Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 69)

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Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 69)

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8.4 II.8.4 Arsenic compounds and other inorganic poisons by Sinichi Suzuki and Yasuhiro Suzuki Introduction The Wakayama Curry Poisoning Incident taking place in August 1998, followed by various imitative poisoning incidents, is still fresh in our memory, because they gave a severe shock and anxiety to the Japanese society. The poison, which had been used in the Wakayama Curry Poisoning Incident was an arsenitea, a classical poison. However, since the acute poisoning case by an arsenite is rare nowadays, it took some time to identify the compound, and caused confusion at the initial step of criminal investigation. Diarsenic trioxide (As2O3, arsenic (III) oxide) is...

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  1. 8.4 II.8.4 Arsenic compounds and other inorganic poisons by Sinichi Suzuki and Yasuhiro Suzuki Introduction The Wakayama Curry Poisoning Incident taking place in August 1998, followed by various imitative poisoning incidents, is still fresh in our memory, because they gave a severe shock and anxiety to the Japanese society. The poison, which had been used in the Wakayama Curry Poisoning Incident was an arsenitea, a classical poison. However, since the acute poisoning case by an arsenite is rare nowadays, it took some time to identify the compound, and caused confu- sion at the initial step of criminal investigation. Diarsenic trioxide (As2O3, arsenic (III) oxide) is a trivalent arsenic compound and thus highly toxic, in contrast to less toxic pentavalent arsenates b being widely distributed in nature. When diarsenic trioxide is dissolved in water, it is immediately converted into the arsenious acidc, which actually exerts its toxicity in humans. The oral LD50 value of diarsenic trioxide in humans is said to be 60–120 mg. As other inorganic poisons, cadmium, thallium, lead, chro- mium and copper can be mentioned; however they and their derivatives are much less toxic than arsenious acid. These inorganic compounds can be analyzed by the similar methods to those for arsenic compounds. In this chapter, analytical methods for arsenic compounds together with other inorganic poisons are described. Reagents Diarsenic trioxide and dimethylarsinic acid (DMAA) can be purchased from Sigma (St. Louis, MO, USA) and other manufacturers. Nitric acid and hydrochloric acid should be of ultra pure grade usable for inductively coupled plasma mass spectrometry (ICP-MS). Other reagents are of special grade. Instrumental conditions i. X-ray fluorescence analysis Instrument: a PW1404 type X-ray fluorescence analysis instrument (Philips, Almelo, Nether- lands). Analytical conditions; X-ray tube: target Rh; operating voltage: 50 kV; operating current: 50 mA; crystal: LiF; detectors: scintillation counter and gas flow proportional counter. © Springer-Verlag Berlin Heidelberg 2005
  2. 638 Arsenic compounds and other inorganic poisons ii. Ion chromatography (IC) analysis Instrument: a DX-500 type ion chromatograph equipped with an autosuppressor (Dionex, Sunnyvale, CA, USA). Analytical conditions; separation column: IonPac AS10 (25 cm × 2 mm i. d., particle size 8.5 µm); guard column: IonPac AC10 (both from Dionex); mobile phase: 75 mM NaOH solu- tion (1-min hold) is subjected to linear gradient up to 150 mM NaOH solution during 7 min; its flow rate: 1.3 mL/min; detectors: conductivity and electrochemical detectors (ECD). iii. Inductively couple plasma atomic emission spectrometry (ICP-AES) Instrument: an SPS-1700 HVR ICP-AES instrument (Seiko Instruments, Chiba, Japan). Analytical conditions; high-frequency output: 1.3 kW; plasma gas: argon (16 L/min); assisting gas: argon (0.5 L/min); carrier gas: argon (1.0 L/min); sample flow rate: 0.5 mL/min. iv. Inductively couple plasma mass spectrometry (ICP-MS) Instrument: an SPQ 8000 type ICP-MS instrument (Seiko Instruments). Analytical conditions; high-frequency output: 1.2 kW; plasma gas: argon (16 L/min); assisting gas (flow rate): argon (0.75 L/min); carrier gas (flow rate): argon (0.45 L/min); sampling posi- tion: 13 mm. v. Ion chromatography/inductively coupled plasma mass spectrometry (IC/ICP-MS) Instrument HPIC 7000-HP 4500 type IC/ICP-MS (Agilent Technologies, Palo Alto, CA, USA). IC conditions; column: anion type IC-A15 (150 × 4.6 mm i.d., Hitachi Chemical, Tokyo, Japan); guard column: IC-A15G (Hitachi Chemical); mobile phase: 0.2 mM EDTA/2.0 mM sodium phosphate buffer solution (pH 6.0); flow rate: 1.0 mL/min; column temperature: room temperature. ICP-MS conditions; high-frequency output: 1.4 kW; plasma gas: argon (1.5 L/min); assist- ing gas: argon (1.0 L/min); carrier gas (flow rate): argon (1.1 L/min); arsenic detection mass number: m/z 75. Procedures i. Foods and vomitus i. A method to be chosen first is the X-ray fluorescence analysis, which is non-invasive and thus does not destroy a specimen. It gives informations on elements included in a speci- men, but cannot discriminate the forms of molecules containing such elements (for exam- ple, trivalent or pentavalent). The X-ray fluorescence analysis should be performed, when the presence of an inorganic poison is suspected, after analysis of organic compounds. > Fig- ure 4.1 shows an X-ray fluorescence spectrum for a food specimen containing poison(s) obtained without any pretreatment. ii. At the second step of examination, IC should be performed to define the form of a poison. By this analytical method, discrimination between trivalent (highly toxic) and pentavalent (less- or non-toxic) arsenic compounds can be made. iii. A 1-g amount of a food specimen is mixed with 5 mL distilled water, stirred for 1 min and centrifuged at 3,000 rpm for 5 min.
  3. Arsenic compounds and other inorganic poisons 639 ⊡ Figure 4.1 X-ray fluorescence spectrum for a food specimen. *, #: elements derived from the tube. iv. The resulting supernatant solution is passed through a cellulose acetate filter (0.45 µm). An appropriate volume of the filtrate is injected into an ion chromatograph. v. An example of the results is shown in > Figure 4.2; an intense peak due to a trivalent arsenite (arsenious acid) appeared at 2.4 min. ii. Stomach contents In the Japanese trial system, the ingestion of a poison is not verified, even if the poison is de- tected from a vomitus. Therefore, a poison or a drug should be detected from stomach con- tents, blood or urine obtained from an antemortem or postmortem human. > Figure 4.3 shows an X-ray fluorescence spectrum for a stomach content specimen obtained without pre- treatment; the Kα and Kβ rays due to arsenic could be observed, showing its presence in the stomach contents. iii. Blood Blood can be an important evidential specimen for proving the ingestion of an arsenite. When the presence of arsenic becomes evident from the results obtained by the above X-ray fluores- cence analysis, the following procedure should be made to clarify a chemical form of an arsenic compound. i. A 1-mL volume of blood is diluted 2–5 times with distilled water. ii. A container containing the above specimen is airtightly capped and sterilized in an autoclave at 120 °C for 10 min. iii. After cooling to room temperature, the aqueous phase is passed through a cellulose acetate filter (0.45 µm). iv. The filtrate is analyzed by IC/ICP-MS; an SIM chromatogram at m/z 75 is obtained. > Figure 4.4 shows an example of SIM chromatograms for an arsenite obtained by IC/ICP- MS. By this method, a trivalent arsenic compound was identified, verifying the ingestion of diarsenic trioxide or other arsenious compound(s).
  4. 640 Arsenic compounds and other inorganic poisons ⊡ Figure 4.2 Ion chromatogram for arsenic compounds after pretreatments of a food specimen. ⊡ Figure 4.3 X-ray fluorescence spectrum for a stomach content specimen. iv. Urine Urine specimens are being used for analysis of drugs and poisons most frequently. Also for inor- ganic compounds, urine is a good specimen for poison analysis. A metabolite of an inorganic poison formed in human body is usually excreted into urine; the presence of the metabolite in urine gives a most definitive evidence for the ingestion or administration of the poison. In the case of a urine specimen obtained from a subject, who had attempted suicide by in- gesting arsenious acid, a 1-mL volume of urine was diluted 10-fold with distilled water and passed through a Gurand-RP cartridge. The eluate was subjected to the analysis by IC/ICP-MS. As results, arsenious acid, its metabolites DMAA and arsenobetaine were detected with the ion at m/z 75 as shown in > Figure 4.5. Their respective structures are shown in > Figure 4.6. v. Organs A piece of an organ is dried by leaving it at room temperature; about 50 mg of a dried specimen is mixed with 2 mL nitric acid and heated with microwave to liquefy the tissue completely. The acid solution is diluted with 10 mL distilled water and analyzed by ICP-MS. An example
  5. Arsenic compounds and other inorganic poisons 641 ⊡ Figure 4.4 SIM chromatogram obtained by IC/ICP-MS for a blood specimen using an ion at m/z 75. ⊡ Figure 4.5 SIM chromatogram obtained by IC/ICP-MS for a urine specimen using an ion at m/z 75.
  6. 642 Arsenic compounds and other inorganic poisons ⊡ Figure 4.6 Structures of main metabolites of arsenious acid. of mass spectra obtained from an organ tissue is shown in > Figure 4.7A. At m/z 75, a peak due to arsenic appeared. Using the intensity of this peak, the content of arsenic in the kidney tissue was calculated using a calibration curve for arsenic; its content was much higher than that in normal subjects. vi. Scalp hair Scalp hair is very useful to specify a time (period) for ingestion of a heavy metal. It is more easily obtainable than organs. i. The hair should be cut off at its root level as closely to the scalp as possible. The growth rate of scalp hair is about 1 cm per month. A bundle of about 30 scalp hairs is obtained and washed with either a surfactant solution, an organic solvent or dilute HCl solution using an ultrasonic cleaner. ii. The hair bundle is cut into 3-mm segments from the roots to the tips. iii. Each segment is digested in nitric acid by heating it with microwave. iv. A small volume of the nitric acid digest is diluted with distilled water in a 10-mL volumet- ric flask before analysis. v. An appropriate volume of the diluted solution is analyzed by ICP-MS for identification and quantitation of arsenic. The mass spectrum of a hair specimen is shown in > Figure 4.7B. A high concentration of arsenic can be detected from a hair segment corresponding to the period of arsenic intake. With the same pretreatment and analytical method, other heavy metals, such as iron, copper and zinc can be also detected by ICP-MS from organs and hair as shown in > Figure 4.7. vii. Discrimination of commercial products of diarsenic trioxide In the criminal analysis of poisons, the identification of a poison used for a crime with the one seized is an important task. There are various limitations for the capability of analytical instru- ments being equipped in common chemical laboratories. Although the cost is high, the most useful instrument for such discrimination analysis of inorganic elements is ICP-MS. However, the concentration of a matrix introducible into the ICP-MS should be not higher than 500 ppm.
  7. Arsenic compounds and other inorganic poisons 643 ⊡ Figure 4.7 ICP mass spectra for kidney (A) and hair (B) specimens after digestion by microwave. Open areas show the peaks of reagent plus a specimen for analysis; solid areas the peaks of a blank specimen with the reagent only. Therefore, trace levels of other heavy metals contaminating the arsenious matrix cannot be analyzed by ICP-MS. Therefore, in place of ICP-MS, ICP-AES was used for impurity profiling analysis of the diarsenite trioxide products. In preliminary experiments, heavy metals, such as bismuth (Bi), antimony (Sb), selenium (Se), lead (Pb) and tin (Sn), which show low abundance ratios in nature and thus not influenced by environments, were chosen for profiling analysis by ICP-AES. Each content of the above heavy metals was measured using each calibration curve, and the concentration ratio of each metal to arsenic was calculated. The values obtained were multiplied 106-fold and plotted in the logarithmic scale as radar charts as shown in > Figure 4.8. The detection wavelengths were 190.0 nm for Sn, 196.1 nm for Se, 206.8 nm for Sb, 220.4 nm for Pb and 223.1 nm for Bi. The radar charts show that diarsenite trioxide products made in China, Japan and Germany/ Switzerland can be clearly discriminated by the profiling of contaminating heavy metals.
  8. 644 Arsenic compounds and other inorganic poisons ⊡ Figure 4.8 Radar charts of impurity profiling analysis for diarsenic trioxide products made in China (I), Japan (II) and Germany/Switzerland (III). Assessment of the methods For trace analysis of arsenic, the method by ICP-MS is most sensitive and is usable for hair, nail and organ specimens. In this method, ArCl+ ion (m/z 75) may interfere with the ICP-MS anal- ysis of As+ (m/z 75), when chloride ion coexists, because of their same mass number. Especially for biomedical specimens, special care should be taken for backgrounds. When such interfe- rence by ArCl+ is remarkable, IC/ICP-MS should be used for separating them. As described before, a blood or urine specimen is useful to verify the acute poisoning with an arsenite compound. For the chronic exposure to the poison, scalp hair, nails and organ tissues are suitable for its verification. Since arsenic can be accumulated in hair and nails, it is possible to specify the time (period) of its ingestion by their segmental analysis. To make impurity profiling analysis for an arsenious compound, which had been mixed with a large amount of a complicated matrix such as foods, it is not possible to accomplish it
  9. Arsenic compounds and other inorganic poisons 645 only by usual instruments of X-ray fluorescence analysis, ICP-MS and ICP-AES being equipped in chemical laboratories. In such a case, the SPring-8, a large scale instrument for photoemis- sion, enables the very sensitive profiling analysis by microprobe X-ray fluorescence using a powerful excitation beam at as high as 116 keV. Poisoning cases, and toxic and fatal concentrations Acute and chronic cases of poisoning by arsenic are summarized in > Tables 4.1 and 4.2 [1–7]. There were many fatalities in acute poisoning cases. In the chronic poisoning cases, the victims were drinking well water originating from an arsenic-containing vein (such as white arsenic stones) for a long period; such a kind of poisoning took place in limited areas ( > Table 4.2). The lethal dose of arsenic is considered to be 1.4 mg/kg (70–180 mg in adults) in the form of arsenious acid. Normal and toxic concentrations of arsenic in human body fluids and organs are summarized in > Table 4.3 [8–10]. ⊡ Table 4.1 Cases of acute arsenic poisoning Incident Food material Year Country Ref. Manchester bear incident bear 1990 United Kingdom [1] dry milk arsenic incident dry milk 1955 Japan [2] “shoyu” arsenic incident shoyu 1956 Japan [3] ⊡ Table 4.2 Cases of chronic arsenic poisoning due to drinking well water Area Country Year Ref. Cordoba Argentine 1938 [4] Antfagastan Chili 1977 [5] South-east coast Taiwan 1968 [6] Sanjyo-shi, Niigata Japan 1962 [7] ⊡ Table 4.3 Normal and toxic concentrations of arsenic in human body fluids and organs (µg/mL or g) Sample Normal Toxic Ref. [8] Ref. [9] Ref. [9] Ref. [10] blood 0.01–0.59 – 0.6–9.3 0.4–1.7 urine 0–0.1 – – 4.6 brain – 0–0.025 0.2–4.0 1.4 lung 0.08–0.17 0–0.085 – – liver 0.09–0.3 0–0.092 2.0–120.0 10.0 kidney 0.07–0.14 0–0.068 0.2–70.0 4.9 scalp hair 0.3–1.17 0–1.92 – 39.0, 226.0 nail 0.02–2.9 0–1.7 – 80.0
  10. 646 Arsenic compounds and other inorganic poisons Notes a) “Arsenite” is a general term for trivalent inorganic arsenic compounds, such as diarsenic trioxide, arsenious acid and sodium arsenite. b) Organic forms of the pentavalent arsenic compounds, such as DMAA, arsenobetaine and arsenocholine, are almost nontoxic and exist naturally in seaweed, fish and shellfish. There- fore, arsenic is incorporated into mammals via their foods. However, disodium arsenate, a pentavalent inorganic arsenic compound showed an i. p. LD50 value of as low as 14–18 mg/kg in rats. c) Arsenious acid is the same as arsenous acid. When diarsenic trioxide is dissolved in water, the following reactions take place. Diarsenic trioxide and arsenite salts, such as sodium arsenite and potassium arsenite, exist as white powder; but arsenious acid only exists in acidic aqueous solution. Because of the above immediate conversion of diarsenic trioxide into arsenious acid in water, the former compound is sometimes called “arsenious acid” popularly.
  11. Arsenic compounds and other inorganic poisons 647 References 1) Reynolds ES (1901) An account of the epidemic outbreak of arsenical poisoning occurring in beer-drinkers in the north of England and Midland countries in 1900. Lancet 1:166–170 2) Hamamoto E (1955) Infant arsenic poisoning by powdered milk. Nihon Iji Shinpo 1649:3–12 3) Mizuta N, Mizuta F, Ito T et al. (1956) An outbreak of arsenic poisoning caused by arsenic contained in soy- sauces shoyu. A clinical report of 220 cases. Bull Yamaguchi Med Sch 4:131–150 4) Arguello RA, Cebge DD, Tello EE (1938) Cancer y arsenicimo regional endemico en Cordoba. Rev Argintina Dermatosifilol 22:461–487 5) Zaldivar R, Guillier A (1977) Environmental and clinical investigations on endemic chronic arsenic poisoning in infants and children. Zbl Bakteriol Hyg 65:226–235 6) Tseng WHP, Chu HW, How SW et al. (1968) Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Natl Cancer Inst 40:453–463 7) Terada H, Katsuta K, Sasagawa C et al. (1960) Clinical observation of chronic arsenic poisoning. Jpn J Clin Med 18:2569–2578 (in Japanese) 8) IARC (1980) Monographs on the Evaluation of the Carcinogenic Risks on Chemicals to Humans, Vol.23. Interna- tional Agency for Research on Cancer, Lyon, pp 75–77 9) Baselt RC, Cravey RH (1995) Disposition of Toxic Drugs and Chemicals in Man, 4th edn. Chemical Toxicology Institute, Foster City, CA, p 56 10) Poklis A, Saady JJ (1990) Arsenic poisoning: acute or chronic? Suicide or murder? Am J Forensic Med Pathol 11:226–232

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