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Re iew a icle
Toenails as bioma ke o exposu e o essen ial ace me als: A e iew.
En ique Gu ié ez-González
a,b,∗∗
, Es he Ga cía-Esquinas
b,c
, Ne ea Fe nández de La ea-Baz
b,d
,
Inmaculada Salcedo-Bellido
b,e
, Ana Na as-Acien
, Vi ginia Lope
b,d
, José Luis Gómez-A iza
g
,
Robe o Pas o
b,d
, Ma ina Pollán
b,d
, Bea iz Pé ez-Gómez
a,b,d,∗
a
Public Heal h & P e en i e Medicine Teaching Uni , Na ional School o Public Heal h, Ca los III Ins i u e o Heal h, Mon o e de Lemos 5, 28029, Mad id, Spain
b
Conso ium o Biomedical Resea ch in Epidemiology & Public Heal h (CIBER en Epidemiología y Salud Pública - CIBERESP), Mon o e de Lemos 5, 28029, Mad id,
Spain
c
Depa men o P e en i e Medicine and Public Heal h, Uni e sidad Au ónoma de Mad id, C/ A zobispo Mo cillo 4, 28029, Mad id, Spain
d
Depa men o Epidemiology o Ch onic Diseases, Na ional Cen e o Epidemiology, Ca los III Ins i u e o Heal h, Mon o e de Lemos 5, 28029, Mad id, Spain
e
Depa men o P e en i e Medicine and Public Heal h, Uni e si y o G anada & Ins i u o de In es igación Biosani a ia de G anada, A . de La In es igación, 11, 18016,
G anada, Spain
Depa men o En i onmen al Heal h Sciences, Columbia Uni e si y Mailman School o Public Heal h, 722 W 168 h S , New Yo k, NY, 10032, USA
g
Depa men o Chemis y, Facul y o Expe imen al Sciences, Uni e si y o Huel a, Campus de El Ca men, Resea ch Cen e on Heal h and En i onmen (RENSMA), C/
Menéndez Pelayo, 21002, Huel a, Spain
ARTICLE INFO
Keywo ds:
Toenail
Biomoni o ing
Bioma ke
Exposu e
Essen ial ace essen ial me als
Sys ema ic e iew
ABSTRACT
Heal h p oblems associa ed wi h essen ial ace me als can esul om bo h inadequa e (i.e., low in ake) and
excessi e exposu es (i.e., om en i onmen al and/o occupa ional sou ce). Thus, measu ing he exposu e le el
is a eal challenge o epidemiologis s. Among non-in asi e bioma ke s ha in end o measu e long- e m ex-
posu e o essen ial ace me als, he oenail is p obably he biological ma ix wi h he g ea es po en ial.
This sys ema ic e iew collec s he cu en e idence ega ding he alidi y o oenail clippings as exposu e
bioma ke o ace me als such as bo on, cobal , coppe , i on, manganese, molybdenum, selenium, silicon,
anadium and zinc. Special a en ion was paid o he ime-window o exposu e e lec ed by he oenail, he
in aindi idual a iabili y in exposu e le els o e ime in his ma ix, and he ela ionship o oenail wi h o he
bioma ke s, pe sonal cha ac e is ics and en i onmen al sou ces.
Ou sea ch iden i ied 139 pape s, wi h selenium and zinc being he mos s udied elemen s. The a iabili y
among s udies sugges s ha oenail le els may e lec di e en deg ees o exposu e and p obably co espond o
exposu es occu ed 3–12 mon hs be o e sampling (i.e., o manganese/selenium). Few s udies assessed he e-
p oducibili y o esul s o e ime and, o samples ob ained 1–6 yea s apa , he co ela ion coe icien we e
be ween 0.26 and 0.66. T ace me al le els in oenails did no co ela e well wi h hose in he blood and u ine and
showed low-mode a e co ela ion wi h hose in he hai and inge nails.
A ailable da a sugges s ha o some elemen s (Se, Mn, Zn) oenail concen a ions e lec long- e m ex e nal
exposu es in ai ly ep oducible le els, while o o he me als, his associa ion has no ye been assessed. Among
die a y ac o s, only oenail selenium showed clea associa ions wi h he in ake o supplemen s o speci ic oods.
The oenail le els could also ep esen occupa ional exposu e, o ins ance, Mn exposu e in welde s. The sca ci y
o in o ma ion on o he essen ial ace elemen s, oge he wi h he g ea he e ogenei y among s udies makes he
alida ion o he usage o oenails as bioma ke s o exposu e o hese elemen s di icul . S anda diza ion o
sample collec ion, quali y con ol, analy ical echniques and epo ing p ocedu es migh acili a e u he e-
sea ch ocused on he clea unde s anding o he signi icance o essen ial le els in his p omising ma ix and
would enhance i s u ili y in epidemiological esea ch.
h ps://doi.o g/10.1016/j.en es.2019.108787
Recei ed 8 July 2019; Recei ed in e ised o m 26 Sep embe 2019; Accep ed 30 Sep embe 2019
∗
Co esponding au ho . Depa men o Epidemiology o Ch onic Diseases, Na ional Cen e o Epidemiology, Ca los III Ins i u e o Heal h, Mon o e de Lemos 5,
28029, Mad id, Spain.
∗∗
Co esponding au ho . Na ional School o Public Heal h, Ca los III Ins i u e o Heal h, A da. Mon o e de Lemos, 5, 28029, Mad id, Spain.
E-mail add esses: [email p o ec ed] (E. Gu ié ez-González), [email p o ec ed] (B. Pé ez-Gómez).
En i onmen al Resea ch 179 (2019) 108787
A ailable online 07 Oc obe 2019
0013-9351/ © 2019 The Au ho s. Published by Else ie Inc. This is an open access a icle unde he CC BY-NC-ND license
(h p://c ea i ecommons.o g/licenses/BY-NC-ND/4.0/).
T
1. In oduc ion
Essen ial ace me als/me alloids ei he a e needed o main ain
physiologically impo an unc ions, o a e pa o o ganic s uc u es
wi h i al unc ions in humans (Me z, 1981). Howe e , in many cases,
excessi e le els o hese elemen s also pose a se ious heal h isk. The
ypical sou ce o hese elemen s is die , bu occupa ional (e.g., Mn in
welde s) and en i onmen al sou ces (e.g., en i onmen al elease o Zn
by me al p oduc ion indus ies o om combus ion o coal in powe
s a ions) may also con ibu e o high exposu e le els. The e o e, mea-
su emen o exposu e a he indi idual le el is a c i ical aspec in he
esea ch o he ole o hese elemen s in human heal h.
Acco ding o he Wo ld Heal h O ganiza ion (WHO) (WHO, 1996),
he lis o essen ial ace me als/me alloids -which will be called as
me als in his e iew pape , since mos o he elemen s s udied belong
o his g oup-, includes ch omium (III) (C ) [now unde discussion]
(Nig a e al., 2016), coppe (Cu), cobal (Co), i on (Fe), molybdenum
(Mo), selenium (Se), zinc (Zn), and [manganese (Mn), which was added
in 2001 o his g oup (Ins i u e o Medicine (US), 2001). Vanadium (V),
silicon (Si) and bo on (B), no s ic ly conside ed essen ial elemen s, a e
o en s udied wi h hem due o hei po en ial heal h bene i s (WHO,
1996;US EPA O, 2014).
A common app oach o measu e he exposu e le el o hese essen-
ial ace me als is he use o bioma ke s due o se e al easons: hey
e lec bo h known and inad e en exposu es; hey a e no a ec ed by
ecall bias, and hey in eg a e all sou ces (i.e., die , ai and wa e ) and
ou es o con ac (San onen e al., 2015). Among hese, oenails a e
non-in asi e ma ices ha ha e become qui e popula in la ge epide-
miological s udies o hei logis ic ad an ages, namely e y easy col-
lec ion and s o age and less in luence o ex e nal con amina ion han
inge nails and hai (Ka agas e al., 2000). In addi ion, he slow a e o
g ow h o oenails has made hese sui able candida es o e alua ing
longe e m exposu es han o he bioma ke s such as blood o u ine, a
key issue in ch onic diseases esea ch (Hopps, 1977;Sukuma , 2006).
Howe e , he alidi y o hese assump ions is unclea and he use ulness
o measu emen o essen ial ace me als in oenails as a bioma ke o
exposu e is s ill unce ain. In his e iew, we condensed a ailable da a
on essen ial ace me al le els in oenails and summa ized he e idence
on hei alidi y as biological ma ices o exposu e. We paid special
a en ion o a) s abili y o e ime and ime-window o exposu e, wo
aspec s c i ical in e alua ing long- e m ch onic exposu es; b) he e-
la ionship wi h o he commonly used bioma ke s, such as blood and
u ine and; c) he associa ion wi h pe sonal cha ac e is ics and se e al
sou ces, in o de o be e unde s and he ac o s ha module o de-
e mine he le els o essen ial ace me als in his subs a e.
2. Ma e ial and me hods
This e iew is epo ed in acco dance wi h he PRISMA publica ion
s anda ds (Mohe e al., 2009) and he p o ocol was egis e ed in
PROSPERO, he in e na ional p ospec i e egis e o sys ema ic e iews
( egis a ion numbe CRD42018085822) (Uni e si y o Yo k, 2018).
2.1. Iden i ica ion o s udies
We conduc ed a sys ema ic li e a u e sea ch o pee - e iewed pa-
pe s p o iding o iginal da a on essen ial ace me al concen a ions in
oenails. The low diag am o he s udy selec ion p ocess is shown in
Fig. A1 (Appendix A). Two e iewe s (EG and BP) independen ly
sc eened abs ac s, e iewed ull- ex a icles, ex ac ed da a and pe -
o med quali y assessmen s. Ini ially, we sea ched he da abases
PubMed/MEDLINE, Web o Science and Scopus om incep ion o
Decembe 31, 2017, using he ollowing exac sea ches: #1 Nail OR
oenail; #2 Exposu e OR biomoni o ing OR bioma ke ; #3 Me als OR
ace elemen s OR be yllium OR anadium OR ch omium OR cobal OR
nickel OR coppe OR zinc OR a senic OR selenium OR cadmium OR
pla inum OR lead OR u anium OR me cu y OR hallium OR aluminium
OR molybdenum OR manganese OR i on OR silicon OR bo on; #4: #1
AND #2 AND #3. This sea ch e ie ed 2632 e e ences. Then, we
manually e iewed he e e ence lis s o all included s udies and iden-
i ied 52 addi ional a icles. S udies ha epo ed o iginal quan i a i e
da a on oenail me al concen a ions in humans in English o Spanish
we e conside ed eligible. When he ype o nail ( inge nail/ oenail) was
no speci ied, he co esponding au ho was con ac ed o cla i ica ion.
A e exclusion o duplica es, 276 a icles me he gene al inclusion
c i e ia. F om hese, o he pu pose o his e iew, we na owed ou
scope o ocus on he pape s (139) wi h in o ma ion on essen ial ace
me als (Co, Cu, Fe, Mn, Mo, V and Zn) o me alloids (B, Se, Si); we did
no include C due o i s dispu ed essen iali y (Nig a e al., 2016) and
he ca cinogenic ole o C (VI) (IARC, 2012).
2.2. Da a collec ion
Da a om included s udies we e ex ac ed in o a cus omized
sp eadshee . Acco ding o a pu pose-designed p o ocol, he ollowing
da a we e ex ac ed om each s udy: a) basic in o ma ion ( i s au ho ,
coun y, yea o publica ion, esea ch p ojec , s udied ace me als); b)
design ea u es ( ype o epidemiological s udy, main objec i e, sample
size, popula ion sample me hod, pa icipan cha ac e is ics, in o med
consen eques , e hical commi ee app o al); c) sample and analy ical
in o ma ion ( oenail ype (i.e., big oe, all oes), sample p epa a ion,
analy ical me hod, quali y con ol measu es, limi s o de ec ion and
a ailabili y o o he biological specimens wi h ace me al da a); d)
me al concen a ions, i.e., measu es o cen al endency (geome ic o
a i hme ic mean, median (p50)) and dispe sion (s anda d de ia ion
(SD) o ange), when a ailable; and e) co ela ion wi h o he bioma ke s,
wi h pe sonal cha ac e is ics, wi h en i onmen al da a, o wi h p e ious
oenail measu es.
Mos s udies epo ed me al le els in mic og ams pe g am (μg/g),
bu many au ho s chose o p o ide o he uni s o concen a ion, namely
nanog ams pe g am (ng/g); mic omoles pe kilog am (μmol/kg); na-
nomoles pe g am (nmol/g); millig ams pe kilog am (mg/kg); pa s
pe million (ppm); and pa s pe billion (ppb). This a iabili y in he
uni s used o exp ess me al concen a ions was no ela ed o any spe-
ci ic elemen o echnique. Fo his e iew, we con e ed all uni s in o
μg/g o allow o an easie compa ison among s udies.
3. Resul s
3.1. S udy cha ac e is ics
We iden i ied a o al o 139 manusc ip s published be ween 1975
and 2017, which p o ided le els o essen ial me als in oenails, om 89
di e en esea ch p ojec s (numbe o pape s pe esea ch p ojec
anged om 1 o 9; 25 p ojec s had 2 o mo e manusc ip s). Almos
40% o he a icles e alua ed exposu e ei he in he USA (49 pape s,
wi h da a om 25 esea ch p ojec s) o in Canada (6 manusc ip s, wi h
da a om 4 esea ch p ojec s) and ano he 39% o he pape s included
in o ma ion om s udies conduc ed in Eu ope ( he Ne he lands −13
manusc ip s om 4 esea ch p ojec s-; I aly −7 pape s om 4 p ojec s-;
and Poland −5 manusc ip s om 5 esea ch p ojec s-we e he mos
common loca ions). The emaining s udies (21%) p esen ed oenail
essen ial me al le els om o he coun ies, wi h a highe p opo ion o
Asian coun ies in he ecen yea s. One esea ch p ojec combined
E. Gu ié ez-González, e al. En i onmen al Resea ch 179 (2019) 108787
2
popula ions om mo e han one con inen (EURAMIC s udy). The
numbe o manusc ip s has inc eased in he las decade (See Fig. A2,
Appendix A), e idencing a g owing in e es in his bioma ke . The
cha ac e is ics o each pape , so ed by esea ch s udy and yea o
publica ion, a e de ailed in Appendix A, Table A1. Sea ch esul s a e
summa ized in Fig. 1.
The majo i y o he esea ch p ojec s (n = 48) we e ocused on a
single elemen , usually selenium. O e all, Se was he mos s udied es-
sen ial ace elemen (n = 94 epo s), ollowed by Zn (n = 44), Cu
(n = 32), Mn (n = 31), Fe (n = 24), Co (n = 20), V (n = 9) and Mo
(n = 8), while no da a we e ound abou oenail concen a ions o B o
Si. Rega ding he aims o he a icles, 71 used oenails as bioma ke s o
exposu e o one o mo e essen ial me als o ied o iden i y hei de-
e minan s, while 78 s udied he associa ion be ween oenail essen ial
me al le els, mainly Se and Zn, and di e en heal h p oblems o bio-
logical cha ac e is ics (i.e., choles e ol le els). The mos common ou -
come s udied was cance (Ga land e al., 1995;Ghadi ian e al., 2000),
al hough o he a icles e alua ed ca dio ascula (Ka dinaal e al.,
1997), me abolic (Pa k and Seo, 2016), o hema ologic e ec s (Lee
e al., 2016), as well as neu ologic (Me ama e al., 2017) o men al-
heal h ela ed p oblems (Colangelo e al., 2014) (Appendix A, Table
A1).
The numbe o pa icipan s in each s udy was highly a iable: 33
esea ch p ojec s included less han 100 indi iduals, 46 s udies, be-
ween 100 and 1000 and 9 ec ui ed mo e han 1000 pa icipan s
( ange: 12–9267). In one p ojec (only 1 pape published), he sample
size was no speci ied (Abdul ahman e al., 2012). Baseline cha ac e -
is ics o hese subjec s we e he e ogeneous ac oss s udies and depended
on he aim o each in es iga ion. Thus, each pape p o ided in o ma-
ion desc ibing some ea u es o he speci ic popula ion unde s udy,
such as age, sex, ace, socioeconomic s a us, occupa ion, o dwelling
place (See Appendix A, Table A1). Howe e , in some cases, his de-
sc ip ion was limi ed o geog aphical a ea o ec ui men , omi ing
basic da a such as age o sex o he pa icipan s.
Rega ding s udy design, mos pape s p esen ed c oss-sec ional
analyses (n = 59, which also included baseline le els in longi udinal
p ojec s), ollowed by case-con ol (30 epo s) s udies; p ospec i e
designs (case-coho : 9 epo s; nes ed case-con ols: 13 epo s; coho :
25 epo s) and andomized ials (3 epo s). Con enience sampling
was he ypical s a egy o ec ui men and only 17 esea ch p ojec s
epo ed pa icipa ion a es, anging om 41.8% (O’Ro ke e al., 2012)
o 98%
22
; usually, in case-con ol s udies pa icipa ion was lowe
among con ols.
Conce ning e hical conside a ions, 47 a icles decla ed ha ing ap-
p o al o an e hics commi ee and in o med consen explici ly appea ed
as an inclusion c i e ion in 49 pape s.
3.2. Analy ical me hodology: sample collec ion, nail p epa a ion, analysis
and quali y con ol (Table A1)
Toenails clippings -which a e he las end o he nail and cons i u e
only a ac ion o he o al nail-we e ob ained using s ainless-s eel
clippe s o scisso s. In ega d o sample s o age, s udies ha included
in o ma ion abou his issue indica ed ha we e kep in pape en el-
opes o in plas ic bags/ ials (polye hylene o non-speci ied), usually a
oom empe a u es. The e ec s o long- e m s o age (6 yea s) we e
e alua ed only o Se by S -Pie e e al., who concluded ha he loss o
humidi y occu ed wi h long- e m s o age led o inc eased Se con-
cen a ions (S -Pie e e al., 2006).
The in luence o sampling da e has no been commonly s udied.
Isola ed epo s ha e sugges ed ha Zn le els migh be highe in win e
(Campos e al., 2008) and ha he e migh be signi ican di e ences in
me al oenail le els depending on he season o sampling collec ion, o
Cu, bu no o Zn (Wilhelm e al., 1991) o Se (Baske e al., 1995).
Mos o he p ojec s (n = 40) did no iden i y he speci ic ype o
oenails analyzed. Among hose ha did, he majo i y (n = 36 s udies)
collec ed clippings om all oes; 8 p ojec s used nails om big oes and,
in ano he wo s udies, specimens om big oes and om he o he oes
Fig. 1. G aphical summa y o he sys ema ic e iew
esul s. Sankey diag am. The i s column ep esen s
he o al numbe o a icles included in he e iew.
The second column shows he geog aphical dis-
ibu ion acco ding o he place whe e he s udies
we e conduc ed. The hi d column illus a es he
numbe o a icles ha assessed each elemen in
oenails (many a icles deal wi h mo e han one
elemen ). The las column shows he main objec i e
o he a icles included in he e iew (some s udies
may sha e bo h objec i es).
E. Gu ié ez-González, e al. En i onmen al Resea ch 179 (2019) 108787
3
we e e alua ed sepa a ely. Two p ojec s p o ided pa ial in o ma ion,
epo ing sampling om bo h ee (Ghadi ian e al., 2000;Vince i e al.,
2005) o om igh oo (Vince i e al., 2012), o using nails om
di e en ee o analysis o each me al, wi hou speci ying which oes
we e conside ed (Vince i e al., 2005). Possible di e ences in me al
le els among oes ha e only been explo ed o Se, compa ing he big oe
o he es o oes (Baske e al., 2001;Kok e al., 1989;Longnecke
e al., 1993) o wi h a pool o all oes ( an ’ Vee e al., 1990), wi hou
inding signi ican a ia ions. Also o his elemen , a high co ela ion
be ween Se concen a ions in he igh and le oenails was obse ed in
one s udy ( = 0.74) (S e en Mo is e al., 1983).
In ega d o he amoun o bio-specimen, mos pape s (n = 105) did
no p o ide any summa y o desc ip i e da a (i.e., mean o ange)
abou he oenail mass used o he analyses. Howe e , se e al au ho s
(Ka dinaal e al., 1997;S e en Mo is e al., 1983;Mo dukho ich e al.,
2012;Pla z e al., 2002;Sande s e al., 2014) ema ked ha he limi o
de ec ion (LOD) o ace me al de e mina ions was dependen on
oenail mass and a leas 25 epo s indica ed ha a minimum weigh
was equi ed o he analyses, which was only speci ied in 15 pape s
(i.e., 10 mg in 12 o hem). In some s udies (Lee e al., 2016;
Abdul ahman e al., 2012;Al-Saleh and Billedo, 2006;Goullé e al.,
2009;Ha man e al., 2002;Michaud e al., 2002;Mo is and C ane,
2013;Saa e al., 2013;Wongwi e al., 2004), esea che s s a ed hey
analyzed aliquo s o oenail wi hin a mass ange (mos ly 10–50 mg). I
should be no ed ha , acco ding o some in es iga o s, he weigh o he
clippings no only limi s he possibili y o measu emen o ace me als,
bu also bias he le els ob ained. Thus, Baske e al. desc ibed an ap-
pa en sys ema ic bias in me al concen a ions (Se, in his case) ha
we e in e sely p opo ional o he mass o he sample (Baske e al.,
1995), which occu ed in clipping samples weighing 23 mg o less.
Addi ionally, Sain Pie e e al. (S -Pie e e al., 2006) ound an in e se
co ela ion be ween sample weigh and Se concen a ion, while Co-
langelo e al. epo ed ha oenail mass was posi i ely associa ed wi h
oenail Se le els (Colangelo e al., 2014). In some o he s udies, his
possible in luence o nail weigh in ace me al concen a ions was
conside ed and was co ec ed o . Thus, some au ho s adap ed analy-
ical p ocedu es o i small samples (Baske e al., 1995); in o he
s udies, oenail weigh was conside ed as a po en ial con ounding ac o
(Colangelo e al., 2014), o measu ed le els we e no malized based on
sample weigh (B ockman e al., 2009). Also, eg ession models we e
i ed wi h log- ans o med oenail elemen le els ( he dependen
a iable) agains he nail weigh ( he independen a iable) (S -Pie e
e al., 2006), o he esidual o each obse a ion was added o he
p edic ed mean oenail alue and he esul was exponen ia ed
(Ga land e al., 1993,1995,1996).
In mos s udies, oenails we e subjec ed o p e ea men a e clip-
ping and s o age, be o e analysis, and he me hods used we e highly
a iable. Table A1 (Appendix A) p esen s a summa y o his in o ma-
ion, de i ed om each epo included in he e iew. Nail polish in
samples was gene ally emo ed wi h ace one and isible di was
manually cleaned. Di ec e ec s o nail polish (Ghadi ian e al., 2000;
an ’ Vee e al., 1990;K ogh e al., 2003) o deb is ( an ’ Vee e al.,
1990) was assessed only o Se, and hese ac o s did no seem o in-
luence oenail Se concen a ions. In o de o educe ex e nal con-
amina ion, oenails we e cleaned by washing wi h de e gen , deionized
wa e , me hanol, T i on solu ion, ace one, o sodium dodecylsul a e,
assis ed by a sonica o o an ul asound ba h. Subsequen ly, samples
we e d ied in an o en, ai -d ied o eeze-d ied.
Neu on ac i a ion analysis (NAA o ins umen al NAA) was he
mos commonly used echnique o elemen measu emen (46 s udies),
ollowed by induc i ely coupled plasma spec ome y (ICP-MS, ICP-
OES, ICP-AES) (29 s udies) and a omic abso p ion spec ome y (AAS)
(14 s udies) (Appendix A, Table A1). In hese wo las cases, diges ion o
samples was pe o med in ni ic acid, wi h o wi hou chlo hyd ic acid,
in pe chlo ic acid, o in hyd ogen pe oxide, when needed; some epo s
speci ied a mic owa e diges ion sys em o a sonica o . Ce ain esea ch
p ojec s, like CARDIA, CLUE II, o ORDET, employed di e en echni-
ques depending on he me als s udied. Less common echniques used
we e he mal neu on lux (G aham e al., 1991) and acid diges ion
luo ome y (Ha man e al., 2002;Michaud e al., 2002;Al han e al.,
1992;Männis ö e al., 2000;O askainen e al., 1993).
Six y epo s men ioned quali y con ol p ocedu es, which included
he use o ce i ied e e ence ma e ial (u ine o hai ) o homemade nail
e e ence ma e ial, eco e y analysis, p ocedu al blanks, duplica e
samples, o spike samples.
3.3. Essen ial ace me al concen a ions in oenails ac oss popula ions
Tables B1–B8 (Appendix B) p esen he le els o each essen ial me al
in each s udy and he subg oup o pa icipan s (mean (SD), median,
ange) ex ac ed om he 139 s udies, included in his e iew. Thei
main da a a e shown g aphically in Fig. 2.
Only 18 (9.5%) esea ch p ojec s, mos ly hose which used IPC-MS,
p o ided in o ma ion on LOD, and e en ewe (n = 4), speci ied limi s
o quan i ica ion (LOQ). The LODs we e calcula ed om p ocedu al
blank analyses, usually as h ee s anda d de ia ions om he mean
blank eading (Al-Saleh and Billedo, 2006;K ogh e al., 2003;He man
e al., 2013;P zybylowicz e al., 2012;N ihabose e al., 2017;Boucha d
e al., 2017). Among he s udies ha epo ed LODs o speci ic me als,
o Co, LODs anged om 0.0003 (Goullé e al., 2009) o 0.01 μg/g
(Chanpiwa e al., 2015); o Cu, om 0.009 (P zybylowicz e al., 2012)
o 0.12 μg/g (Chanpiwa e al., 2015); o Fe, om 1.55 (P zybylowicz
e al., 2012) o 2.93 μg/g (Chanpiwa e al., 2015); o Mn, om 0.001
(Goullé e al., 2009) o 0.33 μg/g (Chanpiwa e al., 2015); o Mo, om
0.0004 (Goullé e al., 2009) o 0.02 μg/g (Chanpiwa e al., 2015); o
Se, om 0.0022 (Emmanuelle e al., 2012) o 0.02 μg/g (Goullé e al.,
2009); and o Zn, om 0.01 (Goullé e al., 2009) o 0.279 μg/g
(P zybylowicz e al., 2012). Only one s udy speci ied he LOD o V,
which was 0.001 μg/g (Goullé e al., 2009). The pe cen age o samples
wi h quan i ies unde LOD, when a ailable, depended on he elemen
s udied. I was low o inexis en o Zn and Se; in con as , some s udies
epo ed a signi ican p opo ion o samples wi h quan i ies unde he
LOD o o he me als, i.e., Cu, Fe, Mn and V (See Appendix B, Tables
B1–B8).
Among he elemen s s udied, Co, Mo, Se and V had he lowes le-
els, and mos s udies ound mean alues < 1 μg/g (Fig. 2a,e, and g;
Tables B1, B5, B.6, B.7). Howe e , a couple o s udies epo ed exposed
popula ions wi h highe mean Co concen a ions: me al wo ke s in wo
owns o no he n I aly (AMs: 18.90 and 53.79 μg/g (Sabbioni e al.,
1994),); and young adul s li ing nea a mining a ea in Zambia (GM:
1.39 μg/g) (Ndilila e al., 2014). Mo is e al. also epo ed ex-
cep ionally high Se le els (AM 8.27 μg/g) among people in USA who
consumed mis o mula ed supplemen s wi h excessi e Se concen a ions
(Mo is and C ane, 2013). In gene al, mean Se le els we e highe in
s udies om USA-Canada, when compa ed wi h o he coun ies.
Fe oenail concen a ions (Table B3 and Fig. 2c) showed he highes
a iabili y ac oss s udies, wi h median le els anging om 8.8 μg/g in a
g oup o 60–80 yea -old women om Spain (Su eda e al., 2017) o
excep ionally high le els (median: 1434 μg/g) in subjec s li ing in
con amina ed a eas o Cambodia (Chanpiwa e al., 2015).
Mean Cu and Mn le els we e usually below 10 μg/g (Tables B.2 and
B.4,Fig. 2b–d, espec i ely), while mean Zn le els (Table B.8,Fig. 2h)
anged mos ly om 50 o 200 μg/g. The highes Cu, Mn and Zn con-
cen a ions we e ound among subjec s li ing in u al a eas nea a
highly indus ialized ci y in Pakis an (AM: 26.2 μg/g o Cu, 52.1 o
Mn and 298 o Zn) (Mohmand e al., 2015). High concen a ions o Mn
E. Gu ié ez-González, e al. En i onmen al Resea ch 179 (2019) 108787
4
we e obse ed in indi iduals li ing in highly pollu ed a eas o Cam-
bodia (AM: 43.9 μg/g) (Chanpiwa e al., 2015) and among welde s
om a local boile make union in he USA (AM: 26.9–55.5 μg/g)
(Laohaudomchok e al., 2011).
3.4. Toenail as a bioma ke o in eg a ed long- e m exposu e: ime-window
o exposu e and in aindi idual s abili y o e ime (Tables 1 and 2)
The ime- ame o exposu e co e ed by oenails, in es iga ed only
o Se and Mn, was explo ed in s udies ha iden i ied a speci ic momen
in which he exposu e occu ed, which allowed o calcula e he ime
elapsed un il de ec ion in oenail samples. Selenium was he mos s u-
died elemen and was e alua ed in h ee esea ch p ojec s.
In he USA, 12 young men pa icipa ed in a esea ch conduc ed o
e alua e he e ec o one-yea in ake o Se-supplemen ed whole whea
b ead on Se oenail le els. The pa icipan s we e classi ied in o h ee
g oups: hose wi h high-dose (4.91 μmol Se/d), medium-dose (2.61 μmol
Se/d) and low-dose (0.41 μmol Se/d), and he concen a ion o Se in
oenail clippings was measu ed e e y 1–2 weeks o 2 yea s (Longnecke
e al., 1993). Se peak le els we e de ec ed in he big oenail a e 24–37
weeks s. 12–24 weeks in o he oes; his di e ence was a ibu ed o he
sho e nail bed in smalle nails. Selenium concen a ion in he big oenail
was s ill high, e en a e one yea o in ake e mina ion and emained o e
baseline o wo yea s; his sugges s ha oenail clippings could p o ide a
ime-in eg a ed measu e o Se in ake o o e 26–52 weeks, se ing as a
good bioma ke o Se in ake o e ospec i e s udies. O he s udies in-
cluded 10 middle-aged men and women p o ided wi h Se-76 supple-
men a ion, and he peak Se concen a ions in oenails we e obse ed a
16–32 (Baske e al., 1995, 2001) and 16–50 (Baske e al., 1998) weeks.
Peak concen a ions we e also epo ed by Mo is e al. a 34 weeks a e
inges ion o high Se mis o mula ed p oduc s, while, in his s udy, baseline
le els we e eco e ed a e 59 weeks (Mo is and C ane, 2013). Fo Mn,
he ime- ame o exposu e was e alua ed in 3 s udies conduc ed among
occupa ionally exposed wo ke s (welde s). Exposu e ime e lec ed by
oenail Mn concen a ions was es ima ed be ween 7 and 9 (G ashow e al.,
2014) and 7–12 mon hs (Laohaudomchok e al., 2011;Wa d e al., 2017)
(Table 2).
Since one yea is an insu icien pe iod o he s udy o exposu e o
mos ch onic diseases, i is c ucial o iden i y he ex en o which in-
di idual poin measu emen s o ace me als in oenails ep esen oe-
nail concen a ion le els in he same pe son in he p e ious yea s.
This s abili y o essen ial ace me als o e ime was e alua ed in 7
epo s by es ima ing he wi hin-pe son co ela ion among samples
ob ained a di e en momen s (Table 1) (Baske e al., 1995;Ga land
e al., 1993;K ogh e al., 2003;Hun e e al., 1990a;Rod igues e al.,
2015;Xun e al., 2010a). The usage o co ela ion coe icien s o assess
ep oducibili y is no ideal, bu no s udies used he in a-class co ela-
ion coe icien .
Fig. 2. Essen ial me al le els [mean o median (μg/g d y weigh ] in human oenails (1975–2017).
E. Gu ié ez-González, e al. En i onmen al Resea ch 179 (2019) 108787
5

Table 1
Rep oducibili y o e ime o essen ial me als in oenails and co ela ion wi h le els in o he biological specimen.
Toenail me al Au ho Yea N Toenails ep oducibili y o e ime * Hai U ine Whole blood Se um Plasma Finge nail O he oenails Feces Co d blood Placen a Sali a
Co Ga land
e
1993 127 = 0.35 (6-yea )
Sabbioni 1994 115 = 0.38 (ns) = 0.25 (ns)
Chanpiwa
e
2015 180 = 0.20 = −0.08 (ns)
Cu Wilhelm 1991 461 = 0.18
Ga land
e
1993 127 = 0.26 (6-yea )
He man 2013 30 = 0.26
Kuipe 2014 239 (ns)
Chanpiwa
e
2015 180 = 0.10 (ns) = −0.08 (ns)
Fe Ga land 1993 127 = 0.43 (6-yea )
Chanpiwa
e
2015 180 = 0.36 = −0.03 (ns)
Mn Wongwi
2004 135 = 0.05 (ns) (ns)
Kuipe 2014 239 (ns)
Coelho
e
2014 122 = 0.23
Chanpiwa
e
2015 180 = 0.32 = −0.10 (ns)
Rod igues
e
2015 711 = 0.37–0.41 (6/7 mon hs)
b
= 0.14 Mo he -in an = 0.39 = 0.14
Hassani
g
2016 83 = 0.65 = 0.65
N ihabose 2017 268 = 0.40 = 0.14
Mo Kuipe 2014 239 (ns)
Chanpiwa
e
2015 180 = 0.08 (ns) = 0.00 (ns)
Se Hun e 1990b 868 = 0.60 (5-yea )
Mo is 1983 62 = −0.3 (ns) = 0.30 (ns) Le -Righ = 0.74
Kok 1989 168 Big-Small (nd)
Van' Vee 1990 372 Big-All (nd)
Longnecke 1991 142 = 0.60 = 0.91 = 0.89
Al han 1992 132 = 0.57
Ga land 1993 127 = 0.48 (6-yea )
Longnecke 1993 12 Big-Small (nd)
Baske 2001 11 Le -Righ **
K ogh 2003 80 = 0.57 (1-yea )
c
Sa ia
e
2006 220 = 0.55
Al Saleh
d
2006 691 = −0.16
Xun 2010b 69 = 0.56 (20-yea )
Vince i
e
2012 105 = 0.27
Coelho
e
2014 122 = 0.33
Kuipe
2014 239 (ns)
Rayman
e
2015 230 = 0.45
Punshon
ae
2016 554
h
V Rainska 2007 33 = 0.61
Zn Mckenzie 1979 110 (ns) (ns) (ns)
Wilhelm
a
1991 461 = 0.03 (ns)
Ga land 1993 127 = 0.58 (6-yea )
Chanpiwa
e
2015 180 = −0.02 (ns) = 0.08 (ns)
Punshon
a
2016 554 (ns)
N = numbe o pa icipan s (samples) in he s udy; = co ela ion coe icien ; (ns) = p > 0.05 excep in Champiwa (2015) (p > 0.01) o au ho only s a ed ha co ela ion was no s a is ically signi ican ;
(nd) = au ho s a ed ha he e we e no di e ences. * = be ween pa en heses is exp essed he in e ale o ime be ween bo h measu emen s.
a
Log ans o med.
b
P egnan women: i s imes e s one mon h pos -pa um.
c
No modi ied by age, menopausal s a us, smoking o ace one ea men .
d
No signi ican di e ences be ween mean le els in bo h specimens using - es .
e
Spea man co ela ion.
Pea son co ela ion.
g
Pa ial co ela ion es .
h
= s ong posi i e signi ican co ela ion wi h ma e nal oenails. No signi ican wi h in an oenails.
E. Gu ié ez-González, e al. En i onmen al Resea ch 179 (2019) 108787
6
Fo mos elemen s, his in o ma ion was ob ained om a single
analysis ca ied ou in 127 emale nu ses pa icipa ing in he Nu se
Heal h S udy I (NHSI), which measu ed 5 ace me als (Co, Cu, Fe, Se
and Zn) in 2 samples o oenails collec ed 6 yea s apa . Co ela ion
alues we e a ound 0.5 o Zn, Se and Fe and less han 0.4 o Co and Cu
(Ga land e al., 1993).
In he case o Se and Mn, ou sea ch iden i ied addi ional s udies
ha e alua ed he ep oducibili y o hei measu emen s in di e en
momen s o ime. Fo Se, he s udies we iden i ied epo ed a Pea son
co ela ion coe icien o 0.57 among samples collec ed a ound 1 yea
apa om 80 women in he ORDET p ospec i e s udy o whom 40 we e
p e-menopausal and 40 we e pos menopausal (K ogh e al., 2003); a
co ela ion coe icien o 0.60 using samples collec ed app oxima ely 5
yea s apa , om he NHS I coho (Hun e e al., 1990a); and a co -
ela ion coe icien o 0.56 using oenail Se samples collec ed 20 yea s
apa om 64 pa icipan s in he CARDIA p ojec (Xun e al., 2010a).
Ano he explo a o y esea ch s a ed ha Se le els we e e y s able in
oenail samples om 2 men and 2 women, ollowed up o 15 mon hs
p io o Se supplemen a ion (Baske e al., 1995). Fo Mn, wo s udies
ha e been conduc ed in his con ex : a s udy which epo ed co ela ion
coe icien s be ween 0.37 and 0.41 in p egnan women, wi h samples
aken du ing he i s imes e o p egnancy and one mon h a e de-
li e y (Rod igues e al., 2015) and ano he explo a o y analysis ha
e alua ed clippings o he i e oenails om he same indi idual, col-
lec ed ou imes o e a 9-mon h pe iod, wi h a la ge a iabili y in he
Mn le els (Gu h ie e al., 2008).
3.5. Co ela ion o ace elemen s in oenails wi h o he biological ma ices
(Table 1)
To be e unde s and oenail me al le els as bioma ke s o exposu e
o essen ial ace elemen s, i is impo an o explo e hei ela ionship
wi h o he subs a es commonly used in his ield, especially blood and
u ine. A o al o 20 s udies wi h a a iable numbe o pa icipan s
( ange: 30–868) e alua ed he co ela ion o ace elemen s in oenails
wi h o he biological ma ices collec ed concu en ly (i.e., whole blood,
se um, plasma, u ine, hai , inge nails, eces, co d blood, placen a and
sali a) (Table 1).
Hai : Hai was he biological ma ix mo e o en compa ed wi h
oenails (n = 10), p obably due o i s sha ed non-in asi eness and i s
simila ke a in-based composi ion. Fo Mo, Se o Zn, no signi ican
associa ions ha e been obse ed be ween le els in his subs a e and in
oenails (Wilhelm e al., 1991;S e en Mo is e al., 1983;Chanpiwa
e al., 2015;Kuipe e al., 2014;McKenzie, 1979). O he me als, such as
Co and Cu, showed weak posi i e (< 0.30) o null co ela ion be ween
bo h bioma ke s (Wilhelm e al., 1991;He man e al., 2013;Chanpiwa
e al., 2015;Sabbioni e al., 1994). In con as , he associa ion was
mode a e (be ween 0.32 and 0.40) o Mn (N ihabose e al., 2017;
Chanpiwa e al., 2015) and Fe (Chanpiwa e al., 2015) and s ong
( = 0.61) o V, (Rainska e al., 2007), al hough he in e p e a ion o
he la e esul was limi ed by he small sample size o he s udy
(n = 33).
U ine: Ou sea ch iden i ied wo s udies which e ealed s ong po-
si i e co ela ions be ween me al le els in oenails and u ine o Mn
( = 0.65 (Hassani e al., 2016)) and Se ( = 0.60 (Longnecke e al.,
1991)). In con as , Co, Cu, Fe, Mo and Zn in oenails and in u ine we e
no ound o be co ela ed in o he s udies (Chanpiwa e al., 2015;
Kuipe e al., 2014;McKenzie, 1979).
Blood: Su p isingly, he e we e only da a compa ing hese wo
ma ices o Se, Mn, Co and Zn. In he case o Se, ou s udies showed
posi i e and signi ican co ela ions wi h whole blood ( = 0.91
(Longnecke e al., 1991) and = 0.45 (Rayman e al., 2015)); se um
( = 0.89 (Longnecke e al., 1991)); and plasma ( = 0.55 (Sa ia e al.,
2006)). Howe e , in he s udy by Al Saleh e al. a nega i e co ela ion
be ween log- ans o med Se concen a ions in oenails and se um was
epo ed ( = −0.16 (Al-Saleh e al., 2006)). Rega ding Mn, Hassani
e al. desc ibed a s ong co ela ion be ween oenails and whole blood
le els ( = 0.65 (Hassani e al., 2016)), bu bo h bioma ke s we e no
ound o be ela ed in a sample o welde s s udied by Wongwi e al.
(2004); mo eo e , Rod igues e al. epo ed a low co ela ion be ween
in an oenails and co d blood concen a ions ( = 0.14 (Rod igues
e al., 2015)). Finally, whole blood Co (Sabbioni e al., 1994) and se um
Zn (McKenzie, 1979) le els we e no signi ican ly co ela ed wi h he
co esponding oenail concen a ions.
Finge nails: Only h ee s udies e alua ed he co ela ion be ween
oenails and inge nails, showing a low co ela ion o Mn ( = 0.23
(Coelho e al., 2014)) and a medium co ela ion o Se ( = 0.33
(Coelho e al., 2014) and = 0.57 (Al han e al., 1992)). In hese
s udies, as well as in he s udies by Baske e al. o Se (Baske e al.,
1995,1998,2001), inge nail concen a ions we e almos wice as high
as hose om oenails.
O he ma ices: Fo Mn le els in oenails, a weak co ela ion has been
epo ed wi h he concen a ion in sali a (N ihabose e al., 2017) and
no co ela ion wi h le els in eces (Wongwi e al., 2004). A mode a e
co ela ion has been epo ed be ween in an and ma e nal oenail Mn
le els ( = 0.39 (Rod igues e al., 2015)). In he case o Se, a posi i e
co ela ion was obse ed be ween ma e nal oenail and placen a Se
concen a ions (Punshon e al., 2016).
3.6. Co ela ion o essen ial me als wi h o he ace me als in oenails
(Table A2)
The co ela ion among essen ial ace elemen s in oenails o wi h
o he oxic me als was explo ed in 14 s udies (Table A2, Appendix A).
Mos o he epo ed co ela ions we e low-mode a e (below 0.40) o
non-signi ican , bo h o essen ial and non-essen ial elemen s. Among
he essen ial me als g oup, he s onges co ela ions we e obse ed
be ween Fe and Co ( = 0.81) (Rainska e al., 2007) and be ween Mn
and V ( = 0.40) (Masi oni e al., 1976). Rega ding he associa ion
be ween essen ial and oxic me als, Mn had he highes p opo ion o
s ong co ela ions (wi h aluminium (Al) (Gu h ie e al., 2008), a senic
(As) (Mo dukho ich e al., 2012;Sande s e al., 2014), ba ium (Ba)
(Kuipe e al., 2014), cadmium (Cd) (Mo dukho ich e al., 2012;
Sande s e al., 2014), ch omium (C ) (Sande s e al., 2014), lead (Pb)
(Mo dukho ich e al., 2012) and u anium (U) (Kuipe e al., 2014)).
O he s ong co ela ions we e epo ed o Co and ungs en (W)
(Sabbioni e al., 1994), Cu and Cd (Wilhelm e al., 1991), Cu and Pb
(Wilhelm e al., 1991;Kuipe e al., 2014), Se and As (nega i e co e-
la ion) (Bu gess e al., 2014), V and Al (Masi oni e al., 1976) and V and
scandium (Sc) (Rainska e al., 2007).
3.7. De e minan s o essen ial me als in oenails
Iden i ica ion o he exposu e sou ces o ac o s ela ed o hem is
c ucial in unde s anding he in o ma ion p o ided by he measu emen
o essen ial me al le els in oenails. Mos o he s udies epo ed on his
issue, al hough he huge a iabili y in he a iables s udied, popula-
ions, designs and indica o s made he calcula ion o quan i a i e
summa y es ima o s p ac ically impossible. No wi hs anding, we ha e
ied o summa ize his in o ma ion in o de o gi e a gene al iew o
he published esul s. Fo his pu pose, we ha e designed wo ables
ha p esen , o each combina ion o me al and ac o s udied, he
iden i ica ion (i.e., au ho and da e) o each epo and he in o ma ion
abou hei possible ela ionship. Table 2 includes da a o non-die a y
ac o s and Table 3 includes he co esponding associa ions wi h in ake
o supplemen s, die a y es ima es, oods and nu ien s.
3.7.1. Pe sonal and an h opome ic cha ac e is ics (Table 2)
Age: Fo oenail Se, mos o he s udies showed ei he no changes
wi h age (Ka dinaal e al., 1997;Colangelo e al., 2014; an ’ Vee
e al., 1990;Al han e al., 1992;O askainen e al., 1993;Sa ia e al.,
2006;E e son e al., 2017;Hashemian e al., 2017;K is al e al., 2014;
E. Gu ié ez-González, e al. En i onmen al Resea ch 179 (2019) 108787
7
Table 2
S udies (Au ho yea ) epo ing associa ion o oenail essen ial ace me als o pe sonal cha ac e is ics and non-die a y exposu es.
(con inued on nex page)
E. Gu ié ez-González, e al. En i onmen al Resea ch 179 (2019) 108787
8
Lipsky e al., 2004;Mo is, 2001;Mo is e al., 2006;Swanson e al.,
1990; an den B and e al., 1993;Xun e al., 2010b), o lowe le els in
elde indi iduals (Ga land e al., 1995;Pa k and Seo, 2016;Hun e
e al., 1990b;Jang e al., 2017;Pa k e al., 2011;Żukowska e al.,
2009). Toenail concen a ions o V we e also in e sely associa ed wi h
age (Masi oni e al., 1976;Rako ic e al., 1997;Slo nick e al., 2005)
and a simila esul was epo ed in he only s udy e alua ing Co and Fe
(Rako ic e al., 1997). The e ec o age was inconsis en o Cu, Mo, Mn
and Zn.
Sex: Women gene ally had highe oenail Se concen a ions han
men (Lee e al., 2016;Baske e al., 2001;Xun e al., 2010a;Rainska
e al., 2007;Mo is, 2001;Mo is e al., 2006;Swanson e al., 1990; an
den B and e al., 1993;Xun e al., 2010b;Żukowska e al., 2009). Fo
Cu, Mo, Mn and V, he s udies showed ei he highe le els in women
(Coelho e al., 2014;Rako ic e al., 1997;Slo nick e al., 2005) o no
a ia ion by sex (Masi oni e al., 1976;McKenzie e al., 1978;Reis
e al., 2015). Fe le els we e simila in bo h sexes (Su eda e al., 2017;
Rako ic e al., 1997). Fo Zn, he a ailable da a showed e y incon-
sis en esul s, wi h some epo s inding no di e ences by sex (Pa k
and Seo, 2016;Me ama e al., 2017;P zybylowicz e al., 2012;Su eda
e al., 2017;Hashemian e al., 2017;Rako ic e al., 1997;McKenzie
e al., 1978), while o he s showed highe concen a ions ei he in
women (Lee e al., 2016;Rainska e al., 2007;Be gomi e al., 2002) o
in men (Campos e al., 2008;Gonzalez e al., 2008). Cobal was he only
me al o which le els we e consis en ly highe in men (Su eda e al.,
2017;Rako ic e al., 1997;Slo nick e al., 2005).
Di e ences by ace/e hnic g oup ha e been e alua ed o Mn and
Se in a ew pape s. Whi e people usually had highe oenail le els o Mn
han o he g oups (Mo dukho ich e al., 2012;Laohaudomchok e al.,
2011); o Se, in some s udies, le els we e ound o be highe in whi es
(E e son e al., 2017;K is al e al., 2014), while o he s udies ound
lowe concen a ions in A ican-Ame icans (Colangelo e al., 2014;
K is al e al., 2014;Xun e al., 2010b,2011). One s udy did no ind any
di e ences wi h espec o e hnici y (Sa ia e al., 2006).
The in luence o body mass index (BMI) was s udied only o Se, Zn
and Fe. Nei he Se (Ka dinaal e al., 1997;Colangelo e al., 2014;
O askainen e al., 1993;Sa ia e al., 2006;Hashemian e al., 2017;
K is al e al., 2014;Lipsky e al., 2004;Mo is e al., 2006; an den
B and e al., 1993;Hun e e al., 1990b), no Zn (Hashemian e al.,
2017;Pa k e al., 2016;Vince i e al., 2015) a ied wi h his ac o ,
while one s udy epo ed a posi i e link be ween Fe in emale oenails
and BMI (Ga land e al., 1996).
Only a ew s udies e alua ed he e ec o ep oduc i e ac o s,
showing ha pa i y may be posi i ely associa ed wi h oenail Mn
(Rod igues e al., 2015) and Se concen a ions ( an Noo d e al., 1993),
while a la e age a i s bi h may be associa ed o lowe Fe le els
(Ga land e al., 1996). An olde age a mena che was ound o be as-
socia ed wi h highe Se concen a ions (Hun e e al., 1990a), bu
menopause did no modi y le els o his elemen in oenails (K ogh
e al., 2003).
3.7.2. Non-die a y li es yle & social ac o s (Table 2)
Educa ional le el was posi i ely co ela ed wi h highe Se con-
cen a ions (Colangelo e al., 2014;Xun e al., 2010a,2011;Rayman
Table 2 (con inued)
E. Gu ié ez-González, e al.
En i onmen al Resea ch 179 (2019) 108787
9
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