Arsenic and inorganic arsenic compounds (with the exception of arsenic hydride and its salts) BLW
50 µg arsenic and methylated metabolites/ 1 l urine Sampling time: end of exposure or end of shift after several previous shifts
Date of evaluation
Molecular weight Melting point (°C)
arsenic arsenic trioxide arsenous acids
7440-38-2 1327-53-3 36465-76-6 13464-58-9
As As2O3 HAsO2 and H3AsO3
74.92 197.82 125.94
817 193 not stated
7784-46-5 1303-28-2 7778-39-4
Na AsO2 As2O5 H3AsO4
191.89 229.82 141.94
not stated 315 35
and their salts, e.g. sodium arsenite arsenic pentoxide arsenic acid and its salts, e.g. lead arsenate calcium arsenate
MAK [last established: 1971, 2002]
Carcinogen category 1
(See also the documentation for carcinogenic substances for arsenic trioxide in Vol. 2)
Arsenic, arsenic trioxide and pentoxide, arsenous acids, arsenic acid and their salts (arsenites and arsenates) are carcinogenic substances (Carcinogen category 1) and do not, therefore, have MAK and BAT values (Greim 2002). The former TRK value (technical exposure limit) for arsenic and its inorganic compounds was 0.10 mg arsenic/m3 (measured as the inhalable fraction of the aerosol; calculated as arsenic). This arsenic concentration in air correlated with an arsenic concentration in urine of 130 µg/l at the end of exposure or the end of the shift after several previous shifts (see the EKA documentation for arsenic trioxide in Volume 2 of this series; Greim and Lehnert 1995). The inorganic arsenic and methylated metabolites are analysed together. 1 2
volatile arsenic compounds determined by means of direct hydrogenation with hydride-AAS with the exception of gallium arsenide
The MAK-Collection Part II: BAT Value Documentations, Vol. 4. DFG, Deutsche Forschungsgemeinschaft Copyright © 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-27049-3
In addition to their carcinogenic effects in man, arsenic and the above-named arsenic compounds have toxic effects on the skin, the nervous system and the vascular system. Even with internal exposure values to arsenic below those corresponding to external exposure to arsenic trioxide at the level of the TRK value (EKATRK), such toxic effects have been described, so that with exposure at the level of the EKATRK value protection against these effects is not guaranteed (Wichmann and Lehnert 1987).
1 Metabolism and Kinetics 1.1 Absorption and distribution Man is exposed to different forms of organic and inorganic arsenic in foodstuffs, water and other matrices. Studies of the kinetics and metabolism of arsenic and its compounds are, therefore, complex. Inhalation exposure to inorganic arsenic occurs mainly at the workplace. In air, arsenic and its inorganic compounds are particle-bound and respiratory absorption therefore takes place in a two-phase process. After deposition of the particles in the respiratory tract and lungs, the arsenic is desorbed from the deposited particles. The extent to which the particles are deposited and the resulting exposure to arsenic therefore also depend on the size of the particles. Desorption of the arsenic compounds from the particles, however, depends on their solubility in water. For the reasons named, pulmonary retention cannot be estimated or quantified with sufficient certainty. All water-soluble inorganic arsenic compounds are absorbed after ingestion to a considerable extent (up to 95 %) in the gastrointestinal tract (Marquardt 1997). The bioavailability depends, however, among other things also on the matrix of the foodstuff. Dermal absorption can be regarded as low compared to absorption after inhalation and gastrointestinal absorption (Wester et al. 1993). Inhaled and ingested inorganic arsenic compounds first of all enter the blood. With a half-time of two hours, inorganic arsenic is rapidly eliminated from the blood. The arsenic compounds are distributed, as investigations with radioactively labelled arsenic compounds showed, in all the organs investigated. In addition to renal elimination, biliary excretion takes place. Experiments showed that elimination occurs in three phases in man. About 66 % of the administered doses is renally eliminated with a half-time of 2.1 days, around 30 % with a half-time of 9.4 days and the rest (4 %) with a half-time of 38.4 days (Marquardt 1997).
1.2 Metabolism The metabolism of arsenic in man and in many species of animal takes place in two steps; first of all arsenic(V) is usually reduced to arsenic(III), which is then methylated to form monomethylated and dimethylated arsenic compounds. A detailed overview of BAT Value Documentations, Volume 4
the metabolism of arsenic compounds can be found in the IPCS programme (WHO 2001) and in the EKA documentation for arsenic trioxide in Volume 2 of this series (Greim and Lehnert 1995).
2 Critical Toxicity A detailed description of the symptoms of acute and chronic intoxication with arsenic can be found in the current WHO monograph on arsenic and arsenic compounds (WHO 2001).
2.1 Acute toxicity The symptoms of intoxication after short-term and long-term absorption of inorganic arsenic compounds are similar and depend on the dose and bioavailability of the substance. The trivalent arsenic compounds are three to four times more toxic than the corresponding pentavalent compounds. The oral LD50 values for inorganic arsenic compounds, depending on the arsenic species and the experimental animal, are in the range from 7 to 100 mg/kg body weight (Marquardt 1997). The clinical symptoms after the ingestion of arsenic compounds occur within 30 to 60 minutes. Described are cardiovascular collapse, CNS depression and severe gastrointestinal symptoms. Death takes place within a few hours. With less dramatic cases of intoxication the main symptoms are gastrointestinal complaints including a metallic taste, a dry mouth, burning lips, dysphagia, vomiting attacks and occasional haematemesis.
2.2 Chronic toxicity The carcinogenic effects of inorganic arsenic compounds have been demonstrated in epidemiological studies in man. In addition to tumours of the bronchi and the lungs, in particular the skin tumours (basaliomas situated on the trunk) are pathognomonic. In addition to the carcinogenic effects, inorganic arsenic compounds cause damage in particular to the cardiovascular system and the nervous system. Long-term exposure to inorganic arsenic compounds is associated with cardiovascular diseases and cerebrovascular impairment. In particular the impairment of the peripheral vascular muscle-coat, even as far as gangrene of the affected extremities, has been consistently observed (WHO 2001). The neurotoxic effects can affect both the peripheral nervous system (Feldman et al. 1979, WHO 2001) and the central nervous system (WHO 2001). Arsenic and its compounds are sensitizing to the skin only in exceptional cases and the described association between exposure to arsenic and diabetes mellitus needs further clarification (Rahman et al. 1995). BAT Value Documentations, Volume 4
3 Exposure and Effects Peripheral vascular diseases were described in persons who consumed spring water with a high arsenic concentration. Symptoms such as acrocyanosis and Raynaud’s phenomenon were described after cumulative absorption of 8 g arsenic (Borgono et al. 1977). After cumulative absorption of 20 g arsenic, gangrene of the feet developed (Pershagen and Vahter 1979). In occupationally exposed copper smelters, vasospastic changes in the arteries of the fingers were reported (Lagerkvist et al. 1986, 1988). The workers were mainly exposed to arsenic trioxide. The exposure was determined by analysing the inorganic arsenic and its metabolites in urine. The mean arsenic concentration in the urine of the exposed workers was 71 µg/l (range 10–340 µg/l), that of the asymptomatic controls 7 µg/l (range 5–20 µg/l). There were statistically significant differences between the exposed persons and the controls in the systolic blood pressure of the finger after cooling and the anamnesis of Raynaud’s syndrome. It cannot be excluded, however, that in the past the exposure of the workers was much higher than at the time of the investigation. In the same group exposed to arsenic, the peripheral nervous system was investigated by means of electromyography and determination of the sensory nerve conduction velocity in the arms and legs. The exposed workers were found to have a slightly reduced nerve conduction velocity, which was interpreted as a subclinical sign of neuropathy (Blom et al. 1985). In another study, an increased incidence of clinically manifest and subclinical neuropathy in copper smelters was reported when the arsenic concentration in urine reached 250 µg/l (Feldman et al. 1979). One publication describes peripheral neuropathy in 51 persons with arsenic concentrations in urine above 100 µg/l (Heyman et al. 1956). Engel et al. (1994) give an overview of the vascular effects after long-term exposure to arsenic in their review based on 177 publications. In studies of the nephrotoxic (Foà et al. 1987) and hepatotoxic effects (Kodama et al. 1976), statistically significant changes were found in exposed workers who excreted mean concentrations of arsenic in the urine of 102 µg/l and 82 µg/l, respectively. To conclude, there are sufficient data from occupational-medical studies (see Table 1) which show adverse effects can occur at relatively low arsenic concentrations in urine, i.e. even below the former EKATRK of 130 µg/l. Table 1. Relationship between adverse effects on health and the arsenic concentrations in occupationally exposed persons (modified from ACGIH (2001) Observed effects
Arsenic in urine (µg/l) median (range)
vasospastic tendency peripheral neuropathy peripheral neuropathy peripheral neuropathy impaired kidney function increase in liver enzymes
71 (10–340) 71 (10–340) < 250 > 100 103 82 ± 49 (SD)
Lagerkvist et al. 1986 Blom et al. 1985 Feldman et al. 1979 Heyman et al. 1956 Foà et al. 1987 Kodama et al. 1976
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4 Selection of the Indicators After exposure to inorganic arsenic there is a significant and specific increase in the arsenic species monomethylarsenic acid, dimethylarsinic acid and inorganic arsenic excreted in urine. The determination of these three arsenic species in urine is therefore the preferred method for the biological monitoring of workers exposed to inorganic arsenic. The determination of these arsenic species is not influenced by organic arsenic compounds, such as arsenobetaine and arsenocholine, taken up with food. Determination of the total amount of arsenic excreted in urine is not suitable for monitoring investigations because organic arsenic compounds of maritime origin are also determined (see the EKA documentation for arsenic trioxide in Volume 2 of this series; Greim and Lehnert 1995). Inorganic arsenic and its metabolites are rapidly excreted after the beginning of exposure. The arsenic concentration in urine increases slowly and remains at a relatively constant level during the first three days of exposure. During the working day and from the end of work to the beginning of the next shift there are no notable changes in the concentration. The elimination kinetics show that during the working week there is significant accumulation of arsenic and its metabolites. Sampling should therefore take place at the end of the working week (see Section 1.1). The determination of arsenic in blood and the arsenic concentrations in hair and finger nail samples have not acquired any importance in the biomonitoring of occupationally exposed persons (see the EKA documentation for arsenic trioxide in Volume 2 of this series; Greim and Lehnert 1995).
5 Methods Inorganic and methylated organic arsenic compounds in urine are transformed for quantitative analysis into volatile hydrides and determined by atomic absorption spectroscopy. As a result of this method of direct hydrogenation of the urine sample only inorganic arsenic compounds and their metabolites monomethylarsenic acid and dimethylarsinic acid are transformed into volatile hydrides and quantified. A tested method can be found in “Analyses of Hazardous Substances in Biological Materials” (Angerer and Schaller 1991). If the urine sample is digested wet or dry the total arsenic content is determined. Therefore preparation of the urine samples should on no account be carried out. The following refers to the determination of inorganic arsenic and its methylated metabolites. In biological monitoring this arsenic fraction should be determined (Angerer and Schaller 1991).
BAT Value Documentations, Volume 4
6 Background Exposure In persons not occupationally exposed, the diet is the main route of absorption for inorganic arsenic compounds. Food, with the exception of sea-food, contains less than 0.25 mg arsenic/kg; various kinds of fish between 1 and 10 mg/kg, and shell fish more than 100 mg/kg. In food of maritime origin the arsenic is in organic form, usually as arsenobetaine and arsenocholine. The daily uptake with food is estimated to be between 0.04 (without fish) and 0.19 mg arsenic (with fish). In comparison, in Germany, insignificant amounts of arsenic are taken up from the drinking water and air. With the hydride-AAS method suggested in Section 5 the aromatic arsenic compounds excreted unmetabolized in the urine are not determined. Under these analytical conditions the background exposure is below 25 µg/l urine. Recent investigations have shown, however, that also the level of excretion of the named arsenic fraction (inorganic arsenic, monomethylarsonic acid and dimethylarsinic acid) can be influenced by the consumption of large amounts of food of maritime origin. These foods can already contain the methylated substances, in particular dimethylarsinic acid (Apostoli et al. 1999). It is therefore recommended that in future only the inorganic arsenic fraction be determined. Separation of the arsenic species is, however, a time-consuming and complicated analytical procedure. Reference values for the various arsenic species in urine samples from the general population of northern Germany have been published (Heinrich-Ramm et al. 2001).
7 Evaluation of the BLW Value The former TRK value for arsenic trioxide and pentoxide, arsenous acids, arsenic acid and their salts was 0.10 mg arsenic/m3 air. In 1994 an EKA correlation was established for arsenic trioxide, in which an arsenic concentration in the air of 0.10 mg/m3 corresponds to the excretion of 130 µg arsenic/l urine. The TRK value was not toxicologically grounded and observation of the value did not provide sufficient protection against the toxic effects named in Section 2.2. For the prevention of (non-carcinogenic) toxic effects of arsenic, irrespective of the carcinogenic potency of arsenic, exposure should remain below 50 µg arsenic/l urine. Taking into account the literature cited, it is to be expected that arsenic-induced effects can develop at arsenic concentrations in urine in the range of 100 µg/l. Changes in the peripheral nerves of occupationally exposed persons were detected even at a mean arsenic concentration of 71 µg/l urine (Blom et al. 1985). The BLW value has therefore been set at 50 µg arsenic/l urine This value is also compatible with the American BEI value (Biological Exposure Indices) (35 µg arsenic/l urine, sampling at the end of the working week), as this refers to the collective median and does not represent an individual ceiling value (ACGIH 2001). BAT Value Documentations, Volume 4
8 Interpretation of Data The toxicologically relevant arsenic concentration in urine is determined with the method described in “Analyses of Hazardous Substances in Biological Materials” (Angerer and Schaller 1991). The arsenic taken up with food of maritime origin is not determined. The use of the so-called hydride method is therefore imperative. The total amount of arsenic renally excreted must not be determined after preparation of the urine sample as the results can be greatly influenced by the food consumed. Fish and other sea-food can contain a high level of organic arsenic compounds. These compounds are rapidly absorbed by the gastrointestinal tract and can lead to the increased excretion of arsenic in urine. Arsenic concentrations in urine in the range of the BLW value can be reached and even exceeded (Mindt-Prüfert et al. 1999). It should also be noted that also with the use of the hydride-AAS method, the excretion of inorganic arsenic and its methylated metabolites can be influenced by high fish consumption (Apostoli et al. 1999). Fish can also frequently contain methylated arsenic compounds (in particular dimethylarsinic acid). The total amount of arsenic in urine can, therefore, be increased. If the BLW is exceeded, the individual should be specifically asked about his fish consumption over the last few days, and if necessary the arsenic concentration should be redetermined after a period without fish. After a single meal containing sea-food contaminated with organic arsenic compounds, the amount of arsenic excreted within 24 hours was 50 % to 70 % of the total amount of arsenic taken up (Marquardt 1997). Shortterm control investigations can therefore be useful. In some countries, such as Bangladesh, Argentina, Chile and India, considerable amounts of arsenic are taken up by the general population with the drinking water from contaminated wells. This causes amounts of arsenic to be excreted in urine which are above the BLW value (WHO 2001).
9 References ACGIH (American Conference of Governmental Industrial Hygienists) (2001) Arsenic and soluble inorganic compounds: BEI® 7th edition, Documentation. Publication # 7DOC-665, ACGIH®, Cincinatti Angerer J, Schaller KH (1991) Arsenic. in: Henschler D (Ed.) Analyses of hazardous substances in biological materials, Vol. 3, VCH, Weinheim Apostoli P, Bartoli D, Alessio L, Buchet JP (1999) Biological monitoring of occupational exposure to inorganic arsenic. Occup Environ Med 56: 825–832 Blom S, Lagerkvist B, Linderholm H (1985) Arsenic exposure to smelter workers. Clinical and neurophysiological studies. Scand J Work Environ Health 11: 265–269 Borgono JM, Vincent P, Venturino H, Infante A (1977) Arsenic in the drinking water of the city of Antofagasta: epidemiological and clinical study before and after the installation of a treatment plant. Environ Health Perspect 19: 103–105 Engel RR, Hopenhayn-Rich C, Receveur O, Smith AH (1994) Vascular effects of chronic arsenic exposure: a review. Epidemiol Rev 16: 184–209 BAT Value Documentations, Volume 4
Feldman RG, Niles CA, Kelly-Hayes M, Sax DS, Dixon WJ, Thompson DJ, Landau E (1979) Peripheral neuropathy in arsenic smelter workers. Neurology 29: 939–944 Foà V, Colombi A, Maroni M, Barbieri F, Franchini I, Mutti A, De Rosa E, Bartolucci GB (1987) Study of kidney function of workers with chronic low level exposure to inorganic arsenic. in: Foà V, Emmett EA, Maroni M, Colombi A (Eds) Occupational and environmental chemical hazards, Cellular and biochemical indices for monitoring toxicity, Ellis Horwood Limited Publishers, Chichester, 362–367 Greim H (Ed.) (2002) Arsen und anorganische Arsenverbindungen (mit Ausnahme von Arsenwasserstoff). Gesundheitsschädliche Arbeitsstoffe, Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten, 35. Lieferung, Wiley-VCH, Weinheim Greim H, Lehnert G (Eds) (1995) Arsenic trioxide. in: Biological exposure values for occupational toxicants and carcinogens – Critical data evaluation for BAT and EKA values, Vol. 2, VCH, Weinheim, pp. 123–136 Heinrich-Ramm R, Mindt-Prüfert S, Szadkowski D (2001) Arsenic species excretion in a group of persons in northern Germany – Contribution to the evaluation of reference values. Int J Hyg Environ Health 203: 475–477 Heyman A, Pfeiffer JB Jr., Willett RW, Taylor HM (1956) Peripheral neuropathy caused by arsenical intoxication. A study of 41 cases with observations on the effect of BAL (2,3, dimercapto-propanol). N Engl J Med 254: 401–409 Kodama Y, Ishinishi N, Kunitake E, Inamasu T, Nobutomo K (1976) Subclinical signs of the exposure to arsenic in a copper refinery. in: Nordberg GF (Ed.) Effects and dose-response relationships of toxic metals, Elsevier Scientific Publishing Company, Amsterdam, 464–470 Lagerkvist B, Linderholm H, Nordberg GF (1986) Vasospastic tendency and Raynaud’s phenomenon in smelter workers exposed to arsenic. Environ Res 39: 465–474 Lagerkvist BE, Linderholm H, Nordberg GF (1988) Arsenic and Raynaud’s phenomenon. Vasospastic tendency and excretion of arsenic in smelter workers before and after the summer vacation. Int Arch Occup Environ Health 60: 361–364 Marquardt H (Ed.) (1997) Lehrbuch der Toxikologie, Spektrum Akademischer Verlag, Heidelberg–Berlin, 510 Mindt-Prüfert S, Heinrich-Ramm R, Szadkowski D (1999) Zum alimentären Einfluß auf die Arsenausscheidung im Urin bei arbeitsmedizinischen Vorsorgeuntersuchungen. in: Rettenmeier AW, Feldhaus C (Ed.) Dokumentationsband über die 39. Jahrestagung der Deutschen Gesellschaft für Arbeitsmedizin und Umweltmedizin e.V., Druckerei Rindt, Fulda, 591–593 Pershagen G, Vahter M (1979) Arsenic: A toxicological and epidemiological appraisal. 071-SNV Rapporter från SNV, Statens naturvårdverk, Solna, Sweden Rahman M, Wingren G, Axelson O (1995) Diabetes mellitus among Swedish art glass workers – an effect of arsenic exposure? Scand J Work Environ Health 22: 146–149 Wester RC, Maibach HI, Sedik L, Melendres J, Wade M (1993) In vivo and in vitro percutaneous absorption and skin decontamination of arsenic from water and soil. Fundam Appl Toxicol 20: 336–340 WHO (World Health Organization) (2001) Arsenic and arsenic compounds. Environmental Health Criteria 224, Geneva Wichmann N, Lehnert G (1987) Arbeitsmedizinische Erfahrungen und TRK-Wert für Arsen. Arbeitsmed Sozialmed Präventivmed 22: 18–20
Author: H. Drexler Approved by the Working Group: 10.02.2002
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