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Edited by E. Merian,M.Anke, M.lhnatand M.Stoeppler

@WILEY-VCH

Elements

and their Compoundsin the EnvironmentOccurence, Analysisand Biological Relevance

Volume2Metals and

Their Compounds

2nd, CompletelyRevised and

EnlargedEdition

,

( L S--1( .

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Elements and Their Compoundsin the Environment

Edited by

E. Merian (n M. Anke, M. Ihnat andM. Stoeppler

Volume 2:

Metals and Their Compounds

Elements and Their Compoundsin the Environment

Occurrence, Analysis and Biological Relevance

2nd, completely revised and enlarged edition

Edited byE. Merian (t), M. Anke, M. Ihnat and M. StoeppJer

Volume 2:

Metals and Their Compounds

GQWILEY-

VCH

WILEY-VCH Verlag GmbH & Co. KGaA

.

Editors: This book was carefully produced. Nevertheless,editors, authors and publisher do not warrant theinformation contained therein to be free of

errors. Readers are advised to keep in mind thatstatements, data illustrations, procedural detailsor other items may inadvertently be inaccurate.

Manfred AnkeAm Steiger 1207743 JenaGermany

MilanIhnat

PacificAgri-FoodResearchCentreAgricultureand Agri-FoodCanadaSummerland, BCVOHIZOCanada

Library of Congress Card No: applied for

British Library Cataloging.in-publication Data:A catalogue record for this book is available fromthe British Library.

Markus StoepplerMariengartenstrasse 1a,52428 JOlichGermany

Bibliographic information published byDie Deutsche Bibliothek

Die Deutsche Bibliothek lists this publicationin the Deutsche Nationalbibliografie; detailedbibliographic data is available in the Internet at<http://dnb.ddb.de>.

@ 2004 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim

All rights reserved (including those of translationinto other languages). No part of this book maybe reproducted in any form - by photoprinting,microfilm, or any other means - nor transmittedor translated into machine language withoutwritten permission from the publishers. Regis-tered names, trademarks, etc. used in this book,even when not specifically marked as such, arenot to be considered unprotected by law.

Printed in the Federal Republic of GermanyPrinted on acid-free paper.

Composition, Printing and Bookbinding:Konrad Triltsch,Print und digitale Medien GmbHOchsenfurt-Hohestadt

ISBN 3-527-30459-2

Contents

Preface V

Overview XXIX

Listof Contributors XXXV

EditoralBoard XLII

Part III Metals and their Compounds 477

1 Alkali Metals 479

1.1 Lithium 479

ULRICH SCHAFER

1.1.1

1.1.2

1.1.2.11.1.2.2

1.1.3

1.1.4

1.1.51.1.6

1.1.7

1.2

Introduction 479

Physical and Chemical Properties and Analytical Methods 480

Physical and Chemical Properties 480

Analytical Methods 481Sources, Production, Important Compounds, Uses, Waste Products and Recy-

cling 481Distribution in the Environment, in Foods, and in Living Organisms 485

Uptake, Absorption and Elimination in Plants, Animals, and Humans 487Effects on Plants, Animals, and Humans 488

Hazard Evaluation and Limiting Concentrations 491

Sodium 497

MANFRED K. ANKE

4.4.3

4.4.44.4.5

4.4.6

4.54.6

4.6.1

4.6.24.6.3

4.7

5

5.15.25.3

5.4

5.5

5.6

5.7

6

6.16.26.2.16.2.26.3

6.4

6.5

6.66.7

7

7.1

Contents I XV

Antimony in Soil 662

Antimony in Plants 663Antimony in Human Foods and Diets 663

Antimony in Humans and Animals 664

Uptake, Absorption and Elimination in Plants, Animals and Humans 664Effects on Animals and Humans 665

Acute Effects on Animals and Humans 665

Genotoxicity and Cytotoxicity 666Miscellaneous Biochemical Effects 666

Hazard Evaluation and Limiting Concentrations (see also Part II, Chapter

8) 667

Bismuth 671

AURORA D. NEAGOE

Introduction 671

Physical and Chemical Properties, and Analytical Methods 671Sources, Production, Important Compounds, Uses, Waste Products,

Recycling 674Distribution in the Environment, in Foods, and in Living Organisms 676

Uptake, Absorption, Transport and Distribution, Metabolism and Eliminationin Plant, Animals, and Humans 677Effects on Plants, Animals and Humans 680

Hazard Evaluation and Limiting Concentrations 683

Cadmium 689

ROBERT F. M. HERBER

Introduction 689

Physical and Chemical Properties, and Analytical Methods 690

Physical and Chemical Properties 690

Analytical Methods 691

Sources, Production, Important Compounds, Uses, Waste Products, and

Recycling 691Distribution in the Environment, in Foods, and in Living Organisms 693

Uptake, Absorption and Elimination in Plants, Animals and Humans 696Effects on Plants, Animals, and Humans 701

Hazard Evaluation and Limiting Concentrations 704

Chromium 709

BARBARA STOECKER

Introduction 709

5Bismuth

Aurora D. Neagoe

5.1Introduction

Bismuth, one of the rarest of elements, was

discovered by miners of Saxonia in the 15thcentury. The name of the element bismuthwas coined in the Ore Mountains (easternGermany), and then latinized by GeorgiusAgricola (Schmutzer 1993). Bismuth wasfirst described in 1527 by the physicianand alchemist Paracelsius (1493-1541),and the atomic symbol Bi was proposed byJ. J. Berzelius in 1814. Bismuth occurs lessrarely than mercury, but shows a more fre-quency of appearance as silver. It is foundin its native form, and also in minerals

such as bismuthite (bismuth sulfide) andbismite (bismuth oxide). The main use ofbismuth is in pharmaceuticals and in low-melting point alloys which are used asfuses (- 4000 tons annually). Occupationalintoxication by these alloys are rare, and inmost instances the adverse effect is caused

by other metals present in the alloys suchas lead and cadmium. Bismuth as a metalis classed as nontoxic.

5.2

Physical and Chemical Properties, andAnalytical Methods

Bismuth is a member of Group V of thePeriodic Table of the elements, but typicallyhas metallic properties and shows somesimilarities to lead, arsenic, and antimony(Emmerling et a1. 1986). The metal has anatomic weight 208.98, atomic number 83,density 9.79 gcm-3 (20°C), melting point271.3 °C, boiling point 1560::1:5°C, hard-ness (Mohs) 2.5, electron configuration[Xe]6s24f45dt06p3, electronegativity 2.02(Pauling), and radius 155 pm (atomic);152 pm (covalent); 240 pm (Van derWaals). Bismuth is the most diamagneticof all metals, and its thermal conductivityis lower than that of any metal except mer-cury. It has a high electrical resistance, andhas the highest Hall effect of any metal(i.e., greatest increase in electrical resistancewhen placed in a magnetic field).

Pure Bi is a lustrous reddish white metal,

is the heaviest naturally occurring stable ele-ment, and is easily malleable. Only one nat-ural isotope (atomic mass 209) is known,though artificial isotopes are known withmasses between 199 and 215 and half-lives

ranging from 2.15 minutes to 3 millionyears. Bi generally shows a valence of 3 +

Elements and their Compounds in the Environment. 2nd Edition.Edited by E. Merian, M. Anke, M. Ihnat, M. StoepplerCopyright @ 2004 WILEY-VCHVerlag GmbH &Co. KGaA, WeinheimISBN: 3-527-30459-2

6721 5 Bismuth

but also shows valencies of 5 + , 4 + , and 2 +

in its compounds. The stability of bismuthsolutions under a variety of conditions hasbeen investigated. Significant losses wereobserved after only 24 hours when the pHvalue was > 1.5, and hence all solutions

should be maintained at pH ~ 1 (Smith1973). On solidification (solid state at289 K with a monoclinic crystal structure),

bismuth expands; this makes it suitablefor the manufacture of sharp castings ofobjects which are subject to damage athigh temperatures (Thomas 1991). Bismuthmetal burns in air with a blue flame, form-

ing yellow fumes of the oxide (Bi20rbis-mite):

4Bi + 302 -+ 2Bi203~HR = -1148.6kJmol-1

With chlorine, bismuth powder reacts underwarm conditions:

2 Bi + 3 Cl2 -+ 2 BiCl3~HR = - 758.8kJmol-I

On heating, bismuth reacts also with bro-mine, iodine, sulfur, selenium, and tellurite,

but it does not react with nitrogen and phos-phorus. With sulfuric acid and nitric acid,bismuth forms salts:

2 Bi + 6 H2S04 -+ Bi2(S04h + 3 S02

+ 6 H20

2Bi + 6HN03 -+ 2Bi(N03h + N02

+ 3H20

For analytical purposes, bismuth can bedetermined without interference by use ofair-acetylene flame atomic absorption spec-troscopy (FAAS) (Welz and Sperling 1998,Ju 2002). The characteristic concentrationat the 222.8 nm resonance line is

0.2 mg L-I; various other analytical linesare compiled in Table 5.1. An improvedsignal-to-noise (SIN) ratio can be obtainedin the air-hydrogen flame with a limit ofdetection (LOD) of - 0.015mgL-1.

In biological and environmental samples,bismuth generally occurs at concentrationstoo low to be determined using FAAS with-out prior pre-concentration. In such cases,bismuth is monitored using either graphitefurnace (GF) AAS or hydride generation(HG) AAS.

In order to determine Bi by GF AAS

under stabilized temperature platform fur-nace (STPF) conditions using the Pd-Mgmodifier, a pyrolysis temperature of1200°C must be applied (Hiltenkamp andWerth 1988). The optimum atomizationtemperature under these conditions is1900°C; the characteristic mass with

Zeeman effect background correction (BC)is 28 pg, while in a non-Zeeman instrumentit is about 20 pg.

Without a modifier, Bi can be determined

at an optimum atomization temperature of

Tab.5.l: Bismuth analytical lines. (From Welz and Sperling 1998)

, Air-acetylene flame, oxidizing (lean, blue). .. With Zeeman-effect Be. ... With Zeemann-effect BC inflames.

Wavelength Energy level Slit width Characteristic concentration.

Spectral

[nmJ [I<] [nmJ [mgL -'J interferences

222.83 0-44865 0.2 0.2 Fe [5894]*'306.77 0-32588 0.7 0.6 OH [3941r'206.17 0-48489 0.7 1.6

227.66 0-43912 0.7 2.7

only 1400°C, with the sensitivity improvedby - 60%.However,this approach is not rec-ommended in practice as the maximumpyrolysis temperature is only 600°C andthe risk of interference is drasticallyincreased. In a transversally heated atomizerthe optimum atomization temperature is1700°C and the characteristic mass with

Zeeman-effect BC is 60 pg. Under STPFconditions, using the Pd-Mg modifier,30 g L-1 sulfate and 1 g L-1 NaCl do not inter-fere with the determination of Bi. Higherconcentrations ofNaCl cause a loss in sensi-

tivity by about 20%, but this does notincrease further up to a NaCl concentrationof 30 g L-1. A spectral interference has been

observed at the 223.1 nm line due to highiron concentrations, as are found in metal-

lurgical samples (Welz and Sperling 1998).Barbosa et al. (2001) described a method

for the determination of Bi in whole blood

and urine using ET AAS. The methodused a pyrolytically coated integrated plat-form tube coated with a tungsten-rhodiummixture, which acted as a permanent chem-ical modifier, and this improved the furnacetube lifetime by 80%. Urine samples werediluted 1 + 1 (v/v) and blood samples 1 + 4(v/v) with 1% HN03 Triton X-100. Samples(20 J.Ll) were injected into the modifiedtube with a 10 ilL volume of Rh. ReportedLaDs were 3 f.LgL-1 and 8 f.LgL-1 for urineand blood, respectively.

Bismuth can also be determined with

excellent sensitivity using HG AAS; theLaD of 0.03 f.LgL-Iis more than an orderof magnitude better than with GF AAS. Var-ious interferences by transition metals havebeen described which may be significant,especially for the analysis of metallurgicalsamples. Measures recommended to elimi-nate these interferences include the addition

of potassium iodide, 8-hydroxyquinoline,thiosemicarbazide, or EDTA, performingthe determination at higher acid concentra-

5.2 Physical and Chemical Properties, and Analytical Methods 1673

tion, and the addition of iron as a buffer

(Welz and Sperling 1998).Bismuth is one of the elements most

easily determined with anodic stripping vol-tammetry (Florence 1972) as it can be depos-ited onto electrodes at potentials at whichmost other elements are in solution.

Glassy carbon electrodes coated with filmsof mercury, but also of gold, have beenused (Florence 1974). In biological materialswith low concentrations of Bi, interference

from other metals is not to be expectedbecause of the low levels of most metals inthese materials. Best results are reached

with solutions containing 0.1 M hydro-chloric acid, with detection limits in the

range of 1 f.LgL-I(Iffiand 1993).Together with some other metals such as

Cu, Hg, and Pb, bismuth may be identifiedchromatographically as the dithiocarbamateusing reversed-phase liquid chromatogra-phy. The chelate is formed in a precolumnpacked with CIs-bonded silica and loaded

with a centrimide-dithiocarbamate ion pair.The metal complexes are preconcentratedon the precolumn and eluted with an aceto-nitrile/water gradient. The dithiocarba-mates are detected with a UV-Visible diodearray detector with a detection limit in the

subnanogram range (Iffiand 1993).Shu et al. (2002) and Chen et al. (2002) de-

scribed a method for to determine Bi usingflow injection-hydride generation. Bismuthhydride gas was collected on-line and deter-

mined via a new flow injection-hydride gen-eration collection-flame atomic absorptionspectrometry system. The performance ofthe gas-liquid separator, hydride gas collec-tion time, acidity of the sample solution,NaBH4 concentration, and the effects of con-

comitant interferents were investigated, andrecoveries of94.7-105.3% for 10 ngmL -1 Biwere obtained after the addition of 0.2%

ascorbic acid-thiourea masking reagents.The sensitivity of this new method was one

6741 5 Bismuth

order of magnitude higher than the contin-uous flow-HG-FAA method, with a detec-

tion limit of 0.25 ngmL -1 and a precisionof2.3%. The method was evaluated by deter-mining trace bismuth in standard biologicalreference material human hair GBW07601,and the results were consistent with the cer-

tified value. The proposed method was thenemployed to determine trace bismuth in tencolored gelatin samples, and recoveries of94.2-105.8% were obtained.

The main advantage of emission spec-trometry is the possibility of determiningseveral elements simultaneously. Onemethod is the hydride generation of BiH]in acid solutions by tetrahydroboratetogether with other elements of Group 15of the Periodic Table. The hydrides are car-ried by argon to the plasma sources of thespectrometer. Moyano et al. (2001) de-scribed a method for the determination of

Bi in urine using flow injection (FI)-HG-ICp.OES with on-line pre-concentration.Bismuth was concentrated by complexationwith quinolyn-8-o1 on an Amberlite anionexchange column and eluted with HNO].An LOD of 0.02 f.,IgL-1 was reported for Bipre-concentrated from a 100 f.Il. samplevolume.

Inductively coupled plasma-mass spec-trometry (ICP-MS) is a modem and moresensitive variation of MS detection of bis-

muth. Bismuthine is generated in a hydridegenerator and swept by argon directly intothe ICP unit. The ions are then introduced

into the mass spectrometer. Optimizationof the mass spectrometer, reagent, and gasflow parameters leads to a detection limitof 20 ngL-1 (Ulland 1993). Phillips et al.(2001) examined the safety aspects of colloi-dal bismuth subcitrate (CBS) quadrupletherapy for Helicobacterpylori. These authorsused ICP-MS to determine blood Bi levels in

34 patients receiving CBS quadruple ther-apy, with whole blood Bi levels being deter-

mined before and at 24 hours after treat-

ment. Three patients were within the"alarm level" for blood Bi of 50-100 f.,IgL-1.The authors advised that caution should be

exercised in prescribing CBS with gastricsuppression, and that alternative Bi prepara-tions should be investigated.

5.3

Sources, Production, Important Compounds,Uses, Waste Products, Recycling.

The most important ores for bismuth pro-duction are the sulfide ores of lead and

copper, and tin dioxide. The production ofmetallic bismuth is linked to lead and

copper refming. Peru, Japan, Mexico, Boli-via, and Canada are major bismuth produc-ers. while much of the bismuth produced inthe United States is obtained as a byproductin the refining lead, copper, tin. silver, andgold ores.

In compounds of bismuth, the mostcommon oxidation number of bismuth is

3. Some binary compounds are alsoknown: with halogens (known as halides- BiF], BiFs, BiCI], BiBr. Bi12' BiI]). withoxygen (known as oxides - Bip], BiPs).and with hydrogen (known as hydrides -BiH]). Bismuth hydride (BiH]) is toxic (likearsenic hydride), but is technically unimpor.tanto Many organic bismuth compounds arenot known, in contrast to those of arsenic.

Also of technological and toxicologicalinterest are bismuth sulfide. bismuth oxy-chloride, and salts of inorganic oxoacids(carbonate. nitrate, sulfate) and of organicacids (salicylate, triglycollate. bismuth cit-rate, gallate. lactate. or campforate). Manyof these salts have a basic form, such asbasic nitrate or subnitrate. Bismuth forms

trialkyls which are unstable in air butstable and insoluble in water (e.g., trime-thylbismuth). Bismuth sodium triglycolla-

5.3 Sources, Production, Important Compounds, Uses,Waste Products, Recycling. 1675

mate is the exception to the rule that bis-muthyl salts are practically insoluble inwater. Thiobismuthite compounds areformed by the reaction of Bi with sulfhydrylgroups. In the 5 + oxidation state, bismuthis a strong oxidizing agent, for example,NaBi06 or BiFs (KrUger et al. 1985). Bis-muth subcitrate forms a colloidal solution

with molecules of the formula [Bix(OH)y-(C6Hs07)J depending of the acidity on thesolution. Bismuth potassium tartrate andbismuth sodium tartrate are soluble in

water, but they decompose with time.Worldwide, about 64.5% of the bismuth

produced is consumed in United States inlow-melting alloys and metallurgical addi-tives, including electronic, photo- and ther-moelectronic applications (Flower andVouk 1986, Hocevar et al. 2002), in produc-ing malleable irons, as a thermocouplematerial (with the highest known negativ-ity), as an oxide catalyst (Cho et al. 2002),as a catalyst for making acrylic fibers, asceramics (Ng et al. 2002), glasses, andenamels. Pearlescent pigments in cosmeticsand paints contain bismuth. Bi2Te) is alsoused as a peltier element (Fowler and Vouk1986, Thomas et al. 1988, Falbe and Regitz1989, Tsalev and Zaprianov 1983). Bismuthis used in the preparation and recycling ofuranium nuclear fuel (Thomas 1991), andhas found application as a carrier for 23SUor 233Ufuel in nuclear reactors. With other

metals such as tin and cadmium, bismuth

forms low-melting alloys which are usedextensively for safety devices in fire detec-tion and extinguishing systems. The MerckIndex (Windholz et al. 1983) lists a total of37 bismuth compounds, 18 of which havepharmaceutical uses. In the United States,46% of the bismuth is used in the pharma-ceutical and cosmetics industry, 26% inengineering, and 27% in various metalindustries (Saager 1984). In medical terms,bismuth has been used (as tripotassium

dicitratobismuthate) for some time to treatstomach upsets, and is currently used incombination with antibiotics to treat some

stomach ulcers. Bismuth is also used (as bis-muth oxide) in hemorrhoid creams such asAnusol@ and Hemocaneas@, and in

Anusol@ ointment (as bismuth subgallate).Soluble salts such as bismuth subsalicylate,sodium triglycollamate and trioglycolatehave been used parenterally to treat infec-tious diseases (notably syphilis). Bismuthsalicylate, subcarbonate, subcitrate, subni-trate, glycobiasol and other salts are usedorally, or have been reported for use in thetreatment of reflux esophagitis (Borkentand Beker 1988), gastritis (McNulty et al.1986), indigestion (Hailey and Newsom1984), diarrhea, and other gastrointestinaldisorders. In particular, colloidal bismuthsubcitrate (CBS), when given in combinationwith antibiotics, is very effective at concentra-tions of 10-16 mg BiL-1 against mucosalCampylobacterpylori. This microorganism isresponsible for gastritis in 80- 90% ofcases, and is an important cofactor for gastricand duodenal ulcers (Trueb 1989).

Several organometallic compounds of Bihave been used as bactericides and fungi-cides (Sharma et al. 2003), as well as dustingpowders, astringents and radioopaqueagents in X-radiographic diagnosis (nowreplaced by barium sulfate). One possibleproblem for the future is that, if the use ofbismuth increases, then difficulties mayarise with regard to waste disposal. How-ever, as bismuth - when applied in suchmanner - is easily dissipated, recycling is

not an important factor. On the otherhand, substitution of bismuth compoundsis often possible, for instance, in therapeu.tics by antibiotica and magnesium or alumi-num oxides, in cosmetics by mica and fish-scales, in low-melting point alloys by plasticmaterials, and in additions to steel by sele-nium or tellurium (Saager 1984).

6761 5 Bismuth

5.4

Distribution in the Environment, in Foods,and in Living Organisms

Bismuth is one of the rarest of elements,

comprising only an estimated 0.00002% ofthe Earth's crust. In general, Bi concentra-tions in argilous sediments do not exceed0.5 f,lgg-I, though Bi accumulation in coalsand graphite shales to - 5 f,Igg-I have beenreported (Kabata Pendias and Pendias1992). Bi reveals chalcophilic properties -that is, during weathering it is readily oxi-dized, but when it becomes carbonated

(e.g., as Biz01C03) it is very stable. Hence,the Bi content of most surface soils is

directly inherited from parent rocks. Thereis a paucity of information on the Bi contentof soils. Vre et al. (1971) reported the meanBi content of arable Scottish soil derived

from different rocks to be 0.25 f,lgg-I(range: 0.13-0.42 f,lgg-I), while Chattopad-hyay and Jervis (1974) reported the rangeof Bi in garden soils of Canada to be from1.33 to 1.52 f,lgg-I. Aubert and Pinta (1977)reported Bi levels of 10 f,lgg-I in the ferra-litic calcareous soils of Madagascar. Anincrease of Bi in soil horizons rich in Fe

oxides and organic matter should beexpected, and Bi levels of3 f,lgg-I were iden-tified in sandstone (Fowler and Vouk 1986,Tsalevand Zaprianov 1983).

The Bi content of plants has not beenstudied widely. Shacklette et a1. (1978)found Bi in only about 15% of Rocky Moun-tain trees, with levels ranging from 1 to15 f,lgg-I air weight (AW). Similarly,Bowen (1987) reported mean Bi concentra-tions of < 0.02 f,lgg-I dry weight (DW) inland plants, and 0.06 ppm DW in theedible parts of vegetables. Erametsa et al.(1973) found a range of Bi in Lycopodiumsp. from < 1 to 11 ppm DW, with about60% detectability. Bi is likely to be concen-trated at polluted sites due to its high con-

centration in some coals and sewagesludges. Air concentrations are low in ruralareas (0.1-0.6 ngm-3) in contrast to cities(1-66 ngm-3), (Fowler and Vouk 1986). InGhent, Belgium, 0.12-0.78 ngm-3 wasmeasured (DeDoncker et a1. 1984). Annu-ally, on a worldwide basis, 14 tons of Bi arereleased on the environment as a result of

burning coals, and 190 tons by weathering(Mueller 1989).

Although bismuth is not detectable indrinking water, soil solutions, or riverwater, it is detectable in sea water at low con-

centrations (Thomas 1991). At the sea sur-face and down to a depth of - 1000 meters,concentrations of 0.2-0.1 pmolL-1 (0.00004-0.00002 f,lgkg-I) are found, while at a depthof 3000 meters the concentration is

0.015 pmolL-1 (0.000003 f,lgkg-I). This con-centration profile is similar to that of man-ganese (Bruland 1983). Bismuth was alsodetected in both rain water (3.2 ng L-I) andlake water « 0.15 ngL-1) in the USA (Lee1982).Bismuth concentrations in individualdietary samples have not been reported. Anumber of studies (e.g., Wolnik et al. 1981,Hahn et a1. 1982) certified by the U.S.National Bureau of Standards have included

analyses of rice flour, wheat flours, spinachand orchard leaves. and have reported Bilevels at < 80 f,lgkg-I. Similar values werealso reported for com, potatoes and soy-beans.

Bismuth levels in land animals were gen-erally below 4-20 f,lgkg-I, and in marineanimals and mammalian blood were consid-

erably lower « 40 to 300 f,lgkg-I DWand10 f,lgkg-I, respectively) (Fowler and Vouk1986, Thomas et a1. 1988, Thomas 1991).In man, small amounts of bismuth are

excreted in the urine, indicating some gas-trointestinal absorption, and small amountsare also detected in the blood (see Table 5.2)(Thomas 1991).

...

Tab. 5.2: Bismuth concentrations in the blood and

urine of normal humans

5.5 Uptake, Absorption, Transport and Distribution, Metabolism and Elimination in Plant, Animals, and 1677

Sample No. of samples Concentration'

Blood 67Urine 64

0.01 ::I:0.009 flIIlol L-1

0.06 ::I:0.14 flIIlol per day

.Values are mean::l: SD (Thomas 1991).

5.5

Uptake, Absorption, Transport andDistribution, Metabolism and Elimination inPlant, Animals, and Humans

Although metallic bismuth is used in indus-try in different alloys, occupational intoxica-tions by these alloys are rare and, in mostinstances, are caused by the presence ofother metals such as lead or cadmium. In

this respect, it might be concluded that bis-muth toxicity in an industrial setting is non-existent (Fowler and Youk 1986).

An important source of exposure to bis-muth for a specific segment of the popula-tion is the therapeutic use of bismuth com-pounds, mostly as injections or long-lastingremedies. In recent years, bismuth com-pounds have been used as therapies andhave been well tolerated (Hiland 1993,Pardi et al. 2002, Alizadeh-Naeeni et al.

2002, Olafsoons et al. 2002); cosmeticsremain a source of bismuth compoundsfor specific groups of the population.

Bismuth is not considered to be an essen-

tial element for plants and animals. Bi wasfound in low concentrations in marine ani-

mals (40-300 mgkg-1; molluscs may con-tain more - Bowen 1979) and in landplants (60 mgkg-1) but it has a lesserextend in land animals (4 mgkg-1)(Thomas 1991).

Bismuth compounds are considered to beslightly to moderately absorbed via the respi-ratory and gastrointestinal tracts, dependingon their solubility; between 0.027 and 0.20%

of an administered Bi dose may be absorbed(Thomas et al. 1988). Gastrointestinalabsorption of bismuth subnitrate has beenreported to increase with concomitantadministration of sulfhydryl compounds.Pre-absorption between the cells of the gas-trointestinal tract has been regarded asabsorption enhanced by promotory substan-ces, or absorption in ionic form (Serfonteinand Mekel 1979). Although, in humans,intestinal absorption is limited by the poorsolubility of bismuth and its propensity toform insoluble oxychloride salts, somedegree of absorption must occur in orderto produce measurable Bi concentrationsin the blood and urine (Table 5.2).

Bismuth absorption through the skin is ofinterest in relation to the use of its com-

pounds in oil-based cosmetics. Toxic symp-toms have been reported (Kriiger et al.1976), but normally these are minimal.The efficacy of intramuscular injections ofbismuth depends on the solubility of thecompounds in both body water and tissues.Water-soluble compounds are readily ab-sorbed within 24-48 hours (Prino andKlantschnigg 1960); hence, bismuth thio-glycollate, which is both water- and tissue-soluble, is rapidly absorbed. Oil suspensionsof insoluble bismuth compounds are oftenprecipitated locally, and this may cause a for-eign body reaction and/or abscess forma-tion, though the same effect can occurwith water-soluble compounds.

The body burden of bismuth is very low;the daily oral intake of Bi, combined withinhalational intake, is estimated at 5 -

20 J.Ig(Tsalev and Zaprianov 1983). Bismuthis one of the trace elements present in tis-sues, with relatively high levels beingfound in the nucleus ruber (Leonov 1956).Following its absorption, bismuth is foundin all tissues, though no relationshipbetween tissue concentration and therapeu-tic effect has yet been established. It is

6781 5 Bismuth

unclear how the biological activity of an ele-ment is maintained when it is "stored" in

the tissues; an example is bismuth deposi-tion in the metaphyses of bones of youngchildren, apparently without affectingnormal bone growth (Goodmann andGilman 1965, Gaucher et al. 1979). Follow-ing the oral administration of bismuth, thehighest tissue levels are found in the kid-neys (as inclusions in the epithelium ofthe proximal renal tubules), followed bythe liver, brain, spleen, small intestine,colon, and lung. Further deposits werefound in the enterocytes of the duodenumand proximal jejunum (Zidenberg-Cherret a1.1987). There appears to be no correla-tion between the storage of Bi in tissuesand biliary excretion. Levels in the intravasalcompartment or urinary excretion dependon the type of Bi compounds; its prepara-tion as powder, liquid, or tablet its solubility;and the amount ingested (Thomas et al.1983).

There exist no reliable criteria to define Bi

absorption, but possible criteria are bloodand plasma levels or daily urinary excretion.Blood levels of Bi > 300 f.IgL-I are dimin-ished by hemodialysis in vitro, and thismay be explained by there being two differ-ent forms of bismuth, namely soluble andbound (Allain 1976). Monitoring ofBi treat-ments should also include the determina-tion of Bi in whole blood as well as in

plasma (Rao and Feldman 1990). Bismuthadministered subcutaneously to rats asBiCI) is deposited in the kidneys, whichwere found to contain > 50% of the "acces-

sible poor' of bismuth. Retention in the kid-neys was diminished, while levels in liverand 12 other tissues were augmented (Jad-wiga et al. 1979).

The intraperitoneal administration of tri-potassium-dicitrato bismuthate (TBD) torats produced considerable amounts of bis-muth in the blood, after both acute and sub-

chronic treatment. In both cases, blood

levels of Bi corresponded to measurablelevels in the brain; this indicated that bis-muth is able to cross the blood - brain bar-

rier, with cerebral Bi levels reaching approx-imately 10- 30% of blood levels. Under suchtreatment conditions, the animals appearedhealthy and did not show any obvious signsof neurotoxicity.

Acute parenteral administration of higherdoses ofTBD (e.g., 328 mgkg-I, equivalentto 100 mgkg-I Bi20)) appears to inducesigns of neurotoxicity which manifest asconvulsive seizures (Abbracchio et al.1985). At 2 hours after injection of bismuthcitrate and sodium bismuth thioglycollate todogs and rabbits, about 3- 5% of the dosewas found in the kidneys, 6-10% in theliver, and 0.4% in the lungs. Within24 hours, the relative concentration in the

kidneys was increased to 7 -12%, but inthe liver was decreased to 1-4%. Within

one week, Bi concentrations in the kidneysand liver were reduced to 2.5%. After 4-5 weeks, the concentration in liver has

risen again (1%) compared with the kidneys(0.45%). Oral intubation of TBD to rats for14 months produced highest tissue concen-trations in the kidneys. Similar resultshave been obtained in the kidneys of dogsand rats, wherein the highest visceral con-centrations of bismuth were found after

3 or 6 months, respectively. In rats, thececum also showed extensive bismuth ac-

cumulation (Fowler and Vouk 1986).Rates of bismuth excretion after intra-

muscular injection into rabbits were moni-tored for 13 different bismuth compounds,and water-soluble compounds were seen tobe excreted more rapidly than those sus-pended or dissolved in oil. Excretion of bis-muth during 4 days ranged from 82.2% ofthe dose for an aqueous solution of bismuththioglycollate to 1.9% for an oil suspensionof bismuth oleate, though excretion contin-

5.5 Uptake, Absorption, Transport and Distribution, Metabolism and Elimination in Plant, Animals, and 1679

ued for least 36 days in both cases. Theretention of bismuth in the kidney wasshort-lived, and by day 17 after injectionalmost 95% of the dose had been excreted

(Fowler and Vouk 1986).Protein binding of bismuth may be seen

as a detoxification process and also as amechanism of metabolism (Fowler andVouk 1986, Thomas et aI. 1988). Nuclearinclusion bodies of bismuth were found

within the proximal tubule cells of the kid-neys in animal models by energy-dispersiveX-ray microanalysis (Fowler and Goyer1975). Bi is bound in the nucleus to nonhi-stone proteins and released with time(Fowler and Goyer 1975). High concentra-tions of bismuth lead to changes of the mito-chondrial membranes and activities of

enzymes with functional sulfhydryl groupsin the liver and renal proximal tubule cells

(Woods and Fowler 1987), and this mayexplain the hepatic and renal toxicity effectsof bismuth (HIland 1993). These findingshave been confirmed with radiotracer mea-

surements in animal models (Zidenberg-Cherr 1987). Bi induces the formation oflow molecular-weight metal-binding proteinsimilar to metallothioneins in the kidneysand, to a lower extent, in liver for the bind-

ing of most intracellular Bi (Slikkerveer

and de Wolff 1989). The excretion of bis-muth is rather rapid, and is dependent

upon the speed of absorption, with most ofthe metal being excreted in the urinewithin 24 hours of administration (Prinoand Klantschnigg 1960). Studies in patientsreceiving Bi subgallate, Bi subcitrate or col-loidal CBS by the oral route showed signifi-cant urinary excretion of Bi (Table 5.3), sug-gesting that this is the main route of elimi-nation of absorbed bismuth. The daily elim-ination of bismuth in untreated people hasbeen estimated at 12 J.1g(Mueller 1989),including 2.9 J.1g excreted via the urine(Gavey et al. 1989). The elimination of bis-muth via the biliary/fecal route is only halfof that via the urine (Fowler and Vouk 1986).

Bismuth ingested from therapeuticagents is mainly eliminated in the feces asbismuth sulfide. In general, 10-20% isexcreted within 5 days, but elimination isstill incomplete after 10 days (Iffland1993). Overall, 99% of ingested bismuthmay be eliminated in this way (Fowler andVouk 1986, Mueller 1989). In cases of ence-

phalopathy, with remarkably high urine andblood levels (2000 and 1500 J.1gL-1, respec-tively), the half-lives of bismuth were calcu-lated for urine (4.5 days) and blood(5.2 days) (Iffland 1993). Cerebrospinalis

Tab. 5.3: Blood concentrations, urinary excretion and renal clearance of bismuth in asymptomatic patients

and in those with "neurotoxicity" after ingestion of bismuth salts

, Values are mean:i: SD (from Thomas et al. 1977). b Mean:i: range, various literature sources. < Estimate

only. Values in parentheses indicate numbers of patients.

Clinical state and salt Blood concentration Urinary excretion Renal clearance

implicated [pmol L-IJ [pmolL -IJ {mLmin-IJ

Asymptomatic

Bismuth subgallate' 0.18:i: 0.11 (10) 1.61 :i: 1.74 (10) 6.2

Bismuth subnitrate b 0.17:i: 0.10 (9) 0.97 :i: 0.61 (9) 4.0<

Bismuth subcitrate' 0.05 :i: 0.03 (8) 1.20 :i: 0.61 (8) 16.7

Neurotoxic

Bismuth subgallate' 1.00 :i: 0.93 (8) 1.52 :i: 0.72 (8) 1.1

Bismuth subnitrateb 4.27 :i: 3.39 (93) 7.74:i: 10.90 (21) 1.3<

680 I 5 Bismuth

liquor levels decreased more slowly, with ahalf-life of 15.9 days (Allain 1976).

The elimination kinetics of bismuth have

been described as a three-compartmentmodel with half-lives of 3.5 minutes,

0.25 hour, and 3.2 hours (Slikkerveer andde Wolff 1989). Biological half-times inhuman have also been reported: wholebody retention 5 days, kidney 6 days, liver15 days, spleen 10 days, and bone 13.3 days(IRCP 1960, Fowler and Wouk 1986).

5.6Effects on Plants, Animals and Humans

The form in which Bi is ingested is impor-tant, and indicates the tenuous nature of

proposed safe and toxic values for concentra-tions of bismuth in blood. For pharmaceut-ical use of Bi-containing compounds, thelower limit of Bi toxicity in blood has beenproposed at 0.48 JJgL-1. Patients who hadbeen ingesting bismuth subgallate but notshowing any toxic symptoms, had a meanblood bismuth concentration of

0.18 J.UIloIL-1,with an overall range of 0.10to 0.48 J.UIloiL-I (Thomas et al. 1977).Except for one patient, all values were< 0.24 J.UIlolL-I. Leonhardt and Klotz(1991) identified blood lower levels in treat-ments with Bi subgallate/nitrate (plasmalevel ~ 60 JJgL-I), Bi subsalicylate (plasmalevels < 6 JJgL-I) (Raedesch et al. 1990,Nwokolo et al. 1990), or Bi subnitrate« 30 JJgL-1) (Conso etal. 1975). Bismuthsubcitrate, in different forms, is the most

extensively studied bismuth compound."Alarm' levels can be exceeded for a short

time after investigation, without toxic conse-quences (Nwokolo et al. 1990, Raedeschet al. 1990, Nwokolo et al. 1990). At2 hours after a single dose of 108 mg Bi ascolloidal subcitrate, plasma levels in two vol-unteers were measured as 1.62 and

24.7 JJgL-I (Versieck et al. 1992), whilesteady-state plasma levels after treatmentfor 4-8 weeks ranged between 3 and58JJgL-1 (Serfontein 1979). Urine levelswere significantly increased at the end oftreatment, from 100-130 JJgL-I to530 JJgL-1 (Nwokolo etal. 1990). Bowen(1979) reported that 160 mg Bi per day waslethal to rats. The oral LDso for bismuthwas 20 gkg-I for rats and 484 mgkg-I forrabbits (KrUger et al. 1985). The lowest pub-lished oral lethal dose for humans was

221 mgkg-I (KrUger et al. 1985).Bismuth appears to have an adverse effect

an microorganisms by interfering with theirgrowth, and this is most likely the basis oforal pharmaceutical preparations contain-ing bismuth to treat various gastrointestinaldisorders, including reduction of fecal odorin patients with colostomies (Burns et al.1974) and treatment of peptic ulcer(McNulty et al. 1986).

Different Bi complexes may be expectedto affect different tissues, and in general aspecific "dangerous" or "toxic" level may beexpected to be associated with each individ-ual compound. A variety of toxic effectshave been described in man after intramus-

cular injection of soluble Bi compounds(Heyman 1944). With large doses, or withsmaller doses repeated over longer periodsof time, toxic effects involved the kidney,liver, and skin, as well as epithelial surfacesin intimate contact with body fluids. One ofthe most common toxic effects was that of

renal tubular damage, extending in somecases to acute tubular necrosis (Urizar andVernier 1966, Randal et al. 1972). Epithelialdamage and tissue necrosis indicate a pred-ilection for bismuth accumulation at sites of

fluid and electrolyte transport. The similar-ity with toxic effects of lead are striking,with the notable exceptions of peripheralneuropathy and encephalopathy associatedwith lead toxicity. There appears to be lim-

,

ited penetration of the "blood-brain bar-rier" when bismuth is administered parent-erally. Mainly bismuth subnitrate, but alsoother salts such as subsalicylate, subcarbon-ate, or sub silicate, were ingested in amountsbetween 5 and 20 g daily over periods ofyears before the disease was attributed tobismuth (Iffland 1993). Not all subjectsingesting Bi subgallate or Bi subnitratedevelop "neurotoxicity", but blood levels inpatients who had been ingesting Bi subni-trate and. exhibiting "neurotoxicity" weregenerally higher (see Table 5.3). Wide differ-ences in bismuth blood levels (72 to

2360 JlgL-1) were reported by several inves-tigating groups (Allain et al. 1976, Bugeet al. 1977, Martin-Boyer et al. 1978, Inde-keu and Laterre 1978, Aimez et al. 1975,Bes et al. 1976, Escourolle et al. 1977).

There appears to be no relationship betweenblood level, age, duration, and the amount ofBi ingested and the severity of clinical symp-toms. Both cerebrospinal fluid levels (10-100 JlgL-1) (Chaleil and Allain 1980, Inde-keu and Laterre 1978, Buge et al. 1977, Beset al. 1976, Emile et al. 1981) and urinarylevels (200-9600 JlgL-1) were also signifi-cantly increased (Chaleil and Allain 1980).The application of trimethyl and triethylbis-muth to the skin of rats and rabbits has been

reported to produce intense inflammationand edema; localized necrosis at the injec-tion sites was also observed. Acute local

effects of inhalation of trimethylbismuth

by rats, cats and dogs included pulmonaryedema, while eye irritation was observedafter inhalational exposure to alkyl-bismuth

(Fowler and Vouk 1986). Kidney damagewas produced in rats by single intramuscu-lar injections (0.03 to 1.5 gkg-1) of 13 differ-ent bismuth compounds; histologicalexamination of 104 rats showed that 36 or

37 animals which died before 21 days had

nephritis of varying degrees of severity, ashad 11of the 67 surviving rats. The proximal

5.6 Effects on Plants, Animals and Humans 1681

tubules constituted the most markedlyaffected site of bismuth toxicity. Immedi-

ately following inhalation exposure to trime-thylbismuth (10-20 minutes, concentrationnot stated), cats and dogs showed ataxia,restlessness, and convulsive seizures, whilebetween attacks the animals were clearly

depressed. Disturbances in conditionedreflexes occurred in rats and rabbits treated

with potassium bismuthate. The blood pres-sure of dogs given hypodermic or intramus-cular injections of trimethylbismuth (fourdoses, 350 mgkg-1 body weight) fell pro-gressively to shock level, without any signif-icant change in heart rate, arrhythmia orheart block (Fowler and Vouk 1986).

A conspicuous feature of Bi toxicity inman is the apparent complete reversibilityof the condition which occurs on cessation

of administration of a bismuth-containingdrug. Recorded fatalities occurred mostlyin children (a prominent feature of bismuthnephropathy) (Gryboski and Gotoff 1961),and in many cases were due to the factthat the cause of the condition was recog-nized too late. Deaths of children occurred

within 2-5 days after the use of supposito-ries containing the bismuth salt of hepta-diencarboxylic acid (Weinstein 1947). Like-wise, in a 45-year-old man with acquiredimmunodeficiency syndrome was hospital-ized for dehydration and water diarrhea,the only successful treatment was with bis-muth subsalicylate solution (lffland 1993).The daily oral doses ranged from 5.2 to4.9 g, but after 7 days the patient showedsymptoms of heavy Bi encephalopathy, anddied 3 days later. The post-mortem Biblood level was 200 JlgL-1 (Mendelowitzet al. 1990). Bi levels were seen to beextremely high in different regions of thebrain in cases of encephalopathy, withmeans of 6-10 gkg-1 wet weight (Beset al. 1976, Escourole et al. 1977) or 12-

54 mgkg-1 dry weight (Liessens et al. 1978).

6821 5 Bismuth

The application of trimethylbismuth tointact human skin produced no markedeffect, but intensive irritation was noted ifthe skin had been scratched. Irritation of

the upper respiratory airways and of theeye were also observed (Sollman and Seifter1939). Although the toxic effects of bismuthdepend on the route of administration, sys-temic involvement may became very seri-ous. Intramuscular injection may causepain, foreign body reaction (to precipitatedBi), and rarely abscess formation. Oraladministration may cause swelling of themucosa, vesiculation of the tongue andmucosa, and pigmentation. The symptoma-tology of systemic bismuth intoxication issimilar to those of lead and mercury.Increased salivation is usually one of thefirst symptoms (Moeschlin 1959). The typi-cal "bismuth line" develops as a bluish dis-coloration of the gums caused by depositionof Bi sulfide in the fibrous tissue, and pyor-rhea might occur with subsequent loss ofthe teeth. Generalized permanent discolora-tion of the skin has been described as a rare

incidence (Plisek et al. 1970). Ulcerative sto-matitis and/or colitis with bloody diarrheaare serious, but rare, complications. Themajor toxic manifestations are seen in thekidneys, with renal lesions perhaps pro-gressing to severe nephrosis with resultantrenal failure and death. Other toxic manifes-

tations include hepatic degeneration,peripheral neuritis, and bone lesions,which in adults include osteoporosis andosteomalacia. The highly characteristic andreversible form of encephalopathy, afteringestion of bismuth subgallate and bis-muth subnitrate and other salts, manifests

through typical symptoms: confusion, hal-lucinations, concentration incapacity, trem-ulousness, inability to walk, clumsiness,myoclonus, bone features, and ataxia. Inthe severe cases, coma, epilepsy and deatheventually occurred (Hiland 1993). Some

cases of intoxication were also reportedwith bismuth subcitrate (Playford et al.1990). Renal damage is a prominent featureof the toxicity syndrome in man of bismuthtriglycollamate, and possibly hepatotoxiceffects with bismuth subgallate (Serfonteinand MekeI1979).

With large bismuth doses, or with smallerdoses repeated over a long period of time,toxic effects involved the kidney, liver, skin,and epithelial surfaces in intimate contactwith body fluids. Subjects complained ofanorexia, nausea, vomiting, colicky abdomi-nal pain and diarrhea. Cervicovaginitis asso-ciated with vaginal pigmentation occurredin females. An exfoliative dermatitis has

also been described (Friedman et al. 2002),and nephrotic syndrome has been recorded.Jaundice and various bleeding disordershave been described, with multifocal hepaticnecrosis as their most likely origin. The onlycentral nervous system effect observed inthis "epithelial-cutaneous" form of toxicity.was that of headache. There was no evidence

of carcinogenicity, mutagenicity, and/or ter-atogenicity of bismuth compounds (KrUgeret al. 1985).

According to Arena (1974), dimercaprol(British Anti-Lewisite; BAL)and D-penicilla-mine are either questionable (Slikkerveerand de Wolff 1989, Nwokolo and Pounder

1990, Goule et al. 1975) or contradictory(Liessens et al. 1978) in the treatment ofbis-muth toxicity. In severe bismuth poison-ings, BAL and 2,2-dimercaptolpropane-1-sulfonate (DMPS) seemed to be successful(Molina et al. 1979, Playford et al. 1990).Other methods used have included the

administration of atropine and meperidineto relieve gastrointestinal discomfort. Cau-tion is required in fluid administrationduring anuric and oliguric phases of neph-rosis, but loss of fluid and electrolytesshould be covered in the subsequent diuricphase (Karlitz and Freedman 1951).

Basinger et al. (1983) reported comparativestudies on nine chelating agents with

regard to bismuth toxicity. The use of chelat-ing agents was proposed to antagonize thetoxicity of bismuth.

At present, the ecotoxicological propertiesof Bi are not known, the main reason beingthe low concentration of the element in the

environment (HIland 1993). One problemmay be foreseen in the increased Bi contentin the vicinity of purification plants wherebismuth salts are prepared for use in thera-peutics (Mueller 1989).

5.7

Hazard Evaluation and LimitingConcentrations

Few data are available on the safety limits ofexposure to metallic bismuth or any of itscompounds (Thomas 1991), and the MAKReport XXIV (1988) does not list bismuthcompounds. A threshold limit value (TLV)of 5 mgm-3 was set for bismuth tellurideby the American Conference of Governmen-tal Industrial Hygienists in 1971 (Plunkett1987). Blood concentrations of Bi in asymp-tomatic subjects were well below the cur-rently stated upper safe limit of0.24 /illlolL-I (50IJgL-I) (see Table5.3).Other authors reported blood levels of-1IJgL-1 (Lee 1981), <3IJgL-1 (Bruceand Vouk 1986), 1-9IJgL-1 (Dekker et al.1986); and in serum, levels of 4.2 IJgL-I (Iff-land 1993), - 2 /lgL-I (Nwokolo et al. 1990),< 0.5 IJgL-I (Raedesch et al. 1990), and< 11JgL-1 (range 1-8IJgL-1) (Nwokoloet al. 1991). The highest mean concentra-tion in healthy human tissue (400/lgkg-1wet weight) was found in the kidney, fol-lowed by bone « 200 IJgkg-I). The brain,lung, and lymph nodes contained Bi in con-centrations from 10 to 40 IJgkg-I, while con-centrations ranging from 2 to 8lJgkg-1 were

References 1683

found in the testis, muscle, liver, and basal

ganglia. All forms of bismuth should bewithheld when blood bismuth concentra-

tions are > 100 IJgL-I. Those individualsin whom blood levels lie between 50 and

100 IJgL-I should be carefully reviewed(Thomas 1991).

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