I i i
`
`Reprinted from
`
`UICC Monograph Series
`Volume 7: Potential Carcinogenic Hazards from Drugs
`Edited by RENE TRUHAUT
`
`Springer-Verlag Berlin· Heidelberg· New York 1967
`
`Printed in Germany / Not a periodical
`On Potential Carcinogenecity of the Iron
`Macromolecular Complexes
`F. J.C. ROE
`Reader in Experimental Pathology, Chester Beatty Research Institute,
`University of London, and Associate Pathologist, Royal Marsden Hospital, London,
`Great Britain
`
`Introduction
`SAUNDERS (1958) provides a brief
`review of the history of iron in medical
`treatment. Oxides and carbonates of
`iron have found a place in therapy from
`ancient times. Their use is mentioned in
`the Ebers Papyrus, and Dioscorides,
`Galen, Celsus and Aetius advocated iron
`therapy in the treatment of splenic
`enlargement and menorrhagia. In 1661
`SYDENHAM described the striking bene(cid:173)
`fit of iron therapy in the treatment of
`chlorosis. LIEBIG, in 1843, gave the
`first clear description of the role of
`haemolgobin, and FoR TES and THIVOLLE,
`in 1925, first demonstrated that plasma(cid:173)
`iron is different from haemoglobin.
`These and related findings demonstrated
`beyond argument that iron is an essen(cid:173)
`tial ingredient of the human diet. ·
`FIGUEROA'S (1958) view that "The
`great majority of patients suffering from
`iron deficiency can be treated with oral
`iron" is probably widely acceptable,
`especially if the word "iron" is inter(cid:173)
`preted as "bivalent organic
`iron"
`(UNDRITZ, 1958). The valid indications
`for parenteral iron therapy in the very
`few patients who require it include,
`according to FIGUEROA (1958): -
`1. Where there is a failure to absorb
`adequate amounts of oral iron.
`
`2. Where a patient cannot tolerate
`orally administered iron, or is unwilling
`or cannot be relied upon to continue
`oral iron therapy.
`3. Where it i_s necessary to replace
`iron stores in cases of severe, predictable
`and frequent blood loss not amenable to
`medical or surgical correction.
`4. Cases of iron-deficiency anaemia
`that have failed to respond to prolonged
`adequate oral iron therapy.
`
`Of these indications the first is rare,
`except in patients with idiopathic stea(cid:173)
`torrhoea, or who have undergone exten(cid:173)
`sive surgical removal of the small
`intestine, and the second is the most
`common. Referring to the use of paren(cid:173)
`teral iron therapy during the third
`trimester of pregnancy, FIGUEROA (1958)
`comments that it is debatable whether
`the small or moderate increase in haemo(cid:173)
`globin more readily achievable by the
`parenteral administration than by the
`oral administration of iron is justified.
`
`Iron macromolecular complexes suitabie
`for parenteral administration.
`1. Saccharated iron-oxide (Ferrive(cid:173)
`nin, Proferrin, Colliron, Neo-Ferrum,
`Iviron). -
`For intravenous injection
`only.
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`

`106
`
`F. J.C. RoE :
`
`2. Iron-dextrin (Dextriferron, Astra-
`injection
`intravenous
`For
`fer).
`only.
`3. Iron-dextran complex (Imferon).
`- For intramuscular or intravenous in(cid:173)
`jection.
`4. Iron-sorbitol-citric-acid complex
`For intramuscular injec(cid:173)
`(Jectofer). -
`tion only.
`5. Iron-polyisomaltose (Ferrum Haus(cid:173)
`For intramuscular injection
`mann). -
`only.
`
`If given in adequate and equivalent
`amounts these preparations are more or
`less equally effective in the treatment of
`iron-deficiency anaemia (FIGUEROA, 1958)
`This is at first sight surprising since
`there are marked differences in the
`degree of retention of iron at the in(cid:173)
`iron(cid:173)
`jection site (FIELDING, 1962):
`dextrin and iron-dextran are both re(cid:173)
`tained locally to a far greater extent than
`iron-sorbitol-citric-acid complex. How(cid:173)
`ever, these differences refer to conditions
`in which animals are overloaded with
`iron. In the absence of overloading the
`somewhat more rapid clearance of the
`iron-sorbitol complex is, from the point
`of view of rapidity of haematological
`response, apparently offset by the more
`rapid excretion of its iron-content by the
`.ANDERSSON,
`(LINDVALL and
`kidneys
`1961).
`
`than carcino(cid:173)
`General toxicity, other
`genicity, of parenteral iron preparations.
`The toxic effects, other than carcino(cid:173)
`genicity, of saccharated iron oxide are
`discussed by NISSIM (1954) and BROWN
`and MooRE (1956). The material is
`strongly alkaline and hypertonic and
`gives rise to marked local inflammation
`if injected extravascularly. Both imme(cid:173)
`diate and delayed systemic toxic effects
`are also frequent; the former are thought
`
`to be due to individual hypersensitivity
`to impurities in the preparation, and the
`latter to the intravascular precipitation
`of the compound. The incidence of
`reactions has varied with the technique
`of administration from less than 0.2%
`to over 50% of injections. Intravenous
`iron-dextrin also gives rise to a range
`of toxic reactions, especially in patients
`simultaneously receiving oral iron (BLA(cid:173)
`ZER and DEL RrnGo, 1962). From the
`point of view of the incidence and se(cid:173)
`verity of such toxic reactions the intro(cid:173)
`duction of iron-dextran for intramuscu(cid:173)
`lar use was a big step forward (Scarr
`and GovAN, 1954). Intramuscular in(cid:173)
`jection of iron-sorbitol-citric acid com(cid:173)
`plex (Jectofer) undoubtedly carries more
`risk of toxic response than does similar
`(SCOTT,
`iron-dextran
`treatment with
`1962), and the simultaneous administra(cid:173)
`tion of iron orally seems to enhance this
`risk. Iron-polyisomaltose is similar to
`iron-dextran both chemically and in its
`relative lack of toxicity (MEREu and
`ToNz, 1961).
`HADDOW and HORNING (1960) des(cid:173)
`cribed the failure of hair to regrow after
`clipping over the site of injection of
`iron-dextran, and BAKER, GOLBERG,
`MARTIN and SMITH (1961) and FIEL(cid:173)
`DING (1962) reported the development
`of alopecia, brown staining and loss of
`tissue elasticity at the site of injection of
`iron-dextran, but not of iron-sorbitol(cid:173)
`citric-acid complex. BERESFORD, GOL(cid:173)
`BERG and SMITH (1957) reported acute
`inflammation and degeneration follo(cid:173)
`wed by rapid and complete regeneration
`following the intramuscular injection of
`iron-polysaccharide complexes of the
`iron-dextrin/iron-dextran type. ROE and
`HADDOW (1965) found that acute tender(cid:173)
`ness and swelling at the injection site
`was more marked in rats injected with
`iron-sorbitol-citric acid complex than
`with iron-dextran.
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`

`nsitivity
`and the
`ipitation
`ence of
`:<::he.ique
`m 0.2%
`·avenous
`a range
`patients
`>n (BLA(cid:173)
`rom the
`and se-
`1e intro(cid:173)
`·amuscu(cid:173)
`l (SCOTI'
`:ular in(cid:173)
`:id com(cid:173)
`ies more
`s similar
`(ScoTI',
`ninistra(cid:173)
`;mce this
`milar to
`1d in its
`IBU and
`
`160) des(cid:173)
`:ow after
`ction of
`rOLBERG,
`1d FIEL(cid:173)
`:lopment
`:l loss of
`ection of
`sorbitol(cid:173)
`o, GoL(cid:173)
`ed acute
`n follo(cid:173)
`:neration
`~ction of
`of the
`RoE and
`e tender(cid:173)
`tion site
`ted with
`lex than
`
`On Potential Carcinogenecity of the Iron Macromolecular Complexes
`
`107
`
`Induction of neoplasms at site of intra(cid:173)
`muscular or subcutaneous i,yection of iron
`preparations
`Reports of the induction of sarcomas
`and histocytomas at the site of sub(cid:173)
`cutaneous
`intramuscular
`injection of
`various iron-carbohydrate complexes is
`summarised in Table I. The repeated
`injection of relatively large doses of
`
`(1961) obtained a low yield of tumours
`in both rats and mice following repeated
`injections ofiron-polyisomaltose (Ferrum
`Hausmann). MEREU and ToNZ (1961)
`referred to negative results in animal
`tests for carcinogenicity of this product
`but gave no details.
`In most of the experimental studies
`control animals have been injected with
`
`Table I. Carcinogenicity of' variou.r iron preparations administered f?y subcutaneous or intramuscular i,ifection
`
`Preparation
`
`Saccharated
`iron-oxide
`
`Iron-dextrin
`
`Iron--dextran
`
`No. of
`tests for
`Carcino(cid:173)
`genicity
`
`No.of
`tests in
`which
`positive
`results
`obtained
`
`3
`
`3
`
`19
`
`2
`
`3
`
`17
`
`Iron sorbitol citric
`acid complex
`Iron polyisomaltose
`
`3
`
`2
`
`1*
`
`2
`
`* Solitary benign fibroma among 20 rats.
`
`Species
`
`References
`
`Mouse
`
`Rat
`Mouse
`Rat
`Mouse
`Hamster
`Rabbit
`
`Rat
`Mouse
`Rat
`Mouse
`
`RICHMOND (1959); HADDOW and
`HORNING (1960); HADDOW, Dmrns
`and MITCHLEY (1961)
`LUNDIN (1961); FIELDING (1962)
`
`RICHMOND (1959); HADDOW and
`HORNING (1960); GOLBERG, MARTIN
`and SMITH (1960); LUNDIN (1961);
`FIELDING (1962); KUNZ, SHAHAB,
`HENZE and HEINZE (1963); HADDOW
`RoE and MITCHLEY (1964); H ADDOW
`and RoE (1964); RoE, HADDOW,
`DUKES and MITCHLEY (1964); RoE
`and HADDOW (1965) ·
`LUNDIN (1961); FIELDING (1962);
`RoE and HADDOW (1965)
`HADDOW, DuKEs and MITCHLEY
`(1961)
`
`saccharated iron-oxide, iron-dextrin or
`iron-dextran may induce such tumours
`in laboratory rodents: in many tests for
`carcinogenicity sarcomas have been in(cid:173)
`duced in upwards of 50 per cent of
`animals injected with these substances.
`Iron-sorbitol-citric-acid complex (Jec(cid:173)
`tofer), on the other hand, has given an
`essentially negative result in 3 fairly
`stringent tests (LUNDIN, 1961; FIEL(cid:173)
`DING, 1962 and RoE and HADDOW,
`1965). HADDOW, DUKES and MITCHLEY
`
`the corresponding carbohydrate moiety
`of iron-carbohydrate complex under
`test. Almost without exception entirely
`negative results have been obtained in
`such control groups. A ·problem here is
`that the carbohydrate by itself has a
`much smaller molecular size ( ca. 2,500)
`than the iron-macromolecular complex
`which it forms with iron (ca. 180,000 -
`see ERIKSSON, 1961). HUEPER (1959),
`however, tested 11 different dextrans
`ranging
`in molecular weight from
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`

`108
`
`F. J.C. RoE:
`
`37,000 to several million in rats, mice
`and rabbits: injection-site sarcomas were
`induced by none of these materials.
`
`Sarcoma-induction in relation to amount
`i,yected at one site
`RoE, HADDOW, DUKES and MITCH(cid:173)
`LEY (1964) compared the effect of giving
`24 weekly injections of 0.5 ml iron(cid:173)
`dextran into one, two, four or six sub(cid:173)
`cutaneous sites in comparable groups of
`
`seen in animals injected in 4 or 6 sites
`tended to be more benign than that
`seen in animals injected in only 1 or 2
`sites. A further interesting observation
`was that multiple tumours were fre(cid:173)
`quently seen at individual injection sites.
`
`Carcinogenicity in relation to iron-over(cid:173)
`loading
`GOLBERG, MARTIN and SMITH (1960)
`studied the effects of overloading animals
`
`Table II. Incidence and time of induction of rapid/y growing tumour, ( RGT) at the injection rite
`
`No. of rats
`
`Injection sites
`per rat
`
`RGT
`
`Time of appearance Average time of
`appearance of RGT
`of first RGT
`
`24
`24
`24
`24
`32
`
`1
`2
`4
`6
`0
`
`14
`6
`9
`3
`0
`
`329
`460
`449
`522
`
`501
`667
`706
`674
`
`Table III. Riik of tumour developing at injection rite
`
`Injection
`sites
`per rat
`
`Sites
`Dose of
`iron-dextran examined
`at autopsy
`per site
`
`Sites with
`malignant
`tumours
`
`(per cent)
`
`(per cent)
`
`Sites with
`benign or
`malignant
`tumours
`
`1
`2
`4
`6
`
`12 ml.
`6 ml.
`4 ml.
`2ml.
`
`22
`46
`96
`138
`
`14
`9
`20
`12
`
`(63.6)
`(19.6)
`(20.8)
`(8.7)
`
`14
`11
`29
`17
`
`(63.6)
`(23.9)
`(30.2)
`(12.3)
`
`rats. A spectrum of local tumours was
`including benign fibromas,
`induced,
`small, slowly growing sarcomas and
`rapidly growing sarcomas. Table II shows
`that the incidence of rapidly growing
`latent
`tumours fell and the average
`interval before they appeared rose as
`the number of injection-sites used in(cid:173)
`that,
`creased. Table III demonstrates
`although the risk of tumour develop(cid:173)
`ment at any one site fell as the number
`of injection-sites increased, the risk that
`the animal would develop a tumour at
`one of its injection-sites actually in(cid:173)
`creased I However, the type of tumour
`
`with iron. Their results indicated that
`the escape of iron from the site of in(cid:173)
`jection was much slower in iron-over(cid:173)
`loaded animals than in normal animals.
`In addition, biochemical changes in the
`liver, serum and region of injection
`were observed in the former but not in
`the latter. Finally they asserted that
`local tumour induction only occurs in
`iron-overloaded animals. They saw, for
`example, no sarcomas in response to
`weekly intramuscular injections of0.02ml
`iron-dextran in mice and only one sar(cid:173)
`coma in 50 mice injected once weekly
`with 0.1 ml. However, in the latter case
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`

`>r 6 sites
`han that
`.y 1 or 2
`servation
`v~r~ fre(cid:173)
`:ion sites.
`
`iron-over-
`
`~H (1960)
`~ animals
`
`·on site
`
`1e of
`ofRGT
`
`!r cent)
`
`i.6)
`i.9)
`1.2)
`!.3)
`
`tted that
`te of in(cid:173)
`·on-over-
`animals.
`es in the
`injection
`ut not in
`ted that
`1ccurs in
`saw, for
`>onse to
`)f0.02ml
`one sar(cid:173)
`! weekly
`Ltter case
`
`On Potential Carcinogenecity of the Iron Macromolecular Complexes
`
`109
`
`survival was poor. More recently HAD(cid:173)
`DOW and RoE (1964) reported a high
`incidence of sarcomas in mice receiving
`0.05 ml iron-dextran weekly (total dose
`2.35 mls) and one out of 20 rats given
`90 weekly injections of 0.01 mls deve(cid:173)
`loped a sarcoma (Table IV, V). In a
`current experiment sarcomas have appe(cid:173)
`ared in response to only 2 injections,
`each of 0.75 ml iron-dextran (see Ta(cid:173)
`ble VI).
`
`Clearly the risk of tumour in(cid:173)
`duction recedes as the size of the local
`dose is reduced, but particularly in the
`light of the results just referred to it is
`by no means certain that the degree of
`general overloading with iron is of
`any significance.
`
`The relationship of dose to body size
`HADDOW and HORNING (1960) and
`RoE (1961) have argued cogently that
`
`Table IV. Carcinogenic response to different doses of iron-dextran (imferon) injected subcutaneously in CB
`er rats (Wistar)
`
`Total dose
`
`Injection site
`sarcomas
`
`No. of rats
`injected
`
`Minimum
`induction time
`(days)
`
`No. of doses
`
`(Imferon)
`
`Size of each
`dose
`(ml.)
`
`30
`20
`64
`90
`
`1.0
`0.5
`0.05
`O.Dl
`
`(ml.)
`
`30
`10
`3.2
`0.9
`
`20
`8
`2
`1
`
`30*
`20
`20
`20
`
`145
`426
`478
`736
`
`* A further 8 rats had local histiocytomas.
`
`Table V. Carcinogenic response lo different doses of iron-dextran ( I mferon) injected .rubcutaneou.r{y in CB
`er mice (Stock)
`
`No. of doses
`
`(Imferon)
`
`Size of each
`dose
`(ml.)
`
`30
`47
`87
`
`0.3
`0.05
`0.01
`
`Total dose
`
`Injection site No. of rats
`sarcomas
`injected
`
`(ml.)
`
`9.0
`2.35
`0.87
`
`14
`12
`0
`
`30
`30
`20
`
`Minimum
`induction time
`(days)
`
`182
`168
`
`Table VI. Effect of do.re in induction of sarcomas at the site of injection of iron-dextran
`
`Group No. of S.C.
`injc,ctions of
`0.75 ml. iron-
`dextran into
`R. flank
`
`Total dose
`of iron-
`dextran
`
`No. of
`rats in
`group
`
`Position 16 months after
`start of experiment
`
`Survivors
`
`Injection site Time of
`sarcomas*
`appearance
`of sarcomas
`(months)
`
`A
`B
`C
`D
`E
`
`16
`8
`4
`2
`0
`
`12ml.
`6ml.
`3ml.
`1.5 ml.
`0
`
`16
`32
`64
`128
`64
`
`3
`17
`29
`71
`33
`
`5
`2
`0**
`3
`0
`
`12, 14, 14, 14,16
`9, 15
`
`13, 14, 14
`
`* All histologically confirmed.
`** One benign fibroma.
`
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`

`110
`
`F. J.C. RoE:
`
`the induction of sarcomas at the site of
`injection is a "local" phenomenon.
`Therefore, it is the actual size of the
`dose and not its size relative to whole
`body size which matters. The size of
`individual cells in man is of the same
`order as in experimental animals and a
`particular volume of injected material
`will come into contact with approxi(cid:173)
`mately the same number of cells in all
`species. Thus the ratio of dose to body
`weight is only of importance if it can
`be shown that the local induction of
`sarcomas by the injected material is
`dependent on a general dose-dependent
`effect on the body as a whole. So far this
`has not been demonstrated.
`
`Evidence for carcinogenicity other than
`local!J at the site of injection
`HuEPER (1957, 1959) examined a
`wide variety of macromolecular sub(cid:173)
`stances for carcinogenicity, administe(cid:173)
`ring them intravenously, subcutaneously
`(by injection or implantation), or intra(cid:173)
`peritoneally to rats, mice or rabbits.
`Only one of 30 substances examined,
`silastic rubber (a silicone polymer), gave
`unequivocal evidence of tumour in(cid:173)
`duction at the site of subcutaneous im(cid:173)
`plantation. On the other hand, many of
`the test substances appeared to increase
`the incidence of tumours of the reticulo(cid:173)
`endothelial system. These findings of
`HuEPER and the observations of HAD(cid:173)
`DOW, DuKES and MrTCHLEY (1961) that
`simple iron salts, such as ferric citrate,
`ferric salicylate, ferrous sulphate, ferrous
`lactate or ferrous gluconate, do not in(cid:173)
`duce injection-site sarcomas, suggest
`that the local carcinogenicity of iron(cid:173)
`macromolecular complexes is attribut(cid:173)
`able neither to the carbohydrate alone,
`nor to the iron alone, but to the com(cid:173)
`plexes themselves. On the other hand,
`the fact that a variety of macromolecules
`seem able to induce cancer of the reti-
`
`culo-endothelial system, suggests that
`there may be a hazard of distant carcino(cid:173)
`genesis, (i.e. the induction of tumours at
`sites distant from the point of injection)
`following the parenteral administration
`of iron-carbohydrate complexes also.
`Most of the tests of iron-carbo(cid:173)
`hydrate complexes for carcinogenicity
`have been designed specifically to study
`the induction of tumours locally at the
`site of injection. For such purposes a
`control group containing the same num(cid:173)
`ber of animals as the test group is appro(cid:173)
`priate. Much larger control groups are
`likely to be necessary for studying the
`effect of treatment on the incidence of
`tumours of all sites and tissues of the
`body. HADDOW and HORNING (1960)
`observed a number of unusual tumours
`in their iron-dextran treated animals,
`including a bronchogenic carcinoma in
`a rat. HADDOW (1963), from a survey of
`his many experiments with iron-dex(cid:173)
`tran, regarded the yield of tumours at
`sites remote from the injection-site as
`"unquestionably significant". But LUN(cid:173)
`DIN (1961) commented on the absence
`of liver tumours in his iron-dextran
`treated animals, despite the large de(cid:173)
`posits of iron in the organ, and RoE and
`LANCASTER (1964) felt that more infor(cid:173)
`mation was necessary before such a
`reached. ROE,
`conclusion could be
`HADDOW, DUKES and MrTCHLEY (1964)
`recorded
`the occurrence of various
`types of tumour in both iron-dextran
`treated rats and in untreated control
`groups. More recently, RoE and HAD(cid:173)
`DOW (1965) observed more
`'distant'
`tumours of various types in rats in(cid:173)
`jected repeatedly with
`iron-sorbitol(cid:173)
`citric-acid than with iron-dextran in
`similar dosage. LANGVAD (1964) repor(cid:173)
`ted an experiment in which 50 male and
`50 female mice of the St/El A strain were
`injected repeatedly with iron-dextran,
`each animal receiving a total of 2 mls
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`

`

`,ts that
`· carcino-
`1ours at
`tjection)
`.stration
`1lso.
`1-carbo-
`genicity
`:o study
`y at the
`poses a
`1e num-
`, appro-
`,ups are
`fog the
`lence of
`, of the
`(1960)
`:umours
`1nimals,
`1oma in
`1rvey of
`·on-dex-
`tours at
`1-site as
`ut LuN-
`absence
`-dextran
`rge de-
`~.OE and
`e infor-
`such a
`RoE,
`r (1964)
`various
`-dextran
`control
`d HAD-
`distant'
`rats in-
`orbitol-
`tran in
`) repor-
`1ale and
`Lin were
`:lextran,
`,f 2 mls
`
`. l
`
`:I
`iJ
`ji
`
`On Potential Carcinogenecity of the Iron Macromolecular Complexes
`
`111
`
`of the substance. Seven per cent of the
`males and 58 % of the females developed
`tumours. The corresponding rates for
`untreated controls were O % and 20 % ,
`respectively. LANGVAD (1964) suggested
`that oncogenic viruses used in other
`experiments in the same laboratory at
`the time might, through contamination,
`have been wholly or partly responsible
`for the differences recorded. However,
`even if it were shown that iron-dextran
`acts as no more than a co-factor in the
`induction of tumours of distant sites,
`its use is hardly to be regarded as being
`without potential carcinogenic hazard
`for man.
`Obviously the problem cannot be
`resolved until the results of careful
`studies on much larger groups of animals
`are available.
`
`Evidence of carcinogenic effect of iron
`macromolecular complexes in man
`To date there has, to our knowledge,
`been no fully acceptable report of the
`occurrence of sarcoma at the site of
`injection of iron-macromolecular com(cid:173)
`plexes in man. CROWLEY and STILL (1960)
`reported the occurrence of a metastasis
`in the buttock at the site of previous
`iron-dextran injections in a case of
`cancer of the cervix uteri. ROBINSON,
`BELL and STURDY (1960) reported a case
`in which an undifferentiated soft-tissue
`sarcoma arose at the site of injection of
`iron dextran into the region of the
`deltoid muscle 3¼ years previously.
`Excess iron was present at the tumour
`site, though it was not proved to be
`iron-dextran. It was thought unlikely
`that the tumour was a metastasis, but the
`possibility could not be excluded. GOL(cid:173)
`BERG (1960) subsequently quoted the
`opinion of Professor R. A. WILLIS that
`the lesion observed by ROBINSON and
`his colleagues was not a neoplasm.
`Where there is a difference in opinion
`
`between pathologists on
`the histo(cid:173)
`pathological nature of a lesion, it is
`logical to take into account the macro(cid:173)
`scopic appearances and clinical details.
`The case history provided by ROBINSON
`and his colleagues is more in keeping
`with neoplasia than with any alternative
`diagnosis.
`In any event, as pointed out by
`many authors, the induction of sarcomas
`in man by injected iron complexes, if
`it occurs at all, is likely to take many
`years. It is still less than 20 years since
`use of this type of iron preparation
`became widespread, so that there re(cid:173)
`mains the possibility that the minimum
`induction period for man has not yet
`been exhausted.
`If the main carcinogenic effect in
`man is a local one, then it is likely that
`it will be observed sooner rather than
`later, since localised soft-tissue sarcomas
`are relatively uncommon. If, however,
`the main danger is a slightly increased
`risk of cancer of many different sites, then
`nothing short of a major long-term
`prospective epidemiological survey is
`likely to reveal the hazard.
`BAKER, GOLBERG, MARTIN and SMITH
`(1961) were interested in establishing
`the carcinogenic safety of iron-dextran
`for man. With this intention, they com(cid:173)
`pared the local tissue response to in(cid:173)
`jection in different species. Rabbits and
`dogs showed less residual iron at the
`injection-site, and a greater hepatic
`uptake of iron than mice and rats.
`Nevertheless, HADDOW, RoE
`and
`MITCHLEY (1964) encountered two cases
`oflocal sarcoma in 6 rabbits injected with
`iron-dextran. Most of the specimens ob(cid:173)
`tained by BAKER etal (1961) from iron(cid:173)
`dextran injection-sites in man showed
`no evidence of fibrosis, but in 2 cases
`fibrosis and the heavy accumulation of
`siderophages were seen. These are
`precisely the changes which precede
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`112
`
`F. J.C. ROE:
`
`tumour formation in experimental ani(cid:173)
`mals.
`
`Is iron, per se, carcinogenic?
`There is no evidence that iron as
`such is carcinogenic, though it is doubt(cid:173)
`ful whether it has been deliberately
`tested for carcinogenicity to an adequate
`extent. There have been no reports of
`incidence of cancer in
`an excessive
`animals deliberately overloaded with
`iron compounds, and with
`simple
`possibly one exception, referred to above
`(see LANGVAD, 1964), the carcinogenic
`effect of iron-macromolecular complexes
`appears to be limited to the site of its
`injection into the body. Overloading
`with iron leads to its excessive storage
`in the liver, i.e. 'haemochromatosis '. In
`this condition the iron is stored as an
`organic complex, for which GOLBERG
`and SMITH (1960) suggested the name
`"haptosiderin ". These workers also sug(cid:173)
`that where haemochromatosis
`gested
`arises spontaneously, it does so as an
`expression of an inborn error of meta(cid:173)
`bolism involving the overproduction of
`haptosiderin. In induced haemochroma(cid:173)
`tosis, on the other hand, the excess of
`haptosiderin is secondary to overloa(cid:173)
`to
`tends
`ding with iron. Cirrhosis
`accompany both spontaneous and in(cid:173)
`duced haemochromatosis, but according
`to GOLBERG and SMITH adequate pro(cid:173)
`tein and vitamin E in the diet delay or
`prevent its occurrence. Although in
`general there is undoubtedly an associa(cid:173)
`tion between cirrhosis and liver cancer,
`in the particular case of the cirrhosis
`which accompanies haemochromatosis
`the association is very weak (SHELDON,
`1935; WILLIS, 1953). FouLDs and STE(cid:173)
`WART (1956) and HuEPER (1956) both
`observed a high incidence of bronchial
`carcinoma in haematite miners, and
`concluded that sidero-silicosis predis(cid:173)
`posed to neoplasia. DOLL (19 58) did
`
`not regard the evidence for the associa(cid:173)
`tion as conclusive, but CAMPBELL (1940)
`reported a higher incidence of adeno(cid:173)
`matous lung tumours in mice exposed to
`mixtures of silica and iron oxide than in
`untreated controls.
`
`The mechanism of carcinogenesis by iron
`macromolecular complexes
`There has been much speculation
`with regard to the mechanism of carci(cid:173)
`nogenesis by macromolecular materials
`in general and by iron-carbohydrate
`complexes in particular. As pointed out
`above, the induction of local tumours
`cannot be attributed solely either to the
`iron or to the carbohydrate moiety of
`the various molecules. Carcinogenicity
`is somehow linked to the nature of the
`complex itself. In this connection it is
`that aluminium(cid:173)
`interest
`of special
`dextran is also highly productive of
`local sarcomas on injection: HADDOW,
`DuKES and MITCHLEY (1961) recorded
`the induction of 11 sarcomas in 40 mice
`given repeated subcutaneous injections
`of this complex. Preparations of chro(cid:173)
`mium-dextran, copper-dextran and bis(cid:173)
`muth-dextran, on the other hand, were
`more or less inactive. The macromole(cid:173)
`cular compounds studied by HuEPER
`(1959) were largely ineffective in the
`induction of local tumours. Hence mac(cid:173)
`romolecularity itself is not a sufficient
`explanation of carcinogenicity.
`HADDOW and HORNING (1960) sug(cid:173)
`gested that blockage of the reticulo(cid:173)
`endothelial system with, perhaps, inter(cid:173)
`ference with immune processes might
`be implicated. FIELDING (1962) saw
`evidence of lymphatic blockage after
`the injection of iron-dextran or iron(cid:173)
`dextrin, but not after injection of iron(cid:173)
`(1959)
`sorbitol-citric-acid. RICHMOND
`suggested that the carbohydrate com(cid:173)
`plex might enable the passage of iron
`across intracellular membranes normally
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`the associa(cid:173)
`·BELL (1940)
`: of adeno(cid:173)
`:-e:i.posed to
`cide than in
`
`nesis by iron
`
`speculation
`;m of carci-
`1r materials
`1rbohydrate
`:>ointed out
`:al tumours
`ither to the
`moiety of
`:inogenicity
`iture of the
`ection it is
`aluminium(cid:173)
`,ductive of
`HADDOW,
`'.) recorded
`in 40 mice
`; injections
`1s of chro(cid:173)
`.n and bis(cid:173)
`hand, were
`nacromole(cid:173)
`,y HuEPER
`ive in the
`-Ience mac-
`1 sufficient
`'{,
`)960) sug(cid:173)
`e reticulo-
`1aps, inter(cid:173)
`sses might
`1962) saw
`kage after
`:1 or iron(cid:173)
`>n of iron(cid:173)
`(1959)
`-.D
`irate com(cid:173)
`ge of iron
`:s normally
`
`On Potential Carcinogenecity of the Iron Macromolecular Complexes
`
`113
`
`impervious
`to
`it. He subsequently
`(RICHMOND, 1962) showed that iron(cid:173)
`dextran gives rise to cytological changes
`indicative of intracellular oxidation. He
`thought that the changes were not
`dissimilar from some of the effects of
`ionising radiation, and suggested that
`they could explain the carcinogenicity of
`iron-dextran. TURNER (1964) reported
`that the response of fowl fibrocytes
`grown in vitro, to iron-dextran, resem(cid:173)
`bled that to known carcinogens. HAD(cid:173)
`DOW and HORNING (1960) reviewed the
`literature concerning the interference
`with iron metabolism by carcinogenic
`agents, but came to no real conclusion
`with regard to the likely mechanism of
`action of iron-complexes.
`It is, perhaps, tempting to regard
`carcinogenesis by iron-carbohydrate com(cid:173)
`plexes as being related to carcinogenesis
`by other metals, e.g. arsenic, beryllium,
`cadmium, chromium, cobalt lead and
`nickel (see RoE and LANCASTER, 1964).
`However, on present evidence it would
`certainly be unwise to presume that this
`is so. In the cases of all the other metals
`the evidence strongly suggests that the
`metal itself is implicated. But in the
`case of iron, the only acceptable evi(cid:173)
`dence of carcinogenicity relates to iron(cid:173)
`carbohydrate complexes and, possibly,
`combinations of iron with silica. Alumi(cid:173)
`nium alone behaves in a similar fashion.
`RoE and LANCASTER (1964) suggested
`that the induction of cancer by the sub(cid:173)
`cutaneous injection of chemically un(cid:173)
`reacti ve materials such as
`the iron
`macromolecular complexes may be more
`akin to the " Oppenheimer effect" than
`to chemical carcinogenesis. On the other
`hand, HuEPER (1959) contended that
`chemical mechanisms have not been
`excluded in the case of sarcoma induc(cid:173)
`tion by the implantation of plastic mate(cid:173)
`rials. Moreover, as RoE and LANCASTER
`(1964) themselves pointed out, by no me-
`
`8 Potential Carcinogenic Hazards
`
`ans all chemically unreactive substances,
`even those which remain permanently
`at the injection-site, induce sarcomas.
`The consideration of the mechanism
`of carcinogenesis by iron-carbohydrate
`complexes should, perhaps, begin with
`a description of the changes which
`precede the appearance of tumours. On
`this subject there is general agreement
`that the first change is the uptake of the
`injected material by histiocytes (sidero(cid:173)
`phages). In these cells the iron is there(cid:173)
`after stored as newly formed ferritin
`(MuIR and GOLBERG, 1961). Sidero(cid:173)
`phages are also found in the local
`lymph nodes, and other cells of the
`reticulo-endothelial system, generally,
`take up and store the iron as ferritin.
`However, the movement of iron away
`from the injection site, certainly in
`animals overloaded with iron, is slow
`(BAKER, GOLBERG, MARTIN and SMITH,
`1961) and both siderophages and extra(cid:173)
`cellular iron-containing material per(cid:173)
`sists locally until tumour development
`ensues. The development of a mass of
`siderophages clearly depends on the
`proliferation of histiocytes and in some
`instances this proliferation leads to the
`formation of a histiocytic neoplasm
`(histiocytoma) in which many of the
`cells are not laden with iron. After a
`period of some months, depending on
`the species, proliferation of histiocytes
`gives place to fibroblastic activity. It is
`not certain whether fibroblasts are deri(cid:173)
`ved from siderophages or merely sti(cid:173)
`mulated to divide by the presence of the
`siderophages. The onset of fibroplasia
`is appreciable, clinically, in that the
`injection site becomes firm and thicke(cid:173)
`ned. Such areas of thickening remain un(cid:173)
`changed or enlarge slowly over a period
`of several months. Suddenly, usually it
`seems from one edge of the thickened
`lesion, a rapidly growing nodule appears.
`The growth of this lesion is progressive
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`114
`
`F. J.C. ROE:
`
`and necessitates
`the sacrifice of the
`animal within a matter of days or weeks
`from the time it first became palpable.
`The stage of fibroblastic prolifera(cid:173)
`tion appears to be an essential prelimi(cid:173)
`nary in the induction of sarcomas. This
`is true not only of their induction by
`iron-macromolecular complexes but by
`all agents, including implanted sponge