EPA-540/1-86-054
Environmental Protection
Agency '
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
HEALTH EFFECTS ASSESSMENT
FOR IRON (AND COMPOUNDS)
Do not remove. This document
should be retained in the EPA
Region 5 Library Collection.
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EPA/540/1-86-054
September 1984
HEALTH EFFECTS ASSESSMENT
FOR IRON (AND COMPOUNDS)
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or In part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adm1n1sr
tratlve review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with Iron (and
compounds). All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data
bases. The basic literature searched supporting this document Is current up
to September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) source has
been extensively utilized:
U.S. EPA. 1981. Multimedia Criteria for Iron and Compounds.
Environmental Criteria and Assessment Office, Cincinnati, OH.
Internal draft.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the llfespan [see U.S. EPA (1980) for a discussion of
this concept]. The AIC Is route specific and estimates acceptable exposure
for a given route with the Implicit assumption that exposure by other routes
1s Insignificant.
111
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Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development Is explained 1n U.S. EPA (1983).
For compounds for which there 1s sufficient evidence of carclnogenldty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
Iron deficiency Is much more prevalent and has been given much greater
attention than Iron toxldty. As a result, minimum required levels are well
defined (10 mg/day, men; 18 mg/day, women) while essentially no quantitative
data are available for maximum tolerable oral exposure.
Limited data are available for Inhalation exposures. Occupational
experience provides some Information. An AIC for Inhalation of 0.6 mg/day
has been suggested based on the ACGIH (1980) recommended TLV-TWA of 0.8
mg/m3. Data were Insufficient for calculation of a CS from either the
oral or the Inhalation data.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was^the Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE ,
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . ,
2.1. ORAL ,
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC ,
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral
3.3.2. Inhalation
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral
6.1.2. Inhalation
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral
6.2.2. Inhalation
Page
1
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7
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8
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10
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11
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18
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TABLE OF CONTENTS
Page
6.3. CARCINOGENIC POTENCY (q-|*) 20
6.3.1. Oral 20
6.3.2. Inhalation 20
7. REFERENCES 21
APPENDIX: Summary Table for Iron (and Compounds) 34
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
CAS Chemical Abstract Service
CS Composite score
DNA Deoxyrlbonuclelc add
EDTA Ethylened1am1netetraacet1c add
LDso Dose lethal to 50% of recipients
ppm Parts per million
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Iron Is a metal belonging to the first transition series of the periodic
table. The CAS Registry number for elemental Iron Is 7439-89-6. The
Inorganic chemistry of Iron 1s dominated by compounds In the +2 and +3
valence states. The primary examples of Iron 1n the 0 valence state are
metal and alloys and the carbonyl compounds. Selected physical properties
of a few environmentally significant Iron compounds are given 1n Table 1-1.
The predominant sources of Iron 1n the atmosphere are natural processes
Including continental dust created by wind erosion of weathering mineral
deposits, volcanic gas and dust and forest fires (Lantzy and Mackenzie,
1979). An Insignificant amount of Iron may enter the atmosphere through
aerosol formation from sea surface (Lantzy and Mackenzie, 1979). Anthropo-
genic sources of atmospheric Iron may contribute -28% of the total atmos-
pheric burden for Iron (Lantzy and Mackenzie, 1979). The principal anthro-
pogenic sources of atmospheric Iron are Industrial emissions and burning of
fossil fuels (Lantzy and Mackenzie, 1979). In the atmosphere, Iron 1s
likely to be present 1n the partlculate form (U.S. EPA, 1981) or different
chemical forms that may undergo chemical or photochemical reactions, fre-
quently with subsequent changes of oxidation states, but these processes may
not be directly responsible for the removal of Iron from the atmosphere.
The processes that may remove Iron from the atmosphere are wet and dry
deposition (U.S. EPA, 1981). It has been estimated that the residence time
of Iron 1n the atmosphere may be 10-20 days (Lantzy and Mackenzie, 1979).
In aquatic media, Iron can undergo primarily chemical reactions
Including precipitation, spedatlon, oxidation-reduction and chelatlon;
photochemical reactions Including photoaquatlon, photosens1t1zat1on and
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TABLE 1-1
Selected Physical Properties of a Few Iron Compounds3
1
INJ
1
Element/Compound
Iron
Iron (III) chloride
Iron (II) sulflde
Iron (III) oxide
Iron (0) pentacarbonyl
Iron (II) sulfate.
heptahydrate
Iron (II) ferrocyanlde
Formula
Fe
FeCl3
FeS
Fe203
Fe(CO)5
FeS047H20
Fe4[Fe(CN)6]3
Molecular/Atomic
Weight
55.847
162.21
87.91
231.54
195.90
278.09
859.25
Specific Gravity/
Density
7.86
2.89B2*
4.74
5.24
1.457 of liquid
at 2TC
1.898
1.80C
Water Solubility
Insoluble
74.4 g/100 ml at 0°C
0.62 mg/100 ml at 18°C
Insoluble
Insoluble
15.65 g/100 mld
Insoluble
Vapor Pressure
(mm Hg)
1 mm at 1787°C
NA
NA
NA
40 mm at 30.3°CC
NA
NA
"Source: Weast (1980)
bNo further data regarding solubility are available from Weast (1980).
cThese data are taken from NIOSH (1980).
^Temperature not specified
NA = Not available
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photoredox; microblal Interactions resulting 1n oxidation, reduction and
precipitation; and sorptlve Interactions (U.S. EPA, 1981). Photochemical
reactions probably are not significant In most natural bodies of water at
Increasing water depths because of reflection and scattering of light. The
chemical reactions 1n bodies of water depends on the pH and oxidation
reduction potential of the body of water. The mlcroblal reaction will
depend primarily on pH and the concentration of microorganisms. Similarly,
the sorptlon process depends on the pH, and concentration and nature of the
sorptlve species. In most bodies of water, Iron 1s expected to be present
largely 1n the form of suspended particles and sediments, although small
amounts of dissolved Iron may occur as Fe(II) or Fe(III) Ions, and Inorganic
and organic complexes of both Fe(II) and Fe(III). Small quantities of Iron
also exist 1n colloidal form, generally as ferric oxyhydroxldes. The
residence time of Iron 1n aquatic media has been estimated to be >140 years
(U.S. EPA, 1981).
Iron 1s present primarily 1n the Fe(III) state 1n most soils, although
Fe(II) may be predominant 1n oxygen deficient soils (flooded soils and soils
rich 1n organic matter). The principal Iron-containing minerals In soils
are the ferric oxyhydroxldes. The fate of Iron compounds 1n soils Is
primarily determined by chemical and microbiological reactions 1n soils and
the capacity of soils to sorb Iron-organic complexes. These processes have
been discussed In detail In a U.S. EPA (1981) report. In most soils, Iron
1s not mobile. Both biological and chemical reactions may cause
precipitation of Iron 1n soils; however, small amounts of Iron are
transported through soil 1n the form of colloidal ferric oxyhydroxldes, and
1n solution as Iron-organic chelates formed under the peptlzlng action of
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dissolved organic compounds. Soil pH 1s one of the most Important
regulators of Iron mobility, with lower pH favoring mobility. The mobility
of Iron 1n soils 1s such that H 1s not Hkely to leach from soil to
groundwater under most conditions. Leaching of Iron Into groundwater,
however, may occur from coal mine drainage areas and from waste burial sites
(U.S. EPA, 1981). The transport of Iron from soils to the atmosphere and
surface waters probably occurs through dusts produced by blowing winds and
the transport of flooded soil water Into receiving surface water,
respectively.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
According to Cook and Monsen (1976), Iron 1s absorbed from two dietary
sources, heme Iron from meats and nonheme Iron from grains and vegetables.
Nonheme Iron 1s absorbed 1n the range of 1-10%, depending on the presence of
enhancing or Inhibiting factors. Absorption of heme Iron does not seem to
be dependent on enhancing or Inhibiting agents, and ranges from 10-25%.
Bjorn-Rasmussen et al. (1974) Investigated the absorption of Iron 1n 32
healthy male human subjects whose dietary Intake of Iron was 17.4 mg/day,
[1 mg of Iron from heme and the remainder (16.4 mg) from nonheme sources].
The total Iron absorbed averaged 1.19 mg/day (-7% of the dally Intake). Of
this, 31% (0.37 mg) was from the heme Iron In the diet, representing 37%
efficiency, and 69% (0.82 mg) was from the nonheme Iron, representing 5%
efficiency.
According to Bothwell and Finch (1962), an approximately linear
relationship exists between the amount of Iron administered and the amount
absorbed 1n normal human subjects given 50-400 mg of ferrous salts.
Bothwell et al. (1979) determined that the availability of the ferrous Iron
for absorption was greater than the availability of the ferric Iron. The
presence of excess reducing agents In the Intestine may, therefore,
Influence the availability of dietary Iron. As Intestinal pH rises above 5,
coincident with passage down the Intestinal tract, less ferric Iron remains
solublUzed 1n the 1on1c form compared with ferrous Iron.
Exogenous Ugands affect the absorption of nonheme Iron. Ascorbic add,
dtrlc add and cystelne form complexes with Iron that facilitate Us uptake
Into mucosal cells. Carbonates, oxalates, phosphates and tannins inhibit
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Iron absorption by forming Insoluble complexes 1n the gut (U.S. EPA, 1981).
EOTA, a common food preservative, can greatly reduce Iron absorption (Cook
and Monsen, 1976).
Absorption of Iron can be divided Into two processes, uptake by mucosal
cells and transfer from the mucosal cells to the plasma. Wheby et al.
(1964) found that uptake 1s the faster process and that H occurs preferen-
tially 1n the proximal duodenum and diminishes 1n the distal region of the
small Intestine. It 1s likely that the brush borders of cells 1n the
proximal regions of the Intestine may bind Iron more specifically than
occurs more dlstally In the gut.
The regulation of Iron absorption and transfer to the plasma depends on
the level of available stores and the rate of erythropolesls, the latter
being the primary factor that depletes available body stores (Bothwell et
al., 1979). Plasma concentrations of ferrltln, which have been shown to
reflect body stores, are Inversely related to Iron absorption (Cook et al.,
1974). Hemolytlc anemia (Bannerman et al., 1964; Ch1ras1r1 and Izak, 1966;
Erlandson et al., 1962; Robertson et al., 1963) has been shown to stimulate
Iron absorption, probably by stimulating erythropolesls regardless of body
stores of Iron. Hypoxla (Hathorn, 1972; Under and Munro, 1977) and anemia
(Mendel, 1961; Schlffer et al., 1965; Under and Munro, 1977) enhance Iron
absorption even when erythropolesls Is Inhibited. Humoral factors have been
suggested to play a role 1n regulating Iron absorption. Apte and Brown
(1969) found a low molecular weight factor 1n the blood of Iron deficient
humans and pregnant women that, when administered, to rats, enhances Iron
absorption.
Gastric achlorhydrla, frequently associated with Iron-deficiency anemia,
has been suspected to decrease Iron absorption (Grace et al., 1954).
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Although hydrochloric acid per se 1s not required for absorption of Iron, at
lower gastric pH dissociation of Iron compounds with solubH1zat1on of Ionic
Iron may be expected to occur. Interaction of the soluble Iron Ions with
Ugands present 1n the chyme (secreted or resulting from food digestion)
will prevent precipitation of Iron hydroxides at the higher pH of the Intes-
tinal tract (Jacobs et al., 1964; Murray and Stein, 1968).
2.2. INHALATION
Pertinent data regarding the absorption of Iron (and compounds) could
not be located 1n the available literature. Pulmonary slderosls, the accu-
mulation of Iron oxide 1n the lungs, has been observed 1n workers exposed to
Iron oxide. The nodules characteristic of this affliction regress gradually
after exposure Is discontinued, suggesting that absorption of these partlcu-
lates from the lung 1s slow (Morgan and Kerr, 1963; Morgan, 1978).
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. In humans, oral exposure to toxic levels of Iron or Its
compounds has the potential for being chronic (Section 3.2.1.). Acute
toxldty 1n humans has been reported by many Investigators (U.S. EPA, 1981).
In children, as little as 0.3-3 g of Iron as ferrous sulfate has been
associated with severe toxic effects (Greenblatt et al., 1976); in adults,
2-10 g of ferrous sucdnate or ferrous sulfate has been associated with
severe toxldty and death (Eriksson et al.. 1974; Lavender and Bell, 1970).
In animals, oral LD™ values range from 12 mg/kg for iron carbonyl In
rabbits to 4000 mg/kg for ferric dimethyldlthiocarbamate in rats (U.S. EPA,
1981). Ferrous sulfate, the Iron compound most commonly Involved 1n human
toxldty, had oral LD5Qs of 979-1520 mg/kg In mice, 1200 mg/kg 1n guinea
pigs and 319 mg/kg in rats.
Majumder et al. (1975) administered 1 or 5 mg of iron as ferrous
sulphate to male Charles Foster rats or male short-hair guinea pigs for 45
or 10-20 days, respectively. These animals were fed diets of unfortified
wheat flour, unfortified rice flour or casein-fortified wheat flour.
Vitamin C was added to 50% of the guinea pig diets.
Guinea pigs treated with 5 mg iron/day in diets not fortified with
vitamin C suffered severe toxldty and mortality. In rats treated with 5 mg
iron/day, reduced growth rate was the only manifestation of toxidty.
Neither rats nor guinea pigs treated with 1 mg of iron/day exhibited any
signs of toxldty. The length of exposure was too short to be used with
confidence in risk assessment.
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3.1.2. Inhalation. Inhalation exposure of humans to Iron and Us
compounds 1s most likely to occur as a result of occupational exposure.
Since the likelihood exists that such exposure would be chronic, repeated
human expo- sure to Iron compounds by Inhalation will be discussed In
Section 3.2.2.
No subchronlc Inhalation studies 1n animals have been located In the
available literature. Netteshelm et al. (1975) reported Iron accumulation
1n the lungs of hamsters exposed to 4 mg ferric oxide dust/m3, 30
hours/week for 1 month.
3.2. CHRONIC
3.2.1. Oral. Chronic toxldty to Iron usually results from prolonged
accumulation of Iron 1n the tissues (slderosls). Excessive amounts of Iron
stored 1n the tissues results 1n a condition called hemochromatosls, a
pathological general tissue flbrosls. Most cases of hemochromatosls prob-
ably result from sources of Iron Intrinsic to the tissues after hemolytlc
anemias or repeated blood transfusions. Id1opath1c or primary hemochroma-
tosls 1s a genetic disorder of Iron metabolism that 1s characterized by
deposition of unusually large amounts of Iron 1n the tissues (Charlton and
Bothwell, 1966; Goossens, 1975; Schelnberg, 1973). Absorption of Iron from
the gut 1s greatly 1n excess of body requirements, therefore Increasing
tissue deposition over several years (Bothwell and Finch, 1962). The liver
and pancreas may typically contain stores of Iron that are 50-100 times the
normal levels. The thyroid, pituitary, heart, spleen and adrenals are other
sites of unusually high Iron deposition (Sheldon, 1935). Males are 10 times
more frequently affected than females; the disease 1s typically manifested
In the fifth or sixth decade of life (Prasad, 1978).
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A similar syndrome has been seen among the Bantu people of South Africa,
who reportedly Ingest large amounts of Iron 1n their home-brewed beer.
Their condition may be exacerbated by unusually high Intake of alcohol,
which reportedly Increases iron absorption (Bothwell et al., 1965). No
estimates of Iron Intake were mentioned.
Pertinent data regarding the chronic oral toxldty of Iron 1n animals
could not be located 1n the available literature.
3.2.2. Inhalation. Chronic Inhalation exposure of man to Iron or Us
compounds 1s likely to result from occupational exposure. Iron-ore mining,
arc welding, iron grinding and polishing, metal working, pigment manufacture
and rubber manufacturing are occupations that predispose workers to
inhalation of dust or fumes of iron or its compounds (Hueper, 1966).
Epidemiological studies of mortality among steel workers have not Indi-
cated an association with exposure to iron oxide (Lerer et al., 1974; Lloyd
and Ciocco, 1969; Lloyd et al., 1970; Redmond et al., 1975). In lung func-
tion studies on workers in these occupations, no relationship was found
between the Incidence of chronic bronchitis and emphysema and exposure to
Iron oxide dusts (Lowe et al., 1970), although the resplrable fraction never
exceeded a mean level of 2 mg/m3.
Pertinent data regarding chronic inhalation exposure of laboratory
animals to iron (and compounds) could not be located in the available
literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. In Sweden, iron or vitamin deficiencies or both have been
associated with the occurrence of dead or malformed Infants (Kullander and
Kallen, 1976). In Scotland, Nelson and Forfar (1971) found associations
between congenital malformations and Insufficient Iron intake in the early
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weeks of pregnancy. Most women taking supplemental Iron during their
pregnancy delivered normal Infants. Forfar and Nelson (1973) reported that
of the 911 pregnant Scottish women studied, 49% took supplemental ferrous
sulphate, 14% took ferrous sucdnate and 14% took ferrous carbonate. Bishop
(1979) recommended that pregnant women should take 30-60 mg supplemental
Iron/day regardless of their apparent nutritional status.
Tadokoru et al. (1979) found that antlanemlc "slow Iron" given orally to
pregnant rats and mice at 120-380 mg/kg/day for 6 days (unspecified) caused
no teratogenlc or toxic effects. Some embryo mortality was seen at doses of
1200 mg/kg/day.
In a study designed to assess the effects of trlsodlum n1tr1lotr1acetate
with and without ferric chloride on methyl mercury teratogenesls 1n rats,
Nolen et al. (1972) found that ferric chloride (7 mg/kg/day) administered In
drinking water on days 6-15 of gestation significantly reduced the Incidence
of fetal malformation Induced by trlsodlum n1tr1lotr1acetate and methyl
mercury. Exposure to ferric chloride alone did not affect fetal development.
3.3.2. Inhalation. Pertinent data regarding teratogenesls associated
with Inhalation exposure of humans or animals to Iron (and compounds) could
not be located 1n the available literature.
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4. . CARCINOGENICITY
4.1. HUMAN DATA
Esophageal carcinoma has been associated with either iron deficiency or
iron overload (MacPhail et al., 1979), although a causal relationship has
not been established. MacPhail et al. (1979) found that the hepatic iron
content of 85 South African blacks who died from esophageal carcinoma was
higher than those of males of the same ages who died of other causes.
Alcohol consumption has also been associated with esophageal carcinoma. It
was unclear, therefore, whether the esophageal carcinoma observed by
MacPhail et al. (1979) was due to excessive iron intake or to the alcohol
contained in home-brewed beer, a substantial part of the diet of the Bantu.
One report on inhalation exposure to iron mining dusts described an
association with excess deaths from lung cancers (Boyd et al., 1970). More
recently, it has been found that the presence of radon gas was a more likely
cause of the reported excess of lung cancers (Hueper, 1979).
IARC (1972) briefly summarized the early .reports of lung tumors asso-
ciated with exposure to iron-ore dusts or fumes from hot metals (i.e., from
welding operations). In these cases, reports of excess lung tumors from
exposure to iron have not been corroborated. Exposure to alcohol, tobacco,
silica, soot and fumes of other metals confound the validity of association
of lung cancers with iron and its compounds. IARC (1972) concluded that,
"exposure to hematite dust may be regarded as increasing the risk of lung
cancer in man...it is not known whether the excess risk is due to radio-
activity in the air of mines, the inhalation of ferric oxide or silica or to
a combination of these or other factors."
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4.2. BIOASSAYS
Pertinent data regarding cardnogenicity related to oral exposure to
Iron (and compounds) could not be located in the available literature.
Iron oxide dust has been used extensively 1n experimental carcinogenesls
as a relatively Inert carrier for known carcinogens. Port et al. (1973)
demonstrated that 10 intratracheal instillations of 5 mg iron oxide dust
(dosing interval not specified) resulted in a complete loss of ciliary cells
and hyperplasia of the tracheobronchlal epithelium in hamsters. These
changes were completely reversible after 7 weeks. It was suggested (Port et
al., 1973) that iron oxide causes hyperplasia of the tracheobronchlal epi-
thelium, which may promote the Induction of cancer by known carcinogens.
According to IARC (1972), Campbell (1940, 1942, 1943) reported a higher
frequency of lung tumors in mice exposed by inhalation to ferric oxide steel
grindlngs, to a mixture of aluminum oxide, ferric oxide and silicon dioxide,
or to a mixture of the oxides of aluminum, silicon, Iron and calcium than 1n
control mice. IARC (1972) suggested that these experiments must be regarded
as inconclusive because of the genetic randomness of the mice used and the
fact that the differences 1n the Incidence of tumors was small.
A series of 15 once-weekly Intratracheal Injections of 3 mg of ferric
oxide dust in 24 male and 24 female Syrian golden hamsters failed to produce
lung tumors (Saff1ott1 et al., 1968). The animals were observed for life
with >50% of the animals surviving for >1 year.
4.3. OTHER RELEVANT DATA
Demerec et al. (1951) reported point mutations in Escherichia coli
Induced by ferrous or ferric chloride and ferric sulfate at "unusually high"
concentrations. In Bacillus subtilis H17 and M45 tests, concentrations of
0.05 M ferrous and ferric chloride, potassium ferro- and ferrl-cyanides were
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not mutagenlc (N1sh1oka, 1975). Ferric sulfate (0.00001-0.5%) and ferric
nitrate (0.00001-0.01%), but not ferric chloride, caused changes In cell
nuclei and disturbances In cell division 1n the roots of the broad bean,
Vlda baba (Komczynskl et al., 1963).
Extensive studies with ferrous sulfate and ferrous gluconate In Salmon-
ella typhlmurium and Saccharomyces cerevlslae have been performed by Litton
B1onet1cs, Inc. (1974, 1975). Ferrous sulfate Induced reverse mutations 1n
S. typhlmurlum strains TA1537 and TA1538, but not in TA1535. Mutagenesls
was most pronounced 1n tests containing mlcrosomal activating systems.
Mutagenesls was not reported 1n S. cerevlslae. More recently, however,
Singh (1983) reported a positive gene conversion at trp 5 and a weak
reversion at 1lv 1 1n S. cerevlslae strain 07 by ferrous sulphate but not
ferric chloride.
Castro et al. (1979) reported that ferrous sulfate and ferrous chloride
Inhibited transformation of Syrian hamster embryo cells by a simian adeno-
vlrus (SA7). This effect was attributed to a relative increase in viral
transformation and to an absolute Increase in the number of transformed foci.
Roblson et al. (1982) tested the ability of many metal compounds to
induce strand breakage, measured as decreased molecular weight of DNA
isolated from Chinese hamster ovary cells. Ferrous chloride, the only Iron
compound tested, produced no significant change in the molecular weight of
DNA.
Incubation of Isolated rat liver nuclei with either ferrous chloride or
ferric chloride resulted in single-strand breaks in DNA (Shires, 1982). The
ferrous salt was about twice as active as the ferric salt.
Patton and Allison (1972) reported that nontoxic concentrations of iron
dextran were not mutagenlc to cultures of human leukocytes.
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4.4. WEIGHT OF EVIDENCE
As mentioned 1n Section 4.1., reports exist associating excessive Inci-
dence of lung cancer with hematite dust 1n underground mining operations.
Coincident exposure to tobacco, alcohol, silica, soot and fumes of other
metals complicates Interpretation of these reports. Inhalation or 1ntra-
tracheal exposure to ferric oxide has not consistently resulted 1n formation
of lung tumors (IARC, 1972).
In mice (Haddow and Horning, 1960; Haddow and Roe, 1964) and rats
(Haddow and Horning, 1960; Langvad, 1968; Roe and Carter, 1967; Roe et al.,
1964; Golberg et al., 1960; Kren et al., 1968; Braun and Kren, 1968), local
Injection-site tumors (sarcomas > hlstlocytomas > flbromas) resulted from
subcutaneous or Intramuscular Injections of 1ron-dextran. Negative results
were obtained by Pal et al. (1967), who administered subcutaneous doses of
0.05, 0.1 or 0.2 ma. 1ron-dextran (concentration not reported) to groups of
10-18 female mice, once weekly for 10 weeks. Observations were -performed
for 7 months after the first treatment.
Local tumors 1n mice were observed after 30 weekly subcutaneous
Injections of Iron-dextran (Fielding, 1962) and after 13 weekly subcutaneous
Injections of saccharated Iron oxide (Haddow and Horning, 1960), but not
after 30 weekly subcutaneous Injections of 1ron-sorb1tol-c1tr1c add complex.
Taken collectively, these studies suggest that Injection of some Iron-
carbohydrate complexes may cause local Injection-site tumors 1n animals.
Since the Introduction of Iron-dextran to clinical practice 1n the 1950s,
only one case of cancer In humans, an Injection-site sarcoma, has been
reported (Robinson et al., 1960). It Is not possible to determine whether
the association 1n this single case 1s causal and no long-term observations
have been made on humans receiving this drug.
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Applying the criteria for evaluating the overall weight of evidence of
cardnogenldty to humans proposed by the Carcinogen Assessment Group of the
U.S. EPA (Federal Register, 1984), Iron and Its compounds, Including ferric
dextran, are most appropriately classified 1n Group C - Possible Human
Carcinogen.
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5. REGULATORY STANDARDS AND CRITERIA
Based primarily on the suggestions of Drinker et al. (1935), who
reviewed the health effects of workers exposed to Iron oxide, and Weber
(1955), who suggested that slderosls occurred 1n workers exposed to -15 mg
Iron as oxlde/m3, the AC6IH (1980) recommended a TWA-TLV of 5 mg 1ron/m3
and a STEL of 10 mg 1ron/m3 for ferric oxide. On the recommendation of
Brief et al. (1967), who recommended an "action point" of 0.1 ppm for
occupational exposure, the TWA-TLV for Iron from Iron pentacarbonyl was
recommended to be 0.1 ppm (-0.8 mg/m3). A STEL of 0.2 ppm (-1.6 mg/m3)
was recommended. To protect from respiratory and skin Irritation, a TWA-TLV
of 1 mg/m3 was suggested for soluble Iron salts. A STEL of 2 mg/m3 was
suggested. The OSHA standard for Iron oxide fume Is 10 mg/m3 (Code of
Federal Regulations, 1981).
In drinking water, the current quality criterion 1s 0.3 mg iron/8.
(NAS, 1974), based primarily on a study by Cohen et al. (1960), that indi-
cated that 20% of those tested were able to distinguish between distilled
water and a solution of 0.3 mg iron/a as ferrous sulfate.
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. In humans, severe acute toxldty has occurred with 1nges-
tion of 300-3000 mg of Iron by children (Greenblatt et al., 1976) or
2000-10,000 mg of Iron by adults (Eriksson et al., 1974; Lavender and Bell,
1970). No subchronlc oral exposure studies of Iron (and compounds) suitable
for use 1n risk assessment were located 1n the available literature. The
scanty oral and Inhalation toxldty data was evaluated for Iron and Us
compounds and H was concluded that data were Insufficient for derivation of
a CS. Although minimal subchronlc oral data 1n animals were available, the
fact that Iron accumulation occurs Indefinitely and may result 1n toxldty
later 1n life precludes the use of these short-term studies to derive a CS.
6.1.2. Inhalation. Netteshelm et al. (1975) reported Iron accumulation
1n the lungs of hamsters exposed to 4 mg ferric oxide dust/m3, 30 hours/
week for 1 month. Unfortunately, reported exposure and effect data were
Insufficient to use this study 1n risk assessment. No other studies of sub-
chronic Inhalation exposure to Iron (and compounds) have been located 1n the
available literature. Therefore, no AIS for Inhalation exposure has been
calculated.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. Chronic toxldty from oral Intake of Iron by humans 1s
rare. Section 3.2.1. mentions hemochromatosls, a primary genetic disorder
that results 1n unusual uptake of dietary Iron and Us distribution to and
storage 1n various tissues of the body. Among the Bantu people of South
Africa, a hemochromatos1s-!1ke syndrome has been Identified and associated
with unusually high dietary Intakes of both Iron and alcohol. No studies of
chronic toxldty In humans or animals relating effects to dosages that are
useful for risk assessment have been located 1n the available literature.
-18-
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Iron deficiency 1s much more common than Iron tox1c1ty. NAS (1980)
suggested the following Recommended Dally Dietary allowances: Infants to 6
months old, 10 mg; 6 months to 6 years, 15 mg; 7 to 10 years, 10 mg; males
11-18, 18 mg; males over 18, 10 mg; females 11-50, 18 mg; over 50, 10 mg.
In addition, Iron supplements of 30-60 mg/day are recommended for pregnant
women. It has also been suggested that dally Intakes of 25-75 mg should be
well tolerated 1n healthy adults (NAS, 1980).
Iron deficiency has been given much greater attention than Iron toxlc-
Hy. Reliable quantitative data are not available which could be used to
estimate an AIC.
6.2.2. Inhalation. Many occupations predispose workers to Inhalation
exposure to various compounds of Iron (Hueper, 1966). Neither epldemlologl-
cal studies of mortality among steel workers exposed to Iron oxides (Lerer
et al., 1974; Lloyd and docco, 1969; Lloyd et al., 1970; Redmond et al.,
1975) nor lung function studies of workers exposed to Iron oxide dusts (Lowe
et al., 1970) Indicated excess risks associated with exposure to Iron
oxides. Additionally, no other reports of toxldty resulting from chronic
Inhalation exposure of humans or animals to Iron (and compounds) have been
located 1n the available literature. Therefore, 1t seems reasonable to use
the TWA-TLV suggested by ACGIH (1980) for the most toxic compound of Iron
for which a recommendation has been made as a starting point 1n deriving an
Inhalation AIC. The ACGIH (1980) has set the TWA-TLV for Iron pentacarbonyl
at 0.8 mg/m3. Based on a human exposed to the workroom for 5 days/week
and Inhaling 10 m3 of air/workday, an Interim ADI can be calculated by
applying an uncertainty factor of 10 to protect unusually sensitive popula-
tion groups. An AIC of 0.6 mg Iron/day Is calculated.
-19-
-------
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Although esophageal cancers have been associated with high
Intakes of beer containing high levels of Iron, alcohol has also been asso-
ciated with esophageal cancers; hence, these high Incidences of esophageal
cancers 1n South African Bantu people are difficult to Interpret properly.
No other reports of cancers 1n humans or animals associated with oral
exposure to Iron (and compounds) have been located in the available litera-
ture; hence, no q * for oral exposure can be calculated.
6.3.2. Inhalation. Boyd et al. (1970) found an association between
excess deaths from lung cancer and exposure to iron mining dusts; however,
Hueper (1979) found that the presence of radon gas 1n these underground
mines was a more likely cause of the lung cancers. Port et al. (1973)
demonstrated that intratracheal administration of iron oxide dust caused
hyperplasia of the tracheobronchlal epithelium in hamsters. Campbell (1940,
1942, 1943) reported a higher Incidence of lung tumors 1n mice exposed to
ferric oxide steel grinding, a mixture of aluminum oxide, ferric oxide and
silicon dioxide, than 1n control mice; however, a series of 15 once-weekly
Intratracheal injections of 3 mg of ferric oxide dust in 24 male and 24
female Syrian golden hamsters failed to produce lung tumors. Over 50% of
the animals survived for >1 year (Saffiottl et al., 1968). IARC (1972)
suggested that these experiments should be regarded as inconclusive because
of the genetic randomness of the mice used and the fact that the Incidence
of tumors was small. Therefore, no q * for Inhalation exposure can be
calculated.
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-33-
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APPENDIX
Summary Table for Iron (and Compounds)
co
4»
I
Species Experimental Effect
Dose/Exposure
Inhalation
AIS
AIC human TWA-TLV: 0.8 mg/m3 none
Oral
AIS
AIC
Acceptable Intake
(AIS or AIC)
ND
0.6 mg/day
ND*
ND*
Reference
ACGIH, 1980
*An RDA has been established but this estimate reflects minimum required Intake not acceptable Intake.
ND = Not derived
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