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[Results]

1. Information was gathered and analyzed in relation to the Guidelines for Analysis of Endocrine Disruptors in Food, temporarily established in the Supplement to the Intermediary Report (December 2001). No information was found that would necessitate its revision.
2. A general method of analysis of chemical substances at low concentrations in biological samples was established. Guidelines for analysis of bisphenol A, phthalates and nonylphenol in food were developed.
3. A general method of analysis of chemical substances in feeds for experimental animals was established. Guidelines for analysis of bisphenol A, phthalates and nonylphenol in feed were developed.
4. Bisphenol A, phthalates, nonylphenol, plant estrogens and estradiol in feed and litter were determined to know animals' exposure to these chemicals in the raising and experimental environment. The substances were indeed found in some samples. Animal experiments should, therefore, be performed with feed and litter of which the lot numbers and the contents of the substances are known as far as possible. Furthermore, feed should be analyzed as necessary for knowing basal exposure to those substances and the results should be reported.

1. Gathering information useful for developing more effective, precise and sensitive analytical procedures in order to improve the analysis guidelines.

[Results]

1. Existing knowledge, including accommodation by endogenous hormones, indicates no need for urgent measures against hazardous effects of suspected endocrine disruptors.
2. Focus of studies on the mechanism of action of those substances is shifting to their effects at critical stages (such as embryonic, fetal, neonatal and pubertal) in morphogenesis, in which the physiological functions are still unstable.
3. The low-dose problem is a complex of closely interrelated problems such as threshold, additive or multiplicative behavior, or dose-action correlation.
4. Studies of the mechanism of action of substances with hormonal activity is revealing the diversity of such mechanisms, as illustrated, for example, by the interaction of allyl hydrocarbon and estrogen receptor signals. These findings may have a certain influence on the studies of low-dose problem and synergistic effects.
5. Endocrine disrupting actions on the higher systems (reproductive, immune, neural) have been attracting attention, and many research results have been reported, but the phenomena are far from being fully understood. Further studies of the mechanism is indispensable.
6. Discovery of membrane receptors advanced understanding hormonal actions independent of genes, and suggests existence of unknown factors.

1. The following studies are needed to solve the low-dose problem:
   
   • Improvement of the reproducibility in detection of hormonal actions at low doses
   • Elucidation of endocrine disrupting mechanism in the highly sensitive fetal, neonatal and pubertal periods in order to establish evaluation criteria
   • In relation to the effects of the substances found at low doses, systematic information gathering along with studies for interpretation of the experimental results with (i) threshold levels, (ii) non-linear dose-effect correlation, and (iii) additive reactions taken into account
   • Studies on effects of the substances on the immune system, thyroid-central nerve system and behavior
   • Review of findings in genomics
2. Comprehensive guidelines should be established for the evaluation of test results on endocrine disrupting actions.

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