i

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

2014

ii

UNIVERSITY OF PITTSBURGHGRADUATE SCHOOL OF PUBLIC HEALTH

This essay is submittedby

Yi Chen

on

April 25th, 2014and approved by

Essay Advisor: James Peterson, Ph.D ______________________________________Associate ProfessorDepartment of Environmental and Occupational HealthGraduate School of Public HealthUniversity of Pittsburgh

Essay Reader:Fernando Holguin, MD. ______________________________________Assistant ProfessorDepartment of Pulmonary, Allergy and Critical Care MedicineUniversity of Pittsburgh Medical CenterUniversity of Pittsburgh

iii

Copyright © by Yi Chen2014

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.

iv

James Peterson, PhD

CADMIUM AND LIVER DISEASE

Yi Chen, MPH

University of Pittsburgh, 2014

For example, 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

vi

Disease………………..15

Potential Mitigating Agents……………………………………………………………......17

CONCLUSIONS……………………………………………………………………………......19

BIBLIOGRAPHY……………………………………………………………………………... 22

vii

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

1

studies focus on the liver (liver disease and liver cancer).2, 6 Several animal studies

have 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

3

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

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

4

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

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

5

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

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 6

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

of cadmium may include larval mortality and temporary reduction in growth.18 Sub-

lethal 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

7

For nonsmokers, food is the major route of exposure to cadmium among the

non-occupational 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

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 70-

kg man and 60 µg of cadmium per day for the average 60-kg woman.16, 17 The PTWI

8

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 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)

9

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, 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

10

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

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

11

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

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

12

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 cadmium-

associated 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

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

13

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, over-

production of ROS is the major reason linked to cadmium hepatotoxicity from in vitro

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

14

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 than in controls, regardless of the period of administration.38 Thus, it is

difficult to draw a conclusion regarding liver cancer associated with cadmium

15

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 liver-

related 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.

16

Higher 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.

17

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. Co-administration 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 N-

Acetylcysteine (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 hepatic-

protective effects of selenium (Na2Se2O3) against cadmium induced toxicity, oxidative

18

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

19

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

20

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

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

21

needed to identify this problem, which might help to set up clinical approaches for

cadmium intoxication.

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.

22

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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

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