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EC number: 235-727-4
CAS number: 12626-81-2
Evidence from studies with rats, and to a lesser extent mice, provide consistent evidence that soluble lead compounds are carcinogenic in laboratory animals. Renal tumours, most often in the male rat, have been reproducibly induced by high-level lead administration in water or food. Limited data suggest that other tissue sites (e.g., the brain) might be impacted. The mechanism by which lead induces tumours in rodents has been actively researched and may entail mechanisms that are both indirect (nongenotoxic) and of uncertain relevance to humans. A number of studies have suggested carcinogenesis in the kidney is secondary to nephropathy and the induction of sustained compensatory cell proliferation.
EU carcinogenicity classification under the
Dangerous Substances Directive applied to only lead acetate (Category 3
R40) indicating adequate evidence for animals but not for humans. The
existing classification for lead acetate is supported by this evaluation
but does not at this time extend to other inorganic lead compounds or
lead metal. Under the Global Harmonised Classification System the cancer
classification for lead acetate has been established at Carc. 2.
the large doses of soluble lead compounds required to induce tumours in
animals, only compounds with significant bioavailability will likely
elicit a carcinogenic response. The bioavailability of most high
production volume lead compounds is not known, but the sparingly soluble
nature of some of the compounds under consideration does not equate with
limited bioavailability under the acidic conditions of the stomach. For
example, both lead oxide and lead carbonate exhibit high bioavailability
in animal feeding studies and when tested in in vitro gastric
simulation systems. While not all lead compounds may exhibit high
bioavailability, extension of Category 3 R40 (DSD or
Carc. 2 (CLP) classification to most inorganic lead compounds can be
Lead has been evaluated for carcinogenicity in multiple animal
species, oftentimes producing positive results. A number of epidemiology
studies have further documented the mortality experience of general
population and occupationally exposed cohorts. Human epiedmiology study
data (described in section 7.10.2) do not support studies with
experimental animals. The following conclusions are drawn from an
evaluation of these studies:
a number of human epidemiology studies have been conducted or updated
over the past several decades, there remains no consistent observation
of a relationship between occupational lead exposure and cancer.
Sporadic increases of lung, kidney, stomach, brain and bladder cancer
have been reported. However, the findings between studies are disparate
and fail to provide a consistent pattern of elevated cancer mortality.
Increases in cancer for lung, kidney and stomach are modest and within
the range of that which might be attributed to uncontrolled confounding.
Registry-based suggestions of a linkage to brain cancer are of interest,
but have not been verified by cohort studies. Studies of general
population exposures are both limited in number and contradictory in
outcome. Given the findings from the study of occupationally exposed
cohorts, risk at general population exposure levels would not be
expected. There is thus insufficient epidemiology evidence to indicate
that inorganic lead or lead compounds pose human cancer risk at most
tissue sites studied.
has recently affirmed that most of the epidemiological literature is not
consistent with a causal relationship between human lead exposure and
cancer at most tissue sites (i.e. studies are not adequate to support
classification in Category 1 or known human carcinogen). Sites of
initial concern (brain, lung and kidney) were ultimately judged to be
the likely result of confounding. Only a modest excess observed in
stomach cancer was judged to be of potential significance. Although
impacts of co-exposures and other confounding factors (e.g. ethnicity,
particulate matter and H. pylori infection)seemed to explain a
proportion of the cancer excess observed in some studies, some impact of
lead exposure could not be precluded. A limited association was thus
judged to exist, but was inadequate for classification as a known human
carcinogen. In accordance with the IARC preamble, the observation of
cancer in animals results in a default classification of category 2B
(possible human carcinogen) that is elevated to category 2A (probable
human carcinogen) based upon limited epidemiological findings for
stomach cancer for inorganic lead compounds.
from studies with rats, and to a lesser extent mice, provide consistent
evidence that soluble lead compounds are carcinogenic in laboratory
animals. Renal tumours, most often in the male rat, have been
reproducibly induced by high-level lead administration in water or food.
Limited data suggest that other tissue sites (e.g., the brain) might be
impacted. Carcinogenicity from a poorly soluble lead compound (lead
phosphate) has been demonstrated following subcutaneous and i.p.
injection. However, the relevance of this route of administration is
questionable. Overall, animal evidence for the carcinogenicity of most
lead compounds in animals is adequate.
4. Rodent inhalation studies with lead oxide have been negative -
but the intensity and duration of exposure was not sufficient to
attribute significance to this negative finding.
mechanism by which lead induces tumours in rodents has been actively
researched and may entail mechanisms that are of uncertain relevance to
humans. A number of studies have suggested carcinogenesis in the kidney
is secondary to nephropathy and the induction of sustained compensatory
cell proliferation. However, tumours have also been induced in the
absence of detected degenerative changes in a single study of
intrauterine exposure. Given the weak and conflicting nature of
genotoxicity studies, indirect mechanisms of carcinogenesis remain the
most probable mode of action have been hypothesised. However, until such
time as such hypotheses have been validated, mechanistic information
based upon effects in the rodent kidney are difficult to apply to an
assessment of risk for humans. Mechanistic inferences are even more
difficult in consideration of human cancer at tissue sites (e.g.
stomach) that are not sites affected by lead in animals.
Carcinogenicity: via oral route (target organ): urogenital: kidneys
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