Lead - Toxicology of Metals - page 612

structural chromosome aberrations—as had been
assumed for a long time—are really associated with an
increased risk of later cancer (Hagmar et al ., 1998). For
micronuclei and SCEs, the picture is less clear.
As to mechanism of the mutagenic effect, evi-
dence shows that lead accumulates in the cell nucleus
( Silbergeld et al ., 2000). However, there is only limited
evidence of direct genotoxic or DNA-damaging effects,
except for lead chromate, where hexavalent chromium
is probably the cause. Hence, lead has mostly been
negative in in vitro gen-tox assays.
Rather, lead-induced nongenotoxic/epigenetic
mechanisms seem to affect DNA (Silbergeld et al .,
2000). Thus, lead exposure may increase the suscepti-
bility to genotoxic agents. Hence, lead may bind to, and
deplete, glutathione (a free-radical scavenger; Hun-
aiti et al ., 2000), interfere with DNA repair (Hartwig,
1994), and bind to histones, thus decreasing their DNA
protection (Quintanilla-Vega et al ., 2000). In accord-
ance with this, there was a multiplicative effect for
coexposure in work environments to lead, cobalt, and
cadmium, as regards induction of DNA single-strand
breaks (Hengstler et al ., 2003).
Lead-induced ALA accumulation (Section 2.6.2.1)
can also generate reactive oxygen species, which may
damage DNA (Silbergeld et al ., 2000). Furthermore,
experimental evidence shows that lead can substitute
for zinc in several proteins that function as transcrip-
tional regulators, including protamines. Lead also
reduces the binding of these proteins to recognition
elements in genomic DNA, which suggests an epige-
netic involvement of lead in altered gene expression.

There is some data indicating that lead exposure in
the general population is associated with cancer risk
(Lustberg and Silbergeld, 2002). Then, the exposure
has been much lower.
However, the carcinogenic pattern in humans is
not consistent (Cocco et al ., 1997; Englyst et al ., 2001;
Ojajärvi et al ., 2000; Steenland et al ., 1992). Furthermore,
there are major problems in terms of confounding (e.g.,
as regards coexposure to arsenic and cadmium in the
occupational cohorts). Also, there may be selection
bias. Hence, lead workers may differ in many ways
besides the lead exposure. In particular, confounding
by smoking is a problem, which has only occasionally
been tackled. Also, the worker may be physically fi t
and may have different diets.

2.11 Reproduction

2.11.1 Females and Offspring

Lead is distributed to the ovary (Barry, 1975). There
is some information indicating an effect of lead on
female sexual maturation (Wu et al ., 2003). Also, lim-
ited information may mean that lead causes a delay of
time-to-pregnancy (longer time to become pregnant in
women after a decision to try; Sallmén et al ., 1995).
During pregnancy, the B-Pb changes in the woman.
First, it decreases because of hemodilution (Lager-
qvist et al ., 1996; Rothenberg et al ., 1994; 2000; Téllez-
Rojo et al ., 2004). Later on, lead is mobilized from the
skeleton, causing an increase of B-Pb (Pires et al ., 2001;
Téllez-Rojo et al ., 2004). In Australian women, B-Pb
rose by 20%, of which 30% originated from the skel-
eton (Gulson et al ., 1998b). Low calcium intake seems
to cause an increase of blood and bone lead at a high
lead exposure (Hernandez-Avila et al ., 1996; Téllez-
Rojo et al ., 2002), but not at a low one (Berglund et al .,
2000a; Téllez-Rojo et al ., 2004; Vahter et al ., 2002). The
B-Pb during pregnancy is associated with a rise in
blood pressure (Rothenberg et al ., 1999a; 2002).
Lead is deposited in the placenta (Hubermont et al .,
1978; Osman et al ., 2000; Schramel et al ., 1988). The levels
in the placenta were higher in occupationally lead-
exposed women than in nonexposed ones (Khera et al .,
1988; Wang et al ., 1989). Low lead levels are present in
amniotic fl uid (Klink et al ., 1983). However, a large part of
the lead mobilized from the skeleton and absorbed from
the gastrointestinal tract is transferred through the pla-
centa into the fetus (Ong et al ., 1993). There is a close asso-
ciation between maternal and cord B-Pb; the cord blood
concentration is approximately 85% of the maternal one.
Lead is embryotoxic and fetotoxic in experimental
animals. Lead exposure in man has frequently been
associated with spontaneous abortion (Hertz-Picciotto,

2.10 Cancer
Animal experiments have shown a tumorigenic
effect of lead (Silbergeld et al ., 2000). Hence, soluble
lead salts, such as lead acetate and subacetate, have
produced kidney and brain tumors, and lead phos-
phate kidney tumors, in rodents after oral or parenteral
administration. Synergistic effects exist for the devel-
opment of cancer between lead acetate and oxide, on
the one hand, and some organic carcinogens, such as
benzo(a)pyrene and nitrosamines, on the other.
In a series of epidemiological studies, lead workers
had increased risks of total, kidney, lung, or stomach
cancers (Anttila et al ., 1995; Carta et al ., 1994; Cocco
et al ., 1994a,b; Fu and Bofetta, 1995; Gerhardsson et al .,
1995b; Wingren and Axelson, 1993; Wong and Harris,
2000). Also, there is limited support for a synergism
with other carcinogens (e.g., diesel exhaust; Anttila
et al ., 1996). The studied cohorts have had a high expo-
sure (mean B-Pb >3

mol/L), at least in most of the
studies (Skerfving, 2005).

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