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R&S 136059
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Occupational carcinogenesis
Cesarc Maltoni
htitutu di Otmilugiu 'F. AddarWand Centro Tumuri, Holoyna. Italy
Occupational carcinogenesis is one of the most interesting, tragic, important and difficult fields in oncology.
It is interesting from the scientific point of view because it represents, dramatically, an experiment in carcinogenesis made on humans and it may teach us a lot about the natural h'story of tumours. It is tragic from a human point of view, because work which is per se a natural necessity of life, should not, at least, cause cancer. It is socially important be.j isc oncogenic factors increasingly are produced and diffused in occupational environ ments. Moreover Stow the factories they spread to the general environment, so that they come to be an ecological problem, Finally, occupational carcinogenesis is a difficult field to approach, because 'he care of the workers1 health is often in conflict with the product ive interests of the factories.
Industry has done a lot for experimental carcinogenesis, related to occupational can cer; often however the result is merely to prove the carcinogenic effect in animals of agents which have already proved to be carcinogenic for man: this is equivalent to saying that many people die of cancer but some make their living from cancer. On the other hand emotional arguments should he avoided. Thus I am aware that speaking on occupa tional carcinogenesis is a complex and diflicull task.
Experimental carcinogenesis did not start with the experiment of Yamagiwa and Ichi kawa in |9|f, but rather in the Ibth century with the observation of the so-called 'mountain disease' in miners of Joachimisthal. This disease was recognized at the end of the last century as pulmonary carcinoma, which we now know is due to radio-active pollution, present in those mines. In 17"*5 I'ercival Pott in Thirurgical Observations' de scribed a cancer of the scrotum in chimney sweepers and he correlated it with the black soot. In 1H94 Unna reported on the frequency of skin cancer found in maritime workers, and he considered it due to excessive exposure to sun light. In IK95 Rehn, a surgeon from Frankfurt, reported at the congress of the German Society of Surgeons, 3 cases of bladder tumours found among 45 workers from a factory which produced fuchsme. He though! that the tumours were caused hy aniline, hut in fact it was shown, several decades later, that they were due to other aromat'c amines. In 1902 at a meeting of the Medical Society of Hamburg, Frieben presented a case of a cutaneous tumour found on the hand of an employee of a factory picducing X-ray apparatus. This employee used his hand for radiological demonstrations.
The frequency of reports on occupational cancer has been increasing wi'h the increase of industrialization, mainly due to the progress of chemistry. The most important thing to do in occupational carcinogenesis is to try to recognize occupations which may re present an oncogenic risk, and to identify the agent or agents which cause the risk, and also to try to assess the degree of risk. If the risk is related to an agent already known to he oncogenic for man, its detection in the occupational environment should be considered sufficient for undertaking preventive measures. On the other hand if the risk is related to agents, whose effects on workers have not yet been studied and arc therefore not yet known, ihen we have to evaluate the risk they represent for workers. This can be done hy means of epidemiological investigations and experimental testing. Most oncogenic occupa tional agents have >>een identified on Ihe basis of retrospective epiJemiological studies.
The progress in and the development of this hranch ot oncology should facilitate systematic experimental testing of agents heavily releaseJ in the occupational environ-
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R&S 136061
meeting aiul annnuuin'>. hut ot course. in tin* meantime the exisim;' >ucupjliona!
exposure continues. Also, impeded testing, tor example the snhcul aiieouc iiiieciioti in the
rat of compounds, to which man is exposeJ tnainl) t*> the respiratory route, may give
some idea of their potential oncogenic rt.sk.
In Cable I. data are reported on the induction of tumours lummijii at the site 1
the subcutaneous injection ot some inorganic pigments. I rom these daU n slcarly appeal,
that chromium and cadmium pigments should l>e considered riskier than iron pigments
I'rom what has been said betore. the compounds shown to l>e carcinogenis m these
conditions, should now be tested by inhalation. I'he latter way ot exposure implies the
availability ot a complex apparatus for continuous tnluljlion <>t controlled doses | he
apparatus is quite rare, js we discovered when we wanted to build one jnd we were not
ahle to find any model in our own or any neighbouring country. Now an apparatus lor
inhalation of gaseous compounds has l*een functioning tor more than two years m the
experimental unit of our institute ll-'ig. I i.
With this apparatus we ate now perlorminc a carcinogenicity t'ioa"j> ot sunt
chloride monomer (VC) and ol vinyl asetate monomer 1VA1. w his li jre t particularly the
first t ol great industrial importance VC is used m the preparation ot polyvinylchloride
resin, as a copolymer in saran and other plastics as a solvent and as a ctiemic.il inlet*
mediate, and it is at present produced jt a rate ot I d.(Mill.who om, por year I arly
results on these bioassaysare shown in I able d
Zymbal glands carcinomas,'liver angiosarcomas luce neser been ot.sen cd as m , urroig
spontaneously in our breed ol Sprague-lJawiey tais
Only 3 cases ol spontaneously occurring /ymh.i! el unis cat. itioinas in rais i Sprague
Dawlcy I have been recorded in I'Kn I o our know ledge, no spontaneous nephroblastomas
and hver angiosarcomas cd rats have been reported m the literature
tat .i' we know,
nephroblastomas have never been reported to be experimcittalk induced m r.ii'. liver
angiosarcomas have been induced in tins species by dieihy liuirosamme
Although hver is the preletetuiai site lot onset <>l aneiosarcomas such kind
tumours have been observed m other tissuev and oig.ins tlierelore St should be con-
sidered in our experimental condition*, cenctully sane erogenic b>r eml.dlielu
Zymbal glands tumours and nephroblastomas may be bilateral licer angiosarcomas are
often multiphocal
Hptdeiuiological investigations and medisal controls should be undertaken on exposed
workers Would such neoplastic neoplasia unhappily be toutul in nun. given the rarity ol
these tumours in both animals and humans, il would be a precise indication *d the high
value of experimental testing in predicting the oncogenic potential ol environmental
agents and would strengthen the recommendation on llie necessity ot sudi bioas.ays
before any new industrial compound is produced and widespread in large scale
Another means of revealing the oncogenic risk ol an jgenl is to examine the exposed
working populations with methods which make it possible to assess the incidence ot
cancer precursors. The incidence of sikli precursors has l>eeii siudied by by exfoliative
cytology among asymptomatic, apparently healthy workers exposed to risk, namely
among workers exposed to aromatic amines (urine cytology), and among workers ex
posed to chromates (sputum cytology I. The incidence of cellulat alypus in these two
groups-of workers is shown in Tjblcs 3 and 4. It tar exceeds the expected incidence.
To evaluate in medical and legal terms the risks represented by occupational oncogenic
agents, we must consider that
1, a direct relation exists between Jose (jiiiouni and length ot exposure) and neo
plastic response.
2, the onVogemc agenis produce mainly non-reversib.e changes, winch may continue
to d p when the exposim* i- i,*ierriipted,
3, me oncogenic* agents occupational or generally environment at i in iy *'e additive in
their effects.
According to our knowledge the occupational carv;nogenic agent' nuy be classilied as
lul detuir'e carcinogens when epiJemiologK.il evidence exists.
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AmnuK lSprapie*l>avUe\ ratsi
Total
Survivors
Zytnhal glands t\m inonus
i A1
No.
AmnuK v.nh lunuum
Nephrobla stomas tU)
No.
Angiosarcomas .... -
1 ivot
Other
to Mies
No. No.
tu\u1ui&r ti j pc and/oi Mte
No.
Total No.
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VA 1.5IH) ppm.
46 15
11 \c 1 I1.IIIH) ppm.
64
I1 1 b
5 lilt
17
Ill V( 6.IHU1 ppm.
IV VC 1 ..Sim ppm.
V Vl- 51 It i ppm.
VI VC 'Ml ppm.
VII \c Ml ppm
7' 6 7-1 16 67 15 67 'll 6-1 It
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i\i Metjsijses lo luny. I Hi Mei.isl jscs to In or jmUor 10 lur^ jnJ spleen K ) McijsIjscs u lune. f I > 1 4n>no\jreotnjs in suhcul jneous llbiovinj: unyioiru. tl I * inlf al'Ji'miiul .inpiovm onus (I revi lo spleen jiuI I nc\i loovjn I: t e>Mh m|' jn^'sjnimu ol iuvA. (Ill pulmonary jn^iosjrcomj: 1 jneiosareorm "l ulerus. (Oil mu jluU'minjl jiihiunju om.t inew lo spleen I. 1 ml rjthor.u i. o*sif> me jnpiosjKom.i. flh - /wnlu] cIjjiJs adenomas; l neurilemmoma ol` Ihe e.ii. \ in.itmii.m e.ireinom.*: I e> si>*.ulen<K .iremorn.i of o/.ir>.(ll SeKjt eoiis ri.iin! v ju inoina ol skm M I /vinlul elamk adenoma. iMi Minimal deviation hepjUMiu |N) t /1 mlul elands .uteri.mu. I v4njj\ el injs <, aiemom.i
M
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V* ot w01 keiv inulei 5 outrol
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l }n 4* 41* > *4 *0
(l> u 4oeie.il 1 losses 1`jp.mu <*1.10111
11 M ill m un\
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1 ji lory
A It r i)
r.iui
No. ot' u'orkers iinJi'i cormul
'12 159 40 41
472
(`yinioniL j!
l 141 It 11-111
Ill ui-iv IV 1V-V
4H 46 114 14
58 'll
49 25
11 H
73
16 15
9l
7i 5 8i
133 H9 179 4 3
:n
V 1
TABl.l. 4 hrt'l/uf/fiT d/ adenomatous typical anJ atypical hyperplasia, and of u/uamout melaptasia and dysplasia. in worker! exposed to chromium cornpounds in one Sonhern Italian factorc
Type ot iH'L'upjiion Vunlui Utin ul' ihft'hiali'v jrui tlu hmmj u*>
I'risJiation m1 t hromiu in piy mem
l ength of exposure (yearvl
l-onylh
No.
V'p to 5
6 10
11 15 Oki 15
25 14
13 17
1 mIjI
69
lip to 5
6 10
11 15 Over 1 5
14 17
8 8
I mi jI
47
Typiiiil j<Jeru>rrutiiu& Kypeiplj-ia
N.i f7
3 12 3 21 3M
9 13
17 l6 l 12 1 25
5 111
Atypicjl jiitrmmjtoui hypttplj\ij No. 1
17 3 23
16
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Squymou* nctjplaiu
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Squamoui dyipbiij
No.
24 '
12 12
15
63
14 14
6 8
42
*'i No. f%t
96 4 16 H6 3 V 1 92 4 30 Hit 4 23
91 15 11 ................... ... ......... -- -- - - ' '
too 82 1 \ 1 75 1 p 100 3 25
89 5 ID
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(h) highly suspected carcinogens, when strong experimental and/or some epidemio
logical evidence is present. (c) potential carcinogens, when experimental data give some indication of carcino
genic action of a compound on an experimental animal. According to their effects, the carcinogenic agents may be classified as strong or
medium. The agents, which have been definitively proved or are suspected to be oncogenic for
man on an epidemiological basis, are listed in Table 5, together with the target tissues and the degree of evidence. The list of the agents present in the occupational environment, which, on an experimental basis should be considered highly suspect or potentially carci nogenic for man, is reported in Table 6.
TABLE 5 Agents proved nr suspected to he oncogenic l"r workers on an epidemiological bans
Agents U.V. radiations X-rays
Uranium ore Arsenic
Asbestos
Chromium Nickel
Iron ore his-chloromethyl ether Benrene tsopropylic oil Soot, tars, mineraloils, suiting oils Carbon black Mustard gas Aromatic amines
Evidence * * * (*J
*
t*) * *
( *) *
*
Tumours
Skin carcinoma-.
Skin carcinomas Leukaemias
l*ulmonaty carcinomas Skin carcinomas (tun): carcinomas! Lung tarcinomjs Pleural mcMithcliomas (abdominal malignancies)
Lung safemomas
Lung carsim-mas Carcinomas ot nasal and parjiusal sjsmc'
Lung cars momas Lung carcinomas
Leukaemias Carcinomas ol paranasal unties
Skin carcinoma
Lung aronumi'
laryngeal cars momas
bladder and upper urinary trji I .jumumn
TABLE 6 Agents suspected t > be ea'i mogenu hie workers on an ecperimen'al Non
Beryllium Cadmium Cobalt Lead
Selenium Zinc Carbon tetrachloride
Chloroform Vinyl chloride
^csticidcs (UUT, aldon. dicldon. Aramitc. I>stl)T.
\nn/ul. Ihruram. I nmurca and rdalrd snmpuurtJs
Tannine IJelc-rgcnls
Alky taring agents N.irosamincs
Aru-dyes
Oe-lrogens
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In lialy carcinog la) exposed to produced; tb) exposed to (i I exposed to workers in factories Idi in factories tel in factories ill in the dye i In our country tioned workers, 21 chromate factory i workers in asbestowho were heavily ITovmee and Tuse among workers in workers had heen lucnsme, ,s.i -mem and hcn/.idine has carcinogenesis is a
1'he methods of 1. correct expe 2. up d^^te <
.1. legisl^^^ m have been shown t especially if the sail
4 measures of be produced or em Public Health Inspe
' specific med preneoplastic lesior r-ckc llirnugh the in
li is my opmior epidemiological, hi mamlc located in We know that thev some way affected
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7
In Italy carcinogenic occur
risk exists lor workers who are
la) exposed to chromates - iy the ones working in factories where chromates are
produced; (h) exposed to nickel, mainly the ones exposed to nickel-carbonyl.
/t ) exposed to asbeslos. mauily the ones who extract it Irom tK natural source, or
worker/; in factories where asbestos is used tor manufacturing;
IJ) in factories making shoes, puncs and raincoats, exposed to benzene.
It) in factories producing carbon black from mineral oils, and
If) in the dye and rubber industries, exposed to aromatic amines
In cur country occupational tumours have been observed in man) o! the above men
tioned workers. 21 lung carcinomas have been found among less than 2 JO workers in a
chromate factory in Northern Italy. Pleural mesotheliomas have l>een discovered among
workers tn asbestos mines. A number ol leukaemias have been found among shoe-makers
who were heavily exposed to benzene, in lactones in I ombardy (Vigevjnoi. Bologna
Province and Tuscany. Ihe incidence of bladder and other urinary tract carcinomas
among -corkers in 5 Italian dye-siufl lactones arc shown m Table 7 |n these factories
workers had been exposed to (3-naphthylamtne. ben/tdtne. o-naphthylamtne. Auramwe.
fuchsmc, S.S'-dichlofoben/idtne Now in our country Ihe production ol .,-naphthy lamtne
and tenzidinc has been withdrawn. One may conclude that prevention ol occupational
carcinogenesis is a very urgent problem.
The methods of prevention may be summarized as follows
1. corTect experimental testing of all newly used agents;
2. up to date epidemiological data from various categories of workers exposed to
risk;
3. legislative measures forbidding the production and the utilization of agents which
have been shown to he oncogenic on an epidemiological and/or an experimental basis,
especially if the said agents are strong carcinogens,
4. measures of technical protection, when weak or doubtful carcinogens continue to
be produced oi employed, these protective measures should be per.odicallv examined *'>
Public Health Inspectors. 5. specific medical checks to msec possible, on the one hand, the early deled' *ti o.
prcncoplaslic lesions and tumours, and on the other, the tfuantiiative evaluation the
risks through the incidence of these changes.
It is my opinion that the value ol medical checks is mainly to evaluate the risk that is
epidemiological. Early delect.on of occupational tumour* which, as already shown, are
nuinlv located in the respiratory and urinary trad, has l-eeit. I think, over-emphasi/cd.
We know that these tumours are multicenlris In other words all the target apparaius is in
some way affected by the carcinogenic process
TABU 7
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( oneerttuijt the unnary trad. in .1 systematic histologicaf study, I have seen that in patients with bladder lumour'. dyspldslic and cancerous loci may he detected Imm renj) prists to unrthn Therefore it t' obvious that in such conditions early dijjuiosis van achieve very little. We may diagnose some tumour' quite early, hut on the basis n| I ' yean' experience with periodic -hecks ol wotkers exposed to hi)th risk. I doubt that periodical medical examination has a real hearing in suvintt people with occupational -ancet although detected early, or in prolonging their life span. I bus my position is in sharp contrast with those who claim to `protect' < ') workers exposed to carcinogenic risk with medical examinations I J<< hrltete Unit the iitrnti</litiei nt mejnu! ex^rtnnutimn thiiulj he eveluiitej jt jn infemu/ionu/ leret
In conclusion, I would like to emphasize the need of a close collaboration among scientists, public health services, workers unions and industries, to evaluate the risks and to device preventive measures tor avoiding or minimizing occupational tumours
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R&S 136066