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Review

Nitrites: An Old Poison or a Current Hazard? Epidemiology of Intoxications Covering the Last 100 Years and Evaluation of Analytical Methods

by
Kaja Tusiewicz
1,
Patryk Kuropka
2,
Elżbieta Workiewicz
2,
Olga Wachełko
2,
Paweł Szpot
1 and
Marcin Zawadzki
3,*
1
Department of Forensic Medicine, Wroclaw Medical University, 4 J. Mikulicza-Radeckiego Street, 50345 Wroclaw, Poland
2
Institute of Toxicology Research, 45 Kasztanowa Street, 55093 Borowa, Poland
3
Faculty of Medicine, Wroclaw University of Science and Technology, 27 Wybrzeże Wyspiańskiego Street, 50370 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Toxics 2023, 11(10), 832; https://doi.org/10.3390/toxics11100832
Submission received: 5 September 2023 / Revised: 22 September 2023 / Accepted: 29 September 2023 / Published: 1 October 2023
(This article belongs to the Special Issue New Insights into Forensic Toxicology)
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Abstract

:
In recent times, there has been a concerning and noteworthy rise in the global use of sodium nitrite for suicidal purposes. This is facilitated either through the employment of specialized “suicide kits” or by acquiring sodium nitrite through alternative means. Additionally, another occurrence contributing to nitrite poisoning is the recreational utilization of nitrites in the form of volatile aliphatic esters of nitrous acid, commonly referred to as “poppers”. Based on current available papers and reports on the subject of nitrates, nitrites, and poppers intoxications, an epidemiological analysis and evaluation of analytical methods were performed. A total of 128 papers, documenting a collective count of 492 intoxication cases, were identified. Additionally, in order to complete the epidemiological profile of nitrite poisoning, the authors briefly examined six cases of nitrite intoxication that were under investigation in our laboratory. Furthermore, a review of nitrite poisoning cases over the past 100 years shows that the old poison is still in use and poses a substantial risk to society.

1. Introduction

The World Health Organization reported in 2019 that more than 700,000 people die from suicide every year [1], accounting for about 1% of all causes of death worldwide. A particularly vulnerable group are young people (15–29 years old) for whom suicide is the fourth most common cause of death [1]. Searching for and being inspired by suicide methods described on the Internet, in social media, and on the darknet is a growing and horrifying phenomenon [2,3,4,5]. In recent years, reports of fatal cases of toxic substances use for suicidal purposes have been rising worldwide, with the Internet contributing significantly to the prevalence. Unintentional fatalities after new psychoactive substances ingestion are well known nowadays [6,7,8,9,10], however, an increasing number of cases of suicide attempts using old, well-known drugs and poisons such as barbiturates [11,12,13,14], cyanide [15,16,17], chloroform [18,19], azide [20,21,22,23], and DMSO [24] (which were ordered online) are reported in the literature as well. The use of such substances is facilitated by the fact that such toxic substances can be easily purchased on websites such as eBay® (https://www.ebay.com/, accessed on 2 August 2023) and Amazon® (https://www.amazon.com/,accessed on 2 August 2023) [24,25,26].
Most recently, a new alarming trend and a significant increase in the use of sodium nitrite for suicide purposes has been observed around the world [27,28,29,30]. Cases of fatal poisonings have already been reported in countries such as the United States [27,31,32,33], Canada [24], South Korea [34,35,36], Japan [37] Australia [38,39], Portugal [30], Spain [40], Poland [41], France [42], and Italy [43,44]. There are websites providing step-by-step instructions on how to commit suicide using sodium nitrite at home, further encouraging and describing this method as ideal due to its simplicity, quickness, and painlessness [45,46]. The origins of promoting the use of sodium nitrite as a method for suicide can be traced back to The Peaceful Pill Handbook, which recommends this method as simple, effective, peaceful, and painless [47]. Suicides occur with the use of “suicide kits” or with sodium nitrite purchased in other ways. So-called “suicide kits” sold on the Internet contain the appropriate amount of substance, as well as all the utensils necessary to commit suicide including instructions of how to use them [46,48]. There are also recommendations to take antiemetic and antacid drugs simultaneously with sodium nitrite ingestion to prevent vomiting, facilitate swallowing, and increase the absorption of sodium nitrite [24,49]. The most frequently detected drug in nitrite poisoning cases is metoclopramide [38,44,46,48], but also other agents such as ranitidine [38,46], ondansetron, olanzapine [30], famotidine, and cimetidine [31] have been reported. Besides nitrite poisonings, intoxication with nitrates is also possible with similar effects.
Between 2020 and 2022, six fatal cases with suspected nitrate poisoning were sent to our laboratory for toxicological analysis. Among these cases, four involved males and two involved females. Their ages ranged from 22 to 29 years old. In four cases, packaging labeled “sodium nitrite” or bottles containing a liquid with a later confirmed presence of sodium nitrite were found near the deceased. Methemoglobin levels were measured in all cases and ranged from 27% to 97.5%. All six cases were classified as suicides. The abovementioned unusual frequency of nitrite intoxications (which has been not observed in our laboratory ever before) was the basis of evaluation of this interesting phenomenon and conceptualization that was presented in this paper review.
Nitrates are present naturally in the environment and in food, especially in plants, they are introduced into the environment in the form of fertilizers, and are also used as a food additive in products such as meats and cheeses [50,51]. Sodium nitrate is considerably less toxic than sodium nitrite, however, approximately 5% of ingested nitrate is reduced to nitrite by bacteria present in the saliva and gastrointestinal tract, making it possible to develop methemoglobinemia when large amounts of nitrate are ingested [51,52]. Nitrate poisoning is not very common among adults; however, infants are particularly vulnerable to poisoning and there are known cases where poisoning has occurred as a result of preparing infant formula with contaminated well water or as a result of eating a meal containing nitrate-rich plants [50,51,53].
Another phenomenon that can lead to nitrite poisoning is the recreational use of nitrites in the form of volatile aliphatic esters of nitrous acid known as “poppers” [54]. Alkyl nitrites when inhaled provide a short-lived euphoric effect and also cause the relaxation of smooth muscles [55]. However, poppers as a source of nitrites can cause methemoglobinemia, especially if accidentally ingested instead of being inhaled. Consequently, cases of “poppers” poisoning including fatal ones have been reported [56,57].
Nitrites are methemoglobin-forming compounds meaning that they cause the oxidation of the hemoglobin Fe ion from the 2nd to the 3rd oxidation state. Nitrite is most often administered by inhalation (in the form of alkyl nitrites) or the oral route, after which it is almost completely metabolized to nitrate, which is eliminated in the urine [58,59]. Three processes can be distinguished in the mechanism of poisoning: hypoxia, metabolic acidosis, and intravascular hemolysis. The change in the degree of oxidation state of Fe in hemoglobin increases the strength of its binding to oxygen and hinders the delivery of oxygen to the tissues, leading to hypoxia. In hypoxic tissues, lactic acid is formed causing the development of metabolic acidosis. Intravascular hemolysis occurs as a result of the accumulation of Heinz bodies in the erythrocytes and oxidative damage to their membranes. With methemoglobin levels above 60%, death of the poisoned person is assumed to occur mainly due to hypoxia. In the post-mortem examination, a brown color of the blood, livor mortis, and organs is characteristic in the case of a high concentration of methemoglobin [58]. The graphical representation of the pathomechanism of nitrite intoxication and the clinical picture is depicted in the Figure 1.
The aim of this work is to highlight the problem of the growing trend of the use of sodium nitrite purchased online for suicidal purposes. The authors have conducted an epidemiological study based on papers dating back to 1920 to examine the severity, changes in as well as the causes of nitrate and nitrite poisonings. A review of cases from the last 100 years has been created and, moreover, the evaluation of analytical methods used in nitrates and nitrites detection was additionally performed. What is more, analytical challenges in nitrite poisoning determination were identified. Other published review papers on this topic [28,38,60] analyze nitrite intoxication cases within a time interval of up to 20 years and do not include a detailed discussion of nitrite determination methods, so for these reasons the challenges of this determination are not pointed up. This work also provides a much more extensive meta-analysis of the poisoning problem than is present in other articles.

2. Epidemiology

Based on currently available papers and reports regarding nitrates, nitrites, and poppers intoxications, an epidemiological analysis was conducted with the use of Google Scholar and the PubMed database. The following phrases were included: “nitrate intoxication”, “nitrite intoxication”, “poppers intoxication”, “nitrate poisoning”, “nitrite poisoning”, and “poppers poisoning”. In addition, references from the literature found in search engines were searched for any omitted significant articles. A total of 128 individual papers [24,29,30,31,32,34,35,36,37,39,40,41,42,43,44,45,46,48,49,53,56,57,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166] describing in total 492 cases of intoxication were found. Analyzed cases were divided into groups according to the cause of intoxication, and how the causes of poisoning changed over the years was studied (Figure 2). Moreover, the number of suicidal intoxications (Figure 3), as well as the sex and age of poisoned people (Figure 4) were studied. Another aspect that was taken into consideration was a type of a conducted toxicological analysis in order to recognize intoxication (Figure 5), and also the level of methemoglobin that was determined in fatal and non-fatal intoxications (Figure 6).
Accidental poisoning comprises almost 54% of nitrates and nitrites intoxications. The second most frequent cause of poisoning is suicide—17% of all studied cases. Poppers intake, workplace accidents, as well as environmental cases represent a similar percentage of all intoxications, i.e., 9% for each cause. In 2% of cases, the cause of intoxication was unknown. Three deliberate poisoning cases (attempted homicide) were also noted.
What is worth mentioning is the fact that causes of intoxication have changed significantly over one hundred years (Figure 2). Until 1980 intoxications comprised mainly accidental and environmental ones. One of the most frequent causes of accidental poisoning was a mistaken usage of sodium nitrite to prepare food instead of kitchen salt or sugar. The origin of sodium nitrite was usually twofold: a non-labeled reagent taken from a workplace that was mistaken for kitchen salt, or the careless and inappropriate use of too much sodium nitrite as a saltpeter [61,62,63,64,65,66,67,68,69,70]. These types of intoxications have still been present in recent years, for example, in 2018 three people were poisoned (one of them fatally) after consumption of a homemade sausage. The meal was delivered by a butcher who had used sodium nitrite as a preservative in a 30-fold higher concentration than permissible [71]. People who do not deal with meat treatment professionally can also have access to sodium nitrite, as it is used as a food additive. In 2016 a man used a 20-fold higher concentration of sodium nitrite than allowable while making homemade beef jerky. As a result, he and his daughter were hospitalized due to methemoglobinemia [72]. In 2013 a mass poisoning took place on a ship with one fatal case. As a result of a chef’s mistake, a spoon of sodium nitrite instead of kitchen salt was added to the meal for all people present on the cruise [73]. As an example of nitrate intoxication, a case of a 62-year-old man should be mentioned, who consumed an antifreeze that contained mainly ethylene glycol, but also 0.27% nitrite and 0.08% nitrate added as anticorrosion agents. The poisoning resulted in the development of methemoglobinemia [74]. Other nitrates salts are also harmful, for example, ammonium nitrate can be found in cooling compresses. A case of an intoxication being the result of drinking such formulation in order to cool body temperature was found in literature [75].
Another cause of intoxication still present over the years is environmental poisoning. Those cases involve mainly infants, who, to the age of 4–6 months, are very sensitive to methemoglobinemia developed as a result of nitrates and nitrites exposure [167]. Described cases were a result of a well water contamination [76,77,78] or the consumption of vegetables containing high concentrations of nitrates that can be reduced to nitrites by bacteria during improper storage [79,80,81,82,83,84]. Intoxications can also be atypical and observed in adults. For example, as a result of a consumption of pickled vegetables, a nitrite-induced acute kidney injury was developed [85]. It is worth mentioning that in cases where well water or vegetables are consumed, pesticide (i.e., fungicide, herbicide, or molluscicide) exposure may occur. Again, children under 3 years of age are especially more vulnerable [168,169,170,171].
At the turn of the 1970s and 1980s a new cause of poisoning occurred and can be observed to this day [54,55]. Poppers poisoning was most commonly the result of mistakenly drinking this product instead of the standard inhalation route [87,88,89,90,91,92], however, it is noteworthy that methemoglobinemia as a result of poppers inhalation has also been reported [56,93,94,95], including rare cases of intoxication with a fatal outcome [96,97]. In addition, a report of a combined non-fatal poisoning with a bupropion and alkyl nitrite overdose [98] and a single case of an unusual intravenous abuse [99] have also been reported.
Two published-to-date papers related to the use of nitrite for criminal purposes can also be found in the literature. The first one involved a daughter-in-law intentionally adding sodium nitrite into bamboo soup to poison her parents-in-law [100]. The other case refers to a series of poisonings at the end of the 20th century in Japan, where adding isobutyl nitrite to a canned coffee drink was reported [101].
Several cases among occupational intoxications are due to the industrial use of nitrates and nitrites. Between 2010 and 2012, the inadequate labelling of packaging led to a series of accidents of unintentional ingestion of antifreeze mixtures containing sodium nitrite at the construction sites in Korea [102]. Another incident occurred in 2019 in a chemical plant during methyl nitrite synthesis resulting in four intoxications due to inhalation, among which three were fatal [103].
The most alarming trend in the causes of poisoning in recent years is the greatly increased number of suicide poisonings (Figure 3). The first reported suicide using sodium nitrite purchased intentionally for this purpose occurred in 2010 [104]. Single cases of poisoning were also reported between 2015 and 2017 [105], including non-fatal cases [37,106]. Since 2018, the number of poisonings worldwide has increased significantly every year, most likely due to the recommendation by suicide-themed websites and forums for the use of sodium nitrite as an effective method of suicide [24,27,28,29,30,31,32,38,41,45,46,48,107]. Such poisonings are becoming increasingly common and have a high mortality rate.
In terms of gender, most poisoning cases involve males, and among them the most numerous age group was 26–40 years old (Figure 4). The most numerous age group among females was 16–25 years old, and the most common cause of poisoning among females of this age was suicide. The second significantly exposed group were infants (0–2 years old), which is due to their naturally greater susceptibility to nitrates and nitrites. Children (3–15 years old) are much less vulnerable and were the smallest age group among those poisoned.
More than 72% of poisoning cases ended with a non-fatal outcome, with the most commonly determined methemoglobin (MetHb) levels ranging from 16 to 35% (Figure 5). However, there are cases of non-fatal poisoning with a MetHb level greater than 75%, for example, after an unsuccessful suicide attempt a MetHb level of 92.7% was determined [108]. Such cases of survival were due to the rapid implementation of medical treatment with the use of methylene blue as an antidote. On the other hand, there are also known cases of fatal poisoning, where the measured MetHb level was less than 15%, however, this was associated with comorbidities [71]. In fatal cases, the most commonly measured level of MetHb was in the range of 75–95%, but slightly less frequently the measured level of MetHb was in the much lower range of 16–35%.
Determination of the MetHb level is a standard practice in cases of nitrate and nitrite intoxication, but it has been measured in only less than half of the described cases (Figure 5). In only about 4% of cases, MetHb measurement with the simultaneous determination of nitrate and/or nitrite in biological evidence specimens was used to confirm poisoning, and in less than 20% of cases both the MetHb measurement and determination of nitrate and/or nitrite in non-biological evidence were used to determine intoxication. In more than half of the cases, MetHb values were not measured and nitrate and/or nitrite determinations in biological evidence material (12%) or non-biological evidence (23%) were used to establish poisoning. Up to one in five cases, neither MetHb concentration testing nor nitrate and/or nitrite determination were used at all to determine the cause of poisoning. In more than 30 cases mentioned in the literature the nitrate or nitrite level was measured in gastric content and in some others in the vitreous humor. This shows the necessity to extend the application of methods used for toxic substances analysis to non-routine biological materials [172,173,174,175,176,177]. In summary, nitrates and/or nitrites were determined in biological material in only about 15% of cases, which illustrates and indicates a major analytical problem and the lack of availability of adequate reliable methods in this area. A table compiling information regarding the measured concentrations of nitrates and nitrites, analytical methods, and methemoglobin concentrations that are described in the literature can be found in the Supplementary Material Table S1.

3. Analytical Methods for the Determination of Nitrite and Nitrate in Biological Material

With the increasing and alarming number of suicide poisonings, there is a great demand for available, efficient, and reliable methods for the determination of nitrite in biological material. Due to the rapid conversion of nitrite to nitrate in blood, it is recommended to determine the nitrate anion as well. Many different analytical methods have been developed for the determination of nitrate and nitrite, but only a fraction of them can be used for the determination of these anions in biological material [178,179,180,181] (Figure 7 and Figure 8).
Even fewer analytical methods have been tested and validated for use in the analysis of complex postmortem matrices [106]. Most of the commonly used analytical techniques are unable to directly determine anions in biological material, with the exception of techniques such as ion chromatography and capillary electrophoresis [182,183,184,185]. The vast majority of the analytical techniques commonly used in forensic toxicology such as batch spectrophotometry, gas chromatography, and liquid chromatography require an appropriate derivatization procedure to create organic products that can be detected [186,187,188,189,190,191]. Many of these procedures can be problematic as they require appropriate sample preparation, can be costly and time-consuming, and are prone to a number of interferences mainly from endogenous substances present in the sample, while the analysis requires advanced instrumentation. An important aspect of the determination of nitrate and nitrite is that some of the derivatization reactions are specific only to nitrate or only to nitrite (Figure 9).
As a result, only one of the anions can be determined directly by a given method and the remaining anion must be determined by another method or by transforming it into the anion that can be derivatized. This approach is common and utilizes the fact that both nitrate and nitrite are readily interconvertible into each other by employing an oxidation reaction to convert nitrite to nitrate or a reduction reaction to convert nitrate to nitrite. The approaches used for the analysis of nitrate and nitrite in biological material, including both appropriate sample preparation, derivatization techniques, and analytical methods, are summarized in Figure 7 and Figure 8. In addition, specific methods developed for the analysis of nitrate and/or nitrite in biological material using various approaches are summarized in Figure 10.
Recently, the methods used in the analysis of nitrate and nitrite in biological material in cases of sodium nitrite poisoning are mainly ion chromatography [159] and spectrophotometric analysis based on the Griess method [30,41]. However, the inexpensive and relatively easily accessible Griess method has a lot of drawbacks and limitations. Griess colorimetric assay is one of the oldest and best-recognized methods for the determination of nitrate and nitrite [191] (Figure 10). Over the years, this reaction has been refined and has many alternative versions, and the most common today involves the diazotization reaction of nitrite with sulfanilamide and subsequent coupling with N-(1-naphthyl)ethylenediamine (Figure 9). The resulting azo compound absorbs radiation in the visible range at about 540 nm [191]. The batch spectrophotometric approach is a simple and easily achievable technique, and the required derivatization reagents can be purchased in ready-to-use kits made for these purposes [191,192,193]. However, this technique has relatively low sensitivity, and success in obtaining accurate results depends on appropriate sample purification. Complex biological matrices contain many compounds that can cause turbidity in the sample but also absorption and interference with detection. In particular, hemoglobin in hemolyzed blood intensely absorbs radiation in the 540 nm range [191,194]. In addition, many endogenous compounds can adversely affect the derivatization reaction causing the risk of false negative results [191,193,194]. The Batch Griess assay is one of the fastest, simplest, and cheapest methods for the determination of nitrate and nitrite and is therefore often chosen for the determination of these anions in cases of fatal poisoning [105]. However, this method often gives different results compared to techniques considered to be more reliable and referential (for example, those based on mass spectrometry), so it should be used with caution and more reliable techniques should be used whenever possible [191,195].
A much more promising method is ion chromatography, which does not require the use of problematic reduction and derivatization processes. IC is characterized by the ability to analyze multiple anions simultaneously in both simple and complex matrices and thus it has been frequently used for the analysis of nitrates and nitrites in poisoning cases [159] (Figure 10). Unfortunately, ion chromatography is not well established and available in all forensic toxicology laboratories.
In forensic toxicology, but also in other related subfields such as entomotoxicology or veterinary forensic toxicology, mass spectrometry remains the gold standard and the most widespread analytical technique for the determination of toxic substances [196,197,198,199,200,201,202]. A great advantage of mass spectrometry methods is the possibility to perform quantitative measurements using internal standards in the form of isotopically labeled analogs of the substances of interest. The use of commercially available 15NO3− and 15NO2− salts as internal standards added to biological material simplifies the analytical process and provides reliable results, as these standards undergo identical transformations and processes (extraction, derivatization, reduction, chromatographic separation) during the whole analytical process as naturally occurring nitrates and nitrites [203,204]. These anions cannot be analyzed directly by GC–MS, but there are two main derivatization techniques that provide thermally stable and volatile products that can be analyzed with this method: nitration and alkylation with pentafluorobenzyl bromide (PFB-Br).
The principle of the nitration method is the nitrate-specific reaction of an aromatic compound with a nitrate anion under acidic conditions [203]. A major drawback of the nitration method is the use of concentrated sulfuric acid as a catalyst for the reaction. There are studies indicating that the use of sulfuric acid causes a positive interference in the determination of nitrate, due to the decomposition and release of nitrate from endogenous compounds present in the plasma, such as various nitroso compounds [203]. Moreover, working with concentrated sulfuric acid itself requires care and caution due to the release of large amounts of heat during its addition to the aqueous phase. The high levels of chlorides found endogenously in the sample make it impossible to perform derivatization, thus they must be removed by chemical precipitation or through special cartridges before adding sulfuric acid. Similarly, the presence of proteins makes derivatization difficult, hence the need to precipitate them or remove them with ultrafiltration [203,205].
The basis of the second derivatization method is the alkylation reaction with the derivatizing reagent pentafluorobenzyl bromide (PFB-Br) (Figure 8). This reagent reacts with both nitrate and nitrite to form the nitric acid ester PFB-ONO2 and the nitro derivative PFB-NO2, respectively. The resulting products are volatile, and the presence of fluorine atoms results in strong electron-capturing properties that enhance the detection and greatly increase the sensitivity of the analysis based on GC–MS [204]. A major advantage of alkylation with PFB-Br is the simultaneous single-step derivatization reaction for both ions, thus not requiring the problematic reduction or oxidation reaction of one anion into the other. The reaction rates for both anions are different and the simultaneous derivatization requires the optimization of conditions including temperature, reaction time, and pH [188,203]. More details regarding other approaches can be found in the Supplementary Material (analysis was extended with other methodological papers [206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221]).

4. Conclusions

The phenomenon of sodium nitrite suicide poisoning is a growing and alarming new trend. An increasing number of countries are reporting more cases of fatal poisonings, and it is possible that many more remain unrecorded. The reason for the prevalence of this method of suicide can be attributed to online sources. The situation is exacerbated by the relative ease of availability of the substance. Thus, the availability of this substance, especially in suicidal quantities, should be limited and controlled. There is a widespread debate about restricting the sale of these type of substances and some websites are recalling products such as sodium nitrite [222]. The UK has listed sodium nitrite as a “notifiable substance”, which means that sellers have to report suspicious purchases to the authorities. However, it is unclear whether such measures will reduce deliberate poisonings [195]. Furthermore, a review of nitrite poisoning cases over the past 100 years shows that the old poison is still in use and poses a significant threat to society.
The postmortem measurement of MetHb concentration appears to be the standard approach in cases of sodium nitrite poisoning. However, determining the cause of poisoning solely on the basis of methemoglobinemia is not recommended, as this condition can also be caused by many other substances, and the determination of MetHb itself can be problematic. In addition, MetHb concentrations reported in fatal poisoning cases occur over a wide range, often not exceeding the minimum 60% reference lethal saturation described in the literature (for more information see Table S1 in the Supplementary Material). Therefore, when determining death from nitrite poisoning, the determination of anions in biological material is recommended, and other factors, such as the description of the scene, the presence of a suicide note, and substances secured at the scene, should also be carefully considered. The determination of nitrite in blood can often be impossible due to its instability in this material. However, it can often be detected in alternative materials such as gastric contents, pericardial fluid, or the vitreous humor where it is not exposed to oxidizing agents, especially red blood cell components. Nevertheless, the negative result of the nitrite presence in these materials cannot exclude sodium nitrite poisoning and an elevated concentration of nitrate in the blood should also be considered as an indicator of poisoning.
There are a number of methods for the determination of nitrite and nitrate, but most of them cannot be or are difficult to use for complex matrices. In addition, although a variety of methods are used in clinical cases, only a small number of methods have been performed and validated for forensically relevant postmortem material. All this makes it necessary to develop techniques that are accessible, relatively inexpensive, and reliable. The cheapest, widely available, and low-cost Griess assay method is often used to determine nitrite in fatal poisonings, but this method is prone to interference, often providing false results. More reliable methods are definitely those using isotopic labeled standards, but these techniques require a complicated sample preparation and derivatization procedure as well as sophisticated instrumentation. Alternatives to these techniques can be ion chromatography and capillary electrophoresis, which do not require a derivatization step. However, these techniques can also have difficulties related to sample preparation, applicability to complex matrices, selectivity, and sensitivity, and are not yet widely used and accessible in forensic toxicology. Future research should focus not only on developing reliable analytical methods capable of determining nitrite in complex biological materials, but also on finding indicators and biomarkers that will enable the unambiguous identification of sodium nitrite poisoning.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/toxics11100832/s1, Figure S1: details regarding other approaches to nitrites and nitrates determination in biological material; Table S1: Measured concentrations of nitrite and/or nitrate in biological material in fatal poisoning cases.

Author Contributions

Writing—original draft preparation, data analysis, visualization, K.T.; Writing—original draft preparation, data analysis, meta-analysis performance, preparation of Supplementary Material, P.K.; data analysis, meta-analysis performance, preparation of Supplementary Material, E.W.; supervision, conceptualization of the article, visualization of epidemiological data, preparation of illustrations O.W.; supervision, writing—review and editing, P.S.; writing—review and editing, resources, M.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest (including financial and personal) that might appear to influence the work reported in this paper.

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Figure 1. Pathomechanism and clinical picture of nitrites intoxication.
Figure 1. Pathomechanism and clinical picture of nitrites intoxication.
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Figure 2. Intoxications divided by the circumstances.
Figure 2. Intoxications divided by the circumstances.
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Figure 3. Number of suicide deaths and attempts in each year (1920–2022).
Figure 3. Number of suicide deaths and attempts in each year (1920–2022).
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Figure 4. Sex of intoxicated victims.
Figure 4. Sex of intoxicated victims.
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Figure 5. Percentage of methemoglobin (MetHb) determined in fatal and non-fatal poisonings.
Figure 5. Percentage of methemoglobin (MetHb) determined in fatal and non-fatal poisonings.
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Figure 6. Toxicological examinations performed in intoxication cases.
Figure 6. Toxicological examinations performed in intoxication cases.
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Figure 7. Preanalytical steps in determination of nitrates and nitrites in biological samples.
Figure 7. Preanalytical steps in determination of nitrates and nitrites in biological samples.
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Figure 8. Summarization of analytical methods and detectors commonly used in nitrate and nitrite determination.
Figure 8. Summarization of analytical methods and detectors commonly used in nitrate and nitrite determination.
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Figure 9. Summarization of derivatization techniques.
Figure 9. Summarization of derivatization techniques.
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Figure 10. Examples of methodological approaches applied in nitrate/nitrite determination (more methods can be found in Supplementary Material Figure S1).
Figure 10. Examples of methodological approaches applied in nitrate/nitrite determination (more methods can be found in Supplementary Material Figure S1).
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MDPI and ACS Style

Tusiewicz, K.; Kuropka, P.; Workiewicz, E.; Wachełko, O.; Szpot, P.; Zawadzki, M. Nitrites: An Old Poison or a Current Hazard? Epidemiology of Intoxications Covering the Last 100 Years and Evaluation of Analytical Methods. Toxics 2023, 11, 832. https://doi.org/10.3390/toxics11100832

AMA Style

Tusiewicz K, Kuropka P, Workiewicz E, Wachełko O, Szpot P, Zawadzki M. Nitrites: An Old Poison or a Current Hazard? Epidemiology of Intoxications Covering the Last 100 Years and Evaluation of Analytical Methods. Toxics. 2023; 11(10):832. https://doi.org/10.3390/toxics11100832

Chicago/Turabian Style

Tusiewicz, Kaja, Patryk Kuropka, Elżbieta Workiewicz, Olga Wachełko, Paweł Szpot, and Marcin Zawadzki. 2023. "Nitrites: An Old Poison or a Current Hazard? Epidemiology of Intoxications Covering the Last 100 Years and Evaluation of Analytical Methods" Toxics 11, no. 10: 832. https://doi.org/10.3390/toxics11100832

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