Title:
Are low-dose effects of endocrine disrupters evaluated adequately?

Hiroaki Aoyama, Ph.D.
Toxicology Division, Institute of Environmental Toxicology

Abstract:
　Much concern has been focused on adverse effects of xenobiotics with endocrine activities on humans and/or wild life, so called an endocrine disrupter issue, since the last decade of the 20th century. Suspected endocrine disrupters include a wide variety of natural and man-made chemicals such as endogenous hormones and vitamins, phytoestrogens (alkyl-phenols of plant origin), pharmaceuticals, pesticides, synthesized chemicals for industrial use and environmental pollutants. Exposures to such endocrine disrupters induce adverse outcomes in animals through receptor-mediated mechanisms and/or hormonal imbalances. Postulated adverse outcome also diverge widely; however, one of the most serious concerns is the induction of reproductive and/or developmental toxicities.
We have been working with pesticides with endocrine activities (suspected endocrine disrupters) to evaluate possible reproductive and/or developmental toxicities for more than 30 years and believe that any adverse outcomes of exposure to these chemicals through modulations of endocrine function can be detected at least at sufficient dose levels. In other words, accumulated data are thought to be reliable enough for the risk assessment. Unfortunately, however, toxicologists often receive the criticism that they fail to notice low-dose effects of endocrine disrupters, although controversy still exists in the field of cutting edge science regarding such effects. The present seminar will provide the strategy for predicting endocrine disrupting effects of xenobiotics at sufficient dose levels based on the most authentic methodology, as well as the results of our study with a typical estrogenic pesticide, methoxychlor, as a model chemical. Then, the limitation of in vivo bioassays with experimental animals will be discussed for use in evaluating low-dose effects of endocrine disrupters from the viewpoints of animal genetics and nutritional sciences.

References:
1. Aoyama H. and Suzuki K. (2003) Enhanced one-generation reproductive toxicity study in rats for detecting endocrine disrupting effects of chemicals. Pure Appl. Chem., 75:2497-2501.
2. Aoyama H. (2005) Applications and limitations of in vivo bioassays for detecting endocrine disrupting effects of chemicals on mammalian species of animals. J. Natl. Inst. Public Health, 54: 29-34 (in Japanese).
3. Aoyama H. et al. (2012) Two-generation reproduction toxicity study in rats with methoxychlor. Congenit. Anom. Kyoto, 52:28–41.
4. Sato A. et al. (2014) A novel mutation in the thyroglobulin gene that causes goiter and dwar?sm in Wistar Hannover GALAS rats. Mutat. Res., 762: 17–23.
5. Aoyama H. and Chapin R.E. (2014) Reproductive toxicities of methoxychlor based on estrogenic properties of the compound and its estrogenic metabolite, hydroxyphenyltrichloroethane. Vitamins and Hormones, 94:193-210.