Toxicological Sciences, Vol 52, 154-161, Copyright © 1999 by Society of Toxicology
MP Waalkes, M Anver and BA Diwan
Cadmium is a known human carcinogen based on findings of lung cancer in
exposed populations. A more controversial target site for cadmium is the
human prostate gland, for which some studies indicate a link between
cadmium exposure and cancer. Our work in various strains of Wistar rats has
shown that cadmium can induce tumors in the ventral lobe of the prostate.
The relevance of this type of lesion to human prostate cancer has been
questioned because the ventral lobe of the rat prostate, unlike the
dorsolateral lobe, has no embryological homolog in the human gland. In this
study we investigated the chronic toxic and carcinogenic effects of cadmium
in the Noble (NBL/Cr) rat, with particular attention to lesions of the
prostate. Cadmium chloride (CdCl2) was given as a single sc injection (0,
1, 2, 4, 8, 16, or 32 micromol/kg) to groups (initially n = 30) of
10-week-old rats. Rats were observed for up to 72 weeks following exposure.
In rats that were injected with the lower doses of cadmium (< or =4
micromol/kg), a clear dose-related increase in proliferative lesions of the
dorsolateral prostate occurred (0 micromol/kg = 36% incidence, 1
micromol/kg = 62%, 2 micromol/kg = 65%; 4 micromol/kg = 79%; trend p <
0.003). Lesions were described as intraepithelial hyperplasia with
occasional areas of atypical epithelial cells, without stromal invasion. At
higher doses (> or =8 micromol/kg) the proliferative-lesion response in
the dorsolateral prostate gradually declined to near control levels (8
micromol/kg = 63%; 16 micromol/kg = 60%; 32 micromol/kg = 52%). The loss of
prostatic response at the higher doses of cadmium was probably due to loss
of testicular function secondary to cadmium treatment. This was reflected
in a very high incidence (>90%) of lesions, indicative of testicular
hypofunction, including tubular degeneration, mineralization, and
interstitial (Leydig) cell tumors, at doses in excess of 16 micromol/kg.
Malignant injection-site sarcomas occurred at the two highest doses of
cadmium, while pituitary adenomas were elevated by cadmium exposure at the
highest dose. These results show that cadmium induces proliferative lesions
in the dorsolateral prostate of the Noble rat, a model having a presumed
relevance to human prostate cancers.
ARTICLES
Carcinogenic effects of cadmium in the noble (NBL/Cr) rat: induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions of the dorsolateral prostate
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. waalkes@niehs.nih.gov
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