Reproductive and Developmental Toxicity of Metals - Toxicology of Metals - page 220

studies have not revealed reproductive effects in con-
trast to experimental evidence in animals. Studies are
needed to determine whether cadmium at low doses
may act as reproductive and developmental toxicant
and whether the fetal toxicity is related to placental
defects or to accumulation of cadmium in the fetus.
In vitro studies have shown effects on calcium and
oxytocin activities in myometrial strips from term
pregnant women (Sipowicz et al ., 1995) and on ster-
oid genesis in granulose cells obtained from ovarian
follicular aspirates (Paksy et al ., 1997). However, the
lowest cadmium concentration that reduced progester-
one production was about 3.5 times higher than levels
reported in the ovary of a female smoker.
After acute and at high-dose administration in rats,
cadmium has been shown to affect various female
reproductive endpoints, resulting in hemorrhagic
changes in the ovary and uterus or in persistent estrous
and ovulation; these effects can be prevented by coad-
ministration of selenium (Saksena, 1982; Watanabe
et al., 1979).
The effects of cadmium vary as to the sensitivity of
early embryos, and studies on cadmium acetate expo-
sure indicate no effects on fertilization, but only at the
blastocyst stage or in vitro reduction of development
to the morula stage (Schmid et al ., 1983; Storeng and
Jonsen, 1980).
Exposure of experimental animals to cadmium
increased uterus weight accompanied by proliferation
of the endometrium and induction of progesterone
receptors, mimicking the effects of estrogens. Female
offspring experienced an earlier onset of puberty and
growth of the mammary gland. In rats, exposure to cad-
mium oxide dusts increased the duration of the estrous
cycle, decreased the preovulatory luteinizing hormone
levels in blood, and inhibited ovulation. These effects
were generally observed after high-dose, acute expo-
sures and, therefore, provide little information for cur-
rent human exposures (Baranski and Sitarek, 1987).
Cadmium given before mating may lead to sterility
in a dose-dependent fashion, because of anovulation
resulting from reversible pituitary dysfunction. How-
ever, animals may develop tolerance and remain fertile
despite cadmium treatment, with normal fetal outcome
and postnatal development (Paksy et al. , 1996).
Piasek et al . (1999) evaluated the direct effects of
in vitro cadmium exposure on steroidogenesis in
Sprague-Dawley rat ovaries; production of proges-
terone and testosterone was affected in proestrous
rats and pregnant dams, whereas estradiol was not
affected. They concluded that cadmium interferes with
the ovarian steroidogenic pathway at more than one
site. These effects may be mediated by interference
with DNA-binding zinc in steroidogenesis or by estro-

gen-like activity (Henson and Chedrese, 2004; Johnson
et al ., 2003).

3.4 Manganese
Reports in humans on the association between man-
ganese exposure and adverse reproductive outcomes
in females are limited. A survey carried out in Austral-
ian general population found more frequent stillbirths
than expected in the group exposed to manganese
(Tsuchiya et al ., 1987).
In rats, manganese exposure reduced the number of
ovarian follicles and induced persistent corpora lutea
(Laskey et al ., 1982). In mice, exposure during gesta-
tion led to fetal growth retardation and anencephaly
(Sanchez et al ., 1993).

3.5 Chromium
Few studies in human females have addressed
potential adverse effects of chromium and chromium
compounds. The effect of chromium (VI) on human
pregnancy outcomes was examined in females working
in manufacturing facilities in Russia (Shmitova, 1978;
1980). Complications during pregnancy and childbirth
(not described further) were reported in women with
higher levels of chromium in blood and urine than
the control group. However, the quality of the data
and reporting limits their interpretation regarding the
potential ability by chromium to produce reproductive
effects.
Bonde (1993) studied the spouses of stainless steel
welders exposed to chromium (VI) for spontaneous
abortions and congenital malformations. The author
concluded that the weak indications of an increased
risk of spontaneous abortion among partners of stain-
less steel welders (odds ratio [OR], 1.9; 95% confi dence
interval [CI], 1.1-3.2) needed to be corroborated. In
a subsequent investigation of a similar population
by Hjollund et al . (2000), information was collected
on exposure and outcomes for 245 clinically recog-
nized pregnancies. Male welding of stainless steel
was associated with an increased risk of spontane-
ous abortion in spouses (adjusted relative risk, 3.5;
95% CI, 1.3-9.1). The mutagenic effect of chromium
(VI) previously found in both somatic and germ cells
could be responsible for the abortions, which in this
case would be a male-mediated effect. In an earlier
study, the same group (Hjollund et al., 1995) examined
outcomes in 2520 pregnancies of spouses of Danish
metal workers exposed to chromium (VI) from 1977 to
1987. The number of spontaneous abortions was not
higher for pregnant women whose spouses worked
in the stainless steel welding industry compared with