Anal Bioanal Chem (2013) 405:7615–7642 DOI 10.1007/s00216-013-7077-9

REVIEW

Analytical methods for the determination of halogens in bioanalytical sciences: a review Paola A. Mello & Juliano S. Barin & Fabio A. Duarte & Cezar A. Bizzi & Liange O. Diehl & Edson I. Muller & Erico M. M. Flores

Received: 26 January 2013 / Revised: 15 May 2013 / Accepted: 17 May 2013 / Published online: 19 June 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Fluorine, chlorine, bromine, and iodine have been studied in biological samples and other related matrices owing to the need to understand the biochemical effects in living organisms. In this review, the works published in last 20 years are covered, and the main topics related to sample preparation methods and analytical techniques commonly used for fluorine, chlorine, bromine, and iodine determination in biological samples, food, drugs, and plants used as food or with medical applications are discussed. The commonest sample preparation methods, as extraction and decomposition using combustion and pyrohydrolysis, are reviewed, as well as spectrometric and electroanalytical techniques, spectrophotometry, total reflection X-ray fluorescence, neutron activation analysis, and separation systems using chromatography and electrophoresis. On this aspect, the main analytical challenges and drawbacks are highlighted. A discussion related to the availability of certified reference materials for evaluation of accuracy is also included, as well as a discussion of the official methods used as references for the determination of halogens in the samples covered in this review.

Published in the topical collection (Bio) Analytical Research in Latin America with guest editors Marco A. Zezzi Arruda and Lauro Kubota.

P. A. Mello : F. A. Duarte : C. A. Bizzi : L. O. Diehl : E. I. Muller : E. M. M. Flores (*) Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS 97105-900, Brazil e-mail: [email protected] J. S. Barin Departamento de Tecnologia e Ciência de Alimentos, Universidade Federal de Santa Maria, Santa Maria, RS 97105-900, Brazil

Keywords Bioanalytical sciences . Sample preparation methods . Determination of halogens . Spectrometric techniques . Chromatographic techniques . Inductively coupled plasma mass spectrometry Abbreviations AAS Atomic absorption spectrometry CE Capillary electrophoresis CRM Certified reference material CS-AAS Continuum source atomic absorption spectrometry CS-MAS Continuum source molecular absorption spectrometry CZE Capillary zone electrophoresis GC Gas chromatography HR-ICPHigh-resolution inductively coupled MS plasma mass spectrometry IC Ion chromatography ICP Inductively coupled plasma INAA Instrumental neutron activation analysis ISE Ion-selective electrode LC Liquid chromatography LOD Limit of detection MAS Molecular absorption spectrometry MIC Microwave-induced combustion MS Mass spectrometry MS/MS Tandem mass spectrometry NAA Neutron activation analysis OES Optical emission spectrometry TMAH Tetramethylammonium hydroxide TXRF Total reflection X-ray fluorescence UV Ultraviolet UV–vis Ultraviolet–visible

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Introduction Bioanalytical sciences have emerged as an important field bringing closer important areas such as medicine, nutrition, pharmacy, chemistry, and biology [1]. The term “bioanalysis” has been increasingly used in the literature and at scientific meetings in recent years mainly owing to recent studies of interactions occurring in biological systems. In this way, bioanalysis has been referred by some authors as the qualitative or quantitative analysis of drugs, metabolites, and biomarkers in biological matrices, such as tissues, plasma, serum, whole blood, urine, and saliva [2]. Despite these matrices being an important tool to provide information about the level of elements and their compounds in organisms, they are complex systems comprising numerous components, such as salts, acids, proteins, cells, and organic molecules (e.g., lipids and lipoproteins) [3]. This complexity makes the development of methods suitable for analysis of these matrices a challenging task [2, 4]. In contrast to the identified role of some metals and metalloids in biological systems [5], halogen toxicity and essentiality have been relatively less explored. Dietary reference intakes and also recommended dietary allowances and adequate intakes are normally expressed in micrograms per day, milligrams per day, and grams per day for iodine, fluorine, and chlorine, respectively [6]. For iodine, its effects and its distribution in human tissues, food, and the environment are relatively well known in comparison with other halogens [4, 7, 8]. Deficiency of iodine is related to several adverse effects known as iodine deficiency disorders [9], and because the most important source of this element is dietary uptake, iodine is added to cooking salts to ensure suitable levels (from 90 to 200 μg per day, depending on the organism) [10]. On the other hand, excessive intake can result in the risk of adverse health consequences (iodine-induced hyperthyroidism, autoimmune thyroid diseases) [9, 10]. The effects and roles in living organisms of fluorine, a reactive element easily converted to fluoride, have been discussed [11, 12]. To maintain the minimum level of this element (from 0.01 to 3 mg per day, depending on the organism), fluoridation of public water for prevention of dental caries and the addition of fluoride to dentifrices have been applied on a large scale. However, studies have shown that in acidic conditions, such as those in the stomach, fluoride is converted to HF. The permeability coefficient of HF is similar to that of water in lipid bilayers. Once absorbed, fluoride is easily distributed and can be accumulated, particularly in calcium-rich areas, such as bones and teeth, and thus overexposure can lead to fluorosis [11, 12]. Chlorine, and to a lesser extent bromine, has also been studied in biological systems because of beneficial or toxic effects. Chlorine is usually present at high levels in most samples, especially in food, as sodium chloride, thus affecting blood pressure. In water, salt concentrations higher than about 250 mg L-1 can even change the taste [13]. Bromine is added to

P.A. Mello et al.

disinfection byproducts (in the same way as chlorine) and to many polymers as flame retardants, which are associated with endocrine disruption [14]. The biological effects of halogens, in their anionic form (as fluoride, bromide, chloride, and iodide) can be less dangerous in comparison with those of organic halogenated compounds [7, 15, 16]. Nevertheless, halogen-containing organic compounds have been largely used in many industrial applications, resulting in great public concern because many of them are toxic, persistent, and subject to bioaccumulation in food chains [7, 15, 17]. On the other hand, the essential nature of some halogens, such as iodine, justifies most of the research performed on these elements in biological systems [18]. In some cases, to increase the metabolic stability and lipophilicity, halogenation of pharmacologically active compounds has been commonly performed. However, this approach can sometimes result in molecules that have undesirable effects or even toxicity [16]. Some of the reported effects for halogens as ions or halogenated organic contaminants and their main properties are presented in Table 1. These effects result in the necessity to control the levels of these elements in organisms, food, and environment, making the development of analytical methods more relevant for this purpose. The occurrence of elements as free ions or coordinating complexes in biological systems is an important aspect to be considered [5]. It makes difficult the development of analytical methods for the identification and determination of halogens in biological systems owing to the different reactivity that can be expected for each compound with a given reagent or even with a specific detection technique. One drawback is related to the volatility of HF, HCl, HBr, and HI that makes unfeasible the use of acidic mixtures for sample preparation, as conventionally performed in wet digestion for further determination of metals [19]. Contamination can be a common problem, particularly for chlorine owing to its ubiquitous presence in biological samples, usually at high content, contributing to cross-contamination [7, 15]. Another drawback lies in the choice of a suitable detection technique. Some halogens are typically difficult to determine even by some well-established techniques, such as inductively coupled plasma (ICP) mass spectrometry (MS) and ICP optical emission spectrometry (OES). Particularly for fluorine, which is not ionized by argon plasmas (the most used plasma source), the relatively high ionization energy (Table 1) partially explains the low number of applications using plasma-based techniques that have been published. Another aspect to consider, in particular for chlorine, is the low mass/charge ratio and the possibility to form isobaric and polyatomic interferences in ICP-MS. However, with use of a collision and/or reaction cell, some interferences can be reduced. With regard to the use of ICPOES, useful emission lines for chlorine, bromine, and iodine lie in the vacuum ultraviolet (UV) region (Table 1), and these are prone to interference from the atmosphere, depending on the spectrometer optical setup [18, 20, 21]. On the other hand,

Analytical methods for the determination of halogens

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Table 1 Selected parameters for fluorine, chlorine, bromine, and iodine and some biological effects for halogen-containing compounds Halogen Mass Isotopic First ionization Emission Reported effects number abundance potential (eV) wavelength (%) (nm) Fluorine 19

Chlorine 35 37

Bromine 79 81

Iodine

127

100

75.76 24.24

50.69 49.31

100

17.42

12.97

11.81

10.45

–

134.72

154.07

178.27 183.04

Fluoride: low doses are not enough to prevent dental caries, whereas high doses can lead to a transient decrease in the ability of the kidney to concentrate urine or can induce an efflux of potassium from red blood cells; on the other hand, a high dose is used in osteoporosis treatment Polyfluorinated compounds: influence in hormone feedback systems, hepatic diseases, and hepatocarcinogenesis as well as carcinogenicity (animal studies) Fluoroquinolones (antimicrobials): emergence of fluoroquinoloneresistant bacterial strains in animals Chloride: toxicity of chloride salts usually is related to the cations that are present; concentrations of about 250 mg L−1 can give rise to detectable taste in water Chlorine and chlorine-containing volatile compounds: injury in lung tissue ranging from mucus membrane irritation to pulmonary edema Chlorine-containing pesticides: associated with adverse birth outcome and deficits in neurodevelopment Polychlorinated biphenyls: health effects include immunotoxicity, developmental and neurodevelopmental effects, and effects on thyroid and steroid hormones and reproductive function, as well as carcinogenicity Organochlorine disinfection by-products: accumulation in fat tissues (animal studies) Bromide: it can replace iodine in both triiodothyronine and thyroxine with no loss of thyroid hormone activity; bromide salts can reverse the malaise and growth depressions caused by high doses of iodine (as KI) added as supplements to the diet Organobromine disinfection by-products: can accumulate in fat tissues Brominated propanes: cause DNA damage and necrogenic effects; affect reproductive and hematopoietic toxicity Brominated flame retardants: the most used compounds are polybrominated diphenyl ethers, which are considered endocrine disruptors Iodide: essential for the synthesis of thyroid triiodothyronine and thyroxine, necessary for the control of cellular metabolism, growth, development of body structures, neuronal function, and development Iodine and iodate: reduced to iodide in the gut and then completely absorbed Organoiodine disinfection by-products: accumulation in fat tissues

emission lines in the near-infrared region, for example, atomic lines of fluorine (733.196 nm), chlorine (912.115 nm), and bromine (889.762 nm), can be used especially when helium ICP or helium microwave-induced plasma is used as the excitation source [22, 23]. Procedures for the determination of halogens are commonly based on sample preparation methods followed by a detection technique or a coupled technique (normally a separation system coupled with a suitable detector). Available methods involve the use of classical sample preparation methods followed by electroanalytical or spectrometric techniques or chromatographic procedures and/or more sophisticated instrumental techniques, for example, liquid chromatography (LC)–tandem MS (MS/MS) and double focusing sector field high-resolution ICP-MS (HR-ICP-MS).

References

[11, 24]

[25, 26]

[26, 27] [24]

[13] [28] [29]

[30] [24]

[30] [31] [14]

[9]

[9] [30]

In the present review, the main methods which have been used in the last 20 years for the determination of total halogens or their inorganic forms (halides or ClO3-, BrO3-, and IO3-) in samples of bioanalytical concern are discussed. The commonest sample preparation methods, as extraction and decomposition using combustion and pyrohydrolysis, are discussed as well as spectrometric and electroanalytical techniques, spectrophotometry, total reflection X-ray fluorescence (TXRF), neutron activation analysis (NAA), and separation methods, using chromatography and electrophoresis. A discussion related to the availability of certified reference materials (CRMs) and official methods is also included. With regard to the matrices which are considered relevant to bioanalytical sciences, the following samples are covered: biological tissues or fluids (plasma, serum, blood,

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urine, and saliva), microorganisms, plants (only those used for medicinal purposes or as food), foods/beverages, and pharmaceutical products. Additionally, details for some key applications are shown in Table 2.

Sample preparation methods for subsequent determination of halogens Extraction Determination of halogens has been performed in biological samples using different techniques, such as NAA [100], TXRF [101, 102], ICP-OES [21], ICP-MS [103], and ion chromatography (IC) [104, 105]. In general, direct application of these techniques has been rarely performed, and a sample preparation step is normally required to bring analytes into solution. Considering the complexity of many matrices, the determination of halogens in biological samples, drugs, food, etc., involves several difficulties. Appropriate sample preparation procedures are based on different parameters such as efficient recovery, selectivity, throughput, cost, and suitability for routine analysis. Moreover, the reagents used for sample preparation should not interfere in the determination step and halogens must be converted to a nonvolatile chemical form [56, 90]. When compared with other sample preparation methods, extraction has advantages for some matrices because it is a simple and efficient method that has been used for many applications for further determination of halogens. Procedures based on extraction have been developed using alkaline solutions [90, 92, 95, 96], water [106], organic solvents [107], and acids [108]. Additionally, it is also possible to perform solidphase extraction [109] or protein precipitation followed by filtration or centrifugation [106] prior to the determination of halogens. Among the extraction procedures for further determination of halogens, the most conventional way is based on the use of alkaline solutions as an extractor. For example, ammonia, sodium hydroxide, tetramethylammonium hydroxide (TMAH), and water-soluble tertiary amine solution (CFA-C) are normally used for sample dilution or dispersion in alkaline medium [55–57, 70, 110]. Some applications involving acid digestion procedures for further determination of halogens can be found in the literature [21, 108]. As observed for most works, sample preparation methods based on extraction can be considered simple and have been routinely used for further determination of halogens. Additionally, extraction normally involves mild temperature conditions (e.g., 90 °C), and the resultant solution is generally suitable for analysis by ICP-MS and ICP-OES. However, sometimes a complete extraction of halogens cannot be achieved [1–5].

P.A. Mello et al.

Sample decomposition Among the most useful decomposition methods for the determination of halogens in biological samples, combustion [32, 58, 110, 111] and pyrohydrolysis [34, 84] methods have received special attention. These methods allow higher efficiency of decomposition or release of halogens, and the risk of analyte losses and contamination is reduced by the use of closed systems in the case of combustion methods. Moreover, digests are compatible with the detection techniques typically used for the determination of halogens, for example, ion-selective electrode (ISE), IC, ICP-OES, and ICP-MS [59, 91, 110]. In general, the conventional decomposition of organic matrices requires the use of concentrated acids. However, their use can result in the formation of volatile acids that can be lost, can also increase blanks, and can cause interferences in some analytical techniques where high acid concentrations might affect the analytical signal [112, 113]. Regarding the combustion methods used for further determination of halogens, the Wickbold apparatus [32], combustion bombs [114], the Trace-O-Mat system [55, 110], the Schöniger flask [56, 57], and microwave-induced combustion (MIC) [58, 91, 115] have been used. In addition to these methods, some devices using a tube-shape furnace combustion have been applied to combustion of organic samples [62]. Some manufacturers, such as Analytik Jena (multi X® 2500 and multi EA® 5000) and Antek® (MultiTek), have developed commercial furnace combustion systems for the decomposition and analysis of petroleum products and related matrices, but few applications can be found for digestion of biological samples and further determination of halogens [62, 116]. Combustion bombs have been applied for many organic matrices, including biological and environmental samples and fossil-fuel-related materials [114, 117]. In this system, samples are burned inside a stainless steel bomb with an excess of oxygen. The gaseous products are absorbed in a suitable solution (5–10 mL) in the same vessel used for combustion. Samples are prepared as pellets and positioned in a metallic cup, and a platinum wire is placed in contact with the pellet and connected to two electrodes for subsequent ignition. After closing the vessel, the combustion system is pressurized with oxygen (20–30 atm) and ignition is performed by an electric current through the platinum wire [118]. However, although combustion bombs have suitable advantages over other classical systems, few applications can be found for further determination of halogens in biological samples [114]. The method using the Schöniger flask is based on the combustion in a closed vessel filled with oxygen where released halogens are absorbed in a suitable solution as the respective halides (e.g., fluorine is absorbed as fluoride). Sample mass is the main limitation of this method because 50–100 mg of the sample is completely combusted in a 500-mL flask. If a higher sample mass is required, a high-volume flask or special devices

Sample

Whole blood

p-Fluorobenzoic acid, dexamethasone, and fluoroacetamide Oyster tissue and plants

Pharmaceutical products

Bonemeal, bovine muscle, and oyster tissue

Blood serum

Toothpaste

Tea

Cancer cells

Toothpaste

Human blood

Element

F

F

F

F

F

F

F

F

F

F

F

Extraction with buffer and detachment: after incubation, the drug-containing medium was removed and the cells were treated twice with phosphatebuffered saline, detached with trypsin, resuspended in 10 mL of DMEM, pelleted by centrifugation (2,300 rpm, 3 min, 4 °C), and washed twice with cold phosphate-buffered saline. The lysate was stored at −20 °C before F determination Solubilization: 1.0 g of sample and solubilization to 50 mL of with ultrapure water. The mixture was homogenized in an ultrasonic bath at 50 °C for 30 min. A 5-mL aliquot containing 6,000 mg L−1 Al was diluted to 10 mL with ultrapure water Extraction: one fraction of sample was extracted with methyl tert-butyl ether and, the residue of the first extraction was extracted again with hexane). The residue after hexane extraction contained inorganic F and any nonextractable F forms. Total F was determined using an aliquot of blood placed on a silica boat, which was introduced directly into the CIC system

Wet digestion: 0.5 g of sample and 7 mL of HNO3. Heating program: microwave heating for 40 min and 30 min for cooling. Alkaline extraction: 0.5 g of sample and 1.5 mL of 25 % TMAH solution. Heating program: 75 °C for 40 min and 60 min for cooling

Wet digestion: 20 μL of sample, 500 μL of ether, and 5 μL of HClO4 and manual or ultrasonic shaking for 15 min. Addition of 2 mL of sodium biphenyl and shaking for 10 min. Addition of 0.5 mL of water to destroy sodium biphenyl, with vortexing for 10 min and centrifugation at 2,500 rpm for 2 min. The supernatant was extracted with ether (2 times with 0.5 mL) and 0.45 mL of acid calcium phosphate was added with vortexing and 1 mL of concentrated NH4OH. Before the determination, extracts were heated to 90 °C for 30 min, cooled for 10 min, and centrifuged at 4,000 rpm for 10 min. Sediment was treated with 0.5 mL of water and centrifuged at 4,000 rpm for 10 min. The calcium phosphate sediment with the absorbed fluoride was dissolved in 100 μL of 20 % formic acid solution and 100 μL of Al (as a modifier) and diluted to 1 mL with ultrapure water Solubilization: 0.01–0.02 g of sample and solubilization to 50 mL with ultrapure water. The mixture was homogenized in an ultrasonic bath for 5 min

Sample pellets were directly irradiated in a nuclear reactor

Wickbold system: 0.5 g of sample and water as absorbing solution. Samples were combusted in a O2/H2 flame Schöniger system: 0.02–0.05 g of sample and 4 mL of H2O as absorbing solution in a 500-mL quartz flask. After combustion, the flask was washed with 10 mL of methanol (3 times) Pyrohydrolysis system: 0.005–0.12 g of sample and V2O5 (3 times the sample mass), no absorbing solution. Heating program: 1,050 °C for 10 min, with continuous flow of water vapor and 300 mL of air per minute UV photolysis: 0.01–0.1 g of sample and 1 mL of concentrated HNO3. This mixture was heated by infrared radiation at 90 °C until there was complete dissolution. The resultant solution was diluted to 10 mL with 10 % (v/v) methanol and subjected to UV photolysis at 80–85 °C for 20–30 min. MAD system: 0.1 g of sample and 4 mL of HNO3. Heating program: ramp to 100 °C in 5 min and hold for 15 min. After cooling, 1 mL of H2O2 was added, the temperature was ramped to 180 °C in 5 min and held for 15 min

Sample preparation

Table 2 Selected applications related to analytical methods for determination of halogens in bioanalytical sciences

Recoveries ranged from 93 to 100 %

Potentiometric titration using F ISE

Agreement with certified value was about 101 %. Agreement with expected values for commercial samples ranged from 97 to 111 % Not stated

CS-MAS using a flame (as AlF) at 227.461 nm (LOD was 5,500 μg L−1) LC–MS/MS (LOD was about 3 μg L−1)

Not stated

CS-MAS using a GF (as GaF) at 211.248 nm (LOD was about 22.8 μg L−1)

[42]

[41]

[40]

[39]

[38] Agreement with values indicated in commercial samples ranged from 98 to 106 % Agreement with certified value was 90 and 98 % for wet digestion and alkaline extraction, respectively CS-MAS using a GF (as GaF) at 211.248 nm (LOD was about 0.0052 ng) CS-MAS using a GF (as CaF) at 606.440 nm (LOD was about 160 μg L−1)

[36]

Agreement with certified value was about 106 %

[37]

[35]

Recoveries ranged from 97 to 101 % and 28 to 78 % for UV photolysis and MAD, respectively

[34]

[33]

[32]

Reference

Recoveries ranged from 98 to 100 %

INAA with thermal energy and fast neutron fluence (LODs ranged from 0.3 to 2 μg g−1 using thermal energy) GF-MAS (as AlF) using a Pt lamp (LOD was not reported)

F ISE (LOD was about 0.15 μg g−1)

Agreement with certified values ranged from 87 to 102 %

Recoveries ranged from 98 to 104 %

F ISE (LOD was about 0.24 μg g−1)

F ISE (LOD was about 1.5 μg g−1)

Accuracy

Detection technique

Analytical methods for the determination of halogens 7619

Sample

Wild rat blood

Saliva, urine, and toothpaste

Plant leaves

Milk powder

Bovine muscle and milk powder

Bovine liver and total diet

Honey

Serum

Salt and organic pharmaceutical pill

Cells of lung and cervix cancer

Vegetable food

Foodstuffs

Element

F

F

F

Cl

Cl

Cl

Cl

Cl

Br

Br

Br

Br

Table 2 (continued)

Up to 2 mL of cell solution was dropped on a polished surface of a silicon wafer and dried Alkaline ashing: the sample (5.0 g) was mixed with 1.5 g of sodium and heated gradually until the temperature of a quiet liquid fusion (approximately 850 °C) was reached and the temperature was then maintained for about 20 min. After cooling, the fusion cake was dissolved in water, filtered, and diluted to 50 mL MAD system: samples (0.5–1.0 g) were digested with a mixture of HNO3 and H2O2 (1.25–7.5 mL) and 1 mol L−1 AgNO3 solution (0.005–0.7 mL). After centrifugation of the digests, the precipitate was washed with Elgastat water and then solubilized with ammonia. Finally, the resulting solution was passed through a cation-exchange column

Solubilization: 0.05 g of salt diluted to 50 mL with ultrapure water; 0.3 g of pharmaceutical pill, 1 mL of HNO3 and dilution to 50 mL with ultrapure water

Ashing: 0.15–3 g of sample and 7.0 g of Na2O2. After solubilization in ultrapure water, residues were neutralized with NaOH (from 0.7 to 0.8 mol L−1), followed by electrodialysis for removal of excess NaOH Solubilization: 1.0 g of sample and 10 mL of ultrapure water. The solution was filtered in a membrane (0.45 μm) Dilution: 2 μL of sample was diluted to 150 μL with water

Extraction and CIC: plasma samples were obtained from rats with different doses of PFOA (0, 1, 3, 5, 10, and 15 mg PFOA per kilogram body weight). Further, one fraction of each sample was extracted with methyl tert-butyl ether and the residue from this extraction was extracted with hexane). Samples were burned in a CIC system before chromatographic separation For saliva, a 0.01 mol L−1 BaCl2 solution was added to remove SO42− interference followed by filtration and pH adjustment to 1.5. The same procedure was used for urine samples diluted in water (1:10). Toothpaste (0.2 g) was dissolved in 2.5 mL of 1.0 mol L−1 HNO3 +10 mL of distilled water under heating before addition of 0.01 mol L−1 BaCl2 solution, filtration, and pH adjustment. Distillation: dried samples (0.3–0.5 g) were placed in the distillation bottle with 5 mL of concentrated H2SO4 and 8 mL of 30 % H2O2 solution was added dropwise. The samples were distilled at 175–180 °C for 10 min. The distillation was continued for 5 min after 2 mL of 30 % H2O2 had been added dropwise. Around 25–30 min was needed to process a sample Wet digestion: 0.3 g of sample and 5 mL of concentrated HNO3. The solution was kept at room temperature for 5 h and diluted to 15 mL with ultrapure water Wet digestion: 0.1 g of sample and 1.5 mL of HNO3. The solution was kept at room temperature for 12 h, filtered (0.45 μm), and diluted to 15 mL with ultrapure water. Digestion/precipitation: 0.1 g of sample, 1 mL of 1 mol L−1 AgNO3, 4 mL of HNO3, and 1 mL of H2O2. Heating program: heating in a water bath at 50 °C for 2 h. The solution was centrifuged at 2,500 rpm for 15 min and the precipitate was washed twice with water and dissolved in 2 mL of ammonia solution

Sample preparation

[44]

[45]

Recoveries ranged from 95 to 106 %

Recoveries ranged from 96 to 104 %

Solid-phase spectrophotometry and visual test methods using ZrOCl2 with methylthymol blue immobilized on silica gel (LODs were 100 and 800 μg L−1, respectively) Spectrophotometry using an La(III)– F–alizarin complex

[49] [50]

[51]

Agreement with certified values ranged from 83 to 101 %. Not stated Not stated

Agreement with results found by IC and WDXRF for salt sample ranged from 97 to 103 %. Agreement with expected values for commercial samples was about 103 % Not stated

IC–conductivity cell (LOD was about 50 μg g−1) CZE (LOD was about 20 μg g−1)

Not stated

Not stated

Spectrophotometry using phenol red solution combined with Oxone® (LOD of 250 μg L−1) Cathodic stripping voltammetry, IC, spectrophotometry, and ICP-MS (LOD of 0.2 μg g−1)

Synchrotron radiation TXRF

Spectrophotometry in a microtiter plate using mercuric thiocyanate and ferric nitrate (LOD was about 250 μg L−1) CS-MAS using a GF (as AlBr and CaBr) at 278.914 and 625.315 nm, respectively (LOD was about 2 ng for both molecules)

[47] Agreement with certified values ranged from 25 to 49 % and from 79 to 115 % for wet digestion and digestion/precipitation method, respectively

[54]

[53]

[52]

[48]

[46]

Agreement with certified value was about 98 %

CS-MAS using a flame (as AlCl) at 267.24 nm (LOD was about 3,000 μg L−1) CS-MAS with a GF (as AlCl) at 261.418 nm (LODs were 18 and 9 μg g−1 for wet digestion and digestion/precipitation methods, respectively)

[43]

Not stated

LC–MS/MS (LOD was about 32 μg L−1)

Reference

Accuracy

Detection technique

7620 P.A. Mello et al.

Sample

Baby food, bonemeal, bovine liver, infant formula, mixed diet, non-fat milk powder, oyster tissue, peach leaves, pine needle, tomato leaves, whole egg powder, and whole milk powder

Cod muscle, oyster tissue, egg powder, hay powder, pig kidney, and spiked skim milk powder

Bovine liver, cod muscle, hay powder, human serum, milk powder, and pig kidney

Bovine liver, cornstarch, milk powder, and wheat flour

Skim milk powder and sea lettuce

Milk powder, non-fat milk powder, oyster tissue, rice flour, seaweed, and tomato leaves

Milk

Element

I

I

I

I

I

I

I

Table 2 (continued)

[59]

Agreement with certified values ranged from 98 to 100 %

Agreement with certified values ranged from 94 to 105 %

Recoveries ranged from 93 to 107 %

ICP-OES with vapor generation (LODs were 0.037 and 0.018 μg g−1 for milk and plant, respectively)

IC (LOD was about 0.01 μg g-1)

CVG-ICP-OES (LOD was about 0.07 μg L−1)

MIC system: 0.08 and 0.18 g of sample (milk and plant, respectively) and 6 mL or 10 mL of 0.25 mol L−1 NaOH solution and 0.2 mL of 30 % H2O2 as absorbing solution; 2–3 drops of 6 mol L−1 NH4NO3 as igniter; pressurization with 10 bar of O2. Heating program: 1,400 W for 5 min and 0 W for 20 min (cooling step). MAD system: 0.2–0.25 g of sample and 5 mL of HNO3 and 0.2 mL HClO4. Heating program: ramp to 1,400 W in 10 min and hold for 15 min; 0 W for 20 min (cooling step) Pyrohydrolysis system: 0.5 g of sample and 25 mL of 0.2 mol L−1 NaOH and 1.0 mL of 10 g L−1 Na2SO3 as absorbing solution. Heating program: 100 °C for 2.5 min, 200 °C for 5 min, 540 °C for 5 min, and 820 °C for 5 min, with continuous flow of water vapor and 50 mL min−1 O2. The extract was neutralized with 1 mL of 5 mol L−1 HCl and diluted to 100 mL with ultrapure water Alkaline ashing: 2 mL of sample or 0.2 g of CRM and 2 mL of 2 mol L−1 KOH (in ethanol) and 2 mL of 0.4 mol L−1 Ca(NO3)2 (in ethanol). Ashing program: oven drying for 10 h at 70 °C and for 5 h at 120 °C. The dried mixtures were heated in a muffle furnace (2 h at 240 °C, 1 h at 340 °C, 1 h at 440 °C, and 4 h at 640 °C). The residue was suspended in 25 mL of water. Extraction: 2 mL of sample and 2.5 mL of 10 % TMAH solution. Heating program: 3 h at 90 °C in a drying oven

[61]

[60]

[58] Agreement with certified values ranged from 96 to 103 % and from 95 to 105 % for the MIC system and extraction methods, respectively

Schöniger system: 0.02–0.05 g of sample and 0.5 % of TMAH as absorbing solution in a 500-mL Erlenmayer flask. The flask was filled with oxygen by simply blowing the gas for 30 s. After combustion, the solution was cooled for 1h MIC system: 0.5 g of sample and 6 mL of 50 mmol L−1 (NH4)2CO3 as absorbing solution; 50 μL of 6 mol L−1 NH4NO3 as igniter; pressurization with 15 bar of O2. Heating program: 1,400 W for 5 min and 0 W for 20 min (cooling step). Extraction: (1) MAE: 0.5 g of sample and 6 mL of 0.11 mol L−1 TMAH solution. Heating program: 1,400 W for 50 min (ramp of 10 min) and 0 W for 20 min (cooling step), with temperature set to 90 °C; (2) conventional extraction in a heating block: 0.2 g of sample and 5 mL of 0.11 mol L−1 TMAH solution in 3 h at 90 °C

ICP-MS and IC (LODs were 0.0007 and 3.0 μg g−1, respectively)

[57]

[56]

[55]

Reference

Agreement with certified values ranged from 82 to 100 %

Agreement with certified values ranged from 98 to 102 %, from 92 to 94 %, from 93 to 101 %, and from 94 to 101 % for the MAD, HPA, Schöniger system and extraction methods, respectively

Agreement with certified values ranged from 92 to 97 %, from 94 to 101 %, and from 69 to 100 % for the Trace-O-Mat, Schöniger system, and extraction methods, respectively.

Accuracy

ICP-MS (LOD was about 0.05 μg g−1)

Extraction: 0.2–0.5 g of sample and 1 mL of 25 % TMAH. The mixture was dried in an oven at 90 °C for 3 h

Schöniger system: 0.02–0.05 g of sample and 0.5 % of TMAH as absorbing solution in a 500-mL Erlenmayer flask. The flask was filled with oxygen by simply blowing the gas for 30 s. After combustion, the solution was cooled for 1 h.

MAD system: 0.1 g of sample and 0.3 mL of H2O, 2.1 mL of HNO3, and 0.5 mL of HClO4. Heating program: 60 % microwave power for 5 min and 20 min for cooling down. HPA system: 0.1 g of sample and 0.3 mL of H2O, 2.1 mL of HNO3, and 0.5 mL of HClO4. Heating program: ramp to 120 °C in 20 min; ramp from 120 to 200 °C in 60 min; ramp from 200 to 280 °C in 60 min; hold at 280 °C for 60 min. ICP-MS (LODs were 0.0025, 0.0025, 0.005, and 0.0005 μg g−1 for the MAD, HPA, Schöniger system and extraction methods, respectively)

ICP-MS (LODs were 0.010, 0.038 and 0.0003 μg g−1 for the Trace-OMat, Schöniger system, and extraction methods, respectively).

Trace-O-Mat: 0.2–0.5 g of sample combusted in an oxygen atmosphere. The residue was refluxed for 30 min with 2 mL of 5 % CFA-C solution. Schöniger system: 0.025–0.075 g of sample and 10 mL of 0.05 mol L−1 CFA-C solution. Following the incineration, the flask was cooled at 4 °C for 60 min and shaken vigorously. Extraction: 0.1–0.25 g of sample and 40 mL of CFA-C solution. An ultrasonic bath was used for 30 min and the extract was diluted to 50 mL with CFA-C solution

Detection technique

Sample preparation

Analytical methods for the determination of halogens 7621

Sample

Citrus leaves, non-fat milk powder, and oyster tissue

Infant formula and milk powder

Iodized edible salt

Infant formula, liquid milk, and milk powder

Infant formula

Infant formula

Iodine-based pill and thyroid hormone pill

Dried vegetables, milk powder, pharmaceutical, tablet salt

Element

I

I

I

I

I

I

I

I

Table 2 (continued)

Solubilization: 1 g of sample (pharmaceutical and tablet salt) was diluted to 50 mL with ultrapure water and cleaned up with SPE. The extract was derivatized with 0.2 mL of phosphate buffer, 0.25 mL of N,N-dimethylaniline, and 0.4 mL of 2iodosobenzoate. Digestion: 0.5 g of sample (dried vegetables and milk powder), 3 g KOH and 3 g K2S2O8 were heated gently to boiling. The extract was derivatized with 0.2 mL of phosphate buffer, 0.25 mL of N,N-dimethylaniline, and 0.4 mL of 2iodosobenzoate.

Alkaline ashing: 0.2 g of sample and 1.0 g of Na2CO3, 1 mL of 6 mol L−1 NaOH, and 10 mL of methanol. Heating program: 110 °C for 2 h in an oven drier and at 500 °C for 3 h in a muffle furnace. The ash content was dissolved in 10 mL of hot ultrapure water, filtered, and diluted to 25 mL. A 2-mL aliquot of this solution was mixed with 2 mL of 1 mg L−1 AgNO3 (as Ag). The precipitate (AgI) was filtered and redissolved with 4 mL of 1 mg L−1 NaCN solution Solubilization: 1 pill was diluted with ultrapure water to 30 or 50 mL

Microwave-assisted distillation: 5 mL (liquid samples) or 10 % (m/v) solution (for solid samples) and 100 μL of 1 % (m/v) NaNO2 solution and 100 μL of 0.1 mol L−1 HCl. Heating program: 2 steps of 1 min at 700 W, with collection of volatile iodine in a glassblowing drier containing 6 mL of 0.1 g L−1 H2NOH HCl solution. The final solution was diluted to 10 mL with ultrapure water. 1 mL of resultant solution was mixed with 55 μL of 15 mg L−1 Hg2+ solution and 30 mL of 0.01 % 2,2’-dipyridyl solution. The mixture was diluted to 5 mL with ultrapure water and submitted to extraction (2 times with 3 mL) with methyl isobutyl ketone. The organic extract was washed with 2 mL of water Extraction: formation of an ion pair between 1,10-phenanthroline, Hg2+ and I, which was selectively extracted with methyl isobutyl ketone

Alkaline ashing: 0.25 g of sample and 2 mL of 2 mol L−1 KOH solution (in ethanol) and 2 mL of 0.4 mol L−1Ca(NO3)2 solution (in ethanol). The mixture was dried in a drying oven at 70 °C for 10 h and at 120 °C for 5 h. Dried mixtures were heated in a muffle furnace at 240 °C for 2 h, at 340 °C for 1 h, at 440 °C for 1 h, and at 500 °C for 4 h. The ash content was dissolved with ultrapure water, 1.3 mL of 1 mol L−1 Na2SO3, and 1 mL of 1 mol L−1 HNO3 and diluted to 10 mL with ultrapure water Solubilization: dilution and conversion to molecular iodine with sulfuric acid

CS-MAS using a GF (as BaI) at 538.308 nm (LOD was about 0.6 ng) GC–MS (LODs were 0.025 and 0.01 μg L−1 for SPME and SDME, respectively)

GF-AAS with indirect Hg determination (LOD was about 1.1 μg g−1) GF-AAS with indirect determination using a Ag lamp at 328.1 nm (LOD was about 3.1 μg g−1)

Gas-phase MAS using a Mg lamp at 518 nm (LOD was about 890 μg L−1) GF-AAS with indirect determination using a Hg electrodeless discharge lamp at 253.7 nm (LOD was about 200 μg L−1)

Flame AAS with indirect determination using a Ag lamp at 328.1 nm (LOD was about 0.11 μg g−1)

[69]

[68]

[66]

Agreement with certified value was about 99 %

Agreement with expected values for commercial samples ranged from 102 to 103 % Recoveries ranged from 96 to 107 %

[65]

Agreement with certified value was about 101 %

[67]

[64]

Not stated

Recovery was about 100 %

[63]

[62]

Reference

Agreement with certified value was about 98 %

Agreement with certified values ranged from 94 to 103 % for the combustion method

UV–photochemical generation–ICPMS (LOD was about 0.075 pg g−1 for the combustion method)

MAD system: 0.5 g sample and 7 mL HNO3. Heating program: microwave heating at 8 bar for 30 min. After cooling, addition of 200 μL 30 % H2O2 and heating using the same microwave program. Solubilization: 0.50 g of sample was used for different methods: (1) 10 mL of concentrated formic acid. After vortexing (1–2 min), the mixture was placed in an ultrasonic bath at 50 °C for 6–8 h; (2) 5 mL of 25 % TMAH. After vortexing (1–2 min), the mixture was heated in a drying oven at 90 °C for at least 3 h; (3) 5 mL of 10 % ammonia solution. After vortexing (1–2 min), the mixture was heated in a drying oven at 90 °C for at least 3 h. Combustion: 0.020–0.4 g was weighed on a platinum boat and introduced into the combustion chamber. Heating program: 1,000 °C for 20 min, with continuous flow of water vapor and 40 mL min−1 O2. Volatile species were trapped in a solution of 5 % acetic acid

Accuracy

Detection technique

Sample preparation

7622 P.A. Mello et al.

Sample

Algae, cod muscle, egg, hay, milk, and pig kidney

Processed and raw milk

Iodized table salt and ophthalmic drugs

Fodder, human blood serum, milk powder, organic substances, and table salt

Milk

Dietary supplement products

Human urine and serum

Food

Foodstuffs and urine

Food and pharmaceuticals

Pharmaceutical products

Element

I

I

I

I

I

I

I

I

I

I

I

Table 2 (continued)

Alkaline ashing: samples (0.2 g) were mixed with 1 g of Na2CO3, 1 mL of a 6 mol L−1 NaOH solution, and 10 mL of methanol. The mixture was dried at 100 °C and then placed in a muffle furnace at 500 °C. The ash was dissolved with 10 mL of hot ultrapure water. Vapor iodine was quantitatively generated from iodide using 1 mL of 1 mol L−1 H2O2 in acidic medium and a 2.5-μL drop of N,N’-dimethylformamide was exposed from the needle tip of the microsyringe to the headspace of the sample, with stirring at 1,400 rpm for 7 min. An aqueous drop of 1 % (m/v) starch with 4×10−5 mol L−1 KI was used as the extractant phase. To obtain UV–vis spectra, 1–2 μL of sample was used Sample tablets were dissolved in water and the solution was then filtered

Alkaline ashing: samples (0.7–1.0 g) were mixed with 2 mL of 3 % sulfamic acid and sonicated for 10 min to decompose nitrite. Then, 1 mL of a 2 mol L−1 KOH solution was added, followed by 1 mL of a 10 % ZnSO4 solution and the mixture was heated at 150 °C for 30 min and at 500 °C by 2 h. Then, about 10 mL of water was added and the digests were centrifuged at 3,000 rpm for 3 min to separate the extract from carbonaceous matter. The extract was decanted, 10 mL of water was added, and the dissolution, centrifugation, and decantation steps were repeated. The combined extracts were diluted to the mark in a calibrated flask Acid digestion: samples (0.2 g and 0.3 mL for solid and liquid samples, respectively) were digested at 230 °C in a hot plate using 0.3 mL of HNO3 and HClO4 and 1.5 mL of H2SO4.

Dilution: (1) direct dilution in water to achieve a 4 % solution; (2) 0.5 g of sample and 3 mL of 25 % NH4OH and kept at room temperature for 12 h Sample preparation was not required

Solubilization: (1) serum samples were acidified with sulfuric acid to a final concentration of 0.1 mol L−1, and centrifuged at 3,500 rpm; (2) table salt, organic substances, fodder, and milk powder samples were dissolved in water. Fodder and milk powder samples were treated in an ultrasound bath for 15 min Ion-exchange resins, solvent extraction, and a precipitation method were used to promote the fractionation of the different species of iodine present in 50 mL of milk

Alkaline extraction: 0.2–0.5 g of sample and 5 mL of ultrapure water and 1 mL of 25 % TMAH solution. Heating program: 90 °C for 3 h. The resultant solution was diluted to 25 mL with ultrapure water and centrifuged or filtered through a membrane (0.45 μm) Digestion: 50 mL of sample, 4 mL of 3 % acetic acid solution, 1 mL of concentrated HNO3, and heating at 40 °C for 5 min. The resultant solution was diluted to 100 mL with ultrapure water, filtered, and centrifuged. The supernatant was passed through a C18 cartridge Dilution: 0.1 mol L−1 sulfuric acid solution

Sample preparation Agreement with certified values ranged from 95 to 102 % (except for BCR 72, with agreement below 70 %) Recoveries ranged from 87 to 114 % and from 91 to 100 % for the ISE and IC, respectively

ICP-MS (LOD was about 0.03 μg g−1)

Flow-injection spectrophotometry using a gas diffusion unit and formation of the I3−–starch complex (LOD of 1,000 μg L−1)

Kinetic spectrophotometry using chlorpromazine and hydrogen peroxide (LOD was about 0.0016 μg). Microvolume spectrophotometry (LOD was about 0.69 μg L−1)

CITP–CZE with a conductivity detector (LOD was about 4.0 μg L−1) Kinetic spectrophotometric method based on a catalytic effect of iodide on the reaction between Janus green and bromate in acidic media (LOD was about 0.12 μg L−1)

[79]

[80]

Recoveries ranged from 93 to 104 %

[78]

Recoveries ranged from 90 to 102 %

Recoveries ranged from 98 to 109 %

[77]

[76]

Not stated

Recoveries ranged from 98 to 103 %

[75]

[74]

[73]

[72]

[71]

[70]

Reference

Not stated

Agreement with certified values ranged from 95 to 101 %

PC-INAA–CSS, INAA–CSS, conventional INAA, and ENAA (LODs were about 20, 60, 80, 100 μg L−1, respectively) TXRF (LOD was about 180 μg L−1)

Amperometric detection with a platinum electrode (LOD was 0.005 μmol L−1)

Agreement with expected values for commercial samples and with the Volhard method was about 95 and 98 %, respectively Agreement with certified value was about 100 %

Cyclic voltammetry using a gold nanodisk electrode (LOD was about 0.3 μmol L−1)

ISE (LOD not stated) and IC– amperometric detection (LOD was about 6 μg L−1)

Accuracy

Detection technique

Analytical methods for the determination of halogens 7623

Sample

Citrus leaves, orchard leaves, pine needles, and spruce needles

Dental rinse, milk powder, mouthwash, and oyster tissue

Cigarette tobacco

Citrus leaves, milk powder, orchard leaves, oyster tissue, and tomato leaves

Salmon egg cell cytoplasm

Cigarette tobacco

Human blood and serum

Element

F and I

F, Cl, and Br

F, Cl, and Br

F, Cl, Br, and I

Cl and Br

Cl and Br

Cl and Br

Table 2 (continued)

Cold plasma ashing: 0.2 mL of sample was firstly freeze-dried. The sample was ashed in a cold plasma asher for 180 min and the ash was diluted in 2 mL of HNO3 and 0.5 mL of H2O2 (internal standard, Ga solution 0.5 mg L−1). 10 μL of sample from all digestion procedures was transferred to a unsiliconized quartz glass sample cell and dried in an oven at 50 °C

Savillex containers: 0.5 mL of sample was mixed with 1 mL of HNO3, 0.5 mL of H2O2, and a Ga solution as an internal standard. Savillex containers were tightly closed and heated to 150 °C for 120 min. After digestion, the solution was diluted with 2 mL of ultrapure water.

Dilution: serum and whole blood samples diluted 1:10 with water. MAD system: 2 mL of serum or 3 mL of whole blood was mixed with 5 mL of HNO3 and 2 mL of H2O2. Samples were digested in a microwave digestion system, and the resulting solution was made up to 20 mL; Ga solution (0.5 mg L−1) was used as an internal standard.

Pyrohydrolysis system: 0.1–1.2 g of sample and V2O5 (same amount of sample mass) and 10 mL of 50 mg L−1 Na2SO3 as absorbing solution. Heating program: 1,100 °C for 15 min, with continuous flow of water vapor and 10 mL min−1 O2. The extract was diluted to 10 mL with ultrapure water Samples were purchased as a whole ovary. Eggs were collected from the ovary, and washed with pure water. Cell cytoplasm and cell membrane were then separately collected from whole egg cells with Teflon tweezers and a Teflon needle. Intracellular fluid was subjected to chromatographic separation after 10-fold dilution with Tris buffer MIC system: 0.5 g of sample and 6 mL of 50 mmol L−1 (NH4)2CO3 as absorbing solution; 50 μL of 6 mol L−1 NH4NO3 as igniter; pressurization with 20 bar of O2. Heating program: 1,400 W for 5 min and 0 W for 20 min. MAE system: 0.5 g of sample and 6 mL of 100 mmol L−1 (NH4)2CO3 or 6 mL of ultrapure water. Heating program: ramp of 10 min to 1,400 W and hold for 30 min at 1,400 W; 0 W for 20 min

MIC system: 0.5 g of sample and 6 mL of 50 mmol L−1 (NH4)2CO3 as absorbing solution; 50 μL of 6 mol L−1 NH4NO3 as igniter; pressurization with 20 bar of O2. Heating program: 1,400 W for 5 min and 0 W for 20 min (cooling step) MAE system: 0.5 g of sample and 6 mL of ultrapure water. Heating program: ramp of 10 min to 1,400 W and hold for 50 min at 1,400 W; 0 W for 20 min

Wet digestion: solid sample (amount not stated) and 10 mL of 7 mol L−1 HNO3 solution and heating on a hot plate

Pyrohydrolysis system: 0.08 g of sample and 0.25 g of V2O5, using (2) 0.5 mL of 2.8 mol L−1 NaOH as absorbing solution for F determination and (2) 2 mL of 8 % HNO3 saturated with silver nitrate as absorbing solution for I determination. Heating program: 1,000 °C for 10 min, with continuous flow of water vapor and 80 mL min−1 N2. The extract was diluted to 4 mL with ultrapure water Dilution: for dental rinse and mouthwash.

Sample preparation

TXRF (LODs were 8 and 807 μg L−1 for Br and Cl, respectively, using direct dilution as sample preparation)

ICP-OES (LODs using MIC were 6 and 12 μg g−1 for Cl and Br, respectively)

ICP-MS (LODs were 0.03 and 0.005 μg g−1 for Br and I, respectively) and IC (LODs were about 1.0 μg g−1 for F, Cl, and Br) ICP-MS (LOD was not stated)

IC (LOQs were 0.1, 0.2, and 0.5 μg g−1 for F, Cl and Br, respectively)

GF-MAS for F (as AlF) using a Pt lamp at 227.5 nm (LOD was about 0.16 ng). Flame MAS for F, Cl, and Br (as AlF, AlCl, and AlBr or InBr, respectively) using a Pt lamp (227.5 nm), a Pb lamp (261.4 nm), and an As lamp (279.0 nm) or a Cr lamp (284.3 nm), respectively. LODs using flame MAS were 13,000 μg L−1 for F, 180,000 μg L−1 for Cl, and 500,000 μg L−1 for Br

F ISE (LOD was about 1.0 μg g−1 for F) and RNAA (LOD was about 0.002 μg g−1 for I).

Detection technique

Agreement with certified values was greater than 92 %

[87]

[86]

[85]

Not stated

Agreement with certified values using MIC was about 99 and 98 % for Cl and Br, respectively

[84]

Agreement with certified values ranged from 89 to 96 % for I

[83]

[82]

Agreement for F by GF-MAS ranged from 86 to 118 %

Agreement with certified values ranged from 98 to 99 %, from 98 to 101 %, and from 98 to 100 % for F, Cl and Br, respectively

[81]

Reference

Agreement with results in the literature ranged from 80 to 120 % and from 79 to 162 % for F and I, respectively

Accuracy

7624 P.A. Mello et al.

Sample

Milk

Soybean and related products

Peat

Grass, komatsuna, potato, radish and spinach

Active pharmaceutical ingredients

Edible seaweed

Edible seaweed

Whole milk powder and seaweed

20 food groups (bread, offal, meat products, etc.)

Edible seaweed

Element

Cl, Br, and I

Cl, Br, and I

Cl, Br, and I

Cl, Br, and I

Br and I

Br and I

Br and I

Br and I

Br and I

Br and I

Table 2 (continued)

Extraction: 0.5 g or 3 mL of sample, 1 mL of ultrapure water, and 1 mL of 25 % TMAH solution (further addition of 3 mL of ultrapure water for dry samples). Heating program: 75–80 °C for 4 h. The resultant solution was diluted to 10 mL with ultrapure water and a 2.5-mL aliquot was transferred to a tube containing 2.5 mL of 0.1 % NaOH and 200 μg L−1 antimony (as an internal standard) solution MAE system: 0.25 g of sample, 10 mL of 25 % TMAH solution, and 10 mL of ultrapure water. Heating program: ramp of 10 min to 200 °C and hold for 5 min

Sample powder (approximately 0.1 g) was microwave-heated for 5 min (from room temperature to 200 °C) with a mixture of 5 mL of ultrapure water and 5 mL of TMAH. After cooling, alkaline extracts were centrifuged at 3,000 rpm for 10 min, and the supernatant was transferred to 50-mL volumetric flasks. Extracts were filtered before ICP-MS measurements Extraction: alkaline digestion was performed to assess total iodine and bromine contents. Sample powder (approximately 0.1 g) was microwave-heated for 15 min (5-min ramp from 20 to 200 °C, stand for 10 min at 200 °C) with a mixture of 5 mL of ultrapure water and 5 mL of TMAH (25 %). After cooling, alkaline extracts were centrifuged at 3,000 rpm for 10 min, and the supernatant was transferred to 50-mL volumetric flasks. Extracts were filtered before ICP-MS measurements MAE system: 0.2 g of sample and 10 mL of 10 % TMAH solution. Heating program: ramp of 3 min to 85 °C and hold for 3 min at 85 °C. MAD system: 0.2 g was digested using 4 mL of concentrated HNO3

MIC system: 0.5 g of sample and 6 mL of 50 mmol L−1 (NH4)2CO3 as absorbing solution; 50 μL of 6 mol L−1 NH4NO3 as igniter; pressurization with 20 bar of O2. Heating program: 1,400 W for 5 min and 0 W for 20 min (cooling step). The digest was diluted to 30 mL with ultrapure water. Extraction: (1) MAE: 0.2 g of sample and 6 mL of 0.11 mol L−1 of TMAH solution. Heating program: 1,400 W for 50 min (ramp of 10 min) and 0 W for 20 min (cooling step), with temperature set to 90 °C; (2) conventional extraction in a heating block: 0.2 g of sample and 5 mL of 0.11 mol L−1 TMAH solution for 3 h at 90 °C. The extracts were diluted to 30 mL with ultrapure water

Combustion system: samples were combusted and gases were trapped in a suitable absorbing solution (water and trace of sodium sulfide) for further chromatographic separation that was performed using a solution of 2.2 mmol L−1 Na2CO3, 0.75 mmol L−1 NaHCO3, and 0.3 mmol L−1 H3BO3 as the eluent (flow rate of 2 mL min−1) Extraction: 0.1 g of sample and 1 mL of 25 % TMAH solution. Heating program: 60 °C for 12 h

MAD system: 0.25 g of sample and 1 mL of 1 mol L−1 AgNO3 solution, 4 mL of 14 mol L−1 HNO3, and 1 mL of 30 % H2O2. Heating program: 250 W for 2 min, 0 W for 2 min, 250 W for 5 min, 400 W for 5 min, and 650 W for 5 min. The digest was centrifuged (2,500 rpm for 15 min) and the precipitate was dissolved by adding 2 mL of 25 % ammonia solution. The resultant solution was diluted to 10 mL with ultrapure water MIC system: 0.1–0.5 g sample and 6 mL of 100 mmol L−1 NH4OH as absorbing solution; 50 μL of 6 mol L−1 NH4NO3 as igniter; pressurization with 20 bar of O2. Heating program: 1,400 W for 5 min and 0 W for 20 min (cooling step). The digest was diluted to 30 mL with ultrapure water

Sample preparation

Agreement with certified values ranged from 100 to 102 % for Br and I, respectively

ICP-MS (LODs were 0.0199 and 0.0246 μg g−1 for Br and I, respectively)

ICP-MS (LODs were 0.020 and 0.025 μg g−1 for Br and I, respectively)

ICP-MS (LODs ranged from 0.03 to 0.2 μg g−1 for Br and I)

[95]

[96]

Agreement with certified values was about 101 % for Br and I

[94]

[93]

[92]

[91]

[90]

[89]

[88]

[21]

Reference

Not stated

Agreement with certified values ranged from to 96 to 101 %

Agreement with certified values ranged from 91 to 116 % for Br and I, respectively

IC–ICP-MS (LODs were 0.083 and 0.0023 μg g−1 for Br and I, respectively).

IC–ICP-MS using DRC mode (LODs were 0.03 and 0.001 μg L−1 for Br and I, respectively)

Agreement with certified values was about 97, 98, and 88–92 % for Cl, Br, and I, respectively Agreement with certified values ranged from 95 to 110 % and from 97 to 104 % for Br and I, respectively

Agreement with certified values ranged from 92 to 101 %, from 97 to 103 %, and from 96 to 97 % for Cl, Br, and I, respectively Not stated

Agreement with certified values was about 99, 100, and 89 % for Cl, Br, and I, respectively

Accuracy

ICP-MS (LODs were 750, 0.05, and 0.007 μg g−1 for Cl, Br, and I, respectively) ICP-MS (LODs were 0.02 and 0.001 μg g−1 for Br and I, respectively) and IC (LODs were 0.3 and 4.2 μg g−1 for Br and I, respectively)

CIC–conductivity cell for Cl (LOD was 20 μg g−1). CIC–UV–vis for Br and I (LODs were 2 and 1 μg g−1, respectively)

ICP-MS (LODs were 1.2, 0.03, and 0.002 μg g−1 for Cl, Br, and I, respectively)

ICP-OES (LODs were 15, 20, and 40 μg g−1 for Cl, Br, and I respectively)

Detection technique

Analytical methods for the determination of halogens 7625

[98]

[99]

Not stated

Recoveries ranged from 94 to 105 % MAE system: 0.2 g of sample, 10 mL of 10 % TMAH solution, and 75 mL of water. Heating program: microwave heating at 90 °C for 10 min Foodstuffs Br and I

Samples were filtered and centrifuged Human saliva Br and I

CE capillary electrophoresis, CIC combustion ion chromatography, CITP capillary isotachophoresis, CRM certified reference material, CS continuum source, CSS Compton suppression spectrometry, CVG chemical vapor generation, CZE capillary zone electrophoresis, DMEM Dulbecco’s modified Eagle’s medium, DRC dynamic reaction cell, ENAA epithermal neutron activation analysis, GC gas chromatography, GF graphite furnace, HPA high pressure asher, IC ion chromatography, ICP inductively coupled plasma, INAA instrumental neutron activation analysis, ISE ionselective electrode, LC liquid chromatography, LOD limit of detection, LOQ limit of quantification, MAD microwave-assisted digestion, MAS molecular absorption spectrometry, MAE microwaveassisted extraction, MIC microwave-induced combustion, MS mass spectrometry, MS/MS tandem mass spectrometry, PC pseudo-cyclic, PFOA pefluorooctanoate, RNAA radiochemical neutron activation analysis, SDME single-drop microextraction, SPE sold-phase extraction, SPME solid-phase microextraction, TMAH tetramethylammonium hydroxide, Tris tris(hydroxymethyl)aminomethane, TXRF total reflection X-ray fluorescence, WDXRF wavelength-dispersive X-ray fluorescence, UV ultraviolet, UV–vis ultraviolet–visible

[97] Not stated

Conventional INAA (LODs were 0.05 μg and 100 μg for Br and I, respectively). CITP–UV detection (LODs were 3.0 and 5.9 μg L−1 for Br and I, respectively) CE–ICP-MS (LODs were 1 and 20– 50 μg L−1 for I and Br, respectively) Rat thyroid Br and I

Samples were previously fractioned using water and ethanol and three different fractions were obtained. Extracts were dried and weighed

Sample Element

Table 2 (continued)

Sample preparation

Detection technique

Reference

P.A. Mello et al.

Accuracy

7626

(e.g., balloons) must be used because of the high pressure during the combustion step [56, 119]. Moreover, an additional reflux step that could improve the analyte recovery cannot be performed using this system. On the other hand, the Trace-OMat combustion method allows the combination of sample combustion and a reflux step. However, although the TraceO-Mat system has been successfully applied for the digestion of organic materials, this system is not widely used for routine analysis because commercial instruments are no longer produced. Most sample decomposition methods are used for subsequent iodine determination mainly owing to its nutritional importance in biological systems. Regarding the extraction methods, the recoveries for iodine are generally low, probably owing to the presence of insoluble iodine compounds, especially because iodine is covalently bound to biological tissues, thus requiring a decomposition step before extraction [116]. In some cases, when microwave-assisted digestion is used, the addition of small volumes (0.1–0.5 mL) of HClO4 in combination with concentrated HNO3 can avoid losses of volatile iodine species [55, 59]. Contrarily to other halogens, fluorine does not require alkaline solutions, and water can be used as an absorbing solution for combustion systems [33]. The main limitations of combustion methods using the Schöniger flask and combustion bombs, such as relatively low sample mass, low throughput, safety, and unavailability of the reflux step were overcome after introduction of MIC [56, 118]. This method involves the combustion of organic samples in closed quartz vessels pressurized with oxygen, and ignition is performed by microwave radiation. The sample, generally prepared as a pellet, is placed in a small piece of filter paper on a quartz holder, which is placed inside a quartz vessel. A few microliters of ammonium nitrate is added to the filter paper to aid combustion [58, 118]. MIC has been applied for many analytes and matrices such as food [58, 111, 120, 121], botanical samples [83, 86, 122, 123], soil [124], and petroleum-related matrices [125–131]. Dilute alkaline solutions are required to ensure quantitative recoveries for halogens when using MIC and to avoid losses, especially for bromine and iodine [58, 91]. However, despite some clear advantages, there are still few applications of MIC in bioanalytical sciences for subsequent determination of halogens [58, 59, 88, 91]. This fact can be explained by considering that MIC was introduced relatively recently and there is only one company (Anton Paar) that commercializes this system. In general, the application of MIC for biological samples comprises the use of sample mass up to 0.5 g, dilute alkaline solutions for absorption of analytes [e.g., 50–250 mmol L-1 (NH4)2CO3, NH4OH, or NaOH], and pressurization with O2 at 10–20 bar. In addition, the residual carbon content in digests is generally below 1 %, showing the high digestion efficiency of this

Analytical methods for the determination of halogens

method. Compared with other combustion methods, the throughput is relatively high because MIC allows up to eight samples to be digested in up to 30 min including cooling time [58, 59, 88, 91]. Pyrohydrolysis is another interesting alternative for sample preparation and further determination of halogens. The instrumentation is relatively simple and can be easily constructed in the laboratory [88, 132]. Although pyrohydrolysis has been mainly applied for fossil fuels and rocks [133–135], some applications can be found for biological samples [34, 60, 81, 84]. Pyrohydrolysis consists of a hydrolysis reaction at high temperature (about 1,000 °C) resulting in the release of halogens generally as their respective acids. As pyrohydrolysis is slow, the reaction rate can be usually improved in the presence of some oxides, such uranium, vanadium, aluminum, and tungsten oxides. In general, water vapor is passed inside a quartz tube into the furnace containing the heated mixture of the sample and the accelerator (V2O5 is the most used for biological samples) [34]. When pyrohydrolysis is applied for biological matrices, the absorption of analytes is generally performed using NH4OH, (NH4)2CO3, NaOH, or Na2SO3 solutions even being possible to use other solutions. However, the use of pyrohydrolysis for subsequent fluorine determination does not require alkaline solutions, and water can be used or even no solution may be required. In general, one of the main advantages of pyrohydrolysis is the complete separation between the matrix and the sample, providing a “clean” extract. In addition, the sample mass is relatively high (up to 0.5 g) and the final volume of extract can be reduced to 4 mL. However, the throughput is relatively low (two to five samples per hour) depending on the characteristics of each system [34, 60, 81, 84].

Determination of halogens in biological samples Atomic absorption spectrometry and molecular absorption spectrometry As a general rule, halogens cannot be determined directly by atomic absorption spectrometry (AAS) since their analytical lines lie wavelengths shorter than 190 nm. Indirect determination has generally been performed using molecular absorption lines or, mainly for iodine, by the use of precipitation reactions or formation of metal complexes [65, 67]. Some of these methods have been modified for flow injection systems [63] and some of them have been performed using electrothermal vaporization and solid sampling systems [136]. Particularly for halogens, the respective absorption spectra can also be used for quantification of elements by

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molecular absorption spectrometry (MAS) [137]. Among the molecules which have been used for quantification of halogens are AlBr, CaBr, InBr, and TlBr for bromine [51, 82], AlCl, GaCl, InCl, and MgCl for chlorine [46, 82], AlF, CaF, and MgF for fluorine [39, 82], and BaI and TlI for iodine [68]. Flame and graphite furnace atomizers are commonly used, but some methods have proposed the introduction of iodine in gaseous form as well as the use of a tungsten coil for iodine determination [64]. Correction of background signals due to the microgram amounts of metals, which are added to promote the formation of the diatomic molecules with halogens, can be corrected by the same setup used in conventional AAS instruments. In this regard, Fender and Butcher [138] demonstrated that deuterium arc background correction was accurate for determination of fluorine, whereas spectrometers using Smith–Hieftje background correction were more feasible for chlorine determination. Table 2 summarizes procedures using MAS for determination of halogens in biological matrices and strategies for their generation. The development of instrumentation, specifically of the spectrometer optics, to achieve high-resolution performance led to the development of continuum source AAS (CSAAS) [137]. The equipment consists of a continuum radiation source (instead of a line source), a high-resolution double monochromator with a high-resolution echelle grating, and a charge-coupled device detector [137]. The atomization systems (flames and furnaces) are the same as those used for classical AAS. Some of the special features of CSAAS are (1) the possibility of spectral correction for continuous and discontinuous events, (2) the ability to access absorption lines for elements from 190 to 900 nm; and (3) the most important feature with regard to this review, the suitability for MAS, thus facilitating the determination of halogens [137]. This technique has been recently applied for the determination of fluorine, chlorine, bromine, and iodine in biological samples, using basically the same molecules (e.g., AlF, CaF, GaF, AlCl, AlBr, CaBr, and BaI) previously investigated for conventional AAS (Table 2). Is spite of the low-cost instrumentation and robustness, the use of MAS, even in conventional spectrometers (flame MAS and graphite furnace MAS) or in high-resolution spectrometers (CS-MAS) is prone to some drawbacks: (1) the relatively poor sensitivity in comparison with determination of metals using AAS spectrometers or determination of halogens by other spectrometric techniques (ICP-OES and ICP-MS); (2) the necessity to promote the formation of a molecule able to absorb radiation, which implies the use of relatively large amount concentrated reagents and chemical modifiers that could contribute to increasing analytical blanks; (3) sometimes a laborious sequence of steps must be performed to produce the volatile molecule (a previous step to perform a permanent coating can be necessary). In

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addition, losses of halogens bound to organic structures have been reported in the literature for some biological samples, making this technique difficult to apply widely without additional pretreatment [37, 40, 47, 82].

also by using this medium to wash the sample introduction system [58].

Inductively coupled plasma mass spectrometry

The determination of halogens by ICP-OES is usually performed in the vacuum UV region. This spectral region (120–190 nm) allows the determination of bromine, chlorine, and iodine with reasonable sensitivity. The most intense emission lines for determination of bromine, chlorine, and iodine at are 154.065, 134.724, and 183.038 nm, respectively [20, 21, 141]. The main drawback of this optical system is the radiation absorbed by air molecules (mainly oxygen, but also water vapor, carbon, nitrogen, etc.). However, this problem can be reduced using vacuum or purged optical systems with an inert gas (e.g., nitrogen or argon), which remove these molecules, reduce the background, and consequently, improve the LODs. The use of a detector that operates in this region is also necessary for the determination of halogens. Interferences generated by the cold region of plasma (when axial view is used) can be reduced using special systems such as “shear gas” (PerkinElmer instruments) and an optical plasma interface (Spectro and Agilent instruments). This type of interference is uncommon using radial view but the sensitivity is lower in comparison with that obtained using axial view [20, 141, 142]. Background levels are significantly increased in the presence of oxygen, but they can be reduced when the radio-frequency power and the nebulizer gas flow rate are increased [20, 21]. The number of applications using ICP-OES for determination of halogens is considerably lower than the number of applications using ICP-MS. Moreover, the difficulties regarding the first ionization energy and memory effects for the determination of halogens by ICP-MS are the same as for ICP-OES [142], which were previously discussed in “Inductively coupled plasma mass spectrometry”. Nevertheless, ICP-OES has been used for the determination of halogens (with the exception of fluorine), and in some cases the results obtained with this technique are comparable to those obtained with ICP-MS. However, the main drawback of ICP-OES is the poor LODs in comparison with ICP-MS, especially for bromine and iodine, which may be up to 1,000 times higher for ICP-OES [21, 96]. Because of the nutritional importance of iodine, it is the commonest halogen determined by ICP-OES [143]. However, nitrogen (183.0527 nm, ionic line) and phosphorus (178.2829 nm, atomic line) are a serious interferences to some iodine atomic lines (183.04 and 178.27 nm). Nitrogen interference may originate from air, nitric acid, and ammonia solutions. In order to overcome drawbacks related to this spectral interference, a high-resolution monochromator is necessary to allow the separation of nitrogen and iodine emission line. Phosphorus is a more serious interference because the wavelength difference between two peaks is

Plasma-based techniques, especially ICP-MS, are widely used for the determination of halogens. This technique provides excellent limits of detection (LODs), suitable sample throughput, suitable linear dynamic range, and multielemental capacity [4, 104]. In general, halogens have a relatively high first ionization potential, making these elements partially ionized in the plasma. In spite of this characteristic, ICP-MS can be considered a better option than other detection techniques, especially for iodine determination [4]. Only in special conditions fluorine can be determined by ICP-MS. For determination of chlorine, bromine, and iodine by ICP-MS, one of the main limitations is related to memory effects, especially when pneumatic nebulization is used, which can be minimized by using alkaline solutions that, in some cases, are the same as those used in the sample preparation step [21, 139]. The organic content in some alkaline solutions (e.g., CFA-C and TMAH) generates an enhancement of sensitivity which has been observed mainly for elements with high first ionization potential (e.g., bromine and iodine). This feature improves the LOD and the signal-to-noise ratio [110]. For example, the LOD for iodine using CFA-C can be improved to about 40 % in comparison with the use of NaOH solution. In addition, owing to the analyte stabilization in the liquid phase when alkaline solutions are used, the relative standard deviation is reduced and the correlation coefficients of the calibration curves are improved [110]. In addition, some works recommend the use of elements such as germanium and indium [55], cesium [90], and tellurium [70] as internal standards. The resolution can be improved using HR-ICP-MS instruments in high resolution mode allowing the detertmination of halogens. In the special case of fluorine determination, this can suffer intense water-derived spectral interference and the sensitivity is extremely low when quadrupole ICP-MS systems are used. With use of HR-ICP-MS even with medium resolution, fluorine can be determined free from common interferences such as 1H316O+, 1H217O+,1H18O+, and 38Ar2+, allowing LODs of about 5,000 μg L-1 to be achieved [140]. One of the drawbacks associated with the determination of halogens by ICP-MS is related to memory effects, especially when reference solutions or digests are prepared or diluted in water or acidic medium. This problem can be solved by preparing all solutions in alkaline medium [dilute (NH4)2CO3, NH4OH, or TMAH] and

Inductively coupled plasma optical emission spectrometry

Analytical methods for the determination of halogens

only 0.0069 nm. With use of a suitable monochromator, it is possible to minimize this interference, except for high concentrations of phosphorus [75]. Electroanalytical methods Electroanalytical methods have been used in bioanalytical sciences for the determination of halogens, especially for iodine [144, 145]. Electrochemical detection is relatively less expensive and has a fast response time, relatively good sensitivity and selectivity for the analytes [145]. Potentiometric methods that use an ISE have been performed as a simple analytical technique for determination of ionic constituents in a variety of samples. The term “ionselective electrode” is normally used for all potentiometric measuring electrodes that are capable of providing data related to the concentration (activity) of a particular chemical ion or species [146]. In the commonest use of the ISE arrangement, membranes are made of glass, water-insoluble precipitate, or polymeric films loaded with water-immiscible liquid, an organic ion exchanger, and a complexing agent (liquid membrane electrodes) [147]. In this way, it can be considered as a good alternative for the determination of halogens because it is a simple device that is commercially available and has been used for direct measurement in many samples. Electrochemical detection using different techniques has been performed for the direct determination of halogens in biological samples [73, 146] or coupled with IC [106]. The commonest electrochemical technique is amperometry, where the current in the working electrode is measured as a function of time according to the analyte concentration [148]. A silver working electrode is normally used, allowing the determination of the current flow, with the concomitant precipitation of silver halide on the electrode surface [149]. Spectrophotometric methods Despite the relatively widespread use of spectrophotometry for fluorine determination in pharmaceutical and health care products [35, 44], few applications of these methods could be found for biological samples (Table 2). For this kind of matrix, procedures for fluorine determination are relatively simple and based on low-cost instrumentation. Zaporozhets and Tsyukalo [44] proposed a spectrophotometric method for fluoride determination in saliva based on the competitive reactions of ZrOCl2 with methylthymol blue immobilized on silica gel and fluoride in solution. The solid-phase spectrophotometry method proposed for fluoride determination had lower sensitivity in comparison with ISEs, but it was more selective especially regarding the interference of Al(III), Fe(III), Mg(II), and Ca(II) ions [44]. For bromine [54] and chlorine [50] determination few applications using spectrophotometry could be found. A

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phenol red solution combined with Oxone® was used by Baso-Cejas et al. [53] for the determination of bromide in vegetables after an alkaline ashing procedure. A similar phenol red method was used by Di Narda et al. [54] for the determination of inorganic bromide residues in foodstuffs fumigated with brominated pesticides after wet digestion in microwave or alkaline ashing. The performance of proposed spectrophotometric method was affected by interferences caused by the presence of ammonium ions in digested samples. For iodine, spectrophotometric methods have widespread use, and the procedures most used for the determination of this element in complex matrices are based on the Sandell– Kolthoff reaction [4]. This spectrophotometric method is based on the catalytic effect of iodide on the reduction of yellow Ce(IV) by As(III) to colorless Ce(III), and the rate of disappearance of the yellow color is measured and related to the iodine content. In general, organic iodine compounds cannot be determined without a previous digestion step, commonly performed using perchloric acid [4]. If thiocyanate is present in higher concentration (e.g., milk and urine) it could interfere in the determination step. Interferences could also occur with traces of metal ions (e.g., silver and mercury) that can react with iodide as well as with substances that readily undergo oxidation, notably nitrite, ascorbic acid, and ferrous iron [4]. The Sandell–Kolthoff reaction was used for the determination of iodine using conventional batch [4, 150, 151] or flow injection [152] devices. Some automated [153, 154] and robotic [155] systems are also used and microtitration devices have been used to reduce the amount of waste and to improve sample throughput [150, 155, 156]. The Sandell–Kolthoff reaction has been used for iodine determination in serum [157] and food [151] samples, but its main application is for urine analysis [150, 153, 154, 156]. Shelor and Dasgupta [4] critically discussed the use of this reaction for determination of iodine by spectrophotometry, as well as different approaches for sample preparation, and it is not included in Table 2. Other methods for the determination of iodine have been developed using the catalytic effect of iodide on some oxidation reactions [79, 80]. Tomiyasu et al. [80] investigated the catalytic effect of iodine on the oxidation of chlorpromazine by hydrogen peroxide. Iron ions also had a catalytic effect on the reaction and mercury was used to mask the effect of iodine. The results were obtained by subtraction of the values in the presence and absence of mercury. An interesting approach was used by Pena-Pereira et al. [158] for iodine determination in food and pharmaceutical samples. A headspace single-drop microextraction was combined with microvolume UV–visible (UV–vis) spectrophotometry. After alkaline ashing, matrix separation and preconcentration of iodide was performed by in situ volatile iodine generation and extraction into a microdrop of N,N’-dimethylformamide. The combination of headspace single-drop microextraction and microvolume UV–vis

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spectrophotometry avoided the dilution of the enriched microdrop before determination. The well-known complex formed between I3- and starch can be used for spectrophotometric determination of iodine [159]. This procedure was proposed by Nacapricha et al. [159] using a flow-injection method for the determination of iodide in pharmaceutical samples. In this work, iodide was oxidized to iodine in a gas diffusion unit that allows selective permeation of iodine through a hydrophobic membrane that allowed the separation of the analyte from interfering species and also from the colored samples. Detection was selective for elemental iodine by the formation of the I3-– starch complex. Therefore, spectrophotometric methods, especially for iodine determination, are still used for the determination of halogens in biological samples. Catalytic methods, particularly the Sandell–Kolthoff reaction, are the most used owing to the suitable LODs (generally from 0.1 to 10 μg L−1) [4] that can be achieved for iodine determination in biological matrices. Neutron activation analysis This technique became applicable after the development of nuclear reactors (1940s) as a source of neutrons. The commonest system is instrumental NAA (INAA), in which nuclear reactions are promoted by neutrons and the radionuclides formed are quantified using a γ-ray detector. It can be considered as an absolute technique, and the concentration of a given element (even at the microgram per kilogram level) depends on the absolute disintegration rate, the probability of the reaction, and the neutron flux [154]. However, absolute analysis is scarcely used because the neutron flux may vary with the neutron energy. Thus, many applications involve a comparison with CRMs as a calibration approach. The major advantage of INAA applied for biological matrices is that most of the elements present in organic matrices (carbon, hydrogen, nitrogen, and oxygen) do not produce substantial interferences in trace element determination. In addition, INAA allows minimum sample pretreatment and it is suitable for simultaneous measurement of chlorine, bromine, and iodine in biological samples [160]. Chlorine is relatively simple to determine owing to its commonly high concentration in biological samples and the high-energy γrays of the 38Cl radionuclide. Neutron activation of bromine is performed using 80Br and 82Br, and interferences of Compton radiation of sodium and chlorine are observed [74]. Regarding interferences, iodine determination in biological samples (e.g., milk) can be affected by the presence of elements such as bromine, chlorine, potassium, magnesium, and sodium [74]. The determination of fluorine also presents some problems such as interferences in the reaction with fast and thermal neutrons and the overwhelming activity

P.A. Mello et al.

of 28Al [36]. Epithermal NAA and Compton suppression spectrometry allowed the minimization of interferences of elements in high concentration in biological samples for halogen determination using INAA techniques [74]. For epithermal NAA, biological samples are irradiated using a capsule that filters thermal neutrons and promotes enhancement of the neutron reaction contribution [161]. By use of a Compton suppressor spectrometer, the signals coming from Compton scattered γ-rays are detected and subsequently suppressed by an electronic circuit. In this case the detector assembly consists of an analyzing detector surrounded by shielding detectors [161]. The absolute LODs for fluorine, chlorine, bromine, and iodine using INAA in a reactor with a neutron flux of 1013 neutrons per square centimeter per second is about 1,000, 10, 0.1, and 1 μg, respectively [162]. To improve the LODs for halogen determination by INAA, samples could be submitted to repeated cycles of irradiation, that is a pseudo-cyclic INAA method [161]. The use of pseudo-cyclic INAA coupled with Compton suppression spectrometry allowed fourfold improvement in the LODs in comparison with the conventional INAA method when dehydrated milk samples were exposed to six cycles of irradiation [74]. Compared with other instrumental methods available for the determination of halogens, NAA is suitable for trace element determination, and solid or liquid samples up to 2 kg can be used [161, 163]. However, as a disadvantage, the NAA technique requires access to a nuclear reactor as the source of neutrons, which is generally not easily available for most laboratories [163]. One of the disadvantages of INAA is that speciation analysis of halogenated compounds can be performed only with previous separation of species [161]. IC [74], solvent extraction [74, 97], and solid adsorption [164] have been applied to the separation of different species of halogens in biological samples and further analysis by INAA. Therefore, NAA can be considered as a useful technique for the determination of chlorine, bromine, and iodine, allowing suitable LODs for the analysis of different biological materials to be achieved. In addition, it dispenses exhaustive sample preparation steps because it allows the direct analysis of a solid sample. Total reflection X-ray fluorescence Analysis by X-ray fluorescence (XRF) is based on the measurement of characteristic intensities of X-rays emitted by elements present in the sample. These excited elements emit X-ray photons (fluorescence) with well-defined energy characteristic for each element. In brief, the analysis by Xrays fluorescence consists of three stages: excitement of the elements that constitute the sample, dispersion of characteristic XRF emitted by the sample, and detection of X-rays [165, 166]. Initially, XRF analysis was performed solely using

Analytical methods for the determination of halogens

dispersive spectrometers for wavelength-dispersive XRF based on Bragg’s law, which requires a precise and synchronized movement between the detector and the diffraction crystal. With the development of semiconductor detectors able to discriminate X-ray energies, the development of the energydispersive XRF technique, and the availability of less expensive instrumentation, more practical use of XRF became possible [166]. The conventional energy-dispersive XRF technique uses a combination of about 45°/45° for the incident and takeoff angles, whereas the TXRF technique uses a combination of angles of 0.1° and 90° [165, 167, 168]. The TXRF technique results in significant reduction in the spectral background because a very small part of the primary beam penetrates into the sample. In addition, a doubled fluorescence intensity signal is observed because the sample is excited by both the incident beam and the reflected beam [167]. Moreover, in the TXRF technique a very small sample amount is used (1 ng to 100 μg). An inherent feature of the TXRF technique is the possibility of analysis of a sample in its original physical state, usually without any previous sample treatment. The LODs for elements with atomic number between 13 and 90 are in the range of the parts per billion level [168]. More recently, the use of synchrotron radiation has allowed the determination of trace elements in biological cells because the sensitivity of synchrotron radiation TXRF is several orders of magnitude higher than that of conventional sources [169]. Halogens, especially chlorine, bromine, and iodine can be determined in biological samples using TXRF, and suitable LODs (microgram per liter range) can be obtained [75, 167]. However, for fluorine, the fluorescence yield and the absorption of radiation in the beam pathway is very low and consequently poor LODs (about 120 μg g−1) are obtained [170, 171]. To overcome these drawbacks, the TXRF spectrometer should be equipped with primary X-ray that increase the fluorescence yield for fluorine determination [170]. TXRF is suitable for the direct analysis of biological samples owing to the low matrix interferences and simultaneous multielement nature. However, sometimes a sample preparation step is required to minimize interferences when biological organic samples are being analyzed [172]. TXRF has been widely used for analysis of biological samples [171], and mainly chlorine and bromine can be determined in blood, plasma, serum, and plant material. On the other hand, works using TXRF to determine iodine are scarce in the literature [75], and some approaches are required to minimize interferences when biological samples are being analyzed, such as acidic microwave digestion and slurry sampling [167, 172]. However, digestion of small samples demands careful control of the digestion conditions in order to avoid contamination, volatilization losses, etc.

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Coupled techniques Chromatography From consideration of the analytical sequence for the determination of halogens, chromatographic techniques can also be an option, and procedures are commonly based on LC [173] and gas chromatography (GC) [18]. Some methods can be found in the literature regarding the use of chromatographic separation related to halogens or halogenated compounds. These methods normally require a previous step for sample pretreatment, such as extraction or sample decomposition, both previously discussed. Therefore, when it is necessary to identify or quantify a halogen or halogenated compound, a detection technique that provides sufficient selectivity, sensitivity, and suitable LODs must be coupled with a separation technique [18]. The chromatographic approach used for determination of halogens is mainly related to speciation analysis of organic halogens compounds, such as pesticides and metabolites [174], which is, however, beyond the scope of this review. LC can be considered as a widespread technique for the determination of halogens, using IC. One of the main advantages related to this technique is the relatively easy coupling of the LC system to different detectors [175, 176], where it is possible to highlight the use of conductivity cell, UV–vis, and ICP-MS detectors [175]. Special attention should be given to chromatographic separation coupled with MS with different sources of ionization, such as electrospray ionization and ICP [173]. One of the more suitable detectors coupled to an LC system for total halogen determination is an ICP-MS system, which allows the determination of chlorine, bromine, and iodine with good sensitivity. However, even though an ICPMS system is a specific detector with relatively high sensitivity, the UV–vis and conductivity cell detectors are still the commonest systems used with LC [104, 175, 177]. As already discussed for LC, the use of GC for separation and determination of halogens is an important field of applications. A promising derivatization procedure was proposed by D’Ulivo et al. [178] and Pagliano et al. [179]. This approach allows the use of GC to separate halogen ions (as well as other anions) using an aqueous phase reaction for further determination of halogens. The sample with the derivatizing agent was left to react at room temperature for 3 h, and 250 μL of the headspace was injected (200 °C, transfer line at 260 °C). Quantitative alkylation of iodide, bromide, and chloride was obtained using trialkyloxonium tetrafluoroborates as the derivatizant agent [178], whereas for fluoride it was necessary to use triethyloxonium tetrachloroferrate(III) as the derivatizant agent in order to convert fluoride to fluoroethane [179]. In addition to the possibility of determining halogens in organic samples, this procedure was applied only for a CRM of water (BCR 612 groundwater) because the respective reagent used as

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the derivatizing agent had a high degree of reactivity with many inorganic and organic materials, which requires an efficient sample preparation procedure, besides avoiding the use of organic solvents. Even though that chromatographic techniques are mainly used for speciation analysis, they can be considered as an efficient tool for total and inorganic halogen species determination. Besides ensuring selectivity and sensitivity for determination of halogens, both LC and GC systems can be relatively simple coupled with many detection systems, allowing one to choose a specific and sensitive detector for the determination of halogens. Capillary electrophoresis Capillary electrophoresis (CE) is a separation technique based on the migration of electrically charged species under the influence of an electric field in a capillary tube. The migration velocity of the analyte is determined by its electrophoretic mobility and the mobility of the buffer within the capillary [180]. Among the different types of CE used to determination of inorganic anions are capillary zone electrophoresis (CZE) and capillary isotachophoresis [181, 182]. Currently, the separation of inorganic anions is preferably conducted using CZE [49, 87, 183], and capillary isotachophoresis is used as pretreatment to increase the power of detection or allow the analysis of high-conductivity matrices [181, 182, 184]. In addition, micellar electrokinetic capillary chromatography can also be used to the determination of inorganic anions in biological samples with suitable optimization of the variables involved in CE separation [185]. The basic instrumentation required to perform CE is a fused-silica capillary, a power supply, a detector, and a recorder [180]. One of the challenges for the use of CE is the detection system, which must comply with all the requirements for good detectability and also allow the analysis of small sample volumes with good resistance against temperature variation [180, 186]. The commonest detectors used for the determination of inorganic anions in different types of biological samples are UV photometric detectors (direct and indirect) and conductivity detectors (contact and contactless) [180, 181]. Moreover, CE may be coupled with other analytical techniques, such as ICP-MS, to improve the sensitivity and selectivity of some inorganic anions (Cl−, Br−, and I−) [99, 187, 188]. The electrolyte system also plays an important role in the performance of the CE technique and migration of species. Usually, the electrolyte system consists of buffered saline solutions and should be optimized for each analysis in order to allow better separation of species and minimize interferences of the matrix [180, 189]. In addition, CE, in particular CZE, allows the simultaneous determination of bromide, chloride, fluoride, and iodide in the microgram per liter range [87, 181]. Speciation analysis can be performed using CE and it is considered as an alternative to LC because

P.A. Mello et al.

the separation in CE is governed by the difference in the charge of the analytes [187, 190]. Regarding halogen determination, it is possible to identify the different ionic species of chlorine [87, 191], bromine [99, 192] and iodine [99, 193] as well as biomolecules [193] or complexes containing these elements [188]. In the literature there are some papers related to the determination of halogens (as anions) in biological samples using CE [181, 194]. However, such matrices of this kind contain a high content of biomolecules that can interfere in analysis by CE, because these molecules have electrophoretic mobilities similar to those of halogen anions. To minimize these interferences, biological samples should be diluted or subjected to some kind of pretreatment [194]. Timerbaev [194] reviewed recent advances in the determination of inorganic analytes in biological fluids using CE. In that review, in particular, the changes in the separation and detection steps to improve the resolution and sensitivity of CE were discussed. According to Timerbaev and on the basis of the methods reviewed, blood serum and urine are very difficult body fluids to analyze because they contain a huge amount of protein and salts. Suitable dilution (up 100-fold), ultrafiltration with membrane filters or units with appropriate molecular weight cutoff, and precipitation followed by centrifugation were used to overcome problems related to determination of halogen anions in blood serum and urine matrices. Finally, nowadays CE is used for the determination only of the major inorganic anions, and also coupling with ICP-MS has been proposed to improve the sensitivity [194]. On the basis of the works discussed above, it is important to mention that CE methods allow the determination of all halogens with suitable LODs in biological samples, especially if an ICPMS system is used as detector.

Certified reference materials and official methods Several parameters contribute to the achievement of reliable and comparable analytical results, such as the competence of the analyst or laboratory, routine checks for evaluation of accuracy and precision of analytical results, validation of analytical methods, and accreditation of laboratories [195]. CRMs are a very important tool to evaluate the accuracy of measurements by laboratories and play a key role in metrological traceability schemes in chemical analyses [196]. Therefore, the demand for several kinds of reference materials is growing, which leads to a wider offer and a continuous increase in the number of producers of such materials [195]. Despite their importance, the availability of biological CRMs for halogens is limited and they do not cover all the range of biological samples. For bromine and fluorine, the number of CRMs is still lower, and only a few materials are available. On the other hand, chlorine and iodine are the elements with

Analytical methods for the determination of halogens

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Table 3 Certified concentration (mass fractions) of halogens in different biological CRMs CRM

Producer/CRM number

F

Cl

Br

I

Apple Apple leaves Beech leaves Bush branches and leaves Cabbage Chicken Corn flour Fish muscle Freeze-dried urine Frozen human serum

NIM/GBW 10019 NIST/SRM 1515 IRMM/BCR 100 NIM/GBW 07602 NIM/GBW 07603 NIM/GBW 10014 NIM/GBW 10018 INCT/CF-3 IRMM/ERMBB 422 NIST/SRM 2670a NIST/SRM 956c

– – – 24±3 μg g−1 23±4 μg g−1 – – – – – –

– – – 2.4±0.4 μg g−1 3.0±0.4 μg g−1 6.0±1.3 μg g−1 1.6±0.4 μg g−1 0.388±0.046 μg g−1 – – –

0.12±0.04 μg g−1 – – – – 0.24±0.03 μg g−1 – – 1.4±0.4 μg g−1 88.2±1.1 μg L−1 –

Frozen human urine

NIST/SRM 3668

–

– 579±23 μg g−1 1490±60 μg g−1 – – 0.64±0.07 % 0.153±0.015 % 397±33 μg g−1 – – 371.8±11.3 mg dL−1 430.7±8.7 mg dL−1 487.2±6.5 mg dL−1 –

–

Hay powder Human serum

IRMM/BCR 129 RCCS/JCCRM 111-6H RCCS/JCCRM 111-6 L RCCS/JCCRM 111-6 M NIST/SRM 1849a NIM/GBW 09108 NIM/GBW 09109 NIM/GBW 09110

– – – – – – – –

– 120±0.4 mmol L−1 89.8±0.2 mmol L−1 106.4±0.3 mmol L−1 – – – –

– – – – – – – –

142.7±1.6 μg L−1 279.0±3.9 μg L−1 0.167±0.024 μg g−1 – – – 1.29±0.11 μg g−1 52.5±0.8 μg L−1 87.4±0.9 μg L−1 258±10 μg L−1

Milk powder NIM/GBW 10017 Multivitamin/multielement tablets NIST/SRM 3280 Non-fat milk powder NIST/SRM 1549 Oyster tissue NIST/SRM 1566b Peach leaves NIST/SRM 1547 Pine needles NIST/SRM 1575a Pork muscle NIM/GBW 08552 Potato powder LGC/ERMBC 402a Processed meat LGC/ERMBB 501a Rice flour NIM/GBW 10010 Skim milk powder IRMM/BCR 063r Skim milk powder IRMM/BCR 150 Soya bean flour INCT/SBF-4 Spinach NIM/GBW 10015 Spruce needles IRMM/BCR 101 Tea NIM/GBW 10016 Tobacco leaves INCT/OBTL-5 Tobacco leaves INCT/PVLT-6 Typical diet NIST/SRM 1548a

– – – – – – – – –

0.81±0.09 % 53000±2300 μg g−1 1.09±0.02 % 0.514±0.010 % 360±19 μg g−1 421±7 μg g−1 0.187±0.007 % – 14.5±0.5 g kg−1 0.040±0.004 % 9.94±0.30 g kg−1 – 64.5±4.7 μg g−1 1.08±0.07 % 688±23 μg g−1 0.044±0.003 % – – 12078±356 μg g−1

5.7±1.4 μg g−1 – – – – – 6.2±0.7 μg g−1 – – 0.56±0.13 μg g−1 – – 2.40±0.17 μg g−1 10±2 μg g−1 – 2.7±0.5 μg g−1 87.4±5.4 μg g−1 19.5±1.0 μg g−1 –

– 132.7±6.6 μg g−1 3.38±0.02 μg g−1 – – – – 1.86±0.24 μg g−1 –

Vegetation

NIST/SRM 2695

–

–

Wheat flour

NIM/GBW 10011

64.0±8.4 μg g−1 – 277±27 μg g−1 – 0.086±0.003 %

–

–

Infant/adult nutritional formula Lyophilized human urine

– – – – – 57±15 μg g−1 – – –

0.81±0.05 μg g−1 1.29±0.09 μg g−1 – 0.36±0.12 μg g−1 – – – – 0.759±0.103 μg g−1

INCT Institute of Nuclear Chemistry and Technology (Poland), IRMM Institute for Reference Materials and Measurements (Belgium), LGC LGC Standards (UK), NIM National Institute of Metrology (National Research Centre for Certified Reference Materials, China), NIST National Institute of Standards and Technology (USA), RCCS Reference Material Institute for Clinical Chemistry Standards Reference Center (Japan)

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highest number of available CRMs, as can be seen in the list of biological CRMs for halogens presented in Table 3. Available CRMs for bromine cover a narrow range of biological materials and vegetables or related samples (e.g., leaves, flour, meat, and milk) with a concentration range from 0.4 to 87 mg kg−1. On the other hand, and despite its importance, for fluorine certified values were found only three CRMs of botanical materials in the concentration range from 23 to 277 mg kg−1. This can be explained by the relatively few options for sample digestion and mainly for determination techniques for fluorine in comparison with other halogens. As mentioned before, for complex matrices the most suitable digestion procedures are those based on combustion in closed vessels, in special combustion bombs, and mainly MIC that allow the decomposition of relatively greater sample masses and final digests that are very dilute solutions fully compatible with most determination techniques. For fluorine, the techniques often used to establish certified values, such as INAA and isotope dilution ICP-MS, have some limitations [197, 198]. Therefore, an ISE or IC could be used for fluorine determination, but they cannot provide results fully traceable to the International System of Units in the same way as INAA and isotope dilution ICP-MS, which makes difficult the establishment of CRMs using those techniques [197, 198]. Certified values for iodine can be found in several CRMs of biological materials (meat, milk powder, human urine). However, despite the importance of this element for health, the number of available CRMs is not enough to cover the range of iodine concentrations in food samples (e.g., seafood). For clinical samples (e.g., human serum) the situation is the same and, as for the other samples, the development of CRMs for iodine could be considered as a need. Fig. 1 Techniques used for determination of fluorine, chlorine, bromine, and iodine according to the topics covered in this review. IC ion chromatography, ICP-OES Inductively coupled plasma optical emission spectrometry, ICP-MS Inductively coupled plasma mass spectrometry, ISE ion-selective electrode, MAS molecular absorption spectrometry, NAA neutron activation analysis, TXRF total reflection X-ray fluorescence

The analytical methods for the determination of halogens in biological and related samples are generally described in official compendia such as pharmacopeias for pharmaceuticals and related products [199, 200] as well as in the Official Methods of Analysis of AOAC International for food samples [201]. A great number of methods are described for chlorine determination in food based on the extraction or alkaline ashing and subsequent determination by titration. For drugs and related products, the determination of chlorine is currently performed using a semiquantitative turbidimetric assay after sample preparation by direct dissolution, extraction, or combustion using an oxygen (Schöniger) flask method [201]. On the other hand, for fluorine the number of methods for its determination in food is relatively low, and different approaches are recommended for sample preparation, such as alkaline ashing, distillation, oxygen flask combustion, and extraction. Titration, spectrophotometry, and ISE are used for fluorine determination. For pharmaceutical samples, similar procedures are used for sample preparation (with the exception of alkaline ashing), and a semiquantitative colorimetric assay and ISE are often used for fluorine determination [199, 200]. Only a few methods are available from AOAC International for iodide determination, and they are focused on milk-based foods [201]. Recommended procedures involve filtration and further determination of iodide by an ISE or ion-pair reversedphase LC. For bromine in Official Methods of Analysis of AOAC International, only a general procedure using oxygen flask combustion and determination of bromide by titration is described. In European and US pharmacopeias, total bromine and iodine determination is performed only as a test for identification or assay where these analytes are present in relatively Chlorine

Fluorine

TXRF ICP-MS

MAS

IC

IC

MAS

ISE

NAA

Spectrophotometry

ICP-OES

Others

Bromine

ICP-MS

Others

Iodine

NAA

Spectrophotometry

TXRF

ICP-MS

ICP-OES

NAA

MAS

MAS

Spectrophotometry

ICP-OES

IC Others

IC Others

Analytical methods for the determination of halogens

high concentration. Oxygen flask combustion is often used for sample digestion and bromine and iodine are determined by titration. In the Brazilian pharmacopeia, in addition to oxygen flask combustion, MIC can also be used for sample digestion [202].

Final considerations On the basis of the articles reviewed and the applications in the last 20 years, it is possible to consider that the determination of halogens in biological samples has been performed using well-established sample preparation methods, mainly extraction approaches. Figure 1 shows the distribution of the most frequently used techniques applied to biological samples. Potentiometry, spectrophotometry, IC, and ICP-MS have been the commonest techniques used for the determination of halogens in bioanalytical samples. Particularly for fluorine, reported works are mainly related to the use of ISEs and MAS. On the other hand, ICP-MS seems to be the method of choice for determination of bromine and iodine. With regard to iodine, it is important to point out the widespread use of spectrophotometry. In addition, NAA has been applied more for chlorine, bromine, and iodine, and TXRF methods have been used for determination of bromine and chlorine. Many applications have been successfully developed combining these methods for research issues and daily routine analyses, contributing to the knowledge of halogen content in many samples, including foods, drugs, and biological fluids and tissues. The sample preparation step is still the main drawback in this field owing to the inherent possibility of losses of halogens or contamination. In this regard, wet digestion methods with inorganic acids, which are effective for decomposition of many matrices, are not useful in the determination of halogens unless additional care is taken in a given procedure. In this way, combustion methods in closed systems can be considered as the preferred choice. In this sense, the suitability of combustion methods in order to improve the LODs and the use of dilute solutions that are compatible with different detection techniques is also another advantage. The oxygen flask combustion system has received more attention in the past but its use in recent applications is less common, mainly because of the relatively low throughput [56]. MIC in open [203] and closed [58, 91, 111] systems is an alternative, but despite the reported applications for matrices considered hard to digest, there are only a few reports for halogens for the samples considered in this review. Extraction with alkaline media has been used in some applications, but the possibility of interferences due to the residual matrix remaining in the extracts and the possibility to damage the nebulizing systems in ICP-OES and ICP-MS equipment or columns in chromatography are common problems [118]. Pyrohydrolysis is another interesting

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option for sample preparation, and requires simple instrumentation. However, it has been less used for biological samples than for other matrices. Biological matrices can result in excessive evolution of gases as well as carbon deposits during pyrohydrolysis and lead to a final digest that is unsuitable for further analysis [34]. Another critical point to consider, especially when dealing with biological samples, is the sample mass used in the whole procedure. It is well known that a greater sample mass is more suitable to improve the LODs, but it is necessary to consider that it can be unavailable in particular for biological fluids and tissues. Thus, the methods must be feasible for working with greater and smaller amounts of a sample and must also be in agreement with green chemistry recommendations. Other options with inherent advantages for the determination of halogens in biological samples are direct sampling [136], electrothermal vaporization [204, 205], and laser ablation coupled with ICP-MS [103, 206, 207]. Additionally, although few applications were found for determination of halogens, laser-induced-breakdown spectrometry can be considered a potential detection technique mainly regarding determination of halogens in pharmaceutical products [208] because it allows analysis almost free of a sample preparation step [209, 210]. These methods have been less used probably owing to the low availability for many laboratories and also because they require greater expertise. However, the development of methods using these alternatives should be encouraged and explored more in order to minimize the main drawbacks related to sample preparation for further determination of halogens. The importance in determining halogens has been discussed in the literature, highlighting the essential role or toxicity that they can represent for organisms. Knowledge of the fluorine, chlorine, and iodine content in biological samples as well as in other samples that can interact with living organisms (e.g., food and drugs) is a necessity. Although the determination of halogens can be considered a difficult analytical task with regard to sample preparation methods and detection techniques, many applications were reviewed, showing that it is still an important and growing issue. Advances have been made in instrumentation for detection of halogens, such as the development of more sensitive detectors and optical design with better resolution. Although many of the main drawbacks of the sample preparation methods and detection techniques have been overcome, some aspects must be still improved. Among these challenges, the development of methods involving suitable throughput, better LODs, and environmentally friendly aspects can be considered a goal still to be reached. Acknowledgments The authors are grateful to Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq), Instituto Nacional de Ciência e Tecnologia de Bioanalítica (INCT-Bioanalítica), and Fundação de Apoio à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) for funding.

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