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Int Arch Occup Environ Health (2008) 81:487–493 491
exposed to Cr and non-smoking controls before the intervention.
However, we noted a signiWcant increase in both
levels after the intervention. Finally, we found a moderate
but signiWcant correlation between Cr-EBC and pulmonary
tissue Cr levels, whereas Cr-U did not signiWcantly correlate
with either Cr-EBC or Cr-tissue.
Although controls were non-smokers and NSCLC
patients prevalently smokers or ex-smokers, no diVerences
were seen in Cr levels in the biological media, thus suggesting
that cigarette smoke is not a source of Cr contamination,
as already noted (Mutti et al. 2006). Moreover, urinary
levels of NSCLC patients were substantially in line with
published Italian reference levels [0.08 g/l with a 95% CI
of 0.24 g/l (Apostoli et al. 1997), and near 0.5 g/l in
Northern Italy, Minoia et al. 1988], even if in those manuscripts
Cr was not reported in g/g creatinine. On the other
hand, pulmonary tissue Cr levels have never been standardised
in literature and very diVerent values have been
reported in subjects unaVected by occupational Cr exposure.
Furthermore, environmental exposure, as well as age,
gender, regional origin (Kollmeier et al. 1990; Takemoto
et al. 1991), and probably also lifestyle, may signiWcantly
inXuence tissue Cr levels. However, our Wndings are consistent
with those of Tsuneta et al. 1980, Raithel et al. 1987
and 1993 and Al-Saleh et al. 1996, and with some of the
reference values reported in the literature (0.01–2.5 g/g
dry, Vanoeteren et al. 1986). Preliminary data in Wve subjects
without lung cancer but with other diseases did not
reveal diVerent lung tissue Cr levels. Finally, as already
observed (Raithel et al. 1989a, 1989b), Cr did not signiWcantly
accumulate in cancerous tissues.
Some authors have reported that tobacco smoke may
increase tissue Cr levels in patients with lung cancer of
non-occupational origin (Paakko et al. 1989; Raithel et al.
1989b; Akslen et al. 1990), but recent studies on cigarette
smoke have found Cr constantly at levels about the limit of
detection (Wagner et al. 2001; Rustemeier et al. 2002),
whereas Cd and Pb, traditionally contaminating tobacco
smoke, were clearly detectable (Chiba and Masironi 1992;
Kalcher et al. 1993). However, we cannot exclude the possibility
that the Cr content of cigarettes may vary from
country to country and thus give rise to diVerent results, or
that it may have decreased over recent years due to more
stringent control procedures.
The signiWcant increase in both Cr-EBC and Cr-U after
surgical intervention suggested the possibility to test if surgical
instruments could be a possible source of Cr, as previously
observed (Raithel et al. 1989a). Our Wndings showed
that they release 3–6 g Cr during surgical operation,
which gives rise to increased levels of Cr-EBC and Cr-U 2–
4 days after the intervention. However, it does not exclude
other Cr sources being present (physiological Xuid, medicines,
etc.). Because the increase in Cr-EBC (from 0.22 to
0.40 g/) was more than one order of magnitude less than
that observed in moderately exposed workers (from a
median of 7.8 g/l at the and of a work shift to 4.0 g/l 24 h
after the last exposure), consistent with changes in Cr-U
(from 0.2 to 0.6 g/g creatinine in this study and from
9.0 g/g creatinine at the and of a work shift to 5.6 g/g
creatinine 24 h after the last exposure in Caglieri et al.
2006), Cr in EBC can be considered a sensitive biomarker
of local exposure. Finally, it was also conWrmed by Murgia
et al. 2006, who found that in exposed workers, the Cr levels
in induced sputum were very similar to Cr- EBC levels
reported by Caglieri et al. 2006.
DiVerences in Cr-EBC before and after the intervention
cannot be related to changes in expiratory Xow. In fact,
EBC volume, which has been demonstrated to reXect overall
subject ventilation (McCaVerty et al. 2004), was
unchanged by intervention.
It is known that occupationally exposed workers with or
without lung cancer have higher pulmonary tissue Cr levels
than controls (Tsuneta et al. 1980; Ishikawa et al. 1994;
Raithel et al. 1993). The present study shows for the Wrst
time a correlation between EBC and pulmonary tissue Cr
levels in subjects who had not been occupationally exposed
to Cr, thus suggesting that EBC Cr levels can be considered
representative of local exposure at target organ level.
On the other hand, Cr-EBC did not signiWcantly correlate
with Cr-U either before or after tumour resection;
moreover, pre-surgery Cr-U did not signiWcantly correlate
with tissue Cr. Although all of these correlations need validation
in a larger number of subjects, they suggest that
EBC and urine Cr levels provide parallel, but diVerent,
information, probably because of the relatively slow kinetics
of Cr in possible exposure routes other than inhalation
or pulmonary contamination. In the case of the study, the
contamination sources were probably not only in contact
with pulmonary tissue but also with blood. On the basis of
our results, it is likely that increased EBC Cr levels are
more representative of pulmonary tissue contamination,
whereas Cr-U could be more representative of blood contamination.
Even though correlation between Cr in tissue and EBC
was moderate, these data seem to conWrm that the measurement
of Cr (and probably other pneumotoxic metals) in
EBC can provide additional information to that obtained by
traditional biomonitoring even at very low levels of exposure.
The relatively low correlation coeYcients are justiWed
by the narrow interval of measured values and the associated
high intra- and extra-individual variability. Moreover,
many authors have reported that pulmonary tissue Cr levels
are not uniform in both exposed and unexposed subjects,
and that Cr tends to accumulate in the upper lung areas and
bronchi (Raithel et al. 1987; Vanoeteren et al. 1986; Ishikawa
et al. 1994; Kondo et al. 2003). Although we measured
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