Nickel - Toxicology of Metals - page 730

reduces growth, especially intrauterine development,
and severely interferes with lipid metabolism in rats
(Stangl and Kirchgessner, 1996). But nickel's essential-
ity in humans has not been proven (National Research
Council, 1986). Because the basis for the essentiality
of nickel in humans has been diffi cult to defi ne, the
nutritional terminology “apparent benefi cial intake
(ABI)” has been deemed more appropriate for ele-
ments including nickel with benefi cial effects as nutri-
tional supplements on the basis of actions that can be
extrapolated from animals (Nielsen, 1996). In bacteria,
at least nine nickel-containing enzymes are known
to date: urease, NiFe-hydrogenase, carbon monoxide
dehydrogenase, acetyl-CoA decarboxylase/synthase,
methyl coenzyme M reductase, certain superoxide
dismutases, some glyoxalases, aci-reductone dioxyge-
nase, and methylenediurease (Kanai et al ., 2003; Lind-
hal, 2004; Mulrooney et al ., 2003). Nickel defi ciency
results in histological and biochemical changes in cells,
such as reduced iron resorption that leads to anemia
in animals. The essentiality of nickel may be related
to its ability to activate heme oxygenase (Sunderman
et al ., 1982) and its participation in the regulation of
intestinal iron absorption through a mechanism that
simulates hypoxic conditions in the tissues (Latunde-
Dada et al ., 2004). Nickel defi ciency also reduces activi-
ties of dehydrogenases and transaminases, including
α

on an empty stomach, which can be an important
consideration for nickel-sensitive individuals who
can also consume low-nickel diets (Veien et al ., 1993).
Nielsen et al . (1999) suggest that food constituents,
such as phosphate, phytate, fi bers, and other metal-
ion-binding components, may bind nickel and render
it less available for absorption than nickel dissolved
in water. It has been reported that approximately
20% of nickel from inhaled sources is absorbed
by the respiratory tract, with approximately 30%
inhaled nickel deposited in the lungs (Sunderman
et al ., 1988). Although nickel does not generally accu-
mulate in tissues because of effi cient excretion, with
high levels of nickel exposure, the kidney is the pri-
mary target organ for nickel retention, followed by
the lung, brain, and pancreas.

5.3 Transport
Until recently, nickel transport was primarily attrib-
uted to albumin and nickeloplasmin (reviewed in Sun-
derman et al ., 1977). Nickel transport into and within
cells has also been found to occur through transport-
ers that are primarily functional in iron homeostasis.
Transferrin, one of the major proteins involved in the
cellular uptake of iron, also binds nickel, vanadium,
and other metals (Boffi , 2003; Harris, 1986; Sun, 1999).
Another iron transport protein, divalent metal trans-
porter-1 (DMT1), transports nickel, manganese, cobalt,
copper, and zinc as well (Chen, et al ., 2005; Garrick,
2003). Thus, nickel can compete with iron for entry
into cells, and adequate iron intake can limit nickel
absorption as shown in a study of 63 Ni uptake into
fully differentiated Caco-2 cells (Tallkvist et al ., 2003).
In addition to competition for iron uptake, nickel can
also disrupt iron homeostasis by lowering cellular
iron levels, thereby increasing the binding of the iron
regulatory protein-1, IRP1, to its response element IRE,
which will increase transferrin receptor mRNA trans-
lation but block the translation of ferritin mRNA (Chen
et al ., 2005).

-amylase, thus affecting carbohydrate metabolism.
Rat-feeding deprivation studies suggest that nickel and
folate interact in metabolic processes, likely involv-
ing one-carbon metabolism and vitamin B 12 -depend-
ent pathways for methionine metabolism (Uthus and
Poellot, 1996; 1997). The daily nickel nutritional sup-
plementation of humans and animals is thought to be
less than 500 µ g/kg.

5.2 Absorption
Nickel absorption from food and water in humans
occurs through intestinal absorption (Nielsen et al .,
1999). Although in animal studies approximately
90% of ingested nickel was found excreted in the
feces and only 10% or less was absorbed (NAS, 1975),
in humans even less nickel (approximately 1%) is
absorbed in the gastrointestinal tract (Sunderman,
1989). In a study of healthy human volunteers who
ingested nickel sulfate in drinking water or food,
Sunderman et al . (1989) found that absorbed nickel
from the drinking water was approximately 40-
fold greater than the nickel absorbed from the same
nickel dose in food. In follow-up studies, Nielsen
et al . (1999) confi rmed the fi nding that nickel inges-
tion with a meal leads to substantially less absorbed
nickel than from nickel-containing drinking water

5.4 Excretion
In animals and humans, nickel is primarily excreted
in the urine, with salivary and sweat excretion being
secondary (Onkelinx et al ., 1973; WHO, 1991). Excre-
tion of nickel in feces is composed of the unabsorbed
dietary nickel intake, as well as biliary and tracheally
cleared nickel. Metallothioneins (MT) are essential low-
molecular weight, cysteine-rich proteins, with numer-
ous thiol metal binding sites, and essential functions
in metal detoxifi cation processes (Waalkes et al ., 1985;
1990). It was recently reported that MT overexpression