Hyperprolactinaemia as an adverse effect in regulatory and clinical toxicology: role in breast and prostate cancer.

Historically, hyperprolactinaemia has been considered of low toxicological relevance when detected in toxicity studies, and even mammary carcinogenesis induced in the rat by prolactin excess has been considered of no relevance to humans. However, recent findings from human epidemiology and molecular biology suggests that prolactin is a risk factor for human breast cancer, and probably prostate cancer. Therefore, this new evidence should be considered in the various decisions to develop and license a new drug or chemical if the compound causes hyperprolactinaemia. This emerging evidence suggests that prolactin can also be produced locally from human breast cancer cells, and that, regardless of source (ie, pituitary or autocrine/paracrine production from cancer cells), prolactin is mitogenic, stimulates proliferation and suppresses apoptosis in breast and prostate cancer cells. This review outlines the evidence that hyperprolactinaemia should be considered a toxicological adverse effect and concludes that prolactin-induced rodent mammary carcinogenesis is relevant to humans and is not species-specific. The effects of prolactin on the prostate gland are also discussed; hyperprolactinaemia may be an additional risk factor for prostate cancer and this also requires consideration in toxicological risk assessments. The implications of increased prolactin secretion as an adverse effect for regulatory toxicology of drugs and chemicals, and in high risk patients receiving therapeutic drugs with hyperprolactinaemic side effects, is discussed. Alteration of prolactin level is also a novel mechanism that requires consideration in endocrine disruption research, since both endogenous oestrogens and also xenoestrogens stimulate prolactin secretion or affect prolactin receptors.

The toxicity of cyanobacterial toxins in the mouse: II anatoxin-a.

Blooms of cyanobacteria are known to have caused poisoning in fish, waterfowl, animals and man. One of the low molecular weight toxins responsible for this is the neurotoxin anatoxin-a which has been detected in reservoirs used for domestic water supplies. While the acute behaviour of this alkaloid is clear, there is uncertainty regarding the effects on man of ingestion of anatoxin-a at low levels over longer periods. In order to assess this risk, a series of in vitro and in vivo experiments were undertaken to investigate the pharmacology, subacute toxicity, and the teratogenicity of anatoxin-a in the mouse. The results of this work were as follows: (1) Pharmacological screening studies confirmed that anatoxin-a is a potent nicotinic agonist which can produce neuromuscular blockade and death by respiratory arrest. Recovery from a single sub-lethal dose is rapid and complete; (2) Repeated sub-lethal oral administration over 28 days in the mouse did not produce any reliable evidence of treatment-related toxicity; (3) From a preliminary screening study anatoxin-a does not appear to be a developmental toxicant in the mouse. These results indicate that a guideline value for anatoxin-a in drinking water of 1 microg l(-1) would provide an adequate margin of safety.

Estrogenic potencies of resorcylic acid lactones and 17 beta-estradiol in female rats.

Uterotrophic response in sexually immature female rats has been used to rank the relative estrogenic potencies of six resorcylic acid lactones (RALs) and to compare their activities with that of 17 beta-estradiol. On oral administration, the estrogenic potency relative to 17 beta-estradiol is as follows: 7 alpha-zearalenol, 10 times less; zeranol, 150 times less; taleranol, 350 times less; zearalanone, 400 times less; zearalenone, 650 times less; 7 beta-zearalenol, 3500 times less. On subcutaneous administration, zeranol is 500 times less estrogenic than 17 beta-estradiol.