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73
Cadmium andPoisoning
Cadmium is considered a highly toxic heavy metal, with a half-life in humans rang-
ing from 10 to 33years. Poisoning from this metal can occur acutely or chronically
through inhalation or the consumption of contaminated water and/or food [8, 9].
Inhalatory exposure to Cd generally occurs at the occupational level and in prox-
imity to industrial or mining areas through dust or vapors generated by mining pro-
cesses. Another signicant source associated with this exposure route is tobacco
consumption, with cadmium concentrations ranging between 1 and 2μg [9].
Regarding food, high concentrations of cadmium have been detected in crusta-
ceans, bivalve mollusks, oysters, cephalopods, and crabs, as well as in offal prod-
ucts such as liver and kidney, oilseeds, cocoa beans, and certain wild mushrooms.
Plant-derived foods, depending on soil contamination levels, generally contain
higher concentrations of Cd than meat, eggs, milk, and dairy products. Among
these, rice and wheat, leafy green vegetables, potatoes, carrots, and celery can con-
tain higher concentrations of the metal compared to other plant-based foods.
Seafood consumers and vegetarians may be exposed to higher cadmium intake than
omnivores, with rice consumption being one of the main routes of cadmium expo-
sure [8, 9, 11, 14].
A historical event related to the consumption of cadmium-contaminated rice
occurred in Toyama Prefecture, Japan, where the metal was released from a zinc
mine into the Jinzu River, whose waters were used for crop irrigation. Cadmium
intoxication resulted in a disease known as Itai-Itai, characterized by severe pain in
individuals with spinal and joint lesions [15]. Itai-Itai patients exhibited a wide
range of symptoms, such as low bone mineralization, severe skeletal decalcica-
tion, a high fracture rate, and distortion of long bones, osteomalacia, intense bone
pain, and osteoporosis. Other complications included cough, anemia, and kidney
failure [9].
Clinical Manifestations ofCadmium Poisoning
Cadmium toxicity depends on the route, quantity, and rate of exposure. Consequently,
poisoning can be acute or chronic, depending on the exposure pathway (Table6.1).
In the case of chronic exposure (low to moderate doses), the following manifesta-
tions may occur:
(a) Renal: Characterized by proximal tubulopathy with initially low molecular
weight proteinuria, progressing to high molecular weight proteinuria. These
events are accompanied by glucosuria, aminoaciduria, phosphaturia, and calci-
uria. This can affect calcium metabolism, cause calciuria, and inhibit the
hydroxylation of vitamin D.
(b) Pulmonary: Obstructive and restrictive syndromes, progressive pulmonary
emphysema, and even pulmonary brosis.
6 Heavy Metal Poisoning andIts Relationship withAllergies
74
Table 6.1 Acute and chronic clinical manifestations of cadmium, mercury, and nickel poisoning
Toxic
metal Acute clinical manifestations Chronic clinical manifestations
Cadmium Respiratory distress, nausea, vomiting,
abdominal pain
Kidney damage, bone fragility,
respiratory issues
Mercury Tremors, insomnia, memory loss,
neuromuscular changes
Cognitive impairment, motor
dysfunction, kidney damage
Nickel Dermatitis, nausea, vomiting, abdominal
cramps
Respiratory issues, skin allergies, lung
brosis
(c) Skeletal: Renal damage with hypercalciuria leading to osteomalacia, which
presents as symmetrical bone ssures, particularly appearing in the femoral
neck. This condition affects postmenopausal women, causing severe pain in the
pelvis and lower limbs (Itai-Itai disease).
(d) Cardiovascular: Alterations in the arterial wall and hypertension (occupational
exposure).
(e) Hematological: Anemia (iron transport), leukocytosis, and lymphocytosis.
(f) Other: Anosmia, weight loss, fatigue, yellow discoloration of teeth, increased dental
caries, and microcytic-hypochromic anemia unresponsive to treatment [9, 11].
Diagnosis ofCadmium Poisoning
The diagnosis is based on the history of exposure and the presence of respiratory com-
plaints (inhalation) or gastroenteritis (acute ingestion) [11]. Cadmium levels in whole
blood can conrm recent exposure; normal levels in non-exposed non- smokers are
below 1mcg/L.Very little cadmium is excreted in the urine until it exceeds the binding
capacity of the kidneys or causes renal damage. Urinary cadmium values are typically
below 1mcg/g creatinine. Measurements of tubular microproteinuria (beta2-microglob-
ulin, retinol-binding protein, albumin, and metallothionein) are used to monitor the early
and toxic effects of cadmium on the kidneys. Other useful laboratory studies include
complete blood count, electrolytes, glucose, blood urea nitrogen, creatinine, arterial
blood gases or oximetry, and chest X-ray [16].
Treatment ofCadmium Poisoning
Emergency andSupport Measures [16]
– Inhalation: Monitor arterial gases and perform a chest X-ray. It is recommended
to observe the patient for at least 6–8h. In case of wheezing and pulmonary
edema, treat the patient with conventional procedures. After signicant expo-
sure, it is suggested to observe the patient for 1–2days to rule out late-onset
non-cardiogenic pulmonary edema.
– Ingestion: Treat uid loss caused by gastroenteritis with IV crystalloid uids.
J. Márquez-Lázaro and Y. E. Navarro
75
Specic Drugs andAntidotes [9, 16]
Acute cadmium poisoning from overexposure is generally treated with chelating
agents; however, there is insufcient evidence that this therapy is effective. The
chelating agents used include EDTA (ethylenediaminetetraacetic acid), BAL
(British Anti-Lewisite, dimercaprol), DMSA (2,3-dimercaptosuccinic acid), and
DMPS (2,3-dimercapto-1-propanesulfonic acid). Unlike DMSA, DMPS is trans-
ported to the intracellular space where it functions as a chelator. DMSA analogs,
such as MmDMSA (monomethyl DMSA), MiADMSA (monoisooctyl DMSA), and
MchDMSA (monocyclohexyl DMSA), are more effective and safer antidotes for
heavy metal poisoning compared to DMSA.BAL, D-penicillamine (DPCN), and
EDTA are contraindicated due to the higher risk of renal damage. On the other hand,
biologically active natural compounds such as polyphenolic substances, melatonin,
carotenoids, quercetin, resveratrol, vitamin E, vitamin C, L-carnitine, and coen-
zyme Q10 may be useful in preventing adverse health effects resulting from heavy
metal exposure, including cadmium.
Decontamination [16]
1. Inhalation: Remove the victim from exposure and administer supplemental oxy-
gen if available.
2. Ingestion: Perform gastric lavage after signicant ingestion.
3. Skin and Eyes: Remove contaminated clothing and wash exposed skin with
water. Irrigate exposed eyes with plenty of warm water or saline solution.
Cadmium andAllergies
Air pollution plays an important role in the exposure to environmental contaminants
from anthropogenic activities, as it contains particulate matter, which serves as a
transport vehicle for these contaminants. In this context, cadmium, like other heavy
metals, spreads from mining and industrial areas to areas with less inuence. Once
in contact with people, the particulate matter easily penetrates the respiratory sys-
tem and deposits in the lungs and bronchi, where the contaminants eventually inter-
act with the immune system, promoting various responses [17]. This effect can also
occur through the consumption of contaminated food and water. Under this context,
cadmium and the development of allergies have become a topic of interest to the
scientic community.
The exact mechanism of cadmium-induced immune response in humans is still
in its early stages; however, invitro and invivo studies have shown that this metal
can directly interact with immune system cells, causing alterations in their state and
functionality [18].
6 Heavy Metal Poisoning andIts Relationship withAllergies
76
Clinical Manifestations ofCadmium-Induced Allergy
Exposure to environments with high levels of cadmium can promote cough, asthma,
rhinitis, wheezing, and atopic dermatitis [19, 20]. Prenatal and postnatal exposure to
cadmium has become a marker for detecting allergies and associated diseases in
children. Thus, environments with high levels of cadmium have been associated
with a higher risk of rhinitis in children [7]. During the early and late weeks of ges-
tation, the presence of cadmium has been linked to a higher incidence of pediatric
asthma and the presence of atopic dermatitis in six-month-old infants [5, 6, 21, 22].
Additionally, elevated cadmium levels in people living near mining and smelting
areas have been negatively associated with low levels of CD14+ monocytes, which
can increase the risk of sepsis-related mortality by affecting the function of immune
cells [17, 18].
Diagnosis andTreatment ofCadmium-Induced Allergy
Currently, there is no specic diagnosis and treatment for allergic processes medi-
ated by cadmium exposure. However, the available evidence is associated with the
metal levels in the blood and the presented allergic symptoms [5–7, 17–22]. To miti-
gate the effects of cadmium, it is suggested to implement strategies that reduce the
environmental levels of this metal.
Mercury
Mercury (Hg) is a highly toxic heavy metal found in nature in elemental (Hg
0
),
inorganic (Hg
+
, Hg
+2
), and organic (methyl and ethyl mercury) forms. Elemental
mercury is liquid at room temperature and can easily evaporate to produce vapor.
Mercury vapor is more dangerous than the liquid form. Organic mercury com-
pounds, such as methyl and ethyl mercury (Me-Hg and Et-Hg, respectively), are
more toxic than inorganic compounds. Me-Hg is known as a neurotoxin, as it pri-
marily affects the brain [23]. The increasing toxicity order of these forms is dened
as Hg0<Hg2+, Hg+<CH3-Hg [4, 24].
Mercury compounds have many applications in mining, for example, gold
extraction, and some industrial processes. In lamp manufacturing plants, Hg is used
in the production of uorescent bulbs, and in dentistry, it has been used for the
preparation of dental amalgams. Me-Hg and Et-Hg have been used as fungicides,
and currently, thimerosal, another organic compound, is used as a preservative in
multi-dose vaccine vials [25, 26].
J. Márquez-Lázaro and Y. E. Navarro
77
Due to its biogeochemical cycle, mercury can interconvert into its three
forms. Hg
0
present in the atmosphere settles in water, where microorganisms
transform it into Me-Hg, which is ingested by smaller creatures and eventually
consumed by larger sh. Fish at the top of the food chain, such as tuna, sword-
sh, or shark, tend to concentrate a considerable amount of this compound in
their tissues [23, 27].
Under this context, people can be exposed to mercury through the inhalation of
Hg
0
vapors from dental amalgams, mining, and accidental spills (thermometers,
barometers, thermostats) and by ingesting seafood and sh (freshwater and saltwa-
ter) that bioaccumulate Me-Hg [25].
Toxicokinetics ofMercury
Hg
0
vapor is easily absorbed from the lungs (80%) and distributed throughout the body.
Hg
0
can cross the blood-brain barrier and the placenta, making its neurotoxicity higher
than that of inorganic Hg, which crosses membranes at a slower rate. Hg
0
is oxidized in
the body to produce Hg
2+
. Liquid Hg
0
is slightly absorbed in the gastrointestinal tract
and does not appear to be toxic. Inorganic Hg concentrates in the kidneys, where it is
reabsorbed from the proximal tubules as Cys-S-Hg-S-Cys or in the basolateral mem-
brane by organic anion transporters. Inorganic Hg cannot cross the blood-brain barrier
or the placenta. Organic Hg is easily absorbed in the gastrointestinal tract (95%) and
distributed throughout the body. Me-Hg binds to thiol- containing molecules (Me-Hg-
Cys) to cross the blood-brain barrier. Mercury is excreted and accumulates in hair as
Me-Hg, which is why this matrix is considered an index of exposure to the metal. Other
forms of excretion are feces and urine [4, 28, 29].
Deposition andEffects ofMercury
In addition to the brain, mercury deposits in the thyroid, breasts, myocardium, mus-
cles, adrenal, sweat, and salivary glands, liver, kidneys, skin, pancreas, enterocytes,
lungs, testicles, and prostate. Mercury also has an afnity for binding sites on the
surface of T cells and for sulfhydryl groups that inuence T cell function.
Specically, Me-Hg easily deposits in the brain, liver, kidneys, placenta, and fetus,
especially in the fetal brain, as well as in peripheral nerves and bone marrow. In the
brain, Me-Hg demethylates to inorganic mercury and forms insoluble complexes
with selenium that persist for years [4, 28, 29]. Additionally, mercury exposure can
affect the immune system, causing allergies [30, 31].
6 Heavy Metal Poisoning andIts Relationship withAllergies
78
Mercury andPoisoning
Two signicant events in history have highlighted the dangers of mercury poison-
ing. The rst occurred in Minamata, Japan, in the late 1950s, where an acetaldehyde
factory contaminated Minamata Bay by releasing mercury-laden waste into
Hyakken Port. In the water, Hg was transformed into Me-Hg and subsequently bio-
accumulated by sh, which were the main food source for the local population. As
a result, cats that ate the sh began to stagger and die. Subsequently, the local popu-
lation was affected, particularly fetuses and developing children, with over two
thousand people dying from this disaster and thousands more suffering irreversible
damage. The second event occurred in Iraq in the 1970s when people consumed
seed grains treated with a mercury-based fungicide [32, 33].
The damage caused by mercury exposure is known as Minamata disease, charac-
terized by signicant pathological changes in the central nervous system. Although
mercury levels in the liver and kidneys are higher than in the central nervous system,
the pathological changes are not as pronounced [28, 34]. Patients exhibit lesions in
the cerebellar cortex, calcarine cortex, precentral gyrus, postcentral gyrus, and
transverse temporal gyrus. Histopathologically, the brain shows a characteristic loss
of neurons with gliosis in cortical layers II and III, regardless of severity.
Characteristic cerebellar changes include the loss of granular cells and relatively
well-preserved Purkinje cells [28, 35].
Mercury poisoning, like cadmium, can be acute or chronic, and its clinical mani-
festations will depend on the chemical form of the metal (see Table6.2).
Clinical Manifestations ofElemental Mercury
(Vapor) Poisoning
The primary target organ of mercury vapor is the brain; however, it is also associ-
ated with effects on peripheral nerves, renal function, immune function, endocrine
and muscle function, and various types of dermatitis [29, 36].
Acute exposure to a large amount of mercury vapor induced erosive bronchi-
tis, which can lead to respiratory failure. This is accompanied by central ner-
vous system effects such as tremors or emotional changes (mood swings,
irritability, nervousness, excessive shyness). In the case of chronic exposure, the
symptoms are more subtle and non-specic: weakness, fatigue, anorexia, weight
loss, and gastrointestinal discomfort. At higher exposures, ne tremors punctu-
ated by a coarse tremor (myoclonus) occur; emotional changes, gingivitis, and
excessive salivation, spasmodic postural tremors, psychotic behaviors, as well
as immune dysfunction have also been described. These symptoms may regress
with the cessation of exposure, but in many cases, they do not. Persistent neuro-
logical symptoms are common [29, 36].
J. Márquez-Lázaro and Y. E. Navarro
79
Table 6.2 Type of poisoning and clinical outcomes
Type of
poisoning Metal/route Inhalation Oral Dermal/ocular Treatment
Acute
Cadmium It can cause cough,
dyspnea, headache, fever,
and, if severe, chemical
pneumonitis and non-
cardiogenic pulmonary
edema within 12–36h after
exposure
Colicky pain, diarrhea, local
irritative processes (nausea,
vomiting sometimes bloody).
Within the rst hour after
consumption, metallic taste,
myalgias, headaches,
dysphagia, and salivation.
Acute kidney failure. Altered
liver function, metabolic
acidosis, and coagulopathy
It can cause local
irritation of the
skin or eyes.
Symptomatic. The effectiveness of chelators
such as EDTA, BAL, DPCN, DMPS, DMSA,
MmDMSA, MiADMSA, MchDMSA, and
DPCN is not fully proven
Mercury Mercury vapor induces
erosive bronchitis and
respiratory failure, tremors,
or emotional changes
Elemental liquid mercury has
not shown toxic effects.
Ingestion of inorganic salts
produces abdominal pain,
bloody vomiting, and
diarrhea with possible
necrosis of the intestinal
mucosa
Exposure to
inorganic mercury
salts: Skin rashes
and dermatitis
Evaluate cardiovascular, respiratory, and
airway status. Remove clothing if necessary.
In case of skin exposure, wash with water and
soap, and clean eyes with saline solution.
Symptomatic patients require immediate
treatment with chelating agents such as BAL,
DPCN, DMPS, and DMSA.Remove the
patient from the source of exposure
Nickel Asthma, bronchitis, rhinitis,
sinusitis, respiratory tract
and eye irritations,
headaches, and fatigue have
been reported
Nausea, vomiting, abdominal
pain, diarrhea, headache,
cough, shortness of breath,
and dizziness
Redness, skin
rashes, papules
The general condition of the patient should be
evaluated considering possible exposure
routes. A full physical examination,
especially of the respiratory tract and skin,
should be conducted management with
chelating agents such as DMPS and DMSA
and removal from exposure sources are
necessary
6 Heavy Metal Poisoning andIts Relationship withAllergies
80
Clinical Manifestations ofInorganic Mercury (Salts) Poisoning
Acute poisoning with mercury salts (HgCl
2
) generally affects the gastrointestinal
tract and kidneys. Extensive precipitation of enterocyte proteins occurs, with
abdominal pain, vomiting, and bloody diarrhea with possible necrosis of the intes-
tinal mucosa. This can lead to death from peritonitis or septic or hypovolemic shock.
Patients who survive usually develop renal tubular necrosis with anuria. Chronic
poisoning with mercury salts is rare and is generally associated with simultaneous
occupational exposure to mercury vapor [29, 36].
Renal toxicity involves renal tubular necrosis or autoimmune glomerulonephri-
tis, or both. Immune dysfunctions include hypersensitivity reactions to mercury
exposure, such as asthma and dermatitis, various types of autoimmunity, and sup-
pression of natural killer cells, as well as alteration of other lymphocyte subpopula-
tions. Brain dysfunction is less evident than with other forms of mercury. Thyroid
dysfunction appears to be associated with the inhibition of 5′ deiodinases, with a
decrease in free T
3
and an increase in reverse T
3
. Accumulation in the testes appears
to inhibit spermatogenesis [29, 36].
Clinical Manifestations ofOrganic Mercury Poisoning
Methylmercury (Me-Hg) and ethylmercury (Et-Hg) produce similar signs and
symptoms; however, most reports focus on Me-Hg. Symptoms are more related to
the magnitude of methylmercury retention than the rate of deposition. Acute expo-
sures tend to have a latency period of one or more weeks; once acquired, toxic doses
are eliminated slowly in some cases [29, 36].
Massive prenatal poisoning can induce a form of cerebral palsy. Lower pre-
natal doses have been associated with delays in neurological development and
cognitive decits. Postnatal exposures generate a variety of symptoms ranging
from paresthesias with minor exposures to ataxia, visual, auditory, and extrapy-
ramidal decits with moderate exposures, and clinic seizures in more severe
exposures [29, 36].
Diagnosis ofMercury Poisoning
Diagnosing mercury concentrations in individuals is challenging. Commonly used
modalities (levels in blood, urine, and/or hair) do not correlate with total body bur-
den and offer little useful diagnostic information [29, 36–38].
In total blood, Hg concentration can be less than 10μg/L, though 20μg/L or less
is considered normal. Blood Hg concentration can increase to 35μg/L after pro-
longed exposure. Meanwhile, a urine Hg concentration >100 μg/L can trigger
J. Márquez-Lázaro and Y. E. Navarro
81
neurological symptoms in the patient, while levels of 800μg/L can be fatal. Mercury
concentrations in hair indicate prolonged exposure to the metal, specically Me-Hg,
with permissible levels being less than 1mg/Kg [36].
Treatment ofMercury Poisoning
When mercury poisoning is suspected, an interview with the patient should be con-
ducted to determine the source of exposure (environmental, occupational), followed
by a physical examination. It is important to ascertain whether the exposure was
chronic or acute and to eliminate the source. Cardiovascular, respiratory, and airway
status should be evaluated. If necessary, clothing should be removed. In the case of
skin exposure, it should be washed with soap and water. If the eyes were exposed,
they should be rinsed with saline solution [36].
If a person has ingested or inhaled mercury, their respiratory status and oxygen
saturation should be carefully monitored. If the patient exhibits symptoms such as
difculty breathing, a chest X-ray and arterial blood gas analysis should be per-
formed, and preparations for intubation and articial ventilation should be made. If
intubation is necessary, removing liquid mercury through tracheal suction is useful
to eliminate contamination [29, 36].
In cases where inorganic mercury compounds, such as liquid elemental mercury
(Hg
0
), have been ingested and there is no vomiting or aspiration, it is necessary to
observe and monitor symptoms until the mercury is excreted from the body. At the
same time, a kidney, ureter, and bladder X-ray can be used to track the movement of
mercury through the gastrointestinal tract.
In the case of inorganic mercury compounds such as mercury chloride (HgCl
2
),
poisoning should be treated in the same manner as ingestion of corrosive substances
due to the risk of damaging and perforating the mucosa of the gastrointestinal tract.
In cases of acute gastrointestinal poisoning, symptomatic treatment is essential,
such as evaluation of the airways, breathing, and cardiovascular status. Extensive
intravenous therapy is necessary for a symptomatic patient. Additionally, the condi-
tion of the laryngopharynx and gastrointestinal tract should be assessed on an empty
stomach. If the examined areas are intact, gastric lavage with activated charcoal is
performed. Finally, blood dialysis is an essential intervention in the treatment of
renal failure caused by inorganic mercury poisoning.
Symptomatic patients with mercury poisoning require immediate treatment with
chelating agents. However, the use of this therapy should be evaluated according to
the patient’s condition. As with cadmium poisoning, BAL, DPCN, DMPS, and
DMSA are commonly used for acute Hg
0
poisoning. Among these chelators, BAL
is contraindicated as a treatment for organic mercury poisoning. DPCN increases
the excretion of lead and mercury (elemental and inorganic) through the urine. For
mercury poisoning, adults are treated with 250mg of DPCN orally four times a day
for 1 or 2weeks, while children receive 20–30mg/kg per day divided into four
doses (maximum 250mg/dose). Adverse effects of the agent include leukopenia,
6 Heavy Metal Poisoning andIts Relationship withAllergies
82
thrombocytopenia, aplastic anemia, proteinuria, hematuria, and nephrotic syn-
drome. DMSA has been frequently used to replace DPCN, given its great metal-
carrying capacity and fewer side effects. BAL is administered only by intramuscular
injection, which causes pain. This agent has a narrow therapeutic window and a risk
of allergic reaction. Recent substitutes for BAL include DMSA and DMPS.
DMSA has a half-life of about 3h, which is prolonged in children and people
poisoned by mercury. When administered orally, its absorption rate is around 20%.
This agent increases urinary excretion of methylmercury and inorganic mercury. In
animal tests, it has been reported to be effective in promoting the excretion of meth-
ylmercury from the brain, so it is widely used to treat severe cases of Me-Hg poison-
ing. DMSA can be taken orally to minimize its adverse effects; however, patients
may rarely experience mucocutaneous rash and toxic epidermal necrolysis, which
resolve once the drug administration is discontinued.
The absorption rate of DMPS is around 39% when taken orally, although due to
its stability, it is frequently administered intravenously. Like DMSA, DMPS induces
the excretion of Me-Hg and inorganic mercury in the urine; however, it is not effec-
tive for eliminating methylmercury through the kidneys to remove methylmercury
from the brain.
Mercury andAllergies
As previously described, mercury can be found in three forms in the environment:
elemental mercury (Hg°), inorganic mercury (Hg
+
and Hg
2+
), and organic mercury
(methyl, ethyl, and phenyl). This metal has been characterized for its use in health
and aesthetic purposes. Mercury is a metal known in the contexts of allergy, hyper-
sensitivity, and even autoimmunity. For sensitization to this metal to occur, there
must have been exposure to low concentrations of metal, which differ from intoxi-
cation because their levels in blood, urine, or hair are normal. Such exposures can
vary due to the forms of mercury, and thus, we commonly nd ethyl mercury in
dental amalgam used for restoration of dental pieces, in the thimerosal preservative
found in vaccines like inuenza, and in makeup; methylmercury in sh consump-
tion; elemental mercury in thermometers, barometers, and other electrical devices
we frequently use; and inorganic mercury, which is widely used in the cosmetology
area, soap and cream making. Therefore, it is very easy to be exposed to mercury
and develop sensitization processes.
When a person is already sensitized and comes into contact with the metal that trig-
gers a type IV hypersensitivity allergic reaction, it can be a delayed reaction; hence, it
may take days to develop and is not mediated by antibodies but by activated CD8 cells.
The metal in its elemental state does not produce a hypersensitive reaction; it must
undergo an ionization process that facilitates its contact with body uids, causing the
metal to bind to proteins. Subsequently, the immune system of sensitized people recog-
nizes these bonds as foreign bodies and reacts, causing chronic inammation that can be
associated with various chronic clinical manifestations.
J. Márquez-Lázaro and Y. E. Navarro