Category: Nutrition & Vitamins

‘To read the article click here.’

‘To read the article click here.‘

‘To read the article click here.’

Toxic metals and antioxidants: part II the role of antioxidants in arsenic and
cadmium toxicity – Toxic Metals Part II

Alternative Medicine Review, May, 2003 by Lyn Patrick

Abstract
Exposure to toxic metals has become an increasingly recognized source of illness
worldwide. Both cadmium and arsenic are ubiquitous in the environment, and
exposure through food and water as well as occupational sources can contribute to a
well-defined spectrum of disease. The symptom picture of arsenic toxicity is
characterized by dermal lesions, anemia, and an increased risk for cardiovascular
disease, diabetes, and liver damage. Cadmium has a significant effect on renal
function, and as a result alters bone metabolism, leading to osteoporosis and
osteomalacia. Cadmium-induced genotoxicity also increases risk for several cancers.
The mechanisms of arsenic- and cadmium-induced damage include the production of
free radicals that alter mitochondrial activity and genetic information. The metabolism
and excretion of these heavy metals depend on the presence of antioxidants and
thiols that aid arsenic methylation and both arsenic and cadmium metallothioneinbinding.
S-adenosyl-methionine, lipoic acid, glutathione, selenium, zinc, Nacetylcysteine
(NAC), methionine, cysteine, alpha-tocopherol, and ascorbic acid
have specific roles in the mitigation of heavy metal toxicity. Several antioxidants
including NAC, zinc, methionine, and cysteine, when used in conjunction with
standard chelating agents, can improve the mobilization and excretion of arsenic and
cadmium.

Introduction
Heavy metals are found in increasingly hazardous concentrations in air, food, and
water. The Agency for Toxic Substances and Disease Registry (ATSDR) lists arsenic
and cadmium among the top seven of the 275 most hazardous substances in the
environment. This listing is based on the toxicity of the substance and the potential
for exposure from air, water, or soil contamination at any one of the 1,560 National
Priorities List Cleanup or “Superfund” sites. (1) Arsenic and cadmium, in addition to
mercury and lead, have been identified as the most probable causes of heavy metalrelated
disease observed in primary care medicine. (2)
As the prevalence of heavy metal exposure is increasingly recognized and identified
in individuals seen in private practice clinics, the need for effective prevention and
treatment will increase. In this article, the clinically relevant aspects of arsenic and
cadmium exposure are reviewed, as are current exposure data. The role of
antioxidants in mitigating the damage of heavy metal toxicity and assisting the
process of chelation has been explored in in vitro and animal studies; however,
clinical trials in humans have been limited. The relationship of oxidant stress to the
toxic effects of arsenic and cadmium is summarized, in addition to the potential role
of antioxidants as adjunctive treatment in heavy metal exposure.

Arsenic
Sources of Exposure and Symptoms of Toxicity
High levels in soil used for agricultural purposes in Denmark are considered over 20
[micro]g per gram. (13) Soils in Butte, Montana, collected near mine tailings (a
source of zinc sulfate for fertilizer), contained as much as 13,800 [micro]g arsenic per
gram of soil, and soil collected from a previous hazardous waste site in Jersey City,
New Jersey, contained 1,120 [micro]g per gram. (14) Adults in Denmark, eating 376
grams (about 4 servings) of vegetables per day grown in soil containing 30 [micro]g
of arsenic per gram of soil, consumed 5.3 [micro]g of arsenic daily. (13) Adults living
near point sources of arsenic exposure may have a constant daily total inorganic
arsenic intake as high as 12 [micro]g/kg body weight/ day. (15) Acute symptoms of
arsenic poisoning–nausea, diarrhea, abdominal cramping, hyperesthesia in
extremities, abnormal patellar reflexes, and abnormal electrocardiograms–have been
estimated to occur at levels of exposure equal to 50 [micro]g/kg body weight/day.
(16).

Arsenic exposure has been linked to cardiovascular disease and diabetes. In
epidemiological studies in Bangladesh, where arsenic toxicity is endemic as a result
of tube well contamination, arsenic has been linked to the prevalence of
hypertension, (17) Exposure to 20 ppb or more in drinking water has been associated
with increased mortality from cardiovascular diseases. (18) Cumulative arsenic
exposure has also been positively associated with the incidence of type 2 diabetes in
Taiwan, another area where arsenic contamination of water is common. (19)

It is estimated that several million people worldwide suffer the effects of chronic
arsenic exposure resulting from environmental release of arsenic. (3) Arsenic was
identified as a hazardous waste at 1,014 of the 1,598 National Priorities List
“Superfund” sites in the United States in 2000. (4) The National Institute of
Occupational Safety and Health (NIOSH) estimates that 55,000 workers in the United
States were exposed to high levels of arsenic in the early 1980s. (5) These estimates
are considered low because they exclude mining and agriculture, two occupational
sources of arsenic exposure. Groundwater contamination provides the majority of
worldwide arsenic exposure. In the United States, groundwater concentrations
exceed the U.S. Environmental Protection Agency (EPA) limit of 50 ppb. (6) Levels
as high as 166 ppb have been measured in public water systems in Utah (7) and a
private well in Nevada was found to contain 1,312 ppb. (8) Levels of 20 ppb or more
are found in the water supply of at least 725,000 people in the United States. (9)
Inorganic arsenic, the form found in soil, water, and crops, is classified by the EPA as
a Group A human carcinogen, meaning that sufficient knowledge exists to
substantiate a causal relationship between human exposure and cancer occurrence.
(10).

The current EPA water standard, known as the Maximum Contaminant Level (MCL)
of 50 ppb (50[micro]g/L), has been criticized by the scientific community, specifically
the National Academy of Sciences. Based on their 1999 Risk Estimates, the lifetime
risk of contracting bladder or lung cancer from arsenic at a 50-ppb concentration is 1
in 100. Even at the EPA-proposed MCL of 10 ppb, rejected by the federal
government in 2001, the lifetime risk is still 1 in 500. This risk estimate is significantly
higher than the EPA’s current acceptable cancer-risk definition for water
contaminants: 1 in 10,000 risk of fatal cancer. (10) Inorganic arsenic is also found in
environmental tobacco smoke and arsenic-treated wood, used in over 90 percent of
the outdoor wooden structures in the United States.

Of growing concern is the presence of high levels of heavy metals in industrial waste
processed for use as fertilizer. The presence of high levels of arsenic in agricultural
fertilizer (which can be legally sold as organic fertilizer) has been shown to exceed
EPA limits for arsenic in biosolids. (11) A minimal risk level (MRL) of 0.8 [micro]g of
arsenic/kg/day (approximately 5.6 [micro]g for an adult) has been established for
chronic arsenic exposure as a result of studies showing that approximately twice that
dose resulted in hyperpigmentation and keratosis, both symptoms of chronic arsenic
exposure-induced skin damage. (12)

Chronic exposure is associated with anemia, peripheral neuropathy, liver and kidney
damage, and irritation of the skin and mucous membranes. Peripheral vascular
disease has also been seen in chronically exposed individuals. (20) Chronic
inhalation of inorganic arsenic has been shown to be strongly associated with the risk
of human lung cancer. (2) Because inorganic arsenic binds to sulfhydryl proteins,
specifically keratin, deposits are left in skin, hair, and nails. Exposure to inorganic
arsenic has been linked to arsenical keratoses, squamous cell carcinoma in situ of
the skin, and basal cell carcinoma. Arsenic exposure has also been linked to
hepatocellular carcinoma, angiosarcoma, cirrhosis, and hepatoportal sclerosis. (21)
While animal studies have shown inorganic arsenic to be fetotoxic and teratogenic,
few studies have looked at arsenic toxicity in pregnant females. Ingested arsenic can
cross the placenta and result in cord blood concentrations that resemble maternal
blood concentrations. (22) Arsenic, however, has not been detected in measurable
amounts in the breast milk of arsenic-exposed women. (23)

Chronic arsenic intoxication may present as diffuse symptoms: headache fatigue,
confusion, polyneuritis with distal weakness, exfoliative dermatitis, hyperkeratosis
(especially on the soles of the feet), hyperpigmentation, and Mees’ lines (transverse
white striae of the fingernails). Anemia, leucopenia, slight proteinuria, and liver
enzyme abnormalities may also develop. (2)

Arsenic Methylation and Detoxification
Arsenic exists in both inorganic and organic states. The organic forms that
accumulate in fish and shellfish, arsenobetaine and arsenocholine, have been found
to be essentially nontoxic. (24) The inorganic forms, airborne arsenic trioxide and
arsenate/arsenite (found in soil, water, and food), are the forms of concern to human
health. Arsenic is well absorbed, 40-60 percent if inhaled (25) and approximately 95
percent if ingested. (26) Arsenic is distributed and stored in all tissues of the body
and is metabolized for elimination by two sequential processes (Figure 1).

The first are oxidation/reduction reactions that interconvert arsenate to arsenite.
Glutathione has been shown to form complexes with arsenic and mediate the
reduction of arsenate to arsenite. These glutathione complexes can be eliminated in
the bile and a positive correlation has been found between glutathione and arsenic
levels in bile. (27) Selenium is also able to complex with glutathione and arsenic to
form a compound that is also excreted through the bile. Binding to unidentified
proteins is another possible mechanism for arsenic detoxification. These proteins
appear to be primary, along with glutathione and possibly selenium, in the removal of
arsenic. (28)

The second step, methylation, which occurs mainly in the liver, requires sadenosyhnethionine
(SAMe) and possibly other methyl donors (choline, cysteine,
glutathione, reduced lipoic acid) to produce monomethylarsinic acid (MMA) and
dimethylarsinic acid (DMA). (29) Several studies have shown that SAMe is actually
essential for the methylation of arsenic and low methionine intakes can inhibit arsenic
methylation in animals. (30) Both MMA and DMA have been found in human urine
and are considered end-products of arsenic metabolism. Because DMA is cleared
from cells more rapidly than MMA or inorganic arsenic, and methylation reduces the
amount of arsenic retained in tissues by increasing the water solubility of arsenite,
methylation is considered by some researchers to be a detoxification mechanism.
(31) Other researchers disagree because MMA may be the most toxic intracellular
form of arsenic due to its ability to induce enzyme inhibition, oxidative stress, and
DNA damage. (32) Therefore, methylation may simply be a way of biotransforming
arsenic rather than detoxifying it. (28)

Dermal and pulmonary tissues are unable to convert MMA to DMA as efficiently as
other tissues, and both are the sites of specific arsenic-induced cancers. DMA is not
a benign metabolite either, and has been shown to produce tree radicals that may
contribute to the mechanisms of arsenic-related cancers.(33) MMA and DMA have
also been shown to complex with glutathione and other sulfhydryl proteins, resulting
in sulfhydryl-related enzyme inhibition and cellular damage. (31)

The methylation of arsenic is a topic of significant debate and interest in the
toxicology field because the ability to methylate and eliminate arsenic is influenced by
nutrition, gender, lifestyle, and individual genetic polymorphisms. (34) There appears
to be significant individual variation in the ability to methylate arsenic. Malnourished
individuals exposed to high levels of arsenic are less able to methylate it and are
more at risk for arsenic toxicity symptoms and diseases than well-nourished
individuals. (35) In a study of an arsenic-exposed population, smoking more than 10
cigarettes daily had a stronger inhibitory effect on the ability to completely methylate
arsenic than gender, age, or ethnicity. (36) However, these factors only accounted for
20 percent of the variation in methylation capacity. The amount of exposure appears
to be the most important factor affecting arsenic methylation; the higher the chronic
exposure the lower the individual’s ability to methylate MMA to DMA. The ability to
transform MMA to DMA is significant; for example, the dermal signs of arsenic
exposure (including skin cancer) are related to a buildup in the body of MMA. (31)

Selenium and Arsenic Toxicity
The presence of selenium also affects arsenic toxicity. Animal research has
established a bidirectional effect of selenium and arsenic with each metal preventing
a toxic effect of the other. (37) As mentioned, selenium is believed to bind to arsenic
to form an insoluble complex in the liver. (28) Animal studies with injected sodium
selenite (0.5 mg/kg) increased the excretion of arsenite-selenium compounds in the
bile and reduced hepatic arsenite concentrations. (38) Rats given selenium-sufficient
diets (0.2 ppm) and toxic doses of arsenic were able to eliminate arsenate, arsenite,
and DMA more quickly than rats on a selenium-deficient diet (0.02 ppm). (39) The
methylation of arsenic can also occur in vitro in the presence of methylcobalamin
(methylated vitamin B12) and glutathione. (40) This methylation reaction was
increased with the addition of selenium (in the form of sodium selenite) or the
chelating agent 2,3-dimercaptopropane sulfonate (DMPS). When both DMPS and
selenium were used, the amount of MMA produced from inorganic arsenic was
approximately doubled (Figure 2). The authors of the paper suggest the vitamin B12,
selenium, and methionine (the essential component of SAMe) content of the diets of
those exposed to inorganic arsenic be carefully considered as factors that assist in
the elimination of arsenic.

Oxidative Stress in Arsenic Toxicity
The exact cellular mechanisms of arsenic’s carcinogenicity are not completely
understood; however, it is believed to be a co-carcinogen and tumor promoter rather
than a tumor initiator. (31) The lack of direct evidence is, at least in part, because
there are no animal models for arsenic-induced carcinogenesis. Arsenic may be the
only agent that has been determined to be a definite human carcinogen even though
there is not enough evidence to prove it is a carcinogen in animals. Therefore, it is
both possible and disconcerting that humans are actually more sensitive to the toxic
effects of arsenic than experimental animals.

The four main areas of research on the cellular mechanisms of arsenic toxicity are:
(1) mutation inductions and chromosomal aberrations; (2) altered signal transduction,
cell-cycle control, cellular differentiation and apoptosis; (3) direct damage from
oxidative stress; and (4) alterations in gene expression. (41) None of these
mechanisms are exclusive, and oxidative stress has been shown to influence all of
them, directly or indirectly. (33)

Arsenic-induced oxidative stress has been shown to cause DNA damage through the
production of superoxide and hydrogen peroxide radicals. (42) This particular form of
genotoxicity has been linked to arsenic-related skin cancers. Oxidant-induced
damage was found significantly more frequently in biopsies of individuals with known
arsenic exposure and measurable arsenic in skin biopsies than in those with
squamous-cell carcinoma who had no known arsenic exposure and no measurable
arsenic in skin biopsies (78 percent versus 9 percent, respectively). (43) In vitro
studies have found superoxide dismutase, catalase, dimethyl sulfoxide (DMSO),
glutathione, N-acetylcysteine (NAC), and vitamin E can effectively block DNA
mutations, prevent the production of high levels of superoxide, and protect fibroblasts
from arsenic-induced chromosomal damage. (44) These studies indicate oxidative
damage-related mechanisms are involved in arsenic genotoxicity.

Arsenic also has a direct toxic effect on cellular respiration in mitochondria. (45) This
toxic effect on cellular respiration occurs because arsenic binds to lipoic acid in the
mitochondria and inhibits pyruvate dehydrogenase. The resulting uncoupling of
mitochondrial oxidative phosphorylation leads to increased production of hydrogen
peroxide. The resulting oxidative damage may play an important role in altering
gene-expression patterns, another mechanism for arsenic-induced carcinogenesis.
(46) The uncoupling of oxidative phosphorylation, decrease in cellular respiration,
and resulting increase in free radical production also lead to hepatotoxicity and
porphyrinuria. These symptoms of arsenic toxicity are seen more commonly with
acute exposure but also occur with low-dose chronic exposure. (47)

Evidence of oxidative stress has also been measured in humans with arsenic
exposure. Studies in those with very high arsenic exposure from groundwater
contamination (a mean of 410 [micro]g/L or 400 ppb) had serum lipid peroxide levels
significantly higher (24 percent) than a control group whose drinking water had much
less arsenic (20 [micro]g/L). (48) The high exposure group also had a 57-percent
reduction in whole blood glutathione levels compared to the lower exposure group.
On the whole, individual glutathione levels were inversely related to both whole blood
inorganic arsenic concentrations and the presence of methylated forms of arsenic
(MMA and DMA).

Another human study of northeastern Taiwan residents confirmed these findings.
(49) The coast of northeastern Taiwan is an area of endemic arsenic toxicity where
well water concentrations vary from 0 to over 3,000 [micro]g/L (3,000 ppb). Arsenic
whole blood concentrations in individuals from this area with high arsenic exposure
have been positively associated with plasma oxidant levels and negatively correlated
with plasma antioxidant capacity. A correlation was also found between lower levels
of plasma antioxidants and a lowered ability to methylate inorganic arsenic. Taiwan
residents living in arsenic-hyperendemic areas diagnosed with arsenic-related
ischemic heart disease had significant decreases in serum alpha- and beta carotene.
(50)

Arsenic, Antioxidants, and Chelating Agents
Both dimercaptosuccinic acid (DMSA) (51) and DMPS (52) can be used as chelating
agents in arsenic toxicity. Studies looking at the effects of antioxidants used in
conjunction with chelating agents have investigated their role as potential aids to
chelators. A study evaluating chronic arsenic intoxication (100 ppm in water for 12
weeks) in rats evaluated the ability of NAC and a chelating agent. DMSA, to preserve
hepatic and brain glutathione levels and to normalize erythrocyte enzyme levels. (53)
Dosages of therapeutic agents were given orally to approximate those used in
human treatment: NAC and DMSA each at a dose of 1 mmol/kg for five days. The
combination treatment significantly elevated reduced glutathione levels in the liver
and decreased levels of oxidized glutathione (Table 1). The simultaneous use of both
compounds was significantly stronger than either individually. NAC treatment alone
decreased levels of hepatic malondialdehyde (the result of arsenic-induced oxidant
activity), while the effect of DMSA by itself was insignificant.

Effects in the brain were less apparent, with neither treatment alone or in
combination able to affect a significant shift in the reduced glutathione/oxidized
glutathione ratio. Brain levels of malondialdehyde were significantly reduced,
however. The ability of arsenic to alter heme synthesis was also evaluated. Arsenic
toxicity is known to interrupt hemoglobin synthesis and changes in the erythrocyte
enzyme delta aminolevulinic acid dehydratase (ALAD) levels were measured to
reflect this. Blood ALAD activity was reduced 62 percent by arsenic exposure. DMSA
alone or with NAC was able to restore ALAD levels to those of controls (not exposed
to arsenic); only the combination of both was able to restore RBC glutathione levels.
The level of acute arsenic exposure in this study (100,000 ppb) was significantly
higher than levels of chronic human exposure, even in hyperendemic areas of
Taiwan and West Bengal where tube well contamination reaches 1,500-3,000 ppb.
(54,55)

Arsenic has been detected in human placental tissue and human fetal tissue.
Neonatal brain tissue has shown significant oxidative damage when exposed to
arsenic, at levels as low as 50 ppb. (56) Four groups of female rats were fed arseniccontaminated
water for the length of gestation at concentrations of 300 ppb. The
study compared arsenic alone to arsenic plus vitamin E, arsenic plus vitamin C, and
arsenic with the chelating agent DMSA added for two days at the end of gestation.
When vitamin C and vitamin E were added, significant improvements occurred in
levels of lipid peroxidation and glutathione content (Table 2). The levels of
antioxidants used were small-vitamin C at 2.5 mg/kg/day and vitamin E at
148[micro]g/kg/day (0.148 IU/kg/day). Vitamin E at that level, however, was able to
almost completely restore glutathione levels in brain tissue and increase catalase
levels 100-percent higher than in the control group. Because arsenic-induced
neuronal damage has been shown to be directly related to lipid peroxidation, (55) the
role of antioxidants in protecting both adult and fetal nervous tissue is of increasing
importance.

Cadmium
Cadmium is considered one of the most toxic substances in the environment due to
its wide range of organ toxicity and long elimination half-life of 10-30 years. (57)
Cadmium was identified as a contaminant at 776 of the 1,467 EPA National Priorities
List sites in 1998. (58) It has been estimated that at least 512,000 U.S. employees
each year work in an environment that potentially exposes them to cadmium. (59)
Cadmium-contaminated topsoil, however, is considered the most likely mechanism
for the greatest human exposure through uptake into edible plants and tobacco. (60)
The EPA estimates approximately 3.4 billion pounds of sewage sludge are
transferred to soil annually in the United States. estimated to contain up to 1,000
[micro]g/g cadmium. (61) Fertilizer raw materials are also contaminated with
cadmium; 1.3 million pounds of cadmium-contaminated zinc sulphate containing up
to 215,000 ppm cadmium entered the United States in November 1999. It is not
known how much of this product has been sold and applied to agricultural lands. (62)
Fertilizers continue to be contaminated with cadmium as a result of the recycling of
industrial waste sold as zinc sulphate or other raw materials for agricultural and home
use fertilizers. Assays of commonly sold dry fertilizer and soil amendment in
Washington State in 1998 revealed concentrations of cadmium as high as 160 mg/kg
dry weight. (63)

Cadmium Exposure
The uptake of cadmium from the soil through produce results in elevated
concentrations in vegetables, fruits, and grains, with the highest levels in leafy greens
and potatoes. High levels are also found in shellfish (up to 30 mg/kg) and organ
meats. (64) The current federal minimal risk level (MRL) for cadmium–a level at
which chronic exposure in humans is not likely to cause cancer or adverse health
effects–is 0.2 [micro]g/kg/ day (14.0 [micro]g for the average adult). The average
American diet in 1986 provided 0.4 [micro]g/kg/day of cadmium. (65) The overall
range of dietary cadmium in Swedish diets in 1994-1996 was 2.0-175 [micro]g/ day
and is estimated to be increasing at a rate of two percent per year. (57) The World
Health Organization has shown that dietary cadmium exposure has a very wide
range: inhabitants of worldwide nonpolluted areas have a daily dietary intake of
approximately 40-100 [micro]g, while inhabitants of polluted areas may obtain 200
[micro]g or more as an average daily intake. (57)

Cadmium Absorption
Between 10-50 percent of cadmium fumes are absorbed through the respiratory tract
and approximately five percent of oral cadmium is absorbed through the digestive
tract. Smokers absorb 1-2 [micro]g cadmium per pack of cigarettes, approximately
doubling the average exposure of a nonsmoker and doubling the average amount of
cadmium found stored in the kidneys. (57) Although absorption through the
gastrointestinal tract is significantly lower, low dietary intakes of calcium, protein,
zinc, iron, and copper may increase cadmium absorption in the gut. (66)

Iron Deficiency as a Risk Factor
Iron deficiency creates a significant risk for increased cadmium exposure by
increasing gastrointestinal absorption from five percent to as much as 20 percent.
(67) Individuals with a serum ferritin less than 12 [micro]g/L are considered to be high
risk for cadmium-induced kidney lesions. (57)

A study of 57 nonsmoking Swedish women found those with a serum ferritin of less
than 20 [micro]g/L (indicating reduced body iron stores) had significantly higher blood
cadmium levels than those with a serum ferritin above 30 [micro]g/L. (68) The
authors concluded that, since 44 percent of the women in the study had depleted
bone marrow stores (serum ferritin less than 15 [micro]g/L) and 23 percent had
reduced body iron stores (serum ferritin less than 30 [micro]g/L), iron deficiency
appears to create a significant high-risk category for cadmium-induced renal damage
in Swedish women. This is consistent with data on the Swedish female population in
which 10-40 percent of women are reported to have depleted iron stores (serum
ferritin less than 12 [micro]g/L) (57) and is probably the reason why women, in
general, tend to have higher blood cadmium levels than men.

Iron deficiency is an international health problem, with an estimated incidence of two
billion, particularly young children and women of reproductive age. (69) Vitamin C,
which has been shown to significantly increase iron uptake, may play a role in
protecting against increased cadmium absorption. In a study of women in the United
States, where the prevalence of low iron stores in females ages 12-49 is 10-19
percent, those who took vitamin C supplements had half the risk of low iron stores.
(69)

Cadmium Metabolism and Mechanisms of Toxicity
When cadmium is absorbed it circulates in erythrocytes or bound to albumin. In the
liver it can induce and bind to metallothionein, a cysteine-rich protein that can
concentrate cadmium up to 3,000-fold. (70) The metallothionein/cadmium complex is
slowly released over time from the liver and circulates to the kidneys where it can
accumulate in renal tissue. Cadmium also accumulates in the bone, pancreas,
adrenals, and placenta. The majority of accumulation, approximately 50 percent of
total body stores, occurs in the liver and kidney. (71) The main pathologies related to
chronic cadmium toxicity, renal disease and bone loss, are reflective of cadmium
concentration in the kidney and the alteration of renal function that ultimately causes
osteoporosis and osteomalacia. (57) Acute exposure (acute occupational exposure is
common in jewelry braziers and sodering) can manifest as dysuria, polyuria,
dyspnea, chest pain, irritability, fatigue, headache, and dizziness. Levels of urinary
alphal-microglobin or beta2-microglobin are often elevated in early cadmium-induced
renal damage. A review of the symptoms of acute cadmium toxicity has been
sumnarized by Wittman et al. (59)

Cadmium Absorption
Between 10-50 percent of cadmium fumes are absorbed through the respiratory tract
and approximately five percent of oral cadmium is absorbed through the digestive
tract. Smokers absorb 1-2 [micro]g cadmium per pack of cigarettes, approximately
doubling the average exposure of a nonsmoker and doubling the average amount of
cadmium found stored in the kidneys. (57) Although absorption through the
gastrointestinal tract is significantly lower, low dietary intakes of calcium, protein,
zinc, iron, and copper may increase cadmium absorption in the gut. (66)

Iron Deficiency as a Risk Factor
Iron deficiency creates a significant risk for increased cadmium exposure by
increasing gastrointestinal absorption from five percent to as much as 20 percent.
(67) Individuals with a serum ferritin less than 12 [micro]g/L are considered to be high
risk for cadmium-induced kidney lesions. (57)

A study of 57 nonsmoking Swedish women found those with a serum ferritin of less
than 20 [micro]g/L (indicating reduced body iron stores) had significantly higher blood
cadmium levels than those with a serum ferritin above 30 [micro]g/L. (68) The
authors concluded that, since 44 percent of the women in the study had depleted
bone marrow stores (serum ferritin less than 15 [micro]g/L) and 23 percent had
reduced body iron stores (serum ferritin less than 30 [micro]g/L), iron deficiency
appears to create a significant high-risk category for cadmium-induced renal damage
in Swedish women. This is consistent with data on the Swedish female population in
which 10-40 percent of women are reported to have depleted iron stores (serum
ferritin less than 12 [micro]g/L) (57) and is probably the reason why women, in
general, tend to have higher blood cadmium levels than men.

Iron deficiency is an international health problem, with an estimated incidence of two
billion, particularly young children and women of reproductive age. (69) Vitamin C,
which has been shown to significantly increase iron uptake, may play a role in
protecting against increased cadmium absorption. In a study of women in the United
States, where the prevalence of low iron stores in females ages 12-49 is 10-19
percent, those who took vitamin C supplements had half the risk of low iron stores.
(69)

Cadmium Metabolism and Mechanisms of Toxicity
When cadmium is absorbed it circulates in erythrocytes or bound to albumin. In the
liver it can induce and bind to metallothionein, a cysteine-rich protein that can
concentrate cadmium up to 3,000-fold. (70) The metallothionein/cadmium complex is
slowly released over time from the liver and circulates to the kidneys where it can
accumulate in renal tissue. Cadmium also accumulates in the bone, pancreas,
adrenals, and placenta. The majority of accumulation, approximately 50 percent of
total body stores, occurs in the liver and kidney. (71) The main pathologies related to
chronic cadmium toxicity, renal disease and bone loss, are reflective of cadmium
concentration in the kidney and the alteration of renal function that ultimately causes
osteoporosis and osteomalacia. (57) Acute exposure (acute occupational exposure is
common in jewelry braziers and sodering) can manifest as dysuria, polyuria,
dyspnea, chest pain, irritability, fatigue, headache, and dizziness. Levels of urinary
alphal-microglobin or beta2-microglobin are often elevated in early cadmium-induced
renal damage. A review of the symptoms of acute cadmium toxicity has been
sumnarized by Wittman et al. (59)

The mechanisms of cadmium toxicity are not completely understood, but some of the
cellular effects are known. Fifty to sixty percent of exposed populations have been
shown to have chromosomal damage. (72) Cadmium is known to bind to the
mitochondria of the cell and is capable of inhibiting both cellular respiration (by 75%)
and oxidative phosphorylation (by 100%) at low concentrations. This mitochondrial
toxicity can completely inhibit the hydroxylation of vitamin D in renal tissue at
concentrations of 0.025 mmol. (67)

Some of the specific changes that lead to tissue damage and death in chronic
exposure have been related to oxidative stress and thiol depletion. (33) Cellular
damage results from cadmium binding to sulfhydryl groups in tissue, the production
of lipid peroxides, and the depletion of glutathione. Cadmium also has a very high
affinity for glutathione and can form a complex with glutathione that is eliminated in
bile. Cadmium also inhibits the activity of antioxidant enzymes, including catalase,
manganese-superoxide dismutase, and copper/zinc-superoxide dismutase. (73)
Cadmium-induced lipid peroxidation has been seen in animal studies in liver, kidney,
brain, lung, heart, and testes. (33) Cadmium can also substitute for zinc or selenium
in metalloenzymes. (71)

Lowered levels of selenium as well as lowered activity of glutathione peroxidase (a
selenium-dependent enzyme) have been seen in cadmium-exposed workers. (74)
Cadmium’s ability to generate tree radicals also leads to the expression of
inflammatory chemokines and cytokines, (75) the oxidation of nucleic acids, the
alteration of DNA repair mechanisms, eventual cell death, and the mutagenic
changes involved in cadmium-induced cancers. (72)

Metallothionein is a zinc-concentrating protein that contains 33-percent cysteine.
Primarily induced and stored in the liver, it forms a complex with cadmium,
sequestering it from inside the hepatic cytosol, thus reducing the amount of cadmium
available to injure hepatocytes and preventing cadmium from depleting glutathione
stores. Metallothionein has also been shown to prevent acute cadmium-induced
hepatotoxicity and cell death in animal studies. (70) Mice with genetically-induced
high levels of hepatic metallothionein and newborn animals with naturally high levels
of metallothionein are resistant to cadmium-induced hepatotoxicity. (76)

Metallothionein also has free-radical scavenging properties and is known to function
like glutathione. (77) The ability of metallothionein to scavenge hydroxyl and
superoxide radicals and function like superoxide dismutase in microorganisms has
been demonstrated. (78)

Metallothionein, although it appears to assist in cadmium detoxification and prevent
cadmium-induced damage, can also contribute to cadmium-induced renal damage.
Cadmium bound to metallothionein can leak into plasma, leave storage sites in the
liver, and be taken up by the kidney. The cadmium-metallothionein complex is
dissolved and free cadmium is released in the kidney and reabsorbed in the proximal
tubules. These tree cadmium ions can again be bound by newly synthesized
metallothionein. If production of kidney metallothionein and non-metallothionein
defense and detoxification systems (glutathione) are not sufficient, free cadmium can
damage cellular membranes in the renal tubules. (70) Mice that are genetically
unable to produce metallothionein are much more susceptible to renal injury and
hepatotoxicity resulting from long-term cadmium toxicity than metallothioneinproducing
mice. (70).

Renal Damage in Cadmium Toxicity
An extensive review by Jarup et al includes an investigation of cadmium and renal
damage. (57) The highest load of cadmium is found in the renal cortex. Renal
concentrations in second trimester fetuses and infants compared to autopsy studies
in adults show renal cadmium concentration increases about 5,000 times from birth
to adulthood. (79) Studies of cortex concentrations have found that women have
significantly higher concentrations than men, in spite of a higher male smoking rate.
The average cadmium exposure leads to kidney concentrations of 20 [micro]g/g for
nonsmokers and 40 [micro]g/g for smokers. (80) At an average total intake of 30
[micro]g/day, it is estimated that renal tubular damage occurs in one percent of the
population.

At an intake of 70 [micro]g/day (the World Health Organization provisional tolerable
weekly intake) seven percent of the adult population and up to 17 percent of high-risk
groups would be expected to develop kidney lesions. (57) A Belgian study examining
kidney cadmium and renal damage estimates that 10 percent of the Belgian
population may currently have kidney cadmium concentrations of 50 [micro]g/g,
resulting in early signs of renal damage, proteinuria, and calcium loss. (81) In Japan,
where cadmium exposure through environmental contamination of food and water
has led to outbreaks of cadmium toxicity-related disease, cadmium-induced tubular
lesions have been identified in more than 20,000 people. In Swedish studies, early
signs of renal damage have appeared in those with urine cadmium levels of 0.5-2.0
[micro]g/g creatinine, corresponding to renal cortex concentrations of 10-40 mg/kg,
levels found in 50 percent of the adult Swedish population. (57) Glomerular damage
and kidney stones have been seen in those with occupational exposure to cadmium.
Studies of workers with cadmium-induced renal damage estimate 40-80 percent
increased annual mortality risk as a result of cadmium exposure and renal damage.
Once cadmium-induced nephropathy is initiated, it is accepted that it is irreversible.
(2)

Cadmium and Bone
The cadmium content of human bone in North America has increased by a factor of
50 in the last 600 years. The majority of that increase is believed to have occurred in
the last 100 years. (82) Classic cadmium poisoning (known at itai-itai disease in
Japan) has been characterized by multiple fractures, osteomalacia, bone pain, and
osteoporosis that occurs along with renal disease. (83) Animal studies indicate
postmenopausal women may be at greater risk for cadmium-related bone loss and
that cadmium may increase bone loss in women with pre-existing postmenopausal
osteoporosis. (57)

Epidemiological studies have found a positive correlation with elevated urinary
cadmium levels and increased urinary calcium loss and elevated serum alkaline
phosphatase levels. (84) Studies have also found correlations between cadmiuminduced
renal tubular damage and bone loss. A study of 1,021 men and women, who
had either worked at a factory or lived in a community in Sweden where nickelcadmium
or lead batteries were produced, evaluated the relationship of cadmium and
lead exposure to kidney and bone disease. (85) Those who were environmentally
exposed and had the highest blood cadmium levels had a four-fold risk of tubular
proteinemia. Older individuals (over 60 years) in that group had a threefold risk of
significant bone loss (Z-score < -1) compared to a same-age group with no known
cadmium exposure. The Z score results from a comparison to the average bone
density scores of a group of similar-aged individuals. A score of less than 0 indicates
bone loss greater than the average of that same group.
The mechanisms behind cadmium and bone loss are related to renal tubular cell
damage that results in elevated levels of urinary calcium and lowered levels of 1,25
dihydroxy-cholecalciferol, a consistent finding in women environmentally exposed to
significant levels of cadmium. (86) Lower levels of activated vitamin D3 alter calcium
homeostasis by decreasing absorption of calcium in the gut and altering deposition in
bone.

Cadmium and Cancer, Heart
Disease, and Reproduction
Cadmium is classified as a group I human carcinogen, meaning sufficient evidence
for carcinogenesis has been found in both animals and humans. Occupational and
environmental exposure has been shown to increase risk for lung cancer with coexposure
to arsenic, (87) and renal cancer with cadmium exposure alone. (88) While
animal studies support a role for cadmium-induced prostate cancer, inconsistent
findings exist for cadmium’s role in human prostate, breast, testicular, and bladder
cancers. (57)

Cadmium appears to be completely filtered by the placenta when adequate zinc and
copper are available for the induction of metallothionein. Studies with newborn rats
reveal newborns whose cadmium-exposed mothers had been given adequate zinc
and copper during pregnancy were cadmium-free at birth, as opposed to newborns
whose cadmium-exposed mothers had a zinc and copper-deficient diet. (89)
Maternal hypertension and low birth weight have been associated with elevated
cadmium levels in infants. (90) Environmental exposure to lead, cadmium, and
arsenic in pregnant women has been correlated with increased levels of lipid
peroxides, and the incidence of threatened spontaneous abortion, toxemia, and
anemia. (91) Only lead and cadmium exposure correlated with decreased levels of
reduced glutathione.

Risk for hypertension and cardiovascular disease in nonpregnant women and in men
is not conclusively a result of cadmium exposure. Studies have found both increased
risk for cardiovascular mortality in one exposed group (92) and no increased risk for
ischemic heart disease or hypertension in another large study. (93)

Antioxidants in Cadmium Toxicity
Zinc and Metallothionein Induction as a Protective Mechanism
Metallothionein production is induced by the presence of metals, including cadmium,
mercury, copper, gold, bismuth, and most powerfully, zinc. (94) Low level zinc
treatments have been used in animal studies to induce metallothionein and protect
against acute cadmium-induced hepatotoxicity. (95) Similarly, hepatocyte cell lines
treated with zinc became resistant to cadmium-induced cell death as a result of
metallothionein induction. (96) In animals, both hepatic and intestinal metallothionein
have been induced using oral zinc, and metallothionein induction using nontoxic zinc
injections has been successful in reducing cadmium toxicity in animals. (97) The
induction of intestinal metallothionein in humans, using zinc acetate, is the
mechanism for the FDA-approved treatment of Wilson’s disease, an inherited
condition where accumulation of copper in the liver, brain, and other organs leads to
copper toxicosis. (98)

The mechanisms of cadmium-induced renal damage result from the dissolution of the
cadmium/metallothionein complex in the kidney, exposing renal tissue to unbound
cadmium. Cadmium/cell membrane binding, cellular apoptosis of renal proximal
tubules, increased calcium loss in the urine, and increased protein excretion are seen
in animals given long-term doses of cadmium or repeated doses of
cadmium/metallothionein complexes. Studies have also shown when the kidney is
able to induce adequate de novo synthesis of metallothionein, no membrane damage
occurs. (70)

Zinc has been used to induce renal metallothionein in animal studies and protects
against cadmium/metallothionein-induced renal injury. (99) Rats pretreated with zinc
or copper have shown less sensitivity to cadmium toxicity, specifically in renal
proximal tubule cells. Proteinuria caused by cadmium-metallothionein injections was
more effectively reduced by pretreatment injections with zinc than with copper. (100)
Although there have been no human clinical trials with zinc or copper to assess
metallothionein induction, zinc acetate, used to stimulate intestinal metallothionein in
the treatment of Wilson’s disease, is nontoxic in 150 mg daily doses and has minimal
side effects. (98) In those without Wilson’s disease, the possibility of inducing a
copper deficiency with high doses of zinc is preventable with copper
supplementation.

Alpha-Lipoic Acid
Alpha-lipoic acid (ALA), rejected in cadmium-exposed murine hepatocytes, was
shown to protect cells from toxic effects of cadmium, including hepatocyte membrane
damage, lipid peroxidation, and depletion of intracellular glutathione. (101) These
protective effects have also been seen in rats who had experimentally-depleted
glutathione stores prior to cadmium exposure. (102) Although the acute toxicity
induced in these studies (150 [micro]M or about 17 mg cadmium) is vastly different
than low level chronic exposure in humans. oxidant stress and glutathione depletion
are also recognized toxic mechanisms of low level exposure.(103,104) The authors
of the first study concluded that dihydrolipoic acid (the reduced form of alpha-lipoic
acid) is an effective extra- and intracellular chelator of cadmium in hepatocytes as a
result of a significant decrease in intra- and extracellular levels of cadmium after ALA
was added to the cells. (101) The authors measured both intra- and extracellular
cadmium/ lipoate and cadmium/dihydrolipoate complexes to conclude that cadmium
was actually being removed from the hepatocytes by lipoic acid compounds
themselves and not glutathione generated by lipoic acid. They also noted, however,
that these effects occurred only at low levels of cadmium exposure and high levels of
lipoic acid concentration. (101)

Selenium
The theory that selenium and cadmium can form complexes has been substantiated
by researchers in animal studies with concomitant selenium and cadmium exposure.
(105,106) In a study with acute cadmium toxicity (8 mg/kg oral cadmium) and
contaminant oral selenium supplementation (350 [micro]g/kg sodium selenite), rats
who received both had a 25-percent reduction in kidney cadmium. The ability of
selenium to decrease the tissue burden of cadmium has been repeated in other
animal studies. (105) Acute toxicity studies have found that, as a result of dosing
selenium and cadmium at the same time, organ tissue levels of both metals
increased and the toxic burden of cadmium decreased, possibly as a result of the
inert nature of the cadmium/selenium complex. (107) A low-level cadmium exposure
study in mice (1 ng/L drinking water) with a varied selenium diet revealed significant
differences in cadmium retention. (108) In mice that received a normal
selenomethionine/sodium selenite diet (99.25 [micro]g selenomethionine and 68
[micro]g sodium selenite/kg food) the whole body retention of cadmium was less than
half of the retention in mice on a low selenium diet (31.25 [micro]g
selenomethionine/kg food) (Table 3). For comparison, the average American gets
approximately 65 [micro]g of selenium per day through diet and supplementation.
Selenium supplementation has a known antioxidant action ill cadmium toxicity.
Selenium supplementation in acute cadmium toxicity has been shown to decrease
lipid peroxidation in rat studies (109) and has also been shown to increase the
production of glutathione S-transferase and glutathione peroxidase in rhesus
monkeys. (106)

The dosage of selenium in the primate study was far beyond what would be used in
human trials, 500 [micro]g/kg body weight, but the cadmium exposure was also
elevated beyond possible environmental or occupational human exposure to 5 mg/kg
body weight/day. Similar results–elevations of glutathione peroxidase and decreased
whole body and renal burden of cadmium were found in rats given daily selenium
supplementation of 350 [micro]g/ kg body weight. (105) Selenium also appears to act
in conjunction with other antioxidants. When selenium was given to rats
simultaneously with vitamin E and glutathione, the cadmium uptake in liver and
kidneys was significantly inhibited. (110) Selenium has also been shown to decrease
lipid peroxidation in testicular tissue of rats, (111) an effect relevant to human health
due to the correlation of blood cadmium levels in men with decreases in sperm
motility and alterations in sperm morphology. (112)

Plant Triterpenes
Triterpenes are common plant compounds shown to have antioxidant, (113)
hepatoprotective, (114) anti-inflammatory, (115) and antitumor (116,117) properties.
Triterpenoids also induce metallothionein in cadmium toxicity. Oleanolic acid, a
triterpenoid present in many plants and one of the active constituents of Ligustrum
lucidum, is used in China to treat hepatitis. It has also been shown to induce hepatic
metallothionein in cadmium toxicity. (118) Doses of 100 mg/kg of oleanolic acid were
given to mice for three clays prior to cadmium injections in doses known to induce
acute liver injury. Oleanolic acid resulted in a 30-fold increase in hepatic
metallothionein and a significant increase in the mobilization of cadmium, preventing
cadmium-binding to intracellular proteins. Liver injury was also significantly reduced,
as indicated by reductions in ALT and sorbitol dehydrogenase levels.

Specific triterpenoids, including oleanolic acid, betulinic acid, ursolic acid,
soyasapogenol A and B (all present in Glycyrrhiza glabra and Betula alba L.), uvaol
(present in Betula alba and Syzgium sp.), and glycyrrhizin have been found to be
effective in reducing the hepatotoxicity of cadmium.”7 Betulin, present in high levels
in white birch bark (Betula alba L.), was found to have the strongest ability to reduce
the cytotoxicity of cadmium-poisoned hepatocytes and completely prevented toxicity
at doses as minimal as 0.1 [micro]g/mL. (119) The mechanism of betulin appears to
be a gene-promoting effect in hepatocytes that eliminates the toxic effects of
cadmium.

Glycyrrhizin
Glycyrrhizin, a triterpenoid saponin, is known to act in hepatic tissues as an
antioxidant by reducing lipid peroxidation. (120) The Japanese drug, Stronger NeoMinophagen
C (SNMC), which contains glycyrrhizin, glycine, and cysteine, has also
been shown to protect against acute cadmium toxicity-related hepatic damage and
renal damage in animal studies. (104,121) The dosage of the glycyrrhizin compound
used in these studies was small–2 mg glycyrrhizin, 20 mg glycine, and 1 mg
cysteine/kg–yet was able to reverse the nephrotoxicity brought on by 19 weeks of
daily high-level cadmium injections. As a result of the SNMC studies, researchers
investigated the effect of glycine to differentiate therapeutic effects of glycine from
those of glycyrrhizin. Studies with glycine (12 mmol/L hepatic perfusion) alone found
it could prevent the decrease in bile flow caused by cadmium, but glycine was unable
to reverse the 30-90 percent decrease in hepatic glutathione caused by cadmium.
(122)

Melatonin
Melatonin, a known antioxidant, has been studied as a preventive agent in cadmiuminduced
lipid peroxidation. Pretreatment by single injection of 15 mg/kg body weight
in hamsters completely prevented lipid peroxidation in the brain and the kidney
induced by cadmium injection. (123)

Antioxidants and Chelating Agents
Cadmium is known to bind tightly to metallothionein in complexes stored
intracellularly in the liver and kidney. (124) Because standard chelating agents do not
work intracellularly, many sources state there is no clinically effective treatment for
cadmium poisoning. (2,59) While DMSA is effective for both Icad and mercury
toxicity, it is not an intracellular chelator, DMPS has limited ability to enter the cell
and chelate cadmium. (124) Diethylenetriaminepentaacetate (DTPA), a chelating
agent used to chelate uranium isotopes, binds tightly to cadmium. (125) Prior animal
studies with lead toxicity have shown methionine (a glutathione precursor), used in
conjunction with chelating agents, increased lead elimination. (126) Two studies have
followed looking at the co-administration of DMPS and DTPA using the glutathione
precursors methionine, cysteine, and NAC in cadmium chelation. (125,127) In the
first study, rats pre-exposed to cadmium were given a combination of oral methionine
and injections of either DMPS or DTPA as chelating agents. (125) Alter three days of
methionine/chelation treatment the cadmium content of organ tissue was compared
to rats receiving either chelating agent or methionine alone, or controls who had
received only cadmium and controls who had not received any treatment (Table 4).
DMPS plus methionine was significantly more effective in removing cadmium from
the liver, kidney, and brain than DTPA plus methionine or any of the treatments
alone.

A second study evaluated a three-day oral dosing of the antioxidants cysteine and
NAC with oral DMPS in acute cadmium-exposed rats. (127) Because DMPS is 60-
percent orally bioavailable, it was administered by mouth. The combination
treatments were more effective than any agent alone at mobilizing cadmium from
body stores and delivering it to the kidney (Table 5), indicated by the elevated renal
cadmium levels in the rats that received combination treatment. The combinations
were also significantly more effective at removing cadmium from the intracellular
hepatic compartments. DMPS/NAC was significantly more effective (p< 0.001) than
the DMPS/cysteine (p<0.01) combination. The authors credited the glutathione
precursor status of cysteine and NAC in their ability to decrease cadmium levels ill
the nuclear fractions of hepatic tissue con/pared to chelation alone. They also
theorized that both cysteine and NAC were able to induce metallothionein, explaining
the significant elevations in renal and hepatic metallothionein in rats receiving
combination treatment as opposed to those receiving DMPS alone.

Zinc has also been given in combination with either DMSA or DTPA to rats preexposed
to low levels of cadmium (10 ppm/liter water). (128) Zinc sulphate (20
mg/100 g body weight) was given with either chelating agent for two five-day periods,
with a seven-day rest period in between (to prevent side effects from the chelating
agents). Only DTPA and zinc had any significant lowering effect on liver
concentrations of cadmium, and only DTPA alone or DTPA with zinc had any effect
on renal cadmium (Table 6). Zinc supplementation alone, however, was able to
normalize serum AST and ALT levels, reflecting cadmium-induced hepatic damage
(Table 7). And zinc, added to DMSA, was able to significantly reduce serum AST and
ALT levels compared to DMSA alone. Zinc alone resulted in a significant increase in
both hepatic and renal metallothionein levels. The authors suggest from the results of
this study that zinc-induced metallothionein is capable of binding cadmium and
reducing cadmium toxicity, and that zinc aids in the mobilization of cadmium from
intracellular storage depots.

Conclusion
Arsenic and cadmium are ubiquitous and dangerous environmental toxins. Arsenic in
groundwater and concentrated in soil and food is a Group A human carcinogen.
Exposure can cause a variety of cancers, most commonly nonmelanoma skin
cancers, and chronic toxicity may manifest as diffuse symptoms not easily
recognizable as chronic heavy metal toxicity. Arsenic is metabolized via a
methylation sequence that uses glutathione and SAMe, eventually being eliminated
through the intestines and kidneys. Recent research suggests the end products of
methylation are also carcinogenic. Methylation is aided by methylcobalamin and
possibly selenium, which has long been known to both aid in arsenic elimination and
bind arsenic in a nontoxic selenium-arsenic complex.

Oxidant stress and lipid peroxidation are well-defined mechanisms of arsenic toxicity
related to arsenic-induced skin cancers and the reduction of whole-blood glutathione
stores in humans with environmental exposure.

In vivo studies with animals and fetal cell cultures exposed to arsenic have shown
that antioxidants, particularly NAC, vitamin E, and vitamin C, given in conjunction
with a chelating agent (DMSA), have been able to restore glutathione levels and
reduce damage secondary to oxidative stress.

Cadmium, through contaminated soil, food, and tobacco smoking, may have
significantly increased toxicity in those with iron, zinc, or calcium deficiency due to
increased gastrointestinal absorption and increased calcium loss. Chronic cadmium
toxicity has been linked to lung and kidney cancers, irreversible renal damage,
osteoporosis, and osteomalacia. Cadmium is stored primarily in the kidneys and liver,
tightly bound to metallothionein in an intracellular complex. Metallothionein has
protective effects on cadmium toxicity, but may also facilitate renal damage if it is not
produced in renal tissues in sufficient quantities. Zinc induces hepatic and renal
metallothionein, and has been shown to protect both organs from cadmium-induced
damage. Lipoic acid, selenium, naturally occurring triterpenoid compounds, and
melatonin have been shown to inhibit oxidant production secondary to cadmium
exposure and to mitigate cadmium toxicity in animal studies. NAC, methionine,
cysteine, and zinc improve the efficacy of the chelating agents DMPS and DMSA by
allowing removal of cadmium from intracellular stores and raising metallothionein
levels.

Table 1. Effects of N-acetylcysteine, meso 2,3-Dimercaptosuccinic Acid
and their Combination

GSH GSSG GSH/GSSG
Group (nmol/mg protein) (nmol/mg protein) Ratio
I. Control 42.3 [+ or -] 1.0 1.40 [+ or -] 0.07 30
II. Arsenic 21.6 [+ or -] 0.9 4.45 [+ or -] 0.34 5
III. Arsenic + NAC 30.1 [+ or -] 2.5 2.97 [+ or -] 0.21 10
IV. Arsenic + DMSA 29.2 [+ or -] 3.2 3.30 [+ or -] 0.10 9
V. Arsenic + NAC +
DMSA 37.2 [+ or -] 1.0 2.17 [+ or -] 0.21 17

NAC, N-acetylcysteine; DMSA, meso 2,3-dimercaptosuccinic acid; GSH,
glutathione; GSSG, oxidized GSH Adapted from: Flora SJ. Arsenic-induced
oxidative stress and its reversibility following combined
administration of N-acetylcysteine and meso 2,3-dimercaptosuccinic acid
in rats. Clin Exp Pharmacol Physiol 1999;26:865-869.

Table 2. Effects of Vitamins C and E and DMSA as Protective Agents

Lipid peroxidation GSH content
([DELTA]OD/mg protein) ([micro]g/mg protein)
Arsenic 131 [+ or -] 7 77 [+ or -] 9
Manic + vitamin C 81 [+ or -] 5 * 82 [+ or -] 11 ***
Arsenic + vitamin E 64 [+ or -] 11 * 98 [+ or -] 8 **
Arsenic + DMSA 38 [+ or -] 14 * 88 [+ or -] 12 ***

* value lower than control

** value same as control

*** p < 0.05 compared to arsenic only

Adapted from: Chattopadhyay S, Bhaumik S, Purkayastha M, et al.
Apoptosis and necrosis in developing brain cells due to arsenic
toxicity and protection with antioxidants. Toxicol Lett 2002;136:65-76.

Table 3. Effects of Dietary Selenium Levels on Whole Body Retention of
Cadmium Chloride

Low selenium diet Normal selenium
cadmium in diet cadmium in
drinking water drinking water

Whole-body 14.4 6.4 *
retention
Liver 0.70 0.48
Kidneys 0.72 0.52

* p < 0.05 compared to low Se diet in the same experiment.

Adapted from: Andersen O, Nielsen JB. Effects of simultaneous
low-level dietary supplementation with inorganic and organic selenium
on whole-body, blood and organ levels of toxic metals in mice.
Environ Health Perspect 1994;102:321-324.

Table 4. Effect of Chelator and/or Methionine on Tissue Cadmium Levels

Treatment Liver
([micro]g/g fresh tissue)

Normal-control 1.67 [+ or -] 0.19
Cd (control) 43.47 [+ or -] 1.77 (a)
Ca[Na.sub.3]DTPA 31.81 [+ or -] 1.83 (c)
DMPS 24.60 [+ or -] 1.29 (c)
Methionine 19.77 [+ or -] 2.54 (c)
Ca[Na.sub.3]DTPA 15.20 [+ or -] 2.76 (c) **
+ Methionine
DMPS + Methionine 13.76 [+ or -] 2.60 (c) *

Treatment Kidney
([micro]g/g fresh tissue)

Normal-control 0.55 [+ or -] 0.12
Cd (control) 47.68 [+ or -] 3.72 (a)
Ca[Na.sub.3]DTPA 29.24 [+ or -] 4.13 (c)
DMPS 22.36 [+ or -] 1.20 (c)
Methionine 17.06 [+ or -] 2.68 (c)
Ca[Na.sub.3]DTPA 12.74 [+ or -] 3.22 (c) ***
+ Methionine
DMPS + Methionine 7.79 [+ or -] 2.62 (c) *

Treatment Brain
([micro]g/g fresh tissue)

Normal-control 0.05 [+ or -] 0.02
Cd (control) 2.59 [+ or -] 0.45 (a)
Ca[Na.sub.3]DTPA 1.54 [+ or -] 0.35 (c)
DMPS 1.75 [+ or -] 0.44 (c)
Methionine 1.42 [+ or -] 0.28 (c)
Ca[Na.sub.3]DTPA 1.47 [+ or -] 0.46 (c)
+ Methionine
DMPS + Methionine 1.04 [+ or -] 0.07 (c) ***

Values are mean ([+ or -] S.D.; n=6).

* p < 0.001; ** p < 0.01; *** p < 0.05 versus Ca[Na.sub.3] DTPA or
methionine/DMPS or methionine at 5% level of significance (ANOVA).

The Cd removal in % control, has been given in parenthesis.

(a) p < 0.001; (b) p < 0.05 versus normal-control (Student’s t-test);
(c) p < 0.01 versus Cd (control).

Adapted from: Tandon SK, Singh S, Prasad S. Influence of methionine
administration during chelation of cadmium by CaNa3DTPA and DMPS in
the rat. Environ Toxicol Pharmacol 1997;3:159-165.

Table 5. Influence of Cysteine or N-acetylcysteine on the Efficacy
of DMPS

Treatment Liver ([micro]g [g.sup.-1] fresh tissue

WT SCF

Normal Animal ND ND
Cd (control) 80.24 [+ or -] 10.55 72.46 [+ or -] 11.95
Cd-cysteine 37.41 [+ or -] 3.43 *** 31.29 [+ or -] 6.85 ***
Cd-Nacetylcysteine
55.36 [+ or -] 3.36 *** 49.28 [+ or -] 5.35 ***
Cd-DMPS 39.79 [+ or -] 5.82 *** 32.19 [+ or -] 5.95 ****
Cd-DMPS +
cysteine 42.85 [+ or -] 4.96 *** 37.68 [+ or -] 3.45 ***
Cd-DMPS
+ Nacetylcysteine
37.13 [+ or -] 3.86 **** 33.99 [+ or -] 3.28 ****

Treatment Liver ([micro]g Kidney ([micro]g
[g.sup.-1] fresh tissue [g.sup.-1] fresh tissue)

NMF WT

Normal Animal ND ND
Cd (control) 3.83 [+ or -] 1.69 57.93 [+ or -] 7.87
Cd-cysteine 6.01 [+ or -] 2.03 33.83 [+ or -] 3.90 ***
Cd-Nacetylcysteine
5.95 [+ or -] 0.79 31.82 [+ or -] 4.64 ***
Cd-DMPS 6.61 [+ or -] 0.54 27.08 [+ or -] 1.52 ***
Cd-DMPS +
cysteine 4.60 [+ or -] 0.69 48.90 [+ or -] 4.89 *
Cd-DMPS **([dagger][dagger]) ([dagger][dagger]
+ N- [dagger])
acetylcysteine 2.16 [+ or -] 0.74 45.72 [+ or -] 5.01 ***
****[dagger][dagger] ([dagger][dagger]
[dagger]) [dagger])

Treatment Kidney ([micro]g [g.sup.-1] fresh tissue)

SCF NMF

Normal Animal ND ND
Cd (control) 48.57 [+ or -] 9.02 8.80 [+ or -] 1.87
Cd-cysteine 24.13 [+ or -] 6.83 *** 9.38 [+ or -] 1.47
Cd-Nacetylcysteine
24.34 [+ or -] 5.46 *** 7.55 [+ or -] 2.16
Cd-DMPS 19.62 [+ or -] 2.04 *** 5.52 [+ or -] 0.80 ***
Cd-DMPS + 43.27 [+ or -] 4.50 ***
cysteine ([dagger][dagger] 5.38 [+ or -] 1.10 ***
[dagger])
Cd-DMPS 41.28 [+ or -] 5.85 *** 5.21 [+ or -] 0.33 ***
+ N- ([dagger][dagger]
acetylcysteine [dagger])

(a) Values are means [+ or -] SD(n=6); WT, whole tissue; SCF,
supernatant cytosol fraction; NMF, nuclear mitochondrial fraction; ND,
not detected; * p < 0.05, *** p < 0.01 and *** p < 0.001 vs Cd-control
and ([dagger][dagger][dagger]) p < 0.01 and ([dagger][dagger][dagger])
p < 0.001 vs Cd + DMPS at 5% level of significance (ANOVA).

Adapted from: Tandon SK, Prasad S, Singh S. Chelation in metal
intoxication: influence of cysteine or N-Acetyl cysteine on the
efficacy of 2,3-dimercaptopropane-1-sulphonate in the treatment of
cadmium toxicity. J Appl Toxicol 2002;22:67-71.

Table 6. Influence of Zinc Supplementation
during Chelation Treatment on Cadmium
Concentration in Liver and Kidneys

Kidneys ([micro]g
Liver ([micro]g [g.sup.-1]) [g.sup.-1])

Normal Animal 0.02 [+ or -] 0.004 0.016 [+ or -] 0.004
Cd (control) 48.2 [+ or -] 4.14 (b) 71.4 [+ or -] 3.94 (b)
Cd + DTPA 38.2 [+ or -] 3.59 54.5 [+ or -] 2.30 (c)
Cd + DMSA 42.7 [+ or -] 2.89 66.2 [+ or -] 3.94
Cd + Zn 50.1 [+ or -] 3.08 78.4 [+ or -] 3.28
Cd + Zn + DTPA 32.7 [+ or -] 1.82 35.8 [+ or -] 1.76 (d)
Cd + Zn + DMSA 43.4 [+ or -] 2.14 64.2 [+ or -] 3.37

(a) values are mean [+ or -] SEM (n=6)

(b) p < 0.001 compared to normal animals

(c) p < 0.01 compared to Cd-exposed control

(d) p < 0.001 compared to Cd-exposed control

Adapted from: Flora SJ, Gubrelay U, Kannan GM, Mathur R. Effects
of zinc supplementation during chelating agent administration in
cadmium intoxication in rats. J Appl Toxicol 1998;18:357-362.

Table 7. Influence of Zinc Supplementation during Chelation Treatment
on the Levels of Biochemical Variables in Liver of Cadmium-exposed Rats

AST ALT

Normal Animal 25.7 [+ or -] 1.98 31.6 [+ or -] 4.25
Cd (Control) 32.8 [+ or -] 0.07 (b) 44.8 [+ or -] 1.60 (c)
Cd + DTPA 26.2 [+ or -] 1.03 *** 29.1 [+ or -] 2.18 ***
Cd + DMSA 39.2 [+ or -] 2.60 ** 47.3 [+ or -] 6.06
Cd + Zn 29.5 [+ or -] 0.76 36.4 [+ or -] 2.50 *
Cd + Zn + DTPA 20.5 [+ or -] 0.81 ** 32.5 [+ or -] 3.12 *
Cd + Zn + DMSA 29.5 [+ or -] 2.50 39.4 [+ or -] 0.59 **

ALP [gamma]-GT

Normal Animal 4.0 [+ or -] 0.85 6.52 [+ or -] 0.32
Cd (Control) 8.5 [+ or -] 0.65 (b) 8.29 [+ or -] 0.21 (d)
Cd + DTPA 4.8 [+ or -] 0.48 ** 6.49 [+ or -] 1.13
Cd + DMSA 7.7 [+ or -] 0.75 9.31 [+ or -] 0.45
Cd + Zn 5.0 [+ or -] 0.47 ** 8.17 [+ or -] 1.23
Cd + Zn + DTPA 3.8 [+ or -] 78.0 ** 9.97 [+ or -] 1.25
Cd + Zn + DMSA 2.4 [+ or -] 0.08 *** 7.75 [+ or -] 0.74

Urea Creatinine

Normal Animal 26.3 [+ or -] 1.72 1.95 [+ or -] 0.52
Cd (Control) 28.0 [+ or -] 0.44 2.41 [+ or -] 0.58
Cd + DTPA 29.0 [+ or -] 2.24 1.97 [+ or -] 0.41
Cd + DMSA 22.7 [+ or -] 1.61 1.83 [+ or -] 0.52
Cd + Zn 33.5 [+ or -] 0.61 2.03 [+ or -] 0.87
Cd + Zn + DTPA 29.4 [+ or -] 5.45 1.92 [+ or -] 0.37
Cd + Zn + DMSA 29.08 [+ or -] 2.11 1.86 [+ or -] 0.26

(a) Values are means [+ or -] SEM(n=6); * p < 0.05 and ** p < 0.01 and
*** p < 0.001 compared to Cd-exposed control.

(b) p < 0.001 compared to normal animals.

(c) P < 0.05 compared to normal animals.

Adapted from: Flora SJ. Gubrelay U, Kannan GM, Mathur R. Effects of
zinc supplementation during chelating agent administration in cadmium
intoxication in rats. J Appl Toxicol 1998;18:357-362.

Table 8. Summary of Nutrients and their Effects on Arsenic and Cadmium

SAMe Necessary for As methylation (30)

Selenium Forms insoluble complexes with As (28,37-39)
In vitro with GSH and methylcobalamin; supports As
methylation (40)
Forms inert complexes with Cd and decreases
toxicity (105,106)
[down arrow] lipid peroxidation, (109,110) a
glutathione-recycling enzymes (106)
[down arrow] tissue retention of Cd(108)
+ GSH and vitamin E results in [down arrow] Cd uptake
in liver (110)

NAC + DMSA [up arrow] hepatic GSH and normalizes RBC GSH
in As toxicity (53)
+ DMPS [up arrow] hepatic metallothionein and
[up arrow] Cd chelation from
intracellular hepatic stores (127)

Lipoic acid Hepatic protection from Cd-induced damage (101)
Mobilizes Cd by forming ALA-Cd complex (101)

Zinc Increases metallothionein levels in liver, kidney,
intestines (93)
+ DTPA [down arrow] hepatic Cd stores (128)

Oleanolic acid [up arrow] hepatic metallothionein and mobilizes
Cd (118)

Betulin [down arrow] hepatoxicity of Cd (117)

Glycyrrhizin Prevents hepatic and renal damage from Cd
toxicity (104, 121)

Melatonin Prevents lipid peroxidation in acute Cd toxicity (123)

Methionine + DMPS improves ability of DMPS to chelate Cd from
liver and kidneys (125)

Gysteine + DMPS [up arrow] hepatic metallothionein and
[up arrow] Cd chelation from intracellular hepatic
stores (127)

References
(1.) National Priorities List. U.S. Environmental Protection Agency. December 24,
2002. http://www.epa.gov/superfund/sites/query/ queryhtm/npltotal.htm
(2.) Hu H. Exposure to metals. Prim Care 2000:27:983-996.
(3.) Centeno JA, Mullick FG, Martinez L, et al. Pathology related to chronic arsenic
exposure. Environ Health Perspect 2002;110:883-886.
(4.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000 Toxicological
Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human Services.
Public Health Service: 2001:244.
(5.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000 Toxicological
Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human Services,
Public Health Service; 2001:244-246.
(6.) Ryker SJ. Mapping arsenic in groundwater. Geotimes 2001;46:34-36.
(7.) Lewis DR, Southwick JW, Ouellet-Hellstrom R, et al. Drinking water arsenic in
Utah: a cohort mortality study. Environ Health Perspect 1999;107:359-365.
(8.) Warner ML, Moore LE, Smith MT, et al. Increased micronuclei in exfoliated
bladder cells of individuals who chronically ingest arsenic-contaminated water in
Nevada. Cancer Epidemiol Biomarkers Prev 1994;3:583-590.
(9.) US EPA Notice of Proposed Rulemaking. National primary drinking water
regulations; arsenic and clarifications to compliance and new source contaminants
monitoring 65. Federal Register. June 22, 2000;38:904.
(10.) National Academy of Sciences. Arsenic in Drinking Welter. Washington, DC:
National Academies Press; 1999:223.
(11.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000
Toxicological Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human
Services, Public Health Service; 2000:243-269.
(12.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000
Toxicological Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human
Services, Public Health Service; 2000:A-5.
(13.) Helgesen H, Larsen EH. Bioavailability and speciation of arsenic in carrots
grown in contaminated soil. Analyst 1998; 123:791-796.
(14.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000
Toxicological Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human
Services, Public Health Service; 2000:282.
(15.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000
Toxicological Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human
Services, Public Health Service; 2000:276.
(16.) Franzblau A, Lilis R. Acute arsenic intoxication from environmental arsenic
exposure. Arch Environ Health 1989;44:385-390.
(17.) Rahman M, Tondel M, Ahmad SA, et al. Hypertension and arsenic exposure in
Bangladesh. Hypertension 1999;33:74-78.
(18.) Engel RR, Smith AH. Arsenic in drinking water and mortality from vascular
disease: an ecologic analysis in 30 counties in the United States. Arch Environ
Health 1994;49:418-427.
(19.) Tseng CH, Tai TY, Chong CK, et al. Long-term arsenic exposure and the
incidence of non-insulin-dependent diabetes mellitus: a cohort study in arseniasishyperendemic
villages in Taiwan. Environ Health Perspect 2000; 108:847-851.
(20.) Wu MM, Kuo TL, Hwang YH, Chen CJ. Dose-response relation between
arsenic concentration in well water and mortality from cancers and vascular
diseases. Am J Epidemiol 1989;130:1123-1132.
(21.) Chen CJ, Wang CJ. Ecological correlation between arsenic level in well water
and age-adjusted mortality from malignant neoplasms. Cancer Res 1990;50:5470-
5474.
(22.) Concha G, Vogler G, Lezcano D, et al. Exposure to inorganic arsenic
metabolites during early human development. Toxicol Sci 1998;44:185-190.
(23.) Concha G, Vogler G, Nennell B, Vahter M. Low-level arsenic excretion in breast
milk of native Andean women exposed to high levels of arsenic in the drinking water.
Int Arch Occup Environ Health 1998;71:42-46.
(24.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000
Toxicological Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human
Services, Public Health Service; 2000:18.
(25.) Vahter M, Friberg L, Rahnster B, et al. Airborne arsenic and urinary excretion of
metabolites of inorganic arsenic among smelter workers. Int Arch Occup Environ
Health 1986;57:79-91.
(26.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000
Toxicological Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human
Services, Public Health Service; 2000:134.
(27.) Gyurasics A, Varga F, Gregus Z. Effect of arsenicals on biliary excretion of
endogenous glutathione and xenobiotics with glutathione-dependent hepatobiliary
transport. Biochem Pharmacol 1991;41:937-944.
(28.) Aposhian HV, Zakharyan RA, Wildfang EK, et al. How is inorganic arsenic
detoxified? In: Chappell WR, Abernathy CO, Calderon RL, eds. Arsenic: Exposure
and Health Effects. New York, NY: Elsevier Science Ltd.; 1999:289-297.
(29.) Agency for Toxic Substances and Disease Registry (ATSDR). 2000
Toxicological Profile for Arsenic. Atlanta, GA: U.S. Department of Health and Human
Services, Public Health Service; 2000:140.
(30.) Vahter M, Marafante E. Effects of low dietary intake of methionine, choline or
proteins on the biotransformation of arsenite in the rabbit. Toxicol Lett 1987;37:41-46.
(31.) Goering PL, Aposhian HV Mass MJ, et al. The enigma of arsenic
carcinogenesis: role of metabolism. Toxicol Sci 1999;49:5-14.
(32.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 2001:81.
(33.) Ercal N, Gurer-Orhan H, Aykin-Burns N. Toxic metals and oxidative stress part
I: mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem
2001;1:529 539.
(34.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 1999:229.
(35.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 1999:238.
(36.) Hopenhayn-Rich C, Biggs ML, Kalman DA, et al. Arsenic methylation patterns
before and after changing from high to low concentrations of arsenic in drinking
water. Environ Health Perspect 1996; 104:1200-1207.
(37.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 1999:240.
(38.) Levander OA. Metabolic interrelationships between arsenic and selenium.
Environ Health Perspect 1977;19:159-164.
(39.) Kenyon EM, Hughes ME Levander OA. Influence of dietary selenium on the
disposition of arsenate in the female B6C3F1 mouse. J Toxicol Environ Health
1997;51:279-299.
(40.) Zakharyan RA, Aposhian HV. Arsenite methylation by methylvitamin B 12 and
glutathione does not require an enzyme. Toxicol Appl Pharmacol 1999;154:287-291.
(41.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 2001:91.
(42.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 2001 : 108-109.
(43.) Matsui M, Nishigori C, Toyokuni S, et al. The role of oxidative DNA damage in
human arsenic carcinogenesis: detection of 8-hydroxy-2′-deoxyguanosine in arsenicrelated
Bowen’s disease. J Invest Dermatol 1999;113:26-31.
(44.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 2001:75-202.
(45.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 2001:76-77.
(46.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 2001:207-208.
(47.) National Academy of Sciences. Arsenic in Drinking Water. Washington, DC:
National Academies Press; 2001:207-210.
(48.) Pi J, Yamauchi H, Kumagai Y, et al. Evidence for induction of oxidative stress
caused by chronic exposure of Chinese residents to arsenic contained in drinking
water. Environ Health Perspect 2002;110:331-336.
(49.) Wu MM, Chiou HY, Want TW, et al. Association of blood arsenic levels with
increased reactive oxidants and decreased antioxidant capacity in a human
population of northeastern Taiwan. Environ Health Perspect 2001:109:1011-1017.
(50.) Hsueh YM, Wu WL, Huang YL, et al. Low serum carotene level and increased
risk of ischemic heart disease related to long-term arsenic exposure. Atheroselerosis
1998; 141:249-257.
(51.) Personal communication. Walter Crinnion, ND.
(52.) Aposhian HV. Maiorino RM, Gonzalez-Ramirez D, et al. Mobilization of heavy
metals by newer, therapeutically useful chelating agents. Toxicology 1995;97:23-38.
(53.) Flora SJ. Arsenic-induced oxidative stress and its reversibility following
combined administration of N-acetylcysteine and meso 2,3-dimercaptosuccinic acid
in rats. Clin Exp Pharmacol Physiol 1999;26:865-869.
(54.) Tseng CH, Chong CK, Chen CJ, Tai TY. Lipid profile and peripheral vascular
disease in arseniasis-hyperendemic villages in Taiwan. Angiology 1997;48:321-335.
(55.) Chaudhuri AN, Basu S, Chattopadhyay S, Das Gupta S. Effect of high arsenic
content in drinking water on rat brain. Indian J Biochem Biophys 1999;36:51-54.
(56.) Chattopadhyay S, Bhaumik S. Purkayastha M, et al. Apoptosis and necrosis in
developing brain cells due to arsenic toxicity and protection with antioxidants. Toxicol
Lett 2002:136:65-76.
(57.) Jarup L, Bergluud M, Elinder CG, et al. Health effects of cadmium exposure–a
review of the literature and a risk estimate. Scand J Work Environ Health 1998;24:1-
51.
(58.) Agency for Toxic Substances and Disease Registry (ATSDR). 1999
Toxicological Profile for Cadmium. Atlanta, GA: U.S. Department of Health and
Human Services, Public Health Service; 1999:242.
(59.) Wittman R, Hu H. Cadmium exposure and nephropathy in a 28-year-old female
metals worker. Environ Health Perspect 2002;110:1261-1266.
(60.) Agency for Toxic Substances and Disease Registry (ATSDR). 1999
Toxicological Profile for Cadmium. Atlanta, GA: U.S. Department of Health and
Human Services, Public Health Service; 1999:258.
(61.) Agency for Toxic Substances and Disease Registry (ATSDR). 1999
Toxicological Profile for Cadmium. Atlanta, GA: U.S. Department of Health and
Human Services, Public Health Service; 1999:249.
(62.) Imported cadmium-contaminated zinc sulfate used in fertilizer and other
products. Washington State Department of Ecology. July 2000. Document 00-04-
025.
(63). Final Report. Screening survey for metals and dioxins in fertilizer products and
soils in Washington state. Washington State Department of Ecology. April 1999.
Publication No. 99-309.
(64.) Agency for Toxic Substances and Disease Registry (ATSDR). 1999
Toxicological Profile for Cadmium. Atlanta, GA: U.S. Department of Health and
Human Services, Public Health Service; 1999:259.
(65.) Agency for Toxic Substances and Disease Registry (ATSDR). 1999
Toxicological Profile for Cadmium. Atlanta, GA: U.S. Department of Health and
Human Services, Public Health Service; 1999:166.
(66.) Fox S. Nutritional factors that may influence bioavailability of cadmium. J
Environ Qual 1988;17:175-180.
(67.) Nordberg GE Kjellstrom T, Norberg M. Kinetics mad metabolism. In: Friberg L,
Elinder CG, Kjellstrom T, et al, eds. Cadmium and Health: A Toxicological and
Epidemiological Appraisal, Vol 1: Exposure Dose and Metabolism. Boca Raton: CRC
Press; 1985: 103-178.
(68.) Berglund M, Akesson A, Nermell B, Vahter M. Intestinal absorption of dietary
cadmium in women depends on body iron stores and fiber intake. Environ Health
Perspect 1994; 102:1058-1066.
(69.) Ramakrishnan U, Frith-Terhune A, Cogswell M, Kettle Khan L, Dietary intake
does not account for differences in low iron stores among Mexican American and
non-Hispanic white women: Third National Health and Nutrition Examination Survey,
1988-1994. J Nutr 2002;132:996-1001.
(70.) Klaassen CD, Liu J, Choudhuri S. Metallothionein: an intracellular protein to
protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 1999;39:267-294.
(71.) Pope A, Rail DE Environmental Medicine. Integrating a Missing Element into
Medical Education. Washington, DC: National Academy Press; 1995:230-231.
(72.) Fowler BA. General subcellular effects of lead, mercury, cadmium, and arsenic.
Environ Health Perspect 1978;22:37-41.
(73.) Casalino E, Calzaretti G, Sblano C, Landriscina C. Molecular inhibitory
mechanisms of antioxidant enzymes in rat liver and kidney by cadmium. Toxicology
2002;179:37-50.
(74.) Wasowicz W, Gromadzinska J, Rydzynski K. Blood concentration of essential
trace elements and heavy metals in workers exposed to lead and cadmium, Int J
Occup Med Environ Health 2001;14:223-229.
(75.) Dong W, Simeonova PR Gallucci R, et al. Toxic metals stimulate inflammatory
cytokines in hepatocytes through oxidative stress mechanisms. Toxicol Appl
Pharmacol 1998; 151:359-366.
(76.) Liu J, Liu Y, Michalska AE, et al. Metallothionein plays less of a protective role
in cadmium-metallothionein-induced nephrotoxicity than in cadmium chloride-induced
hepatotoxicity. J Pharmacol Exp Ther 1996;276:1216-1223.
(77.) Klaassen CD, Cagen SZ. Metallothionein as a trap for reactive organic
intermediates. Adv Exp Med Biol 1981;136:633-646.
(78.) Thornalley PJ, Vasak M. Possible role for metallothionein in protection against
radiation-induced oxidative stress. Kinetics and mechanism of its reaction with
superoxide and hydroxyl radicals. Biochim Biophys Acta 1985;827:36-44.
(79.) Elinder CG, Lind B, Kjellstrom T, et al. Cadmium in kidney cortex, liver, and
pancreas from Swedish autopsies. Estimation of biological half time in kidney cortex,
considering calorie intake and smoking habits. Arch Environ Health 1976;31:292-302.
(80.) Elinder CG, Kjellstrom T, Lind B, et al. Cadmium exposure from smoking
cigarettes: variations with time and country where purchased. Environ Res
1983;32:220-227.
(81.) Buchet JR Lauwerys R, Roels H, et al. Renal effects of cadmium body burden
of the general population. Lancet 1990;336:699-702.
(82.) Ericson JE. Smith DR, Flegal AR. Skeletal concentrations of lead, cadmium,
zinc, and silver in ancient North American Pecos Indians. Environ Health Perspect
1991;93:217-223.
(83.) Noda M, Kitagawa M. A quantitative study of iliac bone histopathology on 62
cases with itai-itai disease. Calcif Tissue Int 1990;47:66-74.
(84.) Staessen J, Bernard A, Buchet JE et al. Effects of cadmium exposure on the
cardiovascular system and on calcium metabolism: results of a cross-sectional
population study. IARC Sci Publ 1992;118:263-269.
(85.) Alfven T, Jarup L, Elinder CG. Cadmium and lead in blood in relation to low
bone mineral density and tubular proteinuria. Environ Health Perspect 2002;110:699-
702.
(86.) Nogawa K, Tsuritani I, Kido T, et al. Mechanism for bone disease found in
inhabitants environmentally exposed to cadmium:decreased serum 1 alpha, 25-
dihydroxyvitamin D level, Int Arch Occup Environ Health 1987;59:21-30.
(87.) Sorahan T, Lancashire RJ. Lung cancer mortality in a cohort of workers
employed at a cadmium recovery plant in the United States: an analysis with detailed
job histories. Occup Environ Med 1997;54:194-201.
(88.) Mandel IS, McLanghlin JK, Schlehofer B, et al. International renal-cell cancer
study. IV: Occupation. Int J Cancer 1995;61:601-605.
(89.) Goyer RA, Cherian MG. Role of metallothionein in human placenta and rats
exposed to cadmium. In: Nordberg GE, Herber RF, Alessio L, eds. Cadmium in the
Human Environment: Toxicity and Carcinogenicity. Lyon, France: IARC; 1992:199-
210.
(90.) World Health Organization (WHO). Cadmium. Environmental Health Criteria.
Geneva, France: WHO; 1992:134:351.
(91.) Tabacova S, Little RE, Balabaeva L, et al. Complications of pregnancy in
relation to maternal lipid peroxides, glutathione, and exposure to metals. Reprod
Toxicol 1994;8:217-224.
(92.) Nishijo M, Nakagawa H, Morikawa Y, et al. Mortality of inhabitants in an area
polluted by cadmium: 15 year follow up. Occup Environ Med 1995;52:181-184.
(93.) Staessen JA, Buchet JR Ginucchio G, et al. Public health implications of
environmental exposure to cadmium and lead: an overview of epidemiological
studies in Belgium. Working Groups. J Cardiovasc Risk 1996;3:26-41.
(94.) Coyle R Philcox JC, Carey LC, Role AM. Metallothionein: the multipurpose
protein. Cell Mol Life Sci 2002;59:627-647.
(95.) Leber AR Miya TS. A mechanism for cadmium-and zinc-induced tolerance to
cadmium toxicity: involvement of metallothionein. Toxicol Appl Pharmacol
1976;37:403-414.
(96.) Shimoda R, Nagamine T, Takagi H, et al. Induction of apoptosis in cells by
cadmium: quantitative negative correlation between basal or induced metallothionein
concentration and apoptotic rate. Toxicol Sci 2001;64:208-215.
(97.) Onosaka S, Tetsuchikawahara N, Min KS. Paradigm shift in zinc: metal
pathology. Tohoku J Exp Med 2002; 196:1-7.
(98.) Brewer GJ. Recognition, diagnosis, and management of Wilson’s disease. Proc
Soc Exp Biol Med 2000;223:39-46.
(99.) Liu YR Liu J, Palmiter RD, Klaassen CD. Metallothionein-I-transgenic mice are
not protected from acute cadmium-metallothione-induced nephrotoxicity. Toxicol Appl
Pharmacol 1996;137:307-315.
(100.) Liu X, Jin T, Nordberg GF, et al. Influence of zinc and copper administration on
metal disposition in rats with cadmium-metallothioncin-induced nephrotoxicity.
Toxicol Appl Pharmacol 1994;126:84 90.
(101.) Muller L, Menzel H. Studies on the efficacy of lipoate and dihydrolipoate in the
alteration of cadmium2+ toxicity in isolated hepatocytes. Biochim Biophys Acta
1990;1052:386 391.
(102.) Sumathi R, Baskaran G, Varalakhsmi R Relationship between glutathione and
DL alphalipoic acid against cadmium-induced hepatoloxicity. Jap J Med Sci Biol
1996;49:39-48.
(103.) Badgchi D, Vuchetich PJ, Bagchi M, et al. Induction of oxidative stress by
chronic administration of sodium dichromate [chromium VI] and cadmium chloride
[cadmium II] to rats. Free Radic Biol Med 1997;22:471-478.
(104.) Shaikh ZA, Vu TT, Zaman K. Oxidative stress as a mechanism of chronic
cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants.
Toxicol Appl Pharmacol 1999;154:256-263.
(105.) Nehru LB, Bansal MR Effect of selenium supplementation on the glutathione
redox system in the kidney of mice after chronic cadmium exposures. J Appl Toxicol
1997;17:81-84.
(106.) Sidhu M, Sharma M, Bhatia M, et al. Effect of chronic cadmium exposure on
glutathione S-transferase and glutathione peroxidase activities in rhesus monkey: the
role of selenium. Toxicology 1993;83:203-213.
(107.) No authors listed. Factors influencing metabolism and toxicity of metals: a
consensus report. Environ Health Perspect 1978;25:3-41.
(108.) Andersen O, Nielsen JB. Effects of simultaneous low-level dietary
supplementation with inorganic and organic selenium on whole-body, blood and
organ levels of toxic metals in mice. Environ Health Perspect 1994;102:321-324.
(109.) Yiin SJ, Chem CL, Sheu JY, Lin TH. Cadmium-induced liver, heart, and spleen
lipid peroxidation in rats and protection by selenium. Biol Trace Elem Res
2000:78:219-230.
(110.) Rana SV, Verma S. Protective effects of GSH, vitamin E, and selenium on lipid
peroxidation in cadmium-fed rats. Biol Trace Elem Res 1996;51:161-168.
(111.) Sugawara N, Sugawara C. Selenium protection against testicular lipid
peroxidation from cadmium. J Appl Biochem 1984;6:199-204.
(112.) Telisman S, Cvitkovic R Jurasovic J, et al. Semen quality and reproductive
endocrine function in relation to biomarkers of lead, cadmium, zinc, and copper in
men. Environ Health Perspect 2000;108:45-53.
(113.) Kleijnen J, Knipschild R Gingko biloba. Lancet 1992;340:1136-1139.
(114.) Liu J, Liu Y, Mao Q, Klaassen CD. The effects of 10 triterpenoid compounds
on experimental liver injury in mice. Fundam Appl Toxicol 1994;22:34-40.
(115.) Mahato SB, Nandy AK, Roy G. Triterpenoids. Phytochemistry 1992;31:2199-
2249.
(116.) Yasukawa K, Takido M, Matsumoto T, et al. Sterol and triterpene derivatives
from plants inhibit the effects of a tumor promoter, and sitosterol and betulinic acid
inhibit tumor formation in mouse skin two-stage carcinogenesis. Oncology
1991;48:72-76.
(117.) Pisha E, Chai H, Lee IS, et al. Discovery of betulinic acid as a selective
inhibitor of human melanoma that functions by induction of apoptosis. Nat Med
1995;1:1046-1051.
(118.) Liu Y, Kreppel H, Liu J, et al. Oleanolic acid protects against cadmium
hepatotoxicity by inducing metallothionein. J Pharmacol Exp Ther 1993;266:400-406.
(119.) Miura N, Matsumoto Y, Miyairi S, et al. Protective effects of triterpene
compounds against the cytotoxicity of cadmium in HepG2 cells. Mol Pharmacol
1999;56:1324-1328.
(120.) Kiso Y, Tohkin M, Hikino H, et al. Mechanism of antihepatotoxic activity of
glycyrrhizin. I: Effect on free radical generation and lipid peroxidation. Planta Med
1984:50:298-302.
(121.) Nomiyama K, Nomiyama H. Cadmium-induced renal dysfunction was
improved by treating hepatic injury with glycyrrhizin. J Trace Elem Exp Med
1993;6:171-178.
(122.) Deters M, Siegers CR Strubelt O. Influence of glycine on the damage induced
in isolated perfused rat liver by five hepatotoxic agents. Toxicology 1998;128:63-72.
(123.) Karbownik M, Gitto E, Lewinski A, Reiter RJ. Induction of lipid peroxidation in
hamster organs by the carcinogen cadmium: melioration by melatonin. Cell Biol
Toxicol 2001;17:33-40.
(124.) Aposhian HV, Maiorino RM, Rivera M, et al. Human studies with the chelating
agents, DMPS and DMSA. J Toxicol Clin Toxicol 1992;30:505-528.
(125.) Tandon SK, Singh S, Prasad S. Influence of methionine administration during
chelation of cadmium by CaNa3DTPA and DMPS in the rat. Environ Toxicol
Pharmacol 1997;3:159-165.
(126.) Tandon SK, Singh S, Flora SJ. Influence of methionme and zinc
supplementation during chelation of lead in rats. J Trace Elem Electrolytes Health Dis
1994;8:75-77.
(127.) Tandon SK, Prasad S, Singh S. Chelation in metal intoxication: influence of
cysteine or N-acetyl cysteine on the efficacy of 2,3-dimercaptopropane-1-sulphonate
in the treatment of cadmium toxicity. J Appl Toxicol 2002;22:67-71.
(128.) Flora SJ, Gubrelay U, Kannan GM, Mathur R. Effects of zinc supplementation
during chelating agent administration in cadmium intoxication in rats. J Appl Toxicol
1998;18:357-362.

Lyn Patrick, ND–1984 graduate, Bastyr University; associate editor, Alternative
Medicine Review; private practice, Tucson, Arizona, 1984-2002.

Correspondence address: 21415 Hwy 140, Hesperus, CO 81326

Email: lpatrick@frontier.net

Taken from www.findarticles.com

This is probably the most commonly asked question we receive from many people.

It is actually quite easy to answer these days, because there has been a lot of research into the subject of toxins and their effect on our health over the past few years.

When we began distributing HMD™ almost ten years ago, we also sold a kit for testing for some of the most common heavy metal toxins, including mercury and lead. We asked for feedback from customers and were surprised when reports began coming in showing that all tested positive for these toxic metals. We were suspicious of the kits and began researching.

We came across an article by the World Wildlife Fund – WWF – who published a report on chemicals found in the placenta of newborn babies. Well over 200 toxins were found in all samples, and many were known to be cancer causing chemicals. Further research showed that these tests had been done in places as remote as Iceland, the Arctic Circle amongst the Inuit population and in the South Atlantic.

It was hoped to find a population unaffected by the toxins found in the developed industrial world. Alas, no population could be found that was free from toxins! Not even on the islands in the middle of the Indian Ocean! We stopped selling these kits, and can now safely say with a high degree of scientific validity that we are all toxic and did not need to waste money on these kits to answer a question for which we knew the answer.

If newly born infant have nearly 300 toxins in their circulation the minute they see the world – all from the mother – then how many would an adult have who has been living on this toxic planet for a number of years? It is safe to now say that there is not a human being on this planet that does not have an element of toxins in their bodies, some more, some less.

At the same time, we found a laboratory that carried out forensic testing of hair samples – Tissue Hair Mineral Analysis (THMA). This is a highly scientific testing procedure using sophisticated machines such as Inductively Coupled Spectrometers. It is a more expensive procedure which requires two hair samples to be analysed over a period of 2 months. The first sample is submitted before beginning the detox to provide a base line sample. The second hair sample is taken two months later to determine if there are toxic metals stored in the organs and tissues of the body. A percentage increase in the second hair test compared to the first is an indication that there are metals stored in the organs, so detoxification should be continued for another two months, then a further hair test taken.

Click here to read a more scientific article about this method – http://www.detoxmetals.com/use-hair-tests-clinical-decision-making/

Research into the toxins carried in our bodies has been verified by reports from the US Centre for Disease Control (CDC). The toxins come primarily as a bi-product of the a petro-chemical industry, worth billions, so don’t expect anything much by way of changes from what quarter. We need to take action ourselves.

More recent research has been carried out by the Environmental Working Group which confirms that we are all toxic from many sources, including fish, plastics, amalgam tooth fillings, vaccines etc. More about these later.

Knowing without doubt that YES, WE ARE ALL TOXIC from the day we are born, and are exposed more every day, we can keep ahead by detoxing to eliminate toxic metals using our scientifically proven method; HMD. Why risk the carcinogenic effects of toxic metals?

Dr. Graham Hutt, Phd. Medical anthropologist and researcher. For the HMD team.

See also:

https://static.ewg.org/reports/2016/mercury-in-seafood/EWG

http://www.cdc.gov/exposurereport/pdf/fourthreport.pdf