Opinion on: Position Paper on Ambient Air Pollution by Nickel Compounds. Final Version October 2000. Opinion expressed at the 22nd CSTEE plenary meeting, Brussels, 6/7 March 2001.
Note: Following the
terms of reference, this
opinion focuses on specific
questions related to human
health issues and does not
cover ecosystem
protection.
Non-Cancer
1. In the
light of the published
literature and the arguments
discussed in the Position
Paper what interpretation
should be placed on the 0.03
mg Ni/m
3 dose level in
the NTP study in rats (using
nickel sulphate
hexahydrate)?
The CSTEE does not find
that the inhalation
concentration of 0.03 mg
Ni/m
3 represents a
NOAEL in rats, since
indications of chronic
active inflammation and
increased lung weights were
seen in animals undergoing
interim sacrifice.
2. What is
the Committee's opinion on
the relative sensitivities of
rats and humans to exposure
by inhalation to soluble
nickel compounds? In the
Committee´s opinion is a
factor of 10 appropriate when
extrapolating from rats to
humans?
The CSTEE cannot see
that there are convincing
data supporting the notion
that rodents should be more
sensitive than humans
towards the respiratory
effects of soluble nickel
compounds. The CSTEE finds
it acceptable to use a
factor of 10 to extrapolate
from experimental animals
to humans. However, in the
development of a limit
value for nickel in ambient
air, it should be
recognised that soluble
nickel species, which are
the key contributors to the
non-cancer respiratory
effects of nickel
compounds, do not appear to
constitute more than
maximally 50 per cent of
the total nickel compounds
in air as judged from the
limited data available.
Thus, the CSTEE finds that
a limit value of 20 ng Ni/m
3, rather that
the value of 10 ng Ni/m
3, is supported
by the totality of the
existing data.
Cancer
1. In the
Committee´s opinion, what
chemical forms of nickel in
ambient air are the most
relevant for the assessment
of humans risk and the
derivation of a limit value
for total nickel
Nickel carcinogenicity
will be dependent on the
time-integrated
intracellular concentration
of nickel ions as the
active entity, so that the
relative potency of various
nickel species will be
related to their
bioavailability and lung
burden. In the rat
experiments it is the
insoluble nickel compounds
that are most potent with
respect to carcinogenicity.
However, epidemiological
evidence clearly points to
the carcinogenic effect of
soluble nickel
compounds.
SPECIFIC COMMENTS TO THE
POSITION PAPER
Exposure
Species
specific measurements of
nickel compounds in ambient
air (daily means) have been
performed at two sites in
Dortmund, Germany:
This
relative distribution between
the various nickel species
has been confirmed by
measurements in several sites
(Feuchtjohann et al., 2000;
Broekart, personal
communication. See also
manuscript by this group
submitted to J. Environm.
Monit. And PhD-thesis of
Feuchtjohann). This indicates
that soluble nickel
constitutes up to approx. 50%
of total nickel in urban air.
Therefore, the relative
proportion of the various
nickel species should be
taken into account when
establishing limit values for
nickel in air (
i.e. a correction for
the relative proportion of
individual species
contributing to an
endpoint).
Non-cancer effects
Nickel subsulfide:
Chronic active inflammation
of the respiratory tract was
seen in 2 year inhalation
study with rats and mice at
all concentrations tested (
> 0.11 mg Ni/m
3).
Nickel oxide: Chronic
active inflammation of the
respiratory tract was seen in
2 year inhalation study with
rats and mice at all
concentrations tested (
> 0.5 mg Ni/m
3).
Nickel sulphate
hexahydrate: Macrophage
hyperplasia was seen in 8 out
of 10 female rats and 10 out
of 10 male rats at 0.03 mg
Ni/m
3 in 13 week
inhalation study. An increase
in chronic active
inflammation at the 7-month
interim evaluation of 2 year
inhalation study was seen in
4 of 5 male rats (0/5
controls) and 2 of 5 female
rats (0/5) controls
administered 0.03 mg Ni/m
3. At 15-month
interim evaluation there was
an increasing trend in the
absolute lung weights of both
male and female rats. At
2-year termination
significant increases in
chronic active inflammation
and fibrosis were seen in
rats and mice at
> 0.6 mg Ni/m
3, but not
significantly increased at
0.03 mg/m
3. Thus, it can be
argued whether 0.03 mg Ni/m
3 should be viewed
as a clear NOAEL in rats. In
female mice there were
clear-cut evidence of chronic
active inflammation,
bronchialisation and
macrophage hyperplasia in the
lung at the lowest inhalation
concentration of 0.06 mg Ni/m
3 so that this is
a LOAEL and a NOAEL was not
identified. Such effects were
also noted at 0.11 mg Ni/m
3 in male
mice.
Genotoxicity
Soluble
and insoluble nickel
compounds have shown slight,
but clearly positive
responses in
in vitro studies of
gene mutations, sister
chromatid exchanges,
micronuclei (only soluble
compounds tested) and cell
transformation in mammalian
cells (reviewed in ATSDR,
1997). Thus, the CSTEE
concludes that a genotoxic
mechanism of action for
soluble nickel compounds
cannot be discounted. There
is evidence that the
genotoxic effects of nickel
compounds may be indirect
through inhibition of DNA
repair systems (Hartwig,
1998). There is very limited
information on the potential
for
in vivo genotoxicity
of nickel compounds.
Carcinogenicity
Nickel oxide, nickel subsulfide and nickel sulphate hexahydrate have been tested by the US National Toxicology Program (NTP) for carcinogenicity in male and female rats and mice for 6 hours/day on 5 days per week for 112 weeks. There was some evidence for carcinogenicity of nickel oxide in male and female rats, clear evidence for carcinogenicity of nickel subsulfide in male and female rats, whereas there were no evidence for carcinogenicity of nickel sulphate hexahydrate in rats. None of the nickel compounds showed carcinogenic potential in mice. The lack of evidence for carcinogenicity of nickel sulphate hexahydrate can be due to the relatively low lung burden that was tested, since the exposure levels had to be kept lower than for nickel oxide and nickel subsulfide due to respiratory toxicity of nickel sulphate hexahydrate. Thus, the lung burden (amount of nickel per g of lung) from the highest exposure concentration of nickel sulphate hexahydrate was approximately 6 times lower than the lowest exposure concentration to nickel subsulfide. In studies with parenteral administration, soluble nickel compounds induce local tumours, albeit with much lower potency than that seen with insoluble nickel compounds. Therefore, the CSTEE concludes that the lack of evidence of carcinogenicity of nickel sulphate hexahydrate in the NTP study cannot be taken as evidence of lack of carcinogenic potential for soluble nickel compounds. Nickel carcinogenicity will be dependent on the time-integrated intracellular concentration of nickel ions as the active entity, so that the relative potency of various nickel species will be related to their bioavailability and lung burden. In the rat experiments it is the insoluble nickel compounds that are most potent with respect to carcinogenicity.
Limit Value Based on
Non-Cancer Effects
Since
there are differences in
opinion about the NOAEL in
rats, the Working Group has
agreed to use 0.06 mg Ni/m
3 as a LOAEL as
the starting point for the
risk assessment. The CSTEE
considers the increased lung
weights noted at 0.03 mg Ni/m
3 in the 15-month
interim evaluation indicative
of an adverse reaction, so
that the 0.03 mg Ni/m
3 does not clearly
represent a NOAEL value. The
Working Group has used 0.06
mgNi/m
3 as a starting
point. In this situation, one
would need to apply a larger
uncertainty factor than usual
for extrapolating from a
LOAEL to a NOAEL than is
customary (
i.e. a factor of at
least 3). Also, this is
indicated due to the high
percentage of animals that
were affected at 0.06 mg Ni/m
3.
An argument has been put forward that humans should be less sensitive than experimental animals towards the respiratory effects of inhaled soluble nickel compounds. This should imply that one should not need a toxicodynamic interspecies uncertainty factor larger than 1. However, the CSTEE cannot see that there are convincing data supporting the notion that rodents should be more sensitive than humans. Thus, a default uncertainty factor for toxicodynamic extrapolation of 3.16 (rather than the conventional 2.5 for organic chemicals) should be applied. Whereas insoluble nickel compounds enter cells via phagocytosis and are retained in the lung tissue for a long time, soluble forms of nickel are inefficiently taken up by cells by the magnesium transport system, but rapidly cleared from the tissues and excreted in the kidneys. However, there are no data to compare the toxicokinetics of soluble nickel compounds between rodents and humans. Thus, also for toxicokinetic extrapolation between experimental animals and humans a default value of 3.16 (rather than the conventional factor of 4 for organic chemicals) can be argued (the position paper uses a default factor of 3).
In the
2-year inhalation studies,
the animals were exposed for
6 hours per day and 5 days
per week. The conversion
factor from this
non-continuous exposure to
continuous, although only
stated as numbers in Table
2.6.6 of the position paper,
is (24/6 x 7/5) = 5.6. The
Working Group has rounded
this off to a conversion
factor of 6, which is deemed
acceptable.
There does not seem to have been any discussion within the Working Group on applying an interindividual (intraspecies) uncertainty factor of 10. It should be remembered that this factor is meant to cover interindividual variability in both toxicodynamics and toxicokinetics. A major source for interindividual variability in toxicokinetics, is metabolic differences among humans. Such processes would not be relevant for inorganic compounds such as nickel ions. Thus, the default uncertainty factor for interindividual variation in toxicokinetics of 3.16 may be too large for nickel sulphate, although processes other than metabolism could also result in interindividual differences in toxicokinetics. However, since there are no real data on toxicokinetic variability for nickel sulphate in humans, a conservative approach would be to retain the default value. Also, there are no data on interindividual variation in nickel toxicodynamics. Therefore, the CSTEE supports the application of an overall interindividual uncertainty factor of 10.
The
Working Group proposes a
limit value of 10 ng Ni/m
3 for nickel based
on non-cancer effects seen
after inhalation exposures to
nickel sulphate hexahydrate
in rats and mice. This value
is reached in the following
way: 0.06 mg Ni/m
3 (60
m
g Ni/m
3) divided by an
uncertainty factor of 10 for
LOAEL to NOAEL extrapolation
gives 6
m
g Ni/m
3. Since this is
for non-continuous exposure,
dividing by the factor of 6
to arrive at continuous
exposure gives a
concentration of 1
m
g Ni/m
3. When dividing
by uncertainty factors of 10
each for interspecies
extrapolation and
intraspecies variability, the
limit value of 10 ng Ni/m
3 is
reached.
The CSTEE
accepts the composite
uncertainty factor of 10 for
animal to human
extrapolation, which the
Working Group has proposed.
Although the CSTEE would
support the use of the
various assessment factors in
this calculation, this limit
value does not take into
account that ambient
exposures to nickel are
composed of different nickel
species with quite large
differences in potency with
respect to non-cancer
effects. From the limited
specific exposure
measurements, it appears that
soluble nickel compounds do
not constitute more than
maximally 50 per cent of the
total nickel compounds in
ambient air. Based on this,
the CSTEE finds that a limit
value of 20 ng Ni/m
3, rather than the
value of 10 ng Ni/m
3, is supported by
the totality of the existing
data.
Limit Value Based on
Carcinogenic Effects
In the EU
insoluble nickel compounds
(nickel oxide, nickel
monoxide and nickel sulphide)
are classified as Category 1
(known human carcinogens),
whereas metallic nickel,
slightly soluble and soluble
nickel compounds (nickel
carbonate, nickel hydroxide,
nickel sulphate and nickel
tetracarbonyl) are classified
as Group 3 (possible
carcinogens). IARC has
classified nickel compounds
(nickel sulphate, and
combinations of nickel
sulphides and oxides
encountered in the nickel
refining industry) as
carcinogenic to humans (Group
1). The increased risk of
lung cancer noted in the
Norwegian Falconbridge
cohort, implicates an
important role of soluble
nickel compounds in cancer
development (IARC, 1990;
Andersen
et al., 1996; Grimsrud
et al., 2000). The recent
updates did not reveal
appreciable differences in
the risk estimates. Excess
risk among Clydach workers
seems likely to be due, at
least partly, to exposure to
soluble nickel (IARC, 1990).
Based on an overall
evaluation of epidemiological
and
in vitro and
in vivo experimental
data, the CSTEE finds that
there is sufficient evidence
for classifying soluble
nickel compounds as known
human carcinogens and that a
genotoxic component in the
mode of carcinogenic action
is probable. Thus, the CSTEE
does not support the
application of a threshold
approach for assessing the
carcinogenic risks associated
with exposure to ambient
nickel compounds. As pointed
out, increasing evidence has
been developed indicating
that the genotoxic effects of
nickel compounds may be
indirect (Hartwig, 1998).
This may mean that nickel
compounds will show
non-linear dose-responses
with respect to
carcinogenicity, however,
based on the available
information it is at present
not possible to sufficiently
evaluate this
possibility.
The CSTEE
supports the recommendation
from WHO (1999) of a unit
risk of 3.8 x 10
-4 (
m
g Ni/m
3)
-1 based on the
excess risk seen in the
Falconbridge nickel worker
cohort. This corresponds to
concentrations of 25 ng Ni/m
3 and 2.5 ng Ni/m
3 for increased
life-time risks of 1:100,000
and 1:1,000,000,
respectively. These estimates
are conservative in nature,
given the linear
extrapolation over many
orders of magnitude from the
observed excess risk in
exposed humans. Also, there
are considerable differences
in carcinogenic potency among
the different nickel species
in ambient air, with the most
potent sulfidic nickel only
constituting up to 10 percent
of the sum of nickel species
in air as judged from the
limited amount of data
available. Thus, the CSTEE
concludes that the limit
value of 20 ng Ni/m
3 proposed for
non-cancer effects, also is
likely to provide reasonable
protection of the general
population to the
carcinogenic effects of
nickel compounds in ambient
air.
References
Andersen
A, Berge SA, Engeland A &
Norseth: Exposure to nickel
compounds and smoking
relation to incidence of lung
and nasal cancer among nickel
refinery workers. Occup.
Environ. Med. 53, 708-713,
1996.
Feuchtjohann L,
Jakubowski N, Gladtke D,
Barnowski C, Klockow D &
Broekaert JAC: Determination
of soluble and insoluble
nickel compounds in ambient
air dust by graphite furnace
atomic absorption
spectrometry and inductively
coupled plasma mass
spectrometry. Fresenius J.
Anal. Chem. 366, 142-145,
2000.
Grimsrud
TK, Berge SR, Resmann F,
Norseth T & Andersen A:
Assessment of historical
exposures in a nickel
refinery in Norway. Scand. J.
Work. Environ. Hlth. 26,
338-345, 2000.
Hartwig A:
Carcinogenicity of metal
compounds: possible role of
DNA repair inhibition.
Toxicol. Lett. 102-103,
235-239, 1998
WHO. World
Health Organisation: Air
Quality Guidelines for
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IARC
Monographs, Vol. 49,
1990