactivation of Rb1. Unlike prior models that take ~4 months to develop, we found that TEAZ leads to tumor onset in ~7 weeks and these develop in fully immunocompetent animals. As the resulting tumors initiated at highly defined locations, we could track their progression via fluorescence and documented deep invasion into tissues and metastatic deposits. TEAZ can be deployed to other tissues and cell types such as the heart with the use of suitable transgenic promoters. The versatility of TEAZ makes it widely accessible for rapid modeling of somatic gene alterations and cancer progression at a scale not achievable in other in vivo systems.
... The zebrafish has a long history as a model for cancer, beginning even before the development of the most recent genetic approaches. Treatment with carcinogens was long ago observed to produce tumors in these animals (Pliss et al., 1982), and treatment with mutagens such as ethylnitrosourea (ENU), dimethylbenz(a)anthracene (DMBA), and N-methyl-nitrosoguanadine (MNNG) was known to lead to a wide variety of tumor types (Beckwith et al., 2000;Spitsbergen et al., 2000aSpitsbergen et al., , 2000b). The zebrafish model is also amenable to many types of unbiased screens for genes and drugs that alter cancer biology. ...
Cancer has joined heart disease as the leading source of mortality in the US. In an era of organoids, patient-derived xenografts, and organs on a chip, model organisms continue to thrive with a combination of powerful genetic tools, rapid pace of discovery, and affordability. Model organisms enable the analysis of both the tumor and its associated microenvironment, aspects that are particularly relevant to our understanding of metastasis and drug resistance. In this Perspective, we explore some of the strengths of fruit flies and zebrafish for addressing fundamental cancer questions and how these two organisms can contribute to identifying promising therapeutic candidates.
... The high fecundity and relatively simple husbandry enable large experimental series in vivo. Early cancer models in zebrafish were largely developed using mutagens such as MNNG or DMBA, which were later supplanted by transgenic technologies ( Beckwith et al., 2000;Pliss et al., 1982;Spitsbergen et al., 2000). The initial transgenic cancer models were developed by injecting 1-cell zebrafish embryos with DNA constructs containing a promoter and oncogene. ...
Transgenic animals are invaluable for modeling cancer genomics, but often require complex crosses of multiple germline alleles to obtain the desired combinations. Zebrafish models have advantages in that transgenes can be rapidly tested by mosaic expression, but these typically lack spatial and temporal control of tumor onset, which limits their utility for the study of tumor progression and metastasis. To overcome these limitations, we have developed a method called Transgene Electroporation in Adult Zebrafish (TEAZ). TEAZ can deliver DNA constructs with promoter elements of interest to drive fluorophores, oncogenes, or CRISPR-Cas9-based mutagenic cassettes in specific cell types. Using TEAZ, we created a highly aggressive melanoma model via Cas9-mediated inactivation of Rb1 in the context of BRAFV600E in spatially constrained melanocytes. Unlike prior models that take ∼4 months to develop, we found that TEAZ leads to tumor onset in ∼7 weeks and these develop in fully immunocompetent animals. As the resulting tumors initiated at highly defined locations, we could track their progression via fluorescence and documented deep invasion into tissues and metastatic deposits. TEAZ can be deployed to other tissues and cell types such as the heart with the use of suitable transgenic promoters. The versatility of TEAZ makes it widely accessible for rapid modeling of somatic gene alterations and cancer progression at a scale not achievable in other in vivo systems.
... (DENA) and MNA should still be regarded as carcinogen of high potency. Many research on nitramines have shown their carcinogenic potential in animals [Pliss et al., 1982, Goodall and Kennedy, 1976, Scherf et al., 1989. The studies [Fjellsbø et al., 2014] confirm the toxicity of some nitramines. ...
The use of amine absorption in carbon capture technologies is related with the formation toxic and potentially carcinogenic amine degradation products such as nitrosamines and nitramines. These substances can be created within both the solvent and the atmosphere when air components (mainly NOx) and amines react with each other. These substances may pose environmental and health risks depending on the level and duration of the exposure. In this paper, formation and occurrence of nitrosamines and nitramines in carbon capture plants were described. Emission reducing technologies have been also mentioned. Furthermore, an overview of experimental data of emission of nitrosamines and other major degradation products has been pointed out.
... Compared to the mouse model, the zebrafish model is very suitable for large-scale genetic and high-throughput screening in many ways, and it allows more powerful induction of tumors by carcinogens [10]. The first zebrafish model of hematological malignancy was generated in 2003 using the mouse Myc gene driven by recombinase activating gene 2 (rag2) promoters. ...
Myeloid malignancies are heterogeneous disorders characterized by uncontrolled proliferation or/and blockage of differentiation of myeloid progenitor cells. Although a substantial number of gene alterations have been identified, the mechanism by which these abnormalities interact has yet to be elucidated. Over the past decades, zebrafish have become an important model organism, especially in biomedical research. Several zebrafish models have been developed to recapitulate the characteristics of specific myeloid malignancies that provide novel insight into the pathogenesis of these diseases and allow the evaluation of novel small molecule drugs. This report will focus on illustrative examples of applications of zebrafish models, including transgenesis, zebrafish xenograft models, and cell transplantation approaches, to the study of human myeloid malignancies.
... In contrast, very little information is available for genotoxic effects of nitramines. Dimethylnitramine (DMA-NO 2 ) was found to be both mutagenic (Frei et al. , 1986Malaveille et al., 1983;Pool et al., 1984) and carcinogenic (Goodall and Kennedy, 1976;Mirvish et al., 1980;Pliss et al., 1982). Furthermore, methylnitramine (MA-NO 2 ) showed carcinogenic potential (CPDB, 2007;Hassel et al., 1987;Scherf et al., 1989) but no evidence was found on mutagenic activity (Frei et al., , 1986Pool et al., 1984). ...
... Xiphophorus species develop spontaneous melanoma, which was found to be due to activating mutations of the tyrosine kinase xiphophorus melanoma receptor kinase (xmrk) 6 . That zebrafish could be useful as a model for cancer was suggested in 1982, when it was found that exposure to carcinogens such as dimethylnitramine caused low-penetrance tumour formation in zebrafish 7 . By 2000, it was recognized that zebrafish exposed to more common mutagens such as ethylnitrosourea (ENU), DMBA and N-methyl-nitrosoguanadine (MNNG) develop various neoplasms, including skin papillomas, hepatic adenomas, rhabdomyosarcoma and seminoma [8][9][10] . ...
The zebrafish is a recent addition to animal models of human cancer, and studies using this model are rapidly contributing major insights. Zebrafish develop cancer spontaneously, after mutagen exposure and through transgenesis. The tumours resemble human cancers at the histological, gene expression and genomic levels. The ability to carry out in vivo imaging, chemical and genetic screens, and high-throughput transgenesis offers a unique opportunity to functionally characterize the cancer genome. Moreover, increasingly sophisticated modelling of combinations of genetic and epigenetic alterations will allow the zebrafish to complement what can be achieved in other models, such as mouse and human cell culture systems.
... These recent works have documented the carcinogenicity of diverse compounds administered at various developmental stages in Florida wild-type zebrafish. When treated with most carcinogens at the fry or embryo stage, zebrafish display a variety of neoplasms derived from epithelial, mesenchymal, neural, and neural crest tissues (Spitsbergen and Kent 2003;Pliss et al. 1982;Khudoley 1984;Mizgireuv et al. 2004;Hendricks 1996;Spitsbergen et al. 2000b;Spitsbergen et al. 2000a;Tsai 1996). These data demonstrate the ease of using zebrafish to assess carcinogen responses in vivo and the capacity of zebrafish to develop a diverse range of cancers histologically similar to tumor types in humans (Goessling et al. 2007). ...
A retrovirus homologue gene of cellular cyclin D₁, walleye dermal sarcoma virus rv-cyclin gene (orf A or rv-cyclin), was expressed in the livers of zebrafish under the control of liver fatty acid-binding protein (lfabp) promoter. To prevent possible fatality caused by overexpression of the oncogene, the GAL4/upstream activation sequence (GAL4/UAS) system was used to maintain the transgenic lines. Thus, both GAL4-activator [Tg(lfabp:GAL4)] and UAS-effector [Tg(UAS:rvcyclin)] lines were generated, and the rv-cyclin gene was activated in the liver after crossing these two lines. Since no obvious neoplasia phenotypes were observed in the double-transgenic line, cancer susceptibility of the transgenic fish expressing rv-cyclin was tested by carcinogen treatment. Unexpectedly, transgenic fish expressing rv-cyclin gene (rvcyclin+) were more resistant to the carcinogen than siblings not expressing this gene (rvcyclin-). Lower incidences of multiple and malignant liver tumors were observed in rvcyclin+ than in rvcyclin- fish, and the liver tumors in the rvcyclin+ group appeared later and were less malignant. These results suggest that expression of rv-cyclin protects the fish liver from carcinogen damage and delays onset of malignancy. These findings indicate that transgenic fish models are powerful systems for investigating mechanisms of inhibition and regression of liver tumors.
The N-nitrosodimethylamine (NDMA) formation pathway in chloraminated drinking water remains unresolved. In pH 7-10 waters amended with 10 μM total dimethylamine and 800 μeq Cl2·L-1 dichloramine (NHCl2), NDMA, nitrous oxide (N2O), dissolved oxygen (DO), NHCl2, and monochloramine (NH2Cl) were kinetically quantified. NHCl2, N2O, and DO profiles indicated that reactive nitrogen species (RNS) formed during NHCl2 decomposition, including nitroxyl/nitroxyl anion (HNO/NO-) and peroxynitrous acid/peroxynitrite anion (ONOOH/ONOO-). Experiments with uric acid (a ONOOH/ONOO- scavenger) implicated ONOOH/ONOO- as a central node for NDMA formation, which were further supported by the concomitant N-nitrodimethylamine formation. A kinetic model accurately simulated NHCl2, NH2Cl, NDMA, and DO concentrations and included (1) the unified model of chloramine chemistry revised with HNO as a direct product of NHCl2 hydrolysis; (2) HNO/NO- then reacting with (i) HNO to form N2O, (ii) DO to form ONOOH/ONOO-, or (iii) NHCl2 or NH2Cl to form nitrogen gas; and (3) NDMA formation via ONOOH/ONOO- or their decomposition products reacting with (i) dimethylamine (DMA) and/or (ii) chlorinated unsymmetrical dimethylhydrazine (UDMH-Cl), the product of NHCl2 and DMA. Overall, updated NHCl2 decomposition pathways are proposed, yielding (1) RNS via
N
H
Cl
2
→
H
N
O
/
N
O
-
→
O
2
O
N
O
O
H
/
O
N
O
O
-
and (2) NDMA via
O
N
O
O
H
/
O
N
O
O
-
→
UDMH
-
Cl
or
DMA
NDMA
.
Amine-based carbon dioxide capture is the most mature technology for reducing flue gas CO2 emissions. It has been postulated and observed during commercialisation of this technology that significant quantities of waste amines are produced. Further industrial implementation of this technology requires adequate disposal or valorisation options for this waste. This review presents an analysis of seven biological and chemical technologies for waste amine amelioration or valorisation. Of these, the biological treatments are identified as being more mature for industrial application with the capacity for marketable product generation. Slow speed is the main drawback of the biological processes but this does not hinder their commercial viability. Using waste amine for NOx reduction in power stations is a secondary option, where it seems probable that the amount of waste amine generated in the CO2 capture plant is sufficient to fulfil the DeNOx requirements of the flue gas. This route, however, requires investigation into the impact of waste amine impurities on the power station and the CO2 capture plant operations.
Liver and pancreatic cancers are amongst the leading causes of cancer death. In recent years, genetic and chemical approaches in zebrafish have elucidated cellular and molecular mechanisms of liver and pancreatic cancer formation and progression. In this chapter, we review the recent approaches and advances in the field to study both hepatocellular carcinomas and pancreatic cancer.
Animal xenografts of human cancers represent a key preclinical tool in the field of cancer research. While mouse xenografts have long been the gold standard, investigators have begun to use zebrafish (Danio rerio) xenotransplantation as a relatively rapid, robust and cost-effective in vivo model of human cancers. There are several important methodological considerations in the design of an informative and efficient zebrafish xenotransplantation experiment. Various transgenic fish strains have been created that facilitate microscopic observation, ranging from the completely transparent casper fish to the Tg(fli1:eGFP) fish that expresses fluorescent GFP protein in its vascular tissue. While human cancer cell lines have been used extensively in zebrafish xenotransplantation studies, several reports have also used primary patient samples as the donor material. The zebrafish is ideally suited for transplanting primary patient material by virtue of the relatively low number of cells required for each embryo (between 50 and 300 cells), the absence of an adaptive immune system in the early zebrafish embryo, and the short experimental timeframe (5–7 days). Following xenotransplantation into the fish, cells can be tracked using in vivo or ex vivo measures of cell proliferation and migration, facilitated by fluorescence or human-specific protein expression. Importantly, assays have been developed that allow for the reliable detection of in vivo human cancer cell growth or inhibition following administration of drugs of interest. The zebrafish xenotransplantation model is a unique and effective tool for the study of cancer cell biology.
This review aims to summarize the available analytical methods in the open literature for the determination of some aliphatic and cyclic nitramines. Nitramines covered in this review are the ones that can be formed from the use of amines in post-combustion CO2 capture (PCC) plants and end up in the environment. Since the literature is quite scarce regarding the determination of nitramines in aqueous and soil samples, methods for determination of nitramines in other matrices have also been included. Since the nitramines are found in complex matrices and/or in very low concentration, an extraction step is often necessary before their determination. Liquid-liquid extraction (LLE) using dichloromethane and solid phase extraction (SPE) with an activated carbon based material have been the two most common extraction methods. Gas chromatography (GC) or reversed phase liquid chromatography (RPLC) has been used often combined with mass spectrometry (MS) in the final determination step. Presently there is no comprehensive method available that can be used for determination of all nitramines included in this review. The lowest concentration limit of quantification (cLOQ) is in the ng L(-1) range, however, most methods appear to have a cLOQ in the μg L(-1) range, if the cLOQ has been given.
During the past decade, the zebrafish has emerged as a leading model for mechanistic cancer research because of its sophisticated genetic and genomic resources, its tractability for tissue targeting of transgene expression, its efficiency for forward genetic approaches to cancer model development, and its cost effectiveness for enhancer and suppressor screens once a cancer model is established. However, in contrast with other laboratory animal species widely used as cancer models, much basic cancer biology information is lacking in zebrafish. As yet, data are not published regarding dietary influences on neoplasm incidences in zebrafish. Little information is available regarding spontaneous tumor incidences or histologic types in wild-type lines of zebrafish. So far, a comprehensive database documenting the full spectrum of neoplasia in various organ systems and tissues is not available for zebrafish as it is for other intensely studied laboratory animal species. This article confirms that, as in other species, diet and husbandry can profoundly influence tumor incidences and histologic spectra in zebrafish. We show that in many laboratory colonies wild-type lines of zebrafish exhibit elevated neoplasm incidences and neoplasm-associated lesions such as heptocyte megalocytosis. We present experimental evidence showing that certain diet and water management regimens can result in high incidences of neoplasia and neoplasm-associated lesions. We document the wide array of benign and malignant neoplasms affecting nearly every organ, tissue, and cell type in zebrafish, in some cases as a spontaneous aging change, and in other cases due to carcinogen treatment or genetic manipulation.
This chapter explains the utility of zebrafish as a model for toxicological research. Zebrafish (Danio rerio) have long been the genetic model of choice for vertebrate developmental biologists, as it provides several advantages for investigating organ and tissue development. Zebrafish have become a powerful model organism for investigating the molecular and cellular mechanisms by which environmental chemicals disrupt normal developmental processes. The utility of zebrafish as a laboratory model organism also makes it an excellent system for studying processes in juvenile and adult organisms, including reproductive development, carcinogenesis, aging, and the influence of environmental chemicals on these processes. The advent of modern genetic tools and genome sequencing projects has elevated zebrafish as a suitable model to effectively study human disease and pathophysiology, ushering in a new era of comparative biology and medicine. The chapter reviews the mechanistic toxicology and advantages of the zebrafish model system.
In support of the potential use of advanced oxidation and reduction process technologies for the removal of carcinogenic nitro-containing compounds in water reaction rate constants for the hydroxyl radical and hydrated electron with a series of low molecular weight nitramines (R(1)R(2)-NNO(2)) have been determined using a combination of electron pulse radiolysis and transient absorption spectroscopy. The hydroxyl radical reaction rate constant was fast, ranging from 0.54-4.35 × 10(9) M(-1) s(-1), and seen to increase with increasing complexity of the nitramine alkyl substituents suggesting that oxidation primarily occurs by hydrogen atom abstraction from the alkyl chains. In contrast, the rate constant for hydrated electron reaction was effectively independent of compound structure, (k(av) = (1.87 ± 0.25) × 10(10) M(-1) s(-1)) indicating that the reduction predominately occurred at the common nitramine moiety. Concomitant steady-state irradiation and product measurements under aerated conditions also showed a radical reaction efficiency dependence on compound structure, with the overall radical-based degradation becoming constant for nitramines containing more than four methylene groups. The quantitative evaluation of these efficiency data suggest that some (~40%) hydrated electron reduction also results in quantitative nitramine destruction, in contrast to previously reported electron paramagnetic measurements on these compounds that proposed that this reduction only produced a transient anion adduct that would transfer its excess electron to regenerate the parent molecule.
Tetryl (N-methyl-N,2,4,6-tetranitroaniline) is a booster explosive that was used in the production of detonators and blasting caps. It is an environmental contaminant that is found in detectable levels in areas associated with its production, use, storage, and disposal. Preliminary microsomal assays showed that one major metabolite was formed under anaerobic and aerobic conditions with both NADH and NADPH as cofactors. Metabolite formation was not inhibited by carbon monoxide but did not form in the absence of cofactor or with heat-killed microsomes. The major metabolite was identified as N-methyl-2,4,6-trinitroaniline (NMPA) by IR spectroscopy, (1)H and (14)C NMR, and chemical ionization/MS. Kinetic parameters of NMPA formation in the microsomal fraction were determined using Lineweaver-Burke plots. A V(max) of 448nmoles/(minmg) of protein and K(m) of 1.25mM was determined when NAD+ was the cofactor. When NADP+ was the cofactor, a V(max) of 139nmoles/(minmg) of protein and a K(m) of 1.4mM was determined. In the microsomal fraction, inhibition studies revealed that NMPA formation was slightly inhibited (10%) by 2'-AMP (2mM) when NADP+, but not NAD+, was used as a cofactor. This suggests that NMPA formation is partially dependent on cytochrome-P450 reductase. NMPA formation was also inhibited by dicumarol (2mM) when NADP+ (14%) and NAD+ (84%) (14%) were cofactors, suggesting that NAD(P)H: quinone oxidoreductase catalyzes NMPA formation in the microsomes. A nonspecific flavoprotein inhibitor, DPI, inhibited NMPA formation (91%) using NADP+ as a cofactor, but not NAD+. Other inhibitors, miconazole (cytochrome-P450), methimazole (flavin monooxygenase), and propylthiouracil (NADH: b5 reductase), did not prevent NMPA formation in the microsomal fraction.
N-Nitrosodiethylamine (NEN) and N-nitrodiethylamine (NEA) are carcinogens and in vitro activators of hepatic UDP-glucuronosyltransferase (GT) toward 2-aminophenol (AP) and 4-nitrophenol (NP). In this communication, they were intraperitoneally administered to male Wistar rats for 7 days and GT activities were determined towards AP, NP, phenolphthalein (PH) and testosterone (TS). Administration of 30 or 20 mg/kg dose of NEN caused marked decrease of liver and body weights, and did not affect hepatic GT activities. Injection of 10 mg/kg dose of NEN did not diminish liver and body weights, and increased the maximally activated GT activities toward AP and NP. In contrast, 30 mg/kg dose of NEA, did not affect either liver and body weights or GT activities. N-Nitrosodimethylamine (NMN), which is a carcinogen and a weak in vitro AP GT activator, was more toxic than NEN, and 3.6 mg/kg dose of NMN appears to induce GT toward NP and AP. Administration of 46.5 mg/kg N-nitrosodibutylamine (NBN), which is a carcinogen but not a GT activator, did not affect GT activities or liver body weights.
Sixteen types of children's pacifiers and baby-bottle nipples, bought in shops in Israel but produced both there and elsewhere in the world, were analyzed for their contents of N-nitrosamines, which have been shown to be potent carcinogens in animals, and of nitrosatable amines. Two methods were used: one, originating in the United States, involved dichloromethane extraction of total volatile N-nitrosamines from the nipples and pacifiers, and the other, from the Federal Republic of Germany, consisted of analysis of N-nitrosamines and their amine precursors that migrated into artificial saliva. N-Nitrosodibutylamine (NDBA). N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA). N-nitrosopiperidine (NPIP), and N-nitrosopyrrolidine (NPYR) were detected by the first method, at individual levels as high as 369 ppb. Using the second method, NDBA, NDEA, NDMA, and N-nitrosomorpholine (NMOR) were detected at concentrations up to 41 ppb, in addition to the three nitrosatable amines dibutylamine, diethylamine, and dimethylamine. Upon nitrosation in the artificial saliva, these amines produced not only the related N-nitrosamines but also relatively high levels of the corresponding N-nitramines (N-nitrodibutylamine, N-nitrodiethylamine, and N-nitrodimethylamine), probably formed by oxidation of the N-nitrosamines by peroxides used for vulcanization of elastomers. Thus, if N-nitramines are not measured in addition to N-nitrosamines after nitrosation, the second method may underestimate the quantities of nitrosatable amines present in artificial saliva extracts. Whether N-nitramines, some of which have been shown to be both mutagenic and carcinogenic, also occur in the saliva of babies exposed to these products remains to be confirmed. Of the samples tested, 50% failed to meet both the U.S. and the FRG regulations. A larger percentage, 60%, would not conform to the new standard suggested in the United States, and more than 80% failed to comply with the even stricter Dutch standard.
The zebrafish (Danio rerio) is now the pre-eminent vertebrate model system for clarification of the roles of specific genes and signaling pathways in development. The zebrafish genome will be completely sequenced within the next 1-2 years. Together with the substantial historical database regarding basic developmental biology, toxicology, and gene transfer, the rich foundation of molecular genetic and genomic data makes zebrafish a powerful model system for clarifying mechanisms in toxicity. In contrast to the highly advanced knowledge base on molecular developmental genetics in zebrafish, our database regarding infectious and noninfectious diseases and pathologic lesions in zebrafish lags far behind the information available on most other domestic mammalian and avian species, particularly rodents. Currently, minimal data are available regarding spontaneous neoplasm rates or spontaneous aging lesions in any of the commonly used wild-type or mutant lines of zebrafish. Therefore, to fully utilize the potential of zebrafish as an animal model for understanding human development, disease, and toxicology we must greatly advance our knowledge on zebrafish diseases and pathology.
Absolute rate constants for hydroxyl radical, *OH, and hydrated electron, e(aq)(-), reactions with low-molecular-weight nitrosamines and nitramines in water at room temperature were measured using the techniques of electron pulse radiolysis and transient absorption spectroscopy. The bimolecular rate constants obtained, k (M(-1) s(-1)), for e(aq)(-) and *OH reactions, respectively, were as follows: methylethylnitrosamine, (1.67 +/- 0.06) x 10(10) and (4.95 +/- 0.21) x 10(8); diethylnitrosamine, (1.61 +/- 0.06) x 10(10) and (6.99 +/- 0.28) x 10(8); dimethylnitramine, (1.91 +/- 0.07) x 10(10) and (5.44 +/- 0.20) x 10(8); methylethylnitramine, (1.83 +/- 0.15) x 10(10) and (7.60 +/- 0.43) x 10(8); and diethylnitramine, (1.76 +/- 0.07) x 10(10) and (8.67 +/- 0.48) x 10(8), respectively. MNP/DMPO spin-trapping experiments demonstrated that hydroxyl radical reaction with these compounds occurs by hydrogen atom abstraction from an alkyl group, while the reaction of the hydrated electron was to form a transient radical anion. The latter adduct formation implies that the excess electron could subsequently be transferred to regenerate the parent chemical, which would significantly reduce the effectiveness of any free-radical-based remediation effort on nitrosamine/nitramine-contaminated waters.
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