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EC number: 200-753-7
CAS number: 71-43-2
Quality scoring results for genotoxic
Among 56 genotoxicity study populations the
top score was 20 (of a possible 24), which was due to the (Qu et al.,
2003) study. Genotoxicity studies showed a wide range (6–20) indicating
marked differences in study quality for each body of literature.
LOAECs and NOAECs for high quality studies
Of the 21 studies in the top tertile, ten
studies were among factory workers, five among fuel handlers and six
among workers exposed to traffic and ambient air. In factory workers,
the five studies with more certain LOAECs were (Qu et al., 2003)
(LOAEC=3.07 ppm), (Xing et al., 2010)(LOAEC>1.6 ppm), (Zhang et al.,
2012) (LOAEC>2.64 ppm), (Zhang et al., 2007) (LOAEC=13.6 ppm) and (Zhang
et al., 2014) (LOAEC=2 ppm). The top tertile study generating a less
certain LOAEC (>0.56 ppm) was (Kim et al., 2004a) due to the presence of
Three studies (Carere et al., 1995; Pandey
et al., 2008 and Rekhadevi et al., 2010) in the top tertile were
associated with a more certain LOAEC and none with a less certain LOAEC.
The three studies showed similar LOAECs of 2 ppm, 2 ppm, and > 1 ppm,
respectively. A NOAEC in the Carere study for micronuclei is 0.47 ppm
and in the Pandey study∼0.9
ppm. The quality scores of the first tertile fuel studies (14.5) are
lower than those from the factory
There were only two studies (Leopardi et
al., NOAEC=0.003 ppm; Maffei et al., LOAEC=0.008 ppm) in the top tertile
which produced a more certain LOAEC or NOAEC. Violante et al. (15.5) has
a less certain NOAEC of 0.005 ppm and Angelini (14.5) has a less certain
LOAEC of 0.006 ppm. Since the exposure concentrations present in the
traffic/ambient air studies are lower than other NOAECs based on fuel
and factory studies, this group of studies does not add meaningful
information to the NOAEC analysis.
Since the single top tertile study that
showed a more certain LOAEC is of lower quality (13.5) than studies from
the factory and fuel sectors (average=16.07), this group of studies also
does not add meaningful information to the LOAEC analysis. Thus, these
studies are not subsequently considered.
Derivation of LOAECs
The highest quality studies (i.e. first
tertile) that generated a more certain LOAEC originated from the factory
and fuel study scenarios. There were five such studies from the factory
scenario: Qu et al. (LOAEC=3.07 ppm), Xing et al. (LOAEC>1.6 ppm), Zhang
et al. (2012) (LOAEC>2.64 ppm), Zhang et al., 2007(LOAEC=13.6 ppm), and
Zhang 2014 (LOAEC=2 ppm).
Zhang et al., 2007 studied mainly higher
exposures, and can therefore be excluded. The four remaining
high-quality factory studies result in an average LOAEC of 2.33 ppm.
This is the best supported LOAEC (leading case) since it is a weighted
average of the highest quality studies, with an average quality score of
17.25. When the three additional studies from the fuel scenario: Carere
et al. (2 ppm), Rekhadavi et al. (1 ppm), and Pandey et al. (2 ppm) are
added, the resulting LOAEC is 2.04 ppm, which can be regarded as the
sensitivity analysis based on the next highest quality studies.
If high quality is defined more inclusively
as studies above the median, adding the one additional study from the
factory setting with a more certain LOAEC (Eastmond et al., 1.29 ppm)
with the other first tertile more certain factory studies, results in an
average LOAEC of 2.12 ppm. The average quality score in this sensitivity
analysis decreases to 16.3 (from 17.25), but still supports a LOAEC of
approximately 2 ppm. There were no additional studies from the fuel nor
ambient scenarios which generated more certain LOAECs above the median
score of 12.5. All high certainty LOAECs above the median score from the
factory and fuel sector combined, result in a LOAEC of 1.95 ppm (average
score – 14.85). Although average quality score has decreased, this also
supports an aggregate LOAEC of∼2ppm.
Consideration of the Less certain LOAECs
included Kim et al., 2004a, >0.56 ppm, potential confounding by PAH
exposure; average LOAEC for all factory studies in the first tertile was
1.97 ppm, quality score of 17.10); Factory studies with a less certain
LOAEC (Bogadi-Sare et al., 2003 LOAEC=13 ppm, Holz et al., 1995,
LOAEC=0.6–1 ppm). The LOAECs from Bogardi-Sare and Holz differ by more
than two orders of magnitude, thus sensitivity analyses are not
The leading case LOAEC of 2.33 ppm is
supported by the leading sensitivity analyses which account for more
studies with a lower quality score and suggest slightly lower LOAECs
near 2 ppm. Interpreted with due regard to quality, in aggregate the
literature supports a LOAEC of 2 ppm.
Derivation of NOAECs. Three studies from the
factory scenario that suggest NOAECs: Bogadi-Sare et al. 1997a (8 ppm),
Zhang et al., 2011 (4.95 ppm) and Basso et al., 2011
(0.029 ppm). These studies differ by more
than two orders of magnitude and as such, do not offer a good “base
case” on which to justify a NOAEC. We face the problem of a NOAEC that
is higher than the LOAEC. Despite the difficulty in isolating an effect
of benzene in impure fuel and (especially) ambient studies, they are the
best avenue at present for estimating a NOAEC for genotoxicity. In the
fuel scenario, two studies scored in the first tertile and were
characterized by more certain NOAECs: Carere et al. (1995) (0.47 ppm)
and Pandey et al. (2008) (0.9 ppm). Combining these gives an average
NOAEC of 0.69 ppm for genotoxicity. There are three other studies:
Fracasso et al. (2010) (0.012 ppm), Pitarque et al. (1996) (0.3 ppm) and
Göethel et al. (2014) (0.6 ppm) from the fuel sector that score above
the median with more certain NOAECs. Using this set of studies as a
sensitivity analysis a NOAEC of 0.45 ppm results. These analyses suggest
that a NOAEC of 0.5 ppm is justified.
Method 1: (Use of the LOAEC)
POINT OF DEPARTURE FOR GENOTOXIC EFFECTS:
This preferred approach is based on four
studies (Table 6) in the factory setting with a more certain LOAEC that
are high quality (top tertile). A fifth study (Zhang et al., 2007) which
showed a higher LOAEC of 13.6 ppm was not considered. This preferred
derivation is supported by additional sensitivity analyses summarized
previously which consider the fuel sector as well as the factory sector,
and the alternative definition of “high quality” using studies above the
median rather than the top tertile.
POTENTIAL ASSESSMENT FACTORS:
• Dose-response (LOAEC to NOAEC).>2.33 ppm
is the lowest level of exposure among four high quality (top tertile).
Subsequently, a NOAEC of 0.69 ppm was calculated (see below). Other
NOAECs which were near or greater than the LOAEC were not considered. In
addition, the preferred LOAEC is noted as greater than 2.33, thus 2.33
should be regarded as the minimum preferred value. Given the degree of
potential overlap in LOAECs and NOAECs, and the fact that there is some
uncertainty in the inequality >2.33 ppm, the factor should be lower than
the usual value of 3. A value of 2 is recommended.
• Intraspecies. A factor lower than 3 is
recommended when a reasonably large human study is used in which a range
of sensitivities are already present and extrapolations from the study
data are to other occupational populations. In aggregate, the LOAEC
studies considered included >2700 benzene exposed individuals. In
addition, all the LOAECs are based on Chinese workers, who may be a more
sensitive population. Thus, a value of 2 is recommended. A value of 1
could also be considered since a possibly more sensitive population
generates the LOAEC, thus, sensitive sub-populations may have already
been accounted for in the selection of this LOAEC.
OEL=2.33 ppm / 4 (=2×2)=0.58 ppm METHOD 1
Method 2: (Use of NOAECs)
Method 2 is derived from the NOAECs of two
studies of high quality in the fuel sector since studies in the factory
sector showed higher NOAECs when compared to the preferred LOAEC. NOAECs
near or above the LOAEC from above are not
considered, thus this could be considered a conservative approach.
POINT OF DEPARTURE FOR GENOTOXIC EFFECTS:
NOAECs from two high quality studies are
used as the basis for a weighted NOAEC of 0.69 ppm. Studies of Zhang et
al., 2011 (NOAEC=4.95) and Bogadi-Šare et al., 2003 (NOAEC=8) were not
considered, thus the value of 0.69 may be conservative. On the other
hand, only two studies are used to calculate the aggregate NOAEC, which
could balance the conservative nature of the selection of studies that
were included. Concordance with method 1, arguably based on stronger
data (average quality score of LOAEC studies=17.25, average quality
score of NOAEC studies=14.5) would also justify an intra-species factor
OEL=0.69 ppm. METHOD 2.
Given that the haematology data suggest an
OEL of 0.5 ppm, the genotoxicity based OELs of 0.58 ppm (Method 1), and
0.69 ppm (Method 2) it can be agreed that both datasets would support an
OEL of 0.5 ppm (8 h TWA).
As was the case for haematotoxicity, the
data supporting this position are mainly derived from worker studies
examining effects in peripheral blood (except for (Xing et al., 2010).
An additional factor of two is proposed for possible subclinical effects
in the bone marrow until additional research clarifies the sensitivity
of peripheral blood versus bone marrow effects. This additional factor
would support an OEL of 0.25 ppm (8 h TWA) for both haematotoxicity and
This paper derives an occupational exposure
limit for benzene using quality assessed data. Seventy-seven
genotoxicity studies in workers were scored for study quality with an
adapted tool based on that of Vlaanderen et al., 2008 (Environ Health.
Perspect. 116 1700−5). Genotoxicity endpoint (as well as
haematotoxicity) was selected as one of most sensitive and relevant
endpoints to the proposed mode of action (MOA) and protecting against it
will protect against benzene carcinogenicity. Lowest and No- Adverse
Effect Concentrations (LOAECs and NOAECs) were derived from the highest
quality studies (i.e. those ranked in the top tertile or top half) and
further assessed as being “more certain” or “less certain”. Several
sensitivity analyses were conducted to assess whether alternative “high
quality” constructs affected conclusions. Genotoxicity, studies showed
effects near 2 ppm and showed no effects at about 0.69 ppm (the findings
supported the haematotoxicity results). Several sensitivity analyses
supported these observations. These data define a benzene LOAEC of 2 ppm
(8 h TWA) and a NOAEC of 0.5 ppm (8 h TWA). Allowing for possible
subclinical effects in bone marrow not apparent in studies of peripheral
blood endpoints, an OEL of 0.25 ppm (8 h TWA) is proposed.
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