Chemistry Reference
In-Depth Information
endogenous exposure. The association between bone
lead and B-Pb is particularly close in retired workers.
The bone lead exerted a greater infl uence on B-Pb
during the winter months than in the summer (Oliviera
et al
., 2002). The explanation was supposed to be enhanced
bone resorption because of decreased levels of activated
vitamin D as a result of lower exposure to sunlight.
8
6
4
2
0
0
5
10
15
20
25
30
Years
FIGURE 7
Blood-lead level (B-Pb) in a worker during 28 years af-
ter end of heavy exposure for years. His initial B-Pb was 7.4
2.5.6 Gene-Environment Interaction
For centuries it has been known that there is a large
interindividual variation in sensitivity to lead, but the
mechanism behind this has been largely unknown.
Genetics seems to play a role, because there was an
association of B-Pb in twins (Björkman
et al
., 2000).
A single gene on chromosome 9q34 encodes ALAD.
Human ALAD is a polymorphic enzyme. Eight ALAD
variants have been described. The allele contains a site-
directed mutagenesis, a G
mol/L.
It is possible to identify three different compartments, representing
soft tissues (half-time approximately 1 month), trabecular bone (ap-
proximately 1 year), and cortical bone (decade) Note: At the end of
the period, the mean B-Pb in the “background population” was ap-
proximately 0.15
µ
µ
mol/L. Skervfi ng
et al
., to be published.
the mainly cortical fi nger bone (Börjesson
et al
., 1997b;
Nilsson
et al
., 1991), and the cortical tibia (Brito
et al
.,
2001) have been estimated to be 1-2 decades.
Evidence suggests increased mobilization of lead
from the skeleton during bone demineralization. Women
loose as much as half of the trabecular bone and a third
of cortical peak bone mass during their later lifetime.
Estrogen supplementation may decrease the lead mobili-
zation (Korrick
et al
., 2003; Latorre
et al
., 2003). Increased
B-Pb has been observed during pregnancy and lacta-
tion (Section 2.11.1), menopause (Berglund
et al
., 2000a;
Grandjean
et al
., 1992; Hernandez-Avila
et al
., 2000;
Korrick
et al
., 2003; Lagerqvist
et al
., 1993; Latorre
et al
.,
2003), old age (Tsaih
et al
., 2001), thyrotoxicosis (Gold-
man
et al
., 1994; Osterode
et al
., 2000), and hyperparathy-
roidism (Osterloh and Clark, 1993; Osterode
et al
., 2004).
Because of the large deposit of lead in the skeleton, bone
tumor (Guijarro
et al
., 1988) and progressive osteoporo-
sis (Shannon
et al
., 1987; Berlin
et al
., 1995) may also
cause “endogenous” lead toxicity in previously exposed
subjects.
There are associations between bone lead, on the
one hand, and both B-Pb (Börjesson
et al
., 1997a; 1997b;
Erkkilä
et al
., 1992; Gerhardsson
et al
., 1998; Wasserman
et al
., 2003) and serum/plasma lead (Bergdahl
et al
.,
1998a; Gerhardsson
et al
., 1998; Hernandez-Avila
et al
.,
1998), on the other. Studies in women immigrating to
Australia, from areas where the exposure was to lead
of a different
206
Pb/
204
Pb isotopic ratio, confi rmed that
release from bone causes an endogenous exposure,
making up 45-70% of total B-Pb (Gulson
et al
., 1995).
The relationships between exposure time, B-Pb and
bone lead are nonrectilinear (Brito
et al
., 2002; Fleming
et al
., 1997). In lead workers, approximately 1.8
C transversion at position
177 of the coding region, resulting in the substitution
of asparagine for lysine at amino acid 59 (proteins K59
and N59, respectively; Figure 6).
The enzyme is codominant, in that both these
alleles are expressed if a copy is present. Hence, there
are three distinct isoenzyme phenotypes: K59-K59
(ALAD 1-1), K59-N59 (ALAD 1-2), and N59-N59
(ALAD 2-2). The fi rst one will be denoted
ALAD
1
,
and the latter two
ALAD
2
. In Caucasian populations,
approximately 80% of the individuals have ALAD
1-1, 19% ALAD 1-2, and 1% ALAD 2-2 (Kelada
et al
.,
2001). Asian and African populations have lower fre-
quencies of
ALAD
2
(approximately 10%; Lee
et al
.,
2001a; Schwartz
et al
., 2000b; Theppeang
et al
., 2005;
see also Chapter 4).
As mentioned previously (Section 2.5.2), ALAD is the
major binding site for lead in red cells and is probably
also important in other tissues. Hence, genetic polymor-
phism in
ALAD
may affect the metabolism of lead. Sev-
eral studies have shown higher B-Pb in
ALAD
2
subjects
than in
ALAD
1
(Wetmur
et al
., 1991; Alexander
et al
.,
1998; Fleming
et al
., 1998; Schwartz
et al
., 2000c); this
has led to the hypothesis that the
ALAD
2
gene product
may bind lead more tightly than the
ALAD
1
one. How-
ever, that is not easily explaining the higher P-Pb/B-Pb
radio observed among
ALAD
2
subjects, as compared to
ALAD
1
subjects (Montengegro
et al
., 2006).
Furthermore, in
ALAD
1
subjects, the urinary excre-
tion of lead, both unprovoked (Süzen
et al
., 2003) and
after chelation (Gerhardsson
et al
., 1999; Schwartz
et al
.,
1997a), was higher than in
ALAD
2
subjects.
The
ALAD
genotype also seems to affect the lead
kinetics in calcifi ed tissues. In several studies,
ALAD
2
subjects had lower bone (Fleming
et al
., 1998; 1999; Hu
et al
., 2001; Kamel
et al
., 2003; Schwartz
et al
., 2000b)
→
µ
mol/L
(Schütz
et al
., 1987b), or 1.7
g/g bone mass
in tibia (Bleecker
et al
., 1995), seemed to originate from
µ
g/L per
µ
