5

Cancer Effects

On the basis of nonhuman experimental evidence, lead and lead compounds have been recognized as probably or likely to be carcinogenic in humans by several authoritative organizations, including the International Agency for Research on Cancer (IARC 2006), the National Toxicology Program (NTP 2004, 2011), and the US Environmental Protection Agency (EPA 2012). In this chapter, in addition to human studies, the committee relied on evidence from animal cancer bioassays and mechanistic studies in evaluating the evidence supporting a causal link between lead and cancer, as has been done by IARC, NTP, and EPA. Several lead compounds have been used in animal and mechanistic studies, but the committee considered all inorganic forms of lead to be applicable to this review.

A number of animal experiments have demonstrated the carcinogenicity of inorganic lead, mostly in the kidney (renal-cell carcinoma), but cancer at other sites has been reported, including brain tumors (gliomas), lung cancer, and cancers of the hematopoietic system. Lead also has genotoxic potential. Relatively low concentrations of lead in vitro (less than 1 μM) have caused mutations in mammalian cells in a dose-dependent manner, possibly through the generation of reactive oxygen species. Lead inhibits the repair of DNA damage caused by ultraviolet light and x rays and so potentially increases the genotoxicity of other agents. It stimulates lipid peroxidation and may increase free radicals through its inhibition of the enzyme delta-aminolevulinic acid dehydratase (ALAD). Lead also induces micronuclei and increases chromosomal aberrations in mammalian studies, although typically at higher doses than in occupational studies. In addition to genotoxicity, lead increases cell proliferation in the absence of cytotoxicity (IARC 2006). Thus, lead may contribute to carcinogenicity through a variety of mechanisms.

The committee reviewed the human, animal, and mechanistic evidence on lead carcinogenicity, first by the reviewing the evaluations of IARC (2006), NTP (2011), and EPA (2012). The NTP Monograph on Health Effects of Low-Level Lead (NTP 2012) reviewed in Chapter 4 did not include cancer end points. Through literature searches, the committee also identified relevant recent studies



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