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Cadmium: cellular effects, modifications of biomolecules, modulation
of DNA repair and genotoxic consequences (a review).Biochimie.
2006 Nov;88(11):1549-59. Epub 2006 Oct 17
Cadmium is an
important toxic environmental heavy metal. Occupational and
environmental pollution with cadmium results mainly from mining,
metallurgy industry and manufactures of nickel-cadmium batteries,
pigments and plastic stabilizers. Important sources of human
intoxication are cigarette smoke as well as food, water and air
contaminations. In humans, cadmium exposures have been associated with
cancers of the prostate, lungs and testes. Acute exposures are
responsible for damage to these organs. Chronic intoxication is
associated with obstructive airway disease, emphysema, irreversible
renal failure, bone disorders and immuno-suppression. At the cellular
level, cadmium affects proliferation, differentiation and causes
apoptosis. It has been classified as a carcinogen by the International
Agency for Research on Cancer (IARC). However, it is weakly genotoxic.
Indirect effects of cadmium provoke generation of reactive oxygen
species (ROS) and DNA damage. Cadmium modulates also gene expression
and signal transduction, reduces activities of proteins involved in
antioxidant defenses. Several studies have shown that it interferes
with DNA repair. The present review focuses on the effects of cadmium
in mammalian cells with special emphasis on the induction of damage to
DNA, membranes and proteins, the inhibition of different types of DNA
repair and the induction of apoptosis. Current data and hypotheses on
the mechanisms involved in cadmium genotoxicity and carcinogenesis are
outlined.
Cadmium and
renal cancer.Toxicol
Appl Pharmacol. 2005 Sep 1;207(2):179-86.
BACKGROUND:
Rates of renal cancer have increased steadily during the past two
decades, and these increases are not explicable solely by advances in
imaging modalities. Cadmium, a widespread environmental pollutant, is
a carcinogen that accumulates in the kidney cortex and is a cause of
end-stage renal disease. Several observations suggest that cadmium may
be a cause of renal cancer. METHODS: We performed a systematic review
of the literature on cadmium and renal cancer using MEDLINE for the
years 1966-2003. We reviewed seven epidemiological and eleven clinical
studies. RESULTS: Despite different methodologies, three large
epidemiologic studies indicate that occupational exposure to cadmium
is associated with increased risk renal cancer, with odds ratios
varying from 1.2 to 5.0. Six of seven studies that compared the
cadmium content of kidneys from patients with kidney cancer to that of
patients without kidney cancer found lower concentrations of cadmium
in renal cancer tissues. CONCLUSIONS: Exposure to cadmium appears to
be associated with renal cancer, although this conclusion is tempered
by the inability of studies to assess cumulative cadmium exposure from
all sources including smoking and diet. The paradoxical findings of
lower cadmium content in kidney tissues from patients with renal
cancer may be caused by dilution of cadmium in rapidly dividing cells.
This and other methodological problems limit the interpretation of
studies of cadmium in clinical samples. Whether cadmium is a cause of
renal cancer may be answered more definitively by future studies that
employ biomarkers of cadmium exposure, such as cadmium levels in blood
and urine.
Cadmium and
prostate cancer: a critical epidemiologic analysis.
Cancer Invest. 2005;23 (3):256-63.
Laboratory data implicate cadmium as a prostate carcinogen. However,
epidemiological studies concerning the association between cadmium and
prostate cancer are inconclusive. This article reviews the
epidemiological literature on cadmium and prostate cancer with a
special focus on highly exposed occupational cohorts. We searched the
MEDLINE database from 1966 to 2002 for articles on cadmium and
prostate cancer. All published analytical and descriptive studies that
included relevant data were reviewed. In addition, we reviewed the
experience of cohorts highly exposed to cadmium in nickel-cadmium
battery plants. Of 4 descriptive studies, 3 reported a positive
association between cadmium and prostate cancer. Of 10 case-control
studies, 5 (50%) reported a positive association. Of 11 cohorts
studies, 3 (33%) found a positive association. Finally, 4 studies on
cohorts exposed in occupational nickel-cadmium batteries were
identified and analyzed. The summary score of the standardized
mortality ratios (SMRs) was weakly but not significantly positive 126
(95% confidence interval C.I.: 83-184). In contrast to laboratory
studies, epidemiological studies do not convincingly implicate cadmium
as a cause of prostate cancer. Future epidemiological studies that
attempt to resolve the discrepancy between laboratory and
epidemiological studies of cadmium carcinogenesis may benefit from
incorporating biological measures of cadmium exposure.
Cadmium, lung and
prostate cancer: a systematic review of recent epidemiological data.J
Toxicol Environ Health B Crit Rev. 2003
May-Jun;6(3):227-55.
Cadmium
(Cd) and its compounds were classified as "carcinogenic to humans
(Group 1)" by IARC in 1993. The observation of an increased number of
lung cancers in a U.S. cohort of cadmium-exposed workers and the
finding of tumors in animals exposed to various cadmium compounds
apparently played an important role in this assessment. Since this
evaluation, several cohorts of cadmium exposed workers have been
updated and some additional data regarding environmental exposure to
cadmium and cancer risk have been published. The main purpose of this
systematic review was to examine whether inclusion of the studies that
were not available for the 1993 evaluation might change the overall
assessment of the carcinogenic potential of cadmium compounds. A
second objective was to examine whether the recent studies are
qualitatively better than the older ones and whether they should
receive more weight in this assessment. A third issue was to
investigate whether a competing effect between nonmalignant
respiratory disease (NMRD) and lung cancer may have affected the
results for lung cancer in occupationally exposed cohorts. Overall,
considering the results of the most recent studies does not suggest
that the effect of cadmium on lung cancer increases with improvement
of the study design but points to a lower relative risk in the groups
exposed to cadmium in the absence of arsenic and nickel. No evidence
was found to support the hypothesis that NMRD represents a competing
cause of death reducing the mortality from lung cancer. The
association between cadmium exposure and prostate cancer was not
confirmed in the latest available updates. Studies in environmentally
exposed populations do not indicate an increased relative risk of
cancer.
Cadmium
carcinogenesis.
Mutat Res. 2003 Dec 10;533(1-2):107-20.
Cadmium is a
heavy metal of considerable environmental and occupational concern.
Cadmium compounds are classified as human carcinogens by several
regulatory agencies. The most convincing data that cadmium is
carcinogenic in humans comes from studies indicating occupational
cadmium exposure is associated with lung cancer. Cadmium exposure has
also been linked to human prostate and renal cancer, although this
linkage is weaker than for lung cancer. Other target sites of cadmium
carcinogenesis in humans, such as liver, pancreas and stomach, are
considered equivocal. In animals, cadmium effectively induces cancers
at multiple sites and by various routes. Cadmium inhalation in rats
induces pulmonary adenocarcinomas, in accord with its role in human
lung cancer. Cadmium can induce tumors and/or preneoplastic lesions
within the rat prostate after ingestion or injection. At relatively
high doses, cadmium induces benign testicular tumors in rats, but
these appear to be due to early toxic lesions and loss of testicular
function, rather than from a specific carcinogenic effect of cadmium.
Like many other metals, cadmium salts will induce mesenchymal tumors
at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections,
but the human relevance of these is dubious. Other targets of cadmium
in rodents include the liver, adrenal, pancreas, pituitary, and
hematopoietic system. With the exception of testicular tumors in
rodents, the mechanisms of cadmium carcinogenesis are poorly defined.
Cadmium can cause any number of molecular lesions that would be
relevant to oncogenesis in various cellular model systems. Most
studies indicate cadmium is poorly mutagenic and probably acts through
indirect or epigenetic mechanisms, potentially including aberrant
activation of oncogenes and suppression of apoptosis.
Cadmium
exposure and nephropathy in a 28-year-old female metals worker.
Environ Health
Perspect. 2002 Dec;110(12):1261-6.
A 28-year-old
female presented for evaluation of left flank pain and polyuria after
having been exposed to cadmium in the jewelry manufacturing industry
for approximately 3 years. This patient possessed both elevated 24-hr
urinary ss2-microglobulin and elevated blood cadmium levels.
Approximately 6 months after initial presentation, the patient
resigned from her job due to shortness of breath, chest pain, and
anxiety. Exposure to cadmium in the jewelry industry is a significant
source of occupational cadmium exposure. Other occupational sources
include the manufacture of nickel-cadmium batteries, metal plating,
zinc and lead refining, smelting of cadmium and lead, and production
of plastics. Cadmium is also an environmental pollutant that
accumulates in leafy vegetables and plants, including tobacco. Major
toxicities anticipated from cadmium exposure involve the renal,
pulmonary, and, to a lesser extent, gastrointestinal systems. These
include the development of renal proximal tubular dysfunction,
glomerular damage with progressive renal disease, and respiratory
symptoms including pneumonitis and emphysema. Low-level cadmium
exposure has also been associated with increased urinary calcium
excretion and direct bone toxicity, effects that recent research
suggests may result in the development of osteoporosis. The body
burden of cadmium, over half of which may reside in the kidneys, is
most often measured through the use of urinary cadmium levels. Blood
cadmium measurements generally reflect current or recent exposure and
are especially useful in cases with a short exposure period and only
minimal accumulation of cadmium in the kidneys. Both ss2-microglobulin
and alpha1-microglobulin serve as organ-specific, early-effect
biomarkers of tubular proteinuria and thus play a role in identifying
early signs of cadmium-induced renal damage in those with potential
exposures. In addition to ensuring workplace compliance with
Occupational Safety and Health Administration-mandated monitoring and
screening measures, it is prudent for those with cadmium exposure to
maintain adequate intake of both iron and calcium, appropriate
measures even in the absence of exposure.
Cadmium
carcinogenesis in review.J
Inorg Biochem. 2000 Apr;79(1-4):241-4.
Cadmium is an
inorganic toxicant of great environmental and occupational concern
which was classified as a human carcinogen in 1993. Occupational
cadmium exposure is associated with lung cancer in humans. Cadmium
exposure has also, on occasion, been linked to human prostate cancer.
The epidemiological data linking cadmium and pulmonary cancer are much
stronger than for prostatic cancer. Other target sites for cadmium
carcinogenesis in humans (liver, kidney, stomach) are considered
equivocal. In rodents, cadmium causes tumors at several sites and by
various routes. Cadmium inhalation in rats results in pulmonary
adenocarcinomas, supporting a role in human lung cancer. Prostate
tumors and preneoplastic proliferative lesions can be induced in rats
after cadmium ingestion or injection. Prostatic carcinogenesis in rats
occurs only at cadmium doses below those that induce chronic
degeneration and dysfunction of the testes, a well-known effect of
cadmium, confirming the androgen dependency of prostate tumors. Other
targets of cadmium in rodents include the testes, adrenals, injection
sites, and hematopoietic system. Various treatments can modify cadmium
carcinogenesis including supplemental zinc, which prevents
cadmium-induced injection site and testicular tumors while
facilitating prostatic tumors. Cadmium is poorly mutagenic and
probably acts through indirect mechanisms, although the precise
mechanisms remain unknown.
Is cadmium a
cause of human pancreatic cancer?Cancer
Epidemiol Biomarkers Prev. 2000
Feb;9(2):139-45.
Little is
known about the etiology of pancreatic cancer, which is an important
cause of cancer mortality in developed countries. We hypothesize that
exposure to cadmium is a cause of pancreatic cancer. Cadmium is a
nonessential metal that is known to accumulate in the human pancreas.
The major risk factors for pancreatic cancer (increasing age,
cigarette smoking, residence in Louisiana, and occupations involving
exposure to metalworking and pesticides) are all associated with
increased exposure to cadmium. Our meta-analysis of cohorts with high
exposure to cadmium is also consistent with an increased risk of
pancreatic cancer (standardized mortality ratio = 166; 95% confidence
interval, 98-280; P = 0.059). Cadmium can cause the
transdifferentiation of pancreatic cells, increases in the synthesis
of pancreatic DNA, and increases in oncogene activation. Thus, cadmium
is a plausible pancreatic carcinogen. The cadmium hypothesis provides
a coherent explanation for much of the descriptive epidemiology of
pancreatic cancer and suggests new avenues for analytical research.
Cadmium and
prostate cancer.
J Toxicol Environ Health.
1994 Nov;43(3):251-69.
Prostatic
cancer is a common and frequently lethal malignant disease. In the
United States and other countries the incidence and mortality rate of
prostate cancer continue to rise. Cancer of the prostate has an
extremely complex etiology and appears dependent on a variety of
factors, making linkage to a single factor very difficult to detect.
Cadmium is a metallic toxin of great environmental and occupational
concern. Cadmium exposure has been associated with human prostatic
cancer in some, but not all, epidemiologic studies. Some studies
indicate that tissue levels of cadmium in the human prostate correlate
with malignant disease. Any association between cadmium and prostatic
cancer has been controversial, in large part because of a previous
lack of relevant animal models. However, several chronic studies in
rats revealing a correlation between cadmium exposure and prostatic
tumors have been published over the last several years. These include
a study of oral cadmium exposure, a route extremely relevant to human
exposure. Several of these chronic studies indicate a hormonal
dependence of cadmium-induced prostate cancer. Other supportive work
continues to accumulate, such as studies showing in vitro malignant
transformation of prostatic epithelial cells with cadmium exposure. In
addition, there are indications that the primary biologic tolerance
system for cadmium (i.e., the metallothionein gene) may be only poorly
active in the specific lobes of the rat prostate in which cadmium
induces tumors. The induction in rats of prostate cancer by cadmium
treatment clearly supports, but does not definitively establish, a
possible role for cadmium as an etiological agent in human prostate
cancer. Further research, however, will be required to establish the
precise role of cadmium in this important human malignancy.
Methodological
aspects of the epidemiological association between cadmium and cancer
in humans.
IARC Sci Publ.
1992;(118):425-34.
The main
epidemiological evidence of an association between cadmium exposure
and human cancer comes from studies on occupational groups such as
smelter and nickel-cadmium battery workers. Lung and prostate are the
sites more frequently reported to be at increased risk of cancer, but
the various epidemiological studies do not enable any definite
conclusion to be reached. Methodological problems in the
interpretation of these studies include: (i) the assessment of
exposure to cadmium; (ii) the dose-response relationship between
indicators of cadmium exposure and cancer risk; (iii) concomitant
exposure to occupational carcinogens, mainly nickel and arsenic; (iv)
confounding by non-occupational risk factors, such as smoking and
diet; and (v) interaction between cadmium and other exposures. The
confounding effect of smoking and diet is particularly interesting
since they may act both as additional uncontrolled sources of cadmium
and as independent cancer risk factors.
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