Comparative assessment of endocrine modulators with oestrogenic activity: I. Definition of a hygiene-based margin of safety (HBMOS) for xeno-oestrogens against the background of European developments

A novel concept - the hygiene-based margin of safety (HBMOS) - is suggested for the assessment of the impact of potential endocrine modulators. It int egrates exposure scenarios and potency data for industrial chemicals and na turally occurring dietary compounds with oestrogenic activity. An HBMOS is defined as a quotient of estimated daily intakes weighted by the relative i n vivo potencies of these compounds. The Existing Chemicals Programme of th e European Union provides Human and Environmental Risk Assessments of Exist ing Chemicals which include human exposure scenarios. Such exposure scenari os, along with potency estimates for endocrine activities, may provide a ba sis for a quantitative comparison of the potential endocrine-modulating eff ects of industrial chemicals with endocrine modulators as natural constitue nts of human diet. Natural phyto-oestrogens exhibit oestrogenic activity in vitro and in vivo. Important phyto-oestrogens for humans are isoflavones ( daidzein, genistein) and lignans, with the highest quantities found in soyb eans and flaxseed, respectively. Daily isoflavone exposures calculated for infants on soy-based formulae were in the ranges of 4.5-8 mg/kg body wt.; e stimates for adults range up to 1 mg/kg body wt. The Senate Commission on t he Evaluation of Food Safety (SKLM) of the Deutsche Forschungsgemeinschaft has also indicated a wide range of dietary exposures. For matters of risk a ssessment, the SKLM has based recommendations on dietary exposure scenarios , implying a daily intake of phyto-oestrogens in the order of 1 mg/kg body wt. On the basis of information compiled within the Existing Chemicals Prog ramme of the EU, it appears that a daily human exposure to nonylphenol of 2 mug/kg body wt. may be a worst-case assumption, but which is based on vali d scenarios. The intake of octylphenol is much lower, due to a different us e pattern and applications, and may be neglected. Data from migration studi es led to estimations of the daily human uptake of bisphenol A of maximally 1 mug/kg body wt. On the basis of comparative data from uterotrophic assay s in rats, with three consecutive days of oral applications involved, and t aking the natural phyto-oestrogen daidzein as reference (=1), relative uter otrophic activities in DA/Han rats follow the sequence: daidzein = 1; bisph enol A = 1; p-tert-octylphenol = 2; o, p'-DDT = 4; ethinyl oestradiol = 40, 000. The derived values from exposure scenarios, as well as these relative potency values and bridging assumptions, led to calculations of HBMOS as a quantitative comparison of potential endocrine-modulating effects of indust rial chemicals with those of natural constituents of human diet. HBMOS esti mates for nonylphenol ranged between 250 and 500, dependent on bridging ass umptions, and around 1000 for bisphenol A. The derivations of HBMOS were in full support of the conclusions reached by the SKLM of the Deutsche Forsch ungsgemeinschaft. The estimated HBMOS values for the industrial chemicals ( nonylphenol, bisphenol A) appear sufficiently high to ensure the absence of a practical risk to human health under the present exposure conditions.