CADMIUM AND LIVER DISEASE
by
Yi Chen
BS in Biotechnology National Talent Base Class, Lanzhou University, China, 2004-2008
MS in Cell Biology, Lanzhou University, China, 2008-2011
Submitted to the Graduate Faculty of
Environmental and Occupational Health
Graduate School of Public Health in partial fulfillment
of the requirements for the degree of
Master of Public Health
University of Pittsburgh
i
2014
UNIVERSITY OF PITTSBURGH
GRADUATE SCHOOL OF PUBLIC HEALTH
This essay is submitted
by
Yi Chen
on
April 25th, 2014
and approved by
Essay Advisor:
James Peterson, Ph.D
______________________________________
Associate Professor
Department of Environmental and Occupational Health
Graduate School of Public Health
University of Pittsburgh
Essay Reader:
Fernando Holguin, MD. ______________________________________
Assistant Professor
Department of Pulmonary, Allergy and Critical Care Medicine
University of Pittsburgh Medical Center
University of Pittsburgh
ii
Copyright © by Yi Chen
2014
iii
James Peterson, PhD
CADMIUM AND LIVER DISEASE
Yi Chen, MPH
University of Pittsburgh, 2014
ABSTRACT
Cadmium, which released into the environment, has increased in past 100 years. Exposure
to cadmium induced harmful environmental effects in the atomsphere and biosphere, contributes
to adverse health effects in humans, including liver damages. Liver disease is one of top 10 causes
of death around all the world, which mostly reduces the quality of life and longevity for humans.
It is important to understand the relationship between liver disease and cadmium exposure in order
to improve public health.
This literature review consults research articles, peer reviews, government reports and
regulations to determine the public health importance regarding cadmium-related liver disease. It
is clear that chronic cadmium exposure is related with some kinds of liver diseases, both in animals
and humans. Although cadmium is classified as a carcinogenic agent, there is insufficient evidence
to support that liver cancer is associated with cadmium exposure.
Further studies are required to investigate whether chronic low-doses of cadmium exposure
could induce liver cancer and other liver diseases. If environmental exposure to cadmium is
ultimately found to cause liver diseases, further efforts should be made to reduce it. For example,
iv
the government could consider developing regulations for cadmium in agriculture products and
tobacco products. Additionally, clinical trial could be initiated to evaluate therapeutic agents to
mitigate toxic exposure to cadmium.
v
TABLE OF CONTENTS
INTRODUCTION……………………………………………………………............................. 1
ENVIRONMENTAL BURDEN OF CADMIUM……………………………………………... 3
Cadmium Properties……………………………………………………………………… 3
Production and Consumption…………………………………………………………….. 3
Environmental Exposure and Effects…………………………………………………….. 4
Human Exposure…………………………………………………………………………...7
ADVERSE HEALTH EFFECTS OF CADMIUM EXPOSURE…………………………...... 9
Adverse Health Effects (Noncancer....……………………………………………………. 9
Carcinogenicity…………………………………………………………………………....10
CADMIUM EXPOSURE AND LIVER DISEASE…………………………….………….…..11
Burden of Liver disease…………………………………………………………………….11
Hepatotoxicity of Cadmium……………………………………………………………….12
Animal Studies of Cadmium-induced Liver Disease……………………………………..14
Epidemiological Studies of Cadmium-dependent Liver-related Disease………………..15
Potential Mitigating Agents……………………………………………………………......17
CONCLUSIONS……………………………………………………………………………......19
BIBLIOGRAPHY……………………………………………………………………………... 22
vi
INTRODUCTION
Cadmium is a toxic heavy metal found widely in the environment. Cadmium
release into the environment is a burden we need to consider1. Due to the fact that
cadmium is not degraded in nature, new release adds to the already existing deposit of
cadmium in the environment and cadmium stays in circulation and enters into the food
chain.1 Everyone is exposed to cadmium since cadmium exists in the earth’s crust and
is released into the air, water and soil1. Environmental exposure to cadmium occurs
primarily through industrial emissions, smoking, and the consumption of contaminated
food and water.1-3 Due to ingestion of contaminated food, the risk of cadmium exposure
is constantly increased.
Cadmium was classified as a human carcinogen by the International Agency for
Research on Cancer (IRAC) in 1993, and is clearly a potent multi-tissue animal
carcinogen.4 Occupational exposure to cadmium is associated with lung cancer in
humans, while cancer of other organs, potentially including the kidney, the prostate and
the liver, are not definitively established.2, 4-6
Aside from the carcinogenicity of cadmium, which is relevant especially to lung
cancer in occupational settings, other serious health effects should be considered for
general exposure to cadmium. Cadmium has an extremely long whole-body half-life,
which is between 15 and 30 years and accumulates in two target tissues: the kidney and
the liver.2, 3
Previous studies mainly focused on the kidney and urinary systems，but newer
studies focus on the liver (liver disease and liver cancer).2, 6 Several animal studies have
-1-
shown that cadmium exposure may cause liver failure.6 An epidemiological study from
Johns Hopkins University showed that chronic cadmium exposure was associated with
liver disease.2 This change in the focus of research is because cadmium also
accumulates in the liver as well as the kidney and because of the unique position of the
liver in the detoxification process of cadmium.
This essay is a literature review intended to communicate to the public the inherit
danger of cadmium pollution and the current research status regarding cadmium
exposure relative to liver disease. Based on review of previous work, this essay points
the way to future potential research regarding the association between cadmium
exposure and liver disease. The expectation is that more public concern will be drawn
to cadmium pollution and to the potential adverse health effects of cadmium, especially
in liver disease.
-2-
ENVIRONMENTAL BURDEN OF CADMIUM
Cadmium Properties
Cadmium (Cd) is a toxic heavy metal with atomic number 48. Cadmium, a soft,
malleable, bluish white metal, chemically similar to the two other stable metals in group
12, zinc and mercury.7 It was discovered in 1817 simultaneously by the German
scientists Stromeyer and Hermann, as an impurity in zinc carbonate.7 The average
concentration of cadmium in the Earth's crust is between 0.1 and 0.5 parts per million
(ppm).8 Cadmium, which is toxic at very low exposure levels, is found widely in the
environment and has acute and chronic effects on the environment and health.1
Compared to other metals, cadmium (as Cd2+) and cadmium compounds, are relatively
water soluble, are more mobile in water and soil, more bioavailable and tend to
accumulate in the environment.1
Production and Consumption
Cadmium’s early use as a pigment stems from the ability of its compounds to
produce brilliant yellow, orange, and red colors.9 Common industrial uses for cadmium
today are in nickel-cadmium (Ni-Cd) rechargeable batteries, alloys, coatings
(electroplating), solar cells, plastic stabilizers, and pigments. Cadmium is also used in
nuclear reactors as a neutron absorber.10, 11 Lithium ion batteries have made significant
gains in popularity for lightweight electronic devices, but new market opportunities for
industrial productions of Ni-Cd batteries will continue to fuel cadmium use.11 Increased
investment in solar power will also prompt cadmium use in the future.10
-3-
Global cadmium production, excluding U.S. production(data unavailable), was
21,100 ton in 2012, a slight increase from the amount produced in 2011.11 Most of the
world’s refined cadmium (63%) was produced in Asia (Australia, China, India, Japan,
North Korea, and the Republic of Korea), followed by 20% in Europe and Central
Eurasia (Bulgaria, Germany, Kazakhstan, the Netherlands, Norway, Poland, and
Russia), 13% in North America (Canada and Mexico), and 4% in South America
(Argentina, Brazil, and Peru).11
According to the World Bureau of Metal Statistics12, global consumption of
primary cadmium was 16,200 ton in 2011 (latest data available).11 The majority of
global cadmium consumption was Ni-Cd battery production. Other uses for cadmium
included alloys, anticorrosive coatings, pigments, polyvinylchloride stabilizers, and
semiconductors for solar cells. Approximately 86% of the cadmium consumed globally
was used in Ni-Cd batteries, 9% in pigments, 4% in coatings, and 1% in various uses
including alloys, solar cells, and stabilizers.11, 13
Environmental Exposure and Effects
Sources and Emissions
Cadmium is released to the biosphere from both natural and anthropogenic sources.
Natural sources
The major natural sources for mobilizations of cadmium from the earth's crust
are volcanoes and weathering of rocks. The volcanoes and weathering of rocks release
cadmium to soils and aquatic systems. The major sources for emission to air from
-4-
natural sources are volcanoes, airborne soil particles, sea spray, biogenic material and
forest fires. The emissions of cadmium from natural sources plays a significant role in
the global cadmium cycle, but only rarely results in adverse environmental effects.
Anthropogenic sources
Cadmium is produced mainly as a by-product from mining, smelting, and
refining sulphide ores of zinc, and to a lesser degree, lead and copper.1 20,900 tons of
cadmium was extracted from the earth's crust by mineral refining and brought into
circulation in the biosphere in 2012.11 Beside this large quantity of cadmium that ended
up in metal extraction residues, cadmium was mobilized as an impurity from extraction
of other minerals like coal and lime.13
Release of cadmium to waste and soil
Cadmium is released to waste disposal by several sources, including cadmium
processing, coal ash, sewage sludge, phosphate processing, iron and steel processing,
cement production, and non-ferrous metals processing.14 A complete wash-out of
cadmium may require hundreds to thousands of years and even more in some cases,
although the mobility of cadmium inside landfills is low. The accumulation of cadmium
in top agricultural soils is supported by risks assessments relating to cadmium in
phosphate fertilizers.15
Environmental Effects
Cadmium is non-degradable and relatively water soluble, unlike other heavy
metals that tend to stay in circulation and accumulate in the environment. Cadmium
-5-
accumulates in many organisms, particularly in microorganisms and molluscs where
the bioconcentration factors are on the order of thousands.1 In animals, cadmium
concentrates in the internal organs rather than in muscle or fat. It is typically higher in
kidney and liver than in muscle. Cadmium concentration in the body usually increases
with age.16, 17
Birds and mammals
Certain marine vertebrates contain markedly high cadmium concentrations in the
kidney that have been linked to markers of kidney damage in the organisms
concerned.17 Seabirds are known to easily accumulate high levels of cadmium.1 Kidney
damages has been reported in wild colonies of pelagic sea birds having cadmium levels
of 60-480 µg/g in the kidney.17
Kidney damage and lung emphysema are the primary effects of high cadmium in
mammals and birds, which are similar to those in human.1 Mammals can tolerate low
levels of chronic cadmium exposure by binding the metal to a special protein that
renders its harmless.16 In this combined form, cadmium can accumulate in the kidney
and liver, with the body needing decades to remove cadmium from the kidney and
liver.17
Other organisms
In aquatic systems, cadmium is most readily absorbed by organisms directly from
the water in its free ionic form Cd2+.18 The acute toxicity of cadmium to aquatic
organisms is related to the free ionic concentration of the metal and is variable, e.g.
salmonoids being particularly susceptible to cadmium.17 Effects of long-term exposure
-6-
of cadmium may include larval mortality and temporary reduction in growth.18 Sublethal effects have been seen on the growth and reproduction of aquatic invertebrates
and structural effects on invertebrate gills.17 An effect on foraging behavior has been
reported in lake trout exposed to different levels of cadmium, leading to lower success
at catching prey.18
Terrestrial plants may accumulate cadmium in the roots, which is found bound to
the cell walls.18 Litter leaf decomposition is largely inhibited by heavy metal pollution,
and cadmium has been identified as the most potentially causative agent for this effect.19
The sub-lethal effect of terrestrial snails exposed to cadmium is on food consumption
and dormancy, but only at very high dose levels.17
Human Exposure
General Exposure
For nonsmokers, food is the major route of exposure to cadmium among the nonoccupational population; other pathways to total uptake are insignificant. Cadmium
levels in some food can be increased by the application of phosphate fertilizers or
sewage sludge to farm fields.20 Tobacco is an important source of cadmium exposure
for smokers, who have about twice as much cadmium in their bodies as nonsmokers.20
Data from experimental animals and humans have shown that the inhalational
absorption via lungs is higher than the gastrointestinal absorption via the stomach.1, 16
Up to 50% of the inhaled cadmium may be absorbed. Only 5% of the total ingested
cadmium is absorbed, because the gastrointestinal absorption of cadmium may be
influenced by the type of diet and nutritional status.16
-7-
A major exposure pathway of cadmium in the human diet comes from
agricultural products, which are susceptible to increases in soil cadmium.1 The
important sources of cadmium to agricultural soils are atmospheric deposition and
direct additives, including the application of phosphate fertilizers and other soil
amendment products.1, 15
Average daily intakes of cadmium from food are 10-40µg in most non-polluted
areas.16 In polluted areas the value has been found to be up to several hundred µg per
day.16 The World Health Organization (WHO) has established a provisional tolerable
weekly intake (PTWI) of 7 µg/kg body weight for cadmium.16, 17 This PTWI value
corresponds to a daily tolerable intake level of 70 µg of cadmium for the average 70kg man and 60 µg of cadmium per day for the average 60-kg woman.16, 17 The PTWI
value may be considered lower than actuality in certain areas where the estimated intake
of cadmium is 140-260 µg/day.16, 17
Occupational Exposure
Cadmium is an important metal for many types of commercial and industrial
processes. The Occupational Safety and Health Administration (OSHA) estimates that
300,000 workers are exposed to cadmium in the United States.10 Cadmium enters
human body of the occupational population through inhaling and incidentally ingesting
dust or smoke which may contain cadmium. Occupational exposure of cadmium mostly
occurs in manufacturing and construction including smelting and refining of metals,
and manufacturing batteries, plastics, coatings, and solar panels. The expanding Ni-Cd
battery recycling industry is a critical source for cadmium occupational exposure.10, 13
-8-
Other industrial operations associated with cadmium exposure are electroplating, metal
machining, welding and painting.10,
13
Compost workers and waste collectors are
potentially exposed to cadmium. Other potential exposure to cadmium includes landfill
operations, the recycling of electronic parts, the recycling of plastics, and incineration
of municipal waste.10
ADVERSE HEALTH EFFECTS OF CADMIUM
EXPOSURE
Adverse Health Effects (Noncancer)
The adverse health effects of cadmium exposure include effects of acute exposure,
effects of chronic exposure and carcinogenicity.
Acute inhalational exposure of high level of cadmium may cause delayed
bronchial irritation, pulmonary irritation, respiratory failure and even death.21, 22 A high
level of acute inhalational cadmium exposure may result in long-lasting impairment of
lung function.10, 20-22 Acute ingestion exposure to low doses of cadmium may lead to
vomiting, abdominal pain, diarrhea and gastrointestinal irritation.23 Acute ingestion
exposure to high doses of cadmium may affect the liver, nervous system and
cardiovascular system, and may lead to renal failure, liver failure and death.16, 23
Many studies relating to the adverse health effects of cadmium focus on the
chronic exposure and carcinogenicity. The kidney is the crucial organ for cadmium
exposure.20 According to current knowledge, kidney damage, including renal tubular
dysfunction and renal failure, is the critical health effects of chronic cadmium exposure,
-9-
both in the general and occupational population.1, 16 Chronic cadmium exposure may
result in skeletal damage, like osteomalacia, osteoporosis and spontaneous fracturing,
since the accumulation of cadmium in the kidney may cause a disruption of calcium
balance by effecting vitamin D metabolism. Liver damage is another effect of chronic
cadmium exposure.2
For occupational chronic cadmium exposure, cadmium is absorbed by inhalation
and may lead to respiratory system damage aside from kidney disease, including
bronchiolitis, emphysema and other lung conditions even lung cancer.21, 23 An increased
mortality rate of obstructive lung disease has been reported among workers with
chronic cadmium exposure.16, 23
Carcinogenicity
The International Agency for Research on Cancer (IARC) classifies cadmium in
Class 1“The agent (mixture) is carcinogenic to humans. The exposure circumstance
entails exposures that are carcinogenic to humans.”4 This classification as a human
carcinogen was prompted primarily by repeated studies of an association between
occupational cadmium exposure and lung cancer, as well as robust rodent experiments
which also showed the pulmonary system as a target site.4, 24
Studies have shown an increase in cancer mortality in populations exposed to low
levels of cadmium for long periods of time.25 Cadmium exposure has been related to
human prostate and renal cancer, but the linkage is weaker than the association between
lung cancer and high-level occupational exposure.24 Other target sites of cadmium
carcinogenesis in human, including liver and stomach, are considered equivocal.6
- 10 -
CADMIUM EXPOSURE AND LIVER DISEASE
Burden of Liver disease
In the United States, the burden of liver-related diseases is important. Over the
last two decades, liver-related mortality ranked among the top 10 causes of death; it has
been repeatedly listed as the fourth leading cause of death in the United States.26 During
the same period, an increase in the number of people has been observed for end-stage
liver disease requiring transplantation and hepatocellular carcinoma.27 Nonalcoholic
fatty liver disease (NAFLD) is thought to be the most common chronic liver disease in
the Western world.28 The Third National Health and Nutrition Examination Survey
(NHANES III) showed that the prevalence of NAFLD was 20% and the prevalence of
nonalcoholic steatohepatitis (NASH) was 2% in the general US population.27
In the United states, liver related disease deaths is up to 2% of all deaths.27 The
economic burden linked with liver disease is approximately 1% of the total national
health care expenditure devoted to the care of patients.27 Moreover, the burden of liver
disease appears to be increasing, due in part to the increasing prevalence of
nonalcoholic fatty liver disease, hepatitis C viral hepatitis, and hepatocellular
carcinoma.27 Many liver diseases with relatively low frequency have substantial impact
on longevity, like fulminant hepatic failure and pediatric liver diseases, or impact on
the quality of life like primary sclerosing cholangitis.27
- 11 -
Hepatotoxicity of Cadmium
The liver is an abdominal organ which plays a crucial role in detoxification and
excretion of many endogenous and exogenous substances, and its detoxification
systems are easily overloaded.29 The liver is a natural chemical factory which aids in
anabolism of complex molecules from simple substances absorbed from the
gastrointestinal tract (GIT).30 Hepatic dysfunction may result from continuous
cadmium exposure like other toxicant exposures in rats.31 The outcome of cadmium
exposure on the liver are hepatic cell changes, such as hepatocyte swelling, fatty
changes, focal necrosis, hepatocyte degeneration and irregularities in biomarkers of
liver function.29
Mechanisms of Cadmium Hepatotoxicity
Several mechanisms have been suggested to potentially induce cadmiumassociated hepatotoxicity. One of the potential mechanisms of cadmium induced liver
toxicity is mediated by the up-regulation of reactive oxygen species (ROS), including
hydroxyl groups, superoxide and hydrogen peroxides, which cause oxidative damage
to lipid membranes.29 The oxidative stress is normally induced by over-production of
ROS, unless ROS is scavenged with endogenous antioxidants.29 Thus, overproduction
of ROS has been identified as an important factor of cadmium-induced hepatotoxicity,
because ROS might deplete antioxidants or directly act with cadmium on peroxidation
reactions and iron-mediated peroxidation.29
- 12 -
Another possible mechanism of toxicity of cadmium toward the liver is primary
injury of cells resulting from binding of cadmium to sulfhydryl groups in mitochondria
and secondary injury initiated by the activation of Kupffer cells.29 Oxidative stress will
be initiated by inactivation of sulfhydryl groups, which could also cause a
mitochondrial permeability transition and mitochondrial dysfunction.29 Kupffer cells
may release pro-inflammatory cytokines and chemokines which stimulate the migration
and accumulation of neutrophils and monocytes in the liver.29
Apoptosis plays a predominant role on cadmium-associated hepatotoxicity in in
vitro studies of rat, mouse and human hepatocytes.32,
33
Cadmium, in isolated
mitochondria from mouse liver, could directly lead to the dysfunction of mitochondria.
Endonuclease G (Endo G), the mitochondria derived protein, has been identified as
potential caspase-independent apoptotic mediator in human hepatoma cell line
Hep3B.34 The mechanism involves the alteration of mitochondrial homeostasis and the
subsequent release of Endo G and AIF.34 Overall, cadmium-induced apoptosis may be
mediated by the release of Ca2+ from intracellular storage and cadmium-induced ER
stress in the liver.35
As mentioned above, cadmium induces hepatocellular damage via imbalance of
the cellular redox status, which leads to oxidative stress. Over-production of ROS can
deplete antioxidants, which benefits in the detoxification process of cadmium.
Although there are other mechanisms of hepatic toxicity with cadmium, overproduction of ROS is the major reason linked to cadmium hepatotoxicity from in vitro
- 13 -
studies. Calcium mediated apoptosis, which is also initiated by ROS, is another possible
pathway to explain cadmium hepatotoxicity from human hepatic cell studies.
Animal Studies of Cadmium-induced Liver Disease
The major features of liver injuries in mice induced by repeated cadmium
exposure are nonspecific chronic inflammation, granulomatous inflammation,
apoptosis, liver cell regeneration, and pre-neoplastic proliferating nodules.36 A mouse
study reported that repeated cadmium exposure might have a carcinogenic potential in
mouse liver and that intracellular metallothionein (MT) is an important protein that may
protect against cadmium-induced liver injury.36 This study also suggested that repeated
cadmium exposure induced nonspecific chronic inflammation, apoptosis and liver cell
regeneration in a null-MT mouse model.36 Animal studies deemed questionable
relevance to humans due to the anatomical differences between humans and animals.
There are some studies suggesting that chronic cadmium exposure may cause
liver cancer in animals, but the amount of such research is small. Waalkes’s study
revealed that cadmium-treated mice had a higher rate of hepatocellular adenomas and
carcinomas than the control group, when experimental mice were exposed to repeated
high doses of cadmium.37 This effect only occurs with the high dose of cadmium
exposure, which is improbable for humans who do not expose to such high doses.
Moreover, another study from Waalkes reported that cadmium had preventive effects
on NDEA-induced liver tumors.38 However, another study reported that cadmium could
prevent liver tumors induced by N-nitrosodiethylamine (NDEA) and sodium barbital.
The incidence of NDEA-induced liver tumors in the cadmium treated group was lower
- 14 -
than in controls, regardless of the period of administration.38 Thus, it is difficult to draw
a conclusion regarding liver cancer associated with cadmium exposure based on above
two animal studies.
Epidemiological Studies of Cadmium-dependent Liver-related Disease
Liver disease
Last year, Hyder and his colleagues analyzed data about 12,732 participants from
the Third National Health and Nutrition Examination Survey (NHANES III), which
included interviews, physical examinations, blood and urine tests and ultrasound
scans.2 The levels of cadmium in urine samples, as well as records of ultrasound results
were used to diagnose various liver diseases. This study found that chronic cadmium
exposure was associated with hepatic necroinflammation and increased risk of liver
disease mortality.2
In this study, cadmium levels in the urine were separated into four quartiles, and
those in the highest quartile were approximately 3.5 times as likely to die of liverrelated diseases than those in the lower three quartiles.2 These liver-related diseases
included nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis
(NASH), which were both marked by fatty deposits in the liver. Fatty deposits can
impede the liver’s efforts to clear the bloodstream of toxins, aid in digestion, produce
hormones and store energy.2
According to this study, people with higher levels of cadmium in their urine are
nearly 3.5 times more likely to die of liver disease than those with lower levels. Higher
- 15 -
levels of cadmium in urine was identified as a marker of chronic exposure due to the
heavy metal found in industrial emissions and tobacco smoke.2
Information from NHANES III might increase the reliability of this study,
because this survey is the only nationwide cohort involving liver damage, hepatic
enzymes as well as cadmium exposure. However, limitation existed in this study due to
some information in this survey was self-reported. This study did not show that
cadmium directly causes liver disease, but did suggest an association which needs more
investigation to develop a cause-and-effect relationship.
There was only one published epidemiological study reported that primary liver
cancer was associated with mean daily intake of cadmium from food of plant origin in
a cross-sectional ecological survey in China.39 Cadmium intake was estimated by
analyzing the county-based composites of plant origin food selected in each survey
county, not from the experimental measurement.39 This study also detected the link with
primary liver cancer and several heavy metals, such as arsenic, lead, mercury and
cadmium, but only intake for cadmium showed a significant association with primary
liver cancer mortality.39 There were three significant risk factors for primary liver
cancer mortality, including plasma cholesterol, hepatitis B virus surface antigen
(HBsAg+) prevalence and cadmium intakes.39 No information about occupational
cadmium exposure of subjects was reported. The result of this study do not definitely
established the relationship between cadmium exposure and liver cancer.
- 16 -
Potential Mitigating Agents
There are increasing research on the potential mitigating agents which ameliorate
with the hepatotoxicity induced by cadmium exposure. Administration of vitamin C
and/or vitamin E have been reported to inhibit cadmium induced hepatotoxicity. Coadministration of vitamin C and E produced synergistic protection against cadmium
induced hepatotoxicity compared to individual agents.40 The mitigating effects of
vitamin C and E can be attributed to their water and lipid soluble antioxidant properties
respectively.29 Vitamin C is known to cause regeneration of oxidized vitamin E
molecule and both vitamins have sparing effect on each other.41
Pretreatment with MnCl2 24 hours before cadmium intoxication completely
prevented or significantly attenuated hepatic damage identified by increases in hepatic
lipid peroxidation and the depletion of endogenous antioxidants.42 These properties of
manganese (II), a constituent of several enzymes, the antioxidant property, and the
attenuation of the disruption of calcium homeostasis, must have contributed to its ability
in mitigating cadmium toxicity of the liver.29, 42
Two hours pre-treatment or 2 hours post-treatment for 24 hours with NAcetylcysteine (NAC) mitigated changes in the liver associated with cadmium.43 NAC
is a kind of antioxidant with direct and indirect activities. The direct effect acts when
its thiol group reacts with the electrophyllic group of ROS. The indirect effect acts by
providing intracellular cysteine for the production of glutathione.44 The hepaticprotective effects of selenium (Na2Se2O3) against cadmium induced toxicity, oxidative
- 17 -
stress and tissue damage could be attributed to its antioxidant and possible chelating
effects with cadmium.45
The administration of Solanum tuberosum extract normalized cadmium-induced
biochemical changes of liver function.46 Blood samples from animals treated with
ethanolic leaf extract from Calycopteris floribunda showed significant reduction in the
serum markers which indicating normal functional ability of the hepatocytes compared
to cadmium treated rats.47 Administration of calyx extract from Hibiscus sabdariffa
normalized cadmium induced changes in serum activities of protein related to liver
function.48
It has been reported that honey may ameliorate the hepatotoxic effect of cadmium
in Wister rats.49 It was also noticed that concurrent administration of honey with
cadmium chloride improved histopathological changes in the liver compared to
cadmium only-treated rats.49 The possible mechanism was that honey via its antioxidant
activity has the ability to protect against cadmium induced hepatotoxicity.49
The addition of Camel's milk to cadmium chloride has been found to normalize
the levels of albumin, hemoglobin, calcium, serum alanine aminotransferase, aspartate
aminotransferase, and serum alkaline phosphatase. The levels of hydro-peroxides,
superoxide dismutase, catalase and glutathione were also normalized in cadmium and
camel’s milk additive treated rats.50
- 18 -
CONCLUSION
Cadmium is a serious environmental hazard discovered in the 19th century and
will continue to adversely impact the environment in future. Cadmium in the
environment comes from both natural sources and industrial activities. Cadmium
emissions from industrial activity related to Ni-Cd batteries, refinery of cadmium
minerals and by-products of zinc production. Cadmium emitted to the environment
stays in the atmosphere, water and soil.
Cadmium can accumulate in organisms, including humans, because cadmium is
not degraded in the environment and its relative water solubility is high compared to
other heavy metals. Due to bioaccumulation, cadmium causes serious environmental
effects, such as reproductive effects and behavior change of aquatic invertebrates.
Cadmium-dependent liver and kidney damage may occur in mammals and birds. Other
environmental effects are related to plants, which absorb the cadmium from
contaminated water or soil.
Cadmium pollution prolongs the decomposition of plants including agricultural
products intended for consumption, which is the major route for non-smoking human
exposure to cadmium. For the occupational population, cadmium is absorbed into the
body by inhaling industrial dust and/or accidentally ingesting it. For the general
population, cadmium is absorbed by inhaling tobacco products and ingesting
contaminated water and food.
Adverse health effects of cadmium occur due to acute exposure and chronic
exposure. Acute exposure to cadmium usually occurs when occupational workers are
- 19 -
exposed to high doses of cadmium in industrial processes. The outcomes due to acute
exposure are respiratory system damage, renal failure and liver failure. Acute exposure
with cadmium happens occasionally, so the effects of chronic exposure with cadmium
is more critical to public health. According to the IRAC, cadmium has been classified
as a group 1 agent which means that cadmium is carcinogenic to humans. Therefore,
more works of the association with chronic cadmium exposure and cancer should be
needed in the future.
Although occupational exposure to cadmium has decreased by protective
equipment and monitoring systems, environmental exposure continues. If such
exposure is ultimately found to cause liver disease, further efforts should be made to
reduce it, including regulation of cadmium in food products and tobacco products and
potential mitigating agents.
Studies suggested that insufficient evidence to support the relationship of
cadmium exposure to liver cancer. A paucity of research, only two studies on animals,
related to cadmium-induced liver cancer. Further study is needed to develop an
unambiguous conclusion about cadmium with regard to liver cancer in animal models,
before approaching an epidemiological study in humans. There are many kinds of
possible mechanisms to explain liver damage induced by cadmium exposure, but the
complete mechanism of hepatocellular damage is not clear. Thus, further research is
needed to identify this problem, which might help to set up clinical approaches for
cadmium intoxication.
- 20 -
There is no confirmed clinical treatment of the hepatotoxicity induced by
cadmium exposure, but some treatment have been proved to mitigate hepatotoxicity
induced by cadmium exposure in animal models. However, future studies are required
to investigate the effects of mitigative agents on chronic cadmium exposure in humans
and evaluate their possible therapeutic value in the clinic.
- 21 -
BIBLIOGRAPHY
1.
Cadmium Review. In: MInisters NCo, ed; 2003.
2.
Hyder O, Chung M, Cosgrove D, et al. Cadmium exposure and liver disease among US adults.
J Gastrointest Surg. Jul 2013;17(7):1265-1273.
3.
Satarug S, Moore MR. Adverse health effects of chronic exposure to low-level cadmium in
foodstuffs and cigarette smoke. Environ Health Perspect. Jul 2004;112(10):1099-1103.
4.
IRAC. Cadmium and Cadmium Compounds. International Agency for Research on Cancer
Monographs Press, Lyon. 1993;58:119-238.
5.
Waalkes MP. Cadmium carcinogenesis in review. J Inorg Biochem. Apr 2000;79(1-4):241-244.
6.
Waalkes MP. Cadmium carcinogenesis. Mutat Res. Dec 10 2003;533(1-2):107-120.
7.
Morrow H. Cadmium and Cadmium Alloys. Kirk-Othmer Encyclopedia of Chemical
Technology. 2010:1-36.
8.
Wedepohl KH. The composition of the continental crust. Geochimica et Cosmochimica Acta.
1995 59(7):1217-1232.
9.
Rowbotham TR, T. L. . The Art of Landscape Painting in Water Colours: Windsor and Newton;
1850.
10.
OSHA. Cadmium. Available at: https://www.osha.gov/SLTC/cadmium/index.html.
11.
USGS. Cadmium In: Minerals Yearbook. U.S. Geological Survey, Reston. 2012.
12.
World metal statistics yearbook 2012:. World Bureau of Metal Statistics,; 2012,:72.
13.
Morrow H. Proceedings of the Eighth International Cadmium Conference Paper presented at:
2011: Brussels, Belgium, International Cadmium Association; November 10-13, 2011;
Kunming, China.
14.
Scoullos M, G. Vonkeman,I. Thornton & Z. Makuch. Mercury, cadmium, lead: Handbook for
sustainable heavy metals policy and regulation. Dordrecht: Kluwer Academic Publishers; 2001.
15.
Hutton M, de Meeus, C. . Analysis and conclusions from Member States' Assessment of the
Risk to Health and the Environment from Cadmium in Fertilisers. European Commision.
Enterprise DG.; 2001.
16.
WHO. Cadmium. Environmental Health Criteria 134. World Health Organisation, International
Programme on Chemical Safety (IPCS). Geneva, Switzerland; 1992.
17.
WHO. Cadmium - environmental aspects. Environmental Health Criteria 135. World Health
Organisation, International Programme on Chemical Safety (IPCS). Geneva, Switzerland; 1992.
18.
AMAP. Assessment report: Arctic pollution issues. Arctic Monitoring and Assessment
Programme. Oslo; 1998.
19.
AMAP. Arctic Pollution 2002. Arctic Monitoring and Assessment Programme. Oslo 2002.
20.
ATSDR. Toxicological Profile for Cadmium. Draft for Public Comment. Public Health Service,
U.S. Department of Health and Human Services. Altanta, GA; 1997.
21.
Bull S. Cadmium Toxicology Overview. Chemical Hazards and Poisons Division, Health
Protection Agency; 2010.
22.
E.M.Kenyon EJCa. Air Toxics and Risk Assessment. Lewis Publisher. Chelsea, MI; 1991.
23.
ATSDR. Toxicological Profile for Cadmium. Draft for public comment. U.S. Department of
Health and Human Services. Atlanta, U.S.; 2008.
- 22 -
24.
Twelfth Report on Carcinogens. National Toxicology Program, U.S. Department of Health and
Human Services. Research Triangle Park, NC; 2011.
25.
Scott V. Adams MNP, Polly A. Newcomb. Cadmium Exposure and Cancer Mortality in the
Third National Health and Nutrition Examination Survey Cohort. Occup Environ Med.
2012;69(2):153-156.
26.
Hoyert DL XJ. Deaths: preliminary data for 2011. In: National Vital Statistics Reports. National
Center for Health Statistics. Vol 6. Hyattsville, MD; 2012.
27.
Kim WR BRJ, Terrault NA, et al. Burden of liver disease in the United States: summary of a
workshop. . Hepatology. 2002;36(1):227-242.
28.
Mariana Lazo RH, Mark S. Eberhardt, Susanne Bonekamp, Ihab Kamel, Eliseo Guallar, Ayman
Koteish, Frederick L. Brancati, Jeanne M. Clark. Prevalence of Nonalcoholic Fatty Liver
Disease in the United States. American Journal of Epidemiology. 2013;178(1):38-45.
29.
Elias Adikwu OD, Oru-Bo Precious Geoffrey. Hepatotoxicity of Cadmium and Roles of
Mitigating Agents. British Journal of Pharmacology and Toxicology. 2013;4(6):222-231.
30.
Buraimoh AA, I.G. Bako and F.B. Ibrahim Hepatoprotective effect of ethanolic leaves extract
of Moringa Oleifera on the histology of paracetamol induced liver damage in wistar rats. Int. J.
Anim. Vet. Adv. 2011;3(1):10-13.
31.
Nithya N, K. Chandrakumar, V. Ganevan and S. Senthilkumar. Efficacy of Momordica charantia
in attenuating abnormalities in cyclophosphomide intoxicated rats. J. Pharmacol. Toxicol.
2012;7(1):38-45.
32.
Arroyo V, Flores K, Ortiz L, Gómez-Quiroz L, Gutiérrez-Ruiz M. Liver and cadmium toxicity.
J Drug Metab Toxicol S. 2012;5:2.
33.
Lasfer M, Vadrot N, Aoudjehane L, et al. Cadmium induces mitochondria-dependent apoptosis
of normal human hepatocytes. Cell Biol Toxicol. Jan 2008;24(1):55-62.
34.
Lemarie A, Lagadic-Gossmann D, Morzadec C, Allain N, Fardel O, Vernhet L. Cadmium
induces caspase-independent apoptosis in liver Hep3B cells: role for calcium in signaling
oxidative stress-related impairment of mitochondria and relocation of endonuclease G and
apoptosis-inducing factor. Free Radic Biol Med. Jun 15 2004;36(12):1517-1531.
35.
Kitamura M, Hiramatsu N. The oxidative stress: endoplasmic reticulum stress axis in cadmium
toxicity. Biometals. Oct 2010;23(5):941-950.
36.
Habeebu SS, Liu J, Liu Y, Klaassen CD. Metallothionein-null mice are more sensitive than wildtype mice to liver injury induced by repeated exposure to cadmium. Toxicol Sci. May
2000;55(1):223-232.
37.
Waalkes MP, Rehm S. Chronic toxic and carcinogenic effects of cadmium chloride in male
DBA/2NCr and NFS/NCr mice: strain-dependent association with tumors of the hematopoietic
system, injection site, liver, and lung. Fundam Appl Toxicol. Jul 1994;23(1):21-31.
38.
M.P. Waalkes BAD, C.M. Weghorst, J.M. Ward, J.M. Rice, M.G. Cherian, R.A. Goyer. Further
evidence of tumor suppressive effects of cadmium in the B6C3F1 mouse liver and lung: late
stage vulnerability of tumors to cadmium and the role of metallothionein. J. Pharmacol. Exp.
Therap. 1993;266:1656-1663.
39.
T. Colin Campbell JC, Chongbo Liu, Junyao Li, and Banoo Parpia. Nonassociation of Aflatoxin
with Primary Liver Cancer in a Cross-Sectional Ecological Survey in the People's Republic of
China1. CANCER RESEARCH. 1990;50:6882-6893.
- 23 -
40.
Layachi NaZK. Combined protective effect of vitamins C and E on cadmium induced oxidative
liver injury in rats. Afr. J. Biotechnol. 2012;11(93):16013-16020.
41.
Obianime AW, N.J. Ahiwe and J.S. Aprioku. Effects of vitamins C and E pretreatments on
cadmium induced serum levels of some biochemical and hormonal parameters in the female
guinea
42.
spig. Afr. J. Biotechnol. 2010;9(39):6582-6587.
Eybl V, Kotyzova D. Protective effect of manganese in cadmium-induced hepatic oxidative
damage, changes in cadmium distribution and trace elements level in mice. Interdiscip Toxicol.
Jun 2010;3(2):68-72.
43.
Odewumi CO, Badisa VL, Le UT, et al. Protective effects of N-acetylcysteine against cadmiuminduced damage in cultured rat normal liver cells. Int J Mol Med. Feb 2011;27(2):243-248.
44.
Dekhuijzen PN. Antioxidant properties of N-acetylcysteine: their relevance in relation to
chronic obstructive pulmonary disease. Eur Respir J. Apr 2004;23(4):629-636.
45.
Jabeen F, Chaudhry AS. Effects of cadmium chloride and sodium selenite alone or in
combination on the liver of male Sprague-Dawley rats assessed by different assays. Biol Trace
Elem Res. Nov 2011;143(2):1077-1090.
46.
Lawal OA, E.O. Farombi and A.F. Lawal. Aqueous extract of potato (Solanum tuberosum)
modulates cadmium-induced liver damage in female Wistar rats. Int. J. Pharmacol. 2011;7:599607.
47.
Rajasekaran AaMP. Hepatoprotective effect of ethanolic leaf extract of Calycopteris floribunda
Lam on cadmium induced hepatotoxicity in rats. Res. J. Pharmaceut. Biol. Chem. Sci.
2012;3(3):382-390.
48.
Muhammad YYaUUC. Effect of calyx extract of hibiscus sabdariffa against cadmium-induced
liver damage. Bayero J. Pure Appl. Sci. 2008;1(1):80-82.
49.
Abdel-Moneim WMaHHG. The potential protective effect of natural honey against cadmiuminduced hepatotoxicity and nephrotoxicity. Mansoura J. Forensic Med. Clin. Toxicol.
2007;15(2):75-98.
50.
Al-Hashem F, M. Dallak, N. Bashir and M. Abbas. Camel's milk protects against cadmium
chloride induced toxicity in white albino rats. Am. J. Pharm. Toxicol. 2009;4(3):107-117.
- 24 -