Chemistry Reference
In-Depth Information
decreased the fi delity of DNA synthesis
in vitro
(Sirover
and Loeb, 1976b). When administered intranasally in
rats, manganese is effectively taken up in the central
nervous system (CNS) through the olfactory system
(Henriksson and Tjalve, 2000). Studies have indicated
that the astrocytes are the initial targets of manganese
toxicity in the CNS and dysfunction of astrocytes possi-
bly involved in neurotoxic action of manganese (Chen
and Liao, 2002).
There are no clinical reports implicating manganese
as a human carcinogen, and no epidemiological stud-
ies that have attempted to relate manganese exposure
to cancer.
exposure has been consistently maintained at very low
levels, making a cancer risk unlikely.
1.11 Titanium
In a long-term survival study, fi brosarcomas and
lymphosarcomas were observed in a small number
of rats injected intramuscularly with fi ne titanium
metal powder suspended in trioctanoin. Tumors
were observed with powdered nickel and powdered
chromium metal but not with powdered copper or
iron administered in a similar way. The organic com-
pound titanocene, dichlorodicyclopentadienyl tita-
nium, administered intramuscularly in rats and mice
in a similar way also gave rise to injection-site fi b-
rosarcoma, and a few animals developed hepatoma
and malignant lymphoma, but details were not given
(Furst and Haro, 1969).
Although titanium compounds such as titanium
dioxide (TiO
2
) are generally regarded as nontoxic mild
pulmonary irritants, some studies have reported lung
adenomas in rats exposed to high levels of TiO
2
. As for
human studies, a retrospective cohort mortality study
was conducted among 4241 TiO
2
workers who were
employed for at least 6 months, on or after January 1,
1960, at four TiO
2
plants in the United States. The result
indicated that the exposures at these plants were not
associated with increases in the risk of death from can-
cer or other diseases. Moreover, workers with likely
higher levels of TiO
2
exposure had similar mortality
patterns to those with less exposure, because internal
analyses among workers revealed no increase in mor-
tality by level of TiO
2
exposure (Fryzek
et al.
, 2003). A
recent human study also did not suggest a carcino-
genic effect of TiO
2
dust on the human lung (Boffetta
et al.
, 2004).
1.10 Platinum
The chance fi nding that certain coordination com-
plexes of platinum have the property of inhibiting cell
division in
E. coli
led to intense investigation of this
group of platinum compounds.
cis
-Dichlorodiammine
platinum(II) (
cis
-DDP) is a potent chemotherapeutic
agent used in the management of, in particular, meta-
static testicular and ovarian tumors. In a well-control-
led study, DDP and analogues have been shown to
signifi cantly increase tumor frequency in rats and mice
(Leopold
et al.
, 1979). Administered intraperitoneally in
mice, DDP increased adenoma frequency, and together
with topical applications of croton oil, produced skin
papillomas and a few epitheliomas. Rats treated with
cis
-dichlorobiscycIopentylamine platinum (II) or
cis
-
dichlorobispyrolidine platinum (II) developed a small
number of injection-site and distant sarcomas. There
were no tumors in the control animals. DDP and its
analogues have been shown to be mutagenic in bacte-
rial test systems without microsomal activation. DDP
forms both intrastrand and interstrand cross-links with
human DNA in cell culture (Roberts and Pascoe, 1972).
The effects of DDP on chromosomes are described ear-
lier in this chapter. Morphological transformation of
hamster embryo cells and enhancement of viral trans-
formation was produced with low concentrations of
platinum, which together with antimony, arsenic, cad-
mium, and chromium, showed the highest activity in
this respect (Casto
et al.
, 1979). Thus, these platinum
complexes fi t the model for electrophilic reactants
binding to cellular nucleophiles, which are direct-act-
ing mutagens and are also capable of cancer initia-
tion.
Cis
-DDP is classifi ed as probably carcinogenic to
humans (group 2A) according to IARC (1987).
There are no reports of cancer related to occupational
exposure to platinum compounds or of epidemiological
studies of cancer mortality in platinum workers. How-
ever, because of the high risk of sensitization to solu-
ble platinum compounds in the working environment,
2 PRINCIPAL METALS SHOWING
MUTAGENIC EFFECTS
Most of the toxic metals have very poor direct
interactions with DNA and, in general, are weakly
mutagenic. Even chromate, which can yield trivalent
chromium DNA adducts, is not highly mutagenic in
many systems. However, it is of interest that carcino-
genic metals can interact with other environmental
carcinogens. For example, metals can inhibit the repair
of benzo(a)pyrene or UV-induced DNA adducts and
potentiate the mutagenicity of benzo(a)pyrene or UV
(Hartwig, 1998; Hu
et al.
, 2004a; 2004b). It is also of
interest to note that there are poor animal models for
metal-induced tumor. Many of the cancers that arise
in humans occupationally exposed to carcinogenic
