Iron - Toxicology of Metals - page 578

to mutations (in the gene for hypoxanthine/guanine
phosphoribosyl transferase) and to transformation of
cells into an anchorage-independent phenotype gener-
ally equated with tumorigenesis (Gao et al ., 2005).

tle as 15%) is absorbed (Reissman et al ., 1955). A failure
to appreciate this factor has contributed to the contro-
versies regarding antidotal therapy. Peak serum iron
concentrations occur within 4-6 hours and half-life is
approximately 6 hours (Harju, 1989). This decline is due
to tissue redistribution, with the liver being the prime
site. Within the vascular compartment, iron is tightly
bound to transferrin. For toxicity to occur, the capacity
of transferrin binding must be exceeded. However, free
plasma iron does not occur; it complexes with other
plasma proteins and organic ligands. This substance,
known as nontransferrin-bound iron, is loosely bound
and readily causes toxicity (Arouma et al ., 1988; Gut-
teridge et al ., 1985; Hershko and Peto, 1987).

8 IRON POISONING

8.1 Introduction
Despite being available without a prescription, iron
is more hazardous than most prescription drugs and is
the most common cause of poisoning death in young
children (Litovitz and Manoguerra, 1992). However,
iron poisoning is not confi ned to this age group,
because purposeful overdoses occur in both adoles-
cents and adults that result in signifi cant morbidity
and mortality (Watson et al ., 2004). Within the realm of
acute poisonings, iron is unique in that it is not a xeno-
biotic. Because iron is highly reactive, there is a need for
complex mechanisms for its absorption, transport, and
storage. These mechanisms are reviewed elsewhere in
this chapter. However, the pharmacokinetics of iron
has not been fully characterized, and its toxicokinetics
are even less well understood. Because of this, there is
not uniform agreement regarding the toxic dose, the
optimal method of gastrointestinal decontamination,
the role of intragastric complexation therapies, or the
use of the specifi c iron chelator, deferoxamine. More
specifi cally, the indications, dose, duration of therapy,
and effi cacy of this antidote are not precise.

8.3 Pathophysiology
Iron toxicity is best thought of in terms of local and
systemic effects. The former is a result of local irritation
of the gastrointestinal tract. The latter consists of tissue
damage and organ dysfunction. Gastrointestinal irrita-
tion manifests as nausea, vomiting, diarrhea, and abdom-
inal pain. As little as 10-20 mg/kg of elemental iron may
produce these symptoms; however, this dose is too small
to cause signifi cant systemic toxicity, which requires at
least 40 mg/kg but typically >60 mg/kg of elemental iron
(Banner and Tong, 1986; Hernretig and Temple, 1984). A
lethal dose is estimated to be 200-250 mg/kg (Henretig
and Temple, 1984; Robotham and Leitman, 1980). How-
ever, deaths have been documented with doses as low
as 75-125 mg/kg of elemental iron (Olenmark et al ., 1987;
Smith et al ., 1950; Spencer, 1951; Thompson, 1947).
Toxicity is a consequence of free radicals generated
by iron catalysis (Halliwell and Gutteridge, 1986). Tar-
get organs and tissues are sites of high iron concentra-
tion and metabolic activity. The gastrointestinal tract is
a prime site, because this is where the highest concen-
tration of iron occurs. Necrosis and hemorrhage can be
signifi cant (Tenenbein et al ., 1990). Signifi cant gastroin-
testinal toxicity may occur without systemic toxicity,
but it may not occur in patients who succumb to iron
poisoning (Reissman et al ., 1955). The chief sites of sys-
temic toxicity are the heart (Tenenbein et al ., 1988) and
the liver. The liver is susceptible because, unlike other
tissues and organs, it is capable of clearing nontransfer-
rin-bound iron (Craven et al ., 1987; Wright et al ., 1986).
Hepatoxicity in iron poisoning has been well described
(Robertson and Tenenbein, 2005; Tenenbein, 2001).

8.2 Iron Preparations
Iron, either alone or in combination with vitamins
and other minerals, is available as ferrous salts. These are
ferrous gluconate (12% elemental iron), ferrous sulfate
(20% elemental iron), ferrous fumarate (33% elemental
iron), and ferrous succinate (35% elemental iron). The
proportion of iron in each salt is important, because the
toxicity of iron is a function of the dosage of elemental
iron ingested. Carbonyl iron is highly purifi ed metallic
iron that is uncharged and not a salt. There have been no
reports of signifi cant morbidity or of mortality from this
type of iron (Madiwale and Liebelt, 2006).
The absorption, transport, and storage of iron has
been discussed previously and is reviewed elsewhere
(Bezkorovainy, 1989a,b; Finch and Huebers, 1986; Harju,
1989). Typically 10% of the ingested dose is absorbed;
however, the proportion is highly variable and is a
function of iron stores and the ingested dose. Because
iron absorption is an active, saturable process, as the
dose increases, the percentage absorbed decreases. In
massive overdose, a relatively small proportion (as lit-

8.4 Clinical Presentation
Iron poisoning is divided into fi ve clinical stages
(Banner and Tong, 1986). These include gastrointesti-