Genotoxic effects of lead: An updated review

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Review

Genotoxic effects of lead: An updated review

Julia García-Lestón a,b, Josefina Méndez b, Eduardo Pásaro a, Blanca Laffon a,⁎a Toxicology Unit, Dept. Psychobiology, University of A Coruña, Edificio de Servicios Centrales de Investigación, Campus Elviña s/n, 15071-A Coruña, Spainb Dept. Cell and Molecular Biology, University of A Coruña, Faculty of Sciences, Campus A Zapateira s/n, 15071-A Coruña, Spain

a b s t r a c ta r t i c l e i n f o

Article history:Received 26 November 2009Accepted 15 April 2010Available online 14 May 2010

Keywords:LeadGenotoxicityChromosome aberrationsSister chromatid exchangesMicronucleus testComet assay

Lead is a ubiquitous toxic heavy metal with unique physical and chemical properties that make it suitable fora great variety of applications. Because of its high persistence in the environment and its use since ancienttimes for many industrial activities, lead is a common environmental and occupational contaminant widelydistributed around the world. Even though the toxic effects of lead and its compounds have beeninvestigated for many years in a variety of systems, the data existing with regard to its mutagenic,clastogenic and carcinogenic properties are still contradictory. The International Agency for Research onCancer has classified lead as possible human carcinogen (group 2B) and its inorganic compounds as probablehuman carcinogens (group 2A). Furthermore, although the biochemical and molecular mechanisms of actionof lead remain still unclear, there are some studies that point out indirect mechanisms of genotoxicity suchas inhibition of DNA repair or production of free radicals. This article reviews the works listed in theliterature that use different parameters to evaluate the genotoxic effects of lead in vitro, in vivo and inepidemiological studies.

© 2010 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6242. Genotoxicity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624

2.1. Hypoxanthine-guanine phosphoribosyl-transferase gene mutation assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6242.2. T-cell receptor mutation assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6242.3. Chromosome aberrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631

2.3.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6312.3.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6312.3.3. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631

2.4. Sister chromatid exchanges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6322.4.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6322.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6322.4.3. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632

2.5. Micronucleus test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6322.5.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6322.5.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6322.5.3. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632

2.6. Comet assay. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6332.6.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6332.6.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6332.6.3. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633

Environment International 36 (2010) 623–636

Abbreviations: BLL, blood lead levels; BNMN, binucleated cells with MN; CA, chromosome aberrations; CHO, Chinese hamster ovary; hprt, hypoxanthine-guaninephosphoribosyl-transferase; IARC, International Agency for Research on Cancer; MCR, mean micronucleated cells rate; MN, micronucleus; MNR, meanmicronuclei rate; NDI, nucleardivision index; SCE, sister chromatid exchanges; TCR, T-cell receptor; TCR-Mf, T-cell receptor mutation frequency; TL, tail length.⁎ Corresponding author. Toxicology Unit, University of A Coruña, Edificio de Servicios Centrales de Investigación, Campus Elviña s/n, 15071-A Coruña, Spain. Tel.: +34 981 167000;

fax: +34 981 167172.E-mail address: [email protected] (B. Laffon).

0160-4120/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.envint.2010.04.011

Contents lists available at ScienceDirect

Environment International

j ourna l homepage: www.e lsev ie r.com/ locate /env int


3. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634

1. Introduction

Lead is a non-essential element that occurs naturally in theenvironment. However, the highest concentrations found in nature arethe result of human activities. Many of its physical and chemicalproperties suchas softness,malleability, ductility, poor conductibility andresistance to corrosion, have favoured that man uses lead and leadcompounds since ancient times for a great variety of applications. TheRomans were the first to use lead on a large scale in the manufacture ofpipes for water supply, manufacture of tableware and kitchen utensils oreven as pigment. Lead acetatewas used later as a sweetener forwine andcider as well as in medicine for treating several diseases. Lead poisoningwas very important during the 16th to 19th centuries due to itswidespreaduse inpottery, pipes, boat building,manufactureofwindows,arms industry, pigments and printing of books. Many of these usesdeclined or disappeared throughout the 19th century, but alsointroduced new ones, as its application for improving the octane ratingof gasoline by the addition of tetraethyl lead, its use in glass containers forcooking or the use of paint with lead compounds (Hernberg, 2000).Nowadays, although thevastmajority of its useshavedisappeared, lead isstill present in many industrial activities such as car repair, manufactur-ing and recycling of batteries, lead paint removal, demolition, refiningand smeltery. It is also used for maintenance of structures found in theopen air as bridges or water towers, in solders of cans of food orbeverages, glazed ceramic, and can also bepresent in drinkingwater or intobacco smoke (Patrick, 2006; Spivey, 2007). In addition to occupationalexposure, given that leadhasbeenused since ancient times and that it is anon-biodegradable element, environmental pollution caused is persis-tent and widespread, affecting the population at large.

It is well documented that lead can cause adverse health effectsthat include neurotoxicity, nephrotoxicity, and deleterious effects onthe haematological and cardiovascular systems (ATSDR, 2007). It hasalso been found to be capable of eliciting a positive response in a widerange of biological and biochemical tests, which include tests forenzyme inhibition, fidelity of DNA synthesis, mutation, chromosomeaberrations (CA), cancer and birth defects (Johnson, 1998). Never-theless, data related to the mutagenic, clastogenic and carcinogenicproperties of inorganic lead compounds are still conflicting. TheInternational Agency for Research on Cancer (IARC) classified lead aspossible human carcinogen (group 2B) (IARC, 1987) and inorganiclead compounds as probable human carcinogens (group 2A) (IARC,2006). In some epidemiological studies exposure to lead has beenlinked to an increased incidence of some cancers such as stomach,lung and bladder cancers (Fu and Boffetta, 1995). There are severalproposed mechanisms to better understand the carcinogenic proper-ties of lead and the conditions required for this purpose. Thesemechanisms include mitogenesis, alterations in gene transcription,oxidative damage and several indirect genotoxicity mechanisms(Hartwig, 1994; Silbergeld, 2003).

A number of studies in different biological systems have usedseveral end-points to evaluate the genotoxic effects of lead. The mostrepresentative ones are the study of DNA lesions such as structuraland numerical CA, sister chromatid exchanges (SCE), micronucleus(MN) test, and DNA strand breaks by means of the single cell gelelectrophoresis (comet) assay that has beingmore andmore used dueto its sensitivity and simplicity (Collins, 2004). Moreover, as manymutational mechanisms are involved in the development of severalspecific types of tumours in humans (Shtivelman et al., 1985; Ponder,2001) different tests have been developed to determine the mutation

frequency caused by mutagenic agents in somatic cells. Among them,hypoxanthine-guanine phosphoribosyl-transferase (hprt) gene and T-cell receptor (TCR) mutation assays are the most frequently used.

Some authors reviewed previously the studies in the literature thatevaluated the genotoxic effects of lead through different genetic end-points in different test systems (Forni, 1980; Gerber et al., 1980;Winder and Bonin, 1993; Johnson, 1998). Evidences gathered in thesereviews are quite equivocal and the results of the compiledinvestigations are similarly variable, so authors could not clearlyconclude whether lead has genotoxic potential or not. Since then, aconsiderable number of new studies have been published which canhelp to clarify the possible interaction of lead, either directly orindirectly, with the genetic material, and to better understand themechanisms involved. This article reviews both former and recentstudies that used some of the most representative techniques toevaluate the genotoxicity of lead and lead compounds, compiling invitro, animal and human studies.

2. Genotoxicity studies

Tables 1, 2 and 3 gather the published studies on lead genotoxicityperformed in vitro, in experimental animals, and in humans, respectively.

2.1. Hypoxanthine-guanine phosphoribosyl-transferase genemutation assay

Most of the studies that used this assay to evaluate the in vitromutagenicity of lead did not show any increase in the mutationfrequency at the hprt locus (Patierno et al., 1988; Patierno andLandolph, 1989; Hartwig et al., 1990; Hwua and Yang, 1998). Onlytwo studies found positive results (Zelikoff et al., 1988; Yang et al.,1996).

Yang et al. (1996) evaluated themutagenicity of lead acetate at thehprt gene of CHO K1 cells. Their results showed that lead acetateinduced a dose-dependent increase of mutant frequency at doseslower than the LD50. To determine the mutational specificity inducedby lead, cDNA and genomic DNA sequences were characterized. Theyfound that the positions and kinds of base substitutions at the hprtgene induced by lead were different from those occurred spontane-ously, suggesting that different mutagenic mechanisms may exist forlead-induced mutants. On the contrary, Hwua and Yang (1998) didnot find any increase in the mutation frequency at the hprt gene indiploid human skin fibroblasts (HFW) at similar cytotoxic dosages oflead acetate than those used by Yang et al. (1996). According to theauthors, the fact that lead mutagenicity was observed in CHO K1 cells,but not in human fibroblasts, may be attributable to the differentdefence mechanisms against lead genotoxicity in HFW and CHO K1cells.

2.2. T-cell receptor mutation assay

To date there are only two studies which used the TCR mutationassay to evaluate the potential genotoxic effects of human exposure tolead. In our laboratory we evaluated 30 workers from two differentfactories engaged in the production of lead-acid batteries and glasschips, respectively (García-Lestón et al., 2008). We found statisticallysignificant differences between exposed and controls, showing theexposed group higher TCRmutation frequency than the control group.However, when the population was stratified according with tobacco

624 J. García-Lestón et al. / Environment International 36 (2010) 623–636


Table1

Invitrostud

ieson

lead

geno

toxicity

(ordered

chrono

logically

).

Test

system

Subs

tanc

eDose

End-po

int

Resu

lts

Referenc

e

CHO

cells

Lead

acetate

10−

6–10

−3M

for16

hCA

Noeffect,e

xcep

tforincrea

seof

gaps

atthe

high

estco

ncen

trationtested

Bauc

hing

eran

dSchm

id(1

972)

Hum

anlymph

ocytes

Lead

acetate

10−

6–10

−2M

for48

and72

hCA

Noeffect

Schm

idet

al.(19

72)

Hum

anleuk

ocytes

Lead

acetate

10−

5M

for24

hCA SC

ESign

ificant

increa

seof

achrom

atic

lesion

s,ch

romatid

brea

ksan

disochrom

atid

brea

ksNoeffect

Beek

andObe

(197

4)

Hum

anlymph

ocytes

Lead

acetate

1×10

−4–1×10

−2M

CASign

ificant

increa

seof

chromosom

efrag

men

tsDek

nudt

andDem

inatti(1

978)

Hum

anlymph

ocytes

Lead

chromate

Lead

chloride

4.3×10

−6–7.7×10

−5M

for6h

5×10

−5–1×10

−3M

for6h

CA SCE

Dose-de

pend

entsign

ificant

increa

seof

SCEan

dCA

freq

uenc

ies

Noeffects

Dou

glas

etal.(19

80)

Hum

anlymph

ocytes

Lead

sulpha

te20

–20

0μM

SCE

Dose-de

pend

entincrea

seW

ulf(1

980)

Hum

anlymph

ocytes

Lead

acetate

10−

3–10

−5M

for3h

CANoeffect

Gasiorekan

dBa

uching

er(1

981)

CHO

cells

Hum

anlymph

ocytes

Lead

sulpha

teLe

adch

romate

Lead

sulpha

teLe

adch

romate

10−

7–10

−4M

10−

8–10

−6M

10−

5–10

−3M

10−

6–10

−4M

SCE

CA MN

Dose-de

pend

entsign

ificant

increa

seof

SCErate

Noeffect

intheindu

ctionof

CADose-de

pend

entsign

ificant

increa

seof

MN

freq

uenc

y

Mon

taldie

tal.(19

87)

CHO

cells

Lead

chromate

10–10

0μM

for5h

hprt

mutationassay

Noeffect

Patierno

etal.(19

88)

Chineseha

mster

V79

cells

Lead

sulphide

Lead

nitrate

Lead

sulphide

Lead

nitrate

100–

938μM

for24

h50

–20

00μM

for5da

ys13

3–93

8μM

for24

h50

0–30

00μM

for24

h

hprt

mutationassay

SCE

Increa

seof

mutan

tfreq

uenc

yNoeffect

Zelik

offet

al.(19

88)

CHO

cells

Lead

chromate

25,5

0an

d100

μMfor5h

hprt

mutationassay

Noeffect

Patierno

andLand

olph

(198

9)Trad

escantia

clon

e44

30Le

adtetraa

cetate

0.44

–88

ppm

for30

hMN

test

Sign

ificant

increa

seof

MN

rate

atlower

doses.

Conc

entrations

≥23

.5pp

mweretoxic

Sand

huet

al.(19

89)

Chineseha

mster

V79

cells

Lead

acetate

0.5–

5μM

for44

h1,

5an

d10

μMfor46

hhp

rtmutationassay

SCE

Noeffectsalon

ebu

ten

hanc

emen

tof

UV-ind

uced

mutag

enicityan

dSC

EHartw

iget

al.(19

90)

Allium

cepa

Lead

nitrate

0.1–

200pp

mCA

Dose-de

pend

entincrea

seof

aberrant

cells

Lerda(1

992)

CHO

cells

Hum

anforeskin

fibrob

lasts(H

FF)

Lead

chromate(sus

pens

ionof

fine

particlesan

dag

greg

ates)

0.4–

8μg

/cm

2for24

h0.08

–2μg

/cm

2for24

hCA

Dose-de

pend

entincrea

seof

%metap

haseswith

damag

eon

lywithfine

particles

Wiseet

al.(19

92)

CHO

cells

Lead

chromate

1,5an

d10

μMfor24

hCA

Dose-de

pend

entincrea

seof

%metap

haseswithda

mag

eXuet

al.(19

92)

CHO

cells

Lead

nitrate

1×10

−3–3×10

−2mM

MN

test

SCE

CA

Noeffect

Sign

ificant

increa

seof

SCErate

Noeffect,b

uttype

sof

CAindu

cedweredifferen

tfrom

thosein

controls

Linet

al.(19

94)

CHO

cells

Lead

chromate

Lead

glutam

ate

Lead

nitrate

0.8an

d8μg

/cm

2for1–

24h

0.5,

1an

d2mM

0.5,

1an

d2mM

CADose-de

pend

entsign

ificant

increa

seof

%metap

haseswithda

mag

eW

eaklyclastoge

nicbu

tsign

ificant

only

at1mM

dose

Noeffect

Wiseet

al.(19

94)

CHO

K1cells

Lead

acetate

0.5–

3mM

for24

hhp

rtmutationassay

Dose-de

pend

entincrea

seof

mutan

tfreq

uenc

yat

lower

doses

Yang

etal.(19

96)

CHO

AA8cells

Lead

nitrate

10−

6,5

×10

−7an

d5×10

−8M

SCE

CASign

ificant

increa

seof

SCErate

Noeffect

Caia

ndArena

z(1

998)

Hum

anfibrob

lasts(H

FW)

Lead

acetate

0.5–

2mM

for24

hhp

rtmutationassay

Noeffect

Hwua

andYa

ng(1

998)

Ratan

dhu

man

kidn

eycells

Lead

acetate

0.56

–1.8mM

for20

hCo

met

assay

Dose-de

pend

entincrea

seof

TLan

dTM

Robb

iano

etal.(19

99)

Hum

anmelan

omacells

(B-M

ellin

e)Le

adacetate

10−

6,1

0−5an

d10

−3mM

for24

h(SCE

)or

44h(M

Ntest)

SCE

MN

test

Dose-de

pend

entincrea

seof

SCErate

Dose-de

pend

entsign

ificant

increa

seof

MN

freq

uenc

yPo

maet

al.(20

03)

Chineseha

mster

V79

cells

Lead

chloride

Lead

acetate

0.01

–10

μMfor18

hMN

test

Dose-de

pend

entindu

ctionof

MNfreq

uenc

yTh

ieret

al.(20

03)

Hum

anlymph

ocytes

Lead

acetate

1–10

0μM

Comet

assay

Sign

ificant

increa

seof

TLW

ozniak

andBlasiak(2

003)

Hum

anlung

fibrob

lastsWTH

BF-6

cells

Lead

chromate

0.1–

5μg

/cm

2for24

hCA

Dose-de

pend

entincrea

seof

%metap

haseswithda

mag

eW

iseet

al.(20

04)

Chineseha

mster

V79

cells

Lead

chloride

Lead

acetate

0.01

–10

μMfor18

hMN

test

Dose-de

pend

entindu

ctionof

MNfreq

uenc

yBo

nack

eret

al.(20

05)

Hum

anlung

fibrob

lastsW

THBF

-6Le

adch

romate

0.1–

5μg

/cm

2CA Co

met

assay

Dose-de

pend

entsign

ificant

increa

seof

%metap

haseswithda

mag

eDose-de

pend

entsign

ificant

increa

seof

tailintegrated

intensityratio

Xie

etal.(20

05)

Hum

anlymph

ocytes

Lead

nitrate

1.2an

d2mM

for2h

2.1–

3.3mM

for2h

CA Comet

assay

Increa

seof

CAfreq

uenc

yDose-de

pend

entsign

ificant

increa

seof

TLSh

aiket

al.(20

06)

Abb

reviations

:TL

,taillen

gth;

TM,tailm

omen

t.

625J. García-Lestón et al. / Environment International 36 (2010) 623–636


Table2

Animal

stud

ieson

lead

geno

toxicity

(ordered

chrono

logically

).

Stud

yan

imal

Subs

tanc

eDose

Adm

inistration

Celltype

End-po

int

Resu

lts

Referenc

e

A/sw

mou

seLe

adacetate

1%lead

inthediet

for2wee

ksOral

Lymph

ocytes

CAIncrea

seof

CArate

Muroan

dGoy

er(1

969)

Cyno

molgu

smon

keys

Lead

acetate

Normal

diet:1.5,

6or

15mg,6da

ysa

wee

kfor3,

10an

d16

mon

ths

Low

Cadiet:6mgsameco

nditions

Oral

Lymph

ocytes

CASign

ificant

increa

seof

“sev

ere”

CAin

thelow

Cadiet

grou

pIncrea

seof

“light”CA

inallg

roup

swithtime

Dek

nudt

etal.(19

77a)

C57B

1mice

Lead

acetate

0.5an

d1%

lead

inthediet

for3mon

ths

25mg/kg

bw,2

times

Oral

Intrap

eriton

eal

Bone

marrow

cells

CA MN

test

Sign

ificant

increa

seof

chromatid

gaps

Noeffects

Jacq

uetet

al.(19

77)

C57B

1mice

Lead

acetate

Normal

diet:0.5%

lead

for1mon

thLo

wCa

diet:sameco

nditions

Oral

Bone

marrow

cells

CASign

ificant

increa

seof

CArate

only

inthelow

Cadiet

mice

Dek

nudt

andGerbe

r(1

979)

Cyno

molgu

smon

keys

Lead

acetate

1or

5mgfor7,

9an

d12

mon

ths

Oral

Lymph

ocytes

CASign

ificant

increa

seof

chromatid

and

chromosom

eab

erration

sJacq

uetan

dTa

chon

(198

1)

Rabb

its

Lead

acetate

0.25

and0.50

mg/kg

bw,3

times/w

eek

for14

wee

ksSu

bcutan

eous

Bone

marrow

erythr

ocytes

Lymph

ocytes

MN

test

SCE

Noeffects

Noeffects

Willem

set

al.(19

82)

ICRmice

Lead

acetate

50–20

0mg/kg

bwin

the13

thda

yof

gestation

Intrap

eriton

eal

Materna

lbon

emarrow

cells

Foetal

liver

cells

SCE

Sign

ificant

increa

seof

SCErate

inmaterna

land

foetal

cells

Sharmaet

al.(19

85)

Spragu

e–Daw

leyrats

Lead

acetate

104mg/kg

bw,1

to5injections

Intrap

eriton

eal

Bone

marrow

cells

CA MN

test

Sign

ificant

increa

seof

CAfreq

uenc

ySign

ificant

increa

seof

MN

freq

uenc

yTa

chie

tal.(19

85)

ICRSw

issW

ebster

mice

Lead

nitrate

100,

150an

d20

0mg/kg

bwin

the

9thda

yof

gestation

Intrav

enou

slyfor

thefemales

andmaterna

lex

posu

reforfoetus

Materna

lbon

emarrow

cells

Foetal

liver

andlung

cells

Materna

lbon

emarrow

cells

Foetal

liver

cells

SCE

CASign

ificant

increa

seof

SCErate

Noeffects

Sign

ificant

increa

seof

structural

aberration

sin

both

celltype

s

Nay

aket

al.(19

89)

Swissalbino

mice

Lead

nitrate

10mg/kg

bwIntrap

eriton

eal

Bone

marrow

cells

SCE

Increa

sedSC

Efreq

uenc

yDhiret

al.(19

93)

Wistarrats

Lead

acetate

10,2

0,80

mg/kg

bw5times/w

eek,

for4wee

ksOral

Bone

marrow

cells

CASign

ificant

increa

seof

numerical

CALo

renc

zet

al.(19

96)

Swissalbino

mice

Lead

nitrate

0.62

5–80

mg/kg

bwfor12

,24an

d36

hIntrap

eriton

eal

Bone

marrow

cells

MN

test

Sign

ificant

increa

seof

MN

freq

uenc

yNot

dose-related

Jage

tiaan

dAruna

(199

8)

Spragu

e–Daw

ley

albino

rats

Lead

acetate

117mg/kg

once

and78

mg/kg

for

3co

nsecutiveda

ysOral

Kidne

ycells

MN

test

Comet

assay

Sign

ificant

increase

ofmicronu

cleatedcells

Sign

ificant

increase

ofTL

Robb

iano

etal.(19

99)

Swissalbino

mice

Lead

nitrate

0.7–

89.6

mg/kg

bwfor24

h,48

h,72

h,1wee

kan

d2wee

ksOralintub

ation

Leuk

ocytes

Comet

assay

Sign

ificant

increa

seof

mea

nTL.

Noclea

rdo

seresp

onse

Dev

ietal.(20

00)

Wistarrats

Lead

acetate

10mg/kg

bw,5

times/w

eek,

for4wee

ksOral

Bone

marrow

cells

CASign

ificant

increa

seof

aberrant

cells

andnu

merical

aberration

sNeh

ézet

al.(20

00)

CD-1

mice

Lead

acetate

0.01

,0.1

and1.0μM

for60

min

Inha

lation

Live

r,kidn

eyan

dlung

cells

Variant

ofthe

comet

assay(w

ith

proteina

seK)

Noincrea

seof

DNAmigration

Valve

rdeet

al.(20

01)

Kun

mingmice

Lead

acetate

1μg

/mld

rink

ingwater,for

three

gene

ration

sOral

Leuk

ocytes

Comet

assay

Sign

ificant

increase

of%of

damaged

cells

insecond

andthirdgene

ratio

nsYu

anan

dTa

ng(2

001)


Author's personal copyTa

ble2(con

tinu

ed)

Stud

yan

imal

Subs

tanc

eDose

Adm

inistration

Celltype

End-po

int

Resu

lts

Referenc

e

White

Swissmice

Lead

acetate

200an

d40

0mg/kg

diet

once

daily

for5da

ysOral

Bone

marrow

Spermatocytecells

CADose-de

pend

entsign

ificant

increa

seof

structural

aberration

sAbo

ul-Ela

(200

2)

CD-1

mice

Lead

acetate

0.00

68μg

/mlfor

60min,2

times/w

eek,

for2,

3an

d4wee

ksInha

lation

Nasal

epithe

lial,lung

,liver,

kidn

ey,b

onemarrow,b

rain

andtesticle

cells

,and

leuk

ocytes.

Comet

assay

Sign

ificant

increa

seof

TLin

allo

rgan

sex

cept

thetesticle.D

NAda

mag

eindu

ctionov

ertime

was

differen

tforea

chorga

n

Valve

rdeet

al.(20

02)

Hop

liasmalab

aricus

PbII

21μg

PbII/gbw

,one

prey

/day

,for

4da

ysov

erape

riod

of13

feed

-cyc

les

Feed

ingwithaprey

specie

(Astya

nax)

prev

ious

lyinjected

withPb

II

Kidne

ycells

Erythr

ocytes

CA MN

test

Comet

assay

Sign

ificant

increa

seof

structural

aberration

sNoincrea

seof

MN

freq

uenc

ybu

tsign

ificant

increa

seof

erythrocytes

withalterednu

clea

rmorph

olog

ySign

ificant

increa

seof

taile

dnu

cleo

ids

Ferraroet

al.(20

04)

Wistarrats

Lead

acetate

2mg/kg

bwada

yfor9da

ys5mg/kg

bwon

6thda

yof

life

Oral

Intrap

eriton

eal

Leuk

ocytes

Reticu

locy

tesan

derythr

ocytes

Comet

assay

MN

test

Sign

ificant

increa

seof

TLin

thetw

oex

posedgrou

psSign

ificant

increa

seof

MN

freq

uenc

yon

lyin

theorally

expo

sedgrou

p

Kašub

aet

al.(20

04)

Wistarrats

Lead

acetate

140,

250an

d50

0mg/kg

bw,

once/w

eek,

for10

wee

ksOrally

byga

vage

Reticu

locy

tes

MN

test

Dose-de

pend

entsign

ificant

increa

seof

MN

rate

Çelik

etal.(20

05)

Clariasga

riep

inus

Lead

nitrate

100,

300an

d50

0μg

/lfrom

6hto

162hpo

stfertilization

Disolve

din

tank

water

Embryo

cells

Comet

assay

Dose-de

pend

entsign

ificant

increa

seof

%TDNAov

ertime

Osm

anet

al.(20

08)

Wistarrats

Lead

acetate

25mg/kg

once

every2da

ys,7

times

Intrap

eriton

eal

Erythr

ocytes

MN

test

Sign

ificant

increase

ofmicronu

cleatedcells

Piao

etal.(20

07)

Wistarrats

Lead

acetate

100mg/ld

rink

ingwater

daily

for12

5da

ysOral

Erythr

ocytes

MN

test

Sign

ificant

increa

seof

MN

rate

Algha

zale

tal.(20

08)

Carassiusau

ratus

auratus

Lead

acetate

10,5

0an

d10

0μg

/lfor2,

4an

d6da

ysDisolve

din

tank

water

Erythr

ocytes

Gill

epithe

lialc

ells

Finep

ithe

lialc

ells

MN

test

Sign

ificant

increa

seof

MN

rate

inall

celltype

s.Th

ehigh

estMN

leve

lin

gillcells

Çava

s(2

008)

Hop

liasmalab

aricus

Lead

nitrate

7–63

μgPb

+2/g

bw,for

96h

Intrap

eriton

eal

Erythr

ocytes

Erythr

ocytes

and

kidn

eycells

MN

test

CA Comet

assay

Nosign

ificant

increa

seof

MN

rate

butalterednu

clea

rmorph

olog

yNoeffect

Sign

ificant

differen

ceof

comet

scorebe

twee

nco

ntrols

andtrea

ted

grou

psbu

tno

tbe

twee

ndo

ses

Ramsd

orfet

al.(20

08)

ICRmice

Lead

acetate

10,5

0an

d10

0mg/kg

bwfor

4wee

ksev

eryothe

rda

yOrally

byga

vage

Lymph

ocytes

Comet

assay

Sign

ificant

increa

seof

TLan

dTM

Xuet

al.(20

08)

Eiseniafetida

Pb+

250

,500

and50

00mg/kg

drysoil

for7da

ysDisolve

din

soil

Coleom

ocytes

Comet

assay

Nosign

ificant

effects

Liet

al.(20

09)

Algerianmice

Lead

acetate

21.5

mg/kg

bwin

altern

ateda

ysfor

11or

21da

ysIntrap

eriton

eal

Bone

marrow

cells

MN

test

SCE

Sign

ificant

increase

ofmicronu

cleated

cells

forbo

thtreatm

entp

eriods

Sign

ificant

increase

ofSC

Efrequency

Tapissoet

al.(20

09)

Rana

nigrom

aculata

Lead

nitrate

0.1–

1.6mg/lfor

30da

ysEp

idermal

absorption

Testis

cells

Comet

assay

Dose-de

pend

entsign

ificant

increa

seof

TL,T

Man

dDNArate.

Wan

gan

dJia

(200

9)

Abb

reviations

:bw

,bod

yweigh

t;TL

,taillen

gth;

TM,tailm

omen

t.



ble3

Hum

anstud

ieson

lead

geno

toxicity

(ordered

chrono

logically

).

Subject

NBloo

dlead

leve

ls(μg/dl)a

End-po

int

Effect

oflead

expo

sure

Referenc

e

Lead

oxideworke

rs8ex

posed

14co

ntrols

74.7±

9.4

14.9±

4.0

CASign

ificant

increa

seof

variou

stype

sof

CASchw

anitzet

al.(19

70)

Lead

man

ufacturing

worke

rs32

expo

sed

20co

ntrols

Not

repo

rted

CANosign

ificant

effect

Schm

idet

al.(19

72)

Ship-break

ingworke

rs35

expo

sed

31co

ntrols

285othe

rsu

rvey

controls

40–N12

0b40

Not

repo

rted

CANoeffects

O'Riordan

andEv

ans(1

974)

Stee

lplant

worke

rs10

5ex

posed

Noco

ntrols

37.7±

20.7

Not

repo

rted

CASlightly

increa

seof

structural

aberration

s.Noco

rrelationwithbloo

dlead

leve

lsSchw

anitzet

al.(19

75)

Malevo

luntee

rs11

inge

sted

10co

ntrols

40±

5Not

repo

rted

CANosign

ificant

effects

Bijls

maan

dde

Fran

ce(1

976)

Storag

eba

tteryplan

tworke

rs(p

rosp

ective

stud

y)11

expo

sed

Samesu

bjects,

pre-em

ploy

men

t

45.1±

17.3

after1mon

thPre-em

ploy

men

t:34

.0±

12.6

CASign

ificant

increa

seof

CArate

Forn

ietal.(19

76)

Child

renliv

ingne

arlead

smelter

20ex

posed

20co

ntrols

N30

7–19

CANosign

ificant

effects

Bauc

hing

eret

al.(19

77)

Storag

eba

tteryplan

tworke

rsfrom

Lyon

(Franc

e)an

dtin

dish

esfactoryworke

rsfrom

Nerem

(Belgium

)

16ex

posedfrom

Lyon

7ex

posedfrom

Nerem

20co

ntrols

44.50–

95.16

Not

repo

rted

Not

repo

rted

CASign

ificant

increa

seof

severe

aberration

son

lyin

thepe

ople

from

Lyon

.Dek

nudt

etal.(19

77b)

Lead

oxidefactoryworke

rs44

expo

sed

15co

ntrols

30–75

15–35

CASign

ificant

increa

seof

chromatid

and

chromosom

eab

erration

sGarza-Cha

paet

al.(19

77)

Smelterworke

rs(exp

osed

toPb

,As)

26ex

posed

Controlm

aterialo

fap

parently

healthy

males

from

Umea

High:

64.77±

10.95

Med

ium:39

.19±

7.13

Low:22

.48±

1.77

Not

repo

rted

CASign

ificant

increa

seof

CAfreq

uenc

yNorde

nson

etal.(19

78)

Sprayceramic

tile,lea

dsm

elter

andba

tteryprod

uction

worke

rs20

expo

sed

20co

ntrols

71.95

Not

repo

rted

CASign

ificant

increa

seof

CArate

and

sign

ificant

correlationwithBL

LSa

rtoet

al.(19

78)

Busdrivers

10ex

posed

Not

repo

rted

CAPo

sitive

correlationbe

twee

nBL

Lan

dpe

rcen

tage

ofCA

.The

smok

ersha

dhigh

erBL

Lan

dpe

rcen

tage

ofCA

Hog

sted

tet

al.(19

79)

Electrical

storag

eba

tteryworke

rs18

expo

sed

12co

ntrols

42.0±

9.6

27.8±

4.8

CASign

ificant

increa

seof

chromatid

and

chromosom

eab

erration

s,exclud

ingga

psFo

rnie

tal.(19

80)

Tank

clea

ners

16ex

posed

16co

ntrols

6–18

3–10

CA MN

test

Sign

ificant

increa

seof

CAan

dMN

freq

uenc

iesco

rrelated

withtime

ofex

posu

re

Hog

sted

tet

al.(19

81)

Lead

smelterworke

rs18

expo

sed

12co

ntrols

49±

1.7

b10

CA SCE

Nosign

ificant

differen

cesin

CAfreq

uenc

ybe

twee

ngrou

ps.A

mon

glead

-exp

osed

worke

rs,significant

increa

sein

72hwithrega

rdto

50hcu

ltures.

Sign

ificant

increa

seof

SCErate

inlead

-exp

osed

smok

ers

Mak

i-Pa

akka

nenet

al.(19

81)

Copp

ersm

elterworke

rs10

expo

sed

15co

ntrols

16.3±

2(in19

76)

34.7±

2.3(in19

78)

29.3±

1.4(in19

79)

Not

repo

rted

CATe

nden

cyto

increa

sethefreq

uenc

yof

CAdu

ring

thepe

riod

ofob

servation

butno

tsign

ificant

Beck

man

etal.(19

82)

Lead

smelterworke

rs29

expo

sed

9co

ntrols

42.0±

2.0

8.4±

0.7

CANosign

ificant

effects

Norde

nson

etal.(19

82)

Child

renliv

ingne

aralead

smelter

19ex

posed

12co

ntrols

29.3–62

.710

.0–21

.0SC

ENosign

ificant

effect

Dalpraet

al.(19

83)

Storag

eba

tteryplan

tworke

rs10

long

-term

expo

sed

18ne

wem

ploy

ees

29.0–74

.56.2–

29.0

SCE

Nosign

ificant

increa

seof

SCErate

after

4mon

thsof

employ

men

t.SC

Erates

correlated

toBL

L,bu

tno

tsign

ificant

Grand

jean

etal.(19

83)

Repa

iran

dreco

nditioning

ofcar

radiatorsworke

rs18

expo

sed

12co

ntrols

31.08–

68.38

4.14

–21

.76

MN

test

Nosign

ificant

effect

Hoffm

annet

al.(19

84)



ble3(con

tinu

ed)

Subject

NBloo

dlead

leve

ls(μg/dl)a

End-po

int

Effect

oflead

expo

sure

Referenc

e

Storag

eba

tteryplan

tworke

rs19

worke

rs9co

ntrols

Not

repo

rted

CASign

ificant

increa

seof

chromatid

andch

romosom

eab

erration

sAl-Hak

kaket

al.(19

86)

Batteryplan

tworke

rs54

expo

sed

13co

ntrols

45.2±

16.6

25.5±

6.4

SCE

Sign

ificant

increa

seof

SCEfreq

uenc

yLe

al-G

arza

etal.(19

86)

Storag

eba

tteryplan

tworke

rs7high

expo

sure

7med

ium

expo

sure

7low

expo

sure

7co

ntrols

86.9±

16.5

52.1±

7.3

33.7±

5.9

7.8±

2.3

CA SCE

Dose-relatedsign

ificant

increa

seof

CAfreq

uenc

yin

high

andmed

ium

expo

sure

grou

psSign

ificant

increa

seof

SCEfreq

uenc

yin

thehigh

expo

sure

grou

p

Hua

nget

al.(19

88)

Printing

indu

stry

worke

rs13

expo

sed

16co

ntrols

Not

repo

rted

SCE

Slight

increa

seof

SCErate

inex

posed

andsign

ificant

increa

sein

expo

sed

smok

ers

Rajahan

dAhu

ja(1

995)

Batteryplan

tworke

rs73

expo

sed

23co

ntrols

67±

2325

±6

MN

test

Sign

ificant

increa

seof

MN

freq

uenc

yVag

leno

vet

al.(19

97)

Minersof

aPb

–Zn

mine

120ex

posed

57co

ntrolg

roup

1(h

ousewives)

100co

ntrolg

roup

2(gen

eral

popu

lation

)

27.91±

1.50

7.26

±0.84

Not

repo

rted

MN

test

CA SCE

Sign

ificant

increa

seof

MN

freq

uenc

ySign

ificant

increa

seof

structural

aberration

sSign

ificant

increa

seof

SCEfreq

uenc

y

Bilban

(199

8)

Metal

powde

rfactoryworke

rs(exp

osed

toPb

,Zn)

32ex

posed

20co

ntrols

13.8±

9.2

2.4±

0.9

SCE

Sign

ificant

increa

seof

SCEfreq

uenc

yDön

mez

etal.(19

98)

Starter-ba

tteryplan

tworke

rs22

expo

sed

19ex

tern

alco

ntrols

19intern

alco

ntrols

61±

3.0

18±

0.6

28±

1.6

MN

test

Sign

ificant

increa

seof

totaln

umbe

rof

MN

andin

BNMN

Vag

leno

vet

al.(19

98)

Lead

smelterworke

rs66

expo

sed

28co

ntrols

4grou

psrang

ing

from

≤13

bto

N37

b

9b

Comet

assay

Sign

ificant

increa

seof

TL,d

ose-related

Yeet

al.(19

99)

Electric

batteryworke

rs43

expo

sed

13co

ntrols

98.5±

25.3

5.4±

3.6

Comet

assay

Sign

ificant

increa

seof

TLGroot

deRe

strepo

etal.(20

00)

Public

build

ingpa

inters

25ex

posed

25co

ntrols

10.48±

3.13

7.10

±2.79

CA SCE

MN

test

Increa

seof

CA,S

CEan

dMN

freq

uenc

ies.

Chromatid

andch

romosom

eda

mag

ewas

theen

d-po

intmoststrong

lyassociated

withoc

cupa

tion

alex

posu

retime

Pintoet

al.(20

00)

Storag

eba

tteryplan

tworke

rs31

expo

sed

20co

ntrols

36.31±

8.28

11.10±

2.13

SCE

Sign

ificant

increa

seof

SCErate.S

ignificant

correlationbe

twee

nBL

Lan

dSC

EDuy

duet

al.(20

01)

Metal

powde

r-prod

ucingfactory

worke

rs(exp

osed

toPb

,Zn,

Cd)

31ex

posed

20co

ntrols

40±

1812

±4

MN

test

Sign

ificant

increa

seof

MN

freq

uenc

yHam

urcu

etal.(20

01)

Storag

eba

tteryplan

tworke

rs10

3worke

rs78

controls

55.94±

2.07

18.86±

0.83

MN

test

Sign

ificant

increa

seof

BNMN

Clea

rrelation

ship

withBL

LVag

leno

vet

al.(20

01)

Batteryplan

tworke

rs37

expo

sed

29co

ntrols

39.6±

7.6

4.4±

1.7

Comet

assay

Sign

ificant

increa

seof

TM,

dose-related

Fracasso

etal.(20

02)

Storag

eba

tteryman

ufacturing

worke

rs23

high

expo

sure

34low

expo

sure

30co

ntrols

32.5±

14.5

9.3±

2.9

4.2±

1.4

SCE

Sign

ificant

increa

seof

SCErate

inthehigh

expo

sedgrou

p.Sign

ificant

positive

relation

ship

withBL

L

Wuet

al.(20

02)

Seco

ndarylead

reco

very

unitworke

rs45

expo

sed

36co

ntrols

24.8±

14.7

2.75

±1.52

Comet

assay

Sign

ificant

increa

seof

cells

with

increa

sedTL

BLLan

dtimeof

expo

sure

sign

i ficantly

correlated

toDNAda

mag

e

Dan

adev

ietal.(20

03)

Storag

eba

tteryman

ufacturing

worke

rs71

expo

sed

20co

ntrols

34.5±

1.5

10.4±

0.4

SCE

Sign

ificant

increa

seof

SCErate

inthegrou

pwith

bloo

dlead

leve

lsN50

μg/dl

Sign

ificantly

associated

withBL

L

Duy

duan

dSü

zen(2

003)

Storag

eba

tteryreno

vation

worke

rsan

dcarpa

inters

10storag

eba

tteryworke

rs10

carpa

inters

10co

ntrols

Not

repo

rted

Comet

assay

MN

test

Sign

ificant

increa

seof

TLan

dda

mag

einde

xSign

ificant

increa

seof

micronu

clea

tedcells

Martino

-Rothet

al.(20

03)

Batteryplan

tworke

rs44

expo

sed

52co

ntrols

50.4±

9.2

5.6±

2.8

SCE

MN

test

Comet

assay

Sign

ificant

increa

seof

SCErate

Sign

ificant

increa

seof

BNMN

Sign

ificant

increa

seof

%of

cells

withcomets

Paluset

al.(20

03)

(con

tinu

edon

next

page)



Table3(con

tinu

ed)

Subject

NBloo

dlead

leve

ls(μg/dl)a

End-po

int

Effect

oflead

expo

sure

Referenc

e

Storag

eba

tteryplan

tworke

rs50

expo

sed

30co

ntrols

40.14±

9.99

9.77

±1.67

SCE

Increa

sedSC

Efreq

uenc

yDuy

duet

al.(20

05)

Recy

clingau

tomotive

batteriesworke

rs26

worke

rs29

controls

35.40±

14.78

1.95

±1.97

MN

test

Sign

ificant

increa

seof

MN

freq

uenc

yan

dde

crea

seof

NDI

Minoz

zoet

al.(20

04)

Lead

smelterworke

rs62

expo

sed

22co

ntrols

42.26±

18.12

8.10

±3.78

Comet

assay

Sign

ificant

increa

seof

levela

ndgrad

eof

DNAda

mag

eSteinm

etz-Be

cket

al.(20

05)

Storag

eba

tteryworke

rs25

expo

sed

25co

ntrols

32±

2.5

2±

0.3

Comet

assay

MN

test

TCRmutationassay

Sign

ificant

increa

seof

TLSign

ificant

increa

seof

MNRan

dMCR

Noeffects

Chen

etal.(20

06)

Child

renliv

ingin

twocities

locatedin

themostpo

lluted

centre

oftheSilesiaprov

ince

74ex

posed

7.69

±4.29

MN

test

SCE

Positive

sign

ificant

correlationbe

twee

nBL

Lan

dMN

freq

uenc

yNosign

ificant

correlationbe

twee

nBL

Lan

dSC

Efreq

uenc

y

Mielzyn

skaet

al.(20

06)

Child

renliv

ingin

aregion

whe

reno

n-ferrou

sores

wereex

tracted

andproc

essed

92ex

posed

49co

ntrols

5.29

±2.09

3.45

±1.2

MN

test

Sign

ificant

increa

seof

MN

freq

uenc

yKap

kaet

al.(20

07)

Batteryplan

tan

dglass

pieces

prod

uction

worke

rs30

expo

sed

30co

ntrols

Not

repo

rted

TCRmutationassay

Sign

ificant

increa

seof

TCR-Mf

García-Le

stón

etal.(20

08)

Indu

strial

painters

102ex

posed

50co

ntrols

Not

repo

rted

CASign

ificant

increa

seof

CArate,

timeof

expo

sure-related

Mad

havi

etal.(20

08)

Child

renattend

ingdifferen

tscho

olsne

arlead

smelter

21ne

ar22

interm

ediate

22distan

tHistorical

labo

ratory

controlv

alue

s

11.4–47

.511

.3–49

.20.1–

8.7

Comet

assay

Sign

ificant

increa

seof

TLan

dof

cells

withTL

≥20

μmMén

dez-Góm

ezet

al.(20

08)

Trafficpo

licem

en10

high

expo

sure

22low

expo

sure

68.38±

12.43

31.08±

12.43

SCE

Sign

ificant

increa

seof

SCEfreq

uenc

yW

iwan

itkitet

al.(20

08)

Batteryplan

tworke

rs11

3ex

posed

102co

ntrols

21.8–88

0.6–

3.4

CA MN

test

Comet

assay

Increa

seof

CAfreq

uenc

y,cells

withMN,a

ndTL

Shaikan

dJamil(2

009)

Abb

reviations

:BL

L,bloo

dlead

leve

ls;BN

MN,b

inuc

leated

cells

withMN;MCR

,mea

nmicronu

clea

tedcells

rate;MNR,

mea

nmicronu

clei

rate;NDI,nu

clea

rdivision

inde

x;TC

R-Mf,TC

Rmutationfreq

uenc

y;TL

,taillen

gth.

aMea

n±

stan

dard

deviationor

rang

e.b

Med

ian.



consumption habits, only the non-smoker group showed significantincrease in the mutation frequency related to the exposure, suggest-ing an enhancement of the DNA repair mechanisms in smokerindividuals. On the contrary, Chen et al. (2006) did not observesignificant differences between exposed and controls when theyevaluated the genotoxic effects of lead exposure in individuals froma workplace producing storage battery. The difference betweenthese two studies may be explained in part by the fact that in thesecond one the impact of smoking on the results obtained was notassessed, and the population size was slightly smaller (25 exposed vs.25 controls).

2.3. Chromosome aberrations

2.3.1. In vitro studiesAll the studies that evaluated the effects of lead nitrate and lead

glutamate on the CA frequencies presented negative results (Lin et al.,1994; Cai and Arenaz, 1998; Shaik et al., 2006), except for Lerda(1992) who found an increase in the frequency of CA in Allium cepainduced by lead nitrate, and Wise et al. (1994) who reported weaklyclastogenic effects of lead glutamate in CHO cells only at 1 mM dose(doses tested 0.05, 1 and 2 mM). On the contrary, consistentlypositive results were obtained with lead chromate (Douglas et al.,1980; Wise et al., 1992; Xu et al., 1992; Wise et al., 1994, 2003, 2004;Xie et al., 2005), although most of the authors related them to theprobable action of chromate.

Treatment of human leukocytes with lead acetate for 24 h showedclearly elevated frequencies of achromatic lesions, chromatid breaksand isochromatid breaks in 72 h cultures (Beek and Obe, 1974).Deknudt and Deminatti (1978) observed that the most commonaberration induced by lead acetate in human lymphocyte cultures wasthe occurrence of chromosome fragments. On the contrary, Schmidet al. (1972) and Gasiorek and Bauchinger (1981) did not obtain effectof lead acetate on the frequency of CA in human lymphocytes.Bauchinger and Schmid (1972) reported the same negative results forChinese hamster cells, although they observed an increase inachromatic lesions or gaps only in the highest concentration tested(10−3 M).

2.3.2. Animal studiesSignificant increases in the CA rate were found in several

mammalian studies: leukocytes from male and female mice fedwith lead acetate (Muro and Goyer, 1969), in cynomolgus monkeys(Macaca irus) administered lead acetate in the diet (Jacquet andTachon, 1981), in bone marrow cells of rats after intraperitonealadministration of lead acetate (Tachi et al., 1985), and in maternalbonemarrow and foetal liver and lung cells of ICR SwissWebster micefollowingmaternal exposure to lead nitrate (Nayak et al., 1989). Otherauthors did not find any increase in the frequencies of CA in mice fedwith lead acetate (Deknudt and Gerber, 1979).

Moreover, Ramsdorf et al. (2008) observed some little structuralaberrations, such as gaps, in fish (Hoplias malabaricus) treated withdifferent doses of lead nitrate by intraperitoneal injections, but thestatistical analysis showed that this increase was not significant.Ferraro et al. (2004) also found in the same fish treated orally withPbII a significant increase in the frequency of CA, but in this case theexposure time was higher than in Ramsdorf et al. (2008).

Other studies reported differential induction of several types of CA.Jacquet et al. (1977) carried out an experiment in which dietary leadat different dose levels was given to female C57B1 mice for periods upto 3 months. They found no severe chromosome or chromatidaberrations at any dose level, but the frequency of chromatid gapsincreased significantly at the highest doses. Deknudt et al. (1977a)reported that the type of CA induced by lead acetate in cynomolgusmonkeys (M. irus) depended on the intake of calcium in the diet. Thefrequency of “severe” abnormalities (dicentrics, rings, translocations

and exchanges) was significantly increased only in the group on a lowcalcium diet, whereas “light” abnormalities (gaps and fragments)increased with time in all groups receiving lead irrespective of thediet. Aboul-Ela (2002) found only structural aberrations like chroma-tid gaps, deletions and fragments in bone marrow cells of male Swissmice after oral administration of lead acetate. Nehéz et al. (2000)investigated the possible genotoxic effects exerted by the pyrethroidcypermethrin and by either of the metals cadmium and lead alone orin combination, on bone marrow cells of outbred male Wistar rats.Treatment with lead acetate only increased significantly the numberof aberrant cells and numerical aberrations but did not alter thenumber of structural aberrations. In contrast, the combination ofcypermethrin and lead caused a significant increase in aberrant cellsand in structural aberrations but not in numerical aberrations. Themost frequently observed structural aberrations were gaps andacentric fragments. These results agree with Lorencz et al. (1996),who found increases in numerical aberrations in Wistar rats treatedwith different doses of lead acetate.

2.3.3. Human studiesGiven the results observed in epidemiological studies using CA

test, most of them performed in occupationally exposed workers,there is a considerable controversy regarding the ability of lead tocause chromosomal damage on exposed individuals.

Several studies reported increases in the frequency of CA in humanpopulations exposed to lead (Schwanitz et al., 1970; Schwanitz et al.,1975; Forni et al., 1976; Deknudt et al., 1977b; Garza-Chapa et al.,1977; Nordenson et al., 1978; Sarto et al., 1978; Hogstedt et al., 1979;Forni et al., 1980; Al-Hakkak et al., 1986; Huang et al., 1988; Bilban,1998; Pinto et al., 2000; Madhavi et al., 2008; Shaik and Jamil, 2009).However, other works found no effects of lead exposure on CAfrequency (Schmid et al., 1972; O'Riordan and Evans, 1974; Bijlsmaand de France, 1976; Bauchinger et al., 1977; Maki-Paakkanen et al.,1981; Nordenson et al., 1982). Moreover, Beckman et al. (1982)carried out a study in which CA frequencies in workers exposed tolead were evaluated at three different occasions (1976, 1978 and1979). The results showed a significant increase of CA rates in lead-exposed workers in 1979, but not in 1976. But, after evaluatingconfounding factors, as altered smoking habits and simultaneousexposure to other toxic agents, the authors concluded that suchvariations in the frequency of CA could not be ascribed with certaintyto changes in lead exposure.

Deknudt et al. (1977b) analysed CA in cultured lymphocytes fromtwo groups of lead-exposed people: workers from a smelting plant forstorage battery in Lyon (France) and workers from a factory of tindishes in Nerem (Belgium). They found an increased number of severeaberrations (rings and dicentrics) in people from Lyon, whereasno such aberrations but an increased number of chromosomefragments were observed in those from Nerem. Furthermore, Huanget al. (1988) obtained mainly “light” CA (gaps, breaks, deletions andfragments) when the frequencies of CA in lead-exposed workersfrom a battery factory were analysed, indicating minor lesions in thechromosomes.

Maki-Paakkanen et al. (1981) studied the frequency of CA inperipheral blood lymphocytes of workers exposed to lead in asmeltery. They found no significant differences in the CA ratesbetween lead-exposed workers and unexposed controls. But similarto Forni et al. (1980), they observed significantly higher rates of totalaberrations in the 72 h cultures regarding to the 52 h cultures. Theseresults favour the previously proposed hypothesis that aberrationsobserved in lymphocyte cultures of lead-exposed subjects may beculture-born (Forni et al., 1976). This may be due to deficiency ofrepair functions in the presence of lead or some lead-inducedmetabolite which could accumulate with increasing culture time(Maki-Paakkanen et al., 1981).



2.4. Sister chromatid exchanges

2.4.1. In vitro studiesThe in vitro studies evaluating alterations in SCE rates induced by

lead also report contradictory results. Increases in the frequency ofSCE were found when analysing the genotoxic effects of different saltsof lead: Douglas et al. (1980) evaluated the effect of lead chromate inhuman lymphocytes; Wulf (1980) tested lead sulphate in humanlymphocytes; Sharma et al. (1985) studied the effects of selectedchemical teratogens among which lead acetate was included inmaternal and foetal cells of ICR mice; Montaldi et al. (1987) analysedSCE induction by lead sulphate and lead chromate, among other heavymetals, in CHO cells; Poma et al. (2003) investigated the induction ofSCE by lead acetate in human melanoma cells (B-Mel); and Lin et al.(1994) and Cai and Arenaz (1998) used lead nitrate in CHO cells. Onthe other hand, no effect of lead exposure on the frequency of SCE wasobserved by Beek and Obe (1974) and Hartwig et al. (1990), whoevaluated the genotoxic effect of lead acetate in human leukocytesand in Chinese hamster V79 cells, respectively, and by Zelikoff et al.(1988), who assessed the genotoxicity of lead sulphide and leadnitrate in V79 cells.

Hartwig et al. (1990) investigated whether the genotoxicity of leadwas due to indirect effects, such as interference with DNA repairprocesses, by means of SCE among other end-points. They found thatlead acetate alone did not induce SCE in V79 Chinese hamster cells.However, lead ions enhanced the number of UV-induced SCEsuggesting that lead interfered with the processing of UV-inducedDNA lesions. The authors reached the conclusion that not only theDNA damage itself but also the genotoxic effects of other chemical orphysical agents may be augmented when repair is inhibited, asillustrated by the enhancement of UV-induced SCE.

2.4.2. Animal studiesOnly four studies conducted in animals evaluated the influence of

lead exposure on the frequency of SCE. Willems et al. (1982)investigated the effect of lead on SCE rate in male rabbits afterexposure to different doses of lead acetate. Statistical analysis of thenumber of SCE per metaphase in lymphocytes indicated no differ-ences between the groups. On the contrary, positive results in SCEwith lead acetate were obtained by Tapisso et al. (2009) in bonemarrow cells of Algerian mice intraperitoneally injected. Nayak et al.(1989) analysed the frequency of SCE in maternal bone marrow andfoetal liver and lung cells of ICR Swiss Webster mice, followingintravenous maternal exposure to lead nitrate. Lead caused amoderate, but statistically significant, increase in the frequency ofSCE in maternal bone marrow cells. On the contrary, lead did notcause any effect on the frequency of SCE in liver or lung cells of thefoetus, although lead was shown to cross the placenta. Finally, Dhiret al. (1993) reported that intraperitoneal injection of low doses oflead nitrate caused a significant increase in SCE rate in bone marrowcells of male Swiss albino mice.

2.4.3. Human studiesIn most studies assessing the genotoxic effects of lead in exposed

people an increase in the frequency of SCE was observed (Grandjeanet al., 1983; Leal-Garza et al., 1986; Huang et al., 1988; Rajah andAhuja, 1995; Bilban, 1998; Dönmez et al., 1998; Pinto et al., 2000;Duydu et al., 2001; Wu et al., 2002; Duydu and Süzen, 2003; Paluset al., 2003; Duydu et al., 2004; Wiwanitkit et al., 2008). Moreover, insome of them a positive relationship between SCE frequency andblood lead levels (Grandjean et al., 1983; Huang et al. 1988; Bilban,1998; Duydu et al., 2001; Wu et al., 2002; Wiwanitkit et al. 2008) wasfound, whereas in other two works this relationship could not beobserved (Dönmez et al., 1998; Pinto et al., 2000).

Nevertheless, Maki-Paakkanen et al. (1981) reported no increasein the frequency of SCE in individuals exposed to lead in a smeltery.

However, they observed an increase in the SCE rate in smoker exposedworkers in comparison to smoker controls, the same as in Rajah andAhuja (1995). This would indicate that tobacco smoke works asenhancer of the genotoxic effects of lead. Two other studies whichassessed the effects of lead in children living in an extensivelycontaminated area did not show effect of the exposure on thefrequency of SCE (Dalpra et al., 1983; Mielzynska et al., 2006).

2.5. Micronucleus test

2.5.1. In vitro studiesPoma et al. (2003) found that lead acetate induced MN in a dose-

dependent manner when evaluated chromosomal damage induced inhuman melanoma cells (B-Mel) using the cytokinesis-blocked MNassay. Similar results were previously reported by Montaldi et al.(1987), who evaluated the effects of lead sulphate and lead chromateon the induction of MN in human lymphocytes. Thier et al. (2003) andBonacker et al. (2005) studied the genotoxic effects of inorganic leadsalts in V79 Chinese hamster fibroblasts by means of MN test. Theyobserved that lead chloride and lead acetate induced MN in a dose-dependent manner, and they determined by means of CREST assay(using an anti-centromere antibody) that the effects of lead werepredominantly aneugenic, which was consistent with the observedmorphology of the MN. Moreover, Sandhu et al. (1989) assessed theclastogenic potential of various chemicals commonly found atindustrial waste sites by means of MN test. They found positiveresults for lead tetraacetate in plant cuttings of Tradescantia clone4430.

Only one in vitro MN study showed negative results for lead (Linet al., 1994). In this study the authors investigated the effects ofcadmium nitrate and lead nitrate in CHO cells by means of a numberof short-term assays, including the MN test. They found that leadnitrate did not significantly increase the frequency of binucleated CHOcells with MN.

2.5.2. Animal studiesSeveral studies that evaluated the genotoxic effects of lead acetate in

rodents bymeans of theMN test showed an increase in the frequency ofMN (Tachi et al., 1985; Robbiano et al., 1999; Çelik et al., 2005; Piao et al.,2007; Tapisso et al., 2009). Alghazal et al. (2008) analysed theMNrate inbone marrow erythrocytes of male and female Wistar rats treated withlead acetate trihydrate. They found a significant increase in the totalnumber of MN in polychromatic erythrocytes of both male and femalerats with regard to the control group.Moreover, therewas a decrease inthe ratio of polychromatic to normochromatic erythrocytes inmale rats,indicating both genotoxic and cytotoxic effects of lead acetate in malerats. Similarly, Jagetia and Aruna (1998) observed an increase in thefrequency of MN in bone marrow cells of male and female mice treatedwith lead nitrate. The frequency of MN did not show a dose-relatedincrease butmalemiceweremore sensitive to the induction ofMN thanfemale mice, evidenced by higher frequencies of micronucleatedpolychromatic erythrocytes.

On the contrary, three studies carried out in mice (Jacquet et al.,1977), rabbits (Willems et al., 1982) and fish (Ramsdorf et al., 2008)did not find any increase in the MN frequency when compared thelead-exposed group to the control group. However, Ramsdorf et al.(2008) related their negative results to the low number of fishanalysed and to the fact that the piscineMN assaymay lack sensitivity,since it does not detect the mitotic disjunctions if they do not provokechromosomal loss in the anaphases neither chromosome aberrationscaused by rearrangement, such as translocations or inversions, if thesedo not originate acentric fragments (Metcalfe, 1989).

2.5.3. Human studiesAgain, most epidemiological studies collected in the literature that

used MN test to evaluate the potential genotoxic effects induced by



exposure to lead were performed in individuals exposed in theworkplace. To date, the vast majority of works showed an increase inthe frequency of MN in individuals occupationally exposed to leadcompared with a control group. Minozzo et al. (2004) assessed thegenetic damage in workers in the recycling of automotive batteries.They observed that both the concentrations of lead in blood and thefrequency of MN in peripheral lymphocytes in the exposed groupwere significantly higher than in the control group. Moreover, thevalues of the nuclear division index (NDI) were significantly higher inthe control group than in the exposed group, indicating a possibleeffect of lead on cell cycle. These results are consistent with otherstudies in individuals occupationally exposed to lead that showed anincrease in the MN rate (Hogstedt et al., 1981; Bilban, 1998; Vaglenovet al., 1997, 1998; Pinto et al., 2000; Hamurcu et al., 2001; Vaglenov etal., 2001; Martino-Roth et al., 2003; Palus et al., 2003; Chen et al.,2006; Kapka et al., 2007; Shaik and Jamil, 2009).

The only epidemiological study that did not find any effect of leadon the geneticmaterial using theMN test was conducted by Hoffmannet al. (1984). They investigated the genotoxic effects in a group of carrepair and reconditioning radiators workers, and they observed nostatistical differences between the exposed group and the controlgroup. They had previously found a statistically significant correlationbetween blood lead values and CA in lymphocytes (Hogstedt et al.,1979, 1981). But, according to the authors, the difference betweenthese results could be explained either by the different cytogeneticmethods employed or, more likely, by the fact that the earlier findingswere due to a confounding exposure to other chemical substanceswith known mutagenicity.

Moreover, there are two studies in the literature that wereconducted in children environmentally exposed to lead. In the firstone, children were exposed to complex mixtures including polycyclicaromatic hydrocarbons and lead (Mielzynska et al., 2006), and in thesecond one children lived in a region where non-ferrous ores wereextracted and processed (Kapka et al., 2007). In those two worksincreases in the frequency of MN were reported.

2.6. Comet assay

2.6.1. In vitro studiesFour studies were conducted in vitro to evaluate the genotoxicity

of lead by means of the comet assay. In all of them a significantincrease in DNA fragmentation was found when different cell typeswere exposed to lead inorganic salts. Robbiano et al. (1999) obtainedsignificant dose-dependent increases in DNA strand breaks in primaryrat and human kidney cells exposed to different concentrations of leadacetate. Wozniak and Blasiak (2003) evaluated the genotoxic effectsof the same salt in human lymphocytes. They found an increase in thecomet tail length due to the induction of DNA strand breaks and/oralkali–labile sites. Lymphocytes exposed to the highest dose showed adecrease in the comet tail length caused by the formation of DNA–DNAand DNA–protein cross-links. In the same study, the neutral version ofthe assay revealed that lead acetate induced DNA double-strand breaksat all concentrations tested. Similarly, Shaik et al. (2006) found asignificant increase in the comet tail length when they analysed humanlymphocytes exposed to lead nitrate, and this increasewas proportionalto the salt concentration. Also, dose-dependent significant increases inthe tail integrated intensity ratio were observed in human lungfibroblasts WTHBF-6 treated with lead chromate (Xie et al., 2005).

2.6.2. Animal studiesAll studies conducted in experimental animals with the comet

assay showed a positive effect of lead on the induction of DNA damagein several tissues and organs. Ramsdorf et al. (2008) evaluated theeffects of inorganic lead in fish (H. malabaricus). They found asignificant difference between control and contaminated groups.Although differences between the doses tested were not observed,

blood cells showed a higher sensitivity than kidney cells, suggested tobe caused by the acute contamination. There was one exception forkidney cells at the lowest dose, probably due to the short exposuretime and also to the low quantity of lead, as the authors explained.These results are in agreement with Ferraro et al. (2004) who found asignificant increase of tailed nucleoids in fish erythrocytes of the samespecies treated with PbII, showing that extended exposures to leadcontaminants are capable of originating damages in the geneticmaterial of fish. Osman et al. (2008) also reported a significantincrease in the percentage of DNA in the comet tail when evaluatedthe genotoxic effects of lead nitrate in the African catfish (Clariasgariepinus) bymeans of the alkaline Comet assay. This increase in DNAdamage was strongly correlated with lead concentration and time ofexposure.

Valverde et al. (2002) used a lead inhalation model in mice inorder to detect the induction of genotoxic damage as single-strandbreaks and alkali–labile sites in several organs. They found a positiveinduction of DNA damage after a single inhalation only in the liver andthe lung. In subsequent inhalations the response was positive in allorgans tested except for the testicle. These results showed that leadacetate inhalations induced systemic DNA damage but some organsare special targets for this metal, such as lung and liver, depending inpart on length of exposure. Devi et al. (2000) also found a significantincrease inmean comet tail length at all time intervals tested after oraltreatment of mice with lead nitrate when compared to controls.

Yuan and Tang (2001) studied the accumulation effect of lead onDNA damage and the protection offered by selenium in mice bloodcells of three generations. A significant induction of DNA damage wasobserved in both sexes of the second and third generations,suggesting that the accumulation effect of lead was very significantstarting from the second generation.

Valverde et al. (2001) explored the capacity of lead, cadmium, or amixture of both metals to interact with acellular DNA in cells fromseveral organs of CD-1 mice by employing a variant of the cometassay. By means of this modified assay, that was described byKasamatsu et al. (1996) and uses an enriched-lysis solution withproteinase K, DNA is no longer held under the regulation of anymetabolic pathway or membrane barrier. They obtained a negativeresponse in the induction of DNA damage in cells derived from theliver, kidney and lung. However, they observed the production of lipidperoxidation and an increase in free radical levels in the differentorgans after inhalation of lead acetate, suggesting the induction ofgenotoxicity and carcinogenicity by indirect interactions, such asoxidative stress.

2.6.3. Human studiesThe comet assay has been used in many epidemiological studies as

an important end-point to determine the possible induction ofgenotoxicity in individuals occupationally exposed to lead. Despitethe controversy regarding the genotoxic properties of lead, all studiesconducted to date in which damage was assessed using the cometassay showed positive results.

Palus et al. (2003) evaluated the genotoxic damage in peripherallymphocytes of workers from a Polish battery plant after high-leveloccupational exposure to lead and cadmium. The results of the cometassay showed a slightly but significantly increased rate in DNAmigration compared to the control group. The same results were alsoreported in workers from battery plants by Groot de Restrepo et al.(2000) and Fracasso et al. (2002), in lead smelter workers (Ye et al.,1999; Steinmetz-Beck et al., 2005), in workers producing storagebattery (Martino-Roth et al., 2003 and Chen et al., 2006), and inworkers from a secondary lead recovery unit (Danadevi et al., 2003),as well as in a study conducted in children environmentally exposedto lead (Méndez-Gómez et al., 2008).

The fact that all studies using the comet assay showed positiveresults, while other tests to assess genotoxic effects, mainly



cytogenetic tests, provided somewhat conflicting results, could be dueto the different kind of damage detected. It is usually considered that,for chronic exposures, cytogenetic tests reflect cumulative damagewhile comet assay provide information on recent exposures and akind of damage that can be easily repaired. In addition, in the cometassay not only is direct damage induced by the agent studied detected,but also the strand breaks produced during excision repair processes.

3. Discussion

The toxicity of lead has been studied for many years throughoutseveral end-points but data related to the mutagenic, clastogenic andcarcinogenic properties of lead and lead compounds is still conflicting.The IARC classified lead as possible human carcinogen (IARC, 1987),on the basis of sufficient evidence for carcinogenicity in experimentalanimals but inadequate evidence for carcinogenicity in humans, andthe inorganic lead compounds are classified as probable humancarcinogens (IARC, 2006), on the basis of sufficient evidence forcarcinogenicity in experimental animals but limited evidence forcarcinogenicity in humans. Most studies reviewed in this articleshowed positive results when evaluated the action of several leadcompounds on different genetic end-points. However, in those studiesthat evaluated the induction of CA by lead chromate (Douglas et al.,1980; Wise et al., 1992; Xu et al., 1992; Wise et al., 1994, Wise et al.,2003; Wise et al., 2004; Xie et al., 2005), the positive results achievedmay be related to the toxic action of chromate and not to lead, basedon the results reported by Douglas et al. (1980). They studiedseparately the contributions of chromium and lead in lead chromatetoxicity by determining the effects of potassium chromate and leadchloride on CA in cultured human lymphocytes. Because no effect wasseen with lead chloride, and potassium chromate was almost aseffective at causing chromosome damage as lead chromate, theyconcluded that mutagenic activity of lead chromate was due tochromate ion.

The variability found in the different studies could be due to theinfluence of different experimental variables that may act asconfounding factors, such as duration and route of lead exposure,cell culturing time following the exposure, smoking habits andsimultaneous exposure to other toxic agents that could act bymodifying the genotoxic response of the cells to lead exposure andsimilarly, modifying the results of the studies. Regarding to this lastfactor, many of the epidemiological studies reviewed suggest thepossibility that multiple exposures present in the occupationalenvironment, and not only lead, are responsible for the obtainedresults.

The type of cell evaluated in eachwork also plays an important rolein the interpretation of results. Most studies conducted in humanpopulations involve the use of blood cells and as they remain in anarrested G0 phase, any lesions induced in DNA may persist for sometime (for instance, until cells are stimulated to divide in culture)(Winder and Bonin, 1993). In addition, different types of cells havedifferent susceptibility to the genotoxic action of lead. This differencecould be due to the presence of proteins, such as metallothionein inerythrocytes, that sequestered lead into a nonbioavailable form,protecting the individual from the toxicity of metal (Groot deRestrepo et al., 2000).

Several works did not report clear evidence on whether inorganiclead compounds exert clastogenic effects themselves, or whether theyenhance the genotoxic effects induced by compounds that occursimultaneously or arise during cell culturing (Beek and Obe, 1974;Deknudt and Leonard, 1975; Forni et al., 1980). Forni et al. (1980) andMaki-Paakkanen et al. (1981) suggested that aberrations observed inlead-exposed workers might be culture-born as they found anincrease in the aberration rates when they cultured the lymphocytes72 h instead of 50–52 h. The authors related this fact to a deficiency of

repair functions in the presence of lead or some lead-inducedmetabolite which could accumulate with increasing culture time.

Moreover, there are some studies which did not find induction ofSCE in workers occupationally exposed to lead but showed increasesin SCE rates in smoker exposed individuals suggesting that tobaccosmoke could act as enhancer of the genotoxic effects of lead (Maki-Paakkanen et al., 1981; Rajah and Ahuja, 1995). Although little isknown on how exactly smoking and lead interact together in theinduction of genetic damage, Rajah and Ahuja (1995) explain thisinteraction as the inhibition of enzymes involved in DNA repair bylead so the lesions formed as a result of the clastogenic effect oftobacco smoke remain unrepaired.

Finally, although the biochemical and molecular mechanisms ofaction of lead remain still unclear, it has been reported thatgenotoxicity of lead could be due to indirect mechanisms (Hartwiget al., 1990; Hartwig, 1994; Landrigan et al., 2000; Silbergeld, 2003;Garza et al., 2005). Lead can substitute calcium and/or zinc in enzymesinvolved in DNA processing and repair leading to an inhibition of DNArepair and an enhancement in the genotoxicity when combined withother DNA damaging agents such as tobacco smoke or UVA. Besides,oxidative stress produced by the increase in free radical levels inducedby lead exposure may also contribute to the indirect genotoxicity ofthis metal.

In conclusion, genotoxicity induction by lead is highly dependenton certain experimental variables, especially culture time, cell typeand simultaneous presence of other contaminants. Furthermore, itseems that lead exerts its genotoxic action through indirect mechan-isms, such as inhibition of DNA repair or production of free radicals,more than direct. Although evidence of a genetic risk associated withlead exposure actually exists, there are still conflicting data on theconditions under which its genotoxicity becomes apparent.

Acknowledgement

This work was funded by a grant from the Xunta de Galicia(INCITE08PXIB106155PR).

References

Aboul-Ela EI. The protective effect of calcium against genotoxicity of lead acetateadministration on bone marrow and spermatocyte cells of mice in vivo. Mutat Res2002;516:1–9.

Alghazal M, Sutiakova I, Kovalkovicova N, Legath J, Falis M, Pistl J, et al. Induction ofmicronuclei in rat bone marrow after chronic exposure to lead acetate trihydrate.Toxicol Ind Health 2008;24:587–93.

Al-Hakkak ZS, Hamamy HA, Murad AM, Hussain AF. Chromosome aberrations inworkers at a storage battery plant in Iraq. Mutat Res 1986;171:53–60.

ATSDR. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Lead.Atlanta, Georgia, USA: ATSDR; 2007.

Bauchinger M, Dresp J, Schmid E, Englert N, Krause C. Chromosome analyses of childrenafter ecological lead exposure. Mutat Res 1977;56:75–80.

Bauchinger M, Schmid E. Chromosome analysis of cultures of Chinese hamster cellsafter treatment with lead acetate. Mutat Res 1972;14:95-100.

Beckman L, Nordenson I, Nordstrom S. Occupational and environmental risks in andaround a smelter in northern Sweden. VIII. Three-year follow-up of chromosomalaberrations in workers exposed to lead. Hereditas 1982;96:261–4.

Beek B, Obe G. Effect of lead acetate on human leukocyte chromosomes in vitro.Experientia. 1974;30:1006–7.

Bijlsma JB, de France HF. Cytogenetic investigations in volunteers ingesting inorganiclead. Int Arch Occup Environ Health 1976;38:145–8.

Bilban M. Influence of the work environment in a Pb–Zn mine on the incidence ofcytogenetic damage in miners. Am J Ind Med 1998;34:455–63.

Bonacker D, Stoiber T, Bohm KJ, Prots I, Wang M, Unger E, et al. Genotoxicity ofinorganic lead salts and disturbance of microtubule function. Environ Mol Mutagen2005;45:346–53.

Cai MY, Arenaz P. Antimutagenic effect of crown ethers on heavy metal-induced sisterchromatid exchanges. Mutagenesis. 1998;13:27–32.

Çavas T. In vivo genotoxicity of mercury chloride and lead acetate: micronucleus test onacridine orange stained fish cells. Food Chem Toxicol 2008;46:352–8.

Çelik A, Ogenler O, Comelekoglu U. The evaluation of micronucleus frequency byacridine orange fluorescent staining in peripheral blood of rats treated with leadacetate. Mutagenesis. 2005;20:411–5.

Collins A. The comet assay for DNA damage and repair. Mol Biotechnol 2004;26:249–61.



Chen Z, Lou J, Chen S, Zheng W, Wu W, Jin L, et al. Evaluating the genotoxic effects ofworkers exposed to lead using micronucleus assay, comet assay and TCR genemutation test. Toxicology. 2006;223:219–26.

Dalpra L, TibilettiMG,NoceraG,Giulotto P, Auriti L, Carnelli V, et al. SCE analysis in childrenexposed to lead emission from a smelting plant. Mutat Res 1983;120:249–56.

Danadevi K, Rozati R, Banu BS, Rao PH, Grover P. DNA damage in workers exposed tolead using comet assay. Toxicology. 2003;187:183–93.

Deknudt G, Colle A, Gerber GB. Chromosomal abnormalities in lymphocytes frommonkeys poisoned with lead. Mutat Res 1977a;45:77–83.

Deknudt G, Deminatti M. Chromosome studies in human lymphocytes after in vitroexposure to metal salts. Toxicology. 1978;10:67–75.

Deknudt G, Gerber GB. Chromosomal aberrations in bone-marrow cells of mice given anormal or a calcium-deficient diet supplemented with various heavy metals. MutatRes 1979;68:163–8.

Deknudt G, Leonard A. Cytogenetic investigations on leucocytes of workers from acadmium plant. Environ. Physiol. Biochem. 1975;5:319–27.

Deknudt G, Manuel Y, Gerber GB. Chromosomal aberrations in workers professionallyexposed to lead. J. Toxicol. Environ. Health. 1977b;3:885–91.

Devi KD, Banu BS, Grover P, Jamil K. Genotoxic effect of lead nitrate on mice using SCGE(comet assay). Toxicology. 2000;145:195–201.

Dhir H, Roy AK, Sharma A. Relative efficiency of Phyllanthus emblica fruit extract andascorbic acid in modifying lead and aluminium-induced sister-chromatidexchanges in mouse bone marrow. Environ Mol Mutagen 1993;21:229–36.

Dönmez H, Dursun N, Ozkul Y, Demirtas H. Increased sister chromatid exchanges inworkers exposed to occupational lead and zinc. Biol Trace Elem Res 1998;61:105–9.

Douglas GR, Bell RD, Grant CE, Wytsma JM, Bora KC. Effect of lead chromate onchromosome aberration, sister-chromatid exchange and DNA damage in mamma-lian cells in vitro. Mutat Res 1980;77:157–63.

Duydu Y, Süzen HS, Aydin A, Cander O, Uysal H, Isimer A, et al. Correlation between leadexposure indicators and sister chromatid exchange (SCE) frequencies in lymphocytesfrom inorganic lead exposed workers. Arch Environ Contam Toxicol 2001;41:241–6.

Duydu Y, Süzen HS. Influence of delta aminolevulinic acid dehydratase (ALAD)polymorphism on the frequency of sister chromatid exchange (SCE) and the numberof high-frequency cells (HFCs) in lymphocytes from lead-exposedworkers.Mutat Res2003;540:79–88.

Duydu Y, Dur A, Süzen HS. Evaluation of increased proportion of cells with unusuallyhigh sister chromatid exchange counts as a cytogenetic biomarker for leadexposure. Biol Trace Elem Res 2005;104:121–9.

Ferraro MV, Fenocchio AS, Mantovani MS, Oliveira-Ribeiro CA, Cestari MM. Mutageniceffects of lead (PbII) on the fish H. malabaricus as evaluated using the comet assay,piscinemicronucleus and chromosome aberrations tests. Genet. Mol. Biol. 2004;27:103–7.

Forni A, Cambiaghi G, Secchi GC. Initial occupational exposure to lead: chromosome andbiochemical findings. Arch Environ Health 1976;31:73–8.

Forni A, Sciame A, Bertazzi PA, Alessio L. Chromosome and biochemical studies inwomen occupationally exposed to lead. Arch Environ Health 1980;35:139–46.

Forni A. Chromosomal effects of lead: a critical review. Rev Environ Health 1980;3:113–29.

Fracasso ME, Perbellini L, Solda S, Talamini G, Franceschetti P. Lead induced DNA strandbreaks in lymphocytes of exposed workers: role of reactive oxygen species andprotein kinase C. Mutat Res 2002;515:159–69.

Fu H, Boffetta P. Cancer and occupational exposure to inorganic lead compounds: ameta-analysis of published data. Occup Environ Med 1995;52:73–81.

García-Lestón J, Laffon B, Roma-Torres J, Teixeira JP, Monteiro S, Pásaro E, et al. Efectosgenotóxicos e inmunotóxicos de la exposición laboral al plomo. Arch. Prev. RiesgosLabor. 2008;11:124–30.

Garza A, Chávez H, Vega R, Soto E. Mecanismos celulares y moleculares de la neurotoxicidadpor plomo. Salud Mental. 2005;28:48–58.

Garza-Chapa R, Leal-Garza CH,Molina-Ballesteros G. Chromosome analysis in professionalsubjects exposed to lead contamination. Arch. Invest. Med. 1977;8:11–20.

Gasiorek K, Bauchinger M. Chromosome changes in human lymphocytes after separateand combined treatment with divalent salts of lead, cadmium, and zinc. Environ.Mutagen. 1981;3:513–8.

Gerber GB, Léonard A, Jacquet P. Toxicity, mutagenicity and teratogenicity of lead.Mutat Res 1980;76:115–41.

Grandjean P, Wulf HC, Niebuhr E. Sister chromatid exchange in response to variationsin occupational lead exposure. Environ Res 1983;32:199–204.

Groot de Restrepo H, Sicard D, Torres MM. DNA damage and repair in cells of leadexposed people. Am J Ind Med 2000;38:330–4.

Hamurcu Z, Donmez H, Saraymen R, Demirtas H. Micronucleus frequencies in workersexposed to lead, zinc, and cadmium. Biol Trace Elem Res 2001;83:97-102.

Hartwig A. Role of DNA repair inhibition in lead- and cadmium-induced genotoxicity: areview. Environ Health Perspect 1994;102(Suppl 3):45–50.

Hartwig A, Schlepegrell R, Beyersmann D. Indirect mechanism of lead-inducedgenotoxicity in cultured mammalian cells. Mutat Res 1990;241:75–82.

Hernberg S. Lead poisoning in a historical perspective. Am J Ind Med 2000;38:244–54.Hoffmann M, Hagberg S, Karlsson A, Nilsson R, Ranstam J, Hogstedt B. Inorganic lead

exposure does not effect lymphocyte micronuclei in car radiator repair workers.Hereditas. 1984;101:223–6.

Hogstedt B, Gullberg B, Mark-Vendel E, Mitelman F, Skerfving S. Micronuclei andchromosome aberrations in bone marrow cells and lymphocytes of humansexposed mainly to petroleum vapors. Hereditas. 1981;94:179–87.

Hogstedt B, Kolnig AM, Mitelman F, Schutz A. Correlation between blood-lead andchromosomal aberrations. Lancet 1979;2:262.

Huang XP, Feng ZY, Zhai WL, Xu JH. Chromosomal aberrations and sister chromatidexchanges in workers exposed to lead. Biomed Environ Sci 1988;1:382–7.

HwuaYS, Yang JL. Effect of 3-aminotriazole on anchorage independence andmutagenicityin cadmium- and lead-treated diploid human fibroblasts. Carcinogenesis. 1998;19:881–8.

IARC (International Agency for Research on Cancer). Lead and lead compounds,Inorganic, Vol. 23 (Suppl. 7). IARC Monographs; 1987. Lyon.

IARC (International Agency for Research on Cancer). Inorganic and organic leadcompounds. IARC monographs on the evaluation of carcinogenic risks to humansvolumeLyon: IARC; 2006.

Jacquet P, Leonard A, Gerber GB. Cytogenetic investigations on mice treated with lead.J. Toxicol. Environ. Health. 1977;2:619–24.

Jacquet P, Tachon P. Effects of long-term lead exposure onmonkey leukocyte chromosomes.Toxicol Lett 1981;8:165–9.

Jagetia GC, Aruna R. Effect of various concentrations of lead nitrate on the induction ofmicronuclei in mouse bone marrow. Mutat Res 1998;415:131–7.

Johnson FM. The genetic effects of environmental lead. Mutat Res 1998;410:123–40.Kapka L, Baumgartner A, Siwińska E, Knudsen LE, Anderson D, Mielzyńska D.

Environmental lead exposures increases micronuclei in children. Mutagenesis.2007;22:201–7.

Kasamatsu T, Kohda K, Kawazoe Y. Comparison of chemically induced DNA breakagein cellular and subcellular systems using the comet assay. Mutat Res 1996;369:1–6.

Kašuba V, Rozgaj R, Fučic A, Varnai VM, Piasek M. Lead acetate genotoxicity in sucklingrats. Biologia Bratislava 2004;59:779–85.

Landrigan PJ, Boffetta P, Apostoli P. The reproductive toxicity and carcinogenicity oflead: a critical review. Am J Ind Med 2000;38:231–43.

Leal-Garza C, Montes de Oca R, Cerda-Flores RM, García-Martínez E, Garza-Chapa R.Frequency of sister chromatid exchange (SCE) in lead exposed workers. Arch.Invest. Med. 1986;17:267–76.

Lerda D. The effect of lead on Allium cepa L. Mutat Res 1992;281:89–92.Li M, Liu Z, Xu Y, Cui Y, Li D, Kong Z. Comparative effects of Cd and Pb on biochemical

response and DNA damage in the earthworm Eisenia fetida (Annelida, Oligo-chaeta). Chemosphere 2009;74:621–5.

Lin RH, Lee CH, Chen WK, Lin-Shiau SY. Studies on cytotoxic and genotoxic effects ofcadmium nitrate and lead nitrate in Chinese hamster ovary cells. Environ MolMutagen 1994;23:143–9.

LorenczR, NehézM,Dési I. Investigationson themutagenic effects of cadmiumand leadonthe chromosomes of the bone marrow cells in subchronic experiments. Abstracts ofthe XXVIIth Meeting of the Hungarian Society of Hygiene (Blatonföldvár, Hungary,September 25–27); 1996. p. 116.

Madhavi D, Devi KR, Sowjanya BL. Increased frequency of chromosomal aberrations inindustrial painters exposed to lead-based paints. J. Environ. Pathol. Toxicol. Oncol.2008;27:53–9.

Maki-Paakkanen J, Sorsa M, Vainio H. Chromosome aberrations and sister chromatidexchanges in lead-exposed workers. Hereditas. 1981;94:269–75.

Martino-Roth MG, Viegas J, Roth DM. Occupational genotoxicity risk evaluationthrough the comet assay and the micronucleus test. Genet. Mol. Res. 2003;2:410–7.

Méndez-Gómez J, Garcia-Vargas GG, Lopez-Carrillo L, Calderon-Aranda ES, Gomez A,Vera E, et al. Genotoxic effects of environmental exposure to arsenic and lead onchildren in region Lagunera. Mexico. Ann. NY Acad. Sci. 2008;1140:358–67.

Metcalfe CD. Testes for predicting carcinogenicity in fish. CRC Cr. Rev. Aquat. Sci. 1989;1:111–29.

Mielzynska D, Siwinska E, Kapka L, Szyfter K, Knudsen LE, Merlo DF. The influence ofenvironmental exposure to complex mixtures including PAHs and lead on genotoxiceffects in children living in Upper Silesia, Poland. Mutagenesis. 2006;21:295–304.

Minozzo R, Deimling LI, Gigante LP, Santos-Mello R. Micronuclei in peripheral bloodlymphocytes of workers exposed to lead. Mutat Res 2004;565:53–60.

Montaldi A, Zentilin L, Venier P, Gola I, Bianchi V, Paglialunga S, et al. Interaction ofnitrilotriacetic acid with heavy metals in the induction of sister chromatidexchanges in cultured mammalian cells. Environ. Mutagen. 1987;7:381–90.

Muro LA, Goyer RA. Chromosome damage in experimental lead poisoning. Arch. Pathol.1969;87:660–3.

Nayak BN, Ray M, Persaud TV, Nigli M. Relationship of embryotoxicity to genotoxicity oflead nitrate in mice. Exp. Pathol. 1989;36:65–73.

Nehéz M, Lorencz R, Desi I. Simultaneous action of cypermethrin and two environmentalpollutant metals, cadmium and lead, on bone marrow cell chromosomes of rats insubchronic administration. Ecotoxicol Environ Saf 2000;45:55–60.

Nordenson I, Beckman G, Beckman L, Nordstrom S. Occupational and environmentalrisks in and around a smelter in northern Sweden. IV. Chromosomal aberrations inworkers exposed to lead. Hereditas. 1978;88:263–7.

Nordenson I, Nordstrom S, Sweins A, Beckman L. Chromosomal aberrations in lead-exposed workers. Hereditas. 1982;96:265–8.

O'Riordan ML, Evans HJ. Absence of significant chromosome damage in malesoccupationally exposed to lead. Nature 1974;247:50–3.

Osman AGM, Mekkawy IA, Verreth J, Wuertz S, Kloas W, Kirschbaum F. Monitoring ofDNA breakage in embryonic stages of the African catfish Clarias gariepinus(Burchell, 1822) after exposure to lead nitrate using alkaline comet assay. Environ.Toxicol. 2008;23:679–87.

Palus J, Rydzynski K, Dziubaltowska E,Wyszynska K, Natarajan AT, Nilsson R. Genotoxiceffects of occupational exposure to lead and cadmium. Mutat Res 2003;540:19–28.

Patierno SR, Banh D, Landolph JR. Transformation of C3H/10 T1/2 mouse embryo cellsto focus formation and anchorage independence by insoluble lead chromate butnot soluble calcium chromate: relationship to mutagenesis and internalization oflead chromate particles. Cancer Res 1988;48:5280–8.

Patierno SR, Landolph JR. Soluble vs insoluble hexavalent chromate. Relationshipof mutation to in vitro transformation and particle uptake. Biol Trace Elem Res1989;21:469–74.



Patrick L. Lead toxicity, a review of the literature. Part I: exposure, evaluation, and treat-ment. Altern. Med. Rev. 2006;11:2-22.

Piao F, Cheng F, Chen H, Li G, Sun X, Liu S, et al. Effects of zinc coadministration on leadtoxicities in rats. Ind Health 2007;45:546–51.

Pinto D, Ceballos JM, Garcia G, Guzman P, Del Razo LM, Vera E, et al. Increasedcytogenetic damage in outdoor painters. Mutat Res 2000;467:105–11.

Poma A, Pittaluga E, Tucci A. Lead acetate genotoxicity on human melanoma cells invitro. Melanoma Res 2003;13:563–6.

Ponder BAJ. Cancer genetics. Nature 2001;411:336–41.Rajah T, Ahuja YR. In vivo genotoxic effects of smoking and occupational lead exposure

in printing press workers. Toxicol Lett 1995;76:71–5.Ramsdorf WA, Ferraro MV, Oliveira-Ribeiro CA, Costa JR, Cestari MM. Genotoxic

evaluation of different doses of inorganic lead (PbII) inHoplias malabaricus. EnvironMonit Assess 2008;158:77–85.

Robbiano L, Carrozzino R, Puglia CP, Corbu C, Brambilla G. Correlation betweeninduction of DNA fragmentation and micronuclei formation in kidney cells fromrats and humans and tissue-specific carcinogenic activity. Toxicol Appl Pharmacol1999;161:153–9.

Sandhu SS, Ma TH, Peng Y, Zhou XD. Clastogenicity evaluation of seven chemicalscommonly found at hazardous industrial waste sites. Mutat Res 1989;224:437–45.

Sarto F, Stella M, Acqua A. Cytogenetic study of a group of workers with increased leadabsorption indices. Med Lav 1978;69:172–80.

Schmid E, Bauchinger M, Pietruck S, Hall G. Cytogenetic action of lead in humanperipheral lymphocytes in vitro and in vivo. Mutat Res 1972;16:401–6.

Schwanitz G, Gebhart E, Rott HD, Schaller KH, Essing HG, Lauer O, et al. Chromosomeinvestigations in subjects with occupational lead exposure. Dtsch. Med.Wochenschr. 1975;100:1007–11.

Schwanitz G, Lehnert G, Gebhart E. Chromosome damage after occupational exposureto lead. Dtsch. Med. Wochenschr. 1970;95:1636–41.

Shaik AP, Sankar S, Reddy SC, Das PG, Jamil K. Lead-induced genotoxicity in lymphocytesfromperipheral blood samplesofhumans: invitro studies. DrugChemToxicol 2006;1:111–24.

Shaik AP, Jamil K. Individual susceptibility and genotoxicity in workers exposed tohazardous materials like lead. J Hazard Mater. 2009;168:918–24.

Sharma RK, Jacobson-Kram D, Lemmon M, Bakke J, Galperin I, Blazak WF. Sister-chromatid exchange and cell replication kinetics in fetal and maternal cells aftertreatment with chemical teratogens. Mutat Res 1985;158:217–31.

Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes inchronic myelogenous leukaemia. Nature 1985;315:550–4.

Silbergeld EK. Facilitative mechanisms of lead as a carcinogen. Mutat Res 2003;533:121–33.

Spivey A. The weight of lead. Effects add up in adults. Environ Health Perspect 2007;115:A31–6.

Steinmetz-Beck A, Szahidewicz-Krupska E, Beck B, Poreba R, Andrzejak R. Genotoxicityeffect of chronic lead exposure assessed using the comet assay. Med Pr 2005;56:295–302.

Tachi K, Nishimae S, Saito K. Cytogenetic effects of lead acetate on rat bone marrowcells. Arch Environ Health 1985;40:144–7.

Tapisso JT, Marques CC, Mathias ML, RamalhinhoMG. Induction of micronuclei and sisterchromatid exchange in bone-marrow cells and abnormalities in sperm of Algerianmice (Mus spretus) exposed to cadmium, lead and zinc. Mutat Res 2009;678:59–64.

Thier R, Bonacker D, Stoiber T, Bohm KJ, Wang M, Unger E, et al. Interaction of metalsalts with cytoskeletal motor protein systems. Toxicol Lett 2003;140–141:75–81.

Vaglenov A, Carbonell E, Marcos R. Biomonitoring of workers exposed to lead.Genotoxic effects, its modulation by polyvitamin treatment and evaluation of theinduced radioresistance. Mutat Res 1998;418:79–92.

Vaglenov A, Creus A, Laltchev S, Petkova V, Pavlova S, Marcos R. Occupational exposureto lead and induction of genetic damage. Environ Health Perspect 2001;109:295–8.

Vaglenov AK, Laltchev SG, Nosko MS, Pavlova SP. Cytogenetic monitoring of workersexposed to lead. Cent. Eur. J. Occup. Environ. Med. 1997;3:298–308.

ValverdeM, Fortoul TI, Diaz-Barriga F,Mejia J, del Castillo ER.Genotoxicity induced inCD-1mice by inhaled lead: differential organ response. Mutagenesis. 2002;17:55–61.

ValverdeM, Trejo C, Rojas E. Is the capacity of lead acetate and cadmium chloride to inducegenotoxicdamagedue todirectDNA-metal interaction?Mutagenesis. 2001;16:265–70.

Wang MZ, Jia XY. Low levels of lead exposure induce oxidative damage and DNAdamage in the testes of the frog Rana nigromaculata. Ecotoxicology 2009;18:94–9.

Willems MI, de Schepper GG, Wibowo AA, Immel HR, Dietrich AJ, Zielhuis RL. Absenceof an effect of lead acetate on spermmorphology, sister chromatid exchanges or onmicronuclei formation in rabbits. Arch Toxicol 1982;50:149–57.

Winder C, Bonin T. The genotoxicity of lead. Mutat Res 1993;285:117–24.Wise JP, Leonard JC, Patierno SR. Clastogenicity of lead chromate particles in hamster

and human cells. Mutat Res 1992;278:69–79.Wise Sr JP, Stearns DM, Wetterhahn KE, Patierno SR. Cell-enhanced dissolution of

carcinogenic lead chromate particles: the role of individual dissolution products inclastogenesis. Carcinogenesis. 1994;15:2249–54.

Wise SS, Schuler JH, Katsifis SP, Wise Sr JP. Barium chromate is cytotoxic and genotoxicto human lung cells. Environ Mol Mutagen 2003;42:274–8.

Wise SS, Schuler JH, Holmes AL, Katsifis SP, Ketterer ME, HartsockWJ, et al. Comparisonof two particulate hexavalent chromium compounds: barium chromate is moregenotoxic than lead chromate in human lung cells. Environ Mol Mutagen 2004;44:156–62.

Wiwanitkit V, Suwansaksri J, Soogarun S. White blood cell sister chromatid exchangeamong a sample of Thai subjects exposed to lead: lead-induced genotoxicity.Toxicol. Environ. Chem. 2008;90:765–8.

Wozniak K, Blasiak J. In vitro genotoxicity of lead acetate: induction of single anddouble DNA strand breaks and DNA-protein cross-links. Mutat Res 2003;535:127–39.

Wu FY, Chang PW, Wu CC, Kuo HW. Correlations of blood lead with DNA–protein cross-links and sister chromatid exchanges in lead workers. Cancer Epidemiol BiomarkersPrev 2002;11:287–90.

Wulf HC. Sister chromatid exchanges in human lymphocytes exposed to nickel andlead. Dan Med Bull 1980;27:40–2.

Xie H, Wise SS, Holmes AL, Xu B, Wakeman TP, Pelsue SC, et al. Carcinogenic leadchromate induces DNA double-strand breaks in human lung cells. Mutat Res2005;586:160–72.

Xu J, Wise JP, Patierno SR. DNA damage induced by carcinogenic lead chromate particlesin cultured mammalian cells. Mutat Res 1992;280:129–36.

Xu J, Lian L, Wu C, Wang X, Fu W, Xu L. Lead induces oxidative stress, DNA damage andalteration of p53, Bax and Bcl-2 expressions in mice. Food Chem Toxicol 2008;46:1488–94.

Yang JL, Yeh SC, Chang CY. Lead acetate mutagenicity and mutational spectrum in thehypoxanthine guanine phosphoribosyltransferase gene of Chinese hamster ovaryK1 cells. Mol Carcinog 1996;17:181–91.

Ye XB, Fu H, Zhu JL, Ni WM, Lu YW, Kuang XY, et al. A study on oxidative stress in lead-exposed workers. J. Toxicol. Environ. Health A. 1999;57:161–72.

Yuan X, Tang C. The accumulation effect of lead on DNA damage in mice blood cells ofthree generations and the protection of selenium. J Environ Sci Health 2001;36:501–8.

Zelikoff JT, Li JH, Hartwig A, Wang XW, Costa M, Rossman TG. Genetic toxicology of leadcompounds. Carcinogenesis. 1988;9:1727–32.


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Genotoxic effects of lead: An updated review

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