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Toxicological information

Carcinogenicity

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Description of key information

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. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
LOAEL
3 mg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
5 mg/m³
Species:
rat

Additional information

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:

1.     Although 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.

2.     IARC 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.

3.     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. 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.

5.     The 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

Justification for classification or non-classification

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.

Given 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 considered.