Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development.

Since June 2018, thousands of drug products from around the world had to be recalled due to the unexpected presence of nitrosamines (NAs). Starting with the pharmaceutical group of sartans, antidiabetic drugs, antihistamines, and antibiotics also became the subject of investigation. The occurrence of NAs has shown that pharmaceutical companies and regulatory agencies did not focus on these substances in the past during drug development. In this study, we incorporated a nitrosation assay procedure into high-resolution supercritical fluid chromatography (SFC)-mass spectrometry screening to test the potential of direct nitrosation of active pharmaceutical ingredients (APIs). The forced degradation study was performed with a four-fold molar excess of sodium nitrite, relative to the drug substance, at pH 3-4 for 4 h at 37°C. Chromatographic separation was performed on a porous graphitic carbon column by SFC. The mass analysis then focused on direct N-nitrosation or N-nitroso compounds (NOCs) formed after dealkylation. Substances (n = 67) from various pharmaceutical classes were evaluated and 49.3% of them formed NOCs, of which 21.2% have not yet been reported in the literature. In addition, for two APIs, which are known to form an unidentified NOC, the structure could be identified. A few substances also showed multiple NOCs and even N,N'-dinitroso-species. As NAs are carcinogens, they have to be eliminated or at least limited to prevent cancer in patients, who rely on these drugs. This study contributes a procedure that can be implemented in preapproval drug development and postapproval risk assessment to prevent unexpected findings in the future.

Analysis of human serum and urine for tentative identification of potentially carcinogenic pesticide-associated N-nitroso compounds using high-resolution mass spectrometry.

Human serum and urine samples were analyzed for a suite of nitrosatable pesticides and potentially carcinogenic pesticide-associated N-nitroso (PANN) compounds. Formation of PANN compounds may occur in vivo after consumption of food or water containing trace amounts of nitrosatable pesticide residues and nitrate. Using a modified version of the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method, nine nitrosatable pesticides and byproducts were extracted from serum and urine from 64 individuals from two different sample populations in Atlantic Canada: (i) Prince Edward Island, a region where nitrate and trace amounts of nitrosatable pesticides have been detected in groundwater; and (ii) Halifax, Nova Scotia, a non-agricultural urban area. Samples were then analyzed using ultra-high pressure liquid chromatography (UHPLC) coupled with high-resolution accurate mass (HRAM) single-stage orbitrap mass spectrometry (MS), which allows for semi-targeted analysis and tentative identification of a virtually limitless number of exposure biomarkers. Two nitrosatable target analytes, ethylenethiourea (ETU) and 3,5,6-trichloro-2-pyridinol (TCPy) were found in serum, while atrazine (ATR) and ETU were detected in urine. Five and six PANN compounds were tentatively identified in serum and urine, respectively. The two PANN compounds that were most frequently tentatively identified in serum were N-nitroso dimethoate (N-DIM) and N-nitroso omethoate (N-OME) with detection frequencies of 78% and 95%, respectively. This is the first biomonitoring study of its kind to investigate PANN compounds in human serum and urine.

Characterization of Nitrite-Related Reaction Products in Beer.

The effect of nitrites in foods and beverages still raises discussion due to the possible formation of harmful nitroso compounds. However, as most of these compounds in beer were not structurally characterized yet, the research about their toxicological relevance for consumers is limited. This study is focused on identification of the products formed by nitrite (or isotopically labeled nitrite 15N) reactions in beer using gas chromatography with tandem mass spectrometry. In total, 19 products were identified, and some of them were structurally characterized and confirmed by comparing retention indices and mass spectra of standard/synthesized compounds. Identified compounds were representatives of nitroso, nitro, oxime, and even cyano compounds. For the peaks which were not structurally identified, primary structural characteristics were also listed. Found products were further screened in 16 authentic beer samples which showed the apparent occurrence of found compounds in non-treated beers.

Determination of the N-Nitroso Compounds in Mouse Following RDX Exposure.

Hexahydro-1,3,5-trinitro-1,3,5-triazine, commonly called RDX, is an important explosive, which is widely used in military and civic activities. As it is used, RDX is widely found in many locations and caused soil and water contamination. Many studies show that RDX is toxic to many organisms, including plants, animals, and microbes. RDX causes genetic toxicity and neurotoxicity as well as potential carcinogenesis. Even it is worse that RDX can be biotransformed into other N-nitroso derivatives, such as MNX, DNX, and TNX; these derivatives can be found in both naturally in RDX-contaminated soil and also in the animal GI tracks. To study the potential effect of RDX and its N-nitroso derivatives, this chapter presents a step-by-step method for detect RDX and its N-nitroso derivatives in animal stomach and GI tracts followed RDX exposure by gas chromatography with electron capture detector (GC/ECD). This method can also be used to detect RDX and its N-nitroso derivatives in other tissues and in other animals and plants.

Photolysis of 5-Azido-3-Phenylisoxazole at Cryogenic Temperature: Formation and Direct Detection of a Nitrosoalkene.

To enhance the versatility of organic azides in organic synthesis, a better understanding of their photochemistry is required. Herein, the photoreactivity of azidoisoxazole 1 was characterized in cryogenic matrices with IR and UV-Vis absorption spectroscopy. The irradiation (λ = 254 nm) of azidoisoxazole 1 in an argon matrix at 13 K and in glassy 2-methyltetrahydrofuran (mTHF) at 77 K yielded nitrosoalkene 3. Density functional theory (DFT) and complete active space self-consistent field (CASSCF) calculations were used to aid the characterization of nitrosoalkene 3 and to support the proposed mechanism for its formation. It is likely that nitrosoalkene 3 is formed from the singlet excited state of azidoisoxazole 1 via a concerted mechanism or from cleavage of an intermediate singlet nitrene that does not undergo efficient intersystem crossing to its triplet configuration.

Inulin-fortification of a processed meat product attenuates formation of nitroso compounds in the gut of healthy rats.

Intake of red and processed meat has been suspected to increase colorectal cancer risk potentially via endogenous formation of carcinogenic N-nitroso compounds or increased lipid and protein oxidation. Here we investigated the effect of inulin fortification of a pork sausage on these parameters. For four weeks, healthy Sprague-Dawley rats (n = 30) were fed one of three diets: inulin-fortified pork sausage, control pork sausage or a standard chow diet. Fecal content of apparent total N-nitroso compounds (ATNC), nitrosothiols and nitrosyl iron compounds (FeNO) were analyzed in addition to liver metabolism and oxidation products formed in liver, plasma and diets. Intriguingly, inulin fortification reduced fecal ATNC (p = 0.03) and FeNO (p = 0.04) concentrations. The study revealed that inulin fortification of processed meat could be a strategy to reduce nitroso compounds formed endogenously after consumption.

Interactions of preservatives in meat processing: Formation of carcinogenic compounds, analytical methods, and inhibitory agents.

Meat products are important for balanced diets because of their nutritional richness. However, noxious compounds may be formed by interactions among reactants and specific conditions in processed meats. N-nitroso compounds, heterocyclic aromatic amines, polycyclic aromatic hydrocarbons, 1,4-dinitro-2-methyl pyrrole (DNMP), and ethyl nitrolic acid (ENA) are among the main compounds of toxicological concern. This review corroborates the International Agency for Research on Cancer (IARC)'s decision to classify those foodstuffs as carcinogenic to humans. Furthermore, this paper also aimed at clarifying how noxious compounds are formed in meat products, as well as their health effects for consumers. The preservatives abuse and the use of forbidden additives may increase the formation of carcinogens. Risks are not only due to preservatives, since some compounds are formed during processing or digestion, without clear link to any additive. Regulation should set specific residue limits for other noxious compounds in meat products, such as DNMP and ENA. The scope of control programs should be extended instead of assessing the proper use of additives only. Thus, reliable analytical methods for the quantitation of carcinogens should be available. Fermentative and enzymatic processes for bioconversion are among the main strategies to solve these problems in foodstuffs. The use of antioxidants is the most common approach, because of its low cost and effectiveness. In the future, the IARC classification should rather consider different categories of processing, as well as the chemical and microbiological composition of meat products. Further studies are still required to clarify the increase on cancer risk due to the consumption of meat products and to elucidate the main mechanisms of carcinogenicity. Notwithstanding, such carcinogens cannot be neglected, but continuously investigated, including their health implications in relation to other foods.

Comparison of sample preparation approaches and validation of an extraction method for nitrosatable pesticides and metabolites in human serum and urine analyzed by liquid chromatography - Orbital ion trap mass spectrometry.

In the acidic environment of the stomach, nitrosatable pesticide residues may react with nitrite to form potentially carcinogenic pesticide-associated N-nitroso compounds (PANOCs). The objective of this study was to develop a method for the analysis of 10 nitrosatable pesticides and breakdown products in human serum and urine. Three sample preparation methods were evaluated for extraction of target analytes from the biomatrices. Deproteinization by methanol for 300-µL aliquots of serum with a final extract volume of 225 µL resulted in excessive ion enhancement of some analytes and suppression of others. Three types of solid-phase extraction cartridges were tested for optimal analyte retention from 200-µL aliquots of serum with a final extract volume of 400 µL; this approach resulted in significant analyte loss for some compounds. The Quick, Easy, Cheap, Effective, Rugged, and Safe approach resulted in a suitable method for extraction of the analytes from each biomatrix. Biofluid samples (500 µL) were spiked to 100 µg L-1 with analytical standards and extracted using 500 µL of acetonitrile (ACN) with 4% acetic acid (AcOH) for serum and 0.1% AcOH in ACN for urine. For extraction, 200 mg magnesium sulfate (MgSO4) and 50 mg sodium acetate were added for serum and 200 mg MgSO4 and 50 mg sodium chloride were added for urine. Final extract volumes for both biomatrices using the QuEChERS method was 400 µL after dilution. Samples were analyzed via ultra-high pressure liquid chromatography/high-resolution accurate mass orbital ion trap mass spectrometry. Mean recoveries for target analytes in serum and urine ranged between 74 and 120% (%RSD < 12) and 96 to 116% (%RSD ≤ 10), respectively. These methods may be used in large-scale biomonitoring studies to analyze PANNs and their parent compounds in human serum and urine.

Separation of rotamers of 5-nitrosopyrimidines and estimation of binding constants of their complexes with ß-cyclodextrin by capillary electrophoresis.

For the first time, capillary electrophoresis has been successfully employed for the fast and highly efficient separations of a novel type of stereoisomers - planar rotamers (planamers) of four newly synthesized 5-nitrosopyrimidine derivatives. These derivatives can form two rotamers differing in the orientation of nitroso group due to strong intramolecular hydrogen bonds. Partial separation of rotamers of two 5-nitrosopyrimidines was achieved in alkaline 50 mM sodium tetraborate, pH 9.3, and in acidic 18.5/42 mM Tris/phosphate, pH 2.3, background electrolytes (BGEs) free of stereoselectors. To improve the separation of these rotamers and to attain the baseline or better separation of rotamers of other two 5-nitrosopyrimidines, various BGEs and different cyclodextrins-based stereoselectors were tested. The most effective, i.e. the fastest and baseline or better separations of rotamers of all analyzed 5-nitrosopyrimidines were achieved within a short time, 3.7-9.3 min, in the above alkaline or acidic BGEs using ß-cyclodextrin (ß-CD) or carboxymethyl-ß-CD as stereoselectors. Moreover, since the experiments with ß-CD resulted in good separations of rotamers of all the investigated 5-nitrosopyrimidines, the apparent binding constants of their complexes with this selector were determined from the dependence of their effective mobilities on the ß-CD concentration in the BGEs. The examined complexes were found to be relatively weak, with the apparent binding constants in the range 11.3-153.0 L/mol.

A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s.

N-nitrosamines are a well-established group of environmental carcinogens, which require cytochrome P450 oxidation to exhibit activity. The accepted mechanism of metabolic activation involves formation of α-hydroxynitrosamines that spontaneously decompose to DNA alkylating agents. Accumulation of DNA damage and the resulting mutations can ultimately lead to cancer. New evidence indicates that α-hydroxynitrosamines can be further oxidized to nitrosamides processively by cytochrome P450s. Because nitrosamides are generally more stable than α-hydroxynitrosamines and can also alkylate DNA, nitrosamides may play a role in carcinogenesis. In this report, we describe a general protocol for evaluating nitrosamide production from in vitro cytochrome P450-catalyzed metabolism of nitrosamines. This protocol utilizes a general approach to the synthesis of the relevant nitrosamides and an in vitro cytochrome P450 metabolism assay using liquid chromatography-nanospray ionization-high resolution tandem mass spectrometry for detection. This method detected N'-nitrosonorcotinine as a minor metabolite of N'-nitrosonornicotine in the example study. The method has high sensitivity and selectively due to accurate mass detection. Application of this method to a wide variety of nitrosamine-cytochrome P450 systems will help determine the generality of this transformation. Because cytochrome P450s are polymorphic and vary in activity, a better understanding of nitrosamide formation could aid in individual cancer risk assessment.

The relationship of red meat with cancer: Effects of thermal processing and related physiological mechanisms.

Red meat is consumed globally and plays an important role in the Western diet. Its consumption is however linked with various types of diseases. This review focuses on the relationship of red meat with cancer, its dependency on the thermal processing methodology and the subsequent physiological effects. The epidemiological evidence is discussed, followed by introduction of the species that were hypothesized to contribute to these carcinogenic effects including polycyclic aromatic hydrocarbons (PAHs), heterocyclic amines (HCAs), N-nitroso compounds (NOCs), heme iron, and macromolecular oxidation products. Their carcinogenic mechanisms were then addressed with further emphasis on the involvement of inflammation and oxidative stress. The thermal processing dependency of the carcinogen generation and the partially elucidated carcinogenic mechanism both represent doorways of opportunities available for the scientific manipulation of their impact after human consumption, to minimize the cancer risks associated with red meat.

Evidencia de la asociación entre cáncer colorrectal y la ingesta de carnes procesadas / Evidence of the association between colorectal cancer and intake of processed meats

Contexto: En 2012 el cáncer colorrectal (CCR) fue el más frecuente tanto en hombres como para mujeres, ocupando el segundo lugar para las mujeres y el tercero para los hombres. Varios mecanismos han sido propuestos para establecer asociaciones entre el consumo de carne roja y procesada y el riesgo de desarrollar CCR. Objetivo: Resumir y evaluar la evidencia disponible sobre la asociación entre el consumo de carne roja y procesada, con el riesgo de desarrollar CCR. Método: Se llevó a cabo una revisión sistemática, realizando una búsqueda en las bases de datos de Pubmed y Scopus, e identificando los artículos relevantes desde 2010 hasta 2015. Resultados: Se incluyeron 19 artículos que respondieron a nuestro objetivo, de los cuales, sólo 8 de mostraron haber encontrado una asociación positiva entre el consumo de carne roja y procesada con el CCR, pero cada uno lo relacionó con un sitio anatómico diferente. Los métodos de cocción y el grado y tiempo de cocinado, concluyeron con resultados contrapuestos, no pudiendo establecerse ninguna asociación clara, solo hubo asociación positiva para la conservación de la carne en escabeche y una asociación negativa para el cocinado al horno. La asociación para los compuestos mutágenos, aminas heterocíclicas (AHCs) y sus biomarcadores, hidrocarburos aromáticos policíclicos (HAPs) y los compuestos N-nitrosos (CONs) sí parecieron contribuir a un mayor riesgo de CCR. Los subtipos de carne roja y procesada fueron clasificados por cada estudio de forma diferente. Factores de confusión como consumo de fibra dietética, frutas y verduras, alcohol, tabaco o patrón de actividad física influyeron en los resultados. Conclusiones: No se dispone de suficiente evidencia científica para apoyar una clara e inequívoca asociación positiva entre el consumo de carne roja y procesada con el riesgo de desarrollar CCR (AU)

Background: In 2012, colorectal cancer (CRC) was the most common in both men and women, ranking second for women and third for men. Several mechanisms have been proposed to establish association between consumption of red and processed meat with the risk of develop CRC. Objective: Summarize and evaluate the available evidence on the association between consumption of red meat and processed meat, with the risk of developing CRC. Methods: A systematic review was performed, by searching in PubMed and Scopus’ databases, and identifying relevant articles from 2010 to 2015. Conclusions: 19 items that responded to our goal, were included. Only 8 of them showed to have found a positive association between the consumption of red and processed meat and CCR, but each associated were with a different anatomic site. Cooking methods, doneness level and cooking time, ended with mixed results, clear association can’ t be established, there were only positive association for the conservation of pickled meat and a negative association for cooking in the oven. The association for mutagenic compounds, heterocyclic amines (HCAs) and biomarkers, polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs) did appear contribute to an increased risk of CRC. Subtypes of red and processed meat were classified by each study differently. Confounding factors such as consumption of dietary fiber, fruits and vegetables, alcohol, smoke or physical activity pattern influenced the results (AU)

Enzymatic Sensor Detects Some Forms of Nitric Oxide Donors Undetectable by Other Methods in Living Tissues.

Studies with the use of highly sensitive enzymatic sensor have shown the presence of various forms of nitrosyl iron complexes, including those undetectable by other methods, in living tissues. All these complexes are long-living compounds and constitute the major part of nitroso compounds in the blood, muscles, liquor, and amniotic fluid.

Analysis of Chlorination, Nitration, and Nitrosylation of Tyrosine and Oxidation of Methionine and Cysteine in Hemoglobin from Type 2 Diabetes Mellitus Patients by Nanoflow Liquid Chromatography Tandem Mass Spectrometry.

The post-translational modification (PTM) of proteins by endogenous reactive chlorine, nitrogen, and oxygen species is implicated in certain pathological conditions, including diabetes mellitus. Evidence showed that the extents of modifications on a number of proteins are elevated in diabetic patients. Measuring modification on hemoglobin has been used to monitor the extent of exposure. This study develops an assay for simultaneous quantification of the extent of chlorination, nitration, and oxidation in human hemoglobin and to examine whether the level of any of these modifications is higher in poorly controlled type 2 diabetic mellitus patients. This mass spectrometry-based assay used the bottom-up proteomic strategy. Due to the low amount of endogenous modification, we first characterized the sites of chlorination at tyrosine in hypochlorous acid-treated hemoglobin by an accurate mass spectrometer. The extents of chlorination, nitration, and oxidation of a total of 12 sites and types of modifications in hemoglobin were measured by nanoflow liquid chromatography-nanospray ionization tandem mass spectrometry under the selected reaction monitoring mode. Relative quantification of these PTMs in hemoglobin extracted from blood samples shows that the extents of chlorination at α-Tyr-24, nitration at α-Tyr-42, and oxidation at the three methionine residues are significantly higher in diabetic patients (n = 19) than in nondiabetic individuals (n = 18). After excluding the factor of smoking, chlorination at α-Tyr-24, nitration at α-Tyr-42, and oxidation at the three methionine residues are significantly higher in the nonsmoking diabetic patients (n = 12) than in normal nonsmoking subjects (n = 11). Multiple regression analysis performed on the combined effect of age, body-mass index (BMI), and HbA1c showed that the diabetes factor HbA1c contributes significantly to the extent of chlorination at α-Tyr-24 in nonsmokers. In addition, age contributes to oxidation at α-Met-32 significantly in all subjects and in nonsmokers. These results suggest the potential of using chlorination at α-Tyr-24-containing peptide to evaluate protein damage in nonsmoking type 2 diabetes mellitus.

The application of targeted mass spectrometry-based strategies to the detection and localization of post-translational modifications.

This review describes some of the more interesting and imaginative ways in which mass spectrometry has been utilized to study a number of important post-translational modifications over the past two decades; from circa 1990 to 2013. A diverse range of modifications is covered, including citrullination, sulfation, hydroxylation and sumoylation. A summary of the biological role of each modification described, along with some brief mechanistic detail, is also included. Emphasis has been placed on strategies specifically aimed at detecting target modifications, as opposed to more serendipitous modification discovery approaches, which rely upon straightforward product ion scanning methods. The authors have intentionally excluded from this review both phosphorylation and glycosylation since these major modifications have been extensively reviewed elsewhere.

S-nitroso-proteome in poplar leaves in response to acute ozone stress.

Protein S-nitrosylation, the covalent binding of nitric oxide (NO) to protein cysteine residues, is one of the main mechanisms of NO signaling in plant and animal cells. Using a combination of the biotin switch assay and label-free LC-MS/MS analysis, we revealed the S-nitroso-proteome of the woody model plant Populus x canescens. Under normal conditions, constitutively S-nitrosylated proteins in poplar leaves and calli comprise all aspects of primary and secondary metabolism. Acute ozone fumigation was applied to elicit ROS-mediated changes of the S-nitroso-proteome. This treatment changed the total nitrite and nitrosothiol contents of poplar leaves and affected the homeostasis of 32 S-nitrosylated proteins. Multivariate data analysis revealed that ozone exposure negatively affected the S-nitrosylation status of leaf proteins: 23 proteins were de-nitrosylated and 9 proteins had increased S-nitrosylation content compared to the control. Phenylalanine ammonia-lyase 2 (log2[ozone/control] = -3.6) and caffeic acid O-methyltransferase (-3.4), key enzymes catalyzing important steps in the phenylpropanoid and subsequent lignin biosynthetic pathways, respectively, were de-nitrosylated upon ozone stress. Measuring the in vivo and in vitro phenylalanine ammonia-lyase activity indicated that the increase of the phenylalanine ammonia-lyase activity in response to acute ozone is partly regulated by de-nitrosylation, which might favor a higher metabolic flux through the phenylpropanoid pathway within minutes after ozone exposure.

O6-carboxymethylguanine DNA adduct formation and lipid peroxidation upon in vitro gastrointestinal digestion of haem-rich meat.

SCOPE: Epidemiological and clinical studies have demonstrated that the consumption of red haem-rich meat may contribute to the risk of colorectal cancer. Two hypotheses have been put forward to explain this causal relationship, i.e. N-nitroso compound (NOC) formation and lipid peroxidation (LPO). METHODS AND RESULTS: In this study, the NOC-derived DNA adduct O(6)-carboxymethylguanine (O(6)-CMG) and the LPO product malondialdehyde (MDA) were measured in individual in vitro gastrointestinal digestions of meat types varying in haem content (beef, pork, chicken). While MDA formation peaked during the in vitro small intestinal digestion, alkylation and concomitant DNA adduct formation was observed in seven (out of 15) individual colonic digestions using separate faecal inocula. From those, two haem-rich meat digestions demonstrated a significantly higher O(6)-CMG formation (p < 0.05). MDA concentrations proved to be positively correlated (p < 0.0004) with haem content of digested meat. The addition of myoglobin, a haem-containing protein, to the digestive simulation showed a dose-response association with O(6)-CMG (p = 0.004) and MDA (p = 0.008) formation. CONCLUSION: The results suggest the haem-iron involvement for both the LPO and NOC pathway during meat digestion. Moreover, results unambiguously demonstrate that DNA adduct formation is very prone to inter-individual variation, suggesting a person-dependent susceptibility to colorectal cancer development following haem-rich meat consumption.

Investigation of spin-trapping artifacts formed by the Forrester-Hepburn mechanism.

Free radical detection with ESR spin trapping relies on the specific addition of the radical to nitrone/nitroso compounds. It also has been proposed that spin traps can react in biological systems to give false-positive results. For nitrone spin traps, the reaction with nucleophiles, first described by Forrester and Hepburn, has been discussed as the most critical source of artifacts. For artifact identification, the ESR preincubation method may be used, which employs isotopically marked spin traps. Here we investigated the influence of fast sulfite-hydroxylamine equilibrium chemistry on the validity of this assay. Using the (faster) aspiration technique, we found that the Forrester-Hepburn mechanism also contributes to DMPO/(•)SO3(-) adduct formation during ferricyanide-mediated sulfite oxidation, but no evidence for artifactual DMPO/(•)SO3(-) formation was found if the more potent horseradish peroxidase was used. This is ESR evidence that the Forrester-Hepburn mechanism can occur under mild conditions, depending on the experimental details. This technique can also be used to test for other artifact mechanisms. We investigated the known ene reaction of DBNBS and tryptophan in more detail. We found that a strong artifact signal is induced by light; however, with atypically long incubations, we found that the artifact is also formed thermally.

Can summary nitrite+nitrate content serve as an indicator of NO synthesis intensity in body tissues?

Studies with the use of a highly specific enzymatic sensor demonstrated that, contrary to the common opinion, normally nitrate is in fact not present in the most important physiological fluids. NO metabolites in the amniotic fluid and semen are mainly presented by NO donor compounds. Therefore, the intensity of NO synthesis can be evaluated by the total content of all its metabolites, but not by the widely used summary nitrite+nitrate content.

Precursors of nitrogenous disinfection by-products in drinking water--a critical review and analysis.

In recent years research into the formation of nitrogenous disinfection by-products (N-DBPs) in drinking water - including N-nitrosodimethylamine (NDMA), the haloacetonitriles (HANs), haloacetamides (HAcAms), cyanogen halides (CNX) and halonitromethanes (HNMs) - has proliferated. This is partly due to their high reported toxicity of N-DBPs. In this review paper information about the formation yields of N-DBPs from model precursors, and about environmental precursor occurrence, has been employed to assess the amount of N-DBP formation that is attributable to known precursors. It was calculated that for HANs and HAcAms, the concentrations of known precursors - mainly free amino acids are insufficient to account for the observed concentrations of these N-DBP groups. However, at least in some waters, a significant proportion of CNX and NDMA formation can be explained by known precursors. Identified N-DBP precursors tend to be of low molecular weight and low electrostatic charge relative to bulk natural organic matter (NOM). This makes them recalcitrant to removal by water treatment processes, notably coagulation, as confirmed by a number of bench-scale studies. However, amino acids have been found to be easier to remove during water treatment than would be suggested by the known molecular properties of the individual free amino acids.