The Role of Asbestos Fiber Dimensions in the Prevention of Mesothelioma

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					                                               Special Contributions

The Role of Asbestos Fiber Dimensions
in the Prevention of Mesothelioma

A recent interpretation of the pathogenetic role of                      Chiappino’s published interpretations need to be
asbestos fiber size in the development of mesothelioma                 corrected or clarified with respect to:
and in the possibility of mesothelioma prevention
needs clarification. This point of view is based on a                     1. the role of fiber dimensions (length and diameter);
biased interpretation of the literature. Epidemiologic,                   2. the alleged predictability, but not preventability,
experimental, and molecular evidence suggests that                     of mesotheliomas until the 1980s, and role of exposure
the arguments for the role of fiber size relative to dose,
                                                                       dose and the dose–response effect;
dose–response effect, and genetic susceptibility are sci-
entifically unsound. Their proponent also states that                     3. the alleged role of genetic susceptibility in deter-
means available in the past for the implementation of                  mining the risk of developing mesothelioma; and
dust-control measures and/or personal protective                          4. the alleged uselessness of dust control measures
equipment would not have contributed to reducing the                   and ineffectiveness of personal respiratory protection
frequency of mesothelioma among exposed subjects,                      equipment for reducing exposures.
an argument again based on invalid assumptions. Key
words: asbestos; mesothelioma; prevention.                             The Role of Fiber Dimensions
I N T J O C C U P E N V I R O N H E A LT H 2 0 0 7 ; 1 3 : 6 4 – 6 9   Chiappino states as a given fact that only “ultrashort”
                                                                       and “ultrathin” asbestos fibers are able to reach the
                                                                       parietal pleura and lead to the development of malig-

          n unsound hypothesis, positing a role for fiber
                                                                       nant pleural mesothelioma. His statement is based
          size in the pathogenesis of mesothelioma and
                                                                       mainly on three publications 2–4 that allow him to assert
          debunking the potential effectiveness of dust-
                                                                       that ultrathin fibers are “the only dimensional size class
control measures that were available by the mid 1980s
                                                                       that can get past the lung–pleura barrier.”
for its prevention, has recently surfaced in the medical
                                                                          A thorough reading of the papers he quotes reveals
literature. Its author, Chiappino,1 has arrived at erro-
neous conclusions based on arbitrary interpretations of
                                                                          According to Paoletti et al.,2 “about 80% (48/60) of
selected earlier reports. A danger is that his conclu-
                                                                       the fibers found were under 5 µm in length, and 68%
sions, which are not scientifically valid, could be used to
                                                                       were under 0.3 µm in diameter,” while according to
support unjustified acquittals of negligent defendants
                                                                       Boutin et al.,3 “a total of 22.5% of fibers were ≥ 5 µm in
in the courts.
                                                                       length in black spots” (the small dot-like spots of the
                                                                       parietal pleura near the lymphatic stomata). In these
    Received from the International Society of Doctors for the Envi-   areas fibers 8 µm or more in length accounted for 8%
ronment (LT); the Occupational Health Unit, National Health Ser-       of all fibers, those 15 µm or longer, 2.1%;, and the max-
vice, Milan, Italy (SC); the Occupational Health Unit, NHS, Flo-       imum length recorded was 29 µm; the geometric mean
rence, Italy (FC); the Venetian Mesothelioma Registry, Occupational    of the diameter was 0.13 µm, greater than that of the
Health Unit, NHS, Padua, Italy (EM); the University of Turin, Italy,
Professor emeritus (FM); the Occupational Health Unit, NHS,
                                                                       fibers found in the lung, which was of 0.10 µm. The
Mantua, Italy (PR); the Tuscany Mesothelioma Registry, Center for      conclusions were that “long amphibole fibers concen-
Study and Cancer Prevention, Florence, Italy (SS); Environmental       trate in the same structures of the parietal pleura that
Epidemiology, Imperial College, London, U.K. (PV); and the Center      trap other particles such as coal dust.”
for Oncological Prevention, CPO, Turin, Italy (BT).                       According to Suzuki and Yuen,4 “the majority of
    Address correspondence and reprint requests to: Benedetto Ter-
racini, Center for Cancer Prevention, Region Piemonte, Torino, Italy
                                                                       asbestos fibers detected in the lung and mesothelial tis-
(via Santena 7, 10126 Torino, Italy); e-mail: <benedetto.terracini@    sues were shorter than 5 µm”; in the study published in>.                                                        2002, the fibers longer than 5 µm represented 10.5%,

while in a previous study5 they reached 18.6%. The                tors to the potential for development of asbestos-
conclusions were that “such short, thin asbestos fibers           related diseases.21
should not be excluded from those contributing to the             Clearly, fibers of the type and size known to be asso-
induction of human malignant mesothelioma,” which                 ciated with the greatest risk of mesothelioma do, in
is very different from saying that they are the sole agent        fact, migrate to pleural tissues.22
in mesothelioma induction.
    Even based on a more recent pathology study,6 the             The large majority of fibers detected in the omen-
principle of “contribution”—not of exclusiveness—of            tum and mesentery of 20 occupationally exposed work-
fibers that are equal to or shorter than 5 µm in length        ers suffering from mesothelioma, inclusive of three
and equal to or smaller than 0.25 µm in diameter in the        shipyard workers affected by peritoneal mesothelioma,
development of mesothelioma is confirmed. There is             were longer than 5 µm, so that Chiappino’s view is def-
no evidence that only ultrathin and ultrashort fibers          initely not valid for peritoneal mesotheliomas, repre-
penetrate the pleura, since, although the smaller fibers       senting about 10% of all mesotheliomas.12
are in the majority, larger fibers are also present in the
parietal pleura, both in the material examined in the          Alleged Predictability, but Not Preventability,
studies cited by Chiappino and in other studies by the         of Mesothelioma until the 1980s, and the Role of
same authors.                                                  Exposure Dose and Dose–Response Effect
    Furthermore, the common occurrence in the pari-
etal pleura of “black spots” shows that the lung–pleura        The first scientific articles on the carcinogenic effect of
barrier is not at all impassable, even for particles much      asbestos on the mesothelium appeared in the 1960s, on
larger than “ultrathin” and “ultrashort” fibers. These         the basis of clinical evidence in exposed workers.23 In
parietal pleura agglomerates, which contain carbona-           1964, the conference on the biological effects of
ceous pigments and mineral fibers, have been found in          asbestos organized by the New York Academy of Sci-
92.7% of 150 consecutive autopsies of inhabitants of           ences ratified the general consensus of the scientific
urban areas in Belgium.7                                       community on the carcinogenic effects of asbestos. In
    Chiappino states such findings as “not physiological,“     that conference the first cases of pleural mesothelioma
and “likely linked to transitory increases in the perme-       in asbestos workers in Italy were described and pre-
ability of the lung–pleura barrier due to inflammatory         sented by Professor Vigliani,24 who had been Chiap-
events or other situations influencing the direction of        pino’s professor at the University of Milan. In 1977, the
the lymphatic flow.” The relevance of such an obvious          IARC classified all types of asbestos in the group of
statement, in respect to asbestos exposure and the con-        known human carcinogens.25 In the 1960s, asbestos-
sequent induction of mesothelioma, is not clear, since it      exposed subjects were already under mandatory health
refers to a phenomenon that certainly is not physio-           surveillance by occupational physicians in many coun-
logic. It is well known that benign effusions (precisely by    tries, including Italy. No occupational physician, there-
pleural transudation and/or exudation) are the first           fore, from the mid 1960s onwards, could be unaware of
reactive manifestations that might later lead to those         the carcinogenic effect of asbestos on the mesothe-
features of diffuse pleural fibrosis considered among          lium, and consequently of the need to give indications
the indicators of previous exposure to asbestos.8,9            to those in charge within the companies of the rigorous
    Moreover, Gibbs et al.10 found long fibers of commer-      measures of environmental prevention and individual
cial amphiboles in subjects with diffuse pleural fibrosis,     protection that were needed.
while Dodson et al.11 have shown the presence of similar           Chiappino states that the means for prevention that
fibers in pleural (parietal) plaques of asbestos workers, as   could have been applied before the 1980s to eliminate or
well as in the peritoneum and in the mesentery.12              reduce the risk related to exposure to dusts were efficient
    Starting from the lung, asbestos fibers can reach          to prevent asbestosis, which is caused by inhaled fibers of
other organs by direct or macrophage-mediated migra-           all dimensions, but not mesothelioma, which is caused,
tion, or by diffusion through the lymphatic and blood          he repeatedly emphasizes, exclusively by ultrathin fibers.
vessels.4,12–19 In addition, once they have reached the        The inconsistency of this argument is shown above.
lung, asbestos fibers can undergo transformation and               It has been repeatedly claimed that mesotheliomas
degradation processes that might result in reducting           can be caused by light and/or brief exposures.26–30 A cut-
length and diameter.20                                         off “in the region” of 5 fibers/mL of air/year was sug-
    Our concerns about Chiappino’s statements are also         gested for amphiboles.31 However, in a later, ample epi-
supported by other scientists conclusions:                     demiologic survey carried out in France,32 a significant
                                                               excess of mesotheliomas was observed for levels of
   Asbestos fibers of all lengths induce pathological          cumulative exposure as low as 5 f/mL/year or lower,
   responses and caution should be exerted when                below the limits of acceptable exposure adopted in many
   attempting to exclude any population of inhaled             industrial countries in the 1980s. The IARC stated, as
   fibers, based on their length, from being contribu-         early as 1977,25 that there is no proof of a cut-off level of

VOL 13/NO 1, JAN/MAR 2007 •                                         Role of Asbestos Fiber Dimensions   •    65
exposure to asbestos below which there is no risk,1 a         ral carcinogenesis caused by asbestos. Indeed, what is
statement that was repeated by Doll and Peto in 198533        known about induction and growth of tumors strongly
and, more recently, citing Selikoff,34 by Motley et al.35     suggests that the progressive and irreversible develop-
   Some authors have declared themselves in favor of          ment of the tumor cannot take place at the beginning
recognizing a cut-off level on the basis of the assumed       of exposure or shortly thereafter. In fact, if models of
levels of exposure of asbestos-related mesothelioma           time of reduplication of tumor cells—developed on the
cases,36 but according to Hodgson and Darnton37 the           basis of studies carried out on this topic59–63—are
direct confirmation of a threshold based on human             applied, for instance, to the period elapsing between
data is virtually impossible, and case–control studies        the beginning of the exposure and the clinical mani-
with measurement of pulmonary asbestos content38–40           festation of a case of mesothelioma with a latency of
do not suggest any threshold, or any tendency of the          >10 years, the tumor mass would reach paradoxical
steepness of the dose–response curve to decrease at the       dimensions. Therefore, “self-sufficiency” of the neo-
lower ends of their scales of exposure.                       plastic process of the mesothelioma at the beginning of
   At the end of the 1960s, it was already evident that       such a period of latency is hardly tenable. If asbestos, as
increased risks of mesothelioma correlate with                is generally recognized, is a complete carcinogen, i.e.,
increases in both intensity and duration of exposures to      it can both induce and promote cancer, its promoting
asbestos, and thus with the overall dose of inhaled           effect must be considered effective up to complete
fibers,41–43 and that lower cumulative doses lead to          induction, and therefore for a prolonged period of
longer latency periods for the onset of mesothelioma.         exposure. Therefore, contrary to Chiappino’s thought,
This observation has led to the consideration that a          the persistence of exposure after an initial first expo-
reduction in dose, i.e., applied prevention, will at least    sure can never be considered irrelevant.
postpone the appearance of mesothelioma.43–46
   Later, the HSE’s asbestos workers’ mortality survey in     The Relevance of Genetic Susceptibility in Determining
England and Wales demonstrated that workers first             the Risk of Developing Mesothelioma
exposed to asbestos before the implementation of the
1969 Regulation, and thus exposed to higher intensities       The argument used by Chiappino is that individual sus-
than thereafter, had a higher frequency of mesothe-           ceptibility must play an important role, since only 10%
lioma than those first exposed only after 1970, showing       of the people exposed to asbestos develop mesothe-
that “prevention,” intended as a reduction of intensity of    lioma.1 This proportion, however, does not differ much
exposure, reduces the occurrence of mesotheliomas.42          from those associated with other environmentally
   These observations then found authoritative confir-        induced carcinogenic events in humans. In addition,
mation, and finally a computation of risk according to        the argument is faulty because it does not consider the
dose and latency.48,49 The doubts raised by some              very long latency period before mesothelioma arises,
authors50 about the existence of a dose–response rela-        sometimes more than 40 years, and that exposure does
tion for mesothelioma refer to particular case studies,       not start at birth and that to observe a 100% incidence
often characterized by very high exposures, whereas           exposed individuals should be followed for time peri-
Peto’s formulas answer the majority of observations and       ods longer than their lifespans.
are almost unanimously supported by the scientific com-          While the development of mesothelioma in individ-
munity. More recently, other authors51 observed a signif-     uals who have had only months of low-level exposures
icant dose–response correlation for pleural mesothe-          to asbestos64 may suggest that individual susceptibility
lioma in a cohort of 5,000 Londoners exposed to               could play a role, other studies actually suggesting
asbestos between 1933 and 1980. Various authors have          familial mesothelioma clusters65 contain serious falla-
verified a significant increase in the risk of mesothelioma   cies66 and provide poor evidence for such a role. Genes
correlated with the increase in pulmonary asbestos con-       that have been implicated in other studies are NAT2,
tent detectable by electron microscopy.52–55                  GSTM1, and DNA repair genes. The evidence is con-
   The epidemiologic findings are also confirmed by           tradictory (e.g., both NAT2 rapid acetylators and slow
experimental studies showing that a reduction in dose         acetylators have been suggested as being at high risk)
lengthens the period of latency of mesotheliomas, and         and associations are weak., making its biological plausi-
in this way reduces their incidence, since the duration       bility highly questionable.
of latency exceeds that of the life of rats.56,57 In-vitro
studies58 of the damaging effect of asbestos corpuscles       The Alleged Uselessness of Dust-control Measures and
on DNA, which is strongly inhibited by the chelating          Ineffectiveness of Personal Respiratory Protection
action of the leukocytes, also supports the relevance of      Equipment for Reducing Exposures
continuous inhalation of “fresh” fibers for the onset of
mesothelioma.                                                 Chiappino states that “mesothelioma in the ’60s,’70s,
   Chiappino emphasizes the role of the “trigger dose”        and ’80s had the requisite of predictability, but it could
as a short-lasting and irreversible phenomenon in pleu-       not be prevented with the technology of dust control

66   •   Tomatis et al.                                         • INT J OCCUP ENVIRON HEALTH
available at that time in occupational settings.” He pos-          Furthermore Chiappino asserts, without citing any
tulates that a systematic error was introduced in the          supporting reference, that personal protective equip-
field of industrial hygiene when it was decided to con-        ment was ineffective for respiratory protection. Indeed,
sider only fibers ”subject to regulation,” neglecting all      filters do not work as “sieves,” but they are able to stop
those under 0.5 µm in diameter, which, instead, are in         particles and fibers of much smaller sizes than those
his view the ones solely responsible for biological reac-      indicated by the manufacturer as filtering capacity. This
tions. He also claims, paradoxically, that air extractors      happens because very small fibers and particles tend to
with filters unable to stop the ultrathin fibers were          deposit around the openings between the threads of the
responsible for disaggregating the large asbestos fibers,      filtering fabric for diffusional and electrostatic reasons,
thus increasing the risk proportionally to their power.        giving more protection than that which could be
This is meant to give credit to the statement that             expected from a simple “sieve” effect.69–72
mesothelioma is caused only by ultrathin fibers that               In conclusion, Chiappino’s argument basically rests
could not have been controlled with the air-treatment          on two points. 1) pleural mesothelioma is induced by
technology available in 1960–1980. With these state-           the ultrathin and ultrashort fibers only; and 2) asbestos
ments, Chiappino seems to be unaware of what the real          persistence in human tissues is extremely long com-
situation was like in work environments in those years,        pared with other known carcinogens.
and introduces misleading elements concerning the                  With regard to the former, several studies provide evi-
characteristics of the air extractors.                         dence that fibers of all lengths and diameters play a role
   Inside the workshops that had large amounts of              in the induction of mesothelioma. With regard to biop-
dust, wall-mounted air extractors were installed to            ersistence, the recognition of this property is used by Chi-
expel polluted air directly outside, with no filtering         appino to exclude the need of repeated and prolonged
system at all. Some of these air extractors were still visi-   exposures to initiate and promote the carcinogenesis that
ble a few years ago in old dismantled industrial sheds         will lead to the development of mesothelioma. All epi-
(e.g., Eternit in Casale Monferrato, Breda in Pistoia,         demiologic, experimental (in vivo and in vitro) and
Italy). These systems were based on dilution ventila-          molecular evidences, however, reject this pathogenetic
tion. The introduction of filtering systems, usually           hypothesis, as well as the negative impact its acceptance
fabric dust collectors, needed outdoor installation.67         would have in terms of actual prevention and regulations
There was neither need nor convenience in recycling            worldwide. It would actually mean the total acquittal of
exhausted air in workshops without heating or air con-         anyone who, being in a position to do so, omits to take
ditioning.                                                     care to prevent asbestos exposure, or at least reduce its
   The 1970 edition of the manual Industrial Ventilation       intensity, leaning on “fatalistic principles” that are not
states, with regard to the recirculation of exhaust air:       substantiated in the international scientific literature.

   Air recycling is not recommended in the cases                                           References
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